Applied Evidence

Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.¹ However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.² Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.³ This review details what makes MAbs unique and what you should know about them.

The uniqueness of monoclonal antibodies

MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.^4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 1^7-9).

MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”¹⁰ MAbs work in several ways, including competitively inhibiting ligand-­receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-­mediated cytotoxicity.^11,12

Monoclonal antibody uses in family medicine

Asthma

Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),¹³ mepolizumab (Nucala),^9,14 and dupilumab (Dupixent).¹⁵All 3 agents can be self-administered subcutaneously (SC), depending on the clinician’s assessment. The Global Initiative for Asthma (GINA) guidelines recommend that, prior to considering MAb therapy for a patient who has asthma, clinicians should assess the patient’s inhaler technique and adherence, treat comorbidities such as gastroesophageal reflux disease, and modify triggering factors such as smoking or allergen exposure.¹⁶ In patients with severe asthma still uncontrolled after receiving high-dose inhaled corticosteroids (ICSs) or the lowest possible dose of oral corticosteroid (OCS), GINA recommends assessing for type 2 airway inflammation: blood eosinophils ≥ 150/μL, sputum eosinophils ≥ 2%, or evidence of allergen stimulation.¹⁶ If these factors are present, consider prescribing anti-immunoglobulin E (anti-IgE) (omalizumab), anti-interleukin-5 (anti-IL-5) (mepolizumab), or anti-IL-4/anti-IL-13 (dupilumab).¹⁶

Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.¹³ A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).¹³

Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.¹⁶ Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.

Mepolizumab is a humanized MAb that inhibits IL-5, effectively blocking the growth, differentiation, recruitment, activation, and survival of eosinophils.¹⁴ Mepolizumab was studied in patients with frequent exacerbations while already taking high-dose ICSs. The mean rate of clinically consequential exacerbations was significantly reduced with mepolizumab compared with placebo (0.83 vs 1.74; P < .001).¹⁷ This translates to about 1 less moderate-to-severe asthma exacerbation per year per person.

Continue to: Another trial found that...

Before considering a monoclonal antibody for asthma, assess the patient’s inhaler technique and adherence, treat comorbidities, and modify triggering factors.

Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.¹⁸ All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.¹⁴ Mepolizumab, according to GINA, is preferred for patients with blood eosinophils ≥ 300/μL and severe exacerbations, nasal polyposis, adult-onset asthma, and maintenance OCS at baseline.¹⁶ Mepolizumab is also approved for use in eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and rhinosinusitis with nasal polyps.

Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).¹⁵ In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.¹⁵

For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.¹⁶

  ❯ Asthma: Test your skills

Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.

Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.

Continue to: Objective data

Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.

Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.

Atopic dermatitis

Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.^15,19 Dupilumab is also approved for children ≥ 6 months old.²⁰ Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.²¹ Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).²¹ Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.²²

In atopic dermatitis, MAbs, unlike other systemic agents, do not require frequent monitoring of factors such as blood pressure and kidney or liver function.

It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or ­hypothalamic-­pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).²³

A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents. For dupilumab, the main adverse reactions (that occurred with > 10% frequency in trials) were injection site reactions and upper respiratory tract infections.¹⁵ Antidrug antibody development occurred in 4.2%.¹⁵ Tralokinumab had > 20% incidence of upper respiratory tract infections.¹⁹

Continue to: Hyperlipidemia

Hyperlipidemia

Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 ­(ANGPTL3) inhibitor evinacumab (Evkeeza)²⁴ and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)²⁵ and alirocumab (Praluent).²⁶

ANGPTL3 inhibitors block ­ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol ­(HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.

Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.

Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.²⁷

Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).²⁸

Continue to: According to the 2018...

According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m²).²⁹ For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.

Osteoporosis

The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)³⁰ and the sclerostin inhibitor romosozumab (Evenity).³¹

Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).³² Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.

Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).³³

Continue to: In another study...

In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).³⁴ There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.³⁴ Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).

Migraine prevention

Four calcitonin gene-related peptide (CGRP) antagonists have been approved for migraine prevention: erenumab (Aimovig),³⁵ eptinezumab (Vyepti),³⁶ fremanezumab (Ajovy),³⁷ and galcanezumab (Emgality).³⁸ CGRP is released at areas in and around the brain, causing vasodilation and inflammation that is thought to be the major causative factor for migraine headaches.³⁹

Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.

Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.

There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.⁴⁰

Continue to: The most commonly reported adverse...

The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).³⁷ Constipation was most notable with the 140-mg dose of erenumab (3%)³⁵; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).

Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.⁴¹ This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.⁴¹ Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.⁴¹

Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.

The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.⁴² CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.

Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.

Continue to: Migraine

❯ Migraine: Test your skills

Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.

History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.

Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.

What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.

CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.^43,44

Continue to: The challenges associated with MAbs

MAbs can be expensive (TABLE 2),⁴⁵ some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.⁴⁶ Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.⁴⁶

MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.

Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.

CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]

Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.¹ However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.² Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.³ This review details what makes MAbs unique and what you should know about them.

The uniqueness of monoclonal antibodies

MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.^4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 1^7-9).

MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”¹⁰ MAbs work in several ways, including competitively inhibiting ligand-­receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-­mediated cytotoxicity.^11,12

Monoclonal antibody uses in family medicine

Asthma

Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),¹³ mepolizumab (Nucala),^9,14 and dupilumab (Dupixent).¹⁵All 3 agents can be self-administered subcutaneously (SC), depending on the clinician’s assessment. The Global Initiative for Asthma (GINA) guidelines recommend that, prior to considering MAb therapy for a patient who has asthma, clinicians should assess the patient’s inhaler technique and adherence, treat comorbidities such as gastroesophageal reflux disease, and modify triggering factors such as smoking or allergen exposure.¹⁶ In patients with severe asthma still uncontrolled after receiving high-dose inhaled corticosteroids (ICSs) or the lowest possible dose of oral corticosteroid (OCS), GINA recommends assessing for type 2 airway inflammation: blood eosinophils ≥ 150/μL, sputum eosinophils ≥ 2%, or evidence of allergen stimulation.¹⁶ If these factors are present, consider prescribing anti-immunoglobulin E (anti-IgE) (omalizumab), anti-interleukin-5 (anti-IL-5) (mepolizumab), or anti-IL-4/anti-IL-13 (dupilumab).¹⁶

Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.¹³ A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).¹³

Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.¹⁶ Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.

Mepolizumab is a humanized MAb that inhibits IL-5, effectively blocking the growth, differentiation, recruitment, activation, and survival of eosinophils.¹⁴ Mepolizumab was studied in patients with frequent exacerbations while already taking high-dose ICSs. The mean rate of clinically consequential exacerbations was significantly reduced with mepolizumab compared with placebo (0.83 vs 1.74; P < .001).¹⁷ This translates to about 1 less moderate-to-severe asthma exacerbation per year per person.

Continue to: Another trial found that...

Before considering a monoclonal antibody for asthma, assess the patient’s inhaler technique and adherence, treat comorbidities, and modify triggering factors.

Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.¹⁸ All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.¹⁴ Mepolizumab, according to GINA, is preferred for patients with blood eosinophils ≥ 300/μL and severe exacerbations, nasal polyposis, adult-onset asthma, and maintenance OCS at baseline.¹⁶ Mepolizumab is also approved for use in eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and rhinosinusitis with nasal polyps.

Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).¹⁵ In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.¹⁵

For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.¹⁶

  ❯ Asthma: Test your skills

Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.

Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.

Continue to: Objective data

Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.

Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.

Atopic dermatitis

Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.^15,19 Dupilumab is also approved for children ≥ 6 months old.²⁰ Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.²¹ Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).²¹ Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.²²

In atopic dermatitis, MAbs, unlike other systemic agents, do not require frequent monitoring of factors such as blood pressure and kidney or liver function.

It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or ­hypothalamic-­pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).²³

A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents. For dupilumab, the main adverse reactions (that occurred with > 10% frequency in trials) were injection site reactions and upper respiratory tract infections.¹⁵ Antidrug antibody development occurred in 4.2%.¹⁵ Tralokinumab had > 20% incidence of upper respiratory tract infections.¹⁹

Continue to: Hyperlipidemia

Hyperlipidemia

Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 ­(ANGPTL3) inhibitor evinacumab (Evkeeza)²⁴ and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)²⁵ and alirocumab (Praluent).²⁶

ANGPTL3 inhibitors block ­ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol ­(HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.

Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.

Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.²⁷

Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).²⁸

Continue to: According to the 2018...

According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m²).²⁹ For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.

Osteoporosis

The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)³⁰ and the sclerostin inhibitor romosozumab (Evenity).³¹

Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).³² Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.

Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).³³

Continue to: In another study...

In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).³⁴ There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.³⁴ Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).

Migraine prevention

Four calcitonin gene-related peptide (CGRP) antagonists have been approved for migraine prevention: erenumab (Aimovig),³⁵ eptinezumab (Vyepti),³⁶ fremanezumab (Ajovy),³⁷ and galcanezumab (Emgality).³⁸ CGRP is released at areas in and around the brain, causing vasodilation and inflammation that is thought to be the major causative factor for migraine headaches.³⁹

Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.

Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.

There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.⁴⁰

Continue to: The most commonly reported adverse...

The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).³⁷ Constipation was most notable with the 140-mg dose of erenumab (3%)³⁵; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).

Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.⁴¹ This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.⁴¹ Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.⁴¹

Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.

The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.⁴² CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.

Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.

Continue to: Migraine

❯ Migraine: Test your skills

Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.

History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.

Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.

What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.

CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.^43,44

Continue to: The challenges associated with MAbs

MAbs can be expensive (TABLE 2),⁴⁵ some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.⁴⁶ Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.⁴⁶

MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.

Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.

CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]

Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.¹ However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.² Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.³ This review details what makes MAbs unique and what you should know about them.

The uniqueness of monoclonal antibodies

MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.^4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 1^7-9).

MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”¹⁰ MAbs work in several ways, including competitively inhibiting ligand-­receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-­mediated cytotoxicity.^11,12

Monoclonal antibody uses in family medicine

Asthma

Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),¹³ mepolizumab (Nucala),^9,14 and dupilumab (Dupixent).¹⁵All 3 agents can be self-administered subcutaneously (SC), depending on the clinician’s assessment. The Global Initiative for Asthma (GINA) guidelines recommend that, prior to considering MAb therapy for a patient who has asthma, clinicians should assess the patient’s inhaler technique and adherence, treat comorbidities such as gastroesophageal reflux disease, and modify triggering factors such as smoking or allergen exposure.¹⁶ In patients with severe asthma still uncontrolled after receiving high-dose inhaled corticosteroids (ICSs) or the lowest possible dose of oral corticosteroid (OCS), GINA recommends assessing for type 2 airway inflammation: blood eosinophils ≥ 150/μL, sputum eosinophils ≥ 2%, or evidence of allergen stimulation.¹⁶ If these factors are present, consider prescribing anti-immunoglobulin E (anti-IgE) (omalizumab), anti-interleukin-5 (anti-IL-5) (mepolizumab), or anti-IL-4/anti-IL-13 (dupilumab).¹⁶

Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.¹³ A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).¹³

Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.¹⁶ Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.

Mepolizumab is a humanized MAb that inhibits IL-5, effectively blocking the growth, differentiation, recruitment, activation, and survival of eosinophils.¹⁴ Mepolizumab was studied in patients with frequent exacerbations while already taking high-dose ICSs. The mean rate of clinically consequential exacerbations was significantly reduced with mepolizumab compared with placebo (0.83 vs 1.74; P < .001).¹⁷ This translates to about 1 less moderate-to-severe asthma exacerbation per year per person.

Continue to: Another trial found that...

Before considering a monoclonal antibody for asthma, assess the patient’s inhaler technique and adherence, treat comorbidities, and modify triggering factors.

Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.¹⁸ All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.¹⁴ Mepolizumab, according to GINA, is preferred for patients with blood eosinophils ≥ 300/μL and severe exacerbations, nasal polyposis, adult-onset asthma, and maintenance OCS at baseline.¹⁶ Mepolizumab is also approved for use in eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and rhinosinusitis with nasal polyps.

Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).¹⁵ In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.¹⁵

For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.¹⁶

  ❯ Asthma: Test your skills

Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.

Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.

Continue to: Objective data

Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.

Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.

Atopic dermatitis

Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.^15,19 Dupilumab is also approved for children ≥ 6 months old.²⁰ Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.²¹ Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).²¹ Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.²²

In atopic dermatitis, MAbs, unlike other systemic agents, do not require frequent monitoring of factors such as blood pressure and kidney or liver function.

It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or ­hypothalamic-­pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).²³

A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents. For dupilumab, the main adverse reactions (that occurred with > 10% frequency in trials) were injection site reactions and upper respiratory tract infections.¹⁵ Antidrug antibody development occurred in 4.2%.¹⁵ Tralokinumab had > 20% incidence of upper respiratory tract infections.¹⁹

Continue to: Hyperlipidemia

Hyperlipidemia

Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 ­(ANGPTL3) inhibitor evinacumab (Evkeeza)²⁴ and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)²⁵ and alirocumab (Praluent).²⁶

ANGPTL3 inhibitors block ­ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol ­(HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.

Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.

Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.²⁷

Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).²⁸

Continue to: According to the 2018...

According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m²).²⁹ For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.

Osteoporosis

The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)³⁰ and the sclerostin inhibitor romosozumab (Evenity).³¹

Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).³² Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.

Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).³³

Continue to: In another study...

In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).³⁴ There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.³⁴ Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).

Migraine prevention

Four calcitonin gene-related peptide (CGRP) antagonists have been approved for migraine prevention: erenumab (Aimovig),³⁵ eptinezumab (Vyepti),³⁶ fremanezumab (Ajovy),³⁷ and galcanezumab (Emgality).³⁸ CGRP is released at areas in and around the brain, causing vasodilation and inflammation that is thought to be the major causative factor for migraine headaches.³⁹

Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.

Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.

There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.⁴⁰

Continue to: The most commonly reported adverse...

The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).³⁷ Constipation was most notable with the 140-mg dose of erenumab (3%)³⁵; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).

Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.⁴¹ This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.⁴¹ Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.⁴¹

Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.

The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.⁴² CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.

Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.

Continue to: Migraine

❯ Migraine: Test your skills

Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.

History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.

Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.

What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.

CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.^43,44

Continue to: The challenges associated with MAbs

MAbs can be expensive (TABLE 2),⁴⁵ some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.⁴⁶ Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.⁴⁶

MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.

Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.

CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]

Type 2 diabetes has been increasing in incidence and prevalence over the past 20 years, with worldwide prevalence estimated at 6.28%.¹ The estimated cost of diagnosed diabetes in the United States was $327 billion in 2017; this included direct medical costs and reduced productivity.² Type 2 diabetes can be prevented in most patients, given that it is a metabolic derangement caused by a complicated interaction between a patient’s genetic predisposition and lifestyle. A consensus statement by the American Academy of Clinical Endocrinologists (AACE) and American College of Endocrinology indicates that the recommended lifestyle modifications for diabetes include medical nutrition therapy with healthy eating patterns, regular physical activity, adequate sleep, behavioral support/counseling, and smoking cessation.³ Evidence shows that adherence to these lifestyle changes alone yields a relative reduction in type 2 diabetes mortality of 57%.⁴

IMAGE: ©ALICIA BUELOW; PATIENT IMAGE © GETTY IMAGES

In the discussion that follows, we review the current guideline recommendations for dietary modifications and physical activity and summarize their effectiveness in the treatment of type 2 diabetes. We also describe practical clinical strategies to promote change in patient behavior, and examine current literature supporting intensive lifestyle changes that, if achieved, may induce disease remission.⁵

Dietary strategies

Low, or very low, carbohydrate diet  

Carbohydrates can affect blood glucose levels in varying degrees depending on their intrinsic properties such as fiber content, sugars, and starches . ⁶ According to the American Diabetes Association’s (ADA) 2019 consensus report, ⁶ the carbohydrate quality that generally should be recommended is high in fiber, vitamins, and minerals, and low in added sugars, fats, and sodium (processed carbohydrates) ( TABLE 1 ^7-10 ). A low-carbohydrate diet (LCD) typically has a carbohydrate content < 130 g/d or < 26% of a 2000 kcal/d diet. ¹¹ A very low–carbohydrate diet (VLCD) is 20-50 g/d or < 10% of the 2000 kcal/day diet. ¹¹

Adherence to lifestyle changes alone yields a relative reduction in type 2 diabetes mortality of 57%.

