- Email: [email protected]
Past, Present, and Future of Pharmacologic Therapy in Obesity
P a s t , P re s e n t , a n d F u t u re o f P h a r m a c o l o g i c Th e r a p y in Obesity José E. Rodríguez,
MD
a,
*, Kendall M. Campbell,
MD
b
KEYWORDS Obesity Stimulants Fat blockers Antidepressants Pharmacology treatment KEY POINTS Obesity medications can be classified into 4 categories: fat blockers, antidepressants, stimulants, and diabetes medications. Because of cost, most obesity medications are not realistic options for poor and underserved patients. Several obesity medications have high abuse potential and should be used with caution. None of the current obesity medications are safe for use in pregnant or breast-feeding women.
THE PAST: A BRIEF HISTORY
Medications for obesity treatment have been available for decades. Synthetic thyroid hormone was first used to treat obesity in the 1920s. When used in obese euthyroid patients, patients experience significant side effects associated with hyperthyroidism, such as exophthalmos, hyperthermia, and palpitations.1 Medications producing rapid fat loss by blocking ATP production in the mitochondria, such as 2 to 4 dinitrophenol (DNP), were used a decade later.2 Side effects included increased body warmth, sweating, and decreased appetite. More than 100,000 Americans were treated with DNP before it was withdrawn from the market in 1938. Patients who continued to use DNP suffered cataracts and hyperthermia, and premature deaths were reported. DNP is still commercially available and is marketed as a weight loss supplement.2
Disclosure Statement: The authors have nothing to disclose. a Department of Family Medicine and Rural Health, The Center for Underrepresented Minorities in Academic Medicine, Florida State University College of Medicine, 1115 West Call Street, #3210 M, Tallahassee, FL 32306, USA; b Department of Family Medicine and Rural Health, The Center for Underrepresented Minorities in Academic Medicine, Florida State University College of Medicine, 1115 West Call Street, #3210 N, Tallahassee, FL 32306, USA * Corresponding author. E-mail address: [email protected] Prim Care Clin Office Pract - (2015) -–http://dx.doi.org/10.1016/j.pop.2015.08.011 primarycare.theclinics.com 0095-4543/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Stimulants, still in use today, appeared on the market in the mid 1930s.3 Stimulant medications decrease appetite by increasing metabolism, and many forms are still available today. Not all commercially available stimulants have an antiobesity indication. This article reviews only those stimulants currently approved for use in the treatment of obesity. Simulant use for weight loss has been widespread over the last 6 decades, but not without significant adverse effects. Most notably, the combination of fenfluramine (approved in 1973) and phentermine (approved in 1959) was marketed as Fen-Phen in the 1980s and 1990s. Both medications are stimulant anorectics. Up to 30% of patients who used this medication developed valvular heart disease. Pulmonary hypertension and several deaths were also reported.4 Fen-Phen was withdrawn from the market in 1997, but phentermine is still commercially available today and is discussed later in this article. Sibutramine, marketed as Meridia or Reductil, is structurally similar to amphetamines and is marketed as an oral anorectic. Sibutramine quickly became popular in the 1990s, but was withdrawn from the US market in 2010, because of an increase in adverse cardiovascular outcomes.5 Sibutramine subsequently was in some commercially available dietary supplements. Attempts have been made to remove these products from the market.6 THE PRESENT: WHAT IS CURRENTLY AVAILABLE
Although the focus of this article is on pharmacologic treatments for obesity, guidelines for non-medication-based interventions exist and are the foundation for treating overweight and obese patients.7 These guidelines take into account nonpharmacologic approaches to patient care and include surgical options. Pharmacologic treatment of obesity is indicated for patients with a body mass index (BMI) of 30 or greater, or for patients with a BMI of 27 or greater who have additional comorbidities. The current list of available medications is included in Table 1. Fat Blockers
The pancreatic lipase inhibitor orlistat (Xenical, Alli) is the most well studied of the obesity drugs currently in use.8 Orlistat was approved in 1999 as a prescription drug. It became available in 2007 as an over-the-counter (OTC) medication. The prescription strength is double the OTC strength. Both formulations are intended to be taken 3 times a day with a fat-containing meal. The generic cost of the OTC preparation averages $59.97 per month. The cost of prescription strength orlistat ranges from $525.33 to $566.00 for a 1-month supply.9 In one meta-analysis of weight loss drugs
Table 1 Currently available medications for the treatment of obesity Drug
Availability
Bupropion/Naltrexone (Contrave)
Widely available
Diethylpropion
Schedule IV
Liraglutide
Widely available
Lorcaserin (Belviq)
Schedule IV
Orlistat (Alli, Xenical)
Widely available (OTC)
Phendimetrazine
Schedule III
Phentermine
Schedule IV
Phentermine/Topiramate (Qsymia)
