All-cause mortality and cardiovascular safety of basal insulin treatment in patients with type 2 diabetes mellitus: A systematic review with meta-analysis and trial sequential analysis.

ABSTRACT

AIM: To evaluate the risk of all-cause and cardiovascular mortality, acute myocardial infarction, and stroke associated with insulin treatment in patients with type 2 diabetes. METHODS: A systematic review with meta-analysis of randomized clinical trials (RCTs) was performed. EMBASE, Cochrane, and PubMed databases were searched for RCTs reporting mortality or cardiovascular events and comparing basal insulin to any treatment in patients with type 2 diabetes. Data were summarized with Mantel-Haenzel relative risk (RR). Trial sequential analysis (TSA) was used to evaluate the reliability of the results considering a 20% relative risk difference between treatments. PROSPERO Registry CRD42018087336. RESULTS: In total, 2351 references were identified, and 26 studies (24348 patients) were included. Most studies evaluated glargine insulin (69%), compared insulin to GLP-1 analogs (57%), and evaluated add-on therapy with metformin (77%). Insulin was not associated with increased all-cause mortality (RR 0.99; 95% confidence interval (CI) 0.92-1.06), cardiovascular mortality (RR 1.01; 95% CI 0.91-1.13), myocardial infarction (RR 1.02; 95% CI 0.92-1.15), or stroke (RR 0.87; 95% CI 0.68-1.12). Insulin treatment increased severe hypoglycemia risk (RR 2.98; 95% CI 2.47-3.61). All analyses had low statistical heterogeneity. TSA confirmed these findings: optimal sample size (myocardial infarction), futility boundary (all-cause mortality, cardiovascular mortality, and stroke) and harm boundary (hypoglycemia) were reached. CONCLUSION: Treatment with basal insulin of patients with type 2 diabetes does not increase the risk of cardiovascular events or death. Despite the increased risk of hypoglycemia, these findings reinforce that insulin is a safe option in the treatment of type 2 diabetes.