Association Between Severe Hypoglycemia and Cardiovascular Disease Risk in Japanese Patients With Type 2 Diabetes

Background It remains unclear whether severe hypoglycemia is associated with cardiovascular disease (CVD) in Asian populations with type 2 diabetes (T2D). Furthermore, no study in Japan, where the prescription patterns differ from those in other countries, has examined this association. Methods and Results We retrospectively included 58 223 patients (18–74 years old) with T2D. First, we examined the potential predictors of severe hypoglycemia. Then, we investigated the association between severe hypoglycemia and CVD risk. Finally, we performed an updated systematic review and meta‐analysis to incorporate our findings and recently published studies into the previous systematic review and meta‐analysis. During 134 597 person‐years from cumulative observation periods, 128 persons experienced severe hypoglycemia and 550 developed CVD events. In a multivariate Cox proportional hazard model, severe hypoglycemia was strongly and positively associated with the risk of CVD (multivariate‐adjusted adjusted hazard ratio, 3.39; 95% CI, 1.25–9.18). In a propensity score–matched cohort that had similar baseline characteristics for patients with severe hypoglycemia and those without, severe hypoglycemia was more strongly associated with the risk of CVD. An updated systematic review and meta‐analysis that included 10 studies found that severe hypoglycemia was associated with an ≈2‐fold increased risk of CVD (pooled relative risk, 1.91; 95% CI, 1.69–2.15). Conclusions Our results suggest that severe hypoglycemia is strongly associated with an increased risk of CVD in Japanese patients with T2D, further supporting the notion that avoiding severe hypoglycemia may be important in preventing CVD in this patient population.