Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis

Aims: Hypoglycemia has been associated with adverse outcomes in patients with diabetes and critical illness. However, such associations in these populations have not been systematically examined. Methods: We conducted a systematic review and meta-analysis of longitudinal follow-up cohort studies to investigate the associations between hypoglycemia and various adverse outcomes. Results: After removing duplicates and critically appraising all screened citations, a total of 19 eligible studies were included. As demonstrated by random-effects meta-analysis, hypoglycemia was strongly associated with a higher risk of adverse events (HR 1.90, 95 % CI 1.63–2.20; P < 0.001). Comparable risk ratios were shown in prespecified stratified analyses investigating above association for different study endpoints, in patients with or without critical illness, in patients with and without diabetes (from 1.47 to 3.31; p for interaction or heterogeneity >0.1). Additionally, a dose-dependent relationship between the severity of hypoglycemia and adverse vascular events and mortality (HR for mild hypoglycemia: 1.68, 95 % CI 1.25–2.26; P < 0.001 and HR for severe hypoglycemia: 2.33, 95 % CI 2.07–2.61; P < 0.001; p for trend 0.02) was observed. Suggested by a bias analysis, the above observations were unlikely to have resulted from unmeasured confounding parameters. Conclusions: This is the first study demonstrating that hypoglycemia was associated with comparable risk ratios in different study populations and various study endpoints, and a trend of a dose-dependent relationship between hypoglycemia severity and adverse events. The findings of this systematic review support the speculation that hypoglycemia is a risk factor for adverse vascular events and mortality.