Help on the SCALE

Two new weight-loss drugs that won Food and Drug Administration (FDA) approval for long-term use could provide important new weapons in the battle against obesity.

The drugs reflect a shift in the way physicians and regulators think of weight loss, from a cosmetic issue to the serious health threat of the obesity epidemic. The drugs could off er a middle ground for some patients between the invasiveness of bariatric surgery and the more modest successes of diet and exercise.

“There are a variety of responses to medications,” says Daniel Bessesen, MD, chief of endocrinology at Denver Health Medical Center. “Some people don’t lose much weight at all, but other people lose a lot of weight. So we are more and more thinking of weight-loss medicines as not having a fixed effect, but something that people could try and see if they have a really good benefit.”

The new drugs could off er a turning point, says Donna Ryan, MD, professor emeritus at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. “We are finally on the verge of understanding when to use the drugs, how to use the drugs, and how to develop safe and effective drugs,” she says.

The two drugs are not radically new. Qsymia is a combination of two drugs already on the market—the appetite suppressant phentermine and an extended-release form of the anti-epileptic topiramate. Belviq, the brand name for lorcaserin hydrochloride, is a new formulation aimed at refining an old approach—suppressing appetite by activating serotonin receptors.

The drugs join orlistat as the only weight-loss drugs approved for long-term use. Th e FDA foresees patients who benefit from the new drugs continuing on them indefinitely, as with statins or blood-pressure medications. Orlistat remains the only drug approved for weight loss in teenagers.

Just Part of the Recipe

Th e two approvals break a long drought with no new weight-loss drugs, and a period when more drugs left the market than joined it. In 1997, the drugs fenfluramine and dexfenfluramine were withdrawn because of evidence that they caused heart valve damage. Sibutramine left the market in 2010 amid concerns about an increased risk of heart attacks and strokes. Th e last addition to the market was in 1999, when the FDA approved orlistat, a lipase inhibitor designed to work by blocking fat absorption by the intestines.

Both Qsymia and lorcaserin are designed to be used in conjunction with a lifestyle intervention program emphasizing diet and exercise. For the drugs to work, the patient must be motivated, according to Ryan. “The drugs are intended to work through the biology of eating behavior, to reinforce your intention to eat less by promoting satiety and reducing hunger,” she says.

And they are definitely not for cosmetic or casual weight loss. Both drugs are approved only for use in obese adults—those with a body mass index (BMI) of 30 or higher—or overweight adults with a BMI of at least 27 who have one or more weight-related condition such as hypertension, degenerative joint disease, type 2 diabetes, or dyslipidemia.

In clinical trials, after a year of treatment with the lowdose, starting formulation of Qsymia, patients lost an average of 6.7 percent of body weight more than with a placebo. With a higher daily dose, they lost 8.9 percent more body weight compared with a placebo. For lorcaserin, the average one-year weight loss was 3 percent to 3.7 percent greater than with a placebo, with 47 percent of patients meeting the FDA’s minimum target of losing at least 5 percent of their body weight. Both drugs are also associated with favorable changes in other metabolic indicators such as blood pressure, high-density cholesterol, and waist circumference.

But the overall averages obscure how much some individuals benefit from the treatment. Qsymia was broadly effective—about 62 percent of patients on the lower dose and 69 percent on the higher dose lost more than 5 percent of their body weight. A sizable number of subjects experienced more than 10 percent weight loss, with some achieving 20 percent, which is approaching the range achieved through bariatric surgery, says Abraham Thomas, MD, MPH, head of the endocrinology, diabetes, bone, and mineral disorders division at Henry Ford Hospital in Detroit and chair of the FDA scientific advisory panel that recommended approval of both drugs.

A New Spin

Marketed by Vivus, Qsymia represents a fresh approach using established drugs. Phentermine has been in short-term use as an appetite suppressant since 1959. Topiramate is FDA-approved for use in epilepsy and migraine prevention, but has a history of off -label use for weight loss, although its mechanism of action is not known.

