BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.

“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.

She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.

“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.

RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.

The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.

“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.

Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.

[email protected]

BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.

“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.

She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.

“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.

RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.

The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.

“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.

Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.

[email protected]

BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.

“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.

She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.

“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.

RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.

The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.

“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.

Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.

[email protected]

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

• Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
• Methods: Review of the literature.
• Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
• Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1). 

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal, 

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently 

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly. 

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

• Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
• Methods: Review of the literature.
• Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
• Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1). 

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal, 

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently 

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly. 

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

• Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
• Methods: Review of the literature.
• Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
• Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1). 

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal, 

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently 

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly. 

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.

From the Department of Physical Therapy, University of Alberta, Edmonton AB (Dr. Jones) and UT MD Anderson Cancer Center, Houston, TX (Dr. Suarez-Almazor).

Abstract

• Objective: To discuss patient expectations of total knee arthroplasty (TKA), instruments used to measure expectations, and the association between expectations, health outcomes, and satisfaction.
• Methods: Review of the literature.
• Results: TKA is an elective surgery for patients with persistent pain and disability caused by knee arthritis. Expectations regarding the surgical procedure and recovery can vary by diagnosis, personal characteristics, functional status, employment status, and trust in physicians. Patients have high overall expectations for recovery, particularly for pain relief and walking. Surgeons’ expectations tend to be more optimistic than patients’, although a subset of patients may have unrealistically high expectations. Although total joint replacement is an effective treatment for advanced arthritis, approximately 30% of potential candidates are unwilling to proceed with surgery. Potential surgical candidates unwilling to proceed with surgery tend to be older, female, and from ethnic minority groups. Several patient-related factors are associated with satisfaction with TKA, including primary diagnosis, preoperative pain and function, and mental health, including depression, but the relationships of satisfaction with gender, age, and comorbid conditions are less certain.
• Conclusion: A better understanding of patient expectations of TKA and recovery can identify knowledge gaps, misconceptions, and communication barriers, and ultimately improve shared decision making. A core set of reliable and valid instruments to measure expectations may encourage their routine use in both clinical and research settings.

Key words: total knee arthroplasty; osteoarthritis; patient expectations; shared decision making; joint replacement.

Total knee arthroplasty (TKA) is an elective surgery for patients with persistent pain and disability caused by knee arthritis. It is viewed as an effective and cost-effective surgical treatment for end-stage osteoarthritis (OA) [1–4]. As the population ages and obesity rates steadily increase, so will the utilization rates for TKA, with projected demand in the United States expected to grow 673% by 2030 [5–7]. The key indicators for receiving primary TKA are end-stage OA and joint pain [8]. Although TKA is a surgical option when conservative management is exhausted, no consensus exists as to the severity of symptoms required to consider surgery [9]. Variation in the utilization of TKA exists with respect to gender, racial/ethnicity, hospital, and geography [10,11]. These differences cannot be explained by prevalence of arthritis or symptoms or by access to health care alone. Increasingly, studies have shown these variations are largely attributable to patients’ preferences, driven by their beliefs, concerns, familiarity with the procedure, and expectations, along with physician opinion [12]. While physician opinions and recommendations clearly influence patients’ decisions, they do so primarily by modulating patients’ beliefs and expectations.

Patient expectations, not only of the effectiveness of the procedure itself but also of the recovery process, influence the decision to undergo an elective surgery such as joint arthroplasty. Ideally, these expectations should be informed by evidence, but often, lack of knowledge, preconceived beliefs, and misconceptions can taint informed decision making. A better understanding of patient expectations of TKA and recovery can identify knowledge gaps, misconceptions, and communication barriers, and ultimately improve shared decision making. Understanding patient expectations and factors that influence expectations provides a fuller appreciation of the outcomes that are meaningful to patients and can guide preoperative education and open dialogue with patients within a shared decision making model of care. In this paper, we discuss patient expectations of TKA, including expectations regarding outcomes and recovery, fulfillment of expectations, and the association of fulfilled expectations with satisfaction.

Measurement of Expectations

The construct of expectation is complex and situational. The ambiguity within the literature occurs most likely because expectations are multifaceted. Expectation involves the notion of expectancy, with respect to health care, that given events are likely to occur as a result of a medical procedure or treatment. This concept is in contrast to wants, which reflects a patient’s desire or wishes that an event will occur [13]. The term patient expectation, however, is commonly confused with patient preference or value. Preference implies a relative valuation or comparison by the patient and, unlike expectation, may not be explicitly expressed by the patient [13]. Different types of health care expectations exist that broadly relate to what patients expect regarding health care structure, process, and outcome [14].

Studies of patient expectations are diverse within the orthopedic research field and reflect differing theoretical underpinnings and lack of standardization. The lack of standardization makes measuring the complex concept of expectations challenging. While a number of conceptual models exist, Bowling and colleagues aptly recognize the multidimensionality of expectations and that no one conceptual model captures patient expectations [14]. The lack of standardization was noted in a systematic review by Haanstra and colleagues who found great variety in the definitions and measurements of expectations in studies examining their relationship with outcomes of total joint arthroplasty [15].

No gold standard measure exists for measuring patient expectations of orthopedic surgery. Zywiel’s systematic review [16] of 66 studies identified 7 validated instruments for measuring patient expectations for orthopedic surgery: of these, 2 were specific to TKA (Hospital for Special Surgery (HSS) Expectation Survey [17] and Expectation Domain of the New Knee Scoring System [18,19]), and 2 were generic to musculoskeletal conditions (Expectation domain of the Musculoskeletal Outcomes Data Evaluation and Management System (MODEMS) Instruments [20] and the Sunnybrook Surgery Expectation Survey [21]). A number of other measures used within the literature were identified; however, the psychometric properties for many of these measures were not reported and any evidence of testing and validation were lacking [16]. Some studies used a single question to measure expectations. As patient expectation is multi-dimensional, using a single item to evaluate expectations is problematic. Zywiel and others have called for a core set of reliable and valid instruments to measure expectations [14,22], which may encourage their routine use in both clinical and research settings.

Patients Expectations for TKA Recovery

Although patient concerns vary in terms of importance and severity [23], pain and physical limitations are primary concerns for patients seeking TKA. Patients have high overall expectations for recovery, particularly for pain relief and walking [24–32]. TKA is an elective surgical procedure that provides substantial pain relief and improvements in function and quality of life, with the largest gains seen within the first 6 months [33,34]. Both short-term and long-term effect sizes for pain relief and functional recovery are large, in excess of 1.0 [34]. Over 70% of patients undergoing TKA expect to be pain-free, and 35% expect to have no limitations with routine activities [24,28,31].

Expectations regarding the surgical procedure and recovery can vary by diagnosis, personal characteristics, functional status [17], employment status, and trust in physicians [32,35]. There is, however, inconsistent evidence on associative preoperative factors of recovery expectations. While some evidence supports an association between higher expectations and younger age and greater preoperative functional limitation [26–28,32,36–38], others have reported no significant association with several preoperative factors including age, gender, and preoperative functional status [24,26,37]. Lower overall expectations [28] and lower expectations for pain relief [21] were also seen for patients with a greater number of comorbid conditions.

It may be that patients with high preoperative expectations are more optimistic, interpret their health-reported quality of life gains more liberally, and are more likely to adhere to rehabilitation treatment [24,25]. Optimism is a generalized expectancy of a positive outcome that is related to indicators of well-being [39]. Presurgical optimism was shown to be associated with less postsurgical pain and anxiety in patients undergoing total hip and knee arthroplasty [40].

In addition to general future-oriented constructs, such as optimism, treatment-specific psychological constructs, such as treatment credibility and treatment expectancy, are seen in patients with total joint arthroplasty. A strong but not redundant association is seen between treatment expectancy and treatment credibility, that is, expectations of a treatment may be related as to how credible the treatment outcomes appear [41,42]. Haanstra and colleagues advocate further clinical work to explore which factor predicts total joint arthroplasty outcomes so that patients who are at a higher risk of poor outcomes can be identified [42].

