Dataset Information

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.

SUBMITTER: Mentz RJ

PROVIDER: S-EPMC6404902 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Mentz Robert J RJ Bethel M Angelyn MA Merrill Peter P Lokhnygina Yuliya Y Buse John B JB Chan Juliana C JC Felício João S JS Goodman Shaun G SG Choi Jasmine J Gustavson Stephanie M SM Iqbal Nayyar N Lopes Renato D RD Maggioni Aldo P AP Öhman Peter P Pagidipati Neha J NJ Poulter Neil R NR Ramachandran Ambady A Reicher Barry B Holman Rury R RR Hernandez Adrian F AF

Journal of the American Heart Association 20181001 19

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 po ...[more]

PMID: 30371301

Similar Datasets

Project description:BACKGROUND:Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW's effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. METHODS:The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. RESULTS:Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77-0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80-0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85-1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68-0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71-0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89-1.29]; interaction P=0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68-0.99]; P=0.038). CONCLUSIONS:In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. CLINICAL TRIAL REGISTRATION:https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Project description:BackgroundTo determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).MethodsEXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A1c (HbA1c) 6.5-10.0% [48-86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models.ResultsMean 6-month placebo-adjusted HbA1c reductions were similar in the four groups (range 0.54-0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (-1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (- 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (-0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races).ConclusionsShort-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians.Trial registration https://clinicaltrials.gov NCT01144338.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disease with substantial morbidity, mortality, and economic impacts. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as once-daily (QD) liraglutide and once-weekly (QW) exenatide, are FDA-approved treatment for T2DM. Head