Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME® trial

Eur Heart J. 2020 Jan 7;41(2):209-217. doi: 10.1093/eurheartj/ehz621.


Aims: Hypoglycaemia, in patients with Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular (CV) events. In EMPA-REG OUTCOME, the sodium-glucose co-transporter-2 inhibitor empagliflozin reduced the risk of CV death by 38% and heart failure hospitalization (HHF) by 35%, while decreasing glycated haemoglobin (HbA1c) without increasing hypoglycaemia. We investigated CV outcomes in patients with hypoglycaemia during the trial and the impact of hypoglycaemia on the treatment effect of empagliflozin.

Methods and results: About 7020 patients with T2D (HbA1c 7-10%) were treated with empagliflozin 10 or 25 mg, or placebo and followed for median 3.1 years. The relationship between on-trial hypoglycaemia and CV outcomes, and effects of empagliflozin on outcomes by incident hypoglycaemia [HYPO-broad: symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia, and HYPO-strict: hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia] was investigated using adjusted Cox regression models with time-varying covariates for hypoglycaemia and interaction with treatment. HYPO-broad occurred in 28% in each group and HYPO-strict in 19%. In the placebo group, hypoglycaemia was associated with an increased risk of HHF for both HYPO-broad [hazard ratio (HR, 95% confidence interval, CI) 1.91 (1.25-2.93)] and HYPO-strict [1.72 (1.06-2.78)]. HYPO-broad (but not HYPO-strict) was associated with an increased risk of myocardial infarction (MI) [HR 1.56 (1.06-2.29)]. Empagliflozin improved CV outcomes, regardless of occurrence of hypoglycaemia (P-for interactions >0.05).

Conclusion: In this post hoc exploratory analysis, hypoglycaemia was associated with an increased risk of HHF and MI. Hypoglycaemia risk was not increased with empagliflozin and incident hypoglycaemia did not attenuate its cardio-protective effects.

Keywords: Cardiovascular disease; Heart failure; Hospitalization; Hypoglycaemia; Mortality; Type 2 diabetes.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / therapeutic use*
  • Blood Glucose / metabolism
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / etiology*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Follow-Up Studies
  • Glucosides / therapeutic use*
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemia / blood
  • Hypoglycemia / complications*
  • Male
  • Middle Aged
  • Prognosis
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use
  • Time Factors


  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Glycated Hemoglobin A
  • Sodium-Glucose Transporter 2 Inhibitors
  • empagliflozin