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.

I spoke with Dr. Steg soon after he lambasted the FDA-mandated cardiovascular safety trials at ESC, and he further explained to me that while he didn’t dispute the importance of better evaluating the cardiovascular safety of these oral hypoglycemic drugs, he believed this could be more efficiently assessed with a more comprehensive approach to postmarketing surveillance. He also highlighted the importance of examining cardiovascular safety in type 2 diabetes patients who better resemble real-world patients instead of in the extreme high-risk patients who have enrolled in the trials. Finally, Dr. Steg told me that he wasn’t nearly as skeptical of these trials when the FDA first announced its guidance 7 years ago, but grew increasingly dismayed as he saw how the laudable goal of collecting data on cardiovascular safety led to such profligate and questionable studies.

Attitudes shifted dramatically fewer than 3 weeks later at EASD when the empagliflozin results came out from the EMPA-REG OUTCOME study. Randomizing 7,028 patients, the study showed that treatment with either of two dosages of empagliflozin, a blocker of the sodium glucose cotransporter 2 (SGLT-2) protein in the kidney, on top of standard oral hypoglycemic and other standard lipid-lowering and antihypertensive therapies produced a “wonderful and quite profound” 38% relative risk reduction in the rate of cardiovascular death, a 32% drop in all-cause death, and a 35% cut in heart failure hospitalizations, noted trial discussant Dr. Hertzel C. Gerstein. The “unexpected” results “will open new research,” Dr. Gerstein added when speaking at EASD. “The claims that people have made that large, randomized clinical trials in patients with diabetes are not needed appear unfounded. Here is a perfect case; we need to do these trials to find lifesaving therapies.”

The empagliflozin results were so dramatic and surprising that you can’t help wondering what would have happened if the FDA had not issued its mandate for cardiovascular safety studies in 2008. Would a trial like EMPA-REG OUTCOME ever have been done? Would this effect, which the researchers suggested was likely a class effect for all SGLT-2 inhibitors, ever have been found?

The empagliflozin findings also raise doubts about the unwavering reliance cardiovascular studies have had on a primary combined outcome that marries patient survival with the incidence of nonfatal ischemic events, strokes, and MIs. The EMPA-REG OUTCOME showed a major survival benefit while simultaneously having no discernible impact on nonfatal ischemic events.

The question of what aside from the FDA’s mandate might have gotten a trial like EMPA-REG OUTCOME off the ground is especially important because the findings hint that SGLT-2 inhibitors may have treatment implications that go beyond patients with type 2 diabetes. The rapid onset of the mortality benefit seemed to point to the diuretic effect of the drug as a major mediating factor, said several at the EASD session. Might SGLT-2 inhibitors be the eagerly sought new option for managing fluid congestion in the organs of patients with acute heart failure? Aside from survival it was heart failure hospitalization where the treatment showed benefit. Better fluid management is currently a desperate need as heart failure physicians increasingly recognize that diuretic treatment alone often is inadequate for purging excess fluid from affected organs in patients with acute heart failure episodes.

Some critics of the FDA mandate weren’t willing to accept that it made EMPA-REG OUTCOME possible. A New York Times news article published on September 18 quoted Dr. Robert E. Ratner from the American Diabetes Association as saying that studies like EMPA-REG OUTCOME get launched through the initiative of drug companies acting on their own, without FDA prodding. Perhaps Dr. Ratner is correct, but which studies out there now reflect this? It certainly doesn’t seem like companies have been motivated to organize trials that assess the cardiovascular impact of oral hypoglycemic drugs outside of meeting the FDA’s requirements.

A comment that nicely summed up the game-changing impact of the empagliflozin study came from a member of the EASD audience in Stockholm, the last attendee to pose a comment from the floor as the session wrapped up on Sept. 17. “I hope everyone in the audience understands what has happened, how important this is, a real landmark study,” commented Dr. Klas Malmberg, a cardiologist and diabetes researcher at the Karolinska Institute in Stockholm.

This unexpected finding from a large outcomes study looks like it may substantially alter the way type 2 diabetes and perhaps other diseases will get treated in the future. The finding also singlehandedly morphed the FDA’s safety study mandate from “a waste of resources” to the heroic driver behind a landmark study.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Empagliflozin’s triumph respins FDA’s diabetes drug mandate