September 11, 2013
Two Incretin Medications Fail to Decrease CV Risk in Patients With Diabetes

Amsterdam, The Netherlands—The quest continues for the gold standard in diabetes drugs—a blood sugar–lowering therapy that is not only safe but also proven to be beneficial for the heart.

Two large, placebo-controlled, cardiovascular-outcome trials involving saxagliptin and alogliptin showed no increase in overall cardiovascular (CV) risk among patients with diabetes taking two incretin class drugs, saxagliptin and alogliptin. But the studies, which were presented at the European Society of Cardiology Congress and simultaneously published in the New England Journal of Medicine, also failed to show reductions in CV events.

The authors note that saxagliptin was associated with a small but unexpected increased risk of hospitalization for heart failure and a high frequency of hypoglycemia, although neither trial showed any increased risk of pancreatic adverse events, including cancer.

Both studies were designed to satisfy FDA requirements to show CV safety.

The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial indicated that patients with type 2 diabetes and high CV risk due to recent acute coronary syndromes had similar rates of CV events when treated with the antidiabetic agent alogliptin compared to placebo.

“It represents the first cardiovascular safety trial of an anti-diabetic drug in patients with acute coronary syndromes. Hence, for those who are likely candidates for the drug in clinical practice with elevated CV risk, including those with a recent acute coronary syndrome, it is reassuring that alogliptin does not increase cardiovascular morbidity or mortality,” said the chair of the study's steering committee William B. White, MD, from the University of Connecticut School of Medicine in Farmington. “However, EXAMINE does not rule out longer-term benefits or risks of alogliptin with respect to cardiovascular end points as the median duration of the trial was approximately 18 months.”

More than 5,300 patients from 898 centers in 49 countries were involved in the EXAMINE trial. They were randomized to receive alogliptin or placebo, administered in a double-blind fashion along with standard-of-care treatment for type 2 diabetes mellitus and CV risk factors. Alogliptin dosing was modified according to kidney function, with 71.4% of patients receiving 25 mg, 25.7% receiving 12.5 mg, and 2.9% receiving 6.25 mg daily.

The primary endpoint, a composite of CV death, myocardial infarction, and stroke, occurred at a similar rate in alogliptin- and placebo-treated patients (11.3% vs. 11.8%, respectively; P < 0.001 for noninferiority) after a median follow-up of 18 months, and up to 40 months.

End-of-study glycated hemoglobin levels were significantly lower, as anticipated, in patients on alogliptin than placebo with a mean change from baseline of -0.33% and +0.03%, respectively. Incidence of hypoglycemia, malignancy, pancreatitis, and dialysis were similar for both groups.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus was a randomized, double-blind, placebo-controlled trial of 16,492 patients designed to evaluate saxagliptin in adults with type 2 diabetes at risk for CV death, heart attack, and stroke.

Study authors write that while saxagliptin met the primary safety objective, demonstrating no increased risk for the primary composite endpoint of CV death, nonfatal myocardial infarction (MI), or nonfatal ischemic stroke, it did not prove superior in preventing CV disease.

Their report points out that CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1,059 patients in the saxagliptin group and in 1,034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan–Meier estimates; hazard ratio, 1.02; 95% CI, 0.94-1.11; P = 0.66).

Furthermore, more patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07-1.51; P = 0.007). Overall, as expected, the drug improved glycemic control compared to placebo.

“DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased,” the authors conclude. “Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.”

In a commentary accompanying the NEJM articles, prominent diabetes and CV researchers William R. Hiatt, MD, Sanjay Kaul, MD, and Robert J. Smith, MD, point out that health care providers have “numerous treatment options, and additional drugs are in development” for patients with diabetes.

“New therapies targeting glycemic control may have cardiovascular benefit, but this has yet to be shown,” they conclude. “The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.”

U.S. Pharmacist Social Connect