20. Major Cardiovascular Outcomes in the EXAMINE Trial According to ACE Inhibitor Use (12-OR)

Activation of the sympathetic nervous system through substance P via DPP-4 inhibition (DPP-4i) in the presence of higher dose ACE inhibition (ACEi) has led to hypothetical concerns of the cardiovascular (CV) safety of these 2 classes of drugs used together. We evaluated adjudicated CV events in EXAMINE, a trial of patients with type 2 diabetes (T2DM) and recent acute coronary syndrome (ACS) according to ACEi use. Patients were randomly assigned to receive alogliptin or placebo added to existing anti-hyperglycemic and CV therapies. Risks of CV death, nonfatal MI and stroke (MACE), and CV death or hospitalized HF (HHF) were analyzed using a Cox proportional hazards model in patients by baseline ACEi use. EXAMINE random ized 5380 patients, 3323 (62%) of whom were using an ACE inhibitor (1681 on alogliptin; 1642 on placebo). Composite rates of MACE were similar for alogliptin vs. placebo with ACEi [11.4% vs. 11.8%, HR = 0.97, 95% CI, 0.79-1.19, p = 0.76] and without ACEi use at baseline [11.2% vs. 11.9%, HR = 0.94, 95% CI, 0.73-1.21, p = 0.62]. The composite of CV death or HHF in patients on ACEi at baseline occurred in 6.8% of patients on alogliptin vs. 7.2% on placebo [HR = 0.93, 95% CI, 0.72-1.2, p = 0.57]. Alogliptin showed no effect on HHF alone in ACEi treated patients, 3.3% vs. 3.1%, (HR = 1.07, 95% CI, 0.73-1.56, p = 0.75) for alogliptin vs. placebo, respectively. Additionally, there was no impact of higher vs. lower doses of ACEi on CV event rates. There were also no differences for these endpoints in patients without ACEi use at baseline. Analyses according to pre-randomization history of HF and ACEi use at baseline showed MACE occurring in 13.9% and 16.5% of patients on alogliptin vs. placebo, respectively [HR = 0.87, 95% CI, 0.63-1.19, p = 0.38] and CV death or HHF in 12.0% and 13.2% of patients on alogliptin vs. placebo, respectively [HR = 1.02, 95% CI, 0.72-1.44, p = 0.92]. In conclusion, CV outcomes were not different for alogliptin compared with placebo in high CV risk patients with T2DM treated with ACE inhibitors in the EXAMINE Trial.