Severe hypoglycemia and the risk of cardiovascular disease and mortality in type 2 diabetes: A nationwide population-based cohort study

Background: We investigated the association regarding severe hypoglycemia episodes with cardiovascular disease risk and all-cause mortality in patients with type 2 diabetes. Methods: Baseline and follow-up data (n = 1,568,097) from patients with type 2 diabetes were retrieved from the National Health Insurance System database (covering the entire Korean population). Type 2 diabetes, severe hypoglycemia, and major comorbidities were identified using International Classification of Diseases 10 codes and medication information. Individuals who were classified as type 2 diabetes in the year of 2009 were screened, and we counted severe hypoglycemia episodes from 2007 to 2009. The primary outcome was newly developed myocardial infarction (MI), stroke, heart failure, or all-cause mortality. Participants were followed from the baseline index date to the date of death or until December 31, 2015. Results: In total, 19,660 (1.2%) patients developed at least one severe hypoglycemia event during the period from 2007 to 2009. Mean follow-up was 5.7 years. After adjustment for confounding factors, the hazard ratio (HR) of MI significantly and sequentially increased: 0 vs. 1 episode, HR 1.56, 95% CI 1.46-1.64; 0 vs. 2 episodes, HR 1.86, 95% CI 1.61-2.15; 0 vs. 3 or more episodes, HR 1.86, 95% CI 1.48-2.35, P for trend < 0.001. Similar findings were noted regarding the relationship of severe hypoglycemia episodes with stroke, heart failure, and all-cause mortality. Risks for all outcomes were highest within 1 year from the index date and showed decreasing trends with follow-up. Sensitivity analyses of the data from the subgroup population and 797,544 subjects who received a national health examination did not change the significance of the main findings. Conclusion: Among adult Korean patients with type 2 diabetes, a severe hypoglycemia episode is associated with increased risk for cardiovascular outcomes and all-cause mortality. Significant results from dose-response, temporal, and sensitivity analyses may suggest the possibility of direct causality between severe hypoglycemia and cardiovascular outcomes and mortality.