Others have recognized that perspectives and expectations of surgical outcomes differ between patient and surgeon [43–45]. Overall, surgeons’ expectations tend to be more optimistic than patients expectations of outcomes, although a subset of patients may have unrealistically high expectations [46]. Patients do not always realize that some of their expectations cannot be met by current orthopedic procedures, and this gap in understanding is an important source of discrepancies in expectations and patient dissatisfaction [46]. Ghomrawi and colleagues reported that approximately one-third of 205 patients undergoing primary TKA had higher expectations than their surgeons did. Being male and having lower preoperative pain was associated with having discordantly higher preoperative expectations [44]. For realistic expectations to be set, patients need accurate and understandable information about expected positive outcomes of surgery such as level of function and symptom relief as well as the risk of joint failure, adverse events, complications, and activity limitations. Although little work has explored the alignment of patient and surgeon’s expectations, setting realistic expectations may be aided by using a shared decision making approach that incorporates patient preferences and values, the best available evidence, and the surgeon’s expertise.

Expectations and Willingness to Undergo Surgery

Although total joint replacement is an effective treatment for advanced arthritis, approximately 30% of potential candidates are “unwilling” to proceed with surgery [47,48]. Willingness is a component of the medical decision making process and is influenced by preferences. Potential surgical candidates unwilling to proceed with surgery tend to be older, female, and from ethnic minor-ity groups [12,47–49]. Preference-sensitive medical decisions, such as whether or not to proceed with TKA, are related to patients’ attitudes and perceptions, which can be affected by sociocultural influences. In a cohort of 627 male patients with moderate to severe OA who were viewed as “good” candidates for total joint arthroplasty, more African Americans (24%) than Caucasian Americans (15%) had lower expectations for outcomes of surgery [35]. In particular, African Americans expressed concerns about postoperative pain and walking. Similar findings were also reported in another study in which minority patients were less likely to consider TKA [12]. Determinants of preferences were patients’ beliefs about the efficacy of the procedure and knowing others who had already undergone TKA [12]. Ibrahim and colleagues postulated that outcome expectations mediated or influenced the willingness to undergo total joint arthroplasty surgery [49]. Interventional work that built upon this premise suggested that willingness to proceed with TKA could be modified by educational interventions. In a randomized controlled trial of 639 African American patients attending Veteran’s Affairs primary clinics who received a decision aid with or without brief counseling, willingness to proceed with TKA increased and patient-provider communication improved among the patients who received any intervention [50]. Yet in another randomized trial involving African American patients who received care from an academic center, a combination decision aid and motivational interviewing strategy was no better than an educational pamphlet in improving patients’ preferences toward joint replacement surgery for knee OA [51]. This led the authors to recommend further exploration of patients’ knowledge, beliefs, and attitudes regarding surgical treatments for OA.

Effect of Expectations on Health Outcomes and Satisfaction

Some evidence suggests that better outcomes are seen in patients with higher expectations of recovery and, in turn, expectations that are met influence patient satisfaction. A systematic review of several chronic conditions showed with consistency across studies that positive recovery expectations were associated with better health outcomes [22]. The effect size varied with the condition and measure; however, none of the 16 studies examined arthritis or joint arthroplasty. Conversely, a systematic review of 18 prospective longitudinal cohort studies examining the association between expectation and outcomes (ie, pain, function, stiffness, satisfaction, overall improvement) reported less than convincing evidence of an association between patient preoperative expectations and treatment outcomes for THA and TKA in terms of short- and long-term postoperative pain and functional outcomes [15]. No consistent associations were seen with adjusted analysis of patient expectations and pain or functional outcomes at greater than 6 weeks [15]. Inconsistencies seen among the reviewed articles may be related to a number of issues centred on terminology, construct, expectation measures, and confounding effects.

Although TKA is an effective surgical procedure with large gains reported, 14% to 25% participants report little or no symptom improvement and/or dissatisfaction up to 1 year after surgery [1,52–59]. In a study with 5 years of follow-up, a decline in the satisfaction rate was seen after 1 year, although this decline was seen more so with physical function than with pain [38]. Although dissatisfaction can be attributed to surgical complications, in many cases, no technical or medical reasons can be identified. In a subset of patients who received TKA, surgical intervention does not adequately address patients’ concerns of pain and activity limitation. To compound matters, fair agreement was reported between patient and surgeon regarding satisfaction at 6 and 12 months postoperative. Disagreement between the patient and surgeon was explained by unmet expectations and postoperative complications [60]. When there was discordance, more often than not patients were less satisfied with TKA outcomes than surgeons [60,61].

While several theories explain patient satisfaction [62–65], evidence from total joint arthroplasty studies support the concept that satisfaction is derived from fulfillment of expectations [17,52]. Preoperative expectations are not to be confused with postoperative fulfilment of expectations, which are reflective of whether expectations of treatment have been met. Satisfaction is a value judgment and can be viewed as an affective domain, whereas expectation is a cognitive domain [66]. Patient satisfaction is regarded as the extent of a person’s experience compared to their expectation. As with expectations, a number of theoretical constructs exist concerning patient satisfaction [14,67]. Many dimensions of satisfaction exist, with patient expectations being central to these constructs. Deviation from expectations, however, does not necessarily correspond to dissatisfaction [67].

Several patient-related factors are associated with satisfaction with TKA, including primary diagnosis, preoperative pain and function, and mental health, including depression, but the relationships of satisfaction with gender, age, and comorbid conditions are less certain [33,38,52,55,56,68]. Greater preoperative pain, postoperative complications, lower 1-year WOMAC scores and functional limitations were associated with dissatisfied patients [38,52,53,59]. While no consistent associations were seen with preoperative expectations, consistent evidence has shown that fulfillment of expectations has an impact on satisfaction [31,36,52,58,69].

It should be acknowledged that the concept of fulfillment of expectations is not the same as satisfaction. A patient can be satisfied with TKA even though their expectations have not been met. The fulfillment of expectations is dependent upon the type of expectation and the postoperative time period. Fulfillment of expectations were seen with pain relief, function, walking and health status [25,31,70] while patients expectations were not always met with leisure activities [38].

Shared Decision Making

The shared decision making process, in which the patient and physician share responsibility and actively participate in the clinical decision making process [71], may help in ensuring that patients’ expectations are met. Shared decision making requires eliciting patients’ preferences and values, providing clear information on the processes that will occur during surgery, recovery, rehabilitation, and in the longer phase of recovery, and what realistic outcomes can be expected. While a more “paternalistic” approach predominated in earlier years, the current trends indicate greater patient involvement in decision making with the surgeon, with open discussion of patient goals and expectations [71]. This approach also aids patients in their preparation for the recovery and rehabilitation stages, which can be challenging, especially if they are unaware as to what to expect. Patient expectations are more likely to be met when there is shared decision making and patients have been given relevant information and understand what is a reasonable outcome. While a shared decision making approach is advocated within orthopedics [72], patient expectations are largely not measured in the clinical setting.

Patient education is an integral component of assisting patients to make informed decisions; however, it is unknown whether education alone can modify expectations. Educational approaches can include group classes, videos, and written materials [73]. Limited evidence from a randomized controlled trial suggests that preoperative expectations can be modified by preoperative education classes by decreasing the number of expectations and having more expectations in agreement with the surgeons’ expectations [29]. Mancuso and colleagues, who looked at whether a preoperative education session could modify expectations found that larger changes in expectations were seen with those patients who had greater baseline expectation scores, worse pain and function, and were older [29]. Others have also reported that preoperative education reduces anxiety by providing patients with an understanding of what to expect [74,75]. An assumption is that expectations can be changed by improving knowledge, which underscores the need for relevant meaningful education to increase knowledge and instill realistic expectations. Others have surmised there is a proportion of patients who will continue to have unexpectedly high unrealistic expectations regardless of educational session [31,37]. This would suggest that education is not the only approach to modify expectations but rather different strategies may need to be implemented for a certain subsets of patients with unrealistic expectations.

Conclusion

Patient expectation is an important element to be considered in shared clinical decision making, as it can influ-ence preferences and subsequent satisfaction. Patients considering TKA have specific needs and expectations that they presume will be addressed with the surgery. If these are realistic, they can be met, and will result in greater patient satisfaction and better ongoing adherence to health care recommendations [76]. While much work has been conducted in identifying which patient characteristics may influence health expectations, additional research is needed to further determine how to shape expectations within a realistic, achievable framework. While traditional patient education is an important element to enhance knowledge, the limited available evidence suggests it is not sufficiently effective on its own. Other strategies such as use of individualized decision aids, provision of peer support, and enhanced provider-patient communication have been effective in many areas of health care and warrant evaluation in this field.

Corresponding author: Allyson Jones, PhD, Rm 2-50, Corbett Hall, University of Alberta, Edmonton, Alberta Canada T6G 2G4, [email protected].

