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Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care - EXAMINE
Description:
Alogliptin is a novel selective dipeptidyl peptidase 4 (DPP-4) inhibitor that lowers glucose. The current trial sought to study the cardiovascular (CV) safety of alogliptin in patients with type 2 diabetes mellitus (DM2) and recent acute coronary syndrome (ACS).
Contribution to the Literature: The EXAMINE trial showed that alogliptin does not increase the risk of CV events, including heart failure hospitalizations, in patients with diabetes mellitus and recent ACS.
Study Design
- Placebo Controlled
- Randomized
- Parallel
- Stratified
Patient Populations:
- Diagnosis of DM2 and receiving antihyperglycemic therapy (single or combination therapies)
- ACS within 15-90 days before randomization
- Receiving local standard of care for DM2 care and secondary CV prevention
Number of enrollees: 5,380
Duration of follow-up: 30 months (median 18 months)
Mean patient age: 61 years
Percentage female: 32%
Exclusions:
- Concomitant use of other DPP-4 inhibitors or GLP-1 agonists
- Dialysis within 14 days of screening
- Type 1 diabetes
- Unstable cardiac disorders
Primary Endpoints:
- Composite of CV death/nonfatal MI/nonfatal stroke
Secondary Endpoints:
- CV death/MI/stroke/urgent revascularization unstable angina
Drug/Procedures Used:
Patients with DM2 and recent ACS were randomized in a double-blind fashion to either alogliptin 25 mg daily (12.5 mg if glomerular filtration rate [GFR] 30-59 ml/min, 6.25 if GFR <30 ml/min) or placebo.
Concomitant Medications:
Aspirin (90.7%), statin (90.4%), beta-blockers (82%), insulin (30%), and metformin (66%)
Principal Findings:
A total of 5,380 patients were randomized, 2,701 to alogliptin and 2,679 to placebo. Baseline characteristics were fairly similar between the two arms. The mean GFR was 71.2 ml/min (29% with GFR <60). The median time between index ACS and randomization was 45 days. Approximately 63% had undergone prior percutaneous coronary intervention and 12.7% coronary artery bypass grafting. The mean glycated hemoglobin (HbA1c) at baseline was 8.0%.
HbA1c levels were lowered modestly from baseline at 3 years in the alogliptin arm compared with placebo (-0.33% vs. 0.03%, p < 0.001). The primary endpoint of CV death/MI/stroke was similar between the alogliptin and placebo arms at 30 months (11.3% vs. 11.8%; HR = 0.96, upper boundary of 95% CI = 1.16; p < 0.001 for noninferiority; p = 0.32 for superiority). The secondary endpoint of CV death/MI/stroke/urgent revascularization due to unstable angina was also similar (12.7% vs. 13.4%, p = 0.26). Individual endpoints including CV death (3.3% vs. 4.1%, p = 0.10), MI (6.9% vs. 6.5%, p = 0.47), and all-cause mortality (5.7% vs. 6.5%, p = 0.23) were all similar. Hospital admission for heart failure: 3.9 % vs. 3.3% (HR 1.19, 95% CI 0.90-1.58); in patients without prior heart failure: 2.2% vs. 1.3%, p = 0.03; p for interaction = 0.07. CV death and hospital admission for heart failure: 7.4% vs. 7.5%, p = 0.98.
The incidences of hypoglycemia, acute or chronic pancreatitis, pancreatic cancer, and angioedema were similar between the two arms.
Interpretation:
The results of the EXAMINE trial indicate that alogliptin, a DPP-4 inhibitor, is not associated with an excess of CV events as compared with placebo in patients with DM2 and recent ACS; the upper margin of 95% CI of 1.16 for the primary endpoint was lower than the threshold set by the Food and Drug Administration (FDA) (1.3) for postmarketing trials. Modest reductions in HbA1c were noted, with no increase in hypoglycemia events. No increase in pancreatitis or pancreatic cancer was noted. Contrary to findings from the SAVOR-TIMI 53 trial with saxagliptin, alogliptin did not appear to increase the risk of new heart failure rehospitalizations, although there was a slight increase in patients without prior history of heart failure.
Following the much publicized CV safety concerns with rosiglitazone, the FDA mandated that all new diabetes drugs conduct studies demonstrating CV safety. The upper limit of the 95% CI for the HR had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the CV safety profile of alogliptin for use in patients with DM2 and even those with recent ACS, traditionally considered a high-risk group. As has been true for almost all diabetes medications, lowering HbA1c was not associated with improved CV outcomes (macrovascular outcomes) in the short-term. Most diabetic drugs have been associated with improvement in microvascular outcomes; however, those were not studied in the current trial. For now, clinicians need to continue to focus on other modifiable risk factors for CV risk reduction among individuals with DM2, such as hypertension and dyslipidemia, in addition to glycemic control.
References:
Zannad F, Cannon CP, Cushman WC, et al., on behalf of the EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385:2067-76.
White WB, Cannon CP, Heller SR, et al., on behalf of the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1327-35.
Presented by Dr. William B. White at the European Society of Cardiology Congress, Amsterdam, Holland, September 2, 2013.
Keywords: Follow-Up Studies, Diabetes Mellitus, Type 2, Risk Factors, Hypoglycemia, Glucose, Pancreatitis, Chronic, Glycated Hemoglobin A, Dyslipidemias, Piperidines, United States Food and Drug Administration, Confidence Intervals, Hypertension, Thiazolidinediones, Stroke, Myocardial Infarction, Uracil, Acute Coronary Syndrome, Dipeptidyl Peptidase 4, Pyridinolcarbamate, Risk Reduction Behavior, Standard of Care, Dipeptidyl-Peptidase IV Inhibitors, Percutaneous Coronary Intervention, Pancreatic Neoplasms, Incretins, Blood Glucose, Glomerular Filtration Rate, Coronary Artery Bypass
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