In a meta-analysis by Goldenberg et al¹¹, the LCD was shown to reduce A1C by 0.47% at 6 months (95% CI, –0.6 to –0.34) and by 0.23% at 12 months when compared with control diets. A review of multiple meta-­analyses also showed a significant reduction in A1C especially with VLCD patterns; however, the results waned at the 12-month follow-up.⁵ In addition, confounding factors were seen when comparing adherence between LCD and VLCD, with patients in the latter group having larger problems with adherence, which decreased the benefit seen in the overall group comparison.¹¹

Very low–carbohydrate/high-fat (ketogenic) diet  

Ketogenic diets generally follow a VLCD with the carbohydrate portion set at 5% to 10% of total caloric intake (generally < 30 g/d) and the rest of the calories taken up by protein (typically 1 g/kg/d) and fat (TABLE 1^7-10).¹² The fat content recommended is primarily polyunsaturated fat such as olive oil, while saturated fats such as butter and lard (animal fat) should be limited.

A recent meta-analysis by Choi et al¹² showed that in overweight or obese patients with type 2 diabetes, the average A1C reduction was 0.62% (95% CI, –0.89 to –0.35) in the ketogenic intervention group. Another meta-analysis showed an even more significant A1C reduction at 1.07% (95% CI, –1.37 to –0.78).¹³ Concerns have been raised about the ketogenic diet, particularly as it relates to lipid metabolism and cholesterol levels; however, in the 2 referenced meta-analyses, the total cholesterol and triglyceride levels actually declined in the ketogenic intervention groups with minimal effect on LDL-C.^12,13 This may alleviate some of the concerns of lipid management with this diet.

Plant-based diet  

Popularized by Dr. T. Colin Campbell, a plant-based diet refers to a low-fat, high-fiber, whole-foods diet (whole fruits, vegetables, and naturally occurring carbohydrates, as opposed to processed foods). Examples of this type of diet include the popular vegan diet, which restricts all animal-derived products, and the vegetarian diet, which is generally limited to foods in the plant category with some addition of animal products, such as milk and cheese. Other variations of these diets exist and include other sources of protein (eg, chicken, eggs, or fish) (TABLE 1^7-10).

Continue to: A review by...

A review by Salas-Salvadó et al¹⁴ showed that a vegan diet yields an average A1C reduction of 0.41% (95% CI, –0.58 to –0.23).Several meta-analyses report similar effects on A1C with vegetarian and vegan eating patterns.^6,15,16 The ADA review notes that weight loss was more significant in the vegan group and concluded that this diet should be studied further while controlling for weight loss.⁶

Mediterranean  diet

The Mediterranean diet emphasizes vegetables, whole grains, fruits, lean meats, nuts, and olive oil. The benefits of the Mediterranean diet are well known and, as a result, the diet is recommended by organizations including the American Heart Association as part of a strategy to reduce cardiovascular risk (TABLE 1^7-10).

Mediterranean diet interventions have generally shown mixed effects on A1C reduction, weight management, and lipid control in type 2 diabetes. ⁶ The PREDIMED trial is the largest and longest randomized controlled trial to date comparing the Mediterranean diet to a low-fat diet. ¹⁷ This trial has reliably shown a reduced risk for type 2 diabetes and a trend to reduced A1C. ¹⁷ A reduction in the need for glucose-lowering medications was demonstrated in a subgroup analysis of the intervention group (adjusted hazard ratio = 0.78; 95% CI, 0.62-0.98). ¹⁸ Also, the Mediterranean diet has shown a significant reduction in the incidence of cardiovascular disease in patients with type 2 diabetes. ⁶

Physical activity and exercise

What do current guidelines recommend?

For most adults with type 2 diabetes, current guidelines by the ADA and by the National Institute of Diabetes and Digestive and Kidney Diseases recommend at least 150 minutes of moderate-to-vigorous intensity exercise every week spread out over at least 3 days, with no more than 2 consecutive days without exercise; and resistance training at least 2 other days per week which should balance all major muscle groups (TABLE 2^19-21). The benefits of exercise for type 2 diabetes have been well reviewed: positive effects on glucose control, insulin sensitivity, cardiovascular disease, lipid profiles, skeletal muscle metabolism, and solid-organ functioning.^19,22,23

Grace et al²⁴ showed in a meta-analysis that moderate aerobic exercise reduced A1C by 0.69% (95% CI, –1.09 to –0.3) at 13 weeks, and a Cochrane review showed an average A1C reduction of 0.6% with moderate-­intensity exercise.²⁵ Borror et al²⁶ demonstrated in a systematic review that postprandial moderate-intensity aerobic exercise starting 1 hour after meals results in a reduced 24-hour prevalence of hyperglycemia (33.5% reduction vs control). A meta-analysis in China showed an average A1C reduction of 0.68% for patients performing a Tai Chi physical activity intervention.²⁷

Continue to: Consider high-intensity interval training

Multiple randomized controlled trials highlight the benefits of high-intensity interval training (HIIT) (TABLE 2^19-21) compared with moderate-intensity continuous training (MICT) on improving A1C. A meta-analysis showed a weighted mean difference in A1C of 0.23% (95% CI, –0.43 to –0.02%).²⁸ Also, a patient could spend less time performing HIIT as opposed to MICT to achieve the same benefits. For example, a patient typically performing 30 minutes of MICT may only need to perform 15 minutes of HIIT,a time-saving option for patients.^20,22

Interrupt sedentary behavior

Risk for incident type 2 diabetes increases when someone is sedentary for more than 6 to 8 hours daily or watches TV for 3 to 4 hours (relative risk [RR] = 1.12).²⁹ Recommendations for interrupting a sedentary lifestyle include standing from a seated position at least every 30 minutes and engaging in a light activity during the break interval for at least 3 minutes.¹⁹ Most studies have reliably shown that interrupting sedentary behavior reduces postprandial and 24-hour average blood glucose levels.¹⁹ Interrupted sitting/sedentary behavior has also been shown to reduce resting blood pressure in patients with type 2 diabetes.³⁰

Other important lifestyle factors

Encourage 7 to 8 hours of sleep

There is a U-shaped association between glycemic control and sleep quantity based on a meta-analysis by Lee et al ³¹ that showed a 0.23% increase in A1C in patients with insufficient sleep (< 4.5-6 hours/night) and a 0.13% increase in patients with ≥ 8 hours of sleep per night. Patients should be encouraged to obtain 7 to 8 hours of sleep per night to help maximize their diabetes control.  

Address stress reduction

Although evidence for stress reduction interventions on glycemic control is mixed, there does seem to be a benefit in diminishing emotional distress in patients with diabetes. A systematic review by Noordali et al³² demonstrated that patients who received mindfulness-based interventions had improvements in stress, anxiety, and depression symptoms which resulted in improved quality of life. These psychological benefits may subsequently lead to positive behavioral changes.

Assist patients with smoking cessation 

A large meta-analysis showed that active smoking increases the risk of cardiovascular events in patients with type 2 diabetes (RR = 1.44; 95% CI, 1.34-1.54).³³ Former smokers still have an increased risk (RR = 1.09; 95% CI, 1.05-1.13), but it is lower than that of current smokers, so patients should be encouraged to quit smoking.^3,33

Continue to: How can I get my patient to change?

How can I get my patient to change?

The AACE recommends using motivational interviewing, behavioral therapy consultation, and wearable feedback devices (eg, accelerometers/pedometers) to stimulate behavioral change in patients.³ Motivational interviewing is the principal counseling strategy and is supported by multiple studies showing the benefits of using this technique in a clinical encounter to induce behavioral changes.³⁴ In general, offer receptive patients intensive behavioral interventions and provide them with resources to accomplish their goals.³⁵ For example, a 7-step yearly intensive behavioral counseling intervention over 3 years showed significant improvements in activity of any intensity, reduced sedentary time, and led to favorable metabolic outcomes.³⁶ Wearable devices result in up to a 1 hour increase in physical activity per week for the wearers vs control, although there was no appreciable effect on A1C.³⁷

A meta-analysis showed that moderate aerobic exercise reduced A1C by 0.69% at 13 weeks.

One systematic review showed a 0.5% reduction in A1C (95% CI, –0.65 to –0.34) by focusing on environmental changes related to the diet, with the most effective intervention being full meal replacement for calorie control (ie, each meal was pre-made and provided to the patients based on macronutrient and caloric goals).³⁸ Additionally, diabetes self-management education includes coping strategies, problem solving, self-­advocacy, and health care system navigation, which have been shown to reduce A1C by an average of 0.6%.²¹ Patient resources are available for further assistance with lifestyle modifications (TABLE 3).

Can your patient achieve remission?

Emerging evidence suggests that patients may achieve remission from type 2 diabetes with intensive lifestyle interventions.³⁹ This is supported by the American College of Lifestyle Medicine.⁵ Although there is no consensus definition for remission, in general it is reasonable to presume remission if a patient achieves normo-glycemia (A1C < 5.7%) for at least 1 year without any medication therapy.⁵ These intensive lifestyle interventions would include a mostly plant-based diet with moderate calorie restriction, appropriate and sustained physical activity, adequate sleep, and stress-reduction techniques.⁵ One study found that 46% of patients in a weight-management program across multiple primary care clinics achieved remission at 12 months.⁴⁰ A meta-analysis showed that a low-carbohydrate diet induced remission at 6 months in 32% of patients (although the result was not controlled for weight loss as a possible confounding factor and an A1C cutoff of 6.5% was used).¹¹ Thus far, most studies have focused on short-term follow-up intervals, but evidence is emerging that with intensive lifestyle interventions the effects are sustained at the 2-year mark.⁴¹

The American Academy of Clinical Endocrinologists recommends using motivational interviewing and wearable feedback devices to stimulate behavioral change in patients.

This evidence could reframe our understanding of type 2 diabetes therapy and could change the conversations we have with patients regarding their treatment. Instead of focusing on an A1C goal that is adequate for control of type 2 diabetes, we would instead focus on achieving remission.

CORRESPONDENCE
Stephen McMullan, MD, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road, Jacksonville, FL 32224; [email protected]

Type 2 diabetes has been increasing in incidence and prevalence over the past 20 years, with worldwide prevalence estimated at 6.28%.¹ The estimated cost of diagnosed diabetes in the United States was $327 billion in 2017; this included direct medical costs and reduced productivity.² Type 2 diabetes can be prevented in most patients, given that it is a metabolic derangement caused by a complicated interaction between a patient’s genetic predisposition and lifestyle. A consensus statement by the American Academy of Clinical Endocrinologists (AACE) and American College of Endocrinology indicates that the recommended lifestyle modifications for diabetes include medical nutrition therapy with healthy eating patterns, regular physical activity, adequate sleep, behavioral support/counseling, and smoking cessation.³ Evidence shows that adherence to these lifestyle changes alone yields a relative reduction in type 2 diabetes mortality of 57%.⁴

IMAGE: ©ALICIA BUELOW; PATIENT IMAGE © GETTY IMAGES

In the discussion that follows, we review the current guideline recommendations for dietary modifications and physical activity and summarize their effectiveness in the treatment of type 2 diabetes. We also describe practical clinical strategies to promote change in patient behavior, and examine current literature supporting intensive lifestyle changes that, if achieved, may induce disease remission.⁵

Dietary strategies

Low, or very low, carbohydrate diet  

Carbohydrates can affect blood glucose levels in varying degrees depending on their intrinsic properties such as fiber content, sugars, and starches . ⁶ According to the American Diabetes Association’s (ADA) 2019 consensus report, ⁶ the carbohydrate quality that generally should be recommended is high in fiber, vitamins, and minerals, and low in added sugars, fats, and sodium (processed carbohydrates) ( TABLE 1 ^7-10 ). A low-carbohydrate diet (LCD) typically has a carbohydrate content < 130 g/d or < 26% of a 2000 kcal/d diet. ¹¹ A very low–carbohydrate diet (VLCD) is 20-50 g/d or < 10% of the 2000 kcal/day diet. ¹¹

Adherence to lifestyle changes alone yields a relative reduction in type 2 diabetes mortality of 57%.

In a meta-analysis by Goldenberg et al¹¹, the LCD was shown to reduce A1C by 0.47% at 6 months (95% CI, –0.6 to –0.34) and by 0.23% at 12 months when compared with control diets. A review of multiple meta-­analyses also showed a significant reduction in A1C especially with VLCD patterns; however, the results waned at the 12-month follow-up.⁵ In addition, confounding factors were seen when comparing adherence between LCD and VLCD, with patients in the latter group having larger problems with adherence, which decreased the benefit seen in the overall group comparison.¹¹

Very low–carbohydrate/high-fat (ketogenic) diet  

Ketogenic diets generally follow a VLCD with the carbohydrate portion set at 5% to 10% of total caloric intake (generally < 30 g/d) and the rest of the calories taken up by protein (typically 1 g/kg/d) and fat (TABLE 1^7-10).¹² The fat content recommended is primarily polyunsaturated fat such as olive oil, while saturated fats such as butter and lard (animal fat) should be limited.

A recent meta-analysis by Choi et al¹² showed that in overweight or obese patients with type 2 diabetes, the average A1C reduction was 0.62% (95% CI, –0.89 to –0.35) in the ketogenic intervention group. Another meta-analysis showed an even more significant A1C reduction at 1.07% (95% CI, –1.37 to –0.78).¹³ Concerns have been raised about the ketogenic diet, particularly as it relates to lipid metabolism and cholesterol levels; however, in the 2 referenced meta-analyses, the total cholesterol and triglyceride levels actually declined in the ketogenic intervention groups with minimal effect on LDL-C.^12,13 This may alleviate some of the concerns of lipid management with this diet.

Plant-based diet  

Popularized by Dr. T. Colin Campbell, a plant-based diet refers to a low-fat, high-fiber, whole-foods diet (whole fruits, vegetables, and naturally occurring carbohydrates, as opposed to processed foods). Examples of this type of diet include the popular vegan diet, which restricts all animal-derived products, and the vegetarian diet, which is generally limited to foods in the plant category with some addition of animal products, such as milk and cheese. Other variations of these diets exist and include other sources of protein (eg, chicken, eggs, or fish) (TABLE 1^7-10).

Continue to: A review by...

A review by Salas-Salvadó et al¹⁴ showed that a vegan diet yields an average A1C reduction of 0.41% (95% CI, –0.58 to –0.23).Several meta-analyses report similar effects on A1C with vegetarian and vegan eating patterns.^6,15,16 The ADA review notes that weight loss was more significant in the vegan group and concluded that this diet should be studied further while controlling for weight loss.⁶

Mediterranean  diet

The Mediterranean diet emphasizes vegetables, whole grains, fruits, lean meats, nuts, and olive oil. The benefits of the Mediterranean diet are well known and, as a result, the diet is recommended by organizations including the American Heart Association as part of a strategy to reduce cardiovascular risk (TABLE 1^7-10).

