Heart Failure Not Increased With Diabetes Drug Alogliptin?

Miriam E Tucker

March 11, 2015

Alogliptin (Nesina, Takeda Pharmaceuticals) was not associated with an increased risk for heart-failure–related outcomes in patients with type 2 diabetes, a new analysis finds.

The new data from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) study were published online March 10 in the Lancet by Faiez Zannad, MD, PhD, from the University of Lorraine, Nancy, France, and colleagues.

EXAMINE is one of two randomized placebo-controlled trials to assess major cardiovascular outcomes in patients with type 2 diabetes treated with glucose-lowering agents of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. EXAMINE enrolled 5380 patients with recent coronary syndrome events, while the other trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) included 16,492 patients with a history or risk of CVD events.

In both studies, no increased risks were seen in composite cardiovascular outcomes with the drugs compared with placebo.

However, in SAVOR-TIMI 53, there was an unexpected increase in the rate of hospital admission for heart failure (3.5% vs 2.8%, hazard ratio [HR], 1.27), prompting overall concern about the class.

Now, Dr Zannad and colleagues report the EXAMINE heart-failure findings from both a prespecified exploratory analysis and a post hoc analysis, in which they found no statistically significant effects on either hospital admission for heart failure or the composite end point of cardiovascular death and hospital admission for heart failure. Some of these findings were first reported at the American College of Cardiology 2014 Scientific Sessions.

"This trial was designed to examine whether alogliptin is safe in patients with diabetes type 2 when initiated shortly after an acute coronary syndrome. The answer is clear. Alogliptin was cardiovascular safe in this high-risk patient population. The primary outcome of major cardiovascular events [MACE] was similar between alogliptin and placebo," Dr Zannad told Medscape Medical News.

And "this safety result was very consistent among a large number of subgroups, including in patients with current or previous heart failure," he added.

As for SAVOR-TIMI 53, he said, "It is hard to understand why saxagliptin [Onglyza, Bristol-Myers Squibb/AstraZeneca] would worsen or produce heart failure. If anything, experimental pharmacology of DPP-4 inhibitors suggests potential beneficial effect in heart-failure patients. So we have yet to understand why an excess of heart-failure events was observed with saxagliptin in SAVOR."

However, in an accompanying editorial, Eberhard Standl, MD, PhD, and Oliver Schnell, MD, PhD, of the Munich Diabetes Research Group, Helmholtz Center, Neuherberg, Germany, sound a cautionary note.

"These are important new findings, but they are not fully comparable with those of SAVOR TIMI 53 because EXAMINE focused on composite outcomes in which hospital admission for heart failure was included, whereas risks were assessed as individual outcomes in SAVOR TIMI 53," they write, pointing out that this difference could result in survivor bias in EXAMINE.

Also, Drs Standl and Schnell note that because EXAMINE was much smaller than SAVOR TIMI 53, the observed 19% difference in hospital admission for heart failure did not achieve statistical significance but could still be clinically meaningful.

"Not finding significant differences despite numerically similar HR values does not preclude an increase in risk.…We believe that some uncertainties prevail concerning the apparent 19% to 27% increase in risk of hospital admission for heart failure in patients taking DPP-4 inhibitors, although these are not associated with excess fatal or other severe cardiovascular complications."

Still Waiting for TECOS Results…

Both the authors and the editorialists point to the importance of the information from a third cardiovascular-end-point trial for another DPP-4 inhibitor, Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), with results to be presented in June at the American Diabetes Association's Scientific Sessions.

"TECOS is yet another trial, soon to deliver, with yet another DPP-4 inhibitor, and we shall see where it would topple the balance. Meanwhile, the results of EXAMINE are reassuring, and if my patients need a DPP-4 inhibitor, I would get them on alogliptin," Dr Zannad told Medscape Medical News.

According to the editorialists, "The TECOS trial, which is studying the use of sitagliptin [Januvia, Merck] in 14,724 patients with type 2 diabetes and a high risk of cardiovascular events, will need to exploit all the statistical methods evolving and address all the questions arising from SAVOR TIMI 53 and EXAMINE to best bridge the gap between science and optimum care for patients with type 2 diabetes."

Prior to that, on April 14 both SAVOR TIMI 53 and EXAMINE will be discussed at a US Food and Drug Administration advisory committee meeting.

Most Heart-Failure Measures Not Increased With Alogliptin

In EXAMINE, which had a median follow-up of 533 days, the exploratory major adverse cardiac events (MACE) end point — all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, urgent hospitalization due to unstable angina, and hospital admission for heart failure — occurred in 16% of alogliptin patients (433 of 2701 patients) and in 16.5% (441 of 2679) randomized to placebo (HR, 0.98; P = .728).

Separate analysis of the MACE end points revealed that hospital admission for heart failure was the first event in 3.1% (85) of the alogliptin group compared with 2.9% (79) taking placebo (HR 1.07; P = .657).

Similarly, no differences were seen between alogliptin and placebo in the post hoc composite of cardiovascular death and hospital admission for heart failure (7.4% vs 7.5%; HR, 1.00; P = .976). The results didn't differ when the patients were divided into those with and without a history of heart failure at baseline (HR, 0.90 and 1.14; P = .446 and .337, respectively).

As the editorialists point out, for the single outcome of hospital admission for heart failure in the post hoc analysis, the overall HR was 1.19 ( P = .220). When divided by those with and without heart failure at baseline, there were no differences among those with the heart-failure history (HR, 1.00; P = .996), but the risk was significantly greater with alogliptin among subjects without a heart-failure history (2.2% vs 1.3%; HR, 1.76; P = .026).

Study coauthor William B White, MD, from the University of Connecticut School of Medicine, Farmington, told Medscape Medical News, "One of the most compelling findings from this new analysis published in the Lancet is how well the highest-risk patient did on alogliptin — the patients with a history of heart failure at baseline did not have an increase in death or heart failure on the drug vs placebo."

And, he added, for patients in the highest quartile of the biomarker N-terminal probrain natriuretic peptide (NT-proBNP), the risk for death was less on alogliptin and the risk for heart failure was neutral. "This clearly supports the notion of safety using this drug for type 2 diabetes in patients with heart disease."

Drs Standl and Schnell are a bit more cautious, however.

"We do not think…that specific practical limitations in the use of DPP-4 inhibitors are warranted at present. Yet, to get a clear notion of what the risks are and for what signs treating physicians need to be vigilant will be important….The general recommendation to look out for the signs and symptoms of emerging heart failure in all patients with diabetes at all times…seems to be particularly helpful in the context of DPP-4 inhibitor therapy," they conclude.

EXAMINE was funded by Takeda Development Center Americas. Dr Zannad has received personal fees from Air Liquide, Bayer, Biotronik, Boston Scientific, Janssen, Novartis, Pfizer, Resmed, Servier, St Jude, and Takeda and nonfinancial support from Cardiorenal Diagnostics and CVCT. Dr White has received personal fees from Ardea Biosciences, AstraZeneca, Forest Research Institute, Roche, Takeda, and Teva and is a member of cardiovascular-end-point committees for other compounds. Disclosures for the coauthors are listed in the article. Dr Standl has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck Serono Excemed, Novartis, and Sanofi. Dr Schnell is managing director of SCIARC, a medical education company.

Lancet. Published online March 10, 2015. Abstract, Editorial

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