Most drugs used for weight loss are appetite suppressants (anorexiants) that act on neurotransmitters (chemical substances that convey impulses from one nerve cell to another) in the brain. Anorexiant drugs vary depending on which neurotransmitters they affect—some have an effect on catecholamines such as dopamine and norepi-nephrine; others affect serotonin; and a third class of drugs acts on more than one neurotransmitter. The drugs act by increasing the secretion of dopamine, norepinephrine, or serotonin, by inhibiting reuptake of neurotransmitters, or by a combination of both mechanisms. For example, sibutramine (Meridia) inhibits the reuptake of norepinephrine and serotonin.
Another class of weight-loss drugs blocks absorption of fat. Orlistat, approved by the U.S. Food and Drug Administration (FDA) in 1999 as Xenical, decreases fat
TABLE 6.3 A guide to selecting treatment| TABLE 6.3 | |||||
|---|---|---|---|---|---|
| A guide to selecting treatment | |||||
| Treatment | BMI category | ||||
| 25-26.9 | 27-29.9 | 30-34.9 | 35-39.9 | ≥40 | |
| The + represents the use of indicated treatment regardless of comorbidities. | |||||
| SOURCE: "Table 3. A Guide to Selecting Treatment," in The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, National Institutes of Health, National Heart, Lung, and Blood Institute, North American Association for the Study of Obesity, October 2000, http://www.nhlbi.nih.gov/guidelines/obesity/practgde.htm (accessed January 12, 2006) | |||||
| Diet, physical activity, and behavior therapy | With comorbidities | With comorbidities | + | + | + |
| Pharmacotherapy | With comorbidities | + | + | + | |
| Surgery | With comorbidities | ||||
|
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absorption by the gut by about one-third. Because it also inhibits absorption of water and vitamins, some users suffer from cramping and diarrhea. The determination of which type of drug to prescribe is based on individual patient characteristics—sibutramine works best for people who are preoccupied with food and feel constantly hungry, while orlistat may be effective for those who are unwilling to reduce fat from their diets. Neither drug has demonstrated remarkable effectiveness. One study found that during the course of a year, orlistat increased weight loss by an average of 2% to 3% beyond that weight loss attributable to dieting alone. Table 6.4 displays the recommended doses of sibutramine and orlistat, potential adverse effects, and compares their mechanisms of action.
Several weight-loss drugs that appeared effective and were popular among consumers have been withdrawn from the U.S. market because of the number and severity of adverse side effects associated with their use. During the 1990s a combination of two drugs—phentermine and fenfluramine, commonly known as "phen-fen" was prescribed for long-term use (more than three months); however, rare but unacceptable side effects, including serious damage to the heart valves, prompted the withdrawal of fenfluramine and a similar drug, dexfenfluramine, in September 1997. Phentermine, one half of the "phen-fen" combination, is still approved for short-term use.
The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults (October 2000), prepared by the National, Heart, Lung, and Blood Institute of the National Institutes of Health (NIH), reminds health-care practitioners that not every patient responds to drug therapy, and reiterates that only patients at increased health risk because of their weight should be given weight-loss medications. Further, it emphasizes that drugs should only be used as part of a comprehensive treatment program and that people taking drugs must be closely monitored for side effects.
Research Focuses on New Weight-Loss Drugs
In "Experimental Drugs Take Aim at Obesity" (Journal of the American Medical Association, vol. 289, no. 14, April 9, 2003), Brian Vastag lamented the fact that five years after the FDA ban of fenfluramine, just three prescription weight-loss drugs remained available in the United States. Only two of the drugs, orlistat and sibutramine, were approved for long-term use, and evidence indicates that many users experience "rebound" weight gain when the use of either of these drugs is discontinued. Although these two FDA-approved weight-loss drugs for long-term use were the only drugs available by prescription to consumers at the close of 2005, more than seventy new drugs were in various stages of development.