Financial disclosures: None.

Author contributions: conception and design, CAJ, MES; analysis and interpretation of data, MES; drafting of article, CAJ, MES; critical revision of the article, CAJ, MES; collection and assembly of data, CAJ.

From the Department of Physical Therapy, University of Alberta, Edmonton AB (Dr. Jones) and UT MD Anderson Cancer Center, Houston, TX (Dr. Suarez-Almazor).

Abstract

• Objective: To discuss patient expectations of total knee arthroplasty (TKA), instruments used to measure expectations, and the association between expectations, health outcomes, and satisfaction.
• Methods: Review of the literature.
• Results: TKA is an elective surgery for patients with persistent pain and disability caused by knee arthritis. Expectations regarding the surgical procedure and recovery can vary by diagnosis, personal characteristics, functional status, employment status, and trust in physicians. Patients have high overall expectations for recovery, particularly for pain relief and walking. Surgeons’ expectations tend to be more optimistic than patients’, although a subset of patients may have unrealistically high expectations. Although total joint replacement is an effective treatment for advanced arthritis, approximately 30% of potential candidates are unwilling to proceed with surgery. Potential surgical candidates unwilling to proceed with surgery tend to be older, female, and from ethnic minority groups. Several patient-related factors are associated with satisfaction with TKA, including primary diagnosis, preoperative pain and function, and mental health, including depression, but the relationships of satisfaction with gender, age, and comorbid conditions are less certain.
• Conclusion: A better understanding of patient expectations of TKA and recovery can identify knowledge gaps, misconceptions, and communication barriers, and ultimately improve shared decision making. A core set of reliable and valid instruments to measure expectations may encourage their routine use in both clinical and research settings.

Key words: total knee arthroplasty; osteoarthritis; patient expectations; shared decision making; joint replacement.

Total knee arthroplasty (TKA) is an elective surgery for patients with persistent pain and disability caused by knee arthritis. It is viewed as an effective and cost-effective surgical treatment for end-stage osteoarthritis (OA) [1–4]. As the population ages and obesity rates steadily increase, so will the utilization rates for TKA, with projected demand in the United States expected to grow 673% by 2030 [5–7]. The key indicators for receiving primary TKA are end-stage OA and joint pain [8]. Although TKA is a surgical option when conservative management is exhausted, no consensus exists as to the severity of symptoms required to consider surgery [9]. Variation in the utilization of TKA exists with respect to gender, racial/ethnicity, hospital, and geography [10,11]. These differences cannot be explained by prevalence of arthritis or symptoms or by access to health care alone. Increasingly, studies have shown these variations are largely attributable to patients’ preferences, driven by their beliefs, concerns, familiarity with the procedure, and expectations, along with physician opinion [12]. While physician opinions and recommendations clearly influence patients’ decisions, they do so primarily by modulating patients’ beliefs and expectations.

Patient expectations, not only of the effectiveness of the procedure itself but also of the recovery process, influence the decision to undergo an elective surgery such as joint arthroplasty. Ideally, these expectations should be informed by evidence, but often, lack of knowledge, preconceived beliefs, and misconceptions can taint informed decision making. A better understanding of patient expectations of TKA and recovery can identify knowledge gaps, misconceptions, and communication barriers, and ultimately improve shared decision making. Understanding patient expectations and factors that influence expectations provides a fuller appreciation of the outcomes that are meaningful to patients and can guide preoperative education and open dialogue with patients within a shared decision making model of care. In this paper, we discuss patient expectations of TKA, including expectations regarding outcomes and recovery, fulfillment of expectations, and the association of fulfilled expectations with satisfaction.

Measurement of Expectations

The construct of expectation is complex and situational. The ambiguity within the literature occurs most likely because expectations are multifaceted. Expectation involves the notion of expectancy, with respect to health care, that given events are likely to occur as a result of a medical procedure or treatment. This concept is in contrast to wants, which reflects a patient’s desire or wishes that an event will occur [13]. The term patient expectation, however, is commonly confused with patient preference or value. Preference implies a relative valuation or comparison by the patient and, unlike expectation, may not be explicitly expressed by the patient [13]. Different types of health care expectations exist that broadly relate to what patients expect regarding health care structure, process, and outcome [14].

Studies of patient expectations are diverse within the orthopedic research field and reflect differing theoretical underpinnings and lack of standardization. The lack of standardization makes measuring the complex concept of expectations challenging. While a number of conceptual models exist, Bowling and colleagues aptly recognize the multidimensionality of expectations and that no one conceptual model captures patient expectations [14]. The lack of standardization was noted in a systematic review by Haanstra and colleagues who found great variety in the definitions and measurements of expectations in studies examining their relationship with outcomes of total joint arthroplasty [15].

No gold standard measure exists for measuring patient expectations of orthopedic surgery. Zywiel’s systematic review [16] of 66 studies identified 7 validated instruments for measuring patient expectations for orthopedic surgery: of these, 2 were specific to TKA (Hospital for Special Surgery (HSS) Expectation Survey [17] and Expectation Domain of the New Knee Scoring System [18,19]), and 2 were generic to musculoskeletal conditions (Expectation domain of the Musculoskeletal Outcomes Data Evaluation and Management System (MODEMS) Instruments [20] and the Sunnybrook Surgery Expectation Survey [21]). A number of other measures used within the literature were identified; however, the psychometric properties for many of these measures were not reported and any evidence of testing and validation were lacking [16]. Some studies used a single question to measure expectations. As patient expectation is multi-dimensional, using a single item to evaluate expectations is problematic. Zywiel and others have called for a core set of reliable and valid instruments to measure expectations [14,22], which may encourage their routine use in both clinical and research settings.

Patients Expectations for TKA Recovery

Although patient concerns vary in terms of importance and severity [23], pain and physical limitations are primary concerns for patients seeking TKA. Patients have high overall expectations for recovery, particularly for pain relief and walking [24–32]. TKA is an elective surgical procedure that provides substantial pain relief and improvements in function and quality of life, with the largest gains seen within the first 6 months [33,34]. Both short-term and long-term effect sizes for pain relief and functional recovery are large, in excess of 1.0 [34]. Over 70% of patients undergoing TKA expect to be pain-free, and 35% expect to have no limitations with routine activities [24,28,31].

Expectations regarding the surgical procedure and recovery can vary by diagnosis, personal characteristics, functional status [17], employment status, and trust in physicians [32,35]. There is, however, inconsistent evidence on associative preoperative factors of recovery expectations. While some evidence supports an association between higher expectations and younger age and greater preoperative functional limitation [26–28,32,36–38], others have reported no significant association with several preoperative factors including age, gender, and preoperative functional status [24,26,37]. Lower overall expectations [28] and lower expectations for pain relief [21] were also seen for patients with a greater number of comorbid conditions.

It may be that patients with high preoperative expectations are more optimistic, interpret their health-reported quality of life gains more liberally, and are more likely to adhere to rehabilitation treatment [24,25]. Optimism is a generalized expectancy of a positive outcome that is related to indicators of well-being [39]. Presurgical optimism was shown to be associated with less postsurgical pain and anxiety in patients undergoing total hip and knee arthroplasty [40].

In addition to general future-oriented constructs, such as optimism, treatment-specific psychological constructs, such as treatment credibility and treatment expectancy, are seen in patients with total joint arthroplasty. A strong but not redundant association is seen between treatment expectancy and treatment credibility, that is, expectations of a treatment may be related as to how credible the treatment outcomes appear [41,42]. Haanstra and colleagues advocate further clinical work to explore which factor predicts total joint arthroplasty outcomes so that patients who are at a higher risk of poor outcomes can be identified [42].

Others have recognized that perspectives and expectations of surgical outcomes differ between patient and surgeon [43–45]. Overall, surgeons’ expectations tend to be more optimistic than patients expectations of outcomes, although a subset of patients may have unrealistically high expectations [46]. Patients do not always realize that some of their expectations cannot be met by current orthopedic procedures, and this gap in understanding is an important source of discrepancies in expectations and patient dissatisfaction [46]. Ghomrawi and colleagues reported that approximately one-third of 205 patients undergoing primary TKA had higher expectations than their surgeons did. Being male and having lower preoperative pain was associated with having discordantly higher preoperative expectations [44]. For realistic expectations to be set, patients need accurate and understandable information about expected positive outcomes of surgery such as level of function and symptom relief as well as the risk of joint failure, adverse events, complications, and activity limitations. Although little work has explored the alignment of patient and surgeon’s expectations, setting realistic expectations may be aided by using a shared decision making approach that incorporates patient preferences and values, the best available evidence, and the surgeon’s expertise.

