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Alogliptin in Combination with ACE Inhibitor May Not Increase Heart Failure Risk

August 22, 2016

By Will Boggs MD

NEW YORK (Reuters Health) - Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in combination with an angiotensin-converting enzyme (ACE) inhibitor may not increase the risk of heart failure in type 2 diabetes, according to results from the EXAMINE trial.

"We performed the study because there was both academic and regulatory interest in the possible attenuation of the effects of ACE inhibitors by a DPP-4 inhibitor - this was relatively well grounded in basic/clinical pharmacology research," said Dr. William B. White from the University of Connecticut School of Medicine in Farmington.

"We feel it is important that we found no overt interaction between high-dose ACE inhibitors and alogliptin on vital signs nor on cardiovascular outcomes in the EXAMINE trial," he told Reuters Health by email.

Based on a review of three randomized clinical trials, the U.S. Food and Drug Administration (FDA) in April 2016 added warnings to the labels of saxagliptin and alogliptin indicating that these DPP-4 inhibitors might increase the risk of heart failure.

Dr. White and colleagues used data from more than 5,300 patients in EXAMINE, which found no more major cardiovascular events with alogliptin versus placebo in patients with type 2 diabetes at high cardiovascular risk, to evaluate vital signs and cardiovascular outcomes according to ACE inhibitor use at baseline.

Among patients using an ACE inhibitor, there were no significant differences in vital sign changes from baseline between patients randomized to alogliptin and those randomized to placebo.

In patients not using an ACE inhibitor, randomization to alogliptin was associated with a 1.3 mmHg mean decline in systolic blood pressure, but no other statistically significant changes in vital signs.

Composite rates of the primary outcome (death because of cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke) were similar for alogliptin (11.4%) and placebo (11.8%) in the ACE inhibitor subgroup, the researchers report in Circulation, online August 1.

The rates were also similar for alogliptin (11.2%) and placebo (11.9%) for those not using an ACE inhibitor at baseline.

Moreover, alogliptin showed no effect on hospitalization rates for heart failure in patients treated with ACE inhibitors or in patients not treated with ACE inhibitors.

There were no differences in the endpoints for alogliptin versus placebo with either lower or higher doses of ACE inhibitors.


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"Physicians managing patients with coronary disease and type 2 diabetes should not be concerned about any interactions of clinical importance between ACE inhibitors and alogliptin; alogliptin + ACE inhibitors versus placebo + ACE inhibitors had comparable effects on heart failure hospitalization, cardiovascular mortality, and acute MI outcomes," Dr. White concluded.

Dr. Nancy J. Brown from Vanderbilt University Medical Center in Nashville, Tennessee, who co-authored a related editorial, told Reuters Health by email, "A drug-drug interaction between DPP-4 inhibition and ACE inhibition does not account for the increased risk of heart failure observed with DPP-4 treatment in some clinical trials."

"We need to continue to understand the mechanism(s) underlying potential adverse (and favorable) effects of DPP-4 inhibitors and other new anti-diabetic drugs," she said.

Takeda Development Center, Inc. funded the study, employed two of the 11 authors, and had various relationships with six other authors, including Dr. White.


Circulation 2016.

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