Does Hypoglycaemia Increase the Risk of Cardiovascular Events? A Report From the ORIGIN Trial

Study Questions:

Does hypoglycemia increase the risk of cardiovascular (CV) events?


This study used the results of the ORIGIN trial, which was designed to assess the relative benefit of glargine insulin-mediated normoglycemia versus standard care with oral glucose-lowering agents in early type 2 diabetes or dysglycemia at high risk for CV outcomes. They prospectively measured both nonsevere (glucose <55 mg/dl) and severe episodes of hypoglycemia <37 mg/dl) in 12,537 people ages >49 years with impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes. Participants were randomly allocated to either the addition of basal insulin glargine titrated to a fasting plasma glucose 95 mg/dl or to standard glycemic treatment according to local guidelines. During a median follow-up period of 6.2 years, there was a neutral effect on the primary and secondary clinical CV outcomes (the composite of CV death, nonfatal myocardial infarction, or stroke; mortality; CV mortality; and arrhythmic death) and microvascular outcomes.


Mean age was approximately 64 years, 34% were women; nearly 60% had coronary disease or stroke; approximately 90% had diabetes, and mean baseline glycated hemoglobin (HgA1c) was approximately 6.5%. During follow-up, approximately 25% of participants had at least one episode of hypoglycemia. Of these, 74.3% occurred in the glargine group and 25.7% in the standard group. Of the 472 participants with at least one episode of severe hypoglycemia, 76.1% occurred in the glargine group and 23.9% in the standard group with an estimated annual incidence of 0.9% and 0.3%, respectively. Nonsevere hypoglycemia was not associated with any outcome following adjustment. Conversely, severe hypoglycemia was associated with a significantly greater risk for the primary outcome (hazard ratio [HR], 1.58), mortality (HR, 1.74), CV death (HR, 1.71), and arrhythmic death (HR, 1.77). Similar findings were noted for severe nocturnal hypoglycemia for the primary outcome and mortality. The severe hypoglycemia hazard for all four outcomes was higher with standard care than with insulin glargine. For both types of episodes, affected participants were more likely to be men than women, had a higher baseline fasting plasma glucose and HbA1c, and were more often treated with a sulfonylurea.


Severe hypoglycemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycemia. Although allocation to insulin glargine versus standard care was associated with an increased risk of severe and nonsevere hypoglycemia, the relative risk of CV outcomes with hypoglycemia was lower with insulin glargine-based glucose-lowering therapy than with the standard glycemic control.


The very important findings are not intuitive, and enforce the messages from other trials. Intense glycemic control (with or without insulin as the primary agent) is not beneficial, and increases CV events. And severe hypoglycemia occurring on oral agents increases the risk of mortality greater than in those on insulin.

Keywords: Hemoglobin A, Risk, Myocardial Infarction, Stroke, Insulin, Follow-Up Studies, Health Resources, Coronary Disease, Hypoglycemia, Sulfonylurea Compounds, Glucose Intolerance, Cardiology, Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus

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