Researchers have identified ghrelin, a hormone that may be involved in establishing hunger and satiety set points. When the stomach is empty it releases ghrelin, which in turn triggers hunger signals in the brain. Blood levels of ghrelin peak before meals and decrease after eating. Since ghrelin appears to increase appetite and slow metabolism, an excess of it may sabotage long-term weight-loss efforts. Small studies show that ghrelin levels are higher in obese patients who have recently lost weight compared with obese patients at a steady weight. During 2005 pharmaceutical companies were seeking to create drugs that safely and effectively block ghrelin's effects. An analogous approach seeks to boost levels of a peptide known as PYY that produces the opposite effects of ghrelin. After eating, the stomach and digestive tract release PYY, conveying the satiety signal to the brain. In one small study, subjects given the hormone ate a third less food from a buffet.
While drugs to inhibit ghrelin and increase PYY have not yet been formulated, during 2004 and 2005, a new appetite-suppressing drug called Axokine was undergoing clinical trials. Axokine is a modified form of a
TABLE 6.4 Weight loss drugs*
| TABLE 6.4 | |||
|---|---|---|---|
| Weight loss drugs* | |||
| Drug | Dose | Action | Adverse effects |
| *Ephedrine plus caffeine, and fluoxetine have also been tested for weight loss but are not approved for use in the treatment of obesity. Mazindol, diethylpropion, phentermine, benzphetanine, and phendimetrazine are approved for only short-term use for the treatment of obesity. Herbal preparations are not recommended as part of a weight loss program. These preparations have unpredictable amounts of active ingredients and unpredictable, and potentially harmful, effects. | |||
| SOURCE: "Table 6. Weight Loss Drugs," in The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, National Institutes of Health, National Heart, Lung, and Blood Institute, North American Association for the Study of Obesity, October 2000, http://www.nhlbi.nih.gov/guidelines/obesity/practgde.htm (accessed January 12, 2006) | |||
| Sibutramine (Meridia) | 5, 10, 15 mg | Norepinephrine, dopamine, and serotonin reuptake inhibitor. | Increase in heart rate and blood pressure. |
| 10 mg orally every day to start, may be increased to 15 mg or decreased to 5 mg | |||
| Orlistat (Xenical) | 120 mg | Inhibits pancreatic lipase, decreases fat absorption. | Decrease in absorption of fat-soluble vitamins; soft stools and anal leakage. |
| 120 mg orally three times a day before meals | |||
Another experimental weight-loss drug, rimonabant, blocks the "munchie receptor" believed to stimulate appetite among people who smoke marijuana. Preliminary data, announced by the French pharmaceutical company Sanofi-Synthelabo in March 2004, showed that patients receiving a daily dose of rimonabant lost an average of twenty pounds (9.07 kg) in a year. By April 2005, the results of a yearlong multicenter study of 1,507 overweight or obese adults showed that subjects that took rimonabant lost more weight than subjects who attempted to lose weight via diet alone. The rimonabant group also had greater improvements in high-density lipoprotein cholesterol and triglycerides. Other cardiovascular risk factors are improved as well, including dyslipidemia and insulin resistance (Luc Van Gaal et al., "Effects of the Cannabinoid-1 Receptor Blocker Rimonabant on Weight Reduction and Cardiovascular Risk Factors in Overweight Patients: One-year Experience from the RIO-Europe Study," Lancet, vol. 365, no. 9,468, April 16, 2005). Since rimonabant blocks cravings, its potential as a smoking-cessation aid is also under investigation.
In 2005 there were also promising preliminary findings from a twenty-eight-day trial of a drug from Arena Pharmaceuticals known only as APD356. Subjects taking the drug lost an average of 2.9 pounds during the twenty-eight-day trial compared with a loss of 0.7 pounds by subjects who took a placebo (http://www.arenapharm.com/wt/page/apd356). The drug acts by stimulating receptors in the hypothalamus, a part of the brain that plays a key role in regulating food intake and metabolism.
Non-Prescription Weight-Loss Aids
The withdrawal of fenfluramine from the market prompted many consumers to seek alternative weight-loss aids, including herbal preparations that were marketed as dietary supplements and available over-the-counter. Some preparations, such as such as Stacker 2 and Metabolife 356, combined ephedra, caffeine, and other ingredients. Ephedra (also known by its traditional Chinese medicine name, ma huang) is a naturally occurring substance that comes from botanicals. Products containing ephedra and ephedrine have been promoted to accelerate weight loss, increase energy, and improve athletic performance. The principal active ingredient in ephedrine is an amphetamine-like compound that stimulates the nervous system and heart. Because ephedrine has some anorectic and thermogenic properties, it may induce weight loss in some people, and some studies have shown that when ephedrine is combined with caffeine, the combination may lead to even more weight loss.