Mediterranean diet interventions have generally shown mixed effects on A1C reduction, weight management, and lipid control in type 2 diabetes. ⁶ The PREDIMED trial is the largest and longest randomized controlled trial to date comparing the Mediterranean diet to a low-fat diet. ¹⁷ This trial has reliably shown a reduced risk for type 2 diabetes and a trend to reduced A1C. ¹⁷ A reduction in the need for glucose-lowering medications was demonstrated in a subgroup analysis of the intervention group (adjusted hazard ratio = 0.78; 95% CI, 0.62-0.98). ¹⁸ Also, the Mediterranean diet has shown a significant reduction in the incidence of cardiovascular disease in patients with type 2 diabetes. ⁶

Physical activity and exercise

What do current guidelines recommend?

For most adults with type 2 diabetes, current guidelines by the ADA and by the National Institute of Diabetes and Digestive and Kidney Diseases recommend at least 150 minutes of moderate-to-vigorous intensity exercise every week spread out over at least 3 days, with no more than 2 consecutive days without exercise; and resistance training at least 2 other days per week which should balance all major muscle groups (TABLE 2^19-21). The benefits of exercise for type 2 diabetes have been well reviewed: positive effects on glucose control, insulin sensitivity, cardiovascular disease, lipid profiles, skeletal muscle metabolism, and solid-organ functioning.^19,22,23

Grace et al²⁴ showed in a meta-analysis that moderate aerobic exercise reduced A1C by 0.69% (95% CI, –1.09 to –0.3) at 13 weeks, and a Cochrane review showed an average A1C reduction of 0.6% with moderate-­intensity exercise.²⁵ Borror et al²⁶ demonstrated in a systematic review that postprandial moderate-intensity aerobic exercise starting 1 hour after meals results in a reduced 24-hour prevalence of hyperglycemia (33.5% reduction vs control). A meta-analysis in China showed an average A1C reduction of 0.68% for patients performing a Tai Chi physical activity intervention.²⁷

Continue to: Consider high-intensity interval training

Multiple randomized controlled trials highlight the benefits of high-intensity interval training (HIIT) (TABLE 2^19-21) compared with moderate-intensity continuous training (MICT) on improving A1C. A meta-analysis showed a weighted mean difference in A1C of 0.23% (95% CI, –0.43 to –0.02%).²⁸ Also, a patient could spend less time performing HIIT as opposed to MICT to achieve the same benefits. For example, a patient typically performing 30 minutes of MICT may only need to perform 15 minutes of HIIT,a time-saving option for patients.^20,22

Interrupt sedentary behavior

Risk for incident type 2 diabetes increases when someone is sedentary for more than 6 to 8 hours daily or watches TV for 3 to 4 hours (relative risk [RR] = 1.12).²⁹ Recommendations for interrupting a sedentary lifestyle include standing from a seated position at least every 30 minutes and engaging in a light activity during the break interval for at least 3 minutes.¹⁹ Most studies have reliably shown that interrupting sedentary behavior reduces postprandial and 24-hour average blood glucose levels.¹⁹ Interrupted sitting/sedentary behavior has also been shown to reduce resting blood pressure in patients with type 2 diabetes.³⁰

Other important lifestyle factors

Encourage 7 to 8 hours of sleep

There is a U-shaped association between glycemic control and sleep quantity based on a meta-analysis by Lee et al ³¹ that showed a 0.23% increase in A1C in patients with insufficient sleep (< 4.5-6 hours/night) and a 0.13% increase in patients with ≥ 8 hours of sleep per night. Patients should be encouraged to obtain 7 to 8 hours of sleep per night to help maximize their diabetes control.  

Address stress reduction

Although evidence for stress reduction interventions on glycemic control is mixed, there does seem to be a benefit in diminishing emotional distress in patients with diabetes. A systematic review by Noordali et al³² demonstrated that patients who received mindfulness-based interventions had improvements in stress, anxiety, and depression symptoms which resulted in improved quality of life. These psychological benefits may subsequently lead to positive behavioral changes.

Assist patients with smoking cessation 

A large meta-analysis showed that active smoking increases the risk of cardiovascular events in patients with type 2 diabetes (RR = 1.44; 95% CI, 1.34-1.54).³³ Former smokers still have an increased risk (RR = 1.09; 95% CI, 1.05-1.13), but it is lower than that of current smokers, so patients should be encouraged to quit smoking.^3,33

Continue to: How can I get my patient to change?

How can I get my patient to change?

The AACE recommends using motivational interviewing, behavioral therapy consultation, and wearable feedback devices (eg, accelerometers/pedometers) to stimulate behavioral change in patients.³ Motivational interviewing is the principal counseling strategy and is supported by multiple studies showing the benefits of using this technique in a clinical encounter to induce behavioral changes.³⁴ In general, offer receptive patients intensive behavioral interventions and provide them with resources to accomplish their goals.³⁵ For example, a 7-step yearly intensive behavioral counseling intervention over 3 years showed significant improvements in activity of any intensity, reduced sedentary time, and led to favorable metabolic outcomes.³⁶ Wearable devices result in up to a 1 hour increase in physical activity per week for the wearers vs control, although there was no appreciable effect on A1C.³⁷

A meta-analysis showed that moderate aerobic exercise reduced A1C by 0.69% at 13 weeks.

One systematic review showed a 0.5% reduction in A1C (95% CI, –0.65 to –0.34) by focusing on environmental changes related to the diet, with the most effective intervention being full meal replacement for calorie control (ie, each meal was pre-made and provided to the patients based on macronutrient and caloric goals).³⁸ Additionally, diabetes self-management education includes coping strategies, problem solving, self-­advocacy, and health care system navigation, which have been shown to reduce A1C by an average of 0.6%.²¹ Patient resources are available for further assistance with lifestyle modifications (TABLE 3).

Can your patient achieve remission?

Emerging evidence suggests that patients may achieve remission from type 2 diabetes with intensive lifestyle interventions.³⁹ This is supported by the American College of Lifestyle Medicine.⁵ Although there is no consensus definition for remission, in general it is reasonable to presume remission if a patient achieves normo-glycemia (A1C < 5.7%) for at least 1 year without any medication therapy.⁵ These intensive lifestyle interventions would include a mostly plant-based diet with moderate calorie restriction, appropriate and sustained physical activity, adequate sleep, and stress-reduction techniques.⁵ One study found that 46% of patients in a weight-management program across multiple primary care clinics achieved remission at 12 months.⁴⁰ A meta-analysis showed that a low-carbohydrate diet induced remission at 6 months in 32% of patients (although the result was not controlled for weight loss as a possible confounding factor and an A1C cutoff of 6.5% was used).¹¹ Thus far, most studies have focused on short-term follow-up intervals, but evidence is emerging that with intensive lifestyle interventions the effects are sustained at the 2-year mark.⁴¹

The American Academy of Clinical Endocrinologists recommends using motivational interviewing and wearable feedback devices to stimulate behavioral change in patients.

This evidence could reframe our understanding of type 2 diabetes therapy and could change the conversations we have with patients regarding their treatment. Instead of focusing on an A1C goal that is adequate for control of type 2 diabetes, we would instead focus on achieving remission.

CORRESPONDENCE
Stephen McMullan, MD, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road, Jacksonville, FL 32224; [email protected]

Type 2 diabetes has been increasing in incidence and prevalence over the past 20 years, with worldwide prevalence estimated at 6.28%.¹ The estimated cost of diagnosed diabetes in the United States was $327 billion in 2017; this included direct medical costs and reduced productivity.² Type 2 diabetes can be prevented in most patients, given that it is a metabolic derangement caused by a complicated interaction between a patient’s genetic predisposition and lifestyle. A consensus statement by the American Academy of Clinical Endocrinologists (AACE) and American College of Endocrinology indicates that the recommended lifestyle modifications for diabetes include medical nutrition therapy with healthy eating patterns, regular physical activity, adequate sleep, behavioral support/counseling, and smoking cessation.³ Evidence shows that adherence to these lifestyle changes alone yields a relative reduction in type 2 diabetes mortality of 57%.⁴

IMAGE: ©ALICIA BUELOW; PATIENT IMAGE © GETTY IMAGES

In the discussion that follows, we review the current guideline recommendations for dietary modifications and physical activity and summarize their effectiveness in the treatment of type 2 diabetes. We also describe practical clinical strategies to promote change in patient behavior, and examine current literature supporting intensive lifestyle changes that, if achieved, may induce disease remission.⁵

Dietary strategies

Low, or very low, carbohydrate diet  

Carbohydrates can affect blood glucose levels in varying degrees depending on their intrinsic properties such as fiber content, sugars, and starches . ⁶ According to the American Diabetes Association’s (ADA) 2019 consensus report, ⁶ the carbohydrate quality that generally should be recommended is high in fiber, vitamins, and minerals, and low in added sugars, fats, and sodium (processed carbohydrates) ( TABLE 1 ^7-10 ). A low-carbohydrate diet (LCD) typically has a carbohydrate content < 130 g/d or < 26% of a 2000 kcal/d diet. ¹¹ A very low–carbohydrate diet (VLCD) is 20-50 g/d or < 10% of the 2000 kcal/day diet. ¹¹

Adherence to lifestyle changes alone yields a relative reduction in type 2 diabetes mortality of 57%.

In a meta-analysis by Goldenberg et al¹¹, the LCD was shown to reduce A1C by 0.47% at 6 months (95% CI, –0.6 to –0.34) and by 0.23% at 12 months when compared with control diets. A review of multiple meta-­analyses also showed a significant reduction in A1C especially with VLCD patterns; however, the results waned at the 12-month follow-up.⁵ In addition, confounding factors were seen when comparing adherence between LCD and VLCD, with patients in the latter group having larger problems with adherence, which decreased the benefit seen in the overall group comparison.¹¹

Very low–carbohydrate/high-fat (ketogenic) diet  

Ketogenic diets generally follow a VLCD with the carbohydrate portion set at 5% to 10% of total caloric intake (generally < 30 g/d) and the rest of the calories taken up by protein (typically 1 g/kg/d) and fat (TABLE 1^7-10).¹² The fat content recommended is primarily polyunsaturated fat such as olive oil, while saturated fats such as butter and lard (animal fat) should be limited.

A recent meta-analysis by Choi et al¹² showed that in overweight or obese patients with type 2 diabetes, the average A1C reduction was 0.62% (95% CI, –0.89 to –0.35) in the ketogenic intervention group. Another meta-analysis showed an even more significant A1C reduction at 1.07% (95% CI, –1.37 to –0.78).¹³ Concerns have been raised about the ketogenic diet, particularly as it relates to lipid metabolism and cholesterol levels; however, in the 2 referenced meta-analyses, the total cholesterol and triglyceride levels actually declined in the ketogenic intervention groups with minimal effect on LDL-C.^12,13 This may alleviate some of the concerns of lipid management with this diet.

Plant-based diet  

Popularized by Dr. T. Colin Campbell, a plant-based diet refers to a low-fat, high-fiber, whole-foods diet (whole fruits, vegetables, and naturally occurring carbohydrates, as opposed to processed foods). Examples of this type of diet include the popular vegan diet, which restricts all animal-derived products, and the vegetarian diet, which is generally limited to foods in the plant category with some addition of animal products, such as milk and cheese. Other variations of these diets exist and include other sources of protein (eg, chicken, eggs, or fish) (TABLE 1^7-10).

Continue to: A review by...

A review by Salas-Salvadó et al¹⁴ showed that a vegan diet yields an average A1C reduction of 0.41% (95% CI, –0.58 to –0.23).Several meta-analyses report similar effects on A1C with vegetarian and vegan eating patterns.^6,15,16 The ADA review notes that weight loss was more significant in the vegan group and concluded that this diet should be studied further while controlling for weight loss.⁶

Mediterranean  diet

The Mediterranean diet emphasizes vegetables, whole grains, fruits, lean meats, nuts, and olive oil. The benefits of the Mediterranean diet are well known and, as a result, the diet is recommended by organizations including the American Heart Association as part of a strategy to reduce cardiovascular risk (TABLE 1^7-10).

Mediterranean diet interventions have generally shown mixed effects on A1C reduction, weight management, and lipid control in type 2 diabetes. ⁶ The PREDIMED trial is the largest and longest randomized controlled trial to date comparing the Mediterranean diet to a low-fat diet. ¹⁷ This trial has reliably shown a reduced risk for type 2 diabetes and a trend to reduced A1C. ¹⁷ A reduction in the need for glucose-lowering medications was demonstrated in a subgroup analysis of the intervention group (adjusted hazard ratio = 0.78; 95% CI, 0.62-0.98). ¹⁸ Also, the Mediterranean diet has shown a significant reduction in the incidence of cardiovascular disease in patients with type 2 diabetes. ⁶

Physical activity and exercise

What do current guidelines recommend?

For most adults with type 2 diabetes, current guidelines by the ADA and by the National Institute of Diabetes and Digestive and Kidney Diseases recommend at least 150 minutes of moderate-to-vigorous intensity exercise every week spread out over at least 3 days, with no more than 2 consecutive days without exercise; and resistance training at least 2 other days per week which should balance all major muscle groups (TABLE 2^19-21). The benefits of exercise for type 2 diabetes have been well reviewed: positive effects on glucose control, insulin sensitivity, cardiovascular disease, lipid profiles, skeletal muscle metabolism, and solid-organ functioning.^19,22,23

Grace et al²⁴ showed in a meta-analysis that moderate aerobic exercise reduced A1C by 0.69% (95% CI, –1.09 to –0.3) at 13 weeks, and a Cochrane review showed an average A1C reduction of 0.6% with moderate-­intensity exercise.²⁵ Borror et al²⁶ demonstrated in a systematic review that postprandial moderate-intensity aerobic exercise starting 1 hour after meals results in a reduced 24-hour prevalence of hyperglycemia (33.5% reduction vs control). A meta-analysis in China showed an average A1C reduction of 0.68% for patients performing a Tai Chi physical activity intervention.²⁷

Continue to: Consider high-intensity interval training

Multiple randomized controlled trials highlight the benefits of high-intensity interval training (HIIT) (TABLE 2^19-21) compared with moderate-intensity continuous training (MICT) on improving A1C. A meta-analysis showed a weighted mean difference in A1C of 0.23% (95% CI, –0.43 to –0.02%).²⁸ Also, a patient could spend less time performing HIIT as opposed to MICT to achieve the same benefits. For example, a patient typically performing 30 minutes of MICT may only need to perform 15 minutes of HIIT,a time-saving option for patients.^20,22

Interrupt sedentary behavior

Risk for incident type 2 diabetes increases when someone is sedentary for more than 6 to 8 hours daily or watches TV for 3 to 4 hours (relative risk [RR] = 1.12).²⁹ Recommendations for interrupting a sedentary lifestyle include standing from a seated position at least every 30 minutes and engaging in a light activity during the break interval for at least 3 minutes.¹⁹ Most studies have reliably shown that interrupting sedentary behavior reduces postprandial and 24-hour average blood glucose levels.¹⁹ Interrupted sitting/sedentary behavior has also been shown to reduce resting blood pressure in patients with type 2 diabetes.³⁰

Other important lifestyle factors

Encourage 7 to 8 hours of sleep

There is a U-shaped association between glycemic control and sleep quantity based on a meta-analysis by Lee et al ³¹ that showed a 0.23% increase in A1C in patients with insufficient sleep (< 4.5-6 hours/night) and a 0.13% increase in patients with ≥ 8 hours of sleep per night. Patients should be encouraged to obtain 7 to 8 hours of sleep per night to help maximize their diabetes control.  

Address stress reduction

Although evidence for stress reduction interventions on glycemic control is mixed, there does seem to be a benefit in diminishing emotional distress in patients with diabetes. A systematic review by Noordali et al³² demonstrated that patients who received mindfulness-based interventions had improvements in stress, anxiety, and depression symptoms which resulted in improved quality of life. These psychological benefits may subsequently lead to positive behavioral changes.

