The Two New Diet Pills Not The Solution
The two most recently introduced new agents for weight loss in the United States, lorcaserin ( Belviq, Eisai) and phentermine-topiramate ( Qysmia, Vivus), represent “slim pickings” for the treatment of obesity based on the available evidence to date, say two doctors. They are particularly concerned about cardiovascular and psychiatric/neurologic side effects with the drugs.
Writing in a “special communication” published online February 10 in JAMA Internal Medicine, Steven Woloshin, MD, MS, and Lisa Schwartz, MD, MS, from the Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, New Hampshire, say there are many unanswered questions regarding the risk/benefit profiles of these two drugs. Both were approved in 2012 in the United States, but neither agent is available in Europe “because of safety concerns,” they point out.
The Food and Drug Administration (FDA) did require postmarketing trials to address specific issues with each product, but these are now “behind schedule,” they add. They also call for the US agency to strengthen the warnings on the products.
“Until there is more convincing evidence about the cardiovascular safety of these drugs, physicians and patients should approach them cautiously. Patients who do not lose at least 5% of their body weight within 12 weeks of starting to take either drug should stop taking it, as stated in the prescribing information,” they assert.
But Eisai Pharmaceuticals, which markets lorcaserin, contends that its postmarketing trial for cardiovascular safety ( CAMELLIA-TIMI 61) is on track, and it told Medscape Medical News that it is “in the process of preparing to reengage European health authorities in order to identify the best path forward for refiling the Belviq marketing authorization application.”
Vivus, the makers of Qsymia, declined to comment.
Both Agents Rejected Initially by US FDA
To judge weight-loss drugs, the US FDA considers two criteria, Drs. Woloshin and Schwartz explain: whether people lose 5% or more of their body weight with the drug vs placebo and whether at least 35% of people taking the drug lose at least 5% of their body weight (and the percentage lost in the treatment group is at least double the percentage lost in the placebo group).
“Lorcaserin met 1 of these criteria; phentermine-topiramate met both…but efficacy is just half the story. Benefit must be weighed against harm,” and these two agents “have been associated with serious harms,” they observe.
Labels on both in the United States “include warnings about memory, attention, or language problems and depression.” For lorcaserin, “the label also warns of valvular heart disease and euphoria,” and for phentermine-topiramate, “the label warns of metabolic acidosis, increased heart rate, anxiety, insomnia, and elevated creatinine levels.”
But despite these warnings, “uncertainties remain,” they say, noting that the clinical trials for both agents “could not exclude important cardiovascular harms. This is why neither drug is on the market in Europe.”
The European Medicines Agency (EMA) reported that it was unlikely to approve lorcaserin because of concerns about possible cancers, psychiatric disorders, and heart-valve problems, “prompting the manufacturer to withdraw its application” in May 2013.
And the EMA “explicitly rejected phentermine-topiramate twice” — first in 2012 and again in 2013 — because of concerns about the medicine’s long-term effects.
The FDA shared many of these concerns and hence did not approve either drug at the first attempt. Some issues were resolved at reapplication, but others, “most importantly those about serious cardiovascular harms, were not resolved,” the doctors maintain.
FDA “Gamble” on Postmarketing Trials
The US approval letters did acknowledge that “there have been signals of a serious risk of major adverse cardiovascular events with some medications
developed for the treatment of obesity, and available data have not definitively excluded the potential for this serious risk with [lorcaserin hydrochloride or phentermine and topiramate extended release],” say Drs. Woloshin and Schwartz.
But the agency requirement for the manufacturers to conduct postapproval trials to assess the potential harms, rather than preapproval safety trials, is “troubling,” they believe.
“In our view, approving the drugs for marketing without more definitive evidence is an unnecessary gamble — one that the EMA was not willing to take.”
And despite the requirement for postmarketing trials to be completed quickly, as of December 2013, “there was no evidence that any of the postmarketing trials for lorcaserin or phentermine-topiramate are on schedule [ according to the FDA’s database],” the doctors say.
None of the final trial protocols had even been submitted at the time of acceptance of this article, they add (1 trial for lorcaserin for cardiovascular events and valvulopathy; two trials for phentermine-topiramate — 1 for cardiovascular events and 1 for renal toxic effects), “even though submission was required 8 to 16 months ago.” Nor have any of studies been registered at ClinicalTrials.gov, including the phentermine-topiramate renal trial that had a required completion date of December 2013.
Eisai told Medscape Medical News, however, that “contrary to what the authors stated, the [cardiovascular safety study with lorcaserin], CAMELLIA-TIMI 61, is on schedule. The protocol was approved by the FDA in August 2013 following several months of discussion, and enrollment began in January 2014.”
But even if the two cardiovascular trials with the two agents were to be performed on time, they have “anticipated completion dates of December 2017,” the Dartmouth doctors note.
“Pending the completion of the required postmarketing studies, we suggest that the FDA highlight the open questions about cardiovascular harms by changing the prescribing information for both lorcaserin and phentermine-topiramate. The statement should be reframed as a clear warning, such as the following: Because of concerns that this drug might increase cardiovascular morbidity or
mortality, the FDA has required a randomized trial to be completed by 2017, ” they conclude.
Drs. Woloshin and Schwartz are cofounders and shareholders of Informulary, a company that provides data about the benefits, harms, and uncertainties of prescription drugs.