Weight Loss Drugs: What Works?

Laura A. Stokowski, RN, MS

Disclosures

December 13, 2010

In This Article

Withdrawn or Awaiting Approval

The fall of 2010 was a discouraging time for those who are desperate for a new obesity treatment, including patients who say they would be willing to accept some risk if they were able to lose weight. Hopes were raised and then dashed as promising therapies slipped off the horizon in October, just after an established drug was withdrawn from the market. But companies touting the new therapies are continuing to collect safety information that they hope will satisfy regulators and ultimately allow them to sell their products.

Sibutramine

Abbott, maker of the sibutramine product Meridia®, issued a voluntary product recall in October upon being asked by the FDA to stop marketing Meridia in the United States; this followed reports of an increased risk for heart attack and stroke in Meridia users. Meridia had already been recalled earlier in Canada and Europe.

Sibutramine hydrochloride is a centrally acting monoamine reuptake inhibitor, affecting primarily serotoninand norepinephrine, and to a lesser extent, dopamine.[1] Originally used to treat depression, patients taking sibutramine experienced weight loss as an unexpected effect. Although diminished hunger and increased satiety are the most likely mechanisms of weight loss, sibutramine may also increase thermogenesis, thus increasing energy expenditure by increasing metabolism.[1]

The Sibutramine Cardiovascular OUTcomes (SCOUT) trial was a 6-year study of 10,000 patients, conducted to assess cardiovascular safety in high-risk patients. It showed that, after 5 years (the end of the trial), the average difference in body weight between patients taking Meridia and those taking a placebo was about 2.5%. On long-term follow-up, a 16% increased risk for nonfatal heart attacks and nonfatal strokes was seen in patients with pre-existing cardiovascular risk factors.[12] This was considered by some to be an unacceptable benefit to risk ratio. However, the manufacturer asserts that the increased cardiovascular events occurred primarily in patients with underlying cardiovascular disease, a patient population in whom Meridia is contraindicated according to enhanced labeling initiated earlier this year.[13]

Lorcaserin

Lorcaserin is an anti-obesity drug of the 5-HT2C agonist class. The stimulation of specific central serotonin receptors suppresses appetite and induces a feeling of satiety. Lorcaserin is highly selective for the 5-HT2C receptor, which modulates fat and caloric intake.[14]Signaling through the 5-HT2A and 5-HT2B receptors (found on cardiac valves), however, is minimal.[2]

In a large trial (3182 patients), those who took lorcaserin lost an average of 5.8% of their baseline body weight compared with 2.2% in those who took placebo (P < .001).[15]Nearly half of the patients taking lorcaserin lost 5% or more of their baseline body weight, compared with 20% of those taking placebo, and more of the lorcaserin patients maintained their weight loss after the study had ended. Very few patients in the lorcaserin group failed to lose weight.

Other improvements associated with lorcaserin were: reduced BMI and waist circumference; lower fasting glucose, insulin, and A1c levels; and lower total cholesterol, LDL cholesterol, and triglycerides. However, despite beneficial effects on risk for cardiovascular disease (reduced C-reactive protein, fibrinogen level, systolic and diastolic blood pressure, and heart rate), the FDA voted against approval of lorcaserin in October, citing concerns about lorcaserin-induced valvular heart disease (as well as brain and breast tumors) in declining to recommend lorcaserin for the treatment of obesity.[16]

The agency requested additional data about lorcaserin from drug maker Arena Pharmaceuticals, and the company says it will meet with the FDA before the end of the year, partly to discuss new, "encouraging" data regarding lorcaserin's effects on obese patients with diabetes.

Phentermine/Topiramate

Qnexa® (made by Vivus, Inc.) combines low-dose phentermine with a controlled-release form of topiramate, an antiepileptic drug often used for the prevention of migraine headache. Topiramate inhibits excitatory neurotransmissions by blocking voltage-gated sodium channels,[17] and is sometimes prescribed as monotherapy for weight loss.[4]Topiramate reduces hunger and promotes weight loss in a dose-dependent fashion, but the peripheral and central nervous system effects (parasthesias, memory impairment, taste disturbance) are significant and intolerable in some patients.[18] Topiramate has the added advantage of having mood-stabilizing properties.[5]

Harnessing the effects of the 2 different but complementary mechanisms of phentermine and topiramate allows the use of lower doses of each agent, which should increase safety.[19] This drug combination reportedly induces substantial weight loss, an average of about 10% after 1 year, and significantly reduces systolic blood pressure. Patients taking lower doses of the drug combination lose less weight, but that is still more than those taking placebo.

Despite evidence of effectiveness in phase 3 trials extending to 1 year, the FDA voted against approval of Qnexa in October, expressing concerns about adverse effects associated with its use, including cognitive disorders, metabolic acidosis, increased heart rate, and birth defects, suggesting possible teratogenicity.

Before Qnexa can be approved, the FDA has requested further evidence of its safety.[19]If approved, it would be a schedule IV drug due to the phentermine component.

Naltrexone/Bupropion

Contrave®, another new dual anti-obesity agent, is the combination of the antidepressant bupropion and sustained-release (SR) naltrexone, a drug used to treat alcoholism and other addictions. Bupropion, approved for both depression and smoking cessation, also increases dopamine levels at specific receptors in the brain, which is believed to be responsible for its appetite-reducing effects.[20] These 2 drugs work on the brain reward system and the hunger centers in the hypothalamus, and are believed to be synergistic in reducing food intake.[21]

If approved, this combination therapy could be useful for patients who have issues with food craving. When used with a mild hypocaloric diet and with exercise instruction in overweight or obese patients, it is associated with greater weight loss and greater improvement in several cardiometabolic risk factors compared with placebo.[22] Combination treatment was generally well tolerated; adverse effects included insomnia, nausea, headache, dry mouth, and a small and transient increase in systolic and diastolic blood pressure.[22]

Contrave has not yet been reviewed by the FDA, but phase 3 clinical trials have been completed. The manufacturer, Orexigen, reports that Contrave met all of its primary endpoints for weight loss in these trials, even in patients with diabetes, it also was associated with improvements in cardiometabolic risk markers such as waist circumference, HDL-C levels, and triglyceride levels.[23] Contrave is up for review by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.[23]

The fate of this anti-obesity agent will not be known until sometime in 2011.

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