Assist patients with smoking cessation 

A large meta-analysis showed that active smoking increases the risk of cardiovascular events in patients with type 2 diabetes (RR = 1.44; 95% CI, 1.34-1.54).³³ Former smokers still have an increased risk (RR = 1.09; 95% CI, 1.05-1.13), but it is lower than that of current smokers, so patients should be encouraged to quit smoking.^3,33

Continue to: How can I get my patient to change?

How can I get my patient to change?

The AACE recommends using motivational interviewing, behavioral therapy consultation, and wearable feedback devices (eg, accelerometers/pedometers) to stimulate behavioral change in patients.³ Motivational interviewing is the principal counseling strategy and is supported by multiple studies showing the benefits of using this technique in a clinical encounter to induce behavioral changes.³⁴ In general, offer receptive patients intensive behavioral interventions and provide them with resources to accomplish their goals.³⁵ For example, a 7-step yearly intensive behavioral counseling intervention over 3 years showed significant improvements in activity of any intensity, reduced sedentary time, and led to favorable metabolic outcomes.³⁶ Wearable devices result in up to a 1 hour increase in physical activity per week for the wearers vs control, although there was no appreciable effect on A1C.³⁷

A meta-analysis showed that moderate aerobic exercise reduced A1C by 0.69% at 13 weeks.

One systematic review showed a 0.5% reduction in A1C (95% CI, –0.65 to –0.34) by focusing on environmental changes related to the diet, with the most effective intervention being full meal replacement for calorie control (ie, each meal was pre-made and provided to the patients based on macronutrient and caloric goals).³⁸ Additionally, diabetes self-management education includes coping strategies, problem solving, self-­advocacy, and health care system navigation, which have been shown to reduce A1C by an average of 0.6%.²¹ Patient resources are available for further assistance with lifestyle modifications (TABLE 3).

Can your patient achieve remission?

Emerging evidence suggests that patients may achieve remission from type 2 diabetes with intensive lifestyle interventions.³⁹ This is supported by the American College of Lifestyle Medicine.⁵ Although there is no consensus definition for remission, in general it is reasonable to presume remission if a patient achieves normo-glycemia (A1C < 5.7%) for at least 1 year without any medication therapy.⁵ These intensive lifestyle interventions would include a mostly plant-based diet with moderate calorie restriction, appropriate and sustained physical activity, adequate sleep, and stress-reduction techniques.⁵ One study found that 46% of patients in a weight-management program across multiple primary care clinics achieved remission at 12 months.⁴⁰ A meta-analysis showed that a low-carbohydrate diet induced remission at 6 months in 32% of patients (although the result was not controlled for weight loss as a possible confounding factor and an A1C cutoff of 6.5% was used).¹¹ Thus far, most studies have focused on short-term follow-up intervals, but evidence is emerging that with intensive lifestyle interventions the effects are sustained at the 2-year mark.⁴¹

The American Academy of Clinical Endocrinologists recommends using motivational interviewing and wearable feedback devices to stimulate behavioral change in patients.

This evidence could reframe our understanding of type 2 diabetes therapy and could change the conversations we have with patients regarding their treatment. Instead of focusing on an A1C goal that is adequate for control of type 2 diabetes, we would instead focus on achieving remission.

CORRESPONDENCE
Stephen McMullan, MD, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road, Jacksonville, FL 32224; [email protected]

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^ahttps://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; [email protected]

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^ahttps://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; [email protected]

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^ahttps://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; [email protected]

The health benefits of maintaining a physically active lifestyle are vast and irrefutable.¹ Physical activity is an important modifiable behavior demonstrated to reduce the risk for many chronic diseases while improving physical function (TABLE 1²).³ Physical inactivity increases with age, making older adults (ages ≥ 65 years) the least active age group and the group at greatest risk for inactivity-­related health consequences.^4-6 Engaging in a physically active lifestyle is especially important for older adults to maintain independence,⁷ quality of life,⁸ and the ability to perform activities of daily living.^3,9

Prescribe physical activity for older adults

The 2018 Physical Activity Guidelines for Americans recommend that all healthy adults (including healthy older adults) ideally should perform muscle-strengthening activities of moderate or greater intensity that involve all major muscle groups on 2 or more days per week and either (a) 150 to 300 minutes per week of moderate-intensity aerobic physical activity, (b) 75 to 150 minutes per week of vigorous-intensity aerobic physical activity, or (c) an equivalent combination, if possible (TABLE 2²).³ It is recommended that older adults specifically follow a multicomponent physical activity program that includes balance training, as well as aerobic and muscle-strengthening activities.³ Unfortunately, nearly 80% of older adults do not meet the recommended guidelines for aerobic or muscle-strengthening exercise.³

Identify barriers to exercise

Older adults report several barriers that limit physical activity. Some of the most commonly reported barriers include a lack of motivation, low self-efficacy for being active, physical limitations due to health conditions, inconvenient physical activity locations, boredom with physical activity, and lack of guidance from professionals.^10-12 Physical activity programs designed for older adults should specifically target these barriers for maximum effectiveness.

Clinicians also face potential barriers for promoting physical activity among older adults. Screening patients for physical inactivity can be a challenge, given the robust number of clinical preventive services and conversations that are already recommended for older adults. Additionally, screening for physical activity is not a reimbursable service. In July, the US Preventive Services Task Force (USPSTF) reaffirmed its 2017 recommendation to individualize the decision to offer or refer adults without obesity, hypertension, dyslipidemia, or abnormal blood glucose levels or diabetes to behavioral counseling to promote a healthy diet and physical activity (Grade C rating).¹³

Treat physical activity as a vital sign

The Exercise is Medicine (EIM) model is based on the principle that physical activity should be treated as a vital sign and discussed during all health care visits. Health care professionals have a unique opportunity to promote physical activity, since more than 80% of US adults see a physician annually. Evidence also suggests clinician advice is associated with patients’ healthy lifestyle behaviors.^14,15

EIM is a global health initiative that was established in 2007 and is managed by the American College of Sports Medicine (ACSM). The primary objective of the EIM model is to treat physical activity behavior as a vital sign and include physical activity promotion as a standard of clinical care. In order to achieve this objective, the EIM model recommends health care systems follow 3 simple rules: (1) treat physical activity as a vital sign by measuring physical activity of every patient at every visit, (2) prescribe exercise to those patients who report not meeting the physical activity guidelines, and/or (3) refer inactive patients to evidence-based physical activity resources to receive exercise counseling.^16,17

Screen for physical activity using this 2-question self-report

Clinicians may employ multiple tactics to screen patients for their current levels of physical activity. Physical Activity Vital Sign (PAVS) is a 2-item self-report measure developed to briefly assess a patient’s level of physical activity; results can be entered into the patient’s electronic medical record and used to begin a process of referring inactive patients for behavioral counseling.^17,18 The PAVS can be administered in less than 1 minute by a medical assistant and/or nursing staff during rooming or intake of patients. The PAVS questions include, “On average, how many days per week do you engage in moderate-to-vigorous physical activity?” and “On average, how many minutes do you engage in physical activity at this level?” The clinician can then multiply the 2 numbers to calculate the patient’s total minutes of ­moderate-to-vigorous physical activity per week to determine whether a patient is meeting the recommended physical activity guidelines.¹⁶ (For more on the PAVS and other resources, see TABLE 3.)

Continue to: The PAVS has been established...

Approximately 80% of older adults do not meet the recommended guidelines for aerobic or muscle-strengthening exercise.

The PAVS has been established as a valid instrument for detecting patients who may need counseling on physical activity for chronic disease recognition, management, and prevention.¹⁷ Furthermore, there is a strong association between PAVS, elevated body mass index, and chronic disease burden.¹⁹ Therefore, we recommend that primary care physicians screen their patients for physical activity levels. It has been demonstrated, however, that many primary care visits for older individuals include discussions of diet and physical activity but do not provide recommendations for lifestyle change.¹⁹ Thus, exploring ways to counsel patients on lifestyle change in an efficient manner is recommended. It has been demonstrated that counseling and referral from primary care centers can promote increased adherence to physical activity practices.^20,21

Determine physical activity readiness

Prior to recommending a physical activity regimen, it is important to evaluate the patient’s readiness to make a change. Various questionnaires—such as the Physical Activity Readiness Questionnaire—have been developed to determine a patient’s level of readiness, evaluating both psychological and physical factors (www.nasm.org/docs/pdf/parqplus-2020.pdf?sfvrsn=401bf1af_24). Questionnaires also help you to determine whether further medical evaluation prior to beginning an exercise regimen is necessary. It’s important to note that, as is true with any office intervention, patients may be in a precontemplation or contemplation phase and may not be prepared to immediately make changes.

Evaluate risk level

Assess cardiovascular risk. Physicians and patients are often concerned about cardiovascular risk or injury risk during physical activity counseling, which may lead to fewer exercise prescriptions. As a physician, it is important to remember that for most adults, the benefits of exercise will outweigh any potential risks,³ and there is generally a low risk of cardiovascular events related to light to moderate–intensity exercise regimens.² Additionally, it has been demonstrated that exercise and cardiovascular rehabilitation are highly beneficial for primary and secondary prevention of cardiovascular disease.²² Given that cardiovascular comorbidities are relatively common in older adults, some older adults will need to undergo risk stratification evaluation prior to initiating an exercise regimen.

Review preparticipation screening guidelines and recommendations

Guidelines can be contradictory regarding the ideal pre-exercise evaluation. In general, the USPSTF recommends against screening with resting or exercise electrocardiography (EKG) to prevent cardiovascular disease events in asymptomatic adults who are at low risk. It also finds insufficient evidence to assess the balance of benefits and harms of screening with resting or exercise EKG to prevent cardiovascular disease events in asymptomatic adults who are at intermediate or high risk.²²

Similarly, the 2020 ACSM Guidelines for Exercise Testing and Prescription reflect that routine exercise testing is not recommended for all older adult patients prior to starting an exercise regimen.¹⁷ However, the ACSM does recommend all patients with signs or symptoms of a cardiovascular, renal, or metabolic disease consult with a clinician for medical risk stratification and potential subsequent testing prior to starting an exercise regimen. If an individual already exercises and is having new/worsening signs or symptoms of a cardiovascular, renal, or metabolic disease, that patient should cease exercise until medical evaluation is performed. Additionally, ACSM recommends that asymptomatic patients who do not exercise but who have known cardiovascular, renal, or metabolic disease receive medical evaluation prior to starting an exercise regimen.¹⁷

Continue to: Is there evidence of cardiovascular, renal, or metabolic disease?

Initial screening can be completed by obtaining the patient’s history and conducting a physical examination. Patients reporting chest pain or discomfort (or any anginal equivalent), dyspnea, syncope, orthopnea, lower extremity edema, signs of tachyarrhythmia/bradyarrhythmia, intermittent claudication, exertional fatigue, or new exertional symptoms should all be considered for cardiovascular stress testing. Patients with a diagnosis of renal disease or either type 1 or type 2 diabetes should also be considered for cardiovascular stress testing.

Ready to prescribe exercise? Cover these 4 points

When prescribing any exercise plan for older adults, it is important for clinicians to specify 4 key components: frequency, intensity, time, and type (this can be remembered using the acronym “FITT”).²³ A sedentary adult should be encouraged to engage in moderate-­intensity exercise, such as walking, for 15 minutes 3 times per week. The key with a sedentary adult is appropriate follow-up to monitor progression and modify activity to help ensure the patient can achieve the goal number of minutes per week. It can be helpful to share the “next step” with the patient, as well (eg, increase to 4 times per week after 2 weeks, or increase by 5 minutes every week). For the intermittent exerciser, a program of moderate exercise, such as using an elliptical, for 30 to 40 minutes 5 times per week is a recommended prescription. FITT components can be tailored to meet individual patient physical readiness.²³

Frequency. While the 2018 Physical Activity Guidelines for Americans recommend a specific frequency of physical activity throughout the week, it is important to remember that some older adults will be unable to meet these recommendations, particularly in the setting of frailty and comorbidities (TABLE 2²). In these cases, the guidelines simply recommend that older adults should be as physically active as their abilities and comorbidities allow. Some exercise is better than none, and generally moving more and sitting less will yield health benefits for older adult patients.

Intensity is a description of how hard an individual is working during physical activity. An older adult’s individual capacity for exercise intensity will depend on many factors, including their comorbidities. An activity’s intensity will be relative to a person’s unique level of fitness. Given this heterogeneity, exercise prescriptions should be tailored to the individual. Light-intensity exercise generally causes a slight increase in pulse and respiratory rate, moderate-intensity exercise causes a noticeable increase in pulse and respiratory rate, and vigorous-intensity exercise causes a significant increase in pulse and respiratory rate (TABLE 4^2,16,17,24).²

The “talk test” is a simple, practical, and validated test that can help one determine an individual’s capacity for moderate- or ­vigorous-intensity exercise.²³ In general, a person performing vigorous-intensity exercise will be unable to talk comfortably during activity for more than a few words without pausing for breath. Similarly, a person will be able to talk but not sing comfortably during moderate-intensity exercise.^3,23

Continue to: Time

Time. The 2018 Physical Activity Guidelines for Americans recommend a specific duration of physical activity throughout the week; however, as with frequency, it is important to remember that duration of exercise is individualized (TABLE 2²). Older adults should be as physically active as their abilities and comorbidities allow, and in the setting of frailty, numerous comorbidities, and/or a sedentary lifestyle, it is reasonable to initiate exercise recommendations with shorter durations.

The PAVS is a 2-item self-report measure used to quickly assess a patient’s level of physical activity.

Type of exercise. As noted in the 2018 Physical Activity Guidelines for Americans, recommendations for older adults include multiple types of exercise. In addition to these general exercise recommendations, exercise prescriptions can be individualized to target specific comorbidities (TABLE 2²). Weight-bearing, bone-strengthening exercises can benefit patients with disorders of low bone density and possibly those with osteoarthritis.^3,23 Patients at increased risk for falls should focus on balance-training options that strengthen the muscles of the back, abdomen, and legs, such as tai chi.^3,23 Patients with cardiovascular risk can benefit from moderate- to high-intensity aerobic exercise (although exercise should be performed below anginal threshold in patients with known cardiovascular disease). Patients with type 2 diabetes achieve improved glycemic control when engaging in combined moderate-intensity aerobic exercise and resistance training.^7,23

Referral to a physical therapist or sport and exercise medicine specialist can always be considered, particularly for patients with significant neurologic disorders, disability secondary to traumatic injury, or health conditions.³

An improved quality of life. Incorporating physical activity into older adults’ lives can enhance their quality of life. Family physicians are well positioned to counsel older adults on the importance and benefits of exercise and to help them overcome the barriers or resistance to undertaking a change in behavior. Guidelines, recommendations, patient history, and resources provide the support needed to prescribe individualized exercise plans for this distinct population. 

CORRESPONDENCE
Scott T. Larson, MD, 200 Hawkins Drive, Iowa City, IA, 52242; [email protected]

The health benefits of maintaining a physically active lifestyle are vast and irrefutable.¹ Physical activity is an important modifiable behavior demonstrated to reduce the risk for many chronic diseases while improving physical function (TABLE 1²).³ Physical inactivity increases with age, making older adults (ages ≥ 65 years) the least active age group and the group at greatest risk for inactivity-­related health consequences.^4-6 Engaging in a physically active lifestyle is especially important for older adults to maintain independence,⁷ quality of life,⁸ and the ability to perform activities of daily living.^3,9

Prescribe physical activity for older adults

The 2018 Physical Activity Guidelines for Americans recommend that all healthy adults (including healthy older adults) ideally should perform muscle-strengthening activities of moderate or greater intensity that involve all major muscle groups on 2 or more days per week and either (a) 150 to 300 minutes per week of moderate-intensity aerobic physical activity, (b) 75 to 150 minutes per week of vigorous-intensity aerobic physical activity, or (c) an equivalent combination, if possible (TABLE 2²).³ It is recommended that older adults specifically follow a multicomponent physical activity program that includes balance training, as well as aerobic and muscle-strengthening activities.³ Unfortunately, nearly 80% of older adults do not meet the recommended guidelines for aerobic or muscle-strengthening exercise.³

Identify barriers to exercise

Older adults report several barriers that limit physical activity. Some of the most commonly reported barriers include a lack of motivation, low self-efficacy for being active, physical limitations due to health conditions, inconvenient physical activity locations, boredom with physical activity, and lack of guidance from professionals.^10-12 Physical activity programs designed for older adults should specifically target these barriers for maximum effectiveness.

