Obesity Drug Safety Debate Escalates in Medical Journal

Miriam E. Tucker

August 04, 2014

Disagreement over the safety of 2 weight-loss drugs recently approved for use by the US Food and Drug Administration (FDA) has escalated in the pages of a major medical journal.

On February 10, 2014, JAMA Internal Medicine published online a "special communication" written by Steven Woloshin, MD, and Lisa Schwartz, MD, from the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire, in which they call lorcaserin (Belviq, Eisai) and phentermine-topiramate (Qysmia, Vivus) "slim pickings" for the treatment of obesity.

Drs. Woloshin and Schwartz wrote that both drugs have been associated with "serious harm" and pointed out that neither has been approved in Europe due to safety concerns. And, they added, the postmarketing safety studies the FDA required of both companies were behind schedule. "Until there is more convincing evidence about the cardiovascular safety of these drugs, physicians and patients should approach them with caution," they concluded.

On August 4, 2014, representatives from 2 obesity organizations responded in letters to the journal accusing Drs. Woloshin and Schwartz of trivializing obesity and also refuted many of their statements, both in matters of opinion and of fact. Steven R. Smith, MD, president of the Obesity Society, wrote one of the letters and Theodore K. Kyle and Joseph Nadglowski Jr., both of the Obesity Action Coalition, wrote the other.

Both letters take issue with Drs. Woloshin and Schwartz's statement that "obesity is not an emergency. It is not even a disease, but rather a risk factor for a disease." Smith, Kyle, and Nadglowski all point out that many organizations, including the National Institutes of Health, the American Association of Clinical Endocrinologists, the Obesity Society, and the American Medical Association (AMA) have called obesity a chronic disease.

Moreover, Dr. Smith writes, "Many diseases are not emergencies yet still warrant medical attention."

In a reply published in the same issue, Drs. Woloshin and Schwartz counter that there isn't consensus about calling obesity a disease and that in fact the AMA did so against the advice of its Council on Science and Public Health. "We agree with the council's conclusion that it is unclear that recognizing obesity as a disease, as opposed to a 'condition' or 'disorder,' will result in improved health outcomes."

FDA Decision Was Correct, or Was It?

Dr. Smith told Medscape Medical News that he believes the FDA's decision to approve the drugs and allow the remaining safety studies to be conducted postmarketing rather than require them premarketing was the right one, because the companies had demonstrated a "reasonable" degree of safety and there are currently few pharmaceutical options for treating obesity: "I think the FDA is taking a position that matches with American values around the physician-patient relationship as opposed to a top-down relationship."

In his letter, Dr. Smith accuses Drs. Woloshin and Schwartz of exaggerating the potential adverse effects of the 2 drugs in describing phentermine-topiramate as "toxic" and lorcaserin as causing heart-valve regurgitation. "To the contrary, the FDA accepted the phase 3 safety data as evidence for the absence of an effect on valvular heart disease."

Drs. Woloshin and Schwartz reply that they did not exaggerate the risks but "simply quoted what the FDA said in the approval letters" about serious risks of cardiovascular events with some obesity medications and that those risks had not being definitively excluded for lorcaserin and phentermine-topiramate.

Regarding possible cardiac valvulopathy, Drs. Woloshin and Schwartz say that the lorcaserin studies did not meet the FDA's criteria for excluding a 50% increase in risk. "In fact, the FDA was sufficiently concerned about potential cardiovascular adverse effects that it required postmarketing cardiovascular outcome studies for both drugs. Unfortunately, the studies appear to be 8 to 16 months behind schedule."

Postmarketing Study With Lorcaserin Under Way

Asked by Medscape Medical News for comment, Eisai responded: "Contrary to what the authors have asserted, our cardiovascular safety study, CAMELLIA-TIMI 61, is on schedule. The protocol was approved by the FDA in January 2014 following several months of discussion, and enrollment began shortly thereafter. The trial is a randomized, double-blind, placebo-controlled outcomes trial to evaluate the long-term cardiovascular safety of Belviq in patients with high cardiovascular risk. Patients will receive Belviq for up to five years in conjunction with a reduced-calorie diet and increased physical activity.

"In addition to satisfying the FDA requirement to conduct a trial to assess the long-term safety of Belviq in patients with high cardiovascular risk, the trial will further evaluate the efficacy of Belviq by assessing the impact of Belviq on major adverse events and new-onset type 2 diabetes," Eisai said.

Vivus declined a request from Medscape Medical News for comment.

Dr. Smith did not address the issue of the trials' schedule in his letter, but he told Medscape Medical News, "Honestly, it's in the companies' best interest to move to a green light....I'm a little less concerned about the pace, because it doesn't change the yellow-light perspective about how patients and physicians view these drugs today."

But Drs. Woloshin and Schwartz think the pace should pick up: "The society and the coalition should advocate with the companies for the completion of these postmarketing studies as soon as possible."

Drs. Woloshin and Schwartz are cofounders and shareholders of Informulary, a company that provides data about the benefits, harms, and uncertainties of prescription drugs. They prepared the drug facts box for lorcaserin, which is posted online by Consumer Reports. Dr. Smith holds stock in Jenrin Discovery and Zafgen; has research grants from Amylin Pharmaceuticals, Eli Lilly, and Takeda; serves on advisory boards for Amylin Pharmaceuticals and Takeda; and is a consultant for Amylin Pharmaceuticals, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Elcelyx, Eli Lilly, Five Prime Therapeutics, GlaxoSmithKline US Processing/Genpact, NGM Pharma, Novo Nordisk, Orexigen Therapeutics, Piramal Life Sciences, Takeda Global Research and Development, and Zafgen. Mr. Kyle is an unpaid board member and chair of the Obesity Action Coalition. Mr. Nadglowski is an employee of the Obesity Action Coalition, a 501 (c)(3 ) organization that receives financial support from Vivus, which markets phentermine-topiramate (Qysmia), and Eisai, which markets lorcaserin hydrochloride (Belviq).

JAMA Intern Med. Published online August 4,2014.


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