Severe Hypoglycemia and Risk of Subsequent Cardiovascular Events: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Intensive glycemic control significantly increases the risk of hypoglycemia in patients with diabetes mellitus. Recent data have shown that hypoglycemia may also be a marker of cardiovascular disease in these patients. We performed a systemic review and a meta-analysis to evaluate the relationship between severe hypoglycemic events (SHEs) and the subsequent risk of mortality and major adverse cardiovascular events (MACE) in patients with diabetes mellitus. PubMed, Cochrane library, and Embase were searched for randomized controlled trials between January 2006 and December 17, 2018 that reported cardiovascular outcomes in diabetic patients with a history of SHEs. The primary outcomes of interest were all-cause mortality, cardiovascular mortality, and MACE. Other outcomes assessed included myocardial infarction and hospitalization for unstable angina or heart failure. Data from 9 RCTs and 3,462 randomized patients were available. Patients who suffered an SHE were found to have a significantly increased risk of subsequent all-cause mortality (hazard ratio [HR] 2.24; 95% confidence interval [CI] 1.70, 2.95; P-value <0.01), cardiovascular mortality (HR 2.32; 95% CI 1.67, 3.22; P-value <0.01), and MACE (HR 1.66; 95% CI 1.35, 2.06; P-value <0.01) compared to the patients without an SHE. The increased risks of subsequent stroke and arrhythmic death (P-value<0.05) were also found. There was no significant association between SHE and the risk of subsequent myocardial infarction or hospitalization for unstable angina or heart failure. In conclusion, the occurrence of an SHE in patients with diabetes mellitus was associated with a significantly increased risk for subsequent cardiovascular morbidity and mortality.