Clinicians also face potential barriers for promoting physical activity among older adults. Screening patients for physical inactivity can be a challenge, given the robust number of clinical preventive services and conversations that are already recommended for older adults. Additionally, screening for physical activity is not a reimbursable service. In July, the US Preventive Services Task Force (USPSTF) reaffirmed its 2017 recommendation to individualize the decision to offer or refer adults without obesity, hypertension, dyslipidemia, or abnormal blood glucose levels or diabetes to behavioral counseling to promote a healthy diet and physical activity (Grade C rating).¹³

Treat physical activity as a vital sign

The Exercise is Medicine (EIM) model is based on the principle that physical activity should be treated as a vital sign and discussed during all health care visits. Health care professionals have a unique opportunity to promote physical activity, since more than 80% of US adults see a physician annually. Evidence also suggests clinician advice is associated with patients’ healthy lifestyle behaviors.^14,15

EIM is a global health initiative that was established in 2007 and is managed by the American College of Sports Medicine (ACSM). The primary objective of the EIM model is to treat physical activity behavior as a vital sign and include physical activity promotion as a standard of clinical care. In order to achieve this objective, the EIM model recommends health care systems follow 3 simple rules: (1) treat physical activity as a vital sign by measuring physical activity of every patient at every visit, (2) prescribe exercise to those patients who report not meeting the physical activity guidelines, and/or (3) refer inactive patients to evidence-based physical activity resources to receive exercise counseling.^16,17

Screen for physical activity using this 2-question self-report

Clinicians may employ multiple tactics to screen patients for their current levels of physical activity. Physical Activity Vital Sign (PAVS) is a 2-item self-report measure developed to briefly assess a patient’s level of physical activity; results can be entered into the patient’s electronic medical record and used to begin a process of referring inactive patients for behavioral counseling.^17,18 The PAVS can be administered in less than 1 minute by a medical assistant and/or nursing staff during rooming or intake of patients. The PAVS questions include, “On average, how many days per week do you engage in moderate-to-vigorous physical activity?” and “On average, how many minutes do you engage in physical activity at this level?” The clinician can then multiply the 2 numbers to calculate the patient’s total minutes of ­moderate-to-vigorous physical activity per week to determine whether a patient is meeting the recommended physical activity guidelines.¹⁶ (For more on the PAVS and other resources, see TABLE 3.)

Continue to: The PAVS has been established...

Approximately 80% of older adults do not meet the recommended guidelines for aerobic or muscle-strengthening exercise.

The PAVS has been established as a valid instrument for detecting patients who may need counseling on physical activity for chronic disease recognition, management, and prevention.¹⁷ Furthermore, there is a strong association between PAVS, elevated body mass index, and chronic disease burden.¹⁹ Therefore, we recommend that primary care physicians screen their patients for physical activity levels. It has been demonstrated, however, that many primary care visits for older individuals include discussions of diet and physical activity but do not provide recommendations for lifestyle change.¹⁹ Thus, exploring ways to counsel patients on lifestyle change in an efficient manner is recommended. It has been demonstrated that counseling and referral from primary care centers can promote increased adherence to physical activity practices.^20,21

Determine physical activity readiness

Prior to recommending a physical activity regimen, it is important to evaluate the patient’s readiness to make a change. Various questionnaires—such as the Physical Activity Readiness Questionnaire—have been developed to determine a patient’s level of readiness, evaluating both psychological and physical factors (www.nasm.org/docs/pdf/parqplus-2020.pdf?sfvrsn=401bf1af_24). Questionnaires also help you to determine whether further medical evaluation prior to beginning an exercise regimen is necessary. It’s important to note that, as is true with any office intervention, patients may be in a precontemplation or contemplation phase and may not be prepared to immediately make changes.

Evaluate risk level

Assess cardiovascular risk. Physicians and patients are often concerned about cardiovascular risk or injury risk during physical activity counseling, which may lead to fewer exercise prescriptions. As a physician, it is important to remember that for most adults, the benefits of exercise will outweigh any potential risks,³ and there is generally a low risk of cardiovascular events related to light to moderate–intensity exercise regimens.² Additionally, it has been demonstrated that exercise and cardiovascular rehabilitation are highly beneficial for primary and secondary prevention of cardiovascular disease.²² Given that cardiovascular comorbidities are relatively common in older adults, some older adults will need to undergo risk stratification evaluation prior to initiating an exercise regimen.

Review preparticipation screening guidelines and recommendations

Guidelines can be contradictory regarding the ideal pre-exercise evaluation. In general, the USPSTF recommends against screening with resting or exercise electrocardiography (EKG) to prevent cardiovascular disease events in asymptomatic adults who are at low risk. It also finds insufficient evidence to assess the balance of benefits and harms of screening with resting or exercise EKG to prevent cardiovascular disease events in asymptomatic adults who are at intermediate or high risk.²²

Similarly, the 2020 ACSM Guidelines for Exercise Testing and Prescription reflect that routine exercise testing is not recommended for all older adult patients prior to starting an exercise regimen.¹⁷ However, the ACSM does recommend all patients with signs or symptoms of a cardiovascular, renal, or metabolic disease consult with a clinician for medical risk stratification and potential subsequent testing prior to starting an exercise regimen. If an individual already exercises and is having new/worsening signs or symptoms of a cardiovascular, renal, or metabolic disease, that patient should cease exercise until medical evaluation is performed. Additionally, ACSM recommends that asymptomatic patients who do not exercise but who have known cardiovascular, renal, or metabolic disease receive medical evaluation prior to starting an exercise regimen.¹⁷

Continue to: Is there evidence of cardiovascular, renal, or metabolic disease?

Initial screening can be completed by obtaining the patient’s history and conducting a physical examination. Patients reporting chest pain or discomfort (or any anginal equivalent), dyspnea, syncope, orthopnea, lower extremity edema, signs of tachyarrhythmia/bradyarrhythmia, intermittent claudication, exertional fatigue, or new exertional symptoms should all be considered for cardiovascular stress testing. Patients with a diagnosis of renal disease or either type 1 or type 2 diabetes should also be considered for cardiovascular stress testing.

Ready to prescribe exercise? Cover these 4 points

When prescribing any exercise plan for older adults, it is important for clinicians to specify 4 key components: frequency, intensity, time, and type (this can be remembered using the acronym “FITT”).²³ A sedentary adult should be encouraged to engage in moderate-­intensity exercise, such as walking, for 15 minutes 3 times per week. The key with a sedentary adult is appropriate follow-up to monitor progression and modify activity to help ensure the patient can achieve the goal number of minutes per week. It can be helpful to share the “next step” with the patient, as well (eg, increase to 4 times per week after 2 weeks, or increase by 5 minutes every week). For the intermittent exerciser, a program of moderate exercise, such as using an elliptical, for 30 to 40 minutes 5 times per week is a recommended prescription. FITT components can be tailored to meet individual patient physical readiness.²³

Frequency. While the 2018 Physical Activity Guidelines for Americans recommend a specific frequency of physical activity throughout the week, it is important to remember that some older adults will be unable to meet these recommendations, particularly in the setting of frailty and comorbidities (TABLE 2²). In these cases, the guidelines simply recommend that older adults should be as physically active as their abilities and comorbidities allow. Some exercise is better than none, and generally moving more and sitting less will yield health benefits for older adult patients.

Intensity is a description of how hard an individual is working during physical activity. An older adult’s individual capacity for exercise intensity will depend on many factors, including their comorbidities. An activity’s intensity will be relative to a person’s unique level of fitness. Given this heterogeneity, exercise prescriptions should be tailored to the individual. Light-intensity exercise generally causes a slight increase in pulse and respiratory rate, moderate-intensity exercise causes a noticeable increase in pulse and respiratory rate, and vigorous-intensity exercise causes a significant increase in pulse and respiratory rate (TABLE 4^2,16,17,24).²

The “talk test” is a simple, practical, and validated test that can help one determine an individual’s capacity for moderate- or ­vigorous-intensity exercise.²³ In general, a person performing vigorous-intensity exercise will be unable to talk comfortably during activity for more than a few words without pausing for breath. Similarly, a person will be able to talk but not sing comfortably during moderate-intensity exercise.^3,23

Continue to: Time

Time. The 2018 Physical Activity Guidelines for Americans recommend a specific duration of physical activity throughout the week; however, as with frequency, it is important to remember that duration of exercise is individualized (TABLE 2²). Older adults should be as physically active as their abilities and comorbidities allow, and in the setting of frailty, numerous comorbidities, and/or a sedentary lifestyle, it is reasonable to initiate exercise recommendations with shorter durations.

The PAVS is a 2-item self-report measure used to quickly assess a patient’s level of physical activity.

Type of exercise. As noted in the 2018 Physical Activity Guidelines for Americans, recommendations for older adults include multiple types of exercise. In addition to these general exercise recommendations, exercise prescriptions can be individualized to target specific comorbidities (TABLE 2²). Weight-bearing, bone-strengthening exercises can benefit patients with disorders of low bone density and possibly those with osteoarthritis.^3,23 Patients at increased risk for falls should focus on balance-training options that strengthen the muscles of the back, abdomen, and legs, such as tai chi.^3,23 Patients with cardiovascular risk can benefit from moderate- to high-intensity aerobic exercise (although exercise should be performed below anginal threshold in patients with known cardiovascular disease). Patients with type 2 diabetes achieve improved glycemic control when engaging in combined moderate-intensity aerobic exercise and resistance training.^7,23

Referral to a physical therapist or sport and exercise medicine specialist can always be considered, particularly for patients with significant neurologic disorders, disability secondary to traumatic injury, or health conditions.³

An improved quality of life. Incorporating physical activity into older adults’ lives can enhance their quality of life. Family physicians are well positioned to counsel older adults on the importance and benefits of exercise and to help them overcome the barriers or resistance to undertaking a change in behavior. Guidelines, recommendations, patient history, and resources provide the support needed to prescribe individualized exercise plans for this distinct population. 

CORRESPONDENCE
Scott T. Larson, MD, 200 Hawkins Drive, Iowa City, IA, 52242; [email protected]

The health benefits of maintaining a physically active lifestyle are vast and irrefutable.¹ Physical activity is an important modifiable behavior demonstrated to reduce the risk for many chronic diseases while improving physical function (TABLE 1²).³ Physical inactivity increases with age, making older adults (ages ≥ 65 years) the least active age group and the group at greatest risk for inactivity-­related health consequences.^4-6 Engaging in a physically active lifestyle is especially important for older adults to maintain independence,⁷ quality of life,⁸ and the ability to perform activities of daily living.^3,9

Prescribe physical activity for older adults

The 2018 Physical Activity Guidelines for Americans recommend that all healthy adults (including healthy older adults) ideally should perform muscle-strengthening activities of moderate or greater intensity that involve all major muscle groups on 2 or more days per week and either (a) 150 to 300 minutes per week of moderate-intensity aerobic physical activity, (b) 75 to 150 minutes per week of vigorous-intensity aerobic physical activity, or (c) an equivalent combination, if possible (TABLE 2²).³ It is recommended that older adults specifically follow a multicomponent physical activity program that includes balance training, as well as aerobic and muscle-strengthening activities.³ Unfortunately, nearly 80% of older adults do not meet the recommended guidelines for aerobic or muscle-strengthening exercise.³

Identify barriers to exercise

Older adults report several barriers that limit physical activity. Some of the most commonly reported barriers include a lack of motivation, low self-efficacy for being active, physical limitations due to health conditions, inconvenient physical activity locations, boredom with physical activity, and lack of guidance from professionals.^10-12 Physical activity programs designed for older adults should specifically target these barriers for maximum effectiveness.

Clinicians also face potential barriers for promoting physical activity among older adults. Screening patients for physical inactivity can be a challenge, given the robust number of clinical preventive services and conversations that are already recommended for older adults. Additionally, screening for physical activity is not a reimbursable service. In July, the US Preventive Services Task Force (USPSTF) reaffirmed its 2017 recommendation to individualize the decision to offer or refer adults without obesity, hypertension, dyslipidemia, or abnormal blood glucose levels or diabetes to behavioral counseling to promote a healthy diet and physical activity (Grade C rating).¹³

Treat physical activity as a vital sign

The Exercise is Medicine (EIM) model is based on the principle that physical activity should be treated as a vital sign and discussed during all health care visits. Health care professionals have a unique opportunity to promote physical activity, since more than 80% of US adults see a physician annually. Evidence also suggests clinician advice is associated with patients’ healthy lifestyle behaviors.^14,15

EIM is a global health initiative that was established in 2007 and is managed by the American College of Sports Medicine (ACSM). The primary objective of the EIM model is to treat physical activity behavior as a vital sign and include physical activity promotion as a standard of clinical care. In order to achieve this objective, the EIM model recommends health care systems follow 3 simple rules: (1) treat physical activity as a vital sign by measuring physical activity of every patient at every visit, (2) prescribe exercise to those patients who report not meeting the physical activity guidelines, and/or (3) refer inactive patients to evidence-based physical activity resources to receive exercise counseling.^16,17

Screen for physical activity using this 2-question self-report

Clinicians may employ multiple tactics to screen patients for their current levels of physical activity. Physical Activity Vital Sign (PAVS) is a 2-item self-report measure developed to briefly assess a patient’s level of physical activity; results can be entered into the patient’s electronic medical record and used to begin a process of referring inactive patients for behavioral counseling.^17,18 The PAVS can be administered in less than 1 minute by a medical assistant and/or nursing staff during rooming or intake of patients. The PAVS questions include, “On average, how many days per week do you engage in moderate-to-vigorous physical activity?” and “On average, how many minutes do you engage in physical activity at this level?” The clinician can then multiply the 2 numbers to calculate the patient’s total minutes of ­moderate-to-vigorous physical activity per week to determine whether a patient is meeting the recommended physical activity guidelines.¹⁶ (For more on the PAVS and other resources, see TABLE 3.)

Continue to: The PAVS has been established...

Approximately 80% of older adults do not meet the recommended guidelines for aerobic or muscle-strengthening exercise.

The PAVS has been established as a valid instrument for detecting patients who may need counseling on physical activity for chronic disease recognition, management, and prevention.¹⁷ Furthermore, there is a strong association between PAVS, elevated body mass index, and chronic disease burden.¹⁹ Therefore, we recommend that primary care physicians screen their patients for physical activity levels. It has been demonstrated, however, that many primary care visits for older individuals include discussions of diet and physical activity but do not provide recommendations for lifestyle change.¹⁹ Thus, exploring ways to counsel patients on lifestyle change in an efficient manner is recommended. It has been demonstrated that counseling and referral from primary care centers can promote increased adherence to physical activity practices.^20,21

Determine physical activity readiness

Prior to recommending a physical activity regimen, it is important to evaluate the patient’s readiness to make a change. Various questionnaires—such as the Physical Activity Readiness Questionnaire—have been developed to determine a patient’s level of readiness, evaluating both psychological and physical factors (www.nasm.org/docs/pdf/parqplus-2020.pdf?sfvrsn=401bf1af_24). Questionnaires also help you to determine whether further medical evaluation prior to beginning an exercise regimen is necessary. It’s important to note that, as is true with any office intervention, patients may be in a precontemplation or contemplation phase and may not be prepared to immediately make changes.

