Reflections on obesity

Obesity defined
The NIH established distinct standards for what constitutes overweight and obesity in June 1998. According to clinical guidelines, overweight is defined as an excess of body weight that may come from muscle, bone, fat, and/or body water as compared with set standards. This is in contrast to obesity, which is defined as an abnormally high proportion of body fat. Thus, while all obese people are overweight, not all overweight people are obese. For example, some athletes are classified as overweight simply because they have a lot of muscle.

Many researchers and health professionals rely on the body mass index (BMI) to determine obesity. This is a nongender-specific calculation based on height (in.) and weight (lb) using the equation:

BMI = [(weight x 704.5)/height]height

(Visit www.nhlbisupport.com/bmi/for a BMI calculator or www.nhlbi.nih.gov/guidelines/obesity/bmi_tbl.htm for a BMI table.) Although the NIH uses a multiplication factor of 704.5, the American Dietetic Association recommends multiplying the weight by 700. Regardless, the results vary insignificantly. The BMI equation eliminates height as a variable and enables researchers and health professionals to compare people regardless of age, gender, and height. According to the NIH, obese people have a BMI of 30 or greater, while the BMI limit for overweight people is 25 or greater.

Health risks associated with obesity include

• high cholesterol,
• diabetes,
• heart disease,
• stroke,
• hypertension,
• gallbladder disease, and
• some forms of cancer, including those of the breast and uterus.

Obesity can also cause emotional distress; psychological consequences include depression and prejudice or discrimination in the workplace and social settings.

more good surfing

National Institute of Diabetes and Digestive and Kidney Diseases: www.niddk.nih.gov/index.htm American Obesity Association: www.obesity.org FDA Medical Products Reporting and Safety Information Program: www.fda.gov/Medwatch

Appetite suppressants
Obesity is a chronic condition, according to the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Therefore, long-term use of prescription medications is appropriate for some people to lose weight and maintain weight loss. Most obesity prescriptions take the form of appetite suppressants. According to Arthur Frank, medical director of the George Washington University Weight Management Program in Washington, DC, these medications decrease the appetite by modifying the level of some of the chemicals in the brain that regulate eating, such as catecholamine, serotonin, dopamine, or norepinephrine.

Weight loss varies among people taking appetite suppressants; some patients can lose more than 10% of their starting body weight, an amount that greatly reduces risk factors for heart disease and diabetes. But most people reach the maximum amount of weight loss within their first six months on the medication, after which point their weight might plateau or even increase. In addition, Frank says that the brain starts to compensate and develop ways of overcoming the appetite suppression of the medications, usually within the first 3–4 months on the medication.

The U.S. FDA has approved most appetite suppressants for short-term use—from a few weeks to a year. Sibutramine—marketed under the trade name Meridia—is the only appetite suppressant approved for longer-term use, although its safety and effectiveness beyond one year have not been determined. Recent studies, published last December in The Lancet, show that sibutramine can help maintain weight loss in conjunction with a reduced-calorie diet for up to two years (reviewed in the April 2001 issue of Modern Drug Discovery, p 16). But even in the short term, the resulting weight reduction can reduce several health risks by lowering blood pressure and decreasing insulin resistance, which inhibits the body’s ability to process sugar.

The fen–phen fiasco
However, controversy surrounds appetite suppressant medication, especially after the FDA banned fenfluramine, which, with its partner phentermine, formed the infamous drug combination fen–phen. In July 1997, the Mayo Clinic reported that numerous patients on a fen–phen regimen were diagnosed with an unusual valvular heart disease. During routine medical visits, doctors had observed 24 women with an average age of 43 years who had been on the medication for an average of one year. All the women, who had shown no signs of heart disease before they started taking the medication, presented symptoms of cardiovascular disease, such as shortness of breath and heart murmurs. Further examination revealed that one or more heart valves in each patient had thickened and that, as the heart beat, blood backflowed into the heart chambers instead of flowing to the arteries. This phenomenon is referred to as regurgitation, and it forces the heart to work harder to pump blood throughout the body. Researchers also voiced concerns that the related drug dexfenfluramine (commercially known as Redux) could cause similar heart damage. In September 1997, both dexfenfluramine and fenfluramine were pulled off the market by their manufacturers following a recommendation from the FDA.

Fenfluramine is thought to be the damaging agent in fen–phen, emphasizes Frank, and phentermine (marketed as Adipex) is probably an innocent bystander in the controversy. Phentermine was not banned by the FDA, and according to Frank, is still the biggest-selling obesity drug in the United States. Fenfluramine operated like many appetite suppressants by stimulating the release of serotonin in selected neurons in the brain. Experts believe that the problem with fenfluramine was that it stimulated serotonin release elsewhere in the body, such as in the pulmonary blood vessels and cardiac valves, tissues that are unusually susceptible to an increase in serotonin. The result of this increase was pulmonary hypertension and heart valve damage.

Five of the women in the Mayo Clinic report needed heart surgery to repair or replace the damaged valves, while another eight patients developed pulmonary hypertension, a potentially fatal disease of the heart and lungs. During this time, the FDA reported cases of abnormalities in mitral, aortic, and tricuspid heart valves in women between the ages of 30 and 72 who had been on fen–phen for 1–28 months. By 1999, the FDA attributed three deaths to fen–phen.

While both fenfluramine and phentermine individually had FDA approval, the agency does not regulate the prescription of medications at different doses, under different conditions, or for different lengths of time. Prescribing a drug in a manner that falls outside of FDA recommendations is known as “off-label” use, and the fen–phen combination is considered off-label. In addition, the NIDDK says that the safety and effectiveness of combining appetite suppressants is largely unknown because there have been few long-term studies evaluating such therapies. Thus, appetite suppressant combinations such as fluoxetine–phentermine, phendimetrazine– phentermine, or herbal fen–phen are not recommended except as part of a supervised medical research study.

The Meridia miracle
But just months after manufacturers withdrew both fenfluramine and dexfenfluramine from the shelves, the FDA approved sibutramine, which was marketed in 1998 as Meridia. In clinical trials, sibutramine helped to reduce food intake when used in conjunction with a reduced-calorie diet and an exercise regimen, and it is considered an agent for weight-loss maintenance. Sibutramine suppresses the appetite by inhibiting the reuptake of serotonin and norepinephrine, or in other words, preventing the brain’s natural process of removing these chemicals. In addition, sibutramine has few side effects because it does not increase the release or production of serotonin from cells like fenfluramine and dexfenfluramine and therefore does not have the potential to damage cardiac valves.

Sibutramine was not shown to cause primary pulmonary hypertension or valvular heart disease in clinical trials, according to the NIDDK. However, federal guidelines warn that sibutramine may cause a slight increase in blood pressure, and it is not recommended for patients with any kind of heart disease in their medical history.

Orlistat: A new angle
Another obesity drug currently on the market is not an appetite suppressant but works in the gastrointestinal tract to block fat absorption. Orlistat, sold under the brand name Xenical, was approved by the FDA in April 1999. Orlistat works as a lipase inhibitor; it blocks the absorption of fat by attaching itself to the enzyme that allows fat to pass across the intestinal wall. Reported to block up to 30% of fat absorption, Orlistat still allows proteins and carbohydrates to be absorbed into the body.

In terms of future obesity research, Frank is hoping for a comprehensive focus on the appetite process. “Appetite is a complicated system with many different parts,” says Frank. “Medications affect one part of the system for a period of time, but then the brain starts to compensate and develop ways of overcoming the appetite suppression. In order to understand obesity, we must take apart the whole system, try to figure out ways to affect the system, and look at how to avoid this compensation.”