OBJECTIVES: To examine potential protective effects of monotherapy and polytherapy exenatide on cardiovascular diseases (CVDs) in Type 2 diabetes. METHODS: This study included 166,776 patients with healthcare encounters between January 2005 and June 2012 in national medical claims data. Patients without history of major adverse cardiac events (MACE), acute myocardial infarction (AMI), congestive heart failure (CHF), and stroke 18 months before initiation of study drugs were assigned to four monotherapy exposure groups: exenatide, metformin, sulfonylureas, pioglitazone, and two poly-therapy exposure groups: exenatide polytherapy, and non-exenatide polytherapy. Incident CVD events (MACE, AMI, CHF, or stroke) were identified by ICD-9-CM diagnosis codes. Baseline demographic and clinical characteristics were matched using propensity scores. Novel analytic methods, counting process models as extended proportional hazards regression, controlled for discontinuous drug intervals and on- and off-drug effects on CVD outcomes. RESULTS: Compared to non-exposure periods, MACE (aHR = 0.53, 95% CI: 0.44-0.63) and stroke (aHR = 0.53, 95% CI: 0.39-0.71) were least likely on exenatide polytherapy.  AMI, however, (aHR = 0.49. 95% CI: 0.31-0.77) was least likely on non-exenatide polytherapy and CHF (aHR = 0.45, 95% CI: 0.40-0.50) least likely on metformin monotherapy.  Compared to metformin monotherapy, sulfonylureas had higher risk of MACE (aHR = 1.29, 95% CI: 1.17-1.42) and CHF (aHR = 1.59, 95% CI: 1.38-1.83).  Pioglitazone had higher risk of CHF (aHR = 1.27, 95% CI: 1.08-1.48).  Non-exenatide polytherapy had higher risk of MACE (aHR = 1.25, 95% CI 1. 11-1.41) and CHF (aHR = 1.41, 95% CI 1.19-1.69).

CONCLUSIONS: Antidiabetic agents were associated with reduced risks of CVD due to their function of improving glycemic control and other pleomorphic effects. No difference was found between exenatide and metformin on cardioprotective effects. This study provides information for clinical decision makers to establish long-term clinical impacts and improve diabetes treatment guidelines.