Katherine H. Saunders, MD, DABOM

Modest weight loss of 5% to 10% among patients who are overweight or obese can result in a clinically relevant reduction in cardiovascular (CV) disease risk.¹ This amount of weight loss can increase insulin sensitivity in adipose tissue, liver, and muscle, and have a positive impact on blood sugar, blood pressure, triglycerides, and high-density lipoprotein cholesterol.^1,2

All patients who are obese or overweight with increased CV risk should be counseled on diet, exercise, and other behavioral interventions.³ Weight loss secondary to lifestyle modification alone, however, leads to adaptive physiologic responses, which increase appetite and reduce energy expenditure.^4–6

Pharmacotherapy can counteract this metabolic adaptation and lead to sustained weight loss. Antiobesity medication can be considered if a patient has a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.^3,7

Until recently, there were few pharmacologic options approved by the US Food and Drug Administration (FDA) for the management of obesity. The mainstays of treatment were phentermine (Adipex-P, Ionamin, Suprenza) and orlistat (Alli, Xenical). Since 2012, however, 4 agents have been approved as adjuncts to a reduced-calorie diet and increased physical activity for long-term weight management.^8,9 Phentermine/topiramate extended-release (ER) (Qsymia) and lorcaserin (Belviq) were approved in 2012,^10,11 and naltrexone sustained release (SR)/bupropion SR (Contrave) and liraglutide 3 mg (Saxenda) were approved in 2014^12,13 (TABLE^9,14–39). These medications have the potential to not only limit weight gain but also promote weight loss and, thus, improve blood pressure, cholesterol, glucose, and insulin.⁴⁰

Despite the growing obesity epidemic and the availability of several additional medications for chronic weight management, use of antiobesity pharmacotherapy has been limited. Barriers to use include inadequate training of health care professionals, poor insurance coverage for new agents, and low reimbursement for office visits to address weight.⁴¹

In addition, the number of obesity medicine specialists, while increasing, is still not sufficient. Therefore, it is imperative for other health care professionals—including ObGyns—to be aware of the treatment options available to patients who are overweight or obese and to be adept at using them.

In this review, we present 4 cases that depict patients who could benefit from the addition of antiobesity pharmacotherapy to a comprehen‑sive treatment plan that includes diet, physical activity, and behavioral modification.

CASE 1 Young obese woman is unable to lose weight

A 27-year-old woman with obesity (BMI 33 kg/m²),hyperlipidemia, and migraine headaches, pre‑sents for weight management. Despite a calorie-reduced diet and 200 minutes per week of exercise for the past 6 months, she has been unable to lose weight. The only medications she is taking are oral contraceptive pills and sumatriptan, as needed. She suffers from migraines 3 times a month and has no anxiety. Laboratory test results are normal with the exception of an elevated low-density lipoprotein (LDL) level.

Which medication is an appropriate next step for this patient?

Ask 2 important questions

When considering an antiobesity agent for any patient, there are 2 important questions to ask:

• Are there contraindications, drug-drug interactions, or undesirable adverse effects associated with this medication that could be problematic for the patient?
• Can this medication improve other symptoms or conditions the patient has?

In addition, see “Before prescribing antiobesity medication . . .” below.

Phentermine/topiramate ER

Phentermine/topiramate ER is a good first choice for this young patient with class I (BMI 30–34.9 kg/m²) obesity and migraines, as she can likely tolerate a stimulant and her migraines might improve with topiramate. Before starting the medication, ask about insomnia and nephrolithiasis in addition to anxiety and other contraindications (ie, glaucoma, hyperthyroidism, recent monoamine oxidase inhibitor use, or a known hypersensitivity or idiosyncrasy to sympathomimetic amines).²³ The most common adverse events reported in phase III trials were dry mouth, paresthesia, and constipation.^24–26

Not for pregnant women. Women of childbearing age must have a negative pregnancy test before starting phentermine/topiramate ER and every month while taking the medication. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to topiramate during the first trimester of pregnancy.⁴² REMS focuses on the importance of pregnancy prevention, the consistent use of birth control, and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

Flexible dosing. Phentermine/topiramate ER is available in 4 dosages: phentermine 3.75 mg/topiramate 23 mg ER; phentermine 7.5 mg/topiramate 46 mg ER; phentermine 11.25 mg/topiramate 69 mg ER; and phentermine 15 mg/topiramate 92 mg ER. Gradual dose escalation minimizes risks and adverse events.²³

Monitor patients frequently to evaluate for adverse effects and ensure adherence to diet, exercise, and lifestyle modifications. If weight loss is slower or less robust than expected, check for dietary indiscretion, as medications have limited efficacy without appropriate behavioral changes.

Discontinue phentermine/topiramate ER if the patient does not achieve 5% weight loss after 12 weeks on the maximum dose, as it is unlikely that she will achieve and sustain clinically meaningful weight loss with continued treatment.²³ In this case, consider another agent with a different mechanism of action. Any of the other antiobesity medications could be appropriate for this patient.

CASE 2 Overweight woman with comorbidities

A 52-year-old overweight woman (BMI 29 kg/m²)with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma has recently hit a plateau with her weight loss. She lost 45 lb secondary to diet and exercise, but hasn’t been able to lose any more. She also struggles with constant hunger. Her medications include metformin 1,000 mg twice per day, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until she undergoes a left knee replacement. Laboratory values are normal except for a hemoglobin A_1c of 7.2%.

The patient is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

What are good choices for this patient?

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. She has worked hard to lose a significant number of pounds and is now at high risk of regaining them. That’s because her appetite has increased with her new exercise regimen, but her energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of her opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

She could try orlistat, especially if she struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for her diabetes and also may promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOMDM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A_1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A_1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of her initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomics testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

CASE 3 A preoccupation with food

A 38-year-old woman with obesity (BMI 42 kg/m²),obstructive sleep apnea, gastroesophageal reflux disease, and depression is eager to get better control over her weight. Her medications include lansoprazole 30 mg/d and a multivitamin. She reports constantly thinking about food and not being able to control her impulses to buy large quantities of unhealthy snacks. She is so preoccupied by thoughts of food that she has difficulty concentrating at work.

The patient smokes a quarter of a pack of cigarettes daily, but she is ready to quit. She views bariatric surgery as a “last resort” and has no anxiety, pain, or history of seizures. Which medication is appropriate for this patient?

Discuss all options

This patient with class III obesity (BMI ≥40 kg/m²) is eligible for bariatric surgery; however, she is not interested in pursuing it at this time. It is important to discuss all of her options before deciding on a treatment plan. For patients like this, who would benefit from more than modest weight loss, consider a multidisciplinary approach including lifestyle modifications, pharmacotherapy, devices (eg, an intragastric balloon), and/or surgery. You would need to make clear to the patient that she may still be eligible for insurance coverage for surgery if she changes her mind after pursuing other treatments as long as her BMI remains ≥35 kg/m² with obesity-related comorbidities.

Naltrexone SR/bupropion SR is a good choice for this patient because she describes debilitating cravings and addictive behavior surrounding food. Patients taking naltrexone SR/bupropion SR in the Contrave Obesity Research (COR)-I and COR-II phase III trials experienced a reduced frequency of food cravings, reduced difficulty in resisting food cravings, and an increased ability to control eating compared with those assigned to placebo.^32,33

Added benefits. Bupropion also could help this patient quit smoking and improve her mood, as it is FDA-approved for smoking cessation and depression. She denies anxiety and seizures, so bupropion is not contraindicated. Even if a patient denies a history of seizure, ask about any conditions that predispose to seizures, such as anorexia nervosa or bulimia or the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Opioid use. Although the patient denies pain, ask about potential opioid use, as naltrexone is an opioid receptor antagonist. Patients should be informed that opioids may be ineffective if they are required unexpectedly (eg, for trauma) and that naltrexone SR/bupropion SR should be withheld for any planned surgical procedure potentially requiring opioid use.

