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Weighing the Long-term Effect of Weight Loss Drugs

More and more people are considering the use of medication in their battle to lose weight, Dr. Louis Aronne, director of the Comprehensive Weight Control Center of New York Presbyterian Hospital talks to us about the long-term effects of using medication in weight management.

According to the Centers for Disease Control and Prevention's recent survey, 61% of Americans are either overweight or obese. More women than men are being affected, and minority women have the highest prevalence. As the quest for the ultimate weight loss program continues, more and more people are considering medication to aid in the weight loss battle. A recent clinical trial published in the December 2000 issue of the medical journal the Lancet suggests that a popular weight loss medication, sibutramine also known as Meridia, is effective in sustaining weight loss in obese patients, but can contribute to increased risk of blood pressure. However, questions remain about the drug's long-term safety.

Interview with Louis Aronne, MD, an internist specializing in weight control, and director of the Comprehensive Weight Control Center of New York Presbyterian Hospital

  1. What does the results of this recent clinical trial mean?

  2. When medication was used in conjunction with a good weight loss program, including diet, exercise and behavior change, patients did substantially better than if they were doing the same weight loss program without medication. The problem is that doctors prescribe a medication, but not a weight loss program. I think that doctors find it hard to implement a program. Insurance companies usually do not pay for nutritionists or dietician treatment.

  3. What types of medication are available for weight loss?

  4. There are only two medications approved by the US Food and Drug Administration for what is loosely called long-term use (long term use is not defined). They are Meridia, which reduces appetite, and Xenical, which reduces the absorption of fat. You must get a prescription from your doctor for both of these drugs. If you are about 30% over your ideal weight or less overweight and have medical problems like diabetes and high cholesterol, then you are most likely eligible.

    A patient needs to go to their doctor for regular checkups. The study in the Lancet suggests that people who took the medication over a long-term showed that they maintained their weight loss. The cost of the medication is about $100 a month. Only half of the insurance companies will cover the cost of the medication.

  5. What are the side effects of using these medications?

  6. The most common side effects of Meridia are dry mouth, headaches, and constipation. The blood pressure problems that occurred in the study appeared in 3% of the people. The only side effect wit Xenical is that it can upset your stomach because the oil is not being absorbed. You also need to take a vitamin supplement with Xenical.

  7. What is the role of medication in a weight loss program?

  8. Medication is an adjunct to a weight loss program. You should combine the use of the medication with a weight loss program that includes diet, exercise and behavior modification, not do one or the other.

  9. What are the long-term effects of using medication in a weight loss program?

  10. The people in the Lancet study took the medication for two years, and they were effective in sustaining weight loss. In my opinion, this establishes the long-term effect. Most drugs are studied for six months to two years before they are released. You cannot promise that there is no longer-term affect, but people are comfortable with the two year study time. I would say that in five to ten years' time, I think the treatment of obesity will be with medicaton. All the evidence supports this.

    The point of using medication for weight loss should be to benefit your health. If you are 15 pounds overweight, I don't recommend that you use medication to lose weight. If you are using it for cosmetic purposes only, then don't use medication. But if there are health benefits such as reducing cholesterol, heart disease, etc, then use medication.

Background Information

Pharmacotherapy was approved by the FDA for long-term treatment. It can be a helpful adjunct for the treatment of obesity in some patients. These drugs should be used only in the context of a treatment program that includes the elements described previously diet, physical activity changes, and behavior therapy. If lifestyle changes do not promote weight loss after six months, drugs should be considered. Pharmacotherapy is currently limited to those patients who have a BMI (Body Mass Index) 30,or those who have a BMI 27 if concomitant obesity- related risk factors or diseases exist. However, not all patients respond to a given drug. If a patient has not lost 4.4 pounds (2kg) after four weeks, it is not likely that this patient will benefit from the drug. Currently, sibutramine and orlistat have been approved by the FDA for long-term use in weight loss. Sibutramine is an appetite suppressant that is proposed to work via norepinephrine and serotonergic mechanisms in the brain. Orlistat inhibits fat absorption from the intestine. Both of these drugs have side effects. Sibutramine may increase blood pressure and induce tachycardia; orlistat may reduce the absorption of fat-soluble vitamins and nutrients. The decision to add a drug to an obesity treatment program should be made after consideration of all potential risks and benefits and only after all behavioral options have been exhausted.

A growing body of evidence makes obesty appear as much a metabolic, endocrine disorder as diabetes and, therefore, deserving of medical and surgical management in clinically appropriate settings.

The publication of a small four-year trial of phentermine and fenfluramine in 1992 by Weintraub and colleagues popularized the notion of chronic treatment. Dexfenfluramine was approved for long-term use in 1996 after 10 years of use around the world. However, concerns about unacceptable side effects, primarily regurgitant valvular lesions of the heart and pulmonary hypertension, led to the withdrawal of fenfluramine and dexfenfluramine in September 1997. In November 1997, the FDA approved sibutramine, for long-term use in obesity, and in April 1999 orlistat was approved for long-term use.