Expectations and Willingness to Undergo Surgery

Although total joint replacement is an effective treatment for advanced arthritis, approximately 30% of potential candidates are “unwilling” to proceed with surgery [47,48]. Willingness is a component of the medical decision making process and is influenced by preferences. Potential surgical candidates unwilling to proceed with surgery tend to be older, female, and from ethnic minor-ity groups [12,47–49]. Preference-sensitive medical decisions, such as whether or not to proceed with TKA, are related to patients’ attitudes and perceptions, which can be affected by sociocultural influences. In a cohort of 627 male patients with moderate to severe OA who were viewed as “good” candidates for total joint arthroplasty, more African Americans (24%) than Caucasian Americans (15%) had lower expectations for outcomes of surgery [35]. In particular, African Americans expressed concerns about postoperative pain and walking. Similar findings were also reported in another study in which minority patients were less likely to consider TKA [12]. Determinants of preferences were patients’ beliefs about the efficacy of the procedure and knowing others who had already undergone TKA [12]. Ibrahim and colleagues postulated that outcome expectations mediated or influenced the willingness to undergo total joint arthroplasty surgery [49]. Interventional work that built upon this premise suggested that willingness to proceed with TKA could be modified by educational interventions. In a randomized controlled trial of 639 African American patients attending Veteran’s Affairs primary clinics who received a decision aid with or without brief counseling, willingness to proceed with TKA increased and patient-provider communication improved among the patients who received any intervention [50]. Yet in another randomized trial involving African American patients who received care from an academic center, a combination decision aid and motivational interviewing strategy was no better than an educational pamphlet in improving patients’ preferences toward joint replacement surgery for knee OA [51]. This led the authors to recommend further exploration of patients’ knowledge, beliefs, and attitudes regarding surgical treatments for OA.

Effect of Expectations on Health Outcomes and Satisfaction

Some evidence suggests that better outcomes are seen in patients with higher expectations of recovery and, in turn, expectations that are met influence patient satisfaction. A systematic review of several chronic conditions showed with consistency across studies that positive recovery expectations were associated with better health outcomes [22]. The effect size varied with the condition and measure; however, none of the 16 studies examined arthritis or joint arthroplasty. Conversely, a systematic review of 18 prospective longitudinal cohort studies examining the association between expectation and outcomes (ie, pain, function, stiffness, satisfaction, overall improvement) reported less than convincing evidence of an association between patient preoperative expectations and treatment outcomes for THA and TKA in terms of short- and long-term postoperative pain and functional outcomes [15]. No consistent associations were seen with adjusted analysis of patient expectations and pain or functional outcomes at greater than 6 weeks [15]. Inconsistencies seen among the reviewed articles may be related to a number of issues centred on terminology, construct, expectation measures, and confounding effects.

Although TKA is an effective surgical procedure with large gains reported, 14% to 25% participants report little or no symptom improvement and/or dissatisfaction up to 1 year after surgery [1,52–59]. In a study with 5 years of follow-up, a decline in the satisfaction rate was seen after 1 year, although this decline was seen more so with physical function than with pain [38]. Although dissatisfaction can be attributed to surgical complications, in many cases, no technical or medical reasons can be identified. In a subset of patients who received TKA, surgical intervention does not adequately address patients’ concerns of pain and activity limitation. To compound matters, fair agreement was reported between patient and surgeon regarding satisfaction at 6 and 12 months postoperative. Disagreement between the patient and surgeon was explained by unmet expectations and postoperative complications [60]. When there was discordance, more often than not patients were less satisfied with TKA outcomes than surgeons [60,61].

While several theories explain patient satisfaction [62–65], evidence from total joint arthroplasty studies support the concept that satisfaction is derived from fulfillment of expectations [17,52]. Preoperative expectations are not to be confused with postoperative fulfilment of expectations, which are reflective of whether expectations of treatment have been met. Satisfaction is a value judgment and can be viewed as an affective domain, whereas expectation is a cognitive domain [66]. Patient satisfaction is regarded as the extent of a person’s experience compared to their expectation. As with expectations, a number of theoretical constructs exist concerning patient satisfaction [14,67]. Many dimensions of satisfaction exist, with patient expectations being central to these constructs. Deviation from expectations, however, does not necessarily correspond to dissatisfaction [67].

Several patient-related factors are associated with satisfaction with TKA, including primary diagnosis, preoperative pain and function, and mental health, including depression, but the relationships of satisfaction with gender, age, and comorbid conditions are less certain [33,38,52,55,56,68]. Greater preoperative pain, postoperative complications, lower 1-year WOMAC scores and functional limitations were associated with dissatisfied patients [38,52,53,59]. While no consistent associations were seen with preoperative expectations, consistent evidence has shown that fulfillment of expectations has an impact on satisfaction [31,36,52,58,69].

It should be acknowledged that the concept of fulfillment of expectations is not the same as satisfaction. A patient can be satisfied with TKA even though their expectations have not been met. The fulfillment of expectations is dependent upon the type of expectation and the postoperative time period. Fulfillment of expectations were seen with pain relief, function, walking and health status [25,31,70] while patients expectations were not always met with leisure activities [38].

Shared Decision Making

The shared decision making process, in which the patient and physician share responsibility and actively participate in the clinical decision making process [71], may help in ensuring that patients’ expectations are met. Shared decision making requires eliciting patients’ preferences and values, providing clear information on the processes that will occur during surgery, recovery, rehabilitation, and in the longer phase of recovery, and what realistic outcomes can be expected. While a more “paternalistic” approach predominated in earlier years, the current trends indicate greater patient involvement in decision making with the surgeon, with open discussion of patient goals and expectations [71]. This approach also aids patients in their preparation for the recovery and rehabilitation stages, which can be challenging, especially if they are unaware as to what to expect. Patient expectations are more likely to be met when there is shared decision making and patients have been given relevant information and understand what is a reasonable outcome. While a shared decision making approach is advocated within orthopedics [72], patient expectations are largely not measured in the clinical setting.

Patient education is an integral component of assisting patients to make informed decisions; however, it is unknown whether education alone can modify expectations. Educational approaches can include group classes, videos, and written materials [73]. Limited evidence from a randomized controlled trial suggests that preoperative expectations can be modified by preoperative education classes by decreasing the number of expectations and having more expectations in agreement with the surgeons’ expectations [29]. Mancuso and colleagues, who looked at whether a preoperative education session could modify expectations found that larger changes in expectations were seen with those patients who had greater baseline expectation scores, worse pain and function, and were older [29]. Others have also reported that preoperative education reduces anxiety by providing patients with an understanding of what to expect [74,75]. An assumption is that expectations can be changed by improving knowledge, which underscores the need for relevant meaningful education to increase knowledge and instill realistic expectations. Others have surmised there is a proportion of patients who will continue to have unexpectedly high unrealistic expectations regardless of educational session [31,37]. This would suggest that education is not the only approach to modify expectations but rather different strategies may need to be implemented for a certain subsets of patients with unrealistic expectations.

Conclusion

Patient expectation is an important element to be considered in shared clinical decision making, as it can influ-ence preferences and subsequent satisfaction. Patients considering TKA have specific needs and expectations that they presume will be addressed with the surgery. If these are realistic, they can be met, and will result in greater patient satisfaction and better ongoing adherence to health care recommendations [76]. While much work has been conducted in identifying which patient characteristics may influence health expectations, additional research is needed to further determine how to shape expectations within a realistic, achievable framework. While traditional patient education is an important element to enhance knowledge, the limited available evidence suggests it is not sufficiently effective on its own. Other strategies such as use of individualized decision aids, provision of peer support, and enhanced provider-patient communication have been effective in many areas of health care and warrant evaluation in this field.

Corresponding author: Allyson Jones, PhD, Rm 2-50, Corbett Hall, University of Alberta, Edmonton, Alberta Canada T6G 2G4, [email protected].

Financial disclosures: None.

Author contributions: conception and design, CAJ, MES; analysis and interpretation of data, MES; drafting of article, CAJ, MES; critical revision of the article, CAJ, MES; collection and assembly of data, CAJ.

From the Department of Physical Therapy, University of Alberta, Edmonton AB (Dr. Jones) and UT MD Anderson Cancer Center, Houston, TX (Dr. Suarez-Almazor).