Other options. While naltrexone SR/bupropion SR is the most appropriate choice for this patient because it addresses her problematic eating behaviors while potentially improving mood and assisting with smoking cessation, phentermine/topiramate ER, lorcaserin, and liraglutide 3 mg also could be used and certainly should be tried if naltrexone SR/bupropion SR does not produce the desired weight loss.

Adverse effects. Titrate naltrexone SR/bupropion SR slowly to the treatment dose to minimize risks and adverse events.³¹ The most common adverse effects reported in phase III trials were nausea, constipation, and headache.^34,35,45,46 Discontinue naltrexone SR/bupropion SR if the patient does not achieve 5% weight loss at 16 weeks (after 12 weeks at the maintenance dose).³¹

CASE 4 Regaining weight after gastric bypass

A 65-year-old woman with obesity (BMI 39 kg/m²)who underwent Roux-en-Y gastric bypass surgery and who has type 2 diabetes, congestive heart failure, coronary artery disease, hypertension, and hyperlipidemia, remains concerned about her weight. She lost 100 lb following surgery and maintained her weight for 3 years, but then regained 30 lb. She comes in for an office visit because she is concerned about her increasing blood sugar and wants to prevent further weight gain. Her medications include metformin 1,000 mg twice per day, lisinopril 5 mg/d, carvedilol 12.5 mg twice per day, simvastatin 20 mg/d, and aspirin 81 mg/d. Laboratory test results are normal except for a hemoglobin A_1c of 8%. She denies pancreatitis and a personal or family history of thyroid cancer.

Which medication is an appropriate next step for this patient?

Pharmacotherapy is an option

Pharmacotherapy is a great option for this patient, who is regaining weight following bariatric surgery. Phentermine/topiramate ER is the only medication that would be contraindicated because of her heart disease. Lorcaserin and naltrexone SR/bupropion SR could be considered, but liraglutide 3 mg is the most appropriate option, given her need for further glucose control.

Furthermore, the recent LEADER (Liraglutide effect and action in diabetes: evaluation of CV outcome results) trial reported a significant mortality benefit with liraglutide 1.8 mg/d among patients with type 2 diabetes and high CV risk.⁴⁷ The study found that liraglutide was superior to placebo in reducing CV events.

Contraindications. Ask patients about a history of pancreatitis before starting liraglutide 3 mg, given the possible increased risk. In addition, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors have been found in rodents given supratherapeutic doses of liraglutide⁴⁸; however, there is no evidence of liraglutide causing C-cell tumors in humans.

For patients taking a medication that can cause hypoglycemia, such as insulin or a sulfonylurea, monitor blood sugar and consider reducing the dose of that medication when starting liraglutide.

Administration and titration. Liraglutide is injected subcutaneously once daily. The dose is titrated up weekly to reduce gastrointestinal symptoms.³⁶ The most common adverse effects reported in phase III trials were nausea, diarrhea, and constipation.^37–39Discontinue liraglutide 3 mg if the patient does not lose at least 4% of baseline body weight after 16 weeks.⁴⁹

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Modest weight loss of 5% to 10% among patients who are overweight or obese can result in a clinically relevant reduction in cardiovascular (CV) disease risk.¹ This amount of weight loss can increase insulin sensitivity in adipose tissue, liver, and muscle, and have a positive impact on blood sugar, blood pressure, triglycerides, and high-density lipoprotein cholesterol.^1,2

All patients who are obese or overweight with increased CV risk should be counseled on diet, exercise, and other behavioral interventions.³ Weight loss secondary to lifestyle modification alone, however, leads to adaptive physiologic responses, which increase appetite and reduce energy expenditure.^4–6

Pharmacotherapy can counteract this metabolic adaptation and lead to sustained weight loss. Antiobesity medication can be considered if a patient has a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.^3,7

Until recently, there were few pharmacologic options approved by the US Food and Drug Administration (FDA) for the management of obesity. The mainstays of treatment were phentermine (Adipex-P, Ionamin, Suprenza) and orlistat (Alli, Xenical). Since 2012, however, 4 agents have been approved as adjuncts to a reduced-calorie diet and increased physical activity for long-term weight management.^8,9 Phentermine/topiramate extended-release (ER) (Qsymia) and lorcaserin (Belviq) were approved in 2012,^10,11 and naltrexone sustained release (SR)/bupropion SR (Contrave) and liraglutide 3 mg (Saxenda) were approved in 2014^12,13 (TABLE^9,14–39). These medications have the potential to not only limit weight gain but also promote weight loss and, thus, improve blood pressure, cholesterol, glucose, and insulin.⁴⁰

Despite the growing obesity epidemic and the availability of several additional medications for chronic weight management, use of antiobesity pharmacotherapy has been limited. Barriers to use include inadequate training of health care professionals, poor insurance coverage for new agents, and low reimbursement for office visits to address weight.⁴¹

In addition, the number of obesity medicine specialists, while increasing, is still not sufficient. Therefore, it is imperative for other health care professionals—including ObGyns—to be aware of the treatment options available to patients who are overweight or obese and to be adept at using them.

In this review, we present 4 cases that depict patients who could benefit from the addition of antiobesity pharmacotherapy to a comprehen‑sive treatment plan that includes diet, physical activity, and behavioral modification.

CASE 1 Young obese woman is unable to lose weight

A 27-year-old woman with obesity (BMI 33 kg/m²),hyperlipidemia, and migraine headaches, pre‑sents for weight management. Despite a calorie-reduced diet and 200 minutes per week of exercise for the past 6 months, she has been unable to lose weight. The only medications she is taking are oral contraceptive pills and sumatriptan, as needed. She suffers from migraines 3 times a month and has no anxiety. Laboratory test results are normal with the exception of an elevated low-density lipoprotein (LDL) level.

Which medication is an appropriate next step for this patient?

Ask 2 important questions

When considering an antiobesity agent for any patient, there are 2 important questions to ask:

• Are there contraindications, drug-drug interactions, or undesirable adverse effects associated with this medication that could be problematic for the patient?
• Can this medication improve other symptoms or conditions the patient has?

In addition, see “Before prescribing antiobesity medication . . .” below.

Phentermine/topiramate ER

Phentermine/topiramate ER is a good first choice for this young patient with class I (BMI 30–34.9 kg/m²) obesity and migraines, as she can likely tolerate a stimulant and her migraines might improve with topiramate. Before starting the medication, ask about insomnia and nephrolithiasis in addition to anxiety and other contraindications (ie, glaucoma, hyperthyroidism, recent monoamine oxidase inhibitor use, or a known hypersensitivity or idiosyncrasy to sympathomimetic amines).²³ The most common adverse events reported in phase III trials were dry mouth, paresthesia, and constipation.^24–26

Not for pregnant women. Women of childbearing age must have a negative pregnancy test before starting phentermine/topiramate ER and every month while taking the medication. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to topiramate during the first trimester of pregnancy.⁴² REMS focuses on the importance of pregnancy prevention, the consistent use of birth control, and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

Flexible dosing. Phentermine/topiramate ER is available in 4 dosages: phentermine 3.75 mg/topiramate 23 mg ER; phentermine 7.5 mg/topiramate 46 mg ER; phentermine 11.25 mg/topiramate 69 mg ER; and phentermine 15 mg/topiramate 92 mg ER. Gradual dose escalation minimizes risks and adverse events.²³

Monitor patients frequently to evaluate for adverse effects and ensure adherence to diet, exercise, and lifestyle modifications. If weight loss is slower or less robust than expected, check for dietary indiscretion, as medications have limited efficacy without appropriate behavioral changes.