Qsymia incorporates the two in much lower doses than when each is used alone, in an attempt to synergize their results while reducing their side effects and allowing long-term use. Th e standard dose when phentermine is given as a single agent is 30 mg, compared with the recommended starting dose of 7.5 mg in Qsymia. Th e topiramate dose for migraine prophylaxis is up to 200 mg, compared with 42 mg in the starting dose of Qsymia. A higher dose formulation of Qsymia is also available with 15 mg of phentermine and 92 mg of topiramate.

Manufactured by Arena Pharmaceuticals, Belviq’s mechanism of action—activating serotonin receptors to suppress appetite and make a patient feel full after eating a smaller amount of food—is reminiscent of fenfl uramine, but lorcaserin is designed to work in a much more targeted fashion.

“Fenfluramine was a dirty drug. It hit all the serotonin receptors. This drug was developed to be very specific,” Ryan says. Fenfluramine is believed to cause problems by attaching to the serotonin 2B receptors in heart valves. Lorcaserin is designed to be more selective, aimed at serotonin 2C receptors in the brain. It does not appear to activate the 2B receptors at the approved dose of 10 mg per day.

To allay concerns that it might activate this receptor, the manufacturer assessed the heart valve function through echocardiography of 8,000 patients during the clinical trials. Although there was some increase in valve abnormalities in the lorcaserin group, it was not statistically significant, and the FDA urges caution in using it in patients with congestive heart failure.

Trial and Error

Both Ryan and Bessesen noted that although lorcaserin did not lead to as much weight loss as Qsymia, the diff erence could be that lorcaserin is a single-agent drug, compared with the double-acting Qsymia. In the future, lorcaserin’s effectiveness could possibly be improved by combining it with another agent, such as phentermine. But they discouraged clinicians from experimenting with such uses pending the publication of clinical data to support it.

“What we have learned in diseases like high blood pressure is that single medicines often don’t do the job. If somebody is on a vasodilator for blood pressure then they will often hold on to salt and water, so they need to be on a second medicine, a diuretic to help with that,” says Bessesen, who was part of the FDA panel that recommended approval of lorcaserin.

The three experts all made the comparison with blood pressure medications in terms of testing their eff ectiveness in a patient and continuing them if they work. The FDA recommends that if a patient does not lose 3 percent of body weight after 12 weeks on Qsymia, the drug should be discontinued or given at the higher dose to see if it can meet a target of a 5 percent loss in another 12 weeks. The FDA recommends discontinuing lorcaserin if it does not deliver a 5 percent loss after 12 weeks.

If it succeeds, the drug should be continued. “The modern view of obesity is that it is a chronic metabolic disorder, much like high blood pressure or high cholesterol,” Bessesen says. “If you use a medicine for your blood pressure, it only works as long as you take it, because it doesn’t fundamentally change your body. And I think that is how we see weightloss medicines now.”

Given the record of weight-loss medications, both drugs will face a high level of scrutiny. The FDA is requiring both manufacturers to conduct several postmarketing studies, including long-term cardiovascular outcomes trials to assess effects on major events such as heart attack and stroke. The European Medicines Agency rejected Qsymia for marketing in the European Union, although observers have ascribed this to internal politics and a wait-and-see attitude rather than genuine problems that the FDA missed. The agency has not yet ruled on lorcaserin.

Among its contraindications and side effects, Qsymia should not be used by patients with glaucoma or hyperthyroidism. It can increase heart rate, so is not recommended for patients with recent heart disease or stroke. Lorcaserin’s side effects include serotonin syndrome, particularly if it is taken with another serotoninergic drug. It may cause disturbances in attention and memory. Neither Qsymia nor lorcaserin should be used during pregnancy.

Only time will tell how effective the new drugs will be under real-world conditions or how physicians will incorporate them into their practices. But as obesity rates continue to rise, they may off er a possible additional option, along with a new challenge for integrating them into treatment.

—Seaborg is a freelance writer in Charlottesville, VA and a regular contributor to Endocrine News.

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