Several drugs approved by the FDA for purposes other than weight loss have been used for the treatment of obesity, including metformin, fluoxetine, bupropion, topiramate, and zonisamide.4 Physicians who decide to try these agents are using them off-label and would be well advised to do so only with signed informed consent from the patient.32
Antidiabetic Drugs that Lower Body Weight
Exenatide Exenatide (Exendin-4) is a 39 amino acid peptide that is produced in the salivary gland of the Gila monster, a species of lizard native to the southwestern United States and Mexico. It has 53% homology with GLP-1, but it has a much longer half-life. Exenatide has been approved by the FDA for treatment of type 2 diabetics who are inadequately controlled while being treated with either metformin or sulfonylureas. In human beings, exenatide reduces fasting and postprandial glucose levels, slows gastric emptying, and decreases food intake by 19%.33 A systematic review of incretin therapy in type 2 diabetes34 showed a weight loss of 2.37 kg for all GLP-1 analogs versus control, 1.44 for exenatide versus placebo injection, and 4.76 for exenatide versus insulin (which often leads to weight gain). A 24-week, multicenter, randomized, placebo-controlled clinical trial of exenatide enrolled diabetics poorly controlled with either metformin or sulfonylurea with a HbA1C between 6.6% and 10.0% and a BMI between 25.0 and 39.9 kg/m2. The decrease in caloric intake by exenatide (378 ± 58 kcal/day) was not significantly different from placebo (295 ± 58 kcal/day). Weight loss was significantly greater and HbA1C and BP were reduced more in the exenatide-treated patients.35 The side effects of exenatide in humans are headache, nausea, and vomiting; they are lessened by gradual dose escalation.36 The interesting feature of this weight loss is that it occurred without prescribing lifestyle modification, diet, or exercise. A 26-week randomized control trial of exenatide produced a 2.3-kg weight loss compared with a gain of 1.8 kg in the group receiving the glargine form of insulin.37
In a 24-week, multicenter, randomized, placebo-controlled clinical trial comparing exenatide with placebo in the treatment of poorly controlled diabetic patients, exenatide produced significantly greater decreases in weight, HbA1C, and blood pressure. The interesting feature of the weight loss is that it occurred with no prescription for lifestyle modification, diet, or exercise.
Liraglutide Liraglutide is another GLP-1 agonist that has a 97% homology to GLP-1. This molecular change extends the circulating half-life from 1–2 minutes to 13 hours. Liraglutide reduces body weight. In a 20-week, multicenter European clinical trial, Astrup et al.38 reported that daily injections of liraglutide at 1.2, 1.8, 2.4, or 3.0 mg produced weight losses of 4.8, 5.5, 6.3, and 7.2 kg, respectively, compared with 2.8 kg in the placebo-treated group and 4.1 kg in the orlistat-treated comparator group. In the group treated with 3.0 mg/day, 76% achieved a > 5% weight loss, compared with 30% in the placebo group. BP was significantly reduced, but there was no change in lipids. The prevalence of prediabetes was reduced by liraglutide. In a head-to-head comparison, liraglutide and exenatide produced similar amounts of weight loss, 3.24 kg with liraglutide versus 2.87 kg with exenatide. In poorly controlled type 2 diabetics on maximally tolerated doses of metformin and/or sulfonylurea, liraglutide reduced mean HbA1C significantly more than did exenatide (−1.12% versus − 0.79%).39 Liraglutide has been approved by the European Medicines Agency and the FDA for the treatment of diabetes.
Combinations of Drugs that Produce Weight Loss
The first important clinical trial for weight loss combining drugs that acted by separate mechanisms used phentermine and fenfluramine.40 This trial showed a highly significant weight loss of nearly 15% below baseline with fewer side effects by using combination therapy. This combination became very popular, but due to reports of aortic valvular regurgitation associated with its use,41 fenfluramine was withdrawn from the market worldwide on September 15, 1997. Several other combinations of existing drugs are now under development and may be the next therapeutic option for treatment of obesity.
Topiramate and Phentermine Topiramate is an anticonvulsant drug that was shown to reduce food intake, but it was not developed clinically because of the side effects at the doses selected for trial. Phentermine is a long-established sympathomimetic drug approved for the short-term treatment of obesity in 1968. It is a “scheduled” drug, meaning that the US Drug Enforcement Agency has concluded that this drug carries risk for habituation and/or addiction. Topiramate and phentermine have been combined in one of 3 combinations: 3.75, 7.5, or 15 mg of phentermine combined, respectively, with 23, 46, or 92 mg of topiramate.