During 2003 the FDA and NIH investigated reports of adverse effects linked to ephedra use. A RAND Corporation study commissioned by the NIH concluded that there was only limited evidence of health benefits resulting from ephedra use. These benefits did not outweigh the serious risks posed by its association with heart palpitations, psychiatric and upper gastrointestinal effects, tremors, and insomnia, especially in formulations in which it was combined with caffeine, or taken with other stimulants. The RAND researchers reviewed 16,000 adverse events and identified two deaths, four heart attacks, nine strokes, one seizure, and five psychiatric cases in which ephedra appeared to be the causative agent.
Another study, "The Relative Safety of Ephedra Compared with Other Herbal Products" (Annals of Internal Medicine vol. 138, no. 6, March 18, 2003), conducted by Stephen Bent and his colleagues, compared the risk for adverse events attributable to ephedra and other herbal products. The investigators found that while ephedra products comprised less than 1% of all dietary supplement sales, they accounted for 64% of adverse events associated with dietary supplements. They concluded that "the risk for an adverse reaction after the use of ephedra is substantially greater than with other herbal products."
In July 2003 the Federal Trade Commission generated more negative publicity for the dietary supplement when it charged marketers of weight-loss products that contain ephedra with making deceptive efficacy (effectiveness) and safety claims. The Federal Trade Commission actions deemed as examples of false advertising claims that ephe-dra causes rapid, substantial, and permanent weight loss without diet or exercise, and that "clinical studies" or "medical research" proved these claims. The Commission also challenged claims that the ephedra weight-loss products are "100% safe," "perfectly safe," or have "no side effects."
On December 30, 2003, the U.S. Department of Health and Human Services and the FDA notified manufacturers of dietary supplements containing ephedra that the sale of these dietary supplements would be banned sixty days following publication of the year-end notice. The same day, the FDA issued an alert to consumers advising them to stop using ephedra products immediately.
During the first months of 2004, dieters flocked to health food stores and Internet sites selling dietary supplements and bought entire inventories of supplements containing ephedra in anticipation of the ban of its sale as early as April 12, 2004. Many of the supplements' fans asserted that the ban was prompted by the publicity surrounding the ephedra-related death of Baltimore Orioles pitcher Steve Bechler on February 17, 2003. Bechler was twenty-three years old when he collapsed from heatstroke at the Orioles' spring training camp in Florida. Two weeks later the FDA ordered warning labels be placed on products containing ephedra, and set in motion plans to ban its sale.
Many health professionals and consumer watchdog agencies such as the advocacy group Public Citizen applauded the FDA action but observed that the FDA first proposed warning labels and a dosage curb for ephedra in 1997, but the supplement industry effectively blocked the move. The December 2003 action was a historic occasion—the first time the FDA completed the steps necessary to ban the sale of a dietary supplement.
WILL HOODIA BE THE NEXT BEST THING FOR DIET ERS?
With ephedra withdrawn from the market, dieters anxiously awaited the introduction of another nonpre-scription drug to replace it. In 2003 reports of an appetite suppressant derived from hoodia, a bitter-tasting cactus that grows in the South African Kalahari desert, generated interest and excitement. The San Bushmen of the Kalahari, one of the world's oldest and most primitive tribes, have been eating hoodia for thousands of years, to stave off hunger during long hunting trips.
The plant contains a molecule, called p57, which is thought to act on the hypothalamus to mimic the sense of satiety that normally results only from eating food. The first clinical trials of hoodia were considered successful when subjects given hoodia consumed an average of 1,000 calories fewer per day than those given placebo. Phytopharm, the company that holds the rights to extracting p57 from hoodia, expects to market products containing hoodia by 2007. In the meantime, following a segment about hoodia that aired on the CBS newsmagazine 60 Minutes (November 21, 2004), demand for hoodia skyrocketed. In response, many importers introduced products that claimed to contain hoodia, and by 2006, dozens of Web sites offered pills, powders, and liquids containing various amounts of hoodia.
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