Discontinue phentermine/topiramate ER if the patient does not achieve 5% weight loss after 12 weeks on the maximum dose, as it is unlikely that she will achieve and sustain clinically meaningful weight loss with continued treatment.²³ In this case, consider another agent with a different mechanism of action. Any of the other antiobesity medications could be appropriate for this patient.

CASE 2 Overweight woman with comorbidities

A 52-year-old overweight woman (BMI 29 kg/m²)with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma has recently hit a plateau with her weight loss. She lost 45 lb secondary to diet and exercise, but hasn’t been able to lose any more. She also struggles with constant hunger. Her medications include metformin 1,000 mg twice per day, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until she undergoes a left knee replacement. Laboratory values are normal except for a hemoglobin A_1c of 7.2%.

The patient is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

What are good choices for this patient?

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. She has worked hard to lose a significant number of pounds and is now at high risk of regaining them. That’s because her appetite has increased with her new exercise regimen, but her energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of her opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

She could try orlistat, especially if she struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for her diabetes and also may promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOMDM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A_1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A_1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of her initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomics testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

CASE 3 A preoccupation with food

A 38-year-old woman with obesity (BMI 42 kg/m²),obstructive sleep apnea, gastroesophageal reflux disease, and depression is eager to get better control over her weight. Her medications include lansoprazole 30 mg/d and a multivitamin. She reports constantly thinking about food and not being able to control her impulses to buy large quantities of unhealthy snacks. She is so preoccupied by thoughts of food that she has difficulty concentrating at work.

The patient smokes a quarter of a pack of cigarettes daily, but she is ready to quit. She views bariatric surgery as a “last resort” and has no anxiety, pain, or history of seizures. Which medication is appropriate for this patient?

Discuss all options

This patient with class III obesity (BMI ≥40 kg/m²) is eligible for bariatric surgery; however, she is not interested in pursuing it at this time. It is important to discuss all of her options before deciding on a treatment plan. For patients like this, who would benefit from more than modest weight loss, consider a multidisciplinary approach including lifestyle modifications, pharmacotherapy, devices (eg, an intragastric balloon), and/or surgery. You would need to make clear to the patient that she may still be eligible for insurance coverage for surgery if she changes her mind after pursuing other treatments as long as her BMI remains ≥35 kg/m² with obesity-related comorbidities.

Naltrexone SR/bupropion SR is a good choice for this patient because she describes debilitating cravings and addictive behavior surrounding food. Patients taking naltrexone SR/bupropion SR in the Contrave Obesity Research (COR)-I and COR-II phase III trials experienced a reduced frequency of food cravings, reduced difficulty in resisting food cravings, and an increased ability to control eating compared with those assigned to placebo.^32,33

Added benefits. Bupropion also could help this patient quit smoking and improve her mood, as it is FDA-approved for smoking cessation and depression. She denies anxiety and seizures, so bupropion is not contraindicated. Even if a patient denies a history of seizure, ask about any conditions that predispose to seizures, such as anorexia nervosa or bulimia or the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Opioid use. Although the patient denies pain, ask about potential opioid use, as naltrexone is an opioid receptor antagonist. Patients should be informed that opioids may be ineffective if they are required unexpectedly (eg, for trauma) and that naltrexone SR/bupropion SR should be withheld for any planned surgical procedure potentially requiring opioid use.

Other options. While naltrexone SR/bupropion SR is the most appropriate choice for this patient because it addresses her problematic eating behaviors while potentially improving mood and assisting with smoking cessation, phentermine/topiramate ER, lorcaserin, and liraglutide 3 mg also could be used and certainly should be tried if naltrexone SR/bupropion SR does not produce the desired weight loss.

Adverse effects. Titrate naltrexone SR/bupropion SR slowly to the treatment dose to minimize risks and adverse events.³¹ The most common adverse effects reported in phase III trials were nausea, constipation, and headache.^34,35,45,46 Discontinue naltrexone SR/bupropion SR if the patient does not achieve 5% weight loss at 16 weeks (after 12 weeks at the maintenance dose).³¹

CASE 4 Regaining weight after gastric bypass

A 65-year-old woman with obesity (BMI 39 kg/m²)who underwent Roux-en-Y gastric bypass surgery and who has type 2 diabetes, congestive heart failure, coronary artery disease, hypertension, and hyperlipidemia, remains concerned about her weight. She lost 100 lb following surgery and maintained her weight for 3 years, but then regained 30 lb. She comes in for an office visit because she is concerned about her increasing blood sugar and wants to prevent further weight gain. Her medications include metformin 1,000 mg twice per day, lisinopril 5 mg/d, carvedilol 12.5 mg twice per day, simvastatin 20 mg/d, and aspirin 81 mg/d. Laboratory test results are normal except for a hemoglobin A_1c of 8%. She denies pancreatitis and a personal or family history of thyroid cancer.

Which medication is an appropriate next step for this patient?

Pharmacotherapy is an option

Pharmacotherapy is a great option for this patient, who is regaining weight following bariatric surgery. Phentermine/topiramate ER is the only medication that would be contraindicated because of her heart disease. Lorcaserin and naltrexone SR/bupropion SR could be considered, but liraglutide 3 mg is the most appropriate option, given her need for further glucose control.

Furthermore, the recent LEADER (Liraglutide effect and action in diabetes: evaluation of CV outcome results) trial reported a significant mortality benefit with liraglutide 1.8 mg/d among patients with type 2 diabetes and high CV risk.⁴⁷ The study found that liraglutide was superior to placebo in reducing CV events.

Contraindications. Ask patients about a history of pancreatitis before starting liraglutide 3 mg, given the possible increased risk. In addition, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors have been found in rodents given supratherapeutic doses of liraglutide⁴⁸; however, there is no evidence of liraglutide causing C-cell tumors in humans.

For patients taking a medication that can cause hypoglycemia, such as insulin or a sulfonylurea, monitor blood sugar and consider reducing the dose of that medication when starting liraglutide.

Administration and titration. Liraglutide is injected subcutaneously once daily. The dose is titrated up weekly to reduce gastrointestinal symptoms.³⁶ The most common adverse effects reported in phase III trials were nausea, diarrhea, and constipation.^37–39Discontinue liraglutide 3 mg if the patient does not lose at least 4% of baseline body weight after 16 weeks.⁴⁹

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Modest weight loss of 5% to 10% among patients who are overweight or obese can result in a clinically relevant reduction in cardiovascular (CV) disease risk.¹ This amount of weight loss can increase insulin sensitivity in adipose tissue, liver, and muscle, and have a positive impact on blood sugar, blood pressure, triglycerides, and high-density lipoprotein cholesterol.^1,2

All patients who are obese or overweight with increased CV risk should be counseled on diet, exercise, and other behavioral interventions.³ Weight loss secondary to lifestyle modification alone, however, leads to adaptive physiologic responses, which increase appetite and reduce energy expenditure.^4–6

Pharmacotherapy can counteract this metabolic adaptation and lead to sustained weight loss. Antiobesity medication can be considered if a patient has a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.^3,7

