The injectable glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, previously approved by the FDA for treatment of type 2 diabetes as Victoza, has now also been approved at a higher dose as Saxenda (Novo Nordisk) for chronic weight management in adults with a BMI ≥30, or a BMI ≥27 with a weight-related comorbidity such as hypertension, dyslipidemia, or diabetes.

Adults with a body mass index (BMI) between 25 and 29.9 kg/m² are considered overweight. Those with a BMI ≥30 are considered obese. Losing even a small amount of weight and increasing physical activity can prevent some of the complications of obesity, particularly type 2 diabetes. Diet and exercise are the preferred methods for losing weight, but long-term failure rates are high. Several drugs have been approved by the FDA for weight reduction, but adherence is poor, adverse effects are common, and patients usually regain the lost weight when the drug is stopped. Bariatric surgery can produce substantial weight loss and significantly reduce obesity-related comorbidities; long-term data on its safety are encouraging, but still limited. Guidelines for the management of overweight or obese adults have recently been published.

The FDA has approved a fixed-dose combination of the opioid receptor antagonist naltrexone (ReVia, and others) and the antidepressant and smoking cessation agent bupropion (Wellbutrin SR, Zyban, and others), as Contrave (Orexigen/Takeda) for weight loss. The combination was approved for use as an adjunct to diet and increased physical activity in patients with a body mass index (BMI) ≥30 kg/m² or a BMI ≥27 kg/m² and one or more weight-related comorbidities such as hypertension, diabetes, or dyslipidemia. Naltrexone/bupropion is not a controlled substance.

In 2013 the FDA approved one new drug and a new combination of 2 old drugs as adjuncts to lifestyle changes for chronic weight management. Lorcaserin (lor-ca-SER-in; Belviq – Arena/Esai) is a selective serotonin 2C receptor agonist. Qsymia (Vivus) is a fixed-dose combination of the weight-loss drug phentermine and an extended-release (ER) formulation of topiramate. The new products are approved for use in obese patients (body mass index [BMI] of ≥30 kg/m²) and for patients who are overweight (BMI ≥27 kg/m²) and have one weight-related risk factor such as hypertension, dyslipidemia or type 2 diabetes.

Adults with a body mass index (BMI=kg/m²) of 25-<30 are considered overweight; those with a BMI of ≥30 are considered obese.

A Medical Letter reader asked if human chorionic gonadotropin (hCG; Novarel, Pregnyl and others) has any value as an adjunct to diet, adding that it is widely used for this indication in his area. Normally secreted by the placenta during pregnancy, the main therapeutic use of this gonad-stimulating polypeptide, which is not absorbed from the GI tract, has been in the parenteral treatment of infertility.1 It has also been injected by male athletes as an undetectable stimulus to production of testosterone.2

Use of hCG as an adjunct to diet goes back to the 1950’s, when a British physician named Simeons recommended daily injections of the hormone combined with a 500 kcal diet, and such use came to be known as the Simeons method. One double-blind study after another throughout the second half of the 20^th century found hCG to be worthless for weight loss or maintenance.3

1. Drugs for assisted reproduction. Treat Guidel Med Lett 2003; 1:89.

2. Performance-enhancing drugs. Med Lett Drugs Ther 2004; 46:57.

3. GK Sabine Lijesen et al. The effect of human chorionic gonadotropin (HCG) in the treatment of obesity by means of the Simeons therapy: a criteria-based meta-analysis. Br J Clin Pharmacol 1995; 40:237.

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The results of a postmarketing study of its cardiovascular safety have led to the removal of the weightloss drug sibutramine (Meridia) from the market in the US and Canada. It has also been withdrawn in Europe and Australia, but remains on the market in many other countries. The study that led the FDA to ask Abbott Laboratories to withdraw the drug randomized 10,744 overweight patients with cardiovascular disease, diabetes or both to sibutramine or placebo for a mean duration of 3.4 years. The primary endpoint (non-fatal myocardial infarction, nonfatal stroke, cardiovascular death or resuscitation after cardiac arrest) occurred in 561 of 4906 patients (11.4%) taking sibutramine and in 490 of 4898 (10%) taking placebo (p = 0.02). Death from any cause occurred in 8.5% of the patients who took sibutramine and in 8.2% of those on placebo; this difference was not statistically significant.1

1. WP James et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363:905.

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A recent article in the New England Journal of Medicine confirms something that others, including The Medical Letter (Treat Guidel Med Lett 2008; 6:23), have been saying for years: no particular combination of protein, carbohydrate and fat in the diet offers any advantage in losing weight. This randomized 2-year trial followed 800 overweight and obese subjects on low fat/average protein, low fat/high protein, high fat/average protein, and high fat/high protein diets. Carbohydrate intake varied from 35% (in the high fat/high protein diet) to 65% (in the low fat/average protein diet). All patients were advised to undertake 90 minutes of moderate exercise per week and given a “caloric prescription” to produce a deficit of 750 kcal per day. Most participants lost weight in the first 6 months and regained some thereafter. There was no significant difference in weight loss between different diets and no indication that any particular diet was more pleasant or less painful than any other. Average weight loss at the end of the trial was 4 kg among the remarkably high 80% of subjects who completed the trial, and 9 kg among those who also attended two thirds of the counseling sessions offered to the participants (FM Sacks et al, N Engl J Med 2009; 360:859).

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Peptic ulcers caused by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly gastric ulcers. Most duodenal and other gastric ulcers are caused by the gram-negative bacillus Helicobacter pylori. Gastroesophageal reflux disease (GERD) is caused by gastric acid reflux into the esophagus. Drugs that suppress gastric acid production are the primary treatment for GERD and peptic ulcers.

