The role of drugs in treating obesity
By Gina Rollins
When the U.S. Surgeon General declared war on obesity late last year, it was medicine's latest attempt to draw attention to a problem that threatens to become a public health crisis.
The Surgeon General estimated that more than half of American adults and 13% of children are obese, and that 300,000 Americans a year die from an illness caused or exacerbated by obesity. Perhaps most alarming, public health officials now predict that obesity-related illnesses may soon surpass tobacco as the nation's leading cause of preventable deaths.
While the Surgeon General focused primarily on lifestyle changes to help Americans lose weight, physicians know first-hand that patients often need more help. That's why weight loss experts are increasingly urging physicians to use drugs to help patients shed unhealthy pounds. The goal is to treat obesity now, before patients develop serious comorbidities.
There are some hurdles, however, to wider use of weight loss drugs. For one, many physicians have steered clear of obesity medications since the 1997 debacle over fen-phen (the fenfluramine-phentermine combination), which was pulled from the market after fenfluramine was linked to cardiac valve problems and primary pulmonary hypertension.
In addition, physicians have only a few drugs to choose from in the battle against the bulge. The FDA has approved a fairly small number of weight loss medications, but it has approved only two for long-term use—typically a year or more. Most other agents have been approved for only short-term use (usually three months or less), which may not be enough time to produce results.
While those obstacles have scared many physicians away from prescribing anti-obesity medications, weight loss experts say it is time for doctors to take another look. With more than 25% of Americans now eligible for weight loss treatment, they say, physicians need to reconsider the role of drugs in combating obesity.
According to the U.S. National Heart, Lung and Blood Institute's 1998 guidelines, physicians should consider using weight loss drugs in patients with a body mass index (BMI) of 27 or higher who have obesity-related risk factors or comorbidities, and in obese patients with a BMI of 30 or higher.
Under certain circumstances, weight loss drugs may also be effective for other patients. For example, gastroenterologist Mark H. DeLegge, ACP-ASIM Member, director of the nutrition section of the Medical University of South Carolina Digestive Disease Center in Charleston, said he considers giving obesity medications to patients with a BMI above 25 who have not responded to a rigorous program combining behavior modification, dietary changes and exercise.
And D. Frank Johnson, FACP, a bariatrician in Billings, Mont., pointed out another type of weight loss drug candidate: "If a woman with a BMI of 26 or 27 has recently gained 25 pounds and tells me she's been exercising daily for a year, her mother weighs 300 pounds and her sister weighs 200, and she fears becoming like them, I would treat her intensively for two or three months, using a weight loss drug in combination with exercise and nutritional programs."
Anti-obesity medications fall into two broad categories based on how they help patients fight fat. One group helps reduce food intake, while the other prevents fat absorption.
Contraindications aside, an appetite suppressant is often the best choice for patients who think constantly about food and have strong cravings and voracious appetites.
The old appetite suppressant standby is phentermine, which has been available in resin form since 1959. This noradrenergic agent inhibits the reuptake of neurotransmitters dopamine and norepinephrine, which act on the feeding center of the brain to reduce appetite.
Available under a variety of brand names such as Ionamin, Adipex and Fastin, phentermine is approved for only short-term use. Like other appetite suppressants, the drug can create dependence in regular users. It can also elevate blood pressure, and cause tachycardia and various central nervous system effects such as dizziness and insomnia.
Although phentermine is approved only for short-term use, off-label use is not uncommon. Dr. Johnson said he maintains patients on the drug for longer periods, but requires re-examination every three months.
Some physicians say they prescribe phentermine for more than three months—longer than the FDA-approved time frame—because patients simply need more time on the drug to lose weight. Longer treatment is possible, Dr. Johnson explained, because phentermine has a good safety record. "It's been around for 40 years and appears to be nontoxic over a long period of time," he said.
Louis J. Aronne, MD, clinical associate professor of medicine at Weill Medical College of Cornell University in New York City, said he also uses phentermine off-label. Before prescribing the drug, however, he asks patients to sign a consent form acknowledging that they may need to take phentermine for more than three months, at which point it is considered an off-label use.
Some physicians have also started to prescribe phentermine in combination with popular antidepressants like fluoxetine (Prozac) and venlafaxine (Effexor). Anecdotal reports say that the combination may produce substantial weight loss in some patients, but no studies have examined the combination's effectiveness or safety.
