Takeda Pharmaceutical Company Limited (Takeda) has announced results of the EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular (CV) safety outcomes trial, showing the primary endpoint of non-inferiority compared to placebo in addition to standard of care was met with no increase in CV risk in a Type 2 diabetes patient population at high-risk for CV events. These data, published in the New England Journal of Medicine (NEJM) and also presented at the ESC Congress 2013, demonstrate that alogliptin does not increase CV risk in Type 2 diabetes patients at high-risk for major adverse cardiac events (MACE) due to a recent acute coronary syndrome (ACS). The trial’s primary objective was to evaluate non-inferiority of CV risk based on a primary composite endpoint of CV death, nonfatal myocardial infarction and nonfatal stroke. The primary endpoint occurred at similar rates in the alogliptin and placebo groups (in 11.3% of patients vs. 11.8% of patients during a median follow-up period of 18 months; hazard ratio, 0.96; one-sided repeated confidence interval [CI] bound, 1.16). Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) for the treatment of Type 2 diabetes in adults to improve glycemic control as an adjunct to diet and exercise.
“There is a need for safer glucose lowering therapies in patients with diabetes who are at an elevated risk for cardiovascular disease,” stated William B. White, MD, FASH, FAHA, FACP, principal investigator of the EXAMINE trial. “Given the EXAMINE study design and high-risk patient population evaluated, these results provide key insights to clinicians treating diabetes patients with coronary disease.”
The global EXAMINE trial is an important evaluation as it assesses CV safety in patients known to be at an elevated risk of cardiovascular disease (CVD), the leading cause of morbidity and mortality in the Type 2 diabetes patient population. A global, large, randomized, double-blind, placebo-controlled clinical trial, EXAMINE was designed to evaluate CV safety following treatment with alogliptin in addition to standard of care, versus placebo in addition to standard of care alone, in patients with Type 2 diabetes and a recent ACS.
During the EXAMINE trial, patients were randomly assigned to receive alogliptin or placebo in addition to standard of care medications for diabetes and CVD. A total of 5,380 patients were randomly assigned and followed for a median of 18 months and up to 40 months. The rate of premature discontinuation of the study drug was similar in the alogliptin and placebo groups. Patients also received high levels of standard of care for treatment of Type 2 diabetes and CV risk factors.
“The EXAMINE trial design and importantly, the safety outcomes measured make it a uniquely informative study for diabetes treatment in some of the most high-risk patients,” said Ajay Ahuja, MD, Vice President, Global Medical Affairs, Takeda. “Over the past 20 years, Takeda has built a strong foundation in and maintained a robust focus on diabetes. EXAMINE reinforces our ongoing commitment to the science behind alogliptin and the diabetes community.”
The principal secondary safety endpoint was the primary composite with the addition of hospitalization for unstable angina that required coronary revascularization within 24 hours of hospital admission. Testing of the secondary composite endpoint of CV death, myocardial infarction, stroke and unstable angina with urgent revascularization showed no difference in rates on alogliptin versus placebo (12.7% vs. 13.4%; hazard ratio, 0.95; one-sided repeated CI bound, 1.14).
Other secondary endpoints included CV death alone and death from any cause. CV death occurred in 112 patients treated with alogliptin (4.1%) and 130 patients treated with placebo (4.9%) for a hazard ratio of 0.85 (95% confidence limits [CL] of 0.66 to 1.10, p=0.21). All-cause mortality (death from any cause) occurred in 153 patients treated with alogliptin (5.7%) and 173 patients treated with placebo (6.5%) for a hazard ratio of 0.88 (95% CL of 0.71 to 1.09, p=0.23). Overall, rates of death from any cause and CV death were not statistically significantly different between alogliptin and placebo groups.
Additional safety endpoints included angioedema, hypoglycemia, pancreatitis, malignancy, and results of laboratory testing. Rates of hypoglycemia, malignancy, pancreatitis, dialysis, and serum aminotransferase elevations were similar for the alogliptin and placebo groups. No events of pancreatic cancer were reported during the trial. The alogliptin and placebo groups did not differ significantly with regard to rates of serious adverse events (33.6% and 35.5%, respectively, p=0.14).
A global, large, randomized, double-blind, placebo-controlled clinical trial, EXAMINE was designed to evaluate CV safety following treatment with alogliptin in addition to standard of care, versus placebo in addition to standard of care alone, in patients with Type 2 diabetes and a recent ACS (within 15 to 90 days prior to randomization). The trial had a primary composite endpoint of CV death, nonfatal myocardial infarction and nonfatal stroke.
In the alogliptin group, 71.4% of patients received 25 mg, 25.7% received 12.5 mg, and 2.9% received 6.25 mg daily. Alogliptin doses were adjusted according to renal function: estimated glomerular filtration rate (eGFR) by the Modification in Diet in Renal Disease formula ≥ 60 ml/min, 25 mg daily; < 60 ml/min but ≥ 30 ml/min, 12.5 mg daily; and < 30 ml/min, 6.25 mg daily. Premature discontinuation of the study drug was similar in the alogliptin and placebo groups (20.9% of patients vs. 22.6%). The median duration of exposure to study drug was 533 days (interquartile range, 280 to 751 days). By the end of the study, the mean change from baseline in HbA1c was -0.33% and 0.03% in the alogliptin and placebo groups, and the least square means difference in HbA1c between alogliptin and placebo was -0.36% (95% CI, -0.43, -0.28, p<0.001). In the analysis of the components of the primary endpoint, the hazard ratios were consistent with the overall result. Hazard ratios for death from any cause and CV death were consistent with the primary composite endpoint.
Takeda conducted the global EXAMINE trial in accordance with the United States (U.S.) Food and Drug Administration’s (FDA) 2008 Guidance, titled “Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” for all new Type 2 diabetes treatments. As a global trial, EXAMINE results will be shared with regulatory agencies upon completion of all analyses, as appropriate.
About Type 2 Diabetes
Type 2 diabetes is the most common form of diabetes affecting millions of people globally. Type 2 diabetes is a progressive and chronic condition and patients should work with a healthcare professional to manage and monitor their disease. In addition to diet and exercise, patients often need to take one or more medications in order to help them manage their blood glucose levels. According to the International Diabetes Federation, the global health care expenditures for diabetes (both Type 1 and 2) were estimated at more than $471 billion USD in 2012. By 2030, this number is projected to exceed $595 billion.