Two clinical trials have been conducted to evaluate long-term efficacy and safety. One is in obese individuals with a BMI ≥ 35 kg/m2 and a normal cardiometabolic profile (BP < 140/90 mm HG, fasting plasma glucose < 110 mg/dL, triglycerides < 200 mg/dL; Healthy Obese Trial). The other is in people with obesity combined with comorbidities (BMI 27–45 kg/m2 and 2 or more of the components for the metabolic syndrome, including treatment for hypertension, diabetes, or dyslipidemia; Obesity with Comorbidities). The LEARN manual provided the behavioral program for both trials. In the Healthy Obese trial, the low and high doses of topiramate/phentermine were used. In the Obesity with Comorbidities trial, topiramate and phentermine were used at the mid and high dose. The medication was titrated over 4 weeks due to the side effects from topiramate. All together, more than 2500 patients were included in these clinical trials. By design, the Obesity with Comorbidities trial had an older population with many more comorbidities but a lower BMI than the other trial. Weight loss among those who completed the trial was similar for the high dose in both trials. The percentage of those losing > 5%, > 10%, or > 15% was also similar between the 2 trials. At the end of 1 year, there was an improvement in all risk factors in the high-dose group, and all but diastolic BP and low-density lipoprotein cholesterol in the middle-dose group. Side effects in both trials included tingling and paresthesias. The prevalence of mental and behavioral side effects noted with topiramate alone was not as prominent in these trials. Using the intent-to-treat basis for analyzing data, the full dose of the combination produced an 11% weight loss at 1 year compared with 1.6% in the placebo-treated group.
Two clinical trials compared a combination of topiramate and phentermine with placebo in the treatment of more than 2500 obese patients with and without comorbidities. Using the intent-to-treat basis for analyzing data, the full dose of the combination produced an 11% weight loss at 1 year compared with 1.6% in the placebo-treated group.
Bupropion and Naltrexone Bupropion reduces food intake by acting on adrenergic and dopaminergic receptors in the hypothalamus. Naltrexone is an opioid receptor antagonist with minimal weight-loss effect on its own. The rationale for combining bupropion with naltrexone is the idea that bupropion, acting on adrenergic receptors, is stimulating the production of a prohormone, proopiomelanocortin, which contains several other peptides within it, including α-melanocyte stimulating hormone (α-MSH), adrenocorticotropin, and β-endorphin. The α-MSH reduces food intake, but β-endorphin stimulates food intake. Naltrexone blocks β-endorphin and increases the release of α-MSH, which can continue to inhibit feeding.42 In a 24-week dose-ranging study, 419 subjects were randomized but only 244 (64%) completed the trial. Among the completers, weight loss was 1.2 kg in the placebo group, 3.1 kg in the bupropion-treated group, but only 1.6 kg with the highest (48 mg/day) dose of naltrexone. When combined, weight loss was greater and similar at all 3 doses of naltrexone, combined with bupropion (7.1 kg at 16 mg/day naltrexone + bupropion, 6.6 kg at 32 mg/day naltrexone + bupropion, and 6.9 kg at 48 mg/day naltrexone + bupropion). Nausea was the predominant side effect.43
Four main trials have been done to evaluate this combination. One trial used both 16 and 32 mg of naltrexone with 360 mg/day of bupropion, and the second used a single dose of naltrexone/bupropion (32 mg/360 mg per day), with rerandomization to 32 mg/day or 48 mg/day of naltrexone + bupropion for nonresponders at week 28. A clinical trial including behavior modification included 793 participants who were randomized in a 1:3 ratio to the combination of naltrexone 32 mg with bupropion 360 mg, provided in 2 doses per day with 2 pills at each containing 8 mg of naltrexone and 90 mg of bupropion. The dose was escalated over 4 weeks. At 56 weeks, weight loss was 5.1% in the placebo group compared with 9.3% in the naltrexone 32 mg/bupropion 360 mg group.44 When only those who completed the trial were examined, the weight loss was 7.3% in the control group and 11.5% in the naltrexone/bupropion group. Nausea, constipation, and headache were among the more prominent side effects. There was no evidence of increased suicidal thoughts.
A randomized clinical trial compared a combination of bupropion, naltrexone, and behavior modification with placebo in the treatment of 793 obese patients. At 56 weeks, weight loss was 5.1% in the placebo group compared with 9.3% in the naltrexone 32 mg/bupropion 360 mg group.
Pramlintide and Leptin Pramlintide is a modified form of amylin, a peptide secreted from the beta cells of the pancreas along with insulin. Pramlintide has been approved by the FDA for treatment of diabetes and produced weight loss in clinical trials. Leptin is a secretory product, primarily from adipocytes, that can act as a negative feedback signal to the brain and inhibit food intake. In clinical trials, leptin produced disappointing weight loss.45 The combination of leptin with pramlintide, however, produced additive weight loss in a 6-month clinical trial that may offer promise for the future.46
Clinical trials have shown weight-loss results with leptin alone to be disappointing, but a 6-month trial combining leptin with pramlintide produced an additive weight loss that may offer promise for the future.