Prescription diet pills: a history of FDA favor

While the FTC has filed complaints against four companies for falsely advertising over-the-counter weight-loss products when their safety and effectiveness are not supported by reliable scientific evidence [See Junkfood Science Special Report], the January issue of the medical journal Lancet reports that not enough is known about the safety and long-term efficacy of the top prescription weight-loss drugs to know if their risks and high costs are justified, either.

As reported in the news, the Lancet article said none of the drugs — Xenical (orlistat), Meridia (sibutramine) or Acomplia (rimonabant) — results in significant weight loss and all have side effects of concern. Yet not enough is known to ensure the safety of these drugs that patients may have to take for years, said Dr. Raj S. Padwal and Dr. Sumit R. Majumdar, from the University of Alberta Hospital in Edmonton, Canada. There is no definitive data showing a benefit of one anti-obesity drug over another, these doctors said. And the evidence on all three drugs is limited by modest short-term effectiveness and low rates of patients who stay on them for any length of time. Inadequacies in the drug trials, leaving major gaps in knowledge, include their short durations and high drop-out rates, and also their failure to measure actual health outcomes, such as cardiovascular morbidity and mortality. The doctors said clinical documentation that these treatments save lives or cut deadly risks, such as heart disease, need to be required before they’re approved for widespread use so that doctors can ascertain if benefits outweigh the risks.

Already apparent in short-term trials use were adverse effects such as gastrointestinal problems with orlistat, high blood pressure and heart rate with sibutramine, and possible mood disorders with rimonabant. It is unknown what might occur with long-term use or the effectiveness of these drugs over the long-term, the Lancet article cautioned.

These professionals are not alone in warning consumers and healthcare professionals about pharmacological weight-loss treatments. A systematic review of fourteen randomized, placebo-controlled trials for the prescription drugs fluoxetine, orlistat and sibutramine among adults with type 2 diabetes was led by Dr. Susan Norris, MD, of the Centers for Disease Control and Prevention and published in the July 2004 issue of the Archives of Internal Medicine. It found very modest weight loss over 26-52 weeks time, but the “long-term health benefits and safety remain unclear,” said Dr. Norris. The weight losses were considerably less impressive than most consumers may be being led to believe: about 3 ounces per week on fluoxetine over a 52 week period; 1 1/2 ounces per week for orlistat over 52 weeks; and half a pound per week for sibutramine over 26 weeks. Despite these minor weight losses, “gastrointestinal adverse effects (explosive diarrhea, fecal incontinence, abdominal cramping, anal leakage and oily discharge) were common with orlistat; tremor, somnolence and sweating with fluoxetine; and palpitations with sibutramine.” Yet eight out of ten of the studies were paid for by the drug manufacturers, said Dr. Norris, and none of the companies provided the reviewers with unpublished studies they’d done on the drugs.

During the 1996 FDA review of Meridia (sibutramine), the Endocrinologic and Metabolic Drugs Advisory Committee voted against approving it on the grounds that the risks of raising blood pressure and heart rate could be dangerous for many patients and outweigh the “meager amount of weight loss seen in clinical trials.” The FDA approved it against the advice of its expert advisors.

The Public Citizen’s Health Research Group petitioned the FDA on March 19, 2002 to remove sibutramine from the market for safety reasons, noting that the FDA’s own public data showed that from the drug’s introduction in February 1998 to September 30, 2001, there were nearly 400 serious adverse reactions, including 19 cardiac deaths (10 in people under age 50, and 3 in women under 30). The Public Citizen again petitioned the FDA on September 3, 2003, for increasing reports of such harm, adding 54 reports of adverse effects from maternal exposure including “heart birth defects, spontaneous abortions, stillbirths and congenital malformations.”

The FDA rejected the Public Citizen’s petitions in August, 2005, saying it couldn’t conclude that the heart attacks were caused by the drugs, since heart attacks are “very common” in obese people, reported Consumer Affairs.

Dr. Sidney M. Wolfe, MD, and colleagues at the Public Citizen’s Health Research Group have been urging consumers since 1997 to not use Xenical (orlistat), stating in Worst Pills Best Pills:

Like other diet drugs, orlistat was approved without scientific evidence showing that there is a health benefit for those who use it. In other words, there is no evidence that orlistat, or any diet drug, will reduce risk of premature death or illness associated with long-term obesity and inactivity.

Another side effect of concern is that orlistat reduces the absorption of fat-soluble vitamins (A, D, E and K) and beta-carotene. Its package insert states that 12% of users become vitamin D deficient over a 2-year time period, and vitamin E and beta-carotene deficiency had been documented in 6%.

Roche launched a direct-to-consumer advertising campaign for Xenical (orlistat) in 1999 that was “one of the largest in the pharmaceutical industry and the first ever branded effort for a Roche product,” according to the company press release. The company said the campaign would approach weight loss as a health priority. “Xenical can significantly improve weight loss and reduce weight-related health risk factors when used as part of a medically supervised treatment plan including a reduced calorie diet,” said the company president. “Xenical has a unique mechanism of action and efficacy that offers patients an important tool in achieving long-term success,” said Louis J. Aronne, MD, Director of the Comprehensive Weight Control Program, Cornell University Medical College.

In January, 2006, GlaxoSmithKline, the current maker of Xenical (orlistat) petitioned the FDA to sell a half-strength version of its drug over-the-counter under the name “Alli.” This time, the FDA’s advisory committee recommended approval of the petition, which would make it the first FDA-approved OTC. However, it was later learned that the FDA advisory panel had not been told of two animal studies documenting “aberrant crypt foci,” possible precancerous changes in the colon, induced by orlistat.

Last April, the Public Citizen petitioned the FDA to immediately remove Xenical (orlistat) from the market citing a review of the manufacturer’s data and an independent confirmation showed it appeared to increase the risk of aberrant crypt foci. While human data is far from conclusive concerning this surrogate biomarker, said Dr. Wolfe, given the lack of demonstrated efficacy of the drug to date, markers should be given greater weight in measuring adverse events than benefits. This pill’s unresolved potential to contribute to cancer, as well as its gastrointestinal side effects, loss of vitamins, and links to kidney stones and hepatitis, only serve to fuel concerns of the drug’s efficacy. Two recent clinical trials showing a mere 2.8% weight loss over placebo after 4 years also called into question the drug’s benefits, said Dr. Wolfe. “[The] FDA is now considering increasing the number of people exposed to the drug by allowing OTC use. There is no scientific justification for this decision,” said the Public Citizen.

Despite the FTC 2002 scientific review finding fat blocking drugs incapable of causing substantial weight loss [See Junkfood Science Special Report], attendees at the 2006 International Congress on Obesity in Sydney, Australia, heard a different story. A study was reported as finding that low-dose orlistat (“Alli”), along with a low-calorie diet, produced meaningful weight loss and improved cholesterol and blood pressure. “These findings provide further support that a lower dose of orlistat can not only effectively help individuals lose weight, but reduce risk factors associated with co-morbid diseases and improve health overall,” said lead investigator at GlaxoSmithKline Consumer Healthcare. The study referenced was done in 2000 by researchers at Hoffman-LaRoche, Inc. and found an additional 6-pound weight loss over a placebo with orlistat after one year.

Advertising and marketing for prescription drugs has been regulated by the FDA since 1962. But the public may be getting the idea that that ball is dropped more effectively than weight when it comes to diet drugs.

© Sandy Szwarc 2007