Until recently, there were few pharmacologic options approved by the US Food and Drug Administration (FDA) for the management of obesity. The mainstays of treatment were phentermine (Adipex-P, Ionamin, Suprenza) and orlistat (Alli, Xenical). Since 2012, however, 4 agents have been approved as adjuncts to a reduced-calorie diet and increased physical activity for long-term weight management.^8,9 Phentermine/topiramate extended-release (ER) (Qsymia) and lorcaserin (Belviq) were approved in 2012,^10,11 and naltrexone sustained release (SR)/bupropion SR (Contrave) and liraglutide 3 mg (Saxenda) were approved in 2014^12,13 (TABLE^9,14–39). These medications have the potential to not only limit weight gain but also promote weight loss and, thus, improve blood pressure, cholesterol, glucose, and insulin.⁴⁰

Despite the growing obesity epidemic and the availability of several additional medications for chronic weight management, use of antiobesity pharmacotherapy has been limited. Barriers to use include inadequate training of health care professionals, poor insurance coverage for new agents, and low reimbursement for office visits to address weight.⁴¹

In addition, the number of obesity medicine specialists, while increasing, is still not sufficient. Therefore, it is imperative for other health care professionals—including ObGyns—to be aware of the treatment options available to patients who are overweight or obese and to be adept at using them.

In this review, we present 4 cases that depict patients who could benefit from the addition of antiobesity pharmacotherapy to a comprehen‑sive treatment plan that includes diet, physical activity, and behavioral modification.

CASE 1 Young obese woman is unable to lose weight

A 27-year-old woman with obesity (BMI 33 kg/m²),hyperlipidemia, and migraine headaches, pre‑sents for weight management. Despite a calorie-reduced diet and 200 minutes per week of exercise for the past 6 months, she has been unable to lose weight. The only medications she is taking are oral contraceptive pills and sumatriptan, as needed. She suffers from migraines 3 times a month and has no anxiety. Laboratory test results are normal with the exception of an elevated low-density lipoprotein (LDL) level.

Which medication is an appropriate next step for this patient?

Ask 2 important questions

When considering an antiobesity agent for any patient, there are 2 important questions to ask:

• Are there contraindications, drug-drug interactions, or undesirable adverse effects associated with this medication that could be problematic for the patient?
• Can this medication improve other symptoms or conditions the patient has?

In addition, see “Before prescribing antiobesity medication . . .” below.

Phentermine/topiramate ER

Phentermine/topiramate ER is a good first choice for this young patient with class I (BMI 30–34.9 kg/m²) obesity and migraines, as she can likely tolerate a stimulant and her migraines might improve with topiramate. Before starting the medication, ask about insomnia and nephrolithiasis in addition to anxiety and other contraindications (ie, glaucoma, hyperthyroidism, recent monoamine oxidase inhibitor use, or a known hypersensitivity or idiosyncrasy to sympathomimetic amines).²³ The most common adverse events reported in phase III trials were dry mouth, paresthesia, and constipation.^24–26

Not for pregnant women. Women of childbearing age must have a negative pregnancy test before starting phentermine/topiramate ER and every month while taking the medication. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to topiramate during the first trimester of pregnancy.⁴² REMS focuses on the importance of pregnancy prevention, the consistent use of birth control, and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

Flexible dosing. Phentermine/topiramate ER is available in 4 dosages: phentermine 3.75 mg/topiramate 23 mg ER; phentermine 7.5 mg/topiramate 46 mg ER; phentermine 11.25 mg/topiramate 69 mg ER; and phentermine 15 mg/topiramate 92 mg ER. Gradual dose escalation minimizes risks and adverse events.²³

Monitor patients frequently to evaluate for adverse effects and ensure adherence to diet, exercise, and lifestyle modifications. If weight loss is slower or less robust than expected, check for dietary indiscretion, as medications have limited efficacy without appropriate behavioral changes.

Discontinue phentermine/topiramate ER if the patient does not achieve 5% weight loss after 12 weeks on the maximum dose, as it is unlikely that she will achieve and sustain clinically meaningful weight loss with continued treatment.²³ In this case, consider another agent with a different mechanism of action. Any of the other antiobesity medications could be appropriate for this patient.

CASE 2 Overweight woman with comorbidities

A 52-year-old overweight woman (BMI 29 kg/m²)with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma has recently hit a plateau with her weight loss. She lost 45 lb secondary to diet and exercise, but hasn’t been able to lose any more. She also struggles with constant hunger. Her medications include metformin 1,000 mg twice per day, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until she undergoes a left knee replacement. Laboratory values are normal except for a hemoglobin A_1c of 7.2%.

The patient is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

What are good choices for this patient?

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. She has worked hard to lose a significant number of pounds and is now at high risk of regaining them. That’s because her appetite has increased with her new exercise regimen, but her energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of her opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

She could try orlistat, especially if she struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for her diabetes and also may promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOMDM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A_1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A_1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of her initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomics testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

CASE 3 A preoccupation with food

A 38-year-old woman with obesity (BMI 42 kg/m²),obstructive sleep apnea, gastroesophageal reflux disease, and depression is eager to get better control over her weight. Her medications include lansoprazole 30 mg/d and a multivitamin. She reports constantly thinking about food and not being able to control her impulses to buy large quantities of unhealthy snacks. She is so preoccupied by thoughts of food that she has difficulty concentrating at work.

The patient smokes a quarter of a pack of cigarettes daily, but she is ready to quit. She views bariatric surgery as a “last resort” and has no anxiety, pain, or history of seizures. Which medication is appropriate for this patient?

Discuss all options

This patient with class III obesity (BMI ≥40 kg/m²) is eligible for bariatric surgery; however, she is not interested in pursuing it at this time. It is important to discuss all of her options before deciding on a treatment plan. For patients like this, who would benefit from more than modest weight loss, consider a multidisciplinary approach including lifestyle modifications, pharmacotherapy, devices (eg, an intragastric balloon), and/or surgery. You would need to make clear to the patient that she may still be eligible for insurance coverage for surgery if she changes her mind after pursuing other treatments as long as her BMI remains ≥35 kg/m² with obesity-related comorbidities.

Naltrexone SR/bupropion SR is a good choice for this patient because she describes debilitating cravings and addictive behavior surrounding food. Patients taking naltrexone SR/bupropion SR in the Contrave Obesity Research (COR)-I and COR-II phase III trials experienced a reduced frequency of food cravings, reduced difficulty in resisting food cravings, and an increased ability to control eating compared with those assigned to placebo.^32,33

Added benefits. Bupropion also could help this patient quit smoking and improve her mood, as it is FDA-approved for smoking cessation and depression. She denies anxiety and seizures, so bupropion is not contraindicated. Even if a patient denies a history of seizure, ask about any conditions that predispose to seizures, such as anorexia nervosa or bulimia or the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Opioid use. Although the patient denies pain, ask about potential opioid use, as naltrexone is an opioid receptor antagonist. Patients should be informed that opioids may be ineffective if they are required unexpectedly (eg, for trauma) and that naltrexone SR/bupropion SR should be withheld for any planned surgical procedure potentially requiring opioid use.

Other options. While naltrexone SR/bupropion SR is the most appropriate choice for this patient because it addresses her problematic eating behaviors while potentially improving mood and assisting with smoking cessation, phentermine/topiramate ER, lorcaserin, and liraglutide 3 mg also could be used and certainly should be tried if naltrexone SR/bupropion SR does not produce the desired weight loss.

