More on HF Hospitalization With Gliptins in Type 2 Diabetes

June 24, 2014

SAN FRANCISCO — A new post hoc analysis of the VIVIDD study with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin (Galvus, Novartis) in patients with type 2 diabetes and heart failure has shown that the drug is not associated with an increase in hospitalizations for HF.

The findings were reported in a poster at the American Diabetes Association (ADA) 2014 Scientific Sessions last week by Wolfgang Kothny, MD, therapeutic area head for diabetes at Novartis Pharma, Basel, Switzerland.

This new analysis of VIVIDD was performed in the wake of a signal of possible heart failure associated with saxagliptin (Onglyza or Kombiglyze XR, Bristol-Myers Squibb/AstraZeneca) from the SAVOR-TIMI 53 trial in patients with type 2 diabetes at high risk for or with a history of cardiovascular events. In this, a significant 27% increased risk for hospitalizations for heart failure came seemingly out of the blue last autumn, and the US Food and Drug Administration (FDA) is currently reviewing this risk.

A second study, EXAMINE, in type 2 patients with acute coronary syndrome, showed a signal for HF with a second DPP-4 inhibitor, alogliptin (Nesina, Takeda Pharmaceuticals), albeit not significant. Doctors have been concerned about this potential side effect with this class of oral type 2 diabetes drugs ever since.

"This is obviously a much smaller study, but the advantage is it's in a dedicated HF [population], and we didn't see any relevant differences between new HF events or HF hospitalizations [between vildagliptin and placebo]," Dr. Kothny told Medscape Medical News.

Asked to comment, Per-Henrik Groop, MD, DMSc, from Helsinki University Central Hospital, Finland, said he thought the new VIVIDD analysis was "very important because you know there are 2 big studies showing that we have a signal, which is of course worrying. This is good news."

But Benjamin M. Scirica, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, a primary investigator of SAVOR-TIMI 53, disagrees. He told Medscape Medical News: "The VIVIDD study by itself was not powered for clinical end points, and any conclusions regarding safety of vildagliptin are statistically unjustified and cannot be supported by this trial."

He added: "Almost by chance, the VIVIDD study may have provided a mechanistic insight into the unexpected finding of an increased risk of hospitalization for heart failure observed in the SAVOR-TIMI 53 and the EXAMINE trials." And, in fact, "the 20% to 25% higher rate of adjudicated hospitalizations for heart failure in patients treated with vildagliptin is consistent with the findings of the larger cardiovascular-outcomes trials of DPP-4 inhibitors," he said.

Many eyes are therefore on the ongoing TECOS study, a cardiovascular-outcomes trial with sitagliptin (Januvia, Merck), which is due to complete in December 2014 and will yield more information on this subject with this drug, which is perhaps the most widely used gliptin in the United States, at least, due to it being the first in class to reach the market there.

VIVIDD Data: Numbers Are Small

In the new VIVIDD poster, Dr. Kothny reported that 13 of 128 (10.2%) patients with diabetes and heart failure randomized to vildagliptin in VIVIDD were hospitalized for heart failure compared with 10 (8%) of those in the trial who received placebo (P = .552).

"We looked in particular at the safety of vildagliptin in patients with heart failure, and that's one of the big differences here with the published big outcomes studies, SAVOR-TIMI and EXAMINE — where they had patients with high CV risk — whereas here, it's established heart failure," he said.

"This is obviously a much smaller study," he conceded, "but the advantage is it's in a dedicated HF [population], and we didn't see any relevant differences between new HF events or HF hospitalizations."

He said, to his mind, doctors should feel confident to treat patients with NYHA class 1 or 2 heart failure with vildagliptin (there are few data on use of the drug in more severe heart failure).

Dr. Groop said: "We need to make sure the signal is there or not....This is of course not proven yet, but [this new analysis] is suggesting there is no big hazard."

But he conceded that the TECOS results will be key. "There is a third big study coming out — TECOS — and if that shows a signal again, then you will have, [for all] gliptins, a warning. If that [study] is neutral, it will be fine."

Dr. Kothny is an employee of Novartis Pharma. Dr. Groop is a member of the Medscape Diabetes & Endocrinology advisory board. He has served as an advisor for Boehringer Ingelheim, Novartis, and Cebix and as a speaker for Boehringer Ingelheim, Novartis, Novo Nordisk, Merck, Abbott Laboratories, Genzyme, and Eli Lilly; he has received research grants from Eli Lilly and Roche and income in an amount equal to or greater than $250 from Boehringer Ingelheim, Novartis, Novo Nordisk, Merck, Abbott Laboratories, Genzyme, and Eli Lilly. Dr. Scirica reports research grants via the TIMI study and Brigham and Women's Hospital from AstraZeneca and Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Bayer Healthcare, Gilead, Eisai, and Merck and consulting fees from AstraZeneca, Gilead, Lexicon, Arena, Eisai, St. Jude's Medical, Forest Pharmaceuticals, Bristol-Myers Squibb, Boston Clinical Research Institute, Covance, University of Calgary, and Elsevier Practice Update Cardiology.

American Diabetes Association 2014 Scientific Sessions; June 15, 2014. Abstract 1028-P

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