Evaluate risk level

Assess cardiovascular risk. Physicians and patients are often concerned about cardiovascular risk or injury risk during physical activity counseling, which may lead to fewer exercise prescriptions. As a physician, it is important to remember that for most adults, the benefits of exercise will outweigh any potential risks,³ and there is generally a low risk of cardiovascular events related to light to moderate–intensity exercise regimens.² Additionally, it has been demonstrated that exercise and cardiovascular rehabilitation are highly beneficial for primary and secondary prevention of cardiovascular disease.²² Given that cardiovascular comorbidities are relatively common in older adults, some older adults will need to undergo risk stratification evaluation prior to initiating an exercise regimen.

Review preparticipation screening guidelines and recommendations

Guidelines can be contradictory regarding the ideal pre-exercise evaluation. In general, the USPSTF recommends against screening with resting or exercise electrocardiography (EKG) to prevent cardiovascular disease events in asymptomatic adults who are at low risk. It also finds insufficient evidence to assess the balance of benefits and harms of screening with resting or exercise EKG to prevent cardiovascular disease events in asymptomatic adults who are at intermediate or high risk.²²

Similarly, the 2020 ACSM Guidelines for Exercise Testing and Prescription reflect that routine exercise testing is not recommended for all older adult patients prior to starting an exercise regimen.¹⁷ However, the ACSM does recommend all patients with signs or symptoms of a cardiovascular, renal, or metabolic disease consult with a clinician for medical risk stratification and potential subsequent testing prior to starting an exercise regimen. If an individual already exercises and is having new/worsening signs or symptoms of a cardiovascular, renal, or metabolic disease, that patient should cease exercise until medical evaluation is performed. Additionally, ACSM recommends that asymptomatic patients who do not exercise but who have known cardiovascular, renal, or metabolic disease receive medical evaluation prior to starting an exercise regimen.¹⁷

Continue to: Is there evidence of cardiovascular, renal, or metabolic disease?

Initial screening can be completed by obtaining the patient’s history and conducting a physical examination. Patients reporting chest pain or discomfort (or any anginal equivalent), dyspnea, syncope, orthopnea, lower extremity edema, signs of tachyarrhythmia/bradyarrhythmia, intermittent claudication, exertional fatigue, or new exertional symptoms should all be considered for cardiovascular stress testing. Patients with a diagnosis of renal disease or either type 1 or type 2 diabetes should also be considered for cardiovascular stress testing.

Ready to prescribe exercise? Cover these 4 points

When prescribing any exercise plan for older adults, it is important for clinicians to specify 4 key components: frequency, intensity, time, and type (this can be remembered using the acronym “FITT”).²³ A sedentary adult should be encouraged to engage in moderate-­intensity exercise, such as walking, for 15 minutes 3 times per week. The key with a sedentary adult is appropriate follow-up to monitor progression and modify activity to help ensure the patient can achieve the goal number of minutes per week. It can be helpful to share the “next step” with the patient, as well (eg, increase to 4 times per week after 2 weeks, or increase by 5 minutes every week). For the intermittent exerciser, a program of moderate exercise, such as using an elliptical, for 30 to 40 minutes 5 times per week is a recommended prescription. FITT components can be tailored to meet individual patient physical readiness.²³

Frequency. While the 2018 Physical Activity Guidelines for Americans recommend a specific frequency of physical activity throughout the week, it is important to remember that some older adults will be unable to meet these recommendations, particularly in the setting of frailty and comorbidities (TABLE 2²). In these cases, the guidelines simply recommend that older adults should be as physically active as their abilities and comorbidities allow. Some exercise is better than none, and generally moving more and sitting less will yield health benefits for older adult patients.

Intensity is a description of how hard an individual is working during physical activity. An older adult’s individual capacity for exercise intensity will depend on many factors, including their comorbidities. An activity’s intensity will be relative to a person’s unique level of fitness. Given this heterogeneity, exercise prescriptions should be tailored to the individual. Light-intensity exercise generally causes a slight increase in pulse and respiratory rate, moderate-intensity exercise causes a noticeable increase in pulse and respiratory rate, and vigorous-intensity exercise causes a significant increase in pulse and respiratory rate (TABLE 4^2,16,17,24).²

The “talk test” is a simple, practical, and validated test that can help one determine an individual’s capacity for moderate- or ­vigorous-intensity exercise.²³ In general, a person performing vigorous-intensity exercise will be unable to talk comfortably during activity for more than a few words without pausing for breath. Similarly, a person will be able to talk but not sing comfortably during moderate-intensity exercise.^3,23

Continue to: Time

Time. The 2018 Physical Activity Guidelines for Americans recommend a specific duration of physical activity throughout the week; however, as with frequency, it is important to remember that duration of exercise is individualized (TABLE 2²). Older adults should be as physically active as their abilities and comorbidities allow, and in the setting of frailty, numerous comorbidities, and/or a sedentary lifestyle, it is reasonable to initiate exercise recommendations with shorter durations.

The PAVS is a 2-item self-report measure used to quickly assess a patient’s level of physical activity.

Type of exercise. As noted in the 2018 Physical Activity Guidelines for Americans, recommendations for older adults include multiple types of exercise. In addition to these general exercise recommendations, exercise prescriptions can be individualized to target specific comorbidities (TABLE 2²). Weight-bearing, bone-strengthening exercises can benefit patients with disorders of low bone density and possibly those with osteoarthritis.^3,23 Patients at increased risk for falls should focus on balance-training options that strengthen the muscles of the back, abdomen, and legs, such as tai chi.^3,23 Patients with cardiovascular risk can benefit from moderate- to high-intensity aerobic exercise (although exercise should be performed below anginal threshold in patients with known cardiovascular disease). Patients with type 2 diabetes achieve improved glycemic control when engaging in combined moderate-intensity aerobic exercise and resistance training.^7,23

Referral to a physical therapist or sport and exercise medicine specialist can always be considered, particularly for patients with significant neurologic disorders, disability secondary to traumatic injury, or health conditions.³

An improved quality of life. Incorporating physical activity into older adults’ lives can enhance their quality of life. Family physicians are well positioned to counsel older adults on the importance and benefits of exercise and to help them overcome the barriers or resistance to undertaking a change in behavior. Guidelines, recommendations, patient history, and resources provide the support needed to prescribe individualized exercise plans for this distinct population. 

CORRESPONDENCE
Scott T. Larson, MD, 200 Hawkins Drive, Iowa City, IA, 52242; [email protected]

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; [email protected]

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; [email protected]

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; [email protected]

CASE

A 35-year-old man arrives for an annual wellness visit with no specific complaints and no significant personal or family history. His normal exam includes a blood pressure of 110/74 mm Hg and a body mass index (BMI) of 23.6. You order “routine labs” for prevention, which include a comprehensive metabolic panel (CMP), fasting lipid profile, and thyroid-stimulating hormone (TSH) and 25(OH) vitamin D tests. Are you practicing value-based laboratory testing?

The answer to this question appears in the Case discussion at the end of the article.

Value-based care, including care provided through laboratory testing, can achieve the Institute for Healthcare Improvement’s Triple Aim of improving population health, improving the patient experience of care (including quality and satisfaction), and reducing cost: Value = (Quality x Patient experience) / Cost.¹

As quality and patient experience rise and cost falls, the value of care increases. Unnecessary lab testing, however, can negatively impact this equation:

• Error introduced by unnecessary testing can adversely affect quality.
• Patients experience inconvenience and sometimes cascades of testing, in addition to financial responsibility, from unnecessary testing.
• Low-value testing also contributes to work burden and provider burnout by requiring additional review and follow-up.

Rising health care costs are approaching 18% of the US gross domestic product, driven in large part by a wasteful and inefficient care delivery system.² One review of “waste domains” identified by the Institute of Medicine estimates that approximately one-quarter of health care costs represent waste, including overtreatment, breakdowns of care coordination, and pricing that fails to correlate to the level of care received.³ High-volume, low-cost testing contributes more to total cost than low-volume, high-cost tests.⁴

Provider and system factors that contribute to ongoing waste

A lack of awareness of waste and how to reduce it contribute to the problem, as does an underappreciation of the harmful effects caused by incidental abnormal results.

Provider intolerance of diagnostic uncertainty often leads to ordering even more tests.

Continue to: Also, a hope of avoiding...

Do not order tests just to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxiety.

Also, a hope of avoiding missed diagnoses and potential lawsuits leads to defensive practice and more testing. In addition, patients and family members can exert pressure based on a belief that more testing represents better care. Of course, financial revenues from testing may come into play, with few disincentives to forgo testing. Something that also comes into play is that evidence-based guidance on cost-­effective laboratory testing may be lacking, or there may be a lack of knowledge on how to access existing evidence.

Automated systems can facilitate wasteful laboratory testing, and the heavy testing practices of hospitals and specialists may be inappropriately applied to outpatient primary care.

Factors affecting the cost of laboratory testing

Laboratory test results drive 70% of today’s medical decisions.⁵ Negotiated insurance payment for tests is usually much less than the direct out-of-pocket costs charged to the patient. Without insurance, lab tests can cost patients between $100 and $1000.⁶ If multiple tests are ordered, the costs could likely be many thousands of dollars.

Actual costs typically vary by the testing facility, the patient’s health plan, and location in the United States; hospital-based testing tends to be the most expensive. Insurers will pay for lab tests with appropriate indications that are covered in the contract with the provider.⁶

Choosing Wisely initiative weighs in on lab testing

Choosing Wisely, a prominent initiative of the American Board of Internal Medicine Foundation, promotes appropriate resource utilization through educational campaigns that detail how to avoid unnecessary medical tests, treatments, and procedures.⁷ Recommendations are based largely on specialty society consensus and disease-oriented evidence. Choosing Wisely recommendations advise against the following⁷:

• performing laboratory blood testing unless clinically indicated or necessary for diagnosis or management, in order to avoid iatrogenic anemia. (American Academy of Family Physicians; Society for the Advancement of Patient Blood Management)
• requesting just a serum creatinine to test adult patients with diabetes and/or hypertension for chronic kidney disease. Use the kidney profile: serum creatinine with estimated glomerular filtration rate and urinary albumin-creatinine ratio. (American Society for Clinical Pathology)
• routinely screening for prostate cancer using a prostate-specific antigen test. It should be performed only after engaging in shared decision-making with the patient. (American Academy of Family Physicians; American Urological Association)
• screening for genital herpes simplex virus infectionFrutiger LT Std in asymptomatic adults, including pregnant women. (American Academy of Family Physicians)
• performing preoperative medical tests for eye surgery unless there are specific medical indications. (American Academy of Ophthalmology)

Sequential steps to takefor value-based lab ordering

Ask the question: “How will ordering this specific test change the management of my patient?” From there, take sequential steps using sound, evidence-based pathways. Morgan and colleagues⁸ outline the following practical approaches to rational test ordering:

• Perform a thorough clinical assessment.
• Consider the probability and implications of a positive test result.
• Practice patient-centered communication: address the patient’s concerns and discuss the risks and benefits of tests and how they will influence management.
• Follow clinical guidelines when available.
• Avoid ordering tests to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxieties.
• Avoid letting uncertainty drive unnecessary testing. Watchful waiting can allow time for the illness to resolve or declare itself.

Let’s consider this approach in the context of 4 areas: preventive care, diagnostic evaluation, ongoing management of chronic conditions, and preoperative testing.

Continue to: Preventive guidance from the USPSTF

An independent volunteer panel of 16 national experts in prevention and evidence-based medicine develop recommendations for the US Preventive Services Task Force (USPSTF).⁹ These guidelines are based on evidence and are updated as new evidence surfaces. Thirteen recommendations, some of which advise avoiding preventive procedures that could cause harm to patients, cover laboratory tests used in screening for conditions such as hyperlipidemia¹⁰ and prostate cancer.¹¹ We review the ones pertinent to our patient later at the end of the Case.

While the target audience for USPSTF recommendations is clinicians who provide preventive care, the recommendations are widely followed by policymakers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and patients.

Take a critical look at how you approach the diagnostic evaluation

To reduce unnecessary testing in the diagnostic evaluation of patients, first consider pretest probability, test sensitivity and specificity, narrowly out-of-range tests, habitually paired tests, and repetitive laboratory testing.

Pretest probability, and test sensitivity and specificity. Pretest probability is the estimated chance that the patient has the disease before the test result is known. In a patient with low pretest probability of a disease, the ability to conclusively arrive at the diagnosis with one positive result is limited. Similarly, for tests in patients with high pretest probability of disease, a negative test cannot be used to firmly rule out a diagnosis.¹²

Reliability also depends on test sensitivity (the proportion of true positive results) and specificity (the proportion of true negative results). A test with high sensitivity but low specificity will generate more false-positive results, with potential harm to patients who do not have a disease.

Reflexively ordering tests together (eg, C-reactive protein with erythrocyte sedimentation rate) often contributes to unnecessary testing.

The pretest probability along with test sensitivity and specificity help a clinician to interpret a test result, and even decide whether to order the test at all. For example, the anti-nuclear antibody (ANA) test for systemic lupus erythematosus (SLE) has a sensitivity of 100% and a specificity of 86%¹³; it will always be positive in a patient with SLE. But when applied to individuals with low likelihood of SLE, false-positives are more common; the ANA is falsely positive in up to 14% of healthy individuals, depending on the population studied.¹³

Ordering a test may be unnecessary if the results will not change the treatment plan. For example, in a female patient with classic symptoms of an uncomplicated urinary tract infection, a urine culture and even a urinalysis may not change treatment.

Continue to: Narrowly out-of-range tests

Narrowly out-of-range tests. Test results that fall just outside the “normal” range may be of questionable significance. When an asymptomatic patient has mildly elevated liver enzymes, should additional tests be ordered to avoid missing a treatable disorder? In these scenarios, a history, including possible contributing factors such as alcohol or substance misuse, must be paired with the clinical presentation to assess pre-test probability of a particular condition.¹⁴ Repeating a narrowly out-of-range test is an option in patients when follow-up is possible. Alternatively, you could pursue watchful waiting and monitor a minor abnormality over time while being vigilant for clinical changes. This whole-patient approach will guide the decision of whether to order additional testing.

Habitually paired tests. Reflexively ordering tests together often contributes to unnecessary testing. Examples of commonly paired tests are serum lipase with amylase, C-reactive protein (CRP) with erythrocyte sedimentation rate (ESR), and TSH with free T4 to monitor patients with treated hypothyroidism. These tests add minimal value together and can be decoupled.^15-17 Evidence supports ordering serum lipase alone, CRP instead of ESR, and TSH alone for monitoring thyroid status.

Unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually

Some commonly paired tests may not even be necessary for diagnosis. The well-established Rotterdam Criteria for diagnosing polycystic ovary syndrome specify clinical features and ovarian ultrasound for diagnosis.¹⁸ They do not require measurement of commonly ordered follicle-­stimulating hormone and luteinizing hormone for diagnosis.

Serial rather than parallel testing, a “2-step approach,” is a strategy made easier with the advent of the electronic medical record (EMR) and computerized lab systems.⁸ These records and lab systems allow providers to order reflex tests, and to add on additional tests, if necessary, to an existing blood specimen.

Repetitive laboratory testing. Repetitive inpatient laboratory testing in patients who are clinically stable is wasteful and potentially harmful. Interventions involving physician education alone show mixed results, but combining education with clinician audit and feedback, along with EMR-enabled restrictive ordering, have resulted in significant and sustained reductions in repetitive laboratory testing.¹⁹

Continue to: Ongoing management of chronic conditions

Ongoing management of chronic conditions

Evidence-based guidelines support choices of tests and testing intervals for ongoing management of chronic conditions such as diabetes, hyperlipidemia, and hypertension.