Adverse effects. Titrate naltrexone SR/bupropion SR slowly to the treatment dose to minimize risks and adverse events.³¹ The most common adverse effects reported in phase III trials were nausea, constipation, and headache.^34,35,45,46 Discontinue naltrexone SR/bupropion SR if the patient does not achieve 5% weight loss at 16 weeks (after 12 weeks at the maintenance dose).³¹

CASE 4 Regaining weight after gastric bypass

A 65-year-old woman with obesity (BMI 39 kg/m²)who underwent Roux-en-Y gastric bypass surgery and who has type 2 diabetes, congestive heart failure, coronary artery disease, hypertension, and hyperlipidemia, remains concerned about her weight. She lost 100 lb following surgery and maintained her weight for 3 years, but then regained 30 lb. She comes in for an office visit because she is concerned about her increasing blood sugar and wants to prevent further weight gain. Her medications include metformin 1,000 mg twice per day, lisinopril 5 mg/d, carvedilol 12.5 mg twice per day, simvastatin 20 mg/d, and aspirin 81 mg/d. Laboratory test results are normal except for a hemoglobin A_1c of 8%. She denies pancreatitis and a personal or family history of thyroid cancer.

Which medication is an appropriate next step for this patient?

Pharmacotherapy is an option

Pharmacotherapy is a great option for this patient, who is regaining weight following bariatric surgery. Phentermine/topiramate ER is the only medication that would be contraindicated because of her heart disease. Lorcaserin and naltrexone SR/bupropion SR could be considered, but liraglutide 3 mg is the most appropriate option, given her need for further glucose control.

Furthermore, the recent LEADER (Liraglutide effect and action in diabetes: evaluation of CV outcome results) trial reported a significant mortality benefit with liraglutide 1.8 mg/d among patients with type 2 diabetes and high CV risk.⁴⁷ The study found that liraglutide was superior to placebo in reducing CV events.

Contraindications. Ask patients about a history of pancreatitis before starting liraglutide 3 mg, given the possible increased risk. In addition, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors have been found in rodents given supratherapeutic doses of liraglutide⁴⁸; however, there is no evidence of liraglutide causing C-cell tumors in humans.

For patients taking a medication that can cause hypoglycemia, such as insulin or a sulfonylurea, monitor blood sugar and consider reducing the dose of that medication when starting liraglutide.

Administration and titration. Liraglutide is injected subcutaneously once daily. The dose is titrated up weekly to reduce gastrointestinal symptoms.³⁶ The most common adverse effects reported in phase III trials were nausea, diarrhea, and constipation.^37–39Discontinue liraglutide 3 mg if the patient does not lose at least 4% of baseline body weight after 16 weeks.⁴⁹

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Medications can have an unpredictable and variable effect on weight. Some drugs trigger weight gain in one patient while inducing weight loss in another. Others may lead to weight loss initially but cause weight gain when taken long term.¹ Often, a drug’s effect on a patient’s weight depends on his or her medical history and lifestyle, including factors like insulin resistance, diet, and exercise level.

To make matters worse, clinical studies of drug-related effects on weight can be misleading. Because researchers often report a mean weight change—an average of those who had little or no change in weight when taking the drug and individuals who may have gained a significant amount of weight—a drug’s potential to cause weight gain may be underestimated. Few studies include an analysis of the range—eg, how many participants gained or lost various percentages of body weight. What’s more, pharmacology studies typically follow participants for a few months to a few years, whereas weight changes can be cumulative when a medication is taken for many years.

The nation’s continually growing obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain. Until recently, the medical literature offered little guidance.

In 2015, the Endocrine Society published clinical practice guidelines for pharmacologic management of obesity, including data on medications that cause weight gain and suggesting alternatives that are weight-neutral or promote weight loss.²

In the pages that follow, we present case studies, tables, and a review of the latest evidence to highlight optimal drug treatment for patients who are overweight or obese, and are also being treated for diabetes, hypertension, and depression. You’ll find a brief discussion of weight management strategies related to other drugs and conditions in the sidebar.^2-5

CASE 1 › 40-year-old man with diabetes and hyperlipidemia

Brian P, who has come in for an annual checkup, has a body mass index (BMI) of 30 kg/m². He also has hyperlipidemia and type 2 diabetes, for which he has been taking metformin for several years. A year ago, his hemoglobin A1c (HbA1c) was 7.3%, so his physician added glyburide to his regimen.

In the year since, Mr. P has gained 12 lbs (5.4 kg) but achieved only a minimal reduction in HbA1c (to 6.8%). He expresses concern about the cardiovascular effects of the extra weight and says that diet and exercise have not helped him control his weight.

CASE 2 › Older woman with hypertension and hypothyroidism

Addie K, age 64, is obese (BMI, 37 kg/m²) and has hypertension and hypothyroidism, for which she takes metoprolol and levothyroxine. Ms. K says that she is careful about what she eats and exercises several times a week, but still has seen her weight increase steadily for the past several years.

The nation's obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain.

CASE 3 › Young man with depression

Charlie D, a 21-year-old college student, is a new patient. He has depression and is obese (BMI, 34 kg/m²). The patient says he was diagnosed with depression by his former primary care physician, who prescribed paroxetine a year ago. He requests a refill of the paroxetine, which he reports has successfully boosted his mood. When asked about his weight, he admits that he has gained 8 lbs (3.6 kg) since he began taking the drug.

If these were your patients, what weight management steps would you take? Before we provide some recommendations, let’s review the evidence.

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶ (TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²

The 2016 Comprehensive Type 2 Diabetes Management Algorithm published by the American Association of Clinical Endocrinologists and American College of Endocrinology recommends that the initiation of diabetes therapies be based on the risks of weight gain and hypoglycemia, among other factors. The algorithm calls for metformin as first-line therapy, followed by a GLP-1 agonist as a second-line therapy, and an SGLT2 inhibitor as a third-line therapy.⁶

Finally, FDA-approved anti-obesity medications may be appropriate for patients with diabetes who are unable to lose weight with lifestyle interventions alone.²² Each medication is associated with improvements in glucose in addition to other metabolic parameters.

CASE 1 › A better choice for Mr. P

Because Mr. P has gained weight—and, indeed, developed obesity—since he started taking glyburide, it is clear that a sulfonylurea is not the best choice for this patient. An antidiabetic agent that is weight-neutral or that promotes weight loss, such as an SGLT2 inhibitor or a GLP-1 agonist, would be more suitable. The drug should be prescribed in conjunction with his metformin, which has a favorable weight profile and helps reduce HbA1c, as both SGLT2 inhibitors and GLP-1 agonists also do.

If Mr. P were to switch to an SGLT2 inhibitor, a combination pill containing metformin would be an effective way to limit the patient’s pill burden.

Treating hypertension without weight gain

Thiazide diuretics are often recommended as first-line agents for the treatment of hypertension, but their dose-related adverse effects, including dyslipidemia and insulin resistance, are undesirable for patients who are overweight or obese and at risk for metabolic syndrome and type 2 diabetes.²³ Beta-adrenergic blockers have been shown to promote weight gain and prevent weight loss, especially in patients who have both hypertension and diabetes.²⁴ In addition to having potential adverse metabolic effects on lipids and/or insulin sensitivity, beta-blockers can decrease metabolic rate by 10% and they may have other negative effects on energy metabolism, as well.²⁵

When a patient who is obese has a condition for which a beta-blocker is a necessity, a selective agent with a vasodilating component is recommended.

In a meta-analysis of 8 RCTs that lasted ≥6 months, changes in body weight were higher in participants on beta-blockers, with a median difference of 1.2 kg (−0.4 to 3.5 kg) between those on beta-blockers and the control group.²⁶ The evidence suggests that beta-blockers should not necessarily be first-line treatment for hypertension in patients who are overweight or obese and that obesity management in patients with hypertension may be harder if they are being treated with a beta-blocker.