Other similar-acting but less popular appetite suppressants include diethylpropion, phendimetrazine and mazindol.
One of the newer appetite suppressants is sibutramine (Meridia), which has been on the market since 1998. Approved for long-term use, it inhibits the reuptake of norepinephrine and serotonin, and to a lesser extent, dopamine.
Side effects range from dry mouth, insomnia and constipation to potentially serious increases in blood pressure and pulse. All patients taking the drug should be regularly monitored, and it is not recommended for people with high blood pressure or other cardiovascular diseases.
Some physicians are also taking a new look at an older type of appetite suppressants—amphetamines—that fell out of favor for obesity treatment because of their potential for dependence. In certain circumstances, drugs like dextroamphetamine might be considered, explained Washington endocrinologist Wayne Callaway, MD.
"If you have a patient who shows evidence of low adrenergic activity, why not go to something that has fewer side effects and doesn't affect another neurotransmitter?" Dr. Callaway asked. By using relatively small doses in longer acting forms, closely monitoring patients and having them take the medication consistently every day, he said, you can reduce the possibility of dependence.
Patients who eat out frequently, have been unsuccessful in cutting fat intake or have cardiovascular conditions may fare better with a drug that fights fat absorption, rather than an appetite suppressant.
Orlistat (Xenical) is the only medication besides sibutramine that has been approved for long-term weight loss use. This lipase inhibitor works by preventing the body from absorbing about 30% of dietary fat.
While orlistat does not produce some of the side effects of sibutramine and other appetite suppressants, it can produce gastrointestinal symptoms like diarrhea and fecal incontinence that are intolerable to some patients. (Two recent studies, however, have shown that when a fiber supplement is taken before bed, the drug's gastrointestinal effects can be reduced by 75%). The drug can also cut down on the absorption of fat-soluble vitamins, so patients taking it may also need multivitamin supplements.
Robert F. Kushner, FACP, professor of medicine at Northwestern University in Chicago, explained that helping patients reduce their fat intake often helps limit those side effects. As a result, he gives patients written materials about the drug and asks them to adhere to a modified fat diet and maintain a food journal for two weeks. "You have to reinforce the absolute need to control fat," he explained.
However, physicians prescribing orlistat have to walk a fine line when limiting fat intake. When patients restrict their fat intake to less than 20% of their overall diet, Dr. Kushner said, the drug loses some of its effectiveness.
Those caveats stop many physicians from using the drug. Montana's Dr. Johnson, for instance, does not prescribe orlistat often, putting his patients instead on controlled, low-calorie, low-fat diets. The modest benefit the drug might bring compared to its cost and potential side effects does not justify its use, he said.
He is more likely, he added, to use sibutramine or phentermine for long-term treatment, while taking into account the fact that sibutramine is relatively expensive and may not be covered by insurance. "If I think patients will need sibutramine long-term and they can afford it or their insurance will pay for it, then I use it," he explained.
Using other drugs off-label
Weight loss experts say that several other drugs can play an important role in weight loss, although none have been approved to treat obesity.
When accompanied by dietary changes and exercise, the antidiabetic agent metformin can reduce insulin levels and help insulin resistant patients shed excess weight. The drug can also help patients who are not diabetic but still have high levels of insulin. Washington's Dr. Callaway noted that women with polycystic ovarian syndrome, who typically have insulin resistance, are also prime candidates for the drug.
The antidepressant bupropion (Wellbutrin) may help patients lose weight who are overweight and suffering from depression. Charleston's Dr. DeLegge said he sometimes gives the drug to obese patients who have symptoms of depression and have not been obese most of their adult lives.
No matter what drug you prescribe, you can realistically expect to help most patients lose 5% to 10% of their starting body weight, or five to 22 pounds. That figure represents up to twice the loss generally possible through conventional behavior modification efforts.
The crucial link between behavior and success with weight loss medications makes it important to establish realistic treatment goals. Dr. DeLegge, for instance, said he aims to help patients lose between 10% and 15% of their body weight within a year.
"If you tell patients that they will see a 25% weight loss, you set them up for failure," he said. "They will feel they've failed, and will have no incentive to keep up with any behavior modification."