Losing even a small amount of weight and increasing physical activity can prevent some of the complications of obesity, particularly type 2 diabetes. Diet and exercise are the preferred methods for losing weight but are associated with high long-term failure rates. Drugs may help some patients, but all currently available drugs for weight reduction have drawbacks. Gastric surgery can produce marked weight loss in the severely obese, but long-term data on safety are limited.

The FDA recently advised health care professionals and consumers not to use a number of dietary supplements found to contain the phosphodiesterase-5 inhibitor sildenafil (Viagra) or an analog of the drug (www.fda.gov). Although the effects of sildenafil may be noticeable (in men), the presence of other, possibly more toxic adulterants in dietary supplements may be more difficult or impossible to detect.

Other drugs previously found in dietary supplements have included lovastatin (Mevacor, and others), estrogen, alprazolam (Xanax, and others), indomethacin (Indocin, and others) and warfarin (Coumadin, and others). Aristolochic acid in Chinese herbal weight loss products caused acute renal failure in about 100 women in Belgium; at least 70 of them required dialysis or transplantation, and at least 18 developed urothelial cancer (Med Lett Drugs Ther 2002; 44:84).

Dietary supplements do not require FDA approval before marketing. The agency does have the power to remove mislabeled or adulterated products from store shelves, but the burden of discovery and proof is entirely on the government.

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The FDA has approved over-the-counter (OTC) sale of the weight-loss drug orlistat (Xenical – Roche)1 as alli (GlaxoSmithKline), to be used in combination with a reduced-calorie, low-fat diet. Orlistat binds to gastric and pancreatic lipases, preventing absorption of about 30% of dietary fat with the 120-mg prescription dose, and 25% with the 60-mg OTC dose. A 16-week controlled trial of the OTC dose (60 mg 3 times daily with meals) in overweight, not obese, patients (average BMI 26.8) on a reduced-calorie, low-fat diet found that patients taking the drug lost 1.15 kg more than those taking placebo.2

Orlistat causes flatulence with oily spotting, loose stools, fecal urgency and occasional incontinence in 20-40% of patients on a low-fat diet; these effects presumably would be more frequent and more severe with a higher fat intake or self-prescription of higher-thanrecommended doses. The drug also interferes with absorption of fat-soluble vitamins (A, D, E, K); the manufacturer recommends that patients also take a multivitamin supplement at bedtime. Orlistat can increase the anticoagulant effect of warfarin and may interfere with the absorption of other drugs.

A “starter pack” of 90 capsules of alli (60 mg each) costs $62.99, compared to $224.64 for 90 capsules of Xenical (120 mg each).3

1. Orlistat for obesity. Med Lett Drugs Ther 1999; 41:55.

2. JW Anderson et al. Low-dose orlistat effects on body weight of mildly to moderately overweight individuals: a 16 week, double-blind, placebo-controlled trial. Ann Pharmacother 2006; 40:1717.

3. Cost based on information from drugstore.com (June 11, 2007).

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Patients may be asking about reports in the lay press that exenatide (Byetta - Med Lett Drugs Ther 2005; 47:45), a synthetic peptide that stimulates release of insulin from pancreatic beta cells, has been used by diabetics and non-diabetics to lose weight. Approved by the FDA to improve glycemic control in patients with type 2 diabetes not controlled by metformin, a sulfonylurea or both, it is given by subcutaneous injection before the morning and evening meals. In clinical trials, some diabetic patients treated with the drug lost weight. No data are available on use in non-diabetics. Exenatide slows gastric emptying and promotes satiety, which is presumably the mechanism of weight loss.

Patients should be warned that exenatide has some adverse effects. Hypoglycemia has occurred when the drug was added to a sulfonylurea but not when it was added to metformin. The risk of hypoglycemia in non-diabetics is unknown. Exenatide often causes nausea, which can be severe, and vomiting. Diarrhea can also occur. Because the drug slows gastric emptying, it can decrease the rate and extent of absorption of other drugs such as antibiotics and oral contraceptives; oral drugs should be taken at least one hour before exenatide.

Perhaps the greatest concern with off-label use of exenatide for weight loss is that 3 times the human dose given to pregnant animals slowed fetal growth and produced skeletal and other developmental abnormalities. The FDA classified it as category C (risk cannot be ruled out) for use during pregnancy. For diabetics and non-diabetics, pregnant or not, exenatide's long-term safety is unknown.

The US Department of Health and Human Services, in conjunction with the US Department of Agriculture, has released the latest update of its Dietary Guidelines (www.health.gov). The emphasis this time is on weight loss through calorie restriction and exercise. A low-fat intake is recommended; a low-carbohydrate diet is not. Fruits, vegetables and whole grains are encouraged. A review of Diet, Drugs and Surgery for Weight Loss appeared in the December 2003 issue of Treatment Guidelines from The Medical Letter.

The latest definitions of overweight and obesity are based on body mass index (BMI). The BMI is calculated by dividing the weight in kilograms by the square of the height in meters (kg/m²). More than half of American adults are considered overweight with a BMI of ≥25, and about one third are obese with a BMI of ≥30. All ages seem to be affected; the proportion of children and adolescents who are overweight has more than doubled in the past 25 years. There is no lack of effort to treat obesity: drugs, diets and programs to change lifestyle are the basis for a large and flourishing industry. The frequent failure of diet and drug treatment sometimes leads to recommendations for surgery, usually restricted to those with a BMI ≥40.