Glycemic Control, Preexisting Cardiovascular Disease, and Risk of Major Cardiovascular Events in Patients with Type 2 Diabetes Mellitus: Systematic Review With Meta‐Analysis of Cardiovascular Outcome Trials and Intensive Glucose Control Trials

Background The value of glycemic control and preexisting cardiovascular disease in determining the risk of major cardiovascular events (MACE) in type 2 diabetes mellitus is uncertain. Intensive glucose control trials suggest that the 9% lower risk of MACE associated with intensive glycemic control, as compared with conventional glycemic control, is only driven by patients with type 2 diabetes mellitus without cardiovascular disease at baseline. Methods and Results We did a meta‐analysis of cardiovascular outcome trials dividing patients with or without preexisting cardiovascular disease; we found that the lower risk of MACE is confined to patients with cardiovascular disease at baseline. Compared with placebo, the use of both glucagon‐like peptide‐1 receptor agonists and sodium‐glucose cotransporter‐2 inhibitors was associated with a significant 14% lower MACE risk in patients with preexisting cardiovascular disease and with a nonsignificant 2% higher MACE risk in those without preexisting cardiovascular disease (P for interaction=0.021). The meta‐regression analysis of all 12 trials demonstrated a significant (P=0.002) association between reductions of glycated hemoglobin in glycated hemoglobin A1C. Accordingly, the reduction of MACE expected if all cardiovascular outcome trials had achieved a 0.9% glycated hemoglobin reduction would have been 33%. Routine clinical care data complement the results of cardiovascular outcome trials but with some differences: the lower risk of MACE with sodium‐glucose cotransporter‐2 inhibitor use is evident in patients with type 2 diabetes mellitus with or without preexisting cardiovascular disease. Conclusions Sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists should be included in the therapeutic plan of patients with type 2 diabetes mellitus and overt cardiovascular disease, with due attention paid to improvement of glycemic control, which may amplify their benefit on MACE.