There are exceptions, however. When beta-blockers are required—for patients with coronary artery disease, heart failure, or an arrhythmia, for example—a selective agent with a vasodilating component, such as carvedilol or nebivolol, is recommended.² These drugs appear to have less potential for weight gain and to have minimal effect on lipid and glucose metabolism.^26,27

In a study of 1106 patients with hypertension, those taking metoprolol had a statistically significant mean weight gain of 1.19 kg (P<.001) compared with patients taking carvedilol (mean weight gain, 0.17 kg; P=.36).²⁴ While 4.5% of those in the metoprolol group gained ≥7% of their body weight, that was true of only 1.1% of those taking carvedilol. Thus, weight gain can sometimes be minimized by choosing a different medication within the same drug class.

ACE inhibitors, ARBs, and calcium channel blockers

Antihypertensive medications that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) (TABLE 2).³ Angiotensin contributes to obesity-related hypertension, as it is overexpressed in obesity, making ACE inhibitors and ARBs desirable options for the treatment of patients who are obese. And, because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.

CASE 2 › Switching antihypertensives

Switching Ms. K from metoprolol, a beta-blocker, to an ACE inhibitor, ARB, or CCB may help prevent further weight gain, and possibly even lead to weight loss. Any drug in any of these 3 classes of medications would be a reasonable choice. However, if the patient had a condition that warranted use of a beta-blocker, a selective agent with a vasodilating component such as carvedilol or nebivolol might be helpful.

Choosing an antidepressant when weight is an issue

For patients with psychiatric conditions, weight gain is often multifactorial. One key issue: Weight gain is a common adverse effect of many antidepressants (TABLE 3).³ Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.²

In a meta-analysis of 116 studies, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline were associated with weight loss in short-term use (4-12 weeks) and weight neutrality when used for >4 months.¹ Patients who had type 2 diabetes as well as depression had an average weight loss from fluoxetine of 5.1 kg (3.3–6.9 kg) at 24- to 26-week follow up.²⁸

Because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.Among SSRI and tricyclic (TCA) antidepressants, paroxetine and amitriptyline, respectively, had the greatest risk for weight gain.^1,29 No significant weight effect was observed for either citalopram or escitalopram. Keep in mind, however, that the effect of each antidepressant on weight may vary greatly from one patient to another.¹ For example, while Mr. D gained 3.6 kg on paroxetine, some patients gain no weight at all.

In the systematic review and meta-analysis of 257 RCTs, weight gain was associated with the use of amitriptyline (1.8 kg) and mirtazapine (1.5 kg), while weight loss was associated with bupropion and fluoxetine (-1.3 kg for each).⁸

Bupropion, a norepinephrine and dopamine reuptake inhibitor, is the only antidepressant that has been consistently shown to cause weight loss.^30,31 Clinical trials have found that it decreases body weight by suppressing appetite and reducing food cravings.³⁰ Bupropion is approved for the treatment of depression and as a smoking cessation aide. And, in 2014, a bupropion-naltrexone combination received FDA approval for chronic weight management, sold under the brand name Contrave.³²

Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.

As different classes of antidepressants are often prescribed for different types of depression, it is important to be aware that the few that are weight-neutral and weight-loss-promoting are not appropriate for all patients with depression. For example, bupropion is an activating agent and can exacerbate anxiety. Thus, a patient with concomitant depression and anxiety might be a better candidate for another antidepressant, which could lead to some weight gain but would better manage the individual’s symptoms. In such cases, the rule of thumb should be to prescribe the lowest dose required for clinical efficacy for the shortest duration necessary.

CASE 3 › Change antidepressants— and keep a close watch

Depending on the nature of Mr. D’s depression, bupropion, fluoxetine, or sertraline might be a reasonable alternative to paroxetine to prevent or reduce further drug-induced weight gain.

Frequent follow-up visits should be scheduled until the transition has been completed and his condition stabilized. If Mr. D’s new antidepressant is bupropion, monitoring him for signs of anxiety would be required.

CORRESPONDENCE
Katherine H. Saunders, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

Medications can have an unpredictable and variable effect on weight. Some drugs trigger weight gain in one patient while inducing weight loss in another. Others may lead to weight loss initially but cause weight gain when taken long term.¹ Often, a drug’s effect on a patient’s weight depends on his or her medical history and lifestyle, including factors like insulin resistance, diet, and exercise level.

To make matters worse, clinical studies of drug-related effects on weight can be misleading. Because researchers often report a mean weight change—an average of those who had little or no change in weight when taking the drug and individuals who may have gained a significant amount of weight—a drug’s potential to cause weight gain may be underestimated. Few studies include an analysis of the range—eg, how many participants gained or lost various percentages of body weight. What’s more, pharmacology studies typically follow participants for a few months to a few years, whereas weight changes can be cumulative when a medication is taken for many years.

The nation’s continually growing obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain. Until recently, the medical literature offered little guidance.

In 2015, the Endocrine Society published clinical practice guidelines for pharmacologic management of obesity, including data on medications that cause weight gain and suggesting alternatives that are weight-neutral or promote weight loss.²

In the pages that follow, we present case studies, tables, and a review of the latest evidence to highlight optimal drug treatment for patients who are overweight or obese, and are also being treated for diabetes, hypertension, and depression. You’ll find a brief discussion of weight management strategies related to other drugs and conditions in the sidebar.^2-5

CASE 1 › 40-year-old man with diabetes and hyperlipidemia

Brian P, who has come in for an annual checkup, has a body mass index (BMI) of 30 kg/m². He also has hyperlipidemia and type 2 diabetes, for which he has been taking metformin for several years. A year ago, his hemoglobin A1c (HbA1c) was 7.3%, so his physician added glyburide to his regimen.

In the year since, Mr. P has gained 12 lbs (5.4 kg) but achieved only a minimal reduction in HbA1c (to 6.8%). He expresses concern about the cardiovascular effects of the extra weight and says that diet and exercise have not helped him control his weight.

CASE 2 › Older woman with hypertension and hypothyroidism

Addie K, age 64, is obese (BMI, 37 kg/m²) and has hypertension and hypothyroidism, for which she takes metoprolol and levothyroxine. Ms. K says that she is careful about what she eats and exercises several times a week, but still has seen her weight increase steadily for the past several years.

The nation's obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain.

CASE 3 › Young man with depression

Charlie D, a 21-year-old college student, is a new patient. He has depression and is obese (BMI, 34 kg/m²). The patient says he was diagnosed with depression by his former primary care physician, who prescribed paroxetine a year ago. He requests a refill of the paroxetine, which he reports has successfully boosted his mood. When asked about his weight, he admits that he has gained 8 lbs (3.6 kg) since he began taking the drug.

If these were your patients, what weight management steps would you take? Before we provide some recommendations, let’s review the evidence.

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶ (TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²

The 2016 Comprehensive Type 2 Diabetes Management Algorithm published by the American Association of Clinical Endocrinologists and American College of Endocrinology recommends that the initiation of diabetes therapies be based on the risks of weight gain and hypoglycemia, among other factors. The algorithm calls for metformin as first-line therapy, followed by a GLP-1 agonist as a second-line therapy, and an SGLT2 inhibitor as a third-line therapy.⁶

Finally, FDA-approved anti-obesity medications may be appropriate for patients with diabetes who are unable to lose weight with lifestyle interventions alone.²² Each medication is associated with improvements in glucose in addition to other metabolic parameters.

