CV Safety of Vildagliptin in HF Unclear

LISBON -- The diabetes medication vildagliptin may be beneficial in patients with type 2 diabetes and heart failure, but its cardiovascular safety is uncertain, a placebo-controlled trial showed.

Both the placebo and vildagliptin groups had increases in left ventricular ejection fraction of 3% to 4% through 1 year, and the between-group difference of 0.54% was not significant (95% CI -1.97%-3.06%) and met criteria for noninferiority, according to John McMurray, MD, of the University of Glasgow in Scotland.

However, a nonsignificantly greater number of patients in the vildagliptin group died from cardiovascular causes (5.5% versus 3.2%) and from any cause (8.6% versus 3.2%), "probably highlighting the importance of studying drugs that lower glucose a lot more carefully in patients who've got both diabetes and heart failure," McMurray reported at the Heart Failure Congress here.

Vildagliptin has not been approved by the FDA but is marketed as Galvus in Europe.

Wolfram Doehner, MD, PhD, of Charité-University Medical School in Berlin and not involved in the trial, said the number of deaths is too low to definitely assess the effects of vildagliptin in that respect.

"What it does show from these very low numbers [is that] it's going in the wrong direction, but only to a nonsignificant degree, so you should really be very cautious to draw any conclusion," he said in an interview, noting that such signals have been seen before in other small trials and have then disappeared in larger studies.

The current trial, VIVIDD, met its primary endpoint by demonstrating noninferiority in the vildagliptin group for the change in left ventricular function through 1 year as measured by echocardiography.

It also met its major secondary endpoint by showing a significant reduction in glycated hemoglobin (HbA1c) through 16 weeks with vildagliptin versus placebo (difference 0.62%, 95% CI 0.30%-0.93%).

In his comments following McMurray's presentation, however, Doehner questioned whether the appropriate endpoints were chosen for the trial.

He pointed out that a similarly designed trial of rosiglitazone (Avandia) also demonstrated noninferiority on the primary endpoint of the change in left ventricular ejection fraction.

It is now known, however, that the glitazones cannot be used in patients with heart failure because of the cardiovascular risks, he said.

So the message is that echocardiographic measurements are important surrogates, but not more important than the clinical signals, he said.

Doehner also questioned whether HbA1c is an appropriate endpoint in patients with heart failure, noting that previous studies have yielded conflicting results about the relationship between HbA1c and outcomes in that population.

Also, he said, previous trials have failed to show that lowering HbA1c improves outcomes in the setting of heart failure.

Targeting increased insulin secretion doesn't get to the root of the problem, which is insulin resistance, Doehner said. Insulin resistance is the primary link between diabetes and chronic heart failure, and there is a need for therapies that address that problem in patients with both diabetes and heart failure, he said.

McMurray and colleagues conducted the VIVIDD trial to assess the cardiovascular safety of vildagliptin, which is a dipeptidyl peptidase 4 (DPP-4) inhibitor.

The drug was approved in Europe in 2007 and the drug's maker, Novartis, had applied to the FDA for approval. However, the agency strengthened its safety requirements for diabetes drugs after the cardiovascular risks of rosiglitazone became apparent, and Novartis pulled its application after the FDA requested more data.

A drug like this is important because a third to a half of patients with heart failure with a reduced ejection fraction also have diabetes, McMurray said, but little is known about the cardiovascular effects of diabetes medications in that patient subset because patients with heart failure are typically excluded from clinical trials of antiglycemic agents.

It is known that the glitazones induce a worsening of heart failure and there is a contraindication to using metformin in patients with severe heart failure because of the risk of lactic acidosis, highlighting the importance of studying the cardiovascular effects of diabetes medications in patients with both type 2 diabetes and heart failure, he added.

In the VIVIDD trial, 253 patients who had type 2 diabetes for at least 3 months, a HbA1c between 6.5% and 10%, New York Heart Association class I to III disease, and a left ventricular ejection fraction of less than 40% were randomized to receive either vildagliptin or placebo on a background of standard diabetes and heart failure therapy.

The mean age of the patients was 63 and about three-quarters were male. The average left ventricular ejection fraction was roughly 30% and the average HbA1c was 7.8%. Follow-up spanned 52 weeks.

There was a significant increase in left ventricular end-diastolic volume and a nonsignificant increase in end-systolic volume in the vildagliptin group that were unexpected in light of the slight increase in ejection fraction.

"The best conclusion we can come up with is that perhaps [the findings are] explained by vildagliptin having an effect on left ventricular compliance," McMurray said.

Brain natriuretic peptide levels decreased in both groups.

The overall rates of cardiovascular events were similar in the two groups, although mortality tended -- nonsignificantly -- to be higher in the vildagliptin group.

Ultimately, it is important to continue researching ways to treat patients with both conditions, and the VIVIDD trial adds significant information that can be used in that search, Doehner said.

Primary source: Heart Failure Congress
Source reference:
McMurray J, et al "The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial" HFC 2013; Abstract 99.

http://www.medpagetoday.com/MeetingCoverage/HFC/39416

Graham