Abstract

• Objective: To discuss patient expectations of total knee arthroplasty (TKA), instruments used to measure expectations, and the association between expectations, health outcomes, and satisfaction.
• Methods: Review of the literature.
• Results: TKA is an elective surgery for patients with persistent pain and disability caused by knee arthritis. Expectations regarding the surgical procedure and recovery can vary by diagnosis, personal characteristics, functional status, employment status, and trust in physicians. Patients have high overall expectations for recovery, particularly for pain relief and walking. Surgeons’ expectations tend to be more optimistic than patients’, although a subset of patients may have unrealistically high expectations. Although total joint replacement is an effective treatment for advanced arthritis, approximately 30% of potential candidates are unwilling to proceed with surgery. Potential surgical candidates unwilling to proceed with surgery tend to be older, female, and from ethnic minority groups. Several patient-related factors are associated with satisfaction with TKA, including primary diagnosis, preoperative pain and function, and mental health, including depression, but the relationships of satisfaction with gender, age, and comorbid conditions are less certain.
• Conclusion: A better understanding of patient expectations of TKA and recovery can identify knowledge gaps, misconceptions, and communication barriers, and ultimately improve shared decision making. A core set of reliable and valid instruments to measure expectations may encourage their routine use in both clinical and research settings.

Key words: total knee arthroplasty; osteoarthritis; patient expectations; shared decision making; joint replacement.

Total knee arthroplasty (TKA) is an elective surgery for patients with persistent pain and disability caused by knee arthritis. It is viewed as an effective and cost-effective surgical treatment for end-stage osteoarthritis (OA) [1–4]. As the population ages and obesity rates steadily increase, so will the utilization rates for TKA, with projected demand in the United States expected to grow 673% by 2030 [5–7]. The key indicators for receiving primary TKA are end-stage OA and joint pain [8]. Although TKA is a surgical option when conservative management is exhausted, no consensus exists as to the severity of symptoms required to consider surgery [9]. Variation in the utilization of TKA exists with respect to gender, racial/ethnicity, hospital, and geography [10,11]. These differences cannot be explained by prevalence of arthritis or symptoms or by access to health care alone. Increasingly, studies have shown these variations are largely attributable to patients’ preferences, driven by their beliefs, concerns, familiarity with the procedure, and expectations, along with physician opinion [12]. While physician opinions and recommendations clearly influence patients’ decisions, they do so primarily by modulating patients’ beliefs and expectations.

Patient expectations, not only of the effectiveness of the procedure itself but also of the recovery process, influence the decision to undergo an elective surgery such as joint arthroplasty. Ideally, these expectations should be informed by evidence, but often, lack of knowledge, preconceived beliefs, and misconceptions can taint informed decision making. A better understanding of patient expectations of TKA and recovery can identify knowledge gaps, misconceptions, and communication barriers, and ultimately improve shared decision making. Understanding patient expectations and factors that influence expectations provides a fuller appreciation of the outcomes that are meaningful to patients and can guide preoperative education and open dialogue with patients within a shared decision making model of care. In this paper, we discuss patient expectations of TKA, including expectations regarding outcomes and recovery, fulfillment of expectations, and the association of fulfilled expectations with satisfaction.

Measurement of Expectations

The construct of expectation is complex and situational. The ambiguity within the literature occurs most likely because expectations are multifaceted. Expectation involves the notion of expectancy, with respect to health care, that given events are likely to occur as a result of a medical procedure or treatment. This concept is in contrast to wants, which reflects a patient’s desire or wishes that an event will occur [13]. The term patient expectation, however, is commonly confused with patient preference or value. Preference implies a relative valuation or comparison by the patient and, unlike expectation, may not be explicitly expressed by the patient [13]. Different types of health care expectations exist that broadly relate to what patients expect regarding health care structure, process, and outcome [14].

Studies of patient expectations are diverse within the orthopedic research field and reflect differing theoretical underpinnings and lack of standardization. The lack of standardization makes measuring the complex concept of expectations challenging. While a number of conceptual models exist, Bowling and colleagues aptly recognize the multidimensionality of expectations and that no one conceptual model captures patient expectations [14]. The lack of standardization was noted in a systematic review by Haanstra and colleagues who found great variety in the definitions and measurements of expectations in studies examining their relationship with outcomes of total joint arthroplasty [15].

No gold standard measure exists for measuring patient expectations of orthopedic surgery. Zywiel’s systematic review [16] of 66 studies identified 7 validated instruments for measuring patient expectations for orthopedic surgery: of these, 2 were specific to TKA (Hospital for Special Surgery (HSS) Expectation Survey [17] and Expectation Domain of the New Knee Scoring System [18,19]), and 2 were generic to musculoskeletal conditions (Expectation domain of the Musculoskeletal Outcomes Data Evaluation and Management System (MODEMS) Instruments [20] and the Sunnybrook Surgery Expectation Survey [21]). A number of other measures used within the literature were identified; however, the psychometric properties for many of these measures were not reported and any evidence of testing and validation were lacking [16]. Some studies used a single question to measure expectations. As patient expectation is multi-dimensional, using a single item to evaluate expectations is problematic. Zywiel and others have called for a core set of reliable and valid instruments to measure expectations [14,22], which may encourage their routine use in both clinical and research settings.

Patients Expectations for TKA Recovery

Although patient concerns vary in terms of importance and severity [23], pain and physical limitations are primary concerns for patients seeking TKA. Patients have high overall expectations for recovery, particularly for pain relief and walking [24–32]. TKA is an elective surgical procedure that provides substantial pain relief and improvements in function and quality of life, with the largest gains seen within the first 6 months [33,34]. Both short-term and long-term effect sizes for pain relief and functional recovery are large, in excess of 1.0 [34]. Over 70% of patients undergoing TKA expect to be pain-free, and 35% expect to have no limitations with routine activities [24,28,31].

Expectations regarding the surgical procedure and recovery can vary by diagnosis, personal characteristics, functional status [17], employment status, and trust in physicians [32,35]. There is, however, inconsistent evidence on associative preoperative factors of recovery expectations. While some evidence supports an association between higher expectations and younger age and greater preoperative functional limitation [26–28,32,36–38], others have reported no significant association with several preoperative factors including age, gender, and preoperative functional status [24,26,37]. Lower overall expectations [28] and lower expectations for pain relief [21] were also seen for patients with a greater number of comorbid conditions.

It may be that patients with high preoperative expectations are more optimistic, interpret their health-reported quality of life gains more liberally, and are more likely to adhere to rehabilitation treatment [24,25]. Optimism is a generalized expectancy of a positive outcome that is related to indicators of well-being [39]. Presurgical optimism was shown to be associated with less postsurgical pain and anxiety in patients undergoing total hip and knee arthroplasty [40].

In addition to general future-oriented constructs, such as optimism, treatment-specific psychological constructs, such as treatment credibility and treatment expectancy, are seen in patients with total joint arthroplasty. A strong but not redundant association is seen between treatment expectancy and treatment credibility, that is, expectations of a treatment may be related as to how credible the treatment outcomes appear [41,42]. Haanstra and colleagues advocate further clinical work to explore which factor predicts total joint arthroplasty outcomes so that patients who are at a higher risk of poor outcomes can be identified [42].

Others have recognized that perspectives and expectations of surgical outcomes differ between patient and surgeon [43–45]. Overall, surgeons’ expectations tend to be more optimistic than patients expectations of outcomes, although a subset of patients may have unrealistically high expectations [46]. Patients do not always realize that some of their expectations cannot be met by current orthopedic procedures, and this gap in understanding is an important source of discrepancies in expectations and patient dissatisfaction [46]. Ghomrawi and colleagues reported that approximately one-third of 205 patients undergoing primary TKA had higher expectations than their surgeons did. Being male and having lower preoperative pain was associated with having discordantly higher preoperative expectations [44]. For realistic expectations to be set, patients need accurate and understandable information about expected positive outcomes of surgery such as level of function and symptom relief as well as the risk of joint failure, adverse events, complications, and activity limitations. Although little work has explored the alignment of patient and surgeon’s expectations, setting realistic expectations may be aided by using a shared decision making approach that incorporates patient preferences and values, the best available evidence, and the surgeon’s expertise.