Schedule IV
Past, Present, and Future of Pharmacologic Therapy
including 10,631 patients with an average BMI of 36.3 kg/m2 and average age of 47 years, participants who took orlistat lost 2.9 kg (95% confidence interval [CI] 2.5–3.2) more than those in the placebo arm, a net BMI reduction of 1.1 kg/m2 (95% CI 1.4–22.3).10 Three of 4 patients who took orlistat reported gastrointestinal side effects, including fatty/oily stool, increased defecation frequency, liquid stools, fecal urgency, flatulence, flatulence with discharge, or oily evacuation.11,12 Although readily accessible, orlistat use is not particularly popular among patients because of the side-effect profile. Antidepressants
The antidepressant combination bupropion/naltrexone (Contrave) is the only antidepressant-containing regimen currently approved for the treatment of obesity. Bupropion increases dopamine activity in the brain, leading to a reduction in appetite and an increase in energy expenditure. Naltrexone blocks opioid receptors, which, when combined with bupropion, is thought to reduce food cravings. Dosing is complicated, involving titration from one daily tablet (90 mg bupropion/8 mg naltrexone) during the first week of treatment to 2 tablets twice daily by the fourth week of treatment. The maintenance dose is typically 360 mg bupropion/32 mg naltrexone daily. Although the individual components of this medication are relatively inexpensive (300 mg bupropion costs $30.07 to $63.25 per month and 50 mg naltrexone costs $37.96 to $102.84 per month), the on-label cost of the combination ranges from $209.60 to $222 per month9 and is not covered by insurance. Manufacturer’s coupons are available to significantly reduce the cost of the first month of treatment. Common side effects of the bupropion/naltrexone combination include nausea (33%), constipation (19%), headache (18%), and vomiting (11%).12 Contrave is contraindicated in patients with uncontrolled hypertension, an underlying seizure disorder, eating disorders, benzodiazepine or opioid dependence, and in patients who are taking other bupropion-containing products.11 Four double-blind, placebo-controlled industrysponsored trials lasting 56 weeks including 4536 patients showed a 5% to 9% weight loss in patients taking bupropion/naltrexone when compared with placebo.13 Because it is not a controlled substance, and because primary care physicians are familiar with both medications, this medication may increase in popularity. Patients should be informed that this medication can cause a false positive test for amphetamines in urine toxicology screens. Stimulants
There are currently 4 stimulant medications approved for the treatment of obesity in the United States: diethylpropion, lorcaserin, phendimetrazine, and phentermine. Phentermine is also available in combination with topiramate (Qsymia). Diethylpropion (tenuate)
Diethylpropion is a central nervous system stimulant similar to bupropion in structure. It is indicated for weight loss and is a schedule IV drug. In a meta-analysis of 13 studies lasting from 6 to 52 weeks, including 80% women who simultaneously received lifestyle treatments, diethylpropion was associated with a 3.0-kg (95% CI 1.6–11.5) weight loss.14 The most common side effects were constipation, dry mouth, palpitations, headache, insomnia, and elevated blood pressure.12 Diethylpropion can be taken daily, 1 hour before meals, 25 mg every 8 hours, or as a 75-mg extended release formula. The generic cost ranges from $20.78 to $36.86 per month for thirty 75-mg tablets.9 Although readily available and relatively inexpensive, it is not a first-line drug for obesity treatment.
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Lorcaserin (belviq)
Lorcaserin was approved in 2013 for long-term use in the treatment of obesity. It is a selective 5-hydroxytryptamine receptor 2c agonist and has been listed as a schedule IV drug. It was approved based on 3 premarketing studies, the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), BLOSSOM, and BLOOM DM studies. The BLOOM study followed 3183 obese adults (mean BMI 36.2 kg/m2) for 2 years.15 Side effects caused high rates of discontinuation (36%–50%) in this study. Lorcaserin was associated with a dose-dependent weight loss. Patients on placebo lost 0.3 kg, whereas patients on lorcacerin 10 mg once a day lost 1.8 kg. Patients on 15 mg once a day lost 2.6 kg and patients on 10 mg twice a day lost 3.6 kg.15 This weight loss was statistically significant and dose-related. Lorcacerin is recommended for use in conjunction with lifestyle modification. Potential adverse effects include headache, dizziness, fatigue, nausea, dry mouth, constipation, cough, reduced heart rate, and hyperprolactinemia.12 Cardiac valvulopathy has been found no more frequently with lorcaserin treatment than with placebo. Lorcaserin should not be used in patients taking selective serotonin reuptake inhibitors (including bupropion), St. John’s Wort, or serotonin 5-hydroxytryptamine receptor agonists (sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan, and elitriptan). Lorcaserin should be used with caution in patients with cognitive impairment, patients with psychiatric disorders, or men with a history of priapism. Lorcacerin is contraindicated for use in pregnant women and nursing mothers.11 Most major insurance carriers in the United States do not cover lorcacerin. The cost for typical lorcacerin dosing of 10 mg twice a day ranges from $209 to $221 per month. Manufacturer subsidies are available for eligible patients. A free 15-day medication trial is available from the manufacturer after which patients can receive ongoing assistance with a manufacturer’s coupon.9 Phendimetrazine (bontril) and phentermine (adipex and suprenza)
