Severe Hypoglycemia and Risk of Vascular Events

Excess mortality seen with intensive glucose control in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial has caused much speculation about the adverse effects of intensive glucose-lowering interventions in patients with type 2 diabetes. Post hoc analyses of data from the ACCORD trial indicate that the excess mortality in the group with intensive control was not directly explained by the high rate of hypoglycemia that is common in diabetes patients when glucose control is intensified. Researchers recently conducted an analysis to examine the associations between severe hypoglycemia and the subsequent risks of vascular complications and death. Data on 11,140 patients with type 2 diabetes who took part in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study were analyzed. Results of the analysis were reported in the New England Journal of Medicine [2010;363(15): 1410-1418]. Of the 11,140 study patients, 2.1% (n=231) reported 299 severe hypoglycemic events during a median follow-up period of 5 years. Of those, 150 patients in the intensive intervention group (2.7% of the 5571 patients in that group) reported 195 events, and 81 patients in the standard intervention group (1.5% of the 5569 patients in that group) reported 104 events. The rate of severe hypoglycemia increased over time in the intensive intervention group (P<.001), but remained relatively stable for the standard treatment group. Minor hypoglycemia was reported by 4975 patients during follow-up: 2898 in the intensive control group and 2077 in the standard control group. Risk factors for severe hypoglycemia were older age, longer duration of diabetes, higher levels of creatinine, lower body mass index, lower cognitive functioning, use of ≥2 oral glucose-lowering medications, a history of smoking or microvascular disease, and assignment to the intensive glucose control group (P<.05 for all comparisons). During follow-up, 2125 patients had a major macrovascular or microvascular event. Of those, 40 reported severe hypoglycemia before the event and 47 reported severe hypoglycemia after the event. Of the 1031 patients who died, 45 had reported severe hypoglycemia. Median time from the episode of hypoglycemia to the first major macrovascular event was 1.56 years; time to the first major microvascular event was 0.99 years. Median time from the severe hypoglycemic event to death was 1.05 years (1.31 years for death from a cardiovascular event and 0.74 years for death from a noncardiovascular cause). Of the patients who reported severe hypoglycemia, 16.8% had a subsequent major macrovascular event, 11.5% had a subsequent major microvascular event, and 19.5% died. The rates for those who did not report severe hypoglycemia were 10.2% who had a major macrovascular event, 10.1% who had a major microvascular event, and 9.0% who died. Severe hypoglycemia was associated with an increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01-4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19-2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72-4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97-3.67) (P<.001 for all comparisons). For noncardiovascular outcomes such as respiratory, digestive, and skin conditions, the analysis found similar associations (P<.01 for all comparisons). There was no relationship between repeated episodes of severe hypoglycemia and vascular outcomes or death. In conclusion, the researchers said that “severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events.”