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Hypoglycemia and Mortality: A Post Hoc Look at LEADER


Severe hypoglycemia was associated with death within ~1 week among patients with T2DM, according to a subanalysis of the LEADER trial.


In this era of focus on tight diabetes control, an important cardiovascular threat may go unnoticed. Achieving A1C values < 7% may be accompanied by recurrent, at times severe, hypoglycemia. Other than the obvious, acute impact of low blood sugar, are there potential future ill effects of hypoglycemia?

The recent follow-up analysis by Zinman and colleatues of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial provided an answer to this critical question.1 The original LEADER trial demonstrated that liraglutide (vs placebo) reduced the risk of cardiovascular events by 13%.2

In the LEADER trial, patients with type 2 diabetes mellitus (T2DM) and a high risk for cardiovascular disease (CVD [n=9,340]) were randomized 1:1 to either liraglutide or placebo in addition to their standard diabetes management.2 Follow-up was 3.5 to 5 years. The primary outcome measure was the time to a first, major adverse cardiovascular event (MACE). The secondary end point in LEADER was the incidence of hypoglycemia.2

A total of 267/9,340 patients experienced severe hypoglycemia, ie, hypoglycemia requiring the assistance of another person to administer resuscitative materials (eg, glucagon, carbohydrate).2 The post hoc analysis of those with severe hypoglycemia vs those without1 found that they experienced more MACE, cardiovascular deaths, and all-cause deaths, shortly after the episode of severe hypoglycemia. The definition for “shortly after” was within a week.1 Patients who experienced severe hypoglycemia had a longer duration of diabetes, increased incidence of heart failure and kidney disease, and, as expected, used insulin more frequently prior to randomization.

The whys and wherefores for cause and effect between severe hypoglycemia and cardiovascular/all cause mortality remain unknown. The catecholamine storm accompanying hypoglycemic reactions may be the culprit, especially short-term.

How do you help protect your T2DM patients from severe hypoglycemia? Let us know with a note to the editor@patientcareonline.com and we’ll post the suggestions.


1. Zinman B, Marso SP, Christiansen E, et al. Hypoglycemia, cardiovascular outcomes, and death: The LEADER experience. Diabetes Care. 2018; 41:1783-1791.

2. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375:311-322.

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