Drugs Physical Activity Surgery and other Treatment for Overweight and Obesity - Medication

Pharmacotherapy for weight loss involves the use of prescription drugs as one of several strategies including diet, physical activity, behavioral therapy, counseling, and participation in group support programs that in combination can work to effect weight loss. Adding weight-loss medications to a comprehensive treatment program consisting of diet, physical activity, and counseling increases weight loss by 5 to 20 pounds during the first six months of treatment. The decision to add prescription drugs to a treatment program usually considers the individual's BMI, other medical problems, or coexisting risk factors. Table 6.4 shows the therapies appropriate for persons with differing BMIs and takes into account the presence of comorbidities such as diabetes, severe sleep apnea, or heart disease.

TABLE 6.1
A sample walking program

	Warmup	Exercising	Cool down	Total time
Week 1
Session A	Walk 5 min.	Then walk briskly 5 min.	Then walk more slowly 5 min.	15 min.
Session B	Repeat above pattern
Session C	Repeat above pattern
Continue with at least three exercise sessions during each week of the program.
Week 2	Walk 5 min.	Walk briskly 7 min.	Walk 5 min.	17 min.
Week 3	Walk 5 min.	Walk briskly 9 min.	Walk 5 min.	19 min.
Week 4	Walk 5 min.	Walk briskly 11 min.	Walk 5 min.	21 min.
Week 5	Walk 5 min.	Walk briskly 13 min.	Walk 5 min.	23 min.
Week 6	Walk 5 min.	Walk briskly 15 min.	Walk 5 min.	25 min.
Week 7	Walk 5 min.	Walk briskly 18 min.	Walk 5 min.	28 min.
Week 8	Walk 5 min.	Walk briskly 20 min.	Walk 5 min.	30 min.
Week 9	Walk 5 min.	Walk briskly 23 min.	Walk 5 min.	33 min.
Week 10	Walk 5 min.	Walk briskly 26 min.	Walk 5 min.	36 min.
Week 11	Walk 5 min.	Walk briskly 28 min.	Walk 5 min.	38 min.
Week 12	Walk 5 min.	Walk briskly 30 min.	Walk 5 min.	40 min.
Week 13 on: Gradually increase your brisk walking time to 30 to 60 minutes, three or four times a week. Remember that your goal is to get the benefits you are seeking and enjoy your activity.
SOURCE: "A sample walking program," 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, Silver Spring, MD, June 1998 [Online ] http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf [accessed December 30, 2003]

TABLE 6.2
Examples of moderate amounts of activity¹

Washing and waxing a car for 45–60 minutes
Washing windows or floors for 45–60 minutes
Playing volleyball for 45 minutes
Playing touch football for 30–45 minutes
Gardening for 30–45 minutes
Wheeling self in wheelchair for 30–40 minutes
Walking 1¾ miles in 35 minutes (20 min/mile)
Basketball (shooting baskets) for 30 minutes
Bicycling 5 miles in 30 minutes
Dancing fast (social) for 30 minutes
Pushing a stroller 1 miles in 30 minutes
Raking leaves for 30 minutes
Walking 2 miles in 30 minutes (15 min/mile)
Water aerobics for 30 minutes
Swimming laps for 20 minutes
Wheelchair basketball for 20 minutes
Basketball (playing a game) for 15–20 minutes
Bicycling 4 miles in 15 minutes
Jumping rope for 15 minutes
Running 1½ miles in 15 minutes (10 min/mile)
Shoveling snow for 15 minutes
Stairwalking for 15 minutes
1A moderate amount of physical activity is roughly equivalent to physical activity that uses approximately 150 calories of energy per day, or 1,000 calories per week.
2Some activities can be performed at various intensities; the suggested durations correspond to expected intensity of effort.
SOURCE: "Table IV-4. Examples of Moderate Amounts of Activity," in Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, National Heart, Lung, and Blood Institute in cooperation with The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, NIH Publication No. 98-4083, September 1998 [Online] http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.htm [accessed December 30, 2003]