Phendimetrazine was first approved for the treatment of obesity in 1959. There are few studies supporting its use. One randomized controlled trial from 1962 included 146 overweight patients, but 36 dropped out. The remaining patients were divided into 4 groups with varying doses of phendimetrazine. The average weight loss for the 4 groups was 3.6 kg. This weight loss is similar to other studies involving phendimetrazine. Patients taking phendimetrazine may experience agitation, changes in libido, blurry vision, dizziness, headache, palpitation, and tachycardia.12 Phendimetrazine is contraindicated in pregnant and nursing women. Phendimetrazine is available generically in the United States. The monthly cost ranges between $9.35 and $12.68.9 Phentermine has been more widely studied than phendimetrazine. A meta-analysis of 9 trials, with an average duration of 24 weeks, showed that participants on phentermine lost more weight compared with those with lifestyle interventions alone ( 3.6 kg [95%CI 0.6–6.0]).14 More than 80% of participants were women, and more than 80% received concurrent lifestyle modification interventions. The meta-analysis indicated that serious adverse events could be as high as 15 per 1000 users. Side effects of phentermine are similar to those of the other stimulants and include tachycardia, increased blood pressure, tremor, dizziness, insomnia, headache, dry mouth, and diarrhea.11 Phentermine costs range from $12 to $30 per month. Phentermine/topiramate (qsymia)
The combination of phentermine and topiramate for the treatment of obesity was approved in late 2013. Topiramate has been used as an anticonvulsant and to treat migraine headaches. An incidental finding for patients on topiramate was weight
Past, Present, and Future of Pharmacologic Therapy
loss. The dosing of phentermine/topiramate also requires titration. Patients generally begin at 3.75 mg/23 mg and increase to 15 mg/92 mg after 6 weeks by doubling the dose bi-weekly. Phentermine/topiramate is a once-daily medication. The EQUIP study was an early trial of the phentermine/topiramate combination.16 Patients with an average BMI of 42 were enrolled for 56 weeks. Study participants were randomized into 3 groups: diet and placebo, diet and low-dose phentermine/ topiramate (3.75/23 mg), and diet and high-dose phentermine/topiramate (15/92 mg). Dropout rates ranged from 47% in the placebo group to 34% in the high-dose medication group. Participants experienced a dose-related reduction in weight, with 1.6% weight loss in the placebo group, 5.1% in the low-dose group, and 10.9% in the high-dose group.16 Side effects are similar to those of phentermine and include paresthesias (20%), dry mouth (19%), constipation (16%), upper respiratory infection (16%), metabolic acidosis (13%), nasopharygitis (12%), and headache (11%).12 Some patients also experience the common side effects of topiramate including difficulty concentrating. Phentermine/topiramate is not covered by most commercial insurance carriers. It is available from $180 to $189 for a 1-month supply of the median dose (7.5 mg/46 mg).9 Manufacturer’s assistance is available to those who qualify. Diabetes Medications Liraglutide (victoza , saxenda)
Liraglutide is an injectable, glucagon-like peptide 1 receptor agonist used to treat type 2 diabetes mellitus. It was approved by the US Food and Drug Administration in late 2014 as an obesity treatment. It comes in a multidose, multiple use pen for daily injection. The starting dose is a daily 0.6-mg subcutaneous injection. The dose is increased 0.6 mg every week to a maximum dose of 3 mg daily. Liraglutide can be administered in the abdomen, thigh, or upper arm. The injection site and timing can be changed without significant alterations in pharmacoavailability. Side effects include nausea (39%), hypoglycemia (23%), diarrhea (21%), constipation (19%), vomiting (16%), and headache (14%). Users also report decreased appetite (10%), dyspepsia (10%), fatigue (8%), dizziness (7%), and abdominal pain (5%). Liraglutide should not be used in patients with a personal or family history of thyroid carcinoma or multiple endocrine neoplasia type 2, because it has been associated with increased risk of medullary thyroid carcinomas. Liraglutide is covered by many insurance policies for the treatment of type 2 diabetes. Saxenda is considered to be an obesity medication and is, therefore, not usually covered by insurance. The cost of 1 month’s treatment ranges from $1087 to $1178. THE FUTURE
Most current obesity medications are stimulant-based. Newer medications are on the horizon that target different mechanisms of action for the treatment of obesity. Three new medications currently being investigated include beloranib, mirabegron, and gelesis 100. Beloranib