Expectations and Willingness to Undergo Surgery

Although total joint replacement is an effective treatment for advanced arthritis, approximately 30% of potential candidates are “unwilling” to proceed with surgery [47,48]. Willingness is a component of the medical decision making process and is influenced by preferences. Potential surgical candidates unwilling to proceed with surgery tend to be older, female, and from ethnic minor-ity groups [12,47–49]. Preference-sensitive medical decisions, such as whether or not to proceed with TKA, are related to patients’ attitudes and perceptions, which can be affected by sociocultural influences. In a cohort of 627 male patients with moderate to severe OA who were viewed as “good” candidates for total joint arthroplasty, more African Americans (24%) than Caucasian Americans (15%) had lower expectations for outcomes of surgery [35]. In particular, African Americans expressed concerns about postoperative pain and walking. Similar findings were also reported in another study in which minority patients were less likely to consider TKA [12]. Determinants of preferences were patients’ beliefs about the efficacy of the procedure and knowing others who had already undergone TKA [12]. Ibrahim and colleagues postulated that outcome expectations mediated or influenced the willingness to undergo total joint arthroplasty surgery [49]. Interventional work that built upon this premise suggested that willingness to proceed with TKA could be modified by educational interventions. In a randomized controlled trial of 639 African American patients attending Veteran’s Affairs primary clinics who received a decision aid with or without brief counseling, willingness to proceed with TKA increased and patient-provider communication improved among the patients who received any intervention [50]. Yet in another randomized trial involving African American patients who received care from an academic center, a combination decision aid and motivational interviewing strategy was no better than an educational pamphlet in improving patients’ preferences toward joint replacement surgery for knee OA [51]. This led the authors to recommend further exploration of patients’ knowledge, beliefs, and attitudes regarding surgical treatments for OA.

Effect of Expectations on Health Outcomes and Satisfaction

Some evidence suggests that better outcomes are seen in patients with higher expectations of recovery and, in turn, expectations that are met influence patient satisfaction. A systematic review of several chronic conditions showed with consistency across studies that positive recovery expectations were associated with better health outcomes [22]. The effect size varied with the condition and measure; however, none of the 16 studies examined arthritis or joint arthroplasty. Conversely, a systematic review of 18 prospective longitudinal cohort studies examining the association between expectation and outcomes (ie, pain, function, stiffness, satisfaction, overall improvement) reported less than convincing evidence of an association between patient preoperative expectations and treatment outcomes for THA and TKA in terms of short- and long-term postoperative pain and functional outcomes [15]. No consistent associations were seen with adjusted analysis of patient expectations and pain or functional outcomes at greater than 6 weeks [15]. Inconsistencies seen among the reviewed articles may be related to a number of issues centred on terminology, construct, expectation measures, and confounding effects.

Although TKA is an effective surgical procedure with large gains reported, 14% to 25% participants report little or no symptom improvement and/or dissatisfaction up to 1 year after surgery [1,52–59]. In a study with 5 years of follow-up, a decline in the satisfaction rate was seen after 1 year, although this decline was seen more so with physical function than with pain [38]. Although dissatisfaction can be attributed to surgical complications, in many cases, no technical or medical reasons can be identified. In a subset of patients who received TKA, surgical intervention does not adequately address patients’ concerns of pain and activity limitation. To compound matters, fair agreement was reported between patient and surgeon regarding satisfaction at 6 and 12 months postoperative. Disagreement between the patient and surgeon was explained by unmet expectations and postoperative complications [60]. When there was discordance, more often than not patients were less satisfied with TKA outcomes than surgeons [60,61].

While several theories explain patient satisfaction [62–65], evidence from total joint arthroplasty studies support the concept that satisfaction is derived from fulfillment of expectations [17,52]. Preoperative expectations are not to be confused with postoperative fulfilment of expectations, which are reflective of whether expectations of treatment have been met. Satisfaction is a value judgment and can be viewed as an affective domain, whereas expectation is a cognitive domain [66]. Patient satisfaction is regarded as the extent of a person’s experience compared to their expectation. As with expectations, a number of theoretical constructs exist concerning patient satisfaction [14,67]. Many dimensions of satisfaction exist, with patient expectations being central to these constructs. Deviation from expectations, however, does not necessarily correspond to dissatisfaction [67].

Several patient-related factors are associated with satisfaction with TKA, including primary diagnosis, preoperative pain and function, and mental health, including depression, but the relationships of satisfaction with gender, age, and comorbid conditions are less certain [33,38,52,55,56,68]. Greater preoperative pain, postoperative complications, lower 1-year WOMAC scores and functional limitations were associated with dissatisfied patients [38,52,53,59]. While no consistent associations were seen with preoperative expectations, consistent evidence has shown that fulfillment of expectations has an impact on satisfaction [31,36,52,58,69].

It should be acknowledged that the concept of fulfillment of expectations is not the same as satisfaction. A patient can be satisfied with TKA even though their expectations have not been met. The fulfillment of expectations is dependent upon the type of expectation and the postoperative time period. Fulfillment of expectations were seen with pain relief, function, walking and health status [25,31,70] while patients expectations were not always met with leisure activities [38].

Shared Decision Making

The shared decision making process, in which the patient and physician share responsibility and actively participate in the clinical decision making process [71], may help in ensuring that patients’ expectations are met. Shared decision making requires eliciting patients’ preferences and values, providing clear information on the processes that will occur during surgery, recovery, rehabilitation, and in the longer phase of recovery, and what realistic outcomes can be expected. While a more “paternalistic” approach predominated in earlier years, the current trends indicate greater patient involvement in decision making with the surgeon, with open discussion of patient goals and expectations [71]. This approach also aids patients in their preparation for the recovery and rehabilitation stages, which can be challenging, especially if they are unaware as to what to expect. Patient expectations are more likely to be met when there is shared decision making and patients have been given relevant information and understand what is a reasonable outcome. While a shared decision making approach is advocated within orthopedics [72], patient expectations are largely not measured in the clinical setting.

Patient education is an integral component of assisting patients to make informed decisions; however, it is unknown whether education alone can modify expectations. Educational approaches can include group classes, videos, and written materials [73]. Limited evidence from a randomized controlled trial suggests that preoperative expectations can be modified by preoperative education classes by decreasing the number of expectations and having more expectations in agreement with the surgeons’ expectations [29]. Mancuso and colleagues, who looked at whether a preoperative education session could modify expectations found that larger changes in expectations were seen with those patients who had greater baseline expectation scores, worse pain and function, and were older [29]. Others have also reported that preoperative education reduces anxiety by providing patients with an understanding of what to expect [74,75]. An assumption is that expectations can be changed by improving knowledge, which underscores the need for relevant meaningful education to increase knowledge and instill realistic expectations. Others have surmised there is a proportion of patients who will continue to have unexpectedly high unrealistic expectations regardless of educational session [31,37]. This would suggest that education is not the only approach to modify expectations but rather different strategies may need to be implemented for a certain subsets of patients with unrealistic expectations.

Conclusion

Patient expectation is an important element to be considered in shared clinical decision making, as it can influ-ence preferences and subsequent satisfaction. Patients considering TKA have specific needs and expectations that they presume will be addressed with the surgery. If these are realistic, they can be met, and will result in greater patient satisfaction and better ongoing adherence to health care recommendations [76]. While much work has been conducted in identifying which patient characteristics may influence health expectations, additional research is needed to further determine how to shape expectations within a realistic, achievable framework. While traditional patient education is an important element to enhance knowledge, the limited available evidence suggests it is not sufficiently effective on its own. Other strategies such as use of individualized decision aids, provision of peer support, and enhanced provider-patient communication have been effective in many areas of health care and warrant evaluation in this field.

Corresponding author: Allyson Jones, PhD, Rm 2-50, Corbett Hall, University of Alberta, Edmonton, Alberta Canada T6G 2G4, [email protected].

Financial disclosures: None.

Author contributions: conception and design, CAJ, MES; analysis and interpretation of data, MES; drafting of article, CAJ, MES; critical revision of the article, CAJ, MES; collection and assembly of data, CAJ.

Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.

The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.

[email protected]

Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.

The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.

[email protected]

Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.

The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.

[email protected]

MADRID – Is there a need for an enterovirus-A71 vaccine?

This is a new question for North American and European physicians, but not so new in Asia.

“China says yes, with more than 15 million cases of hand, foot, and mouth disease resulting in 3,500 deaths since surveillance started in 2009,” Heli Harvala, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

Copyright MidgleyDJ/Wikimedia Commons

[email protected]


 

MADRID – Is there a need for an enterovirus-A71 vaccine?

