Three Anti-Obesity Drugs Compared

Summarized by Robert W. Griffith, MD
March 5, 2007

Summary

For overweight or obese people having difficulty in losing weight, additional medication may help. This is a short review comparing three current drugs - orlistat, sibutramine, and rimonabant.

Introduction

We may paraphrase Mr. Micawber¹, who said: "Annual income twenty pounds, annual expenditure nineteen pounds nineteen and six, result happiness. Annual income twenty pounds, annual expenditure twenty pounds ought and six, result misery." For our purpose, the mantra is "Daily dietary intake 2,550 calories, daily activity expenditure 2,600 calories, result happiness. Daily dietary intake 2,550 calories, daily activity expenditure 2,500 calories, result fatness." Put more simply, "Calories in minus calories out = weight change". In spite of this overriding principle, people want, and manufacturers strive to provide, magic bullets in the form of medications and supplements. Three relatively new drugs used in helping to treat obesity have been appraised in The Lancet; the reviews are summarized here.

Orlistat (Xenical®)

Orlistat was approved for use in the USA in 1998. It works by inhibiting gastric and pancreatic lipases, enzymes that break down fats (triglycerides) in the intestine. Without lipases, triglycerides in the diet cannot be hydrolyzed into absorbable free fatty acids, and are excreted undigested. The usual dose is 120 milligrams three times a day, taken with meals. The FDA has just approved half-strength orlistat to be sold over-the-counter, as Alli^®. The drug is safe, as only 1% is absorbed.

In a meta-analysis of 11 placebo-controlled studies, each one year or longer, in over 6000 patients, orlistat reduced weight by 3%. In fact, 21% of patients lost 5% and 12% lost 10% of their weight with orlistat. It also reduces blood pressure, low- density lipoprotein (LDL) cholesterol, and fasting glucose levels in diabetics, all by small amounts.

The major side effects are gastrointestinal, not surprisingly. Fatty, oily feces, fecal leakage or incontinence occur in up to 15% to 30% of orlistat patients, compared with up to 7% treated with placebo. This may render it unacceptable for some patients. It may be advisable for patients to take a daily multivitamin, to prevent possible deficiency of fat-soluble vitamins.

Sibutramine (Meridia®)

This drug was originally developed as an antidepressant, and was approved in 1997 in the USA. It is a monoamine-reuptake inhibitor (MAOI) that increases the sense of fullness when eating. It's also increases body temperature, although this plays only a minor part in a weight reduction. The typical dose is 10 to 15 mg once daily. In three large trials of at least one year duration, in almost 1000 patients, sibutramine reduced weight by 4.5%.

In clinical studies, the number of patients reaching 5% and 10% weight loss was 34% and 15% greater with sibutramine than with placebo, respectively. Effectiveness seems greater when combined with intensive lifestyle modification and frequent doctors visits. There was little effect on LDL cholesterol and blood sugar and other lipids.

Side effects include insomnia, nausea, dry mouth, and constipation. It has been linked to small increases in blood pressure and pulse rate, but there is no definitive evidence of cardiovascular toxicity. However, the drug is not recommended for patients with any cardiovascular risk factors.

Rimonabant (Acomplia®)

This drug is not yet approved for use in the USA, but is under active review by the FDA. It is a selective cannabinoid CB1 receptor antagonist, which means it works in by blocking the cannabinoids (marijuana) receptors in the brain; those are the same receptors that give people the urge to eat when exposed to marijuana - the 'munchies'. Apart from this effect on appetite, it's supposed to affect the muscles (raising temperature), the liver and fatty tissues (reducing the formation of fat). The usual dose is 20 mg daily.

In clinical trials, rimonabant reduces weight to roughly the same extent as sibutramine - about 4.5% over one year. The proportion of patients reaching 5% and 10% weight reduction was 29% to 39% and 17% to 25% greater, respectively, for rimonabant than placebo. Rimonabant also significantly reduced the frequency of the metabolic syndrome² in 4 of 4 clinical trials, and the HbA1c level (a diabetes diagnostic test) by 0.7%. LDL-cholesterol levels and blood pressure were hardly affected, however. A large study (more than 17,000 obese participants) is ongoing to study the possible benefits of rimonabant on heart attack, stroke, and cardiovascular deaths.

Nausea, dizziness, diarrhea, and insomnia are the most frequent adverse effects, each seen at 1% to 9% more frequently than placebo in clinical trials. Almost twice as many patients discontinued rimonabant (13% to 16%) than the placebo because of adverse effects. Of particular concern were psychiatric disorders, which occurred in 8.5% of patients taking rimonabant compared with 3% of those on placebo.

Which medication to choose?

There's no good medical evidence of the superiority of any of these drugs over the others - such proof remains to be established. All three of them have only modest effectiveness and fairly high drop-out rates with continued use. The authors of the review make the following suggestions:

• Use orlistat for patients at high risk of developing type 2 diabetes, because of its potential to reduce LDL-cholesterol and slightly reduce blood pressure. Avoid it in people with chronic diarrhea.
• Sibutramine may be best for patients with a frequent snacking problem. It should be avoided in people with poorly controlled high blood pressure or cardiovascular problems.
• When rimonabant is available, it should probably be considered for people with the lipid features of metabolic syndrome (low HDL-cholesterol, high triglycerides), and those wishing to stop smoking. It must be avoided in people with depression, anxiety, or other psychiatric conditions.

For all three drugs, if there's no relevant weight loss within the first 3 to 6 months, there's little point in continuing with the same drug. But it's reasonable to continue for several years, provided there are no serious side effects and weight loss is maintained.

The Future

It may be that extended clinical studies will show whether the important side effects of obesity - cardiovascular disease, osteoarthritis, gastro-esophageal reflux disease (GERD), sleep apnea, and chronic obstructive pulmonary disease (COPD) - can be helped by one or other of the existing anti-obesity drugs.

Until a 'magic bullet' arrives (and it probably won't - remember "Calories in minus calories out. . ."), lifestyle changes are the best solution, helped in stubborn cases by one of these three anti-obesity drugs. Fad diets may work for a time, but a good exercise routine plus a sensible calorie-driven diet will produce the best results. And, of course, there's always surgery . . .

Source

• Drug treatments for obesity: orlistat, sibutramine, and rimonabant. RS. Padwal, SR. Majumdar, Lancet, 2007, vol. 369, pp. 71--77

Footnotes
1. Quoted in "David Copperfield" by Charles Dickens, 1850
2. The metabolic syndrome requires 3 of the following risk factors to be present: (a) Waist size over 40 inches (102 cm) in men, or 35 inches (88 cm) in women. (b) Serum triglyceride level over 150 mg/dL (1.7 mmol/L). (c) Serum HDL ('good') cholesterol below 40 mg/dL (1.0 mmol/L) in men, or 50 mg/dL (1.29 mmol/L) in women. (d) Blood pressure over 130/85 mm Hg (either number), or being on blood pressure medication. (e) Fasting blood sugar over 110 mg/dL (6.1 mmol/L). Take the self-test, at the link below.

Related Links
Do You Have the Metabolic Syndrome?
Weight Loss Surgery
Keyhole Surgery or Intense Dieting for Obesity?
American Obesity Association - Consumer Alerts

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