Physicians' Academy for Cardiovascular Education

Severe hypoglycemia associated with increased risk of CV events and mortality

Hypoglycemia, Cardiovascular Outcomes, and Death: The LEADER Experience

Literature - Zinman B, Marso SP, Christiansen E, et al. - Diabetes Care 2018; published online ahead of print

Introduction and Methods

There is an association between hypoglycemia and an increased risk of CV events and mortality, although the evidence for a causal effect is limited [1-3]. In this post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial [4], the associations between hypoglycemia and CV outcomes and mortality were investigated in patients with type 2 diabetes (T2DM).

In the double-blind, randomized, placebo-controlled LEADER trial, the glucagon-like peptide 1 analog liraglutide significantly reduced CV events and mortality compared with placebo, in T2DM patients at high CV risk, who additionally received standard care, and were followed for 3.5-5 years.

The primary end point in LEADER was the time to first occurrence of a major adverse CV event (MACE), including CV death, non-fatal myocardial infarction, or non-fatal stroke. Hypoglycemia was a secondary self-reported safety endpoint, and severe hypoglycemia was defined according to the American Diabetes Association criteria [5].

Main results


In the LEADER trial, patients with severe hypoglycemia episodes had a higher risk of MACE, CV death, non-CV death, and all-cause death compared with patients without severe hypoglycemia, particularly in the first 7 days after the hypoglycemic episode. These associations were independent of treatment group.


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