Empagliflozin’s triumph respins FDA’s diabetes drug mandate



What a difference a few weeks and the unexpected results from a home run–hitting trial made in the medical community’s take on the Food and Drug Administration’s demand to assess the cardiovascular safety of drugs for type 2 diabetes.

On August 31, the relatively ho-hum, noninferiority results from the two latest, large outcomes trials to assess the cardiovascular safety of new oral hypoglycemic drugs led to bashing of these trials by several cardiologists speaking from the main stage of the European Society of Cardiology’s (ESC) annual congress in London. On Sept. 17, less than 3 weeks later, the remarkably beneficial survival effect seen with another new oral hypoglycemic, empagliflozin (Jardiance) in a cardiovascular safety study and reported at the European Association for the Study of Diabetes (EASD) annual meeting in Stockholm and in a simultaneously-published article resulted in researchers calling the results “amazing” and audience members hailing the trial a “landmark.”

Courtesy Wikimedia Commons/Henry Vandyke Carter/Public Domain

Is the biomedical field really so fickle, or did physicians just need proof of the serendipitous possibilities when running a large outcomes clinical trial using a potent drug with underexplored potential?

The back story to this attitudinal change began in 2008, when the FDA issued guidance that called on companies to collect evidence for the cardiovascular safety of new drugs that treat type 2 diabetes, a stand that launched a fleet of big studies. Reports of the results from the first two trials conducted to meet this mandate came out 2 years ago from studies of new dipeptidyl peptidase 4 (DPP-4) inhibitors, the SAVOR-TIMI-53 trial of saxagliptin (Onglyza), and the EXAMINE trial of alogliptin (Nesina). Results from the two studies were notable not only for generally showing cardiovascular safety but also for showing a small but apparently real uptick in the rate of hospitalization for heart failure associated with saxagliptin treatment.

Findings from the next two trials in the series came out in reports in June at the American Diabetes Association annual meeting in Boston, with follow-up reports on the same two studies presented at the ESC meeting on August 31. Results from the TECOS study of yet a third new DDP-4 inhibitor, sitagliptin (Januvia), showed no cardiovascular safety signals with notably no suggestion of causing any sort of heart failure problem. The fourth study, ELIXA, was the first of the FDA mandates to report on a drug from a different class, lixisenatide (Lyxumia), a glucagonlike–peptide 1 receptor agonist, and it too provided a clean outcome with no excess of cardiovascular events, compared with the control arm.

It was this steady drumbeat of neutral results showing no evidence of cardiovascular harm – aside from the problem of heart-failure exacerbation with saxagliptin – that triggered criticism of the FDA’s mandate and its consequences at ESC, specifically in remarks by Dr. Philippe Gabriel Steg, the ESC’s designated discussant for the ELIXA report.

“Are these trials a waste of resources?” asked Dr. Steg in his comments. He questioned how representative and generalizable the studies are, by enrolling patients at very high cardiovascular risk, usually patients with a recent acute coronary syndrome event. He also critiqued the trials’ relatively short follow-up, on the order of 2-3 years, saying that this is generally too brief to demonstrate a potential benefit. Most of all, he questioned launching a series of safety trials that have enrolled a total of roughly 150,000 patients in randomized, controlled trials designed to test noninferiority for cardiovascular safety against standard-treatment control arms, studies that he posited divert money and resources from investigations focused on finding new treatments and could be accomplished in a different way for a lot less money.

Dr. Steg further complained that the series of neutral results have fostered misleading beliefs about their implications. The noninferiority results “have been mistakenly interpreted as lack of efficacy,” resulting in “greater skepticism among nonspecialists about treatment of diabetes and the need to control glycemia,” he said. He also said that the noninferiority design shortchanged enrolled patients, inconveniencing them by the demands of the trial when the best they could expect was to fare no worse than control patients.

Even more striking, Dr. Steg’s critique received immediate support from the next two speakers at the meeting, Dr. Jaakko Tuomilehto, designated discussant for the TECOS sidy, and then Dr. Thomas M. MacDonald, who followed at the podium to report results from an entirely different study. “I fully agree. I think it’s a waste of resources,” said Dr. Tuomilehto.

Was it reasonable for these trialists to anticipate anything more from studies designed to confirm cardiovascular safety? “Some think the results [from these four trials] have been disappointing, others think it’s what you would expect,” commented Dr. Bernard Zinman a few weeks later in September at the EASD meeting.


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