Pharmacotherapy for Obesity: Is There a Magic Bullet?
Dr Myerson is Director of Preventive Cardiology, St. Luke’s-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY.
The obesity epidemic is getting a lot of attention these days. Even former president Bill Clinton has joined the ranks of those trying to rally Americans to slim down. Along with promoting greater public awareness, the medical community is trying to find the best way to treat the problem. Diet and exercise form the cornerstone of weight-loss programs but are fraught with problems, such as lack of adherence and sustainability. Surgical approaches can be helpful but are not without risks and are generally reserved for the morbidly obese. Another option is pharmacotherapy. Many doctors feel that drug treatment will be key to the war against obesity.
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The majority of Americans are either overweight (body mass index [BMI] 25.0-29.9 kg/m2) or obese (BMI ≥30 kg/m2) (. 2006;295:1549-1555). Extra weight puts people at risk for a host of medical problems, including diabetes, heart disease, cancer, and arthritis (. 2004;110: 2952-2967).
Pharmacotherapy: The Early Years
Amphetamines, the first drugs used as adjunctive treatment for obesity, were approved for this indication in 1943. The following decades brought more amphetamines and their congeners—drugs that were modified to keep the anorectic affect but lose the stimulatory properties. In 1972, the FDA released the results of its Amphetamine Anorectic Drug Project, a meta-analysis of 200 weight-loss studies of amphetamines and congeners, which concluded that these drugs were effective. At the time, FDA approval was less rigorous, and many studies that were included were neither well designed nor well controlled.
Amphetamine use soared in the 1990s, when it was “discovered” that a combination of 2 drugs, phentermine and fenfluramine, known as “phen-fen,” produced dramatic results. Unfortunately, most of the evidence was from individual experiences and press reports, not from well-designed clinical trials.
The next to emerge was dexfenfluramine, an isomer of fenfluramine. After the FDA asked for evidence from clinical trials, it was approved in 1996 as the first drug indicated for long-term use. Soon thereafter, dexfenfluramine was found to be associated with left-sided heart valve abnormalities and was taken off the market. Follow-up studies published years later confirmed association with valvular problems.
Amphetamines.
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Phentermine (Adipex-P, Pro-Fast) remains on the market but is approved only for short-term use. It is the most frequently prescribed anorexiant medication in the United States (. 2003;163:1046-1050). Two other preparations are also available, benzphetamine (Didrex) and phendimetrazine (Bontril SR, Melfiat, Prelu-2).
Antiabsorptive.
Orlistat (Xenical) acts locally to inhibit gastrointestinal lipases, blocking the absorption of approximately 30% of dietary fat. It is indicated for the treatment of obese patients and overweight patients with other risk factors.
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Many large, randomized clinical trials have been conducted, most of which have shown that at 1 year, more weight is lost with orlistat than with placebo (. 2004;110:2952-2967). In one of the few long-term studies, XENical in the Prevention of Diabetes in Obese Subjects, orlistat was associated with significant weight loss (11%) in the first year compared with placebo (6%); by the end of 4 years, the orlistat group had a mean weight loss of 6.9% compared with 4.1% in the placebo group (. 2004;27:155-161).
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Orlistat has a favorable influence on cardiovascular (CV) risk factors, mostly secondary to weight loss, although there may be independent effects as well. The side-effect profile is known to be more socially embarrassing than medically undesirable. Although severity may diminish over time, most patients have oily rectal discharge, flatus with discharge, fecal urgency, fatty/oily stool, and fecal incontinence ( (). doi:10.1038/sj.ijo.0803323). Orlistat is dosed at 120 mg 3 times daily and is taken with a meal containing fat.
Sibutramine
(Meridia) is a B-phenethylamine derivative that blocks the reuptake of norepinephrine, sibutramine, and dopamine in the central nervous system (CNS). Effects on the appetite control center in the brain result in early satiety.
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Randomized trials have supported its efficacy. After 1 year, patients who received 15 mg/day sibutramine combined with lifestyle modification counseling lost a mean of 12.1 kg, whereas those receiving lifestyle modification counseling alone lost 5 kg (. 2005;353:2111-2120).
Side effects are dry mouth, constipation, and insomnia. CV effects are a mixed bag, with improvements in lipids directly related to the magnitude of weight loss. However, sibutramine has also been shown to increase heart rate and produce a dose-related rise in blood pressure (BP).
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Research suggests that a 10- to 15-mg daily dose increases systolic BP by 2 to 4 mm Hg, most likely because of its sympathomimetic properties (. 1998;98:S27-S30). This amounts to a BP risk in people who are already at increased risk for CV disease. The goal is to reduce, not raise, heart disease risk. The effect on BP was seen in preapproval trials, but the drug was approved for long-term use in 1997, after regulators weighed the risks and benefits (. 2005; 143:380-385). Sibutramine is available in 5-, 10-, and 15-mg strengths.
Rimonabant: A Magic Bullet?
The selective cannabinoid-1 receptor blocker rimonabant (known as Acomplia, which will likely be changed if approved for use in the United States) is currently under FDA review. The endocannabinoid system regulates energy homeostasis through cannabinoid-1 receptors in the CNS and the periphery. Central receptors stimulate appetite; blocking them will suppress it.
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Large, multicenter, well-controlled studies in both the United States and Europe have found rimonabant safe and effective. At 20 mg/day, when combined with a calorie-restricted diet, rimonabant has produced sustained weight loss over 2 years. There were also consistent reductions in waist circumference, BP, and lipids—effects that were greater than would be expected based on weight loss alone. The investigators acknowledge that, as in other weight-loss trials, their findings may be limited by high dropout rates (. 2005;353:2121-2134; . 2006;295:761-775).
More studies with rimonabant are ongoing, but these early results suggest that cannabinoid-1 receptor blockers may have the best safety and efficacy profile of any obesity drug to date, with significant CV benefits.
Clear Sailing for Weight-Loss Therapy?
Despite the promise offered by new drugs like rimonabant, pharmacotherapy for obesity can still be problematic.
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Pharmacotherapy is not for everyone. Medications are currently approved only for patients who are obese or who are overweight and have an obesity-related medical complication. Because overweight and obesity are socially and medically undesirable, these drugs will always be used inappropriately. Data from the Behavioral Risk Factor Surveillance Study (. 2004; 39:1243-1248) indicate that almost one third of prescription weight-loss drug users were not obese before they started taking the medications. In addition to physicians, their sources of pharmacotherapy included family and friends.
Both sibutramine and orlistat have been approved for long-term use. They may need to be taken for life, as most people regain weight when they stop taking them. But do we really know how safe years, much less decades, of therapy will be? Complications may only emerge after large numbers of people have been taking them for a long time. This is what happened with phen-fen, which had been used for years; only after being used by more people for more years did the adverse effects become apparent.
Perhaps most concerning is the question—Will it become too easy to simply pop a pill? For high-risk obese patients, adjunctive drug therapy is better than diet and exercise alone. However, for mildly overweight patients who are at less risk, nondrug treatments are reasonable, appropriate, and safe.
With new-generation drug treatments for obesity and more rigorous demonstrations of their safety and efficacy, we may one day be able to win the battle against obesity. But we have yet to determine if the new drugs represent a magic bullet. In the meantime, diet and exercise are 2 powerful weapons that we already have.
