CV-Outcomes Trials With Diabetes Drugs: 'A Waste of Resources'

September 03, 2015

London — One eminent cardiologist has questioned the whole practice of conducting noninferiority cardiovascular-safety trials with new type 2 diabetes drugs, as required by the US Food and Drug Administration from 2008 onward, following the debacle with rosiglitazone.

Commenting on the latest results to be reported from one of these trials, at the European Society of Cardiology (ESC) 2015 Congress, cardiologist Gabriel Steg, MD, from Hôpital Bichat-Claude Bernard, Paris, France, said: "We have a flurry of trials on the cardiovascular safety of diabetes drugs — I've counted more than 150,000 patients enrolled in [such] completed or ongoing trials. One has to wonder whether this is…diverting [money] from more important tasks.

"I suggest that it is time to stop wasting resources on noninferiority trials and to work on truly improving diabetes care," Dr Steg asserted.

"In addition, I'm seeing that noninferiority trials are often being misinterpreted as lack of efficacy trials and they tend, among nonspecialists, to generate skepticism regarding the treatment of diabetes or the need to control glycemia — and this is an important side effect of this whole story in the general public of physicians," he told meeting attendees.

Dr Steg was the discussant for a presentation from Eldrin Lewis, MD, MPH, of the cardiovascular medicine division at Brigham and Women's Hospital, Boston, Massachusetts, who reported an extended analysis of the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, drilling down into the heart-failure findings.

Dr Eldrin Lewis

Dr Lewis told the meeting: "Whether you look at [diabetic] patients with preexisting heart failure or patients thereafter, the overall cardiovascular safety is present, and there is a neutral effect seen across the wide spectrum of heart-failure risk…suggesting that this particular agent [lixisenatide] is a safe way of reducing glucose."

The main results of the ELIXA trial, assessing the cardiovascular safety of this injectable glucagonlike peptide 1 (GLP-1) agonist in 6000 high-risk patients with type 2 diabetes, were first reported at the American Diabetes Association meeting in June and indicated no concerns — lixisenatide was neutral on all cardiovascular outcomes compared with placebo.

Jaakko Tuomilehto, MD, PhD, from the University of Helsinki, Finland, who was the discussant for another similar trial, TECOS, agrees wholeheartedly with Dr Steg.

"I think it's really a waste of resources to do these sorts of trials. There are so many things to do in the way of research, and the money could be used for that [instead] and to improve the care [of those with diabetes]," Dr Tuomilehto noted.

Cardiovascular-Outcomes Trials May Even Indicate Benefit…Eventually

ELIXA was designed to satisfy the FDA's 2008 requirement for cardiovascular-safety studies for all new type 2 diabetes drugs and is the first such study with a GLP-1 agonist to complete.

"The [ELIXA] trial clearly shows that the cardiovascular safety of lixisenatide in post–acute coronary syndrome [ACS] patients [with diabetes] appears excellent. The findings are clear and unequivocal," Dr Steg commented in his discussion.

This is important, he said, "because we know the ELIXA patients were really at the extreme end of the high-risk spectrum among diabetics with established atherosclerotic thrombosis." However, he pointed out, these patients "are not representative of the general diabetes population, which typically has no prior event and no established cardiovascular disease."

And importantly, in ELIXA and other cardiovascular-outcomes trials, diabetes is long-standing, and follow-up is very short. For example, in ELIXA, patients had duration of diabetes of 9 years, and the mean follow-up was only approximately 27 months.

"Yet we know that it took more than 10 years to detect the benefit of intensive glucose control in the prevention of myocardial infarction [MI] in the UKPDS trial," Dr Steg explained. So 27 months "is far too short to rule out a potential [cardiovascular] benefit" of this glucose-lowering drug, he stressed.

Indeed, one such upcoming trial with a diabetes drug, this time an oral sodium glucose cotransporter 2 (SGLT2) inhibitor, has apparently shown some evidence of cardiovascular benefit.