TABLE 6.3
Examples of moderate amounts of physical activity¹

Common chores	Sporting activities
Washing and waxing a car for 45–60 minutes	Playing volleyball for 45–60 minutes
Washing windows or floors for 45–60 minutes	Playing touch football for 45 minutes
Gardening for 30–45 minutes	Walking 1¾ miles in 35 minutes (20 min/mile)
Wheeling self in wheelchair for 30–40 minutes	Basketball (shooting baskets) for 30 minutes
Pushing a stroller 1 ½ miles in 30 minutes	Bicycling 5 miles in 30 minutes
Raking leaves for 30 minutes	Dancing fast (social) for 30 minutes
Walking 2 miles in 30 minutes (15 min/mile)	Water aerobics for 30 minutes
Shoveling snow for 15 minutes	Swimming laps for 20 minutes
Stairwalking for 15 minutes	Basketball (playing a game) for 15–20 minutes
	Jumping rope for 15 minutes
	Running 1½ miles in 15 minutes(15 min/mile)
1A moderate amount of physical activity is roughly equivalent to physical activity that uses approximately 150 calories of energy per day, or 1,000 calories per week.
2Some activities can be performed at various intensities; the suggested durations correspond to expected intensity of effort.
SOURCE: "Table 5. Examples of Moderate Amounts of Physical Activity," 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, Silver Spring, MD, June 1998 [Online ] http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf [accessed December 30, 2003]

TABLE 6.4
A guide to selecting treatment

	BMI category
Treatment	25–26.9	27–29.9	30–34.9	35–39.9	≥40
Diet, physical activity, and behavior therapy	With comorbidities	With comorbidities	+	+	+
Pharmacotherapy		With comorbidities	+	+	+
Surgery			With comorbidities
• Prevention of weight gain with lifestyle therapy is indicated in any patient with a BMI ≥ 25 kg/m2, even without comorbidities, while weight loss is not necessarily recommended for those with a BMI of 25–29.9 kg/m2 or a high waist circumference, unless they have two or more comorbidities.
• Combined therapy with a low-calorie diet (LCD), increased physical activity, and behavior therapy provide the most successful intervention for weight loss and weight maintenance.
• Consider pharmacotherapy only if a patient has not lost 1 pound per week after 6 months of combined lifestyle therapy.
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, Silver Spring, MD, June 1998 [Online ] http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf [accessed December 30, 2003]

TABLE 6.5
Weight loss drugs*

Drug	Dose	Action	Adverse effects
Sibutramine (Meridia)	5, 10, 15 mg 10 mg orally every day to start, may be increased to 15 mg or decreased to 5 mg	Norepinephrine, dopamine, and serotonin reuptake inhibitor.	Increase in heart rate and blood pressure.
Orlistat (Xenical)	120 mg 120 mg orally three times a day before meals	Inhibits pancreatic lipase, decreases fat absorption.	Decrease in absorption of fat-soluble vitamins; soft stools and anal leakage.
*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, benzphetamine, 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, Silver Spring, MD, June 1998 [Online ] http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf [accessed December 30, 2003]

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 act on—some affect catecholamines such as dopamine and norepinephrine; 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 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 persons 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 percent beyond that weight loss attributable to dieting alone. Table 6.5 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); how-ever, 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, prepared by the National, Heart, Lung, and Blood Institute of the National Institutes of Health (NIH), reminds healthcare 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 persons 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 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.

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. As of 2004 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 a new appetite-suppressing drug called Axokine was undergoing clinical trials. Axokine is a modified form of a naturally occurring protein, called ciliary neurotrophic factor, and acts by signaling the satiety center of the brain to decrease food intake. In March 2003 preliminary data from about 2,000 subjects taking Axokine showed that subjects treated with Axokine lost more weight than those who received a placebo (an inactive substance used as a control in an experiment), and suggested that it may not produce the same rebound effect seen with sibutramine. Another experimental weight-loss drug, rimonabant, blocks the "munchie receptor" believed to stimulate appetite among persons 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 20 pounds (9.07 kg) in a year. Since rimonabant blocks cravings, its potential as a smoking-cessation aid is also under investigation.

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 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 percent of all dietary supplement sales, they accounted for 64 percent 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 ephedra 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 percent 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 in 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 March 1, 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.