CASE 1 › A better choice for Mr. P

Because Mr. P has gained weight—and, indeed, developed obesity—since he started taking glyburide, it is clear that a sulfonylurea is not the best choice for this patient. An antidiabetic agent that is weight-neutral or that promotes weight loss, such as an SGLT2 inhibitor or a GLP-1 agonist, would be more suitable. The drug should be prescribed in conjunction with his metformin, which has a favorable weight profile and helps reduce HbA1c, as both SGLT2 inhibitors and GLP-1 agonists also do.

If Mr. P were to switch to an SGLT2 inhibitor, a combination pill containing metformin would be an effective way to limit the patient’s pill burden.

Treating hypertension without weight gain

Thiazide diuretics are often recommended as first-line agents for the treatment of hypertension, but their dose-related adverse effects, including dyslipidemia and insulin resistance, are undesirable for patients who are overweight or obese and at risk for metabolic syndrome and type 2 diabetes.²³ Beta-adrenergic blockers have been shown to promote weight gain and prevent weight loss, especially in patients who have both hypertension and diabetes.²⁴ In addition to having potential adverse metabolic effects on lipids and/or insulin sensitivity, beta-blockers can decrease metabolic rate by 10% and they may have other negative effects on energy metabolism, as well.²⁵

When a patient who is obese has a condition for which a beta-blocker is a necessity, a selective agent with a vasodilating component is recommended.

In a meta-analysis of 8 RCTs that lasted ≥6 months, changes in body weight were higher in participants on beta-blockers, with a median difference of 1.2 kg (−0.4 to 3.5 kg) between those on beta-blockers and the control group.²⁶ The evidence suggests that beta-blockers should not necessarily be first-line treatment for hypertension in patients who are overweight or obese and that obesity management in patients with hypertension may be harder if they are being treated with a beta-blocker.

There are exceptions, however. When beta-blockers are required—for patients with coronary artery disease, heart failure, or an arrhythmia, for example—a selective agent with a vasodilating component, such as carvedilol or nebivolol, is recommended.² These drugs appear to have less potential for weight gain and to have minimal effect on lipid and glucose metabolism.^26,27

In a study of 1106 patients with hypertension, those taking metoprolol had a statistically significant mean weight gain of 1.19 kg (P<.001) compared with patients taking carvedilol (mean weight gain, 0.17 kg; P=.36).²⁴ While 4.5% of those in the metoprolol group gained ≥7% of their body weight, that was true of only 1.1% of those taking carvedilol. Thus, weight gain can sometimes be minimized by choosing a different medication within the same drug class.

ACE inhibitors, ARBs, and calcium channel blockers

Antihypertensive medications that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) (TABLE 2).³ Angiotensin contributes to obesity-related hypertension, as it is overexpressed in obesity, making ACE inhibitors and ARBs desirable options for the treatment of patients who are obese. And, because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.

CASE 2 › Switching antihypertensives

Switching Ms. K from metoprolol, a beta-blocker, to an ACE inhibitor, ARB, or CCB may help prevent further weight gain, and possibly even lead to weight loss. Any drug in any of these 3 classes of medications would be a reasonable choice. However, if the patient had a condition that warranted use of a beta-blocker, a selective agent with a vasodilating component such as carvedilol or nebivolol might be helpful.

Choosing an antidepressant when weight is an issue

For patients with psychiatric conditions, weight gain is often multifactorial. One key issue: Weight gain is a common adverse effect of many antidepressants (TABLE 3).³ Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.²

In a meta-analysis of 116 studies, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline were associated with weight loss in short-term use (4-12 weeks) and weight neutrality when used for >4 months.¹ Patients who had type 2 diabetes as well as depression had an average weight loss from fluoxetine of 5.1 kg (3.3–6.9 kg) at 24- to 26-week follow up.²⁸

Because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.Among SSRI and tricyclic (TCA) antidepressants, paroxetine and amitriptyline, respectively, had the greatest risk for weight gain.^1,29 No significant weight effect was observed for either citalopram or escitalopram. Keep in mind, however, that the effect of each antidepressant on weight may vary greatly from one patient to another.¹ For example, while Mr. D gained 3.6 kg on paroxetine, some patients gain no weight at all.

In the systematic review and meta-analysis of 257 RCTs, weight gain was associated with the use of amitriptyline (1.8 kg) and mirtazapine (1.5 kg), while weight loss was associated with bupropion and fluoxetine (-1.3 kg for each).⁸

Bupropion, a norepinephrine and dopamine reuptake inhibitor, is the only antidepressant that has been consistently shown to cause weight loss.^30,31 Clinical trials have found that it decreases body weight by suppressing appetite and reducing food cravings.³⁰ Bupropion is approved for the treatment of depression and as a smoking cessation aide. And, in 2014, a bupropion-naltrexone combination received FDA approval for chronic weight management, sold under the brand name Contrave.³²

Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.

As different classes of antidepressants are often prescribed for different types of depression, it is important to be aware that the few that are weight-neutral and weight-loss-promoting are not appropriate for all patients with depression. For example, bupropion is an activating agent and can exacerbate anxiety. Thus, a patient with concomitant depression and anxiety might be a better candidate for another antidepressant, which could lead to some weight gain but would better manage the individual’s symptoms. In such cases, the rule of thumb should be to prescribe the lowest dose required for clinical efficacy for the shortest duration necessary.

CASE 3 › Change antidepressants— and keep a close watch

Depending on the nature of Mr. D’s depression, bupropion, fluoxetine, or sertraline might be a reasonable alternative to paroxetine to prevent or reduce further drug-induced weight gain.

Frequent follow-up visits should be scheduled until the transition has been completed and his condition stabilized. If Mr. D’s new antidepressant is bupropion, monitoring him for signs of anxiety would be required.

CORRESPONDENCE
Katherine H. Saunders, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

Medications can have an unpredictable and variable effect on weight. Some drugs trigger weight gain in one patient while inducing weight loss in another. Others may lead to weight loss initially but cause weight gain when taken long term.¹ Often, a drug’s effect on a patient’s weight depends on his or her medical history and lifestyle, including factors like insulin resistance, diet, and exercise level.

To make matters worse, clinical studies of drug-related effects on weight can be misleading. Because researchers often report a mean weight change—an average of those who had little or no change in weight when taking the drug and individuals who may have gained a significant amount of weight—a drug’s potential to cause weight gain may be underestimated. Few studies include an analysis of the range—eg, how many participants gained or lost various percentages of body weight. What’s more, pharmacology studies typically follow participants for a few months to a few years, whereas weight changes can be cumulative when a medication is taken for many years.

The nation’s continually growing obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain. Until recently, the medical literature offered little guidance.

In 2015, the Endocrine Society published clinical practice guidelines for pharmacologic management of obesity, including data on medications that cause weight gain and suggesting alternatives that are weight-neutral or promote weight loss.²

In the pages that follow, we present case studies, tables, and a review of the latest evidence to highlight optimal drug treatment for patients who are overweight or obese, and are also being treated for diabetes, hypertension, and depression. You’ll find a brief discussion of weight management strategies related to other drugs and conditions in the sidebar.^2-5

CASE 1 › 40-year-old man with diabetes and hyperlipidemia

Brian P, who has come in for an annual checkup, has a body mass index (BMI) of 30 kg/m². He also has hyperlipidemia and type 2 diabetes, for which he has been taking metformin for several years. A year ago, his hemoglobin A1c (HbA1c) was 7.3%, so his physician added glyburide to his regimen.

