Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes Mellitus

A nationwide population-based study

Published online before print December 5, 2012, doi:10.2337/dc12-0916

OBJECTIVE Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes mellitus who have experienced hypoglycemia episodes is largely unknown.

RESEARCH DESIGN AND METHODS The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998–2009, comprised 77,611 patients with newly diagnosed type 2 diabetes mellitus. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.

RESULTS There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR, 2.09; 95% CI, 1.63–2.67), all-cause hospitalization (2.51 [2.00–3.16]), and total mortality (2.48 [1.41–4.38]).

CONCLUSIONS Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.

 COMMENT: The association of hypoglycemia and cardiovascular deaths was seen in the VA diabetes study.  Additionally the intensive insulin treatment arm of the ACCORD was stopped because of increased mortality.  This timely survey from Taiwan suggests that in the general population with diabetes, symptomatic hypoglycemia is associated with subsequent adverse outcomes.  More disconcerting is the observation that the severity of the symptoms was not predictive.  That is, even clinically mild hypoglycemia was associated with adverse outcomes.