Beloranib is an injectable medication under investigation for use in the treatment of Prader-Willi syndrome. Beloranib is a methionine aminopeptidase II inhibitor, which reduces hepatic fatty acid production and promotes breakdown of existing fatty acids into glucose. Beloranib is also associated with reduced hunger and food intake. In
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phase 1b clinical trials, belonarib was associated an average 1 kg per week weight loss in subjects with Prader-Willi syndrome. Associated improvements in cardiovascular risk due to reductions in body fat were also noted.17 Side-effect and tolerability profiles are pending. Phase 2 clinical trials are underway, and results are expected in 2016. Mirabegron
Marketed as Myrbetriq as a treatment for overactive bladder, mirabegron was discovered to activate brown fat in rats. When tested in humans, mirabegron was associated with an increase in basal metabolic rate of 40 kcal/d as well as an increase in brown adipose tissue metabolic activity as measured by PET.18 Gelesis 100
Gelesis 100 is a proprietary product made from food-grade material that expands in the stomach on consumption; this slows gastric emptying. An industry-sponsored 12-week trial showed that obese subjects who took Gelesis 100 and consumed fewer calories and lost more weight than those on placebo (6.1% on 2.25 g of Gelesis100, 4.5% for 3.75 g of Gelesis 100, and 4.1% on placebo).19 Another trial showed that obese subjects who took Gelesis 100 consumed less carbohydrates and more protein than those taking placebo ([mean SD] –4.6 9.1 [P 5 .003], –2.9 11.6 [P 5 .043], and 4.7 11.1, with Gelesis 100 2.25 g, Gelesis 100 3.75 g, and placebo, respectively).20 If approved by the US Food and Drug Administration, Gelesis 100 will be regulated as a medical device. SUMMARY
Pharmacologic therapy for obesity is one tool in a multifaceted approach to obesity treatment. Over the years, obesity medications have evolved from being mostly stimulant based to newer pharmacologic treatments that work through different mechanisms. Many of these medicines have a variety of indications and are not just used for obesity. In addition to stimulants, current medications block fat uptake or work as antidepressants, and also several are diabetes medications. For maximum benefit, medications need to be part of a comprehensive patient-centered treatment approach to weight loss. Like most therapies, pharmacologic therapies work best when patient adherence is high. Patients who stop taking their antiobesity medications, without proper lifestyle modification, are unlikely to maintain long-term results. Several medications are in the pipeline, further increasing options for patients struggling with the complex problem of obesity. REFERENCES
1. Halpern B, Halpern A. Why are anti-obesity drugs stigmatized? Expert Opin Drug Saf 2015;14(2):185–9. 2. Grundlingh J, Dargan PI, El-Zanfaly M, et al. 2,4-Dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol 2011; 7(3):205–12. 3. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: a short history. Circulation 2012;125(17):2156–64. 4. Sachdev M, Miller WC, Ryan T, et al. Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. Am Heart J 2002; 144(6):1065–73.
Past, Present, and Future of Pharmacologic Therapy
5. Khorassani FE, Misher A, Garris S. Past and present of antiobesity agents: focus on monoamine modulators. Am J Health Syst Pharm 2015;72(9):697–706. 6. Kim JW, Kweon SJ, Park SK, et al. Isolation and identification of a sibutramine analogue adulterated in slimming dietary supplements. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013;30(7):1221–9. 7. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014;129(25 Suppl 2):S102–38. 8. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311(1):74–86. 9. Good Rx. 2015. Available at: http://www.goodrx.com. Accessed May 10, 2015. 10. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2003;(4):CD004094. 11. Seger JC, Horn DB, Westman EC, et al. Obesity Algorithm, presented by the Obesity Medicine Association, 2014-2015. Available at: http://www. obesityalgorithm.org. Accessed May 21, 2015. 12. Medscape Drugs and Diseases. 2015. Available at: http://www.reference. medscape.com. Accessed July 14, 2015. 13. Greig SL, Keating GM. Naltrexone ER/Bupropion ER: a review in obesity management. Drugs 2015;75(11):1269–80. 14. Li Z, Maglione M, Tu W, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005;142(7):532–46. 15. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363(3):245–56. 16. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012;20(2):330–42. 17. Zafgen. The Science. 2015. Available at: http://www.zafgen.com/zafgen/ourapproach/the-science. Accessed July 14, 2015. 18. Cypess AM, Weiner LS, Roberts-Toler C, et al. Activation of human brown adipose tissue by a b3-adrenergic receptor agonist. Cell Metab 2015;21(1):33–8. 19. ’Smart pill’ reduces weight in overweight and obese subjects. ScienceDaily 2014. Available at: http://www.sciencedaily.com/releases/2014/06/140623141859.htm. Accessed July 13, 2015. 20. 22nd European Congress on Obesity (ECO2015), Prague, Czech Republic, May 6-9, 2015: abstracts. Obes Facts 2015;8(Suppl 1):1–272.
