P6268Cardiovascular outcomes of new anti-diabetic agents - A meta-analysis of randomized controlled trials

Abstract

Abstract Background and purpose The risk of major cardiovascular events (MACE) is increased in patients with diabetes mellitus. Recently published clinical trials of three different pharmacological classes (DPP4 inhibitors (DPP4i), SGLT2-inhibitors (SGLT2i), GLP-1-receptor-antagonists (GLP1RA)) of new anti-diabetic agents (ADA) showed potential benefits for cardiovascular (CV) outcomes. We thus aimed to perform a meta-analysis of randomized controlled trials (RCTs) of these ADA to elucidate benefits on CV outcomes in diabetic patients. Methods Following a systematic online database search, all RCTs reporting CV outcomes of DPP4i, SGLT2i or GLP1RA vs. Placebo in diabetic patients up until December 2018 were eligible for inclusion in the meta-analysis. Studies including patients with acute coronary syndrome (ACS) were excluded. Data were abstracted and analyzed with the inverse-variance method and a random-effects model, hazard ratios (HR) with 95% confidence intervals (CI) were used as summary statistics. CV outcomes of MACE, myocardial infarction (MI), stroke, heart failure (HF), CV death and all-cause mortality were analyzed. Results Eleven RCTs (DPP4i: SAVOR, TECOS, CARMELINA; GLP1RA: LEADER, SUSTAIN-6, EXSCEL, Harmony; SGLT2i: EMPA-REG OUTCOME, CANVAS Program, DECLARE) with 109,316 patients were selected for inclusion. ELIXA and EXAMINE were excluded due to their inclusion of patients with ACS, CAROLINA was excluded for lack of placebo-control. In the pooled meta-analysis of all trials, ADA significantly reduced the risk for MACE (Hazard ratio (HR) 0.91, CI 0.86–0.96, p=0.0004), MI (HR 0.91, CI 0.85–0.96, p=0.02), CV death (HR 0.9, CI 0.82–0.99, P=0.02) and all-cause mortality (HR 0.92, CI 0.85–0.99, p=0.03). There was no difference in the risk for stroke (HR 0.94, CI 0.87–1.02, p=0.16) and HF (HR 0.88, CI 0.76–1.02, p=0.08). In agent-specific subgroup analyses, GLP1RA and SGLT2i showed significant reductions in MACE (GLP1RA: HR 0.85, CI 0.78–0.92, p<0.0001; SGLT2i: HR 0.89, CI 0.83–0.96, p=0.001), MI (GLP1RA: HR 0.86, CI 0.76–0.98, p=0.02; SGLT2i: HR 0.88, CI 0.79–0.97, p=0.01) and all-cause mortality (GLP1RA: HR 0.88, CI 0.81–0.95; p=0.001; SGLT2i: HR 0.83, CI 0.70–0.99; p=0.03). GLP1RA significantly reduced risk for stroke (HR 0.85, CI 0.75–0.96, p=0.008) and CV death (HR 0.86, CI 0.78–0.95, p=0.002). SGLT2I were especially effective in the reduction of risk for HF (HR 0.69, CI 0.61–0.79; p<0.0001). DPP4i inhibitors however failed to show superiority in all analyzed outcomes. Conclusions This meta-analysis lends evidence to GLP1RA and SGLT2i benefits for MACE, MI and all-cause mortality, while DPP4i failed to show superiority in cardiovascular outcomes. Individualized medication for diabetic patients depending on CV disease status should be considered.