This is a new question for North American and European physicians, but not so new in Asia.

“China says yes, with more than 15 million cases of hand, foot, and mouth disease resulting in 3,500 deaths since surveillance started in 2009,” Heli Harvala, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

Copyright MidgleyDJ/Wikimedia Commons

[email protected]


 

MADRID – Is there a need for an enterovirus-A71 vaccine?

This is a new question for North American and European physicians, but not so new in Asia.

“China says yes, with more than 15 million cases of hand, foot, and mouth disease resulting in 3,500 deaths since surveillance started in 2009,” Heli Harvala, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

Copyright MidgleyDJ/Wikimedia Commons

[email protected]


 

Following the directive of the “Military Service by Transgender Individuals” Presidential Memorandum to reinstitute a ban on service for transgender service members, the Secretary of Defense has called for a new study of the impact of transgender service members on “military readiness, lethality, and unit cohesion, with due regard for budgetary constraints and consistent with applicable law.” Secretary of Defense Jim Mattis announced that he will “establish a panel of experts serving within the Departments of Defense and Homeland Security to provide advice and recommendations on the implementation of the president’s direction.”

The study follows on the heels of a July 2016 study issued by the RAND Corporation, which found that there are between 1,300 to 6,600 transgender active duty service members. According to the study, the “costs of gender transition-related health care are relatively low” and they had a “minimal” impact on force readiness.

The new study is due to President Trump by February 21, 2018 and is required to include a plan for implementing the ban. The potential ban on transgender service members is still set to go into effect March 23, 2018. However, there is some disagreement over whether the Presidential Memorandum leave the DoD with latitude to protect currently serving transgender service members or not.

The expected health care costs associated with transgender service members remains a significant factor in the policy decision. The RAND study estimated that health care costs would increase by between $2.4 million and $8.4 million annually with transgender service members out of an estimated $6.2 billion spent on active component health care spending, which would represent a 0.04% to 0.13% of the budget.

Following the directive of the “Military Service by Transgender Individuals” Presidential Memorandum to reinstitute a ban on service for transgender service members, the Secretary of Defense has called for a new study of the impact of transgender service members on “military readiness, lethality, and unit cohesion, with due regard for budgetary constraints and consistent with applicable law.” Secretary of Defense Jim Mattis announced that he will “establish a panel of experts serving within the Departments of Defense and Homeland Security to provide advice and recommendations on the implementation of the president’s direction.”

The study follows on the heels of a July 2016 study issued by the RAND Corporation, which found that there are between 1,300 to 6,600 transgender active duty service members. According to the study, the “costs of gender transition-related health care are relatively low” and they had a “minimal” impact on force readiness.

The new study is due to President Trump by February 21, 2018 and is required to include a plan for implementing the ban. The potential ban on transgender service members is still set to go into effect March 23, 2018. However, there is some disagreement over whether the Presidential Memorandum leave the DoD with latitude to protect currently serving transgender service members or not.

The expected health care costs associated with transgender service members remains a significant factor in the policy decision. The RAND study estimated that health care costs would increase by between $2.4 million and $8.4 million annually with transgender service members out of an estimated $6.2 billion spent on active component health care spending, which would represent a 0.04% to 0.13% of the budget.

Following the directive of the “Military Service by Transgender Individuals” Presidential Memorandum to reinstitute a ban on service for transgender service members, the Secretary of Defense has called for a new study of the impact of transgender service members on “military readiness, lethality, and unit cohesion, with due regard for budgetary constraints and consistent with applicable law.” Secretary of Defense Jim Mattis announced that he will “establish a panel of experts serving within the Departments of Defense and Homeland Security to provide advice and recommendations on the implementation of the president’s direction.”

The study follows on the heels of a July 2016 study issued by the RAND Corporation, which found that there are between 1,300 to 6,600 transgender active duty service members. According to the study, the “costs of gender transition-related health care are relatively low” and they had a “minimal” impact on force readiness.

The new study is due to President Trump by February 21, 2018 and is required to include a plan for implementing the ban. The potential ban on transgender service members is still set to go into effect March 23, 2018. However, there is some disagreement over whether the Presidential Memorandum leave the DoD with latitude to protect currently serving transgender service members or not.

The expected health care costs associated with transgender service members remains a significant factor in the policy decision. The RAND study estimated that health care costs would increase by between $2.4 million and $8.4 million annually with transgender service members out of an estimated $6.2 billion spent on active component health care spending, which would represent a 0.04% to 0.13% of the budget.

When Jennifer Gunter, MD, learned that Marie Claire magazine published an article suggesting that the recent solar eclipse affected menstrual cycles, she turned to social media to dismantle that assertion.

“If the new moon were associated with menstruation, then all women all over the world would be menstruating at the same time,” Dr. Gunter wrote in an Aug. 21, 2017 entry on her personal blog, which includes the slogan “Wielding the Lasso of Truth.” “Have none of these people ever considered that? Maybe that happens in the “Mists of Avalon,” but it doesn’t happen on Earth.”

• Be HIPAA compliant. “I don’t think I’ve ever used my work day to inform what I write about because there’s so much going on in the news,” she said. “You have to be HIPAA compliant because your patients may be following you online. In many ways, I hope that people I’m going to care for do read some of the things that I put out there because I’m trying to give good health information.”
• Be authentic. “When people meet me and have probably read some of my tweets and have heard me talk, they say they can match the voice with the person,” Dr. Gunter said. “People can tell when you’re not being authentic. That doesn’t work for me. I don’t have time to invent another persona!”
• Share articles you think are worthwhile. “If I have a friend who is in the tech industry, and if he posts an article on that topic, I figure he curated that, so maybe I’ll read it,” she said. “Likewise, if you’re a doctor and you have people following you on Facebook who are not physicians, they might say, ‘My friend who I went to high school with who’s a doctor thinks this New York Times article is worth reading. Maybe I should read it.’ People can lurk and share things, and that helps. I follow lots of doctors on Twitter that I don’t regularly engage with, but they post articles, and I’ll read them.”
• Make it clear who you’re speaking for. Are you speaking for your employer or for yourself? Are you giving medical advice, or is the content your opinion only? Include an appropriate disclaimer in your profile. Dr. Gunter’s Twitter profile reads: “Appropriately Confident OB/GYN, Canadian Spice, Sexpert, Lasso of Truth, Pegasister, Not medical advice, I speak for no one but me.”
• If you post regularly, expect criticism at some point. “If social media is not for you, you shouldn’t do it,” Dr. Gunter said. “But if you have a small Facebook account, why not share some good quality articles that you found interesting? You’d be surprised. What you might think is a throwaway message might be of real help to someone who doesn’t practice medicine. There’s a real hunger for good quality curated information.”

[email protected]

When Jennifer Gunter, MD, learned that Marie Claire magazine published an article suggesting that the recent solar eclipse affected menstrual cycles, she turned to social media to dismantle that assertion.

“If the new moon were associated with menstruation, then all women all over the world would be menstruating at the same time,” Dr. Gunter wrote in an Aug. 21, 2017 entry on her personal blog, which includes the slogan “Wielding the Lasso of Truth.” “Have none of these people ever considered that? Maybe that happens in the “Mists of Avalon,” but it doesn’t happen on Earth.”

• Be HIPAA compliant. “I don’t think I’ve ever used my work day to inform what I write about because there’s so much going on in the news,” she said. “You have to be HIPAA compliant because your patients may be following you online. In many ways, I hope that people I’m going to care for do read some of the things that I put out there because I’m trying to give good health information.”
• Be authentic. “When people meet me and have probably read some of my tweets and have heard me talk, they say they can match the voice with the person,” Dr. Gunter said. “People can tell when you’re not being authentic. That doesn’t work for me. I don’t have time to invent another persona!”
• Share articles you think are worthwhile. “If I have a friend who is in the tech industry, and if he posts an article on that topic, I figure he curated that, so maybe I’ll read it,” she said. “Likewise, if you’re a doctor and you have people following you on Facebook who are not physicians, they might say, ‘My friend who I went to high school with who’s a doctor thinks this New York Times article is worth reading. Maybe I should read it.’ People can lurk and share things, and that helps. I follow lots of doctors on Twitter that I don’t regularly engage with, but they post articles, and I’ll read them.”
• Make it clear who you’re speaking for. Are you speaking for your employer or for yourself? Are you giving medical advice, or is the content your opinion only? Include an appropriate disclaimer in your profile. Dr. Gunter’s Twitter profile reads: “Appropriately Confident OB/GYN, Canadian Spice, Sexpert, Lasso of Truth, Pegasister, Not medical advice, I speak for no one but me.”
• If you post regularly, expect criticism at some point. “If social media is not for you, you shouldn’t do it,” Dr. Gunter said. “But if you have a small Facebook account, why not share some good quality articles that you found interesting? You’d be surprised. What you might think is a throwaway message might be of real help to someone who doesn’t practice medicine. There’s a real hunger for good quality curated information.”

