Ischemic Cardiac Outcomes and Hospitalizations According to Prior Macrovascular Disease Status in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome from the Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care Trial
By Chris DeFrancesco, UConn Today
People with the most common form of diabetes can take the new drug Alogliptin without concern for an increased risk of heart failure or cardiovascular disease, according to research by a UConn cardiologist just published in the British medical journal, The Lancet.
Dr. William White, professor of medicine and chief of the Calhoun Cardiology Center Division of Hypertension and Clinical Pharmacology at UConn Health, analyzed data from a global clinical trial called EXAMINE. Regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new diabetic therapies.
“This new analysis shows that Alogliptin was safe in patients with Type 2 diabetes who we considered at high cardiovascular risk because they had had an acute coronary syndrome before entering the trial,” says White.
Even in patients who had a history of heart failure – 28 percent of participants – there was no increase in hospitalization.
The information is significant because of the prevalence of heart disease morbidity and mortality in patients with Type 2 diabetes. According to the World Health Organization, heart disease is responsible for between 50 percent and 80 percent of deaths among diabetics.
Also, the findings contradict a previous clinical trial of another diabetes medication in the same drug class that showed a modest increase in heart failure risk, leading to a closer scrutiny of Alogliptin – an orally administered anti-diabetic drug in the DPP-4 inhibitor class – in the medical community.
EXAMINE is an acronym for “Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome.” The study included nearly 5,400 diabetics in 49 countries, all of whom were within 90 days of hospitalization for either a heart attack or chest pain related to coronary heart disease. The trial was funded by Japanese pharmaceutical company Takeda, which makes Alogliptin.
The following poster was presented to the European Association on the Study of Diabetes (EASD) in Vienna, Austria, September 2014.
Two posters were presented at the American College of Cardiology, held in Washington D.C., March 29-31, 2014.
William B. White, M.D., Christopher P. Cannon, M.D., Simon R. Heller, M.D., Steven E. Nissen, M.D., Richard M. Bergenstal, M.D., George L. Bakris, M.D., Alfonso T. Perez, M.D., Penny R. Fleck, M.B.A., Cyrus R. Mehta, Ph.D., Stuart Kupfer, M.D., Craig Wilson, Ph.D., William C. Cushman, M.D., and Faiez Zannad, M.D., Ph.D., for the EXAMINE Investigators
To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.
We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, −0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.
Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)
W. B. White, R. Pratley, P. Fleck, M. Munsaka, M. Hisada, C. Wilson3 & V. Menon
As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin.
We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke.
The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2,023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1,169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies.
These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of alogliptin in patients with type 2 diabetes mellitus.
William B. White, M.D., George L. Bakris, M.D., Richard M. Bergenstal, M.D., Christopher P. Cannon, M.D., William C. Cushman, M.D., Penny Fleck, B.S., Simon Heller, M.D., Cyrus Mehta, Ph.D., Steven E. Nissen, M.D., Alfonso Perez, M.D., Craig Wilson, Ph.D., and Faiez Zannad, M.D., Ph.D.; Farmington, CT; Chicago, and Deerfiield, IL; Minneapolis, MN; Boston, MA; Memphis, TN; Sheffield, United Kingdom; Cleveland, OH; and Nancy, France
Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events. (Am Heart J 2011;162:620-626.e1.)