7
MD
a,
*, Kendall M. Campbell,
MD
b
KEYWORDS Obesity Stimulants Fat blockers Antidepressants Pharmacology treatment KEY POINTS Obesity medications can be classified into 4 categories: fat blockers, antidepressants, stimulants, and diabetes medications. Because of cost, most obesity medications are not realistic options for poor and underserved patients. Several obesity medications have high abuse potential and should be used with caution. None of the current obesity medications are safe for use in pregnant or breast-feeding women.
THE PAST: A BRIEF HISTORY
Medications for obesity treatment have been available for decades. Synthetic thyroid hormone was first used to treat obesity in the 1920s. When used in obese euthyroid patients, patients experience significant side effects associated with hyperthyroidism, such as exophthalmos, hyperthermia, and palpitations.1 Medications producing rapid fat loss by blocking ATP production in the mitochondria, such as 2 to 4 dinitrophenol (DNP), were used a decade later.2 Side effects included increased body warmth, sweating, and decreased appetite. More than 100,000 Americans were treated with DNP before it was withdrawn from the market in 1938. Patients who continued to use DNP suffered cataracts and hyperthermia, and premature deaths were reported. DNP is still commercially available and is marketed as a weight loss supplement.2
Disclosure Statement: The authors have nothing to disclose. a Department of Family Medicine and Rural Health, The Center for Underrepresented Minorities in Academic Medicine, Florida State University College of Medicine, 1115 West Call Street, #3210 M, Tallahassee, FL 32306, USA; b Department of Family Medicine and Rural Health, The Center for Underrepresented Minorities in Academic Medicine, Florida State University College of Medicine, 1115 West Call Street, #3210 N, Tallahassee, FL 32306, USA * Corresponding author. E-mail address: [email protected] Prim Care Clin Office Pract - (2015) -–http://dx.doi.org/10.1016/j.pop.2015.08.011 primarycare.theclinics.com 0095-4543/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Stimulants, still in use today, appeared on the market in the mid 1930s.3 Stimulant medications decrease appetite by increasing metabolism, and many forms are still available today. Not all commercially available stimulants have an antiobesity indication. This article reviews only those stimulants currently approved for use in the treatment of obesity. Simulant use for weight loss has been widespread over the last 6 decades, but not without significant adverse effects. Most notably, the combination of fenfluramine (approved in 1973) and phentermine (approved in 1959) was marketed as Fen-Phen in the 1980s and 1990s. Both medications are stimulant anorectics. Up to 30% of patients who used this medication developed valvular heart disease. Pulmonary hypertension and several deaths were also reported.4 Fen-Phen was withdrawn from the market in 1997, but phentermine is still commercially available today and is discussed later in this article. Sibutramine, marketed as Meridia or Reductil, is structurally similar to amphetamines and is marketed as an oral anorectic. Sibutramine quickly became popular in the 1990s, but was withdrawn from the US market in 2010, because of an increase in adverse cardiovascular outcomes.5 Sibutramine subsequently was in some commercially available dietary supplements. Attempts have been made to remove these products from the market.6 THE PRESENT: WHAT IS CURRENTLY AVAILABLE
Although the focus of this article is on pharmacologic treatments for obesity, guidelines for non-medication-based interventions exist and are the foundation for treating overweight and obese patients.7 These guidelines take into account nonpharmacologic approaches to patient care and include surgical options. Pharmacologic treatment of obesity is indicated for patients with a body mass index (BMI) of 30 or greater, or for patients with a BMI of 27 or greater who have additional comorbidities. The current list of available medications is included in Table 1. Fat Blockers
The pancreatic lipase inhibitor orlistat (Xenical, Alli) is the most well studied of the obesity drugs currently in use.8 Orlistat was approved in 1999 as a prescription drug. It became available in 2007 as an over-the-counter (OTC) medication. The prescription strength is double the OTC strength. Both formulations are intended to be taken 3 times a day with a fat-containing meal. The generic cost of the OTC preparation averages $59.97 per month. The cost of prescription strength orlistat ranges from $525.33 to $566.00 for a 1-month supply.9 In one meta-analysis of weight loss drugs
Table 1 Currently available medications for the treatment of obesity Drug
Availability
Bupropion/Naltrexone (Contrave)
Widely available
Diethylpropion
Schedule IV
Liraglutide
Widely available
Lorcaserin (Belviq)
Schedule IV
Orlistat (Alli, Xenical)
Widely available (OTC)
Phendimetrazine
Schedule III
Phentermine
Schedule IV
Phentermine/Topiramate (Qsymia)
Schedule IV
Past, Present, and Future of Pharmacologic Therapy