Eli Lilly and Boehringer Ingelheim have so far announced only the top-line results of their cardiovascular-safety trial with empagliflozin (Jardiance), but the companies have said that the drug, given on top of standard care, reduced the primary composite end point of cardiovascular mortality, nonfatal MI, or nonfatal stroke compared with patients receiving placebo in the 7000 diabetes patient trial.

The full results of the EMPA-REG OUTCOME study will be presented September 17, 2015 at the European Association for the Study of Diabetes meeting in Stockholm, Sweden, and are eagerly awaited.

Speaking during a press conference on the topic at the ESC meeting, Paul Armstrong, MD, of University of Alberta, Edmonton, observed: "All of us look forward to seeing whether the data, which have been suggested in the press release, are validated in a proper scientific, peer-reviewed forum."

If the results hold up, such a drug and its advantage in terms of reducing clinical cardiovascular outcomes would have the potential to alter existing guidelines, he added.

Heart Failure Data With Lixisenatide From ELIXA

At the ESC meeting, Dr Lewis said that drilling down into heart-failure outcomes in trials such as ELIXA is important, because in some other of these cardiovascular-outcomes studies, there has been a signal for heart failure.

This was most notable with oral antidiabetic agents called DPP-4 inhibitors, particularly in the SAVOR-TIMI 53 trial with saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca), resulting in the FDA requiring a label change for this agent and a related drug, alogliptin (Nesina, Takeda Pharmaceuticals).

However, the latest of these studies to report, TECOS, with another DPP-4 inhibitor, sitagliptin (Januvia, Merck), showed no such signal, with again a closer look at heart failure reported at the ESC.

Doctors can now be reassured that sitagliptin is safe to use in diabetes patients, even if they have a history of heart failure, doctors said here, and indeed, Dr Armstrong said he believes sitagliptin should be the preferred DPP-4 inhibitor in diabetic patients.

In reporting the outcomes in ELIXA by heart-failure status, Dr Lewis noted that those patients who were hospitalized for heart failure during the course of the study had a ninefold higher risk of dying than those who weren't (76 of 434 deaths [18%] in ELIXA; hazard ratio [HR], 9.3 compared with patients not hospitalized for HF).

This "suggests HF hospitalization is a very meaningful end point; this excess mortality suggests there are important events to capture among patients with diabetes," he observed.

But whether or not patients were taking lixisenatide or placebo had no impact on these outcomes — nor did it in terms of the 22% of patients in the trial who had a history of heart failure at randomization.

"As you would expect, their overall risk for [subsequent] HF hospitalization was higher than those who didn't carry a history of chronic HF at the time of randomization," Dr Lewis noted.

But randomization to lixisenatide rather than placebo was not associated with any excess risk, even in this group that was high risk at baseline — there was the same neutrality (HF hospitalization occurred in 9.7% of lixisenatide patients with a history of HF vs 10.2% of those taking placebo [HR, 0.93]).

"In this particularly high-risk population, there was no concern in terms of the use of lixisenatide," Dr Lewis stressed.

For those without a history of heart failure prior to the trial, heart-failure hospitalization was much lower, and again there was no impact of lixisenatide on this outcome (2.4% of patients hospitalized for HF in lixisenatide group vs 2.5% of placebo group [HR, 0.97]).

He and his colleagues also stratified risk by BNP quartiles, but again found no interaction with lixisenatide use.

"These additional analyses indicate safety with respect to the heart-failure events [with lixisenatide]…so we can extend the ELIXA conclusions…beyond just the ACS population to one of the highest-risk populations, ACS with HF," Dr Lewis concluded.

Dr Lewis reports receiving research funding from Sanofi, Amgen, and Novartis. Dr Steg reports he has been a speaker or a member of a speaker's bureau for Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Medtronic, Otsuka, Pfizer, Roche, Sanofi, Servier, Takeda, the Medicines Company, and Vivus and holds stock in Aterovax.

European Society of Cardiology (ESC) Congress 2015. Presented August 31, 2015. Abstracts 3154 and 3155.

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