Diabetes. Guidelines also define quality standards that are applied to value-based contracts. For example, the American Diabetes Association recommends assessing A1C every 6 months in patients whose type 2 diabetes is under stable control.²⁰

Hyperlipidemia. For patients diagnosed with hyperlipidemia, 2018 clinical practice guidelines published by multiple specialty societies recommend assessing adherence and response to lifestyle changes and LDL-C–lowering medications with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.²¹

Hypertension. With a new diagnosis of hypertension, guidelines advise an initial assessment for comorbidities and end-organ damage with an electrocardiogram, urinalysis, glucose level, blood count, electrolytes, creatinine, calcium, lipids, and urinary albumin/creatinine ratio. For ongoing monitoring, guidelines recommend assessment for end-organ damage through regular measurements of creatinine, glomerular filtration rate, and urinary microalbumin/creatinine ratio. Initiation and alteration of medications should prompt appropriate additional lab follow-up—eg, a measurement of serum potassium after starting a diuretic.²²

Preoperative testing

Preoperative testing is overused in low-risk, ambulatory surgery. And testing, even with abnormal results, does not affect postoperative outcomes.²³

Continue to: The American Society of Anesthesiologists (ASA) Physical Status Classification System

The American Society of Anesthesiologists (ASA) Physical Status Classification System, which has been in use for more than 60 years, considers the patient’s physical status (ASA grades I-VI),²⁴ and when paired with surgery grades of minor, intermediate, and major/complex, can help assess preoperative risk and guide preoperative testing (TABLE).^24-26

Preoperative medical testing did not reduce the risk of medical adverse events during or after cataract surgery when compared with selective or no testing.²⁷ Unnecessary preoperative testing can lead to a nonproductive cascade of additional investigations. In a 2018 study of Medicare beneficiaries, unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually.²⁸

CASE

You would not be practicing value-based laboratory testing, according to the USPSTF, if you ordered a CMP, fasting lipid profile, and TSH and 25(OH) vitamin D tests for this healthy 35-year-old man whose family history, blood pressure, and BMI do not put him at elevated risk. Universal lipid screening (Grade B^a) is recommended for all adults ages 40 to 75. Thyroid screening tests and measurement of 25(OH) vitamin D level (I statements^a) are not recommended. The USPSTF has not evaluated chemistry panels for screening.

The USPSTF would recommend the following actions for this patient:

• Screen for HIV (ages 15 to 65 years; and younger or older if patient is at risk). (A recommendation^a,29)
• Screen for hepatitis C virus (in those ages 18 to 79). (B recommendation³⁰)

The following USPSTF recommendations might have come into play if this patient had certain risk factors, or if the patient had been a woman:

• Screen for diabetes if the patient is overweight or obese (B recommendation).
• Screen for hepatitis B in adults at risk (B recommendation).
• Screen for gonorrhea and chlamydia in women at risk (B recommendation). Such screening has an “I”statement for screening men at risk.

Continue to: As noted, costs of laboratory...

As noted, costs of laboratory testing vary widely, depending upon what tests are ordered, what type of insurance the patient has, and which tests the patient’s insurance covers. Who performs the testing also factors into the cost. Payers negotiate reduced fees for commercial lab testing, but potential out-of-­pocket costs to patients are much higher.

For our healthy 35-year-old man, the cost of the initially proposed testing (CMP, lipid panel, TSH, and 25[OH] vitamin D level) ranges from a negotiated payer cost of $85 to potential patient out-of-pocket cost of more than $400.⁶

Insurance would cover the USPSTF-­recommended testing (HIV and hepatitis C screening tests), which might incur only a patient co-pay, and cost the system about $65.

The USPSTF home page, found at www.uspreventiveservicestaskforce.org/uspstf/ includes recommendations that can be sorted for your patients. A web and mobile device application is also available through the website.

^a USPSTF grade definitions:

A: There is high certainty that the net benefit is substantial. Offer service.

B: There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer service.

C: There is at least moderate certainty that the net benefit is small. Offer service selectively.

D: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Don’t offer service.

I: Current evidence is insufficient to assess the balance of benefits and harms of the service.

CORRESPONDENCE
Mitchell Kaminski, MD, MBA, 901 Walnut Street, 10th Floor, Jefferson College of Population Health, Philadelphia, PA 19107; [email protected]

CASE

A 35-year-old man arrives for an annual wellness visit with no specific complaints and no significant personal or family history. His normal exam includes a blood pressure of 110/74 mm Hg and a body mass index (BMI) of 23.6. You order “routine labs” for prevention, which include a comprehensive metabolic panel (CMP), fasting lipid profile, and thyroid-stimulating hormone (TSH) and 25(OH) vitamin D tests. Are you practicing value-based laboratory testing?

The answer to this question appears in the Case discussion at the end of the article.

Value-based care, including care provided through laboratory testing, can achieve the Institute for Healthcare Improvement’s Triple Aim of improving population health, improving the patient experience of care (including quality and satisfaction), and reducing cost: Value = (Quality x Patient experience) / Cost.¹

As quality and patient experience rise and cost falls, the value of care increases. Unnecessary lab testing, however, can negatively impact this equation:

• Error introduced by unnecessary testing can adversely affect quality.
• Patients experience inconvenience and sometimes cascades of testing, in addition to financial responsibility, from unnecessary testing.
• Low-value testing also contributes to work burden and provider burnout by requiring additional review and follow-up.

Rising health care costs are approaching 18% of the US gross domestic product, driven in large part by a wasteful and inefficient care delivery system.² One review of “waste domains” identified by the Institute of Medicine estimates that approximately one-quarter of health care costs represent waste, including overtreatment, breakdowns of care coordination, and pricing that fails to correlate to the level of care received.³ High-volume, low-cost testing contributes more to total cost than low-volume, high-cost tests.⁴

Provider and system factors that contribute to ongoing waste

A lack of awareness of waste and how to reduce it contribute to the problem, as does an underappreciation of the harmful effects caused by incidental abnormal results.

Provider intolerance of diagnostic uncertainty often leads to ordering even more tests.

Continue to: Also, a hope of avoiding...

Do not order tests just to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxiety.

Also, a hope of avoiding missed diagnoses and potential lawsuits leads to defensive practice and more testing. In addition, patients and family members can exert pressure based on a belief that more testing represents better care. Of course, financial revenues from testing may come into play, with few disincentives to forgo testing. Something that also comes into play is that evidence-based guidance on cost-­effective laboratory testing may be lacking, or there may be a lack of knowledge on how to access existing evidence.

Automated systems can facilitate wasteful laboratory testing, and the heavy testing practices of hospitals and specialists may be inappropriately applied to outpatient primary care.

Factors affecting the cost of laboratory testing

Laboratory test results drive 70% of today’s medical decisions.⁵ Negotiated insurance payment for tests is usually much less than the direct out-of-pocket costs charged to the patient. Without insurance, lab tests can cost patients between $100 and $1000.⁶ If multiple tests are ordered, the costs could likely be many thousands of dollars.

Actual costs typically vary by the testing facility, the patient’s health plan, and location in the United States; hospital-based testing tends to be the most expensive. Insurers will pay for lab tests with appropriate indications that are covered in the contract with the provider.⁶

Choosing Wisely initiative weighs in on lab testing

Choosing Wisely, a prominent initiative of the American Board of Internal Medicine Foundation, promotes appropriate resource utilization through educational campaigns that detail how to avoid unnecessary medical tests, treatments, and procedures.⁷ Recommendations are based largely on specialty society consensus and disease-oriented evidence. Choosing Wisely recommendations advise against the following⁷:

• performing laboratory blood testing unless clinically indicated or necessary for diagnosis or management, in order to avoid iatrogenic anemia. (American Academy of Family Physicians; Society for the Advancement of Patient Blood Management)
• requesting just a serum creatinine to test adult patients with diabetes and/or hypertension for chronic kidney disease. Use the kidney profile: serum creatinine with estimated glomerular filtration rate and urinary albumin-creatinine ratio. (American Society for Clinical Pathology)
• routinely screening for prostate cancer using a prostate-specific antigen test. It should be performed only after engaging in shared decision-making with the patient. (American Academy of Family Physicians; American Urological Association)
• screening for genital herpes simplex virus infectionFrutiger LT Std in asymptomatic adults, including pregnant women. (American Academy of Family Physicians)
• performing preoperative medical tests for eye surgery unless there are specific medical indications. (American Academy of Ophthalmology)

Sequential steps to takefor value-based lab ordering

Ask the question: “How will ordering this specific test change the management of my patient?” From there, take sequential steps using sound, evidence-based pathways. Morgan and colleagues⁸ outline the following practical approaches to rational test ordering:

• Perform a thorough clinical assessment.
• Consider the probability and implications of a positive test result.
• Practice patient-centered communication: address the patient’s concerns and discuss the risks and benefits of tests and how they will influence management.
• Follow clinical guidelines when available.
• Avoid ordering tests to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxieties.
• Avoid letting uncertainty drive unnecessary testing. Watchful waiting can allow time for the illness to resolve or declare itself.

Let’s consider this approach in the context of 4 areas: preventive care, diagnostic evaluation, ongoing management of chronic conditions, and preoperative testing.

Continue to: Preventive guidance from the USPSTF

An independent volunteer panel of 16 national experts in prevention and evidence-based medicine develop recommendations for the US Preventive Services Task Force (USPSTF).⁹ These guidelines are based on evidence and are updated as new evidence surfaces. Thirteen recommendations, some of which advise avoiding preventive procedures that could cause harm to patients, cover laboratory tests used in screening for conditions such as hyperlipidemia¹⁰ and prostate cancer.¹¹ We review the ones pertinent to our patient later at the end of the Case.

While the target audience for USPSTF recommendations is clinicians who provide preventive care, the recommendations are widely followed by policymakers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and patients.

Take a critical look at how you approach the diagnostic evaluation

To reduce unnecessary testing in the diagnostic evaluation of patients, first consider pretest probability, test sensitivity and specificity, narrowly out-of-range tests, habitually paired tests, and repetitive laboratory testing.

Pretest probability, and test sensitivity and specificity. Pretest probability is the estimated chance that the patient has the disease before the test result is known. In a patient with low pretest probability of a disease, the ability to conclusively arrive at the diagnosis with one positive result is limited. Similarly, for tests in patients with high pretest probability of disease, a negative test cannot be used to firmly rule out a diagnosis.¹²

Reliability also depends on test sensitivity (the proportion of true positive results) and specificity (the proportion of true negative results). A test with high sensitivity but low specificity will generate more false-positive results, with potential harm to patients who do not have a disease.

Reflexively ordering tests together (eg, C-reactive protein with erythrocyte sedimentation rate) often contributes to unnecessary testing.

The pretest probability along with test sensitivity and specificity help a clinician to interpret a test result, and even decide whether to order the test at all. For example, the anti-nuclear antibody (ANA) test for systemic lupus erythematosus (SLE) has a sensitivity of 100% and a specificity of 86%¹³; it will always be positive in a patient with SLE. But when applied to individuals with low likelihood of SLE, false-positives are more common; the ANA is falsely positive in up to 14% of healthy individuals, depending on the population studied.¹³

Ordering a test may be unnecessary if the results will not change the treatment plan. For example, in a female patient with classic symptoms of an uncomplicated urinary tract infection, a urine culture and even a urinalysis may not change treatment.

Continue to: Narrowly out-of-range tests

Narrowly out-of-range tests. Test results that fall just outside the “normal” range may be of questionable significance. When an asymptomatic patient has mildly elevated liver enzymes, should additional tests be ordered to avoid missing a treatable disorder? In these scenarios, a history, including possible contributing factors such as alcohol or substance misuse, must be paired with the clinical presentation to assess pre-test probability of a particular condition.¹⁴ Repeating a narrowly out-of-range test is an option in patients when follow-up is possible. Alternatively, you could pursue watchful waiting and monitor a minor abnormality over time while being vigilant for clinical changes. This whole-patient approach will guide the decision of whether to order additional testing.

Habitually paired tests. Reflexively ordering tests together often contributes to unnecessary testing. Examples of commonly paired tests are serum lipase with amylase, C-reactive protein (CRP) with erythrocyte sedimentation rate (ESR), and TSH with free T4 to monitor patients with treated hypothyroidism. These tests add minimal value together and can be decoupled.^15-17 Evidence supports ordering serum lipase alone, CRP instead of ESR, and TSH alone for monitoring thyroid status.

Unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually

Some commonly paired tests may not even be necessary for diagnosis. The well-established Rotterdam Criteria for diagnosing polycystic ovary syndrome specify clinical features and ovarian ultrasound for diagnosis.¹⁸ They do not require measurement of commonly ordered follicle-­stimulating hormone and luteinizing hormone for diagnosis.

Serial rather than parallel testing, a “2-step approach,” is a strategy made easier with the advent of the electronic medical record (EMR) and computerized lab systems.⁸ These records and lab systems allow providers to order reflex tests, and to add on additional tests, if necessary, to an existing blood specimen.

Repetitive laboratory testing. Repetitive inpatient laboratory testing in patients who are clinically stable is wasteful and potentially harmful. Interventions involving physician education alone show mixed results, but combining education with clinician audit and feedback, along with EMR-enabled restrictive ordering, have resulted in significant and sustained reductions in repetitive laboratory testing.¹⁹

Continue to: Ongoing management of chronic conditions

Ongoing management of chronic conditions

Evidence-based guidelines support choices of tests and testing intervals for ongoing management of chronic conditions such as diabetes, hyperlipidemia, and hypertension.

Diabetes. Guidelines also define quality standards that are applied to value-based contracts. For example, the American Diabetes Association recommends assessing A1C every 6 months in patients whose type 2 diabetes is under stable control.²⁰

Hyperlipidemia. For patients diagnosed with hyperlipidemia, 2018 clinical practice guidelines published by multiple specialty societies recommend assessing adherence and response to lifestyle changes and LDL-C–lowering medications with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.²¹

Hypertension. With a new diagnosis of hypertension, guidelines advise an initial assessment for comorbidities and end-organ damage with an electrocardiogram, urinalysis, glucose level, blood count, electrolytes, creatinine, calcium, lipids, and urinary albumin/creatinine ratio. For ongoing monitoring, guidelines recommend assessment for end-organ damage through regular measurements of creatinine, glomerular filtration rate, and urinary microalbumin/creatinine ratio. Initiation and alteration of medications should prompt appropriate additional lab follow-up—eg, a measurement of serum potassium after starting a diuretic.²²

Preoperative testing

Preoperative testing is overused in low-risk, ambulatory surgery. And testing, even with abnormal results, does not affect postoperative outcomes.²³

Continue to: The American Society of Anesthesiologists (ASA) Physical Status Classification System

The American Society of Anesthesiologists (ASA) Physical Status Classification System, which has been in use for more than 60 years, considers the patient’s physical status (ASA grades I-VI),²⁴ and when paired with surgery grades of minor, intermediate, and major/complex, can help assess preoperative risk and guide preoperative testing (TABLE).^24-26

Preoperative medical testing did not reduce the risk of medical adverse events during or after cataract surgery when compared with selective or no testing.²⁷ Unnecessary preoperative testing can lead to a nonproductive cascade of additional investigations. In a 2018 study of Medicare beneficiaries, unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually.²⁸

CASE

You would not be practicing value-based laboratory testing, according to the USPSTF, if you ordered a CMP, fasting lipid profile, and TSH and 25(OH) vitamin D tests for this healthy 35-year-old man whose family history, blood pressure, and BMI do not put him at elevated risk. Universal lipid screening (Grade B^a) is recommended for all adults ages 40 to 75. Thyroid screening tests and measurement of 25(OH) vitamin D level (I statements^a) are not recommended. The USPSTF has not evaluated chemistry panels for screening.