In general, medication helps patients to comply with a reduced calorie regimen. Not every patient responds to a given medicine. If a patient loses more than four pounds during the first month, the prognosis for losing more than 5% of body weight is good. If not, consideration should be given to changing medication after another month of treatment.

Weight Loss Drugs Approved for Long Term Use

Drug and Dose

  • Action Sibutramine (Meridia) - 5, 10, 15 mg

    • 10mg po qd to start, may be increased to 15mg or decreased to 5 mgnorepinephrine, serotonin and dopamine re uptake inhibitor

    • reduces appetite, may increase thermogenesis

  • Orlistat (Xenical) - 120 mg

    • 120 mg po tid before meals inhibits pancreatic lipase, decreases fat absorption

Sibutramine, or Meridia, is a norepinephrine and serotonin re uptake inhibitor (SNRI) which was originally developed as an antidepressant but was shown to be effective at reducing weight. Although a schedule IV compound, it has demonstrated no evidence for abuse or habituation like the other drugs ithe SNRI category. A one-year long trial showed that among patients who received 15mg of sibutramine daily, 65% lost more than 5% of body weight compared to only 29% of patients taking placebo, and 39% lost more than 10% of their body weight compared to 8% in the placebo group.

Health benefits demonstrated with the use of sibutramine include reductions in triglycerides, uric acid, total cholesterol, LDL cholesterol and an increase in HDL cholesterol. Adverse events seen during randomized trials include dry mouth, constipation, insomnia, increased appetite, dizziness, and nausea. Sibutramine is relatively contraindicated in patients with poorly controlled hypertension and atherosclerotic cardiovascular diseases including stroke and myocardial infarction. A mean increase in blood pressure of 4 mm Hg has been seen in trials. Approximately 12% of patients have an increase in systolic BP of 15 mm Hg or more: however, less than 1% of patients treated had to be withdrawn from trials as a reult of a sustained increase in blood pressure. Of note, a decrease in blood pressure is most often seen in patients who lose more than 5% of body weight and in whom treatment would be most likely to continue.

It is recommended that blood pressure and pulse be checked two to four weeks after the drug is started and then monthly for the first six months; thereafter every two to three month, monitoring is adequate, or more often if indicated. Behavioral and dietary intervention are an integral part of the long-term management of a patient on medication, and should be included as part of the follow-up visit. If the resources to counsel a patient do not exist in a practitioner's office, liaisons should be made with dieticians, psychologists, nurses, or other health care practitioners with interest and expertise in the field to deliver it.

Orlistat, or Xenical, is an inhibitor of pancreatic lipases which prevents the absorption of about one-third of dietary fat. Analysis of patients completing a two year long placebo-controlled trial demonstrated a mean weight loss of 8% after one year compared to 4% in the placebo group. Orlistat slowed down the rate of weight regain in the second year, with 6 % maintained after two years of treatment compared to 2% in the placebo-treated group. Health benefits demonstrated in clinical trials of orlistat include a reduction in LDL and increase in HDL cholesterol, reduction in blood pressure and fasting insulin levels, improvement in oral glucose tolerance test outcomes, and improved glycemic control in obese diabetics. The gastrointestinal side effects associated with orlistat use are usually mild in intensity, happen early in treatment, and may enhance compliance with a low-fat diet. No effect on mineral balance, gallstone, or renal stone formation was seen. Studies of colonic mucosal turnover and tumor markers show no abnormalities, suggesting no increased risk of colon cancer. A mild reduction in the levels of vitamin D and beta-carotene was noted in some treated patients during trials and supplementation with a multi vitamin taken remotely from a dose of orlistat has been recommended.

Noradrenergic agents such as the Schedule IV drugs phentermine, or Ionamin, Fastin, Adipex and diethylpropion or Tenuate, and the over-the-counter drug phenylpropanolamine or Dexatrim, and Accutrim have been shown to be slightly better than placebo in short-term studies. However, no long-term studies of efficacy, safety, or health benefit have been performed. While many over-the-counter products are available for weight loss, there is little or no short or long-term evidence to support their claims of efficacy.

Among others, chromium picolinate, a trace mineral, chitosan, a fiber product, L-carnitine, pyruvate, and hydoxycitric acid show insufficient efficacy in the doses suggested to recommend their use. These products are marketed as nutritional supplements, outside the regulation of the Food and Drug AdministratonThe combination of ephedrine (ephedra, ma hang, herbal fen/phen) and caffeine (guarana, kola nut) often seen in fat-burning products acts as a non-specific beta agonist and has been shown to be more effective than placebo but is not considered to be safe for unsupervised use because of the risk of side effects such as tachycardia and hypertension; furthermore, they are not approved for the treatment of obesity in the United States.

Phenylpropanolamine, a sympathomimetic also used widely in over-the-counter decongestants, is also available as an over-the-counter appetite suppressant for short-term use. The future of the pharmacological treatment of obesity is particularly promising, with more than fifty new drugs in the early stages of development.

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