including 10,631 patients with an average BMI of 36.3 kg/m2 and average age of 47 years, participants who took orlistat lost 2.9 kg (95% confidence interval [CI] 2.5–3.2) more than those in the placebo arm, a net BMI reduction of 1.1 kg/m2 (95% CI 1.4–22.3).10 Three of 4 patients who took orlistat reported gastrointestinal side effects, including fatty/oily stool, increased defecation frequency, liquid stools, fecal urgency, flatulence, flatulence with discharge, or oily evacuation.11,12 Although readily accessible, orlistat use is not particularly popular among patients because of the side-effect profile. Antidepressants
The antidepressant combination bupropion/naltrexone (Contrave) is the only antidepressant-containing regimen currently approved for the treatment of obesity. Bupropion increases dopamine activity in the brain, leading to a reduction in appetite and an increase in energy expenditure. Naltrexone blocks opioid receptors, which, when combined with bupropion, is thought to reduce food cravings. Dosing is complicated, involving titration from one daily tablet (90 mg bupropion/8 mg naltrexone) during the first week of treatment to 2 tablets twice daily by the fourth week of treatment. The maintenance dose is typically 360 mg bupropion/32 mg naltrexone daily. Although the individual components of this medication are relatively inexpensive (300 mg bupropion costs $30.07 to $63.25 per month and 50 mg naltrexone costs $37.96 to $102.84 per month), the on-label cost of the combination ranges from $209.60 to $222 per month9 and is not covered by insurance. Manufacturer’s coupons are available to significantly reduce the cost of the first month of treatment. Common side effects of the bupropion/naltrexone combination include nausea (33%), constipation (19%), headache (18%), and vomiting (11%).12 Contrave is contraindicated in patients with uncontrolled hypertension, an underlying seizure disorder, eating disorders, benzodiazepine or opioid dependence, and in patients who are taking other bupropion-containing products.11 Four double-blind, placebo-controlled industrysponsored trials lasting 56 weeks including 4536 patients showed a 5% to 9% weight loss in patients taking bupropion/naltrexone when compared with placebo.13 Because it is not a controlled substance, and because primary care physicians are familiar with both medications, this medication may increase in popularity. Patients should be informed that this medication can cause a false positive test for amphetamines in urine toxicology screens. Stimulants
There are currently 4 stimulant medications approved for the treatment of obesity in the United States: diethylpropion, lorcaserin, phendimetrazine, and phentermine. Phentermine is also available in combination with topiramate (Qsymia). Diethylpropion (tenuate)
Diethylpropion is a central nervous system stimulant similar to bupropion in structure. It is indicated for weight loss and is a schedule IV drug. In a meta-analysis of 13 studies lasting from 6 to 52 weeks, including 80% women who simultaneously received lifestyle treatments, diethylpropion was associated with a 3.0-kg (95% CI 1.6–11.5) weight loss.14 The most common side effects were constipation, dry mouth, palpitations, headache, insomnia, and elevated blood pressure.12 Diethylpropion can be taken daily, 1 hour before meals, 25 mg every 8 hours, or as a 75-mg extended release formula. The generic cost ranges from $20.78 to $36.86 per month for thirty 75-mg tablets.9 Although readily available and relatively inexpensive, it is not a first-line drug for obesity treatment.
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Lorcaserin (belviq)
Lorcaserin was approved in 2013 for long-term use in the treatment of obesity. It is a selective 5-hydroxytryptamine receptor 2c agonist and has been listed as a schedule IV drug. It was approved based on 3 premarketing studies, the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), BLOSSOM, and BLOOM DM studies. The BLOOM study followed 3183 obese adults (mean BMI 36.2 kg/m2) for 2 years.15 Side effects caused high rates of discontinuation (36%–50%) in this study. Lorcaserin was associated with a dose-dependent weight loss. Patients on placebo lost 0.3 kg, whereas patients on lorcacerin 10 mg once a day lost 1.8 kg. Patients on 15 mg once a day lost 2.6 kg and patients on 10 mg twice a day lost 3.6 kg.15 This weight loss was statistically significant and dose-related. Lorcacerin is recommended for use in conjunction with lifestyle modification. Potential adverse effects include headache, dizziness, fatigue, nausea, dry mouth, constipation, cough, reduced heart rate, and hyperprolactinemia.12 Cardiac valvulopathy has been found no more frequently with lorcaserin treatment than with placebo. Lorcaserin should not be used in patients taking selective serotonin reuptake inhibitors (including bupropion), St. John’s Wort, or serotonin 5-hydroxytryptamine receptor agonists (sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan, and elitriptan). Lorcaserin should be used with caution in patients with cognitive impairment, patients with psychiatric disorders, or men with a history of priapism. Lorcacerin is contraindicated for use in pregnant women and nursing mothers.11 Most major insurance carriers in the United States do not cover lorcacerin. The cost for typical lorcacerin dosing of 10 mg twice a day ranges from $209 to $221 per month. Manufacturer subsidies are available for eligible patients. A free 15-day medication trial is available from the manufacturer after which patients can receive ongoing assistance with a manufacturer’s coupon.9 Phendimetrazine (bontril) and phentermine (adipex and suprenza)
