Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes: A nationwide population-based study

OBJECTIVE

Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes 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. 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.Hypoglycemia is a major side effect of glucose-lowering therapy in patients with type 1 or type 2 diabetes. Patients with type 2 diabetes are usually believed to have less frequent hypoglycemia episodes than type 1 diabetic patients (1). Prodromal symptoms of hypoglycemia, including tremor, diaphoresis, tachycardia, and anxiety, are sometimes noticed by the patient; consequently, severe complications can be avoided. If left untreated, however, neuroglycopenia may develop, resulting in neurologic damage (2,3).Hypoglycemia has also been associated with adverse cardiovascular events in type 2 diabetic patients beyond hypoglycemic episodes themselves (4). The surge of sympathetic activity during hypoglycemic episodes has been suggested to be the underlying mechanism leading to destabilization of atherosclerotic plaques (5), increased arrhythmia attributable to increased corrected QT interval (6), and induction of cardiac and cerebral ischemia. Studies including epidemiological cohort studies and clinical trials (7–10) have already suggested that hypoglycemia also is a risk factor for cardiovascular outcomes. However, some patients in these studies had comorbidities on admission, such as unstable angina and acute myocardial infarction (11–14). Recently, the ADVANCE study suggested that hypoglycemia is associated with increased risks of a range of adverse clinical outcomes, and it is considered to be a marker for vulnerability to such events for type 2 diabetic patients (15).Whether hypoglycemia is a risk factor or a marker, it is important to evaluate the possible correlates to both hypoglycemia and serious health conditions, including hepatic disease, malignancy, renal disease, and use of various medications. Furthermore, in real-world clinical practice, it is intriguing to identify hypoglycemic events based solely on symptoms or a physician’s diagnosis rather than on glucose levels, as most previous studies have. Moreover, patient selection bias, especially the Berkson bias, in hospital-based observational or case-control studies probably confounds and casts doubt on the associations between hypoglycemia and clinical outcomes. Finally, the clinical impact of mild self-reported hypoglycemic episodes is largely unknown. We therefore conducted this nationwide random-sampling cohort study of type 2 diabetic patients to characterize their comorbidities and evaluate the influences of mild and severe hypoglycemia and their outcomes.