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

Abstract

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.

Figure 1

Summary of predictive models for (A) all‐cause mortality (ACM) and (B) major adverse cardiovascular events (MACE). BMI indicates body mass index; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; hx, history; MI, myocardial infarction; Revasc, revascularization.

Figure 2

Calibration plots for predictive models for (A) ACM and (B) MACE. ACM indicates all‐cause mortality; MACE, major adverse cardiovascular events.

Figure 3

Treatment effect by risk score quintile for (A) ACM and (B) MACE. ACM indicates all‐cause mortality; CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular events.