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Alogliptin Effects on Cardiovascular Diseases — the EXAMINE Trial

In Depth: 76th ADA Scientific Sessions

Is alogliptin use increasing heart failure in type 2 diabetes?

Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an incretin which lowers glucose. DPP-4 inhibitors are efficient and used in the management of type 2 diabetes mellitus. They also act on blood vessels and the heart, thereby improving several cardiovascular risk factors, such as: improving postprandial hyperglycemia, reducing blood pressure, improving glucose control, and being weight neutral. They also reduce inflammatory markers, lessen oxidative stress, reduce platelet aggregation and improve endothelial function in type 2 diabetes mellitus patients. The relationship between DPP-4 and cardiovascular outcomes therefore needs to be investigated. It is in this respect that previous studies like the Sitagliptin Cardiovascular Outcome Study (TECOS) on sitagliptin were done.

The aim of this study is to investigate whether alogliptin causes heart failure in type 2 diabetes patients. The EXAMINE trial looks at alogliptin effect on cardiovascular deaths for patients previously hospitalized with heart failure. In a randomized trial of 5,380 patients with type 2 diabetes mellitus, their cardiovascular risk was evaluated using alogliptin (n=2701) as an interventional drug and placebo (2,679) being the control. Patients were closely monitored and both groups were given standard of care, with trial lasting 18 months. The primary outcome was hospitalized heart failure whilst the secondary outcomes were hospitalization for unstable angina, coronary revascularization, and hospitalization for stroke. They were separated, measured and analyzed. The statistical analyses method used was the propensity score match.

736 patients (13.7%) had a cardiovascular event with heart attacks (5.9%), stroke (1.1%), hospitalization for heart failure (3.0%) and finally an unstable angina (3.8%). 326 patients died during this trial, with most of the patients being those who did not experience a non-fatal cardiovascular event. Of the hospitalized patients who also had type 2 diabetes mellitus (159), they had the highest risk of death due to cardiovascular causes having four times higher than those who did not have non-fatal cardiovascular event. For those who experienced a non-fatal stroke, (8.8%) died whilst (8.2%) died of non-fatal heart attack. 3.4% of the 204 patients admitted for unstable angina also died. For patients who were treated with alogliptin, (4.1%) of them died as compared to 4.9% who were treated with placebo. This shows a no significant increase when treated with alogliptin. For the placebo, the (HR=0.85, CI 95%, 0.66-1.10). This goes to confirm an earlier study that alogliptin did not cause an increase in the risk of death or non-fatal cardiovascular events.

Heart failure, often referred to as congestive heart failure, is an inability of the heart to pump sufficiently to maintain blood flow to meet the body’s needs. It is therefore a vital predictor of mortality in both type 2 diabetes and coronary heart disease, according to Dr. White of ADA. It is therefore important to understand heart failure and know the underlying causes to help prevent any mortality. It is also important to use evidence based secondary prevention in the management of type 2 diabetes. Another question that should be asked after this trial is whether the FDA need to reconsider their warning label on alogliptin, since no link has been shown to exist between alogliptin and heart failures through various studies done.

In conclusion, there wasn’t any statistical increase in cardiovascular risk by the use of alogliptin, as compared to those who were on placebo in the treatment of type 2 diabetes. Also, patients with type 2 diabetes who were admitted to the hospital with heart failure had the highest risk of deaths due to cardiovascular causes.

Practice Pearls:

  • Alogliptin is efficient and safe in the management of type 2 diabetes even in patients who have cardiovascular disease as a comorbidity.
  • Heart failure is an important predictor of mortality rates in patients with coronary artery disease and type 2 diabetes, and therefore measures should be taken to avoid heart failure.
  • FDA needs to reconsider their label restrictions pertaining to alogliptin, since there is no link between the use of alogliptin and heart failure increase.

 

White, W.B. et al. (2016) Cardiovascular Mortality in Patients with Type 2 Diabetes and Recent Acute Coronary Syndromes from the EXAMINE Trial. Diabetes Care. Web June 16, 2016.

Heller, Simon, Cannon, C.P., et al. Alogliptin in Triple Therapy with Metformin and Sulfonylureas Provides Significant Reductions in HbA1c and is Well Tolerated; an Analysis from the EXAMINE Trial. Abstract Presentation. American Diabetes Association Annual Scientific Sessions. Web June 16 2016.

 

White, W.B. et al. (2013) Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. The New England Journal of Medicine. Web June 16 2016