HF Can No Longer Be Ignored in Diabetes, Say Experts

March 12, 2014

GLASGOW, SCOTLAND — The drumbeat to recognize heart failure as a serious risk in patients with diabetes is getting louder and louder as experts are calling on the diabetes community to recognize that heart failure occurs frequently and is of "ominous prognostic importance"[1].

In addition, clinical trialists testing new glucose-lowering treatments for diabetic patients need to be aware of this heightened risk of hospital admissions for heart failure, an end point that should be emphasized as an equal to MI and stroke. In fact, heart-failure hospitalizations could "even be added as a component of the primary composite cardiovascular outcome of trials to more fully capture the potential cardiovascular risks and benefits."

The experts, including Dr John McMurray (University of Glasgow, Scotland), Dr Hertzel Gerstein (McMaster University, Hamilton, ON), Dr Rury Holman (University of Oxford, UK), and Dr Marc Pfeffer (Brigham and Women's Hospital, Boston, MA), published their viewpoint March 13, 2014 in Lancet Diabetes & Endocrinology and conclude that heart failure is a "cardiovascular outcome in diabetes that can no longer be ignored."

In a presentation last year at the European Association for the Study of Diabetes (EASD), McMurray made a similar plea to the diabetologists in attendance, telling the audience that heart failure is killing their patients and not getting the attendance it deserves.

In 2008, the US Food and Drug Administration (FDA) issued guidelines for industry that recommended sponsors prospectively demonstrate cardiovascular safety with drugs designed for the treatment of diabetes. The recommendations were echoed by the European Medicines Agency (EMA) in its own 2012 guidelines. Cardiovascular safety typically requires showing the drugs do not increase the risk of major adverse cardiovascular events (MACE), an end point that usually includes cardiovascular death, MI, or stroke.

In their viewpoint, McMurray and colleagues say the recommendations have led to approximately 150 000 patients with known cardiovascular disease or those at high risk for cardiovascular disease being followed in randomized trials with new glucose-lowering drugs.

"A major concern, however, is the universal absence in any of these trials of hospital admission for heart failure as a prespecified component of their primary composite cardiovascular outcomes," they write. "In our opinion, hospital admission for heart failure is one of the most common and prognostically important cardiovascular complications of diabetes and the one cardiovascular outcome for which the risk has been shown unequivocally to be increased by certain glucose-lowering therapies."

The group notes that in recent large-scale clinical trials, the development of heart failure occurred at a frequency similar to the development of stroke and MI. Clinical trials of diabetic therapy with pioglitazone and rosiglitazone (Avandia, GlaxoSmithKline) have shown a substantial increase in heart-failure risk, as did the SAVOR-TIMI 53 trial testing the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca). In SAVOR-TIMI 53, the risk of heart failure was increased 27% compared with placebo. In the EXAMINE trial with alogliptin (Nesina, Takeda Pharmaceuticals), there did not appear to be an increased risk of heart failure, although different analyses have suggested a possible trend.

As reported previously at the World Diabetes Congress 2013, others have stated that while patients with type 2 diabetes who are at high risk for or who already have heart failure should not be precluded from receiving DPP-4 inhibitor glucose-lowering agents, physicians should be vigilant in monitoring their patients when prescribing them.

Saxagliptin is approved in the US, Canada, Europe, and elsewhere as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, but the FDA is now investigating a possible risk of heart failure among patients treated with the drug. Alogliptin is approved in Europe, the US, and Canada.

Glasgow University, McMurray's employer, is paid for his time spent as a steering-committee member, data-safety-monitoring-board member, and end-point-committee member in diabetes trials by Bayer, GlaxoSmithKline, Lilly, Merck, Novartis, Sanofi, and Oxford University. Gerstein reports consulting fees from Sanofi, Novo Nordisk, Lilly, Bristol-Myers Squibb, Roche, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; lecture fees from Sanofi and Bayer; and research support through his institution from Sanofi, Lilly, Merck, Novo Nordisk, Boehringer Ingelheim, Bristol-Myers Squibb, Takeda, and AstraZeneca. Holman has received research funding from Bayer, Bristol-Myers Squibb, and Merck and advisory-board honoraria from Bayer, Elcelyx, Merck, Novartis, and Novo Nordisk. Pfeffer has received research grant support from Amgen, Celladon, Novartis, and Sanofi; consults for Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Fibrogen, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Roche, Servier, Teva, and the University of Oxford; and Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in selected survivors of MI with Novartis, for which Pfeffer is a coinventor, but "his share of the licensing agreement is irrevocably transferred to charity."

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