The USPSTF would recommend the following actions for this patient:

• Screen for HIV (ages 15 to 65 years; and younger or older if patient is at risk). (A recommendation^a,29)
• Screen for hepatitis C virus (in those ages 18 to 79). (B recommendation³⁰)

The following USPSTF recommendations might have come into play if this patient had certain risk factors, or if the patient had been a woman:

• Screen for diabetes if the patient is overweight or obese (B recommendation).
• Screen for hepatitis B in adults at risk (B recommendation).
• Screen for gonorrhea and chlamydia in women at risk (B recommendation). Such screening has an “I”statement for screening men at risk.

Continue to: As noted, costs of laboratory...

As noted, costs of laboratory testing vary widely, depending upon what tests are ordered, what type of insurance the patient has, and which tests the patient’s insurance covers. Who performs the testing also factors into the cost. Payers negotiate reduced fees for commercial lab testing, but potential out-of-­pocket costs to patients are much higher.

For our healthy 35-year-old man, the cost of the initially proposed testing (CMP, lipid panel, TSH, and 25[OH] vitamin D level) ranges from a negotiated payer cost of $85 to potential patient out-of-pocket cost of more than $400.⁶

Insurance would cover the USPSTF-­recommended testing (HIV and hepatitis C screening tests), which might incur only a patient co-pay, and cost the system about $65.

The USPSTF home page, found at www.uspreventiveservicestaskforce.org/uspstf/ includes recommendations that can be sorted for your patients. A web and mobile device application is also available through the website.

^a USPSTF grade definitions:

A: There is high certainty that the net benefit is substantial. Offer service.

B: There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer service.

C: There is at least moderate certainty that the net benefit is small. Offer service selectively.

D: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Don’t offer service.

I: Current evidence is insufficient to assess the balance of benefits and harms of the service.

CORRESPONDENCE
Mitchell Kaminski, MD, MBA, 901 Walnut Street, 10th Floor, Jefferson College of Population Health, Philadelphia, PA 19107; [email protected]

CASE

A 35-year-old man arrives for an annual wellness visit with no specific complaints and no significant personal or family history. His normal exam includes a blood pressure of 110/74 mm Hg and a body mass index (BMI) of 23.6. You order “routine labs” for prevention, which include a comprehensive metabolic panel (CMP), fasting lipid profile, and thyroid-stimulating hormone (TSH) and 25(OH) vitamin D tests. Are you practicing value-based laboratory testing?

The answer to this question appears in the Case discussion at the end of the article.

Value-based care, including care provided through laboratory testing, can achieve the Institute for Healthcare Improvement’s Triple Aim of improving population health, improving the patient experience of care (including quality and satisfaction), and reducing cost: Value = (Quality x Patient experience) / Cost.¹

As quality and patient experience rise and cost falls, the value of care increases. Unnecessary lab testing, however, can negatively impact this equation:

• Error introduced by unnecessary testing can adversely affect quality.
• Patients experience inconvenience and sometimes cascades of testing, in addition to financial responsibility, from unnecessary testing.
• Low-value testing also contributes to work burden and provider burnout by requiring additional review and follow-up.

Rising health care costs are approaching 18% of the US gross domestic product, driven in large part by a wasteful and inefficient care delivery system.² One review of “waste domains” identified by the Institute of Medicine estimates that approximately one-quarter of health care costs represent waste, including overtreatment, breakdowns of care coordination, and pricing that fails to correlate to the level of care received.³ High-volume, low-cost testing contributes more to total cost than low-volume, high-cost tests.⁴

Provider and system factors that contribute to ongoing waste

A lack of awareness of waste and how to reduce it contribute to the problem, as does an underappreciation of the harmful effects caused by incidental abnormal results.

Provider intolerance of diagnostic uncertainty often leads to ordering even more tests.

Continue to: Also, a hope of avoiding...

Do not order tests just to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxiety.

Also, a hope of avoiding missed diagnoses and potential lawsuits leads to defensive practice and more testing. In addition, patients and family members can exert pressure based on a belief that more testing represents better care. Of course, financial revenues from testing may come into play, with few disincentives to forgo testing. Something that also comes into play is that evidence-based guidance on cost-­effective laboratory testing may be lacking, or there may be a lack of knowledge on how to access existing evidence.

Automated systems can facilitate wasteful laboratory testing, and the heavy testing practices of hospitals and specialists may be inappropriately applied to outpatient primary care.

Factors affecting the cost of laboratory testing

Laboratory test results drive 70% of today’s medical decisions.⁵ Negotiated insurance payment for tests is usually much less than the direct out-of-pocket costs charged to the patient. Without insurance, lab tests can cost patients between $100 and $1000.⁶ If multiple tests are ordered, the costs could likely be many thousands of dollars.

Actual costs typically vary by the testing facility, the patient’s health plan, and location in the United States; hospital-based testing tends to be the most expensive. Insurers will pay for lab tests with appropriate indications that are covered in the contract with the provider.⁶

Choosing Wisely initiative weighs in on lab testing

Choosing Wisely, a prominent initiative of the American Board of Internal Medicine Foundation, promotes appropriate resource utilization through educational campaigns that detail how to avoid unnecessary medical tests, treatments, and procedures.⁷ Recommendations are based largely on specialty society consensus and disease-oriented evidence. Choosing Wisely recommendations advise against the following⁷:

• performing laboratory blood testing unless clinically indicated or necessary for diagnosis or management, in order to avoid iatrogenic anemia. (American Academy of Family Physicians; Society for the Advancement of Patient Blood Management)
• requesting just a serum creatinine to test adult patients with diabetes and/or hypertension for chronic kidney disease. Use the kidney profile: serum creatinine with estimated glomerular filtration rate and urinary albumin-creatinine ratio. (American Society for Clinical Pathology)
• routinely screening for prostate cancer using a prostate-specific antigen test. It should be performed only after engaging in shared decision-making with the patient. (American Academy of Family Physicians; American Urological Association)
• screening for genital herpes simplex virus infectionFrutiger LT Std in asymptomatic adults, including pregnant women. (American Academy of Family Physicians)
• performing preoperative medical tests for eye surgery unless there are specific medical indications. (American Academy of Ophthalmology)

Sequential steps to takefor value-based lab ordering

Ask the question: “How will ordering this specific test change the management of my patient?” From there, take sequential steps using sound, evidence-based pathways. Morgan and colleagues⁸ outline the following practical approaches to rational test ordering:

• Perform a thorough clinical assessment.
• Consider the probability and implications of a positive test result.
• Practice patient-centered communication: address the patient’s concerns and discuss the risks and benefits of tests and how they will influence management.
• Follow clinical guidelines when available.
• Avoid ordering tests to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxieties.
• Avoid letting uncertainty drive unnecessary testing. Watchful waiting can allow time for the illness to resolve or declare itself.

Let’s consider this approach in the context of 4 areas: preventive care, diagnostic evaluation, ongoing management of chronic conditions, and preoperative testing.

Continue to: Preventive guidance from the USPSTF

An independent volunteer panel of 16 national experts in prevention and evidence-based medicine develop recommendations for the US Preventive Services Task Force (USPSTF).⁹ These guidelines are based on evidence and are updated as new evidence surfaces. Thirteen recommendations, some of which advise avoiding preventive procedures that could cause harm to patients, cover laboratory tests used in screening for conditions such as hyperlipidemia¹⁰ and prostate cancer.¹¹ We review the ones pertinent to our patient later at the end of the Case.

While the target audience for USPSTF recommendations is clinicians who provide preventive care, the recommendations are widely followed by policymakers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and patients.

Take a critical look at how you approach the diagnostic evaluation

To reduce unnecessary testing in the diagnostic evaluation of patients, first consider pretest probability, test sensitivity and specificity, narrowly out-of-range tests, habitually paired tests, and repetitive laboratory testing.

Pretest probability, and test sensitivity and specificity. Pretest probability is the estimated chance that the patient has the disease before the test result is known. In a patient with low pretest probability of a disease, the ability to conclusively arrive at the diagnosis with one positive result is limited. Similarly, for tests in patients with high pretest probability of disease, a negative test cannot be used to firmly rule out a diagnosis.¹²

Reliability also depends on test sensitivity (the proportion of true positive results) and specificity (the proportion of true negative results). A test with high sensitivity but low specificity will generate more false-positive results, with potential harm to patients who do not have a disease.

Reflexively ordering tests together (eg, C-reactive protein with erythrocyte sedimentation rate) often contributes to unnecessary testing.

The pretest probability along with test sensitivity and specificity help a clinician to interpret a test result, and even decide whether to order the test at all. For example, the anti-nuclear antibody (ANA) test for systemic lupus erythematosus (SLE) has a sensitivity of 100% and a specificity of 86%¹³; it will always be positive in a patient with SLE. But when applied to individuals with low likelihood of SLE, false-positives are more common; the ANA is falsely positive in up to 14% of healthy individuals, depending on the population studied.¹³

Ordering a test may be unnecessary if the results will not change the treatment plan. For example, in a female patient with classic symptoms of an uncomplicated urinary tract infection, a urine culture and even a urinalysis may not change treatment.

Continue to: Narrowly out-of-range tests

Narrowly out-of-range tests. Test results that fall just outside the “normal” range may be of questionable significance. When an asymptomatic patient has mildly elevated liver enzymes, should additional tests be ordered to avoid missing a treatable disorder? In these scenarios, a history, including possible contributing factors such as alcohol or substance misuse, must be paired with the clinical presentation to assess pre-test probability of a particular condition.¹⁴ Repeating a narrowly out-of-range test is an option in patients when follow-up is possible. Alternatively, you could pursue watchful waiting and monitor a minor abnormality over time while being vigilant for clinical changes. This whole-patient approach will guide the decision of whether to order additional testing.

Habitually paired tests. Reflexively ordering tests together often contributes to unnecessary testing. Examples of commonly paired tests are serum lipase with amylase, C-reactive protein (CRP) with erythrocyte sedimentation rate (ESR), and TSH with free T4 to monitor patients with treated hypothyroidism. These tests add minimal value together and can be decoupled.^15-17 Evidence supports ordering serum lipase alone, CRP instead of ESR, and TSH alone for monitoring thyroid status.

Unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually

Some commonly paired tests may not even be necessary for diagnosis. The well-established Rotterdam Criteria for diagnosing polycystic ovary syndrome specify clinical features and ovarian ultrasound for diagnosis.¹⁸ They do not require measurement of commonly ordered follicle-­stimulating hormone and luteinizing hormone for diagnosis.

Serial rather than parallel testing, a “2-step approach,” is a strategy made easier with the advent of the electronic medical record (EMR) and computerized lab systems.⁸ These records and lab systems allow providers to order reflex tests, and to add on additional tests, if necessary, to an existing blood specimen.

Repetitive laboratory testing. Repetitive inpatient laboratory testing in patients who are clinically stable is wasteful and potentially harmful. Interventions involving physician education alone show mixed results, but combining education with clinician audit and feedback, along with EMR-enabled restrictive ordering, have resulted in significant and sustained reductions in repetitive laboratory testing.¹⁹

Continue to: Ongoing management of chronic conditions

Ongoing management of chronic conditions

Evidence-based guidelines support choices of tests and testing intervals for ongoing management of chronic conditions such as diabetes, hyperlipidemia, and hypertension.

Diabetes. Guidelines also define quality standards that are applied to value-based contracts. For example, the American Diabetes Association recommends assessing A1C every 6 months in patients whose type 2 diabetes is under stable control.²⁰

Hyperlipidemia. For patients diagnosed with hyperlipidemia, 2018 clinical practice guidelines published by multiple specialty societies recommend assessing adherence and response to lifestyle changes and LDL-C–lowering medications with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.²¹

Hypertension. With a new diagnosis of hypertension, guidelines advise an initial assessment for comorbidities and end-organ damage with an electrocardiogram, urinalysis, glucose level, blood count, electrolytes, creatinine, calcium, lipids, and urinary albumin/creatinine ratio. For ongoing monitoring, guidelines recommend assessment for end-organ damage through regular measurements of creatinine, glomerular filtration rate, and urinary microalbumin/creatinine ratio. Initiation and alteration of medications should prompt appropriate additional lab follow-up—eg, a measurement of serum potassium after starting a diuretic.²²

Preoperative testing

Preoperative testing is overused in low-risk, ambulatory surgery. And testing, even with abnormal results, does not affect postoperative outcomes.²³

Continue to: The American Society of Anesthesiologists (ASA) Physical Status Classification System

The American Society of Anesthesiologists (ASA) Physical Status Classification System, which has been in use for more than 60 years, considers the patient’s physical status (ASA grades I-VI),²⁴ and when paired with surgery grades of minor, intermediate, and major/complex, can help assess preoperative risk and guide preoperative testing (TABLE).^24-26

Preoperative medical testing did not reduce the risk of medical adverse events during or after cataract surgery when compared with selective or no testing.²⁷ Unnecessary preoperative testing can lead to a nonproductive cascade of additional investigations. In a 2018 study of Medicare beneficiaries, unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually.²⁸

CASE

You would not be practicing value-based laboratory testing, according to the USPSTF, if you ordered a CMP, fasting lipid profile, and TSH and 25(OH) vitamin D tests for this healthy 35-year-old man whose family history, blood pressure, and BMI do not put him at elevated risk. Universal lipid screening (Grade B^a) is recommended for all adults ages 40 to 75. Thyroid screening tests and measurement of 25(OH) vitamin D level (I statements^a) are not recommended. The USPSTF has not evaluated chemistry panels for screening.

The USPSTF would recommend the following actions for this patient:

• Screen for HIV (ages 15 to 65 years; and younger or older if patient is at risk). (A recommendation^a,29)
• Screen for hepatitis C virus (in those ages 18 to 79). (B recommendation³⁰)

The following USPSTF recommendations might have come into play if this patient had certain risk factors, or if the patient had been a woman:

• Screen for diabetes if the patient is overweight or obese (B recommendation).
• Screen for hepatitis B in adults at risk (B recommendation).
• Screen for gonorrhea and chlamydia in women at risk (B recommendation). Such screening has an “I”statement for screening men at risk.

Continue to: As noted, costs of laboratory...

As noted, costs of laboratory testing vary widely, depending upon what tests are ordered, what type of insurance the patient has, and which tests the patient’s insurance covers. Who performs the testing also factors into the cost. Payers negotiate reduced fees for commercial lab testing, but potential out-of-­pocket costs to patients are much higher.

For our healthy 35-year-old man, the cost of the initially proposed testing (CMP, lipid panel, TSH, and 25[OH] vitamin D level) ranges from a negotiated payer cost of $85 to potential patient out-of-pocket cost of more than $400.⁶

Insurance would cover the USPSTF-­recommended testing (HIV and hepatitis C screening tests), which might incur only a patient co-pay, and cost the system about $65.

The USPSTF home page, found at www.uspreventiveservicestaskforce.org/uspstf/ includes recommendations that can be sorted for your patients. A web and mobile device application is also available through the website.

^a USPSTF grade definitions:

A: There is high certainty that the net benefit is substantial. Offer service.

B: There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer service.

C: There is at least moderate certainty that the net benefit is small. Offer service selectively.

D: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Don’t offer service.

I: Current evidence is insufficient to assess the balance of benefits and harms of the service.

CORRESPONDENCE
Mitchell Kaminski, MD, MBA, 901 Walnut Street, 10th Floor, Jefferson College of Population Health, Philadelphia, PA 19107; [email protected]