Dr. Johnson, however, said he goes further and tries to help patients lose 10% to 20% of their body weight. To make that goal, he prescribes medications in conjunction with aggressive lifestyle changes. An important part of that strategy includes educating patients to stay on low-calorie, low-fat maintenance diets after going off the more restrictive diet he prescribes while they are losing weight.
Dr. Aronne from Weill Medical College pointed out that he considers even a 5% weight loss effective because visceral fat is lost first, which yields immediate benefits. He also noted that he is concerned about encouraging patients to lose 10% or more of body weight, explaining that we can't control how much someone loses because certain mechanisms in the body seem to prevent weight loss. The result could be a disappointed—and demoralized—patient who gives up.
While patients may not be impressed by a weight loss of only 5%, data show that they can reap dramatic health benefits from shedding even a few pounds. The diabetes prevention program of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, for example, found that losing 5% of overall body weight and making other lifestyle changes reduced the risk of developing type 2 diabetes by 58% in at-risk patients.
It is not uncommon for patients to regain weight once they stop taking medications, which raises the possibility of continuing therapy beyond approved time frames. It also underscores the need for ongoing nutritional and psychological support.
"The medicines provide a boost," explained James Grendell, MD, chief of the division of gastroenterology, hepatology and nutrition at Winthrop-University in Mineola, N.Y., "but they are not enough to resolve the problem."
To be even moderately successful, weight loss experts say, physicians must couple anti-obesity medications with a treatment plan that includes behavior modification, dietary changes and exercise. The need to link drug therapy and lifestyle changes with ongoing support, however, makes some physicians nervous. "Doctors think they need a PhD in nutrition to do the right thing," explained Dr. Aronne, "but they can rely on other people, either in their practice or in consultation, to support patients."
If professional nutritional services are not available in your area, he said, consider steering patients to commercial programs like Weight Watchers or Internet-based services such as eDiets.com. Those types of support groups are better than prescribing drugs alone.
Finally, weight loss experts claim, physicians should feel confident enough about the effectiveness of drug therapies to start treating obesity and stop focusing solely on the condition's comorbidities. While treating obesity may not be easy, they say, the payoff can be much greater than honing in on a condition like heart disease.
"The appeal of obesity treatment is that you're treating several cardiovascular risk factors at one time," explained Dr. Aronne. "It's the mother of a whole lot of problems."
Gina Rollins is a freelance writer in Silver Spring, Md.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.
- "A Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," produced by the NHLBI and the North American Association for the Study of Obesity, is available online at www.nhlbi.nih.gov/guidelines/obesity/practgde.htm
- See the "Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults," from by the National Heart, Lung and Blood Institute online at www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm.
While drugs can help obese patients shed unhealthy pounds, physicians need to take into account patient motivation and its role in weight loss before prescribing any weight loss drug.
"Anti-obesity medications are unique in that there is such a drug-behavior interaction," explained Robert F. Kushner, FACP, professor of medicine at Northwestern University in Chicago. "But they are effective only if the patient also follows lifestyle modification recommendations."
That's why experts suggest exploring your patient's weight loss expectations and motivations before you pull out a prescription pad. "Patients need to know weight loss is a long-term process with no quick fixes," explained James Grendell, MD, chief of the division of gastroenterology, hepatology and nutrition at Winthrop-University in Mineola, N.Y. "There's no magic bullet that allows you to lose weight no matter how much you eat. That's an important point, because patients come in with that thought."
There can be other major benefits to focusing on patients' behavior and lifestyle. In some instances, addressing underlying medical conditions and changing existing medications may obviate the need to prescribe anti-obesity drugs.
Patients with untreated sleep apnea, for instance, "find it hard to concentrate on maintaining a healthy diet," explained Louis J. Aronne, MD, clinical associate professor of medicine at Weill Medical College of Cornell University in New York City. "If you treat the sleep apnea, it won't cause them to lose weight specifically, but it can help them focus on their diet."
Some medicines like beta-blockers can cause patients to gain weight. Depending on a patient's cardiac status, a switch to angiotensin-converting enzyme (ACE) inhibitors may be just as effective—and lead to weight loss.
And the anti-epileptic topiramate is a good substitute for two drugs notorious for putting on pounds, gabapentin—which is commonly used to treat diabetic neuropathy-and the mood stabilizer valproic acid.
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