Effect of Once-Weekly Exenatide on Clinical Outcomes According to Baseline Risk in Patients With Type 2 Diabetes Mellitus: Insights From the EXSCEL Trial

J Am Heart Assoc. 2018 Oct 2;7(19):e009304. doi: 10.1161/JAHA.118.009304.


Background In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once-weekly resulted in a nonsignificant reduction in major adverse cardiovascular events ( MACEs ) and a nominal 14% reduction in all-cause mortality in 14 752 patients with type 2 diabetes mellitus (T2 DM ) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all-cause mortality using step-wise selection of baseline characteristics. A risk score was calculated for each patient, and a time-to-event model for each end point was developed including the risk score, treatment assignment, and risk-treatment interaction. Interaction P values evaluating for a differential treatment effect by baseline risk were reported. Over a median follow-up of 3.2 years (interquartile range, 2.2, 4.4), 1091 (7.4%) patients died and 1744 (11.8%) experienced a MACE . Independent predictors of MACEs and all-cause mortality included age, sex, comorbidities (eg, previous cardiovascular event), body mass index, blood pressure, hemoglobin A1c, and estimated glomerular filtration rate. The all-cause mortality and MACE risk models had modest discrimination with optimism-corrected c-indices of 0.73 and 0.71, respectively. No interaction was observed between treatment effect and risk profile for either end point (both interactions, P>0.1). Conclusions Baseline characteristics (eg, age, previous cardiovascular events) and routine laboratory values (eg, hemoglobin A1c, estimated glomerular filtration rate) provided modest prognostic value for mortality and MACEs in a broad population of patients with type 2 diabetes mellitus. Exenatide's effects on mortality and MACEs were consistent across the spectrum of baseline risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01144338.

Trial registration: ClinicalTrials.gov NCT01144338.

Keywords: glucagon‐like peptide‐1 receptor agonis; major adverse cardiac event; mortality; type 2 diabetes mellitus.

Publication types

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

MeSH terms

  • Aged
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control*
  • Cause of Death / trends
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Exenatide / administration & dosage*
  • Female
  • Follow-Up Studies
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Incidence
  • Male
  • Middle Aged
  • Retrospective Studies
  • Risk Assessment / methods*
  • Risk Factors
  • Survival Rate / trends
  • Time Factors
  • Treatment Outcome
  • United States / epidemiology


  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • hemoglobin A1c protein, human
  • Exenatide

Associated data

  • ClinicalTrials.gov/NCT01144338