[email protected]

When Jennifer Gunter, MD, learned that Marie Claire magazine published an article suggesting that the recent solar eclipse affected menstrual cycles, she turned to social media to dismantle that assertion.

“If the new moon were associated with menstruation, then all women all over the world would be menstruating at the same time,” Dr. Gunter wrote in an Aug. 21, 2017 entry on her personal blog, which includes the slogan “Wielding the Lasso of Truth.” “Have none of these people ever considered that? Maybe that happens in the “Mists of Avalon,” but it doesn’t happen on Earth.”

• Be HIPAA compliant. “I don’t think I’ve ever used my work day to inform what I write about because there’s so much going on in the news,” she said. “You have to be HIPAA compliant because your patients may be following you online. In many ways, I hope that people I’m going to care for do read some of the things that I put out there because I’m trying to give good health information.”
• Be authentic. “When people meet me and have probably read some of my tweets and have heard me talk, they say they can match the voice with the person,” Dr. Gunter said. “People can tell when you’re not being authentic. That doesn’t work for me. I don’t have time to invent another persona!”
• Share articles you think are worthwhile. “If I have a friend who is in the tech industry, and if he posts an article on that topic, I figure he curated that, so maybe I’ll read it,” she said. “Likewise, if you’re a doctor and you have people following you on Facebook who are not physicians, they might say, ‘My friend who I went to high school with who’s a doctor thinks this New York Times article is worth reading. Maybe I should read it.’ People can lurk and share things, and that helps. I follow lots of doctors on Twitter that I don’t regularly engage with, but they post articles, and I’ll read them.”
• Make it clear who you’re speaking for. Are you speaking for your employer or for yourself? Are you giving medical advice, or is the content your opinion only? Include an appropriate disclaimer in your profile. Dr. Gunter’s Twitter profile reads: “Appropriately Confident OB/GYN, Canadian Spice, Sexpert, Lasso of Truth, Pegasister, Not medical advice, I speak for no one but me.”
• If you post regularly, expect criticism at some point. “If social media is not for you, you shouldn’t do it,” Dr. Gunter said. “But if you have a small Facebook account, why not share some good quality articles that you found interesting? You’d be surprised. What you might think is a throwaway message might be of real help to someone who doesn’t practice medicine. There’s a real hunger for good quality curated information.”

[email protected]

You probably aren’t surprised to learn that the jobless rate for young people aged 16-24 years has fallen to the lowest rate recorded since 1969. Those “Hiring” signs you see in every storefront tell the story. Although the jobless rate for young people is still twice that for adults, clearly there are jobs out there.

However, it appears that there are fewer young people looking for those jobs. In fact, the decline in what is referred to as the “labor force participation rate” is down significantly to 60.6% from a high point of 77.5% in 1989 (Summer Youth Unemployment Falls to Lowest Level Since 1969, by Eric Morath. Wall Street Journal. 2017 Aug 17).

Koji_Ishii/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

You probably aren’t surprised to learn that the jobless rate for young people aged 16-24 years has fallen to the lowest rate recorded since 1969. Those “Hiring” signs you see in every storefront tell the story. Although the jobless rate for young people is still twice that for adults, clearly there are jobs out there.

However, it appears that there are fewer young people looking for those jobs. In fact, the decline in what is referred to as the “labor force participation rate” is down significantly to 60.6% from a high point of 77.5% in 1989 (Summer Youth Unemployment Falls to Lowest Level Since 1969, by Eric Morath. Wall Street Journal. 2017 Aug 17).

Koji_Ishii/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

You probably aren’t surprised to learn that the jobless rate for young people aged 16-24 years has fallen to the lowest rate recorded since 1969. Those “Hiring” signs you see in every storefront tell the story. Although the jobless rate for young people is still twice that for adults, clearly there are jobs out there.

However, it appears that there are fewer young people looking for those jobs. In fact, the decline in what is referred to as the “labor force participation rate” is down significantly to 60.6% from a high point of 77.5% in 1989 (Summer Youth Unemployment Falls to Lowest Level Since 1969, by Eric Morath. Wall Street Journal. 2017 Aug 17).

Koji_Ishii/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma is an interventional trial currently recruiting patients with early to intermediate stage HPVOPC.

People with HPVOPC are generally curable, are young, and will live for extended periods of time, and are also at high risk for long-term toxicity and morbidity from chemotherapy and radiation. The study will explore the necessity of additional intervention in HPVOPC after surgery, and it is estimated that more than half of patients will not require additional therapy.

[email protected]

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma is an interventional trial currently recruiting patients with early to intermediate stage HPVOPC.

People with HPVOPC are generally curable, are young, and will live for extended periods of time, and are also at high risk for long-term toxicity and morbidity from chemotherapy and radiation. The study will explore the necessity of additional intervention in HPVOPC after surgery, and it is estimated that more than half of patients will not require additional therapy.

[email protected]

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma is an interventional trial currently recruiting patients with early to intermediate stage HPVOPC.

People with HPVOPC are generally curable, are young, and will live for extended periods of time, and are also at high risk for long-term toxicity and morbidity from chemotherapy and radiation. The study will explore the necessity of additional intervention in HPVOPC after surgery, and it is estimated that more than half of patients will not require additional therapy.

[email protected]

BARCELONA – Catheter ablation of symptomatic atrial fibrillation produced significantly better quality of life after 12 months than did continued treatment with antiarrhythmic drugs in a randomized, multicenter trial with 155 patients who had a history of failed drug treatment.

The trial was notable as the first prospective comparison of atrial fibrillation (AF) management by ablation with drug treatment to use quality of life as the primary efficacy endpoint. Such a quality of life–oriented assessment has been lacking “even though the main indication for ablation is symptom relief,” Carina Blomström-Lundqvist, MD, said at the annual congress of the European Society of Cardiology.

Clinicians have traditionally measured residual or recurrent AF after treatment with a periodic ECG to see whether patients experience AF episodes that last at least 30 seconds, but this is “hardly a measure of successful treatment,” said Dr. Blomström-Lundqvist, an electrophysiologist at the University Hospital in Uppsala, Sweden.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

BARCELONA – Catheter ablation of symptomatic atrial fibrillation produced significantly better quality of life after 12 months than did continued treatment with antiarrhythmic drugs in a randomized, multicenter trial with 155 patients who had a history of failed drug treatment.

The trial was notable as the first prospective comparison of atrial fibrillation (AF) management by ablation with drug treatment to use quality of life as the primary efficacy endpoint. Such a quality of life–oriented assessment has been lacking “even though the main indication for ablation is symptom relief,” Carina Blomström-Lundqvist, MD, said at the annual congress of the European Society of Cardiology.

Clinicians have traditionally measured residual or recurrent AF after treatment with a periodic ECG to see whether patients experience AF episodes that last at least 30 seconds, but this is “hardly a measure of successful treatment,” said Dr. Blomström-Lundqvist, an electrophysiologist at the University Hospital in Uppsala, Sweden.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

BARCELONA – Catheter ablation of symptomatic atrial fibrillation produced significantly better quality of life after 12 months than did continued treatment with antiarrhythmic drugs in a randomized, multicenter trial with 155 patients who had a history of failed drug treatment.

The trial was notable as the first prospective comparison of atrial fibrillation (AF) management by ablation with drug treatment to use quality of life as the primary efficacy endpoint. Such a quality of life–oriented assessment has been lacking “even though the main indication for ablation is symptom relief,” Carina Blomström-Lundqvist, MD, said at the annual congress of the European Society of Cardiology.

Clinicians have traditionally measured residual or recurrent AF after treatment with a periodic ECG to see whether patients experience AF episodes that last at least 30 seconds, but this is “hardly a measure of successful treatment,” said Dr. Blomström-Lundqvist, an electrophysiologist at the University Hospital in Uppsala, Sweden.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler