EXAMINE: Alogliptin Doesn’t Increase Cardiovascular Events

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The DPP-4 inhibitor alogliptin doesn't appear to increase cardiovascular risk in patients with diabetes taking ACE inhibitors.

BOSTON — Two analyses of the EXAMINE trial indicate that cardiovascular (CV) event rates were no higher with the dipeptidyl-peptidase-4 (DPP-4) inhibitor alogliptin, as compared with placebo, in certain high-risk patients with type 2 diabetes.

The data were presented at the American Diabetes Association (ADA) 75th Scientific Sessions.

CV Outcomes With Alogliptin and ACE Inhibitors

“The background of the present analysis originated with concern that activation of the sympathetic nervous system through substance P occurs when there is DPP-4 inhibition in the presence of high-dose ACE inhibition. These findings have led to concerns about potential increases in CV events, destabilization of blood pressure or an increase in heart rate when these two classes of drugs are used together,” William B. White, MD, of the University of Connecticut Health Center in Farmington, said during his presentation.

Using data from the EXAMINE trial, White and colleagues evaluated adjudicated CV events in patients with type 2 diabetes and recent acute coronary syndrome (ACS) according to ACE inhibitor use. In the trial, they randomly assigned patients to alogliptin or placebo in addition to existing antihyperglycemic and CV therapies.

Outcomes included risks for CV death, nonfatal myocardial infarction (MI) and nonfatal stroke (major adverse CV events [MACE]), and the composite of CV death or hospitalized heart failure.

Of 5,380 patients, 3,323 (62%) —1,681 in the alogliptin group and 1,642 in the placebo group — were taking an ACE inhibitor, according to the data

Similar composite rates of MACE were noted in both the alogliptin and placebo groups with ACE inhibitor (11.4% vs. 11.8%; HR=0.97; 95% CI, 0.79-1.19) and without ACE inhibitor use at baseline (11.2% vs. 11.9%; HR=0.94; 95% CI, 0.73-1.21).

Results also indicated that the composite of CV death or hospitalization for heart failure in patients using ACE inhibitors at baseline occurred in 6.8% of patients in the alogliptin group and 7.2% in the placebo group (HR=0.93; 95% CI, 0.72-0.73).

Additionally, alogliptin appeared to have no effect on hospitalization for heart failure alone in patients treated with ACE inhibitors, as compared with those treated with placebo (3.3% vs. 3.1%; HR=1.07; 95% CI, 0.73-1.56).

Moreover, higher doses of ACE inhibitors did not have a greater effect than lower doses on CV events.

According to analyses based on pre-randomization history of heart failure and use of ACE inhibitors at baseline indicated that MACE occurred in 13.9% of those treated with alogliptin vs. 16.5% of those who received placebo (HR=0.87; 95% CI, 0.63-1.19). Also, CV death or hospitalization for heart failure occurred in 12.0% of the alogliptin group vs. 13.2% of the placebo group (HR=1.02; 95% CI, 0.72-1.44).

“In patients with type 2 diabetes and recent ACS, rates of the composite endpoint of death from CV causes, nonfatal MI and nonfatal stroke were similar on the DPP-4 inhibitor alogliptin vs. placebo in patients receiving ACE inhibitor therapy. Rates of the composite endpoint of death from CV causes and hospitalization for heart failure were also similar on the DPP-4 inhibitor alogliptin compared to placebo in those receiving ACE inhibitors,” White said.

“These data do not support an interaction between ACE inhibitors and the DPP-4 inhibitor alogliptin in high-risk CV patients with type 2 diabetes.”

Alogliptin in Patients With ACS

In another analysis of the EXAMINE trial, Yuichi J. Shimada, MD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues evaluated all cardiac ischemic events and CV hospitalizations in study participants.

Specifically, they looked at incident rates of MI and unstable angina, coronary revascularization, CV hospitalizations and composites of these endpoints.

Results revealed HRs for alogliptin vs. placebo of 1.02 (95% CI, 0.89-1.17) for CV hospitalization, 0.98 (95% CI, 0.82-1.16) for coronary revascularization and 0.98 (95% CI, 0.87-1.10) for the composite of CV death, nonfatal MI, nonfatal stroke, unstable angina and revascularization.

When evaluating the composite of cardiac ischemic outcomes according to treatment allocation, event rates were generally high in both groups for various combinations of endpoints, according to Shimada.

However, he noted that the HRs were similar between the two treatment groups in each endpoint, ranging from 0.91 to 0.98 with no significant P value.

“These new data demonstrate that alogliptin does not increase the risk of cardiac ischemic events or CV hospitalization in the high-risk post-ACS patient population,” Shimada said.

“In addition, since CV hospitalizations are the main driver of overall health care costs, data suggest that there would be no adverse impact on health care resource utilization and costs.”


  1. White WB et al. Abstract 12-OR: Major Cardiovascular Outcomes in the EXAMINE Trial According to ACE Inhibitor Use.
  2. Shimada YJ et al. Abstract 13-OR: Cardiac Ischemic Outcomes and Hospitalizations in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome Treated with Alogliptin or Placebo: New Insights from the EXAMINE Trial. Both presented at: American Diabetes Association (ADA) 75th Scientific Sessions; June 5-9, 2015; Boston.