In the year since, Mr. P has gained 12 lbs (5.4 kg) but achieved only a minimal reduction in HbA1c (to 6.8%). He expresses concern about the cardiovascular effects of the extra weight and says that diet and exercise have not helped him control his weight.

CASE 2 › Older woman with hypertension and hypothyroidism

Addie K, age 64, is obese (BMI, 37 kg/m²) and has hypertension and hypothyroidism, for which she takes metoprolol and levothyroxine. Ms. K says that she is careful about what she eats and exercises several times a week, but still has seen her weight increase steadily for the past several years.

The nation's obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain.

CASE 3 › Young man with depression

Charlie D, a 21-year-old college student, is a new patient. He has depression and is obese (BMI, 34 kg/m²). The patient says he was diagnosed with depression by his former primary care physician, who prescribed paroxetine a year ago. He requests a refill of the paroxetine, which he reports has successfully boosted his mood. When asked about his weight, he admits that he has gained 8 lbs (3.6 kg) since he began taking the drug.

If these were your patients, what weight management steps would you take? Before we provide some recommendations, let’s review the evidence.

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶ (TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²

The 2016 Comprehensive Type 2 Diabetes Management Algorithm published by the American Association of Clinical Endocrinologists and American College of Endocrinology recommends that the initiation of diabetes therapies be based on the risks of weight gain and hypoglycemia, among other factors. The algorithm calls for metformin as first-line therapy, followed by a GLP-1 agonist as a second-line therapy, and an SGLT2 inhibitor as a third-line therapy.⁶

Finally, FDA-approved anti-obesity medications may be appropriate for patients with diabetes who are unable to lose weight with lifestyle interventions alone.²² Each medication is associated with improvements in glucose in addition to other metabolic parameters.

CASE 1 › A better choice for Mr. P

Because Mr. P has gained weight—and, indeed, developed obesity—since he started taking glyburide, it is clear that a sulfonylurea is not the best choice for this patient. An antidiabetic agent that is weight-neutral or that promotes weight loss, such as an SGLT2 inhibitor or a GLP-1 agonist, would be more suitable. The drug should be prescribed in conjunction with his metformin, which has a favorable weight profile and helps reduce HbA1c, as both SGLT2 inhibitors and GLP-1 agonists also do.

If Mr. P were to switch to an SGLT2 inhibitor, a combination pill containing metformin would be an effective way to limit the patient’s pill burden.

Treating hypertension without weight gain

Thiazide diuretics are often recommended as first-line agents for the treatment of hypertension, but their dose-related adverse effects, including dyslipidemia and insulin resistance, are undesirable for patients who are overweight or obese and at risk for metabolic syndrome and type 2 diabetes.²³ Beta-adrenergic blockers have been shown to promote weight gain and prevent weight loss, especially in patients who have both hypertension and diabetes.²⁴ In addition to having potential adverse metabolic effects on lipids and/or insulin sensitivity, beta-blockers can decrease metabolic rate by 10% and they may have other negative effects on energy metabolism, as well.²⁵

When a patient who is obese has a condition for which a beta-blocker is a necessity, a selective agent with a vasodilating component is recommended.

In a meta-analysis of 8 RCTs that lasted ≥6 months, changes in body weight were higher in participants on beta-blockers, with a median difference of 1.2 kg (−0.4 to 3.5 kg) between those on beta-blockers and the control group.²⁶ The evidence suggests that beta-blockers should not necessarily be first-line treatment for hypertension in patients who are overweight or obese and that obesity management in patients with hypertension may be harder if they are being treated with a beta-blocker.

There are exceptions, however. When beta-blockers are required—for patients with coronary artery disease, heart failure, or an arrhythmia, for example—a selective agent with a vasodilating component, such as carvedilol or nebivolol, is recommended.² These drugs appear to have less potential for weight gain and to have minimal effect on lipid and glucose metabolism.^26,27

In a study of 1106 patients with hypertension, those taking metoprolol had a statistically significant mean weight gain of 1.19 kg (P<.001) compared with patients taking carvedilol (mean weight gain, 0.17 kg; P=.36).²⁴ While 4.5% of those in the metoprolol group gained ≥7% of their body weight, that was true of only 1.1% of those taking carvedilol. Thus, weight gain can sometimes be minimized by choosing a different medication within the same drug class.

ACE inhibitors, ARBs, and calcium channel blockers

Antihypertensive medications that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) (TABLE 2).³ Angiotensin contributes to obesity-related hypertension, as it is overexpressed in obesity, making ACE inhibitors and ARBs desirable options for the treatment of patients who are obese. And, because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.

CASE 2 › Switching antihypertensives

Switching Ms. K from metoprolol, a beta-blocker, to an ACE inhibitor, ARB, or CCB may help prevent further weight gain, and possibly even lead to weight loss. Any drug in any of these 3 classes of medications would be a reasonable choice. However, if the patient had a condition that warranted use of a beta-blocker, a selective agent with a vasodilating component such as carvedilol or nebivolol might be helpful.

Choosing an antidepressant when weight is an issue

For patients with psychiatric conditions, weight gain is often multifactorial. One key issue: Weight gain is a common adverse effect of many antidepressants (TABLE 3).³ Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.²

In a meta-analysis of 116 studies, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline were associated with weight loss in short-term use (4-12 weeks) and weight neutrality when used for >4 months.¹ Patients who had type 2 diabetes as well as depression had an average weight loss from fluoxetine of 5.1 kg (3.3–6.9 kg) at 24- to 26-week follow up.²⁸

Because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.Among SSRI and tricyclic (TCA) antidepressants, paroxetine and amitriptyline, respectively, had the greatest risk for weight gain.^1,29 No significant weight effect was observed for either citalopram or escitalopram. Keep in mind, however, that the effect of each antidepressant on weight may vary greatly from one patient to another.¹ For example, while Mr. D gained 3.6 kg on paroxetine, some patients gain no weight at all.

In the systematic review and meta-analysis of 257 RCTs, weight gain was associated with the use of amitriptyline (1.8 kg) and mirtazapine (1.5 kg), while weight loss was associated with bupropion and fluoxetine (-1.3 kg for each).⁸

Bupropion, a norepinephrine and dopamine reuptake inhibitor, is the only antidepressant that has been consistently shown to cause weight loss.^30,31 Clinical trials have found that it decreases body weight by suppressing appetite and reducing food cravings.³⁰ Bupropion is approved for the treatment of depression and as a smoking cessation aide. And, in 2014, a bupropion-naltrexone combination received FDA approval for chronic weight management, sold under the brand name Contrave.³²

Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.

As different classes of antidepressants are often prescribed for different types of depression, it is important to be aware that the few that are weight-neutral and weight-loss-promoting are not appropriate for all patients with depression. For example, bupropion is an activating agent and can exacerbate anxiety. Thus, a patient with concomitant depression and anxiety might be a better candidate for another antidepressant, which could lead to some weight gain but would better manage the individual’s symptoms. In such cases, the rule of thumb should be to prescribe the lowest dose required for clinical efficacy for the shortest duration necessary.

CASE 3 › Change antidepressants— and keep a close watch

Depending on the nature of Mr. D’s depression, bupropion, fluoxetine, or sertraline might be a reasonable alternative to paroxetine to prevent or reduce further drug-induced weight gain.

Frequent follow-up visits should be scheduled until the transition has been completed and his condition stabilized. If Mr. D’s new antidepressant is bupropion, monitoring him for signs of anxiety would be required.

CORRESPONDENCE
Katherine H. Saunders, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].