Phendimetrazine was first approved for the treatment of obesity in 1959. There are few studies supporting its use. One randomized controlled trial from 1962 included 146 overweight patients, but 36 dropped out. The remaining patients were divided into 4 groups with varying doses of phendimetrazine. The average weight loss for the 4 groups was 3.6 kg. This weight loss is similar to other studies involving phendimetrazine. Patients taking phendimetrazine may experience agitation, changes in libido, blurry vision, dizziness, headache, palpitation, and tachycardia.12 Phendimetrazine is contraindicated in pregnant and nursing women. Phendimetrazine is available generically in the United States. The monthly cost ranges between $9.35 and $12.68.9 Phentermine has been more widely studied than phendimetrazine. A meta-analysis of 9 trials, with an average duration of 24 weeks, showed that participants on phentermine lost more weight compared with those with lifestyle interventions alone ( 3.6 kg [95%CI 0.6–6.0]).14 More than 80% of participants were women, and more than 80% received concurrent lifestyle modification interventions. The meta-analysis indicated that serious adverse events could be as high as 15 per 1000 users. Side effects of phentermine are similar to those of the other stimulants and include tachycardia, increased blood pressure, tremor, dizziness, insomnia, headache, dry mouth, and diarrhea.11 Phentermine costs range from $12 to $30 per month. Phentermine/topiramate (qsymia)
The combination of phentermine and topiramate for the treatment of obesity was approved in late 2013. Topiramate has been used as an anticonvulsant and to treat migraine headaches. An incidental finding for patients on topiramate was weight
Past, Present, and Future of Pharmacologic Therapy
loss. The dosing of phentermine/topiramate also requires titration. Patients generally begin at 3.75 mg/23 mg and increase to 15 mg/92 mg after 6 weeks by doubling the dose bi-weekly. Phentermine/topiramate is a once-daily medication. The EQUIP study was an early trial of the phentermine/topiramate combination.16 Patients with an average BMI of 42 were enrolled for 56 weeks. Study participants were randomized into 3 groups: diet and placebo, diet and low-dose phentermine/ topiramate (3.75/23 mg), and diet and high-dose phentermine/topiramate (15/92 mg). Dropout rates ranged from 47% in the placebo group to 34% in the high-dose medication group. Participants experienced a dose-related reduction in weight, with 1.6% weight loss in the placebo group, 5.1% in the low-dose group, and 10.9% in the high-dose group.16 Side effects are similar to those of phentermine and include paresthesias (20%), dry mouth (19%), constipation (16%), upper respiratory infection (16%), metabolic acidosis (13%), nasopharygitis (12%), and headache (11%).12 Some patients also experience the common side effects of topiramate including difficulty concentrating. Phentermine/topiramate is not covered by most commercial insurance carriers. It is available from $180 to $189 for a 1-month supply of the median dose (7.5 mg/46 mg).9 Manufacturer’s assistance is available to those who qualify. Diabetes Medications Liraglutide (victoza , saxenda)
Liraglutide is an injectable, glucagon-like peptide 1 receptor agonist used to treat type 2 diabetes mellitus. It was approved by the US Food and Drug Administration in late 2014 as an obesity treatment. It comes in a multidose, multiple use pen for daily injection. The starting dose is a daily 0.6-mg subcutaneous injection. The dose is increased 0.6 mg every week to a maximum dose of 3 mg daily. Liraglutide can be administered in the abdomen, thigh, or upper arm. The injection site and timing can be changed without significant alterations in pharmacoavailability. Side effects include nausea (39%), hypoglycemia (23%), diarrhea (21%), constipation (19%), vomiting (16%), and headache (14%). Users also report decreased appetite (10%), dyspepsia (10%), fatigue (8%), dizziness (7%), and abdominal pain (5%). Liraglutide should not be used in patients with a personal or family history of thyroid carcinoma or multiple endocrine neoplasia type 2, because it has been associated with increased risk of medullary thyroid carcinomas. Liraglutide is covered by many insurance policies for the treatment of type 2 diabetes. Saxenda is considered to be an obesity medication and is, therefore, not usually covered by insurance. The cost of 1 month’s treatment ranges from $1087 to $1178. THE FUTURE
Most current obesity medications are stimulant-based. Newer medications are on the horizon that target different mechanisms of action for the treatment of obesity. Three new medications currently being investigated include beloranib, mirabegron, and gelesis 100. Beloranib
Beloranib is an injectable medication under investigation for use in the treatment of Prader-Willi syndrome. Beloranib is a methionine aminopeptidase II inhibitor, which reduces hepatic fatty acid production and promotes breakdown of existing fatty acids into glucose. Beloranib is also associated with reduced hunger and food intake. In
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phase 1b clinical trials, belonarib was associated an average 1 kg per week weight loss in subjects with Prader-Willi syndrome. Associated improvements in cardiovascular risk due to reductions in body fat were also noted.17 Side-effect and tolerability profiles are pending. Phase 2 clinical trials are underway, and results are expected in 2016. Mirabegron
Marketed as Myrbetriq as a treatment for overactive bladder, mirabegron was discovered to activate brown fat in rats. When tested in humans, mirabegron was associated with an increase in basal metabolic rate of 40 kcal/d as well as an increase in brown adipose tissue metabolic activity as measured by PET.18 Gelesis 100
Gelesis 100 is a proprietary product made from food-grade material that expands in the stomach on consumption; this slows gastric emptying. An industry-sponsored 12-week trial showed that obese subjects who took Gelesis 100 and consumed fewer calories and lost more weight than those on placebo (6.1% on 2.25 g of Gelesis100, 4.5% for 3.75 g of Gelesis 100, and 4.1% on placebo).19 Another trial showed that obese subjects who took Gelesis 100 consumed less carbohydrates and more protein than those taking placebo ([mean SD] –4.6 9.1 [P 5 .003], –2.9 11.6 [P 5 .043], and 4.7 11.1, with Gelesis 100 2.25 g, Gelesis 100 3.75 g, and placebo, respectively).20 If approved by the US Food and Drug Administration, Gelesis 100 will be regulated as a medical device. SUMMARY
Pharmacologic therapy for obesity is one tool in a multifaceted approach to obesity treatment. Over the years, obesity medications have evolved from being mostly stimulant based to newer pharmacologic treatments that work through different mechanisms. Many of these medicines have a variety of indications and are not just used for obesity. In addition to stimulants, current medications block fat uptake or work as antidepressants, and also several are diabetes medications. For maximum benefit, medications need to be part of a comprehensive patient-centered treatment approach to weight loss. Like most therapies, pharmacologic therapies work best when patient adherence is high. Patients who stop taking their antiobesity medications, without proper lifestyle modification, are unlikely to maintain long-term results. Several medications are in the pipeline, further increasing options for patients struggling with the complex problem of obesity. REFERENCES
1. Halpern B, Halpern A. Why are anti-obesity drugs stigmatized? Expert Opin Drug Saf 2015;14(2):185–9. 2. Grundlingh J, Dargan PI, El-Zanfaly M, et al. 2,4-Dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol 2011; 7(3):205–12. 3. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: a short history. Circulation 2012;125(17):2156–64. 4. Sachdev M, Miller WC, Ryan T, et al. Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. Am Heart J 2002; 144(6):1065–73.
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5. Khorassani FE, Misher A, Garris S. Past and present of antiobesity agents: focus on monoamine modulators. Am J Health Syst Pharm 2015;72(9):697–706. 6. Kim JW, Kweon SJ, Park SK, et al. Isolation and identification of a sibutramine analogue adulterated in slimming dietary supplements. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013;30(7):1221–9. 7. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014;129(25 Suppl 2):S102–38. 8. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311(1):74–86. 9. Good Rx. 2015. Available at: http://www.goodrx.com. Accessed May 10, 2015. 10. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2003;(4):CD004094. 11. Seger JC, Horn DB, Westman EC, et al. Obesity Algorithm, presented by the Obesity Medicine Association, 2014-2015. Available at: http://www. obesityalgorithm.org. Accessed May 21, 2015. 12. Medscape Drugs and Diseases. 2015. Available at: http://www.reference. medscape.com. Accessed July 14, 2015. 13. Greig SL, Keating GM. Naltrexone ER/Bupropion ER: a review in obesity management. Drugs 2015;75(11):1269–80. 14. Li Z, Maglione M, Tu W, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005;142(7):532–46. 15. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363(3):245–56. 16. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012;20(2):330–42. 17. Zafgen. The Science. 2015. Available at: http://www.zafgen.com/zafgen/ourapproach/the-science. Accessed July 14, 2015. 18. Cypess AM, Weiner LS, Roberts-Toler C, et al. Activation of human brown adipose tissue by a b3-adrenergic receptor agonist. Cell Metab 2015;21(1):33–8. 19. ’Smart pill’ reduces weight in overweight and obese subjects. ScienceDaily 2014. Available at: http://www.sciencedaily.com/releases/2014/06/140623141859.htm. Accessed July 13, 2015. 20. 22nd European Congress on Obesity (ECO2015), Prague, Czech Republic, May 6-9, 2015: abstracts. Obes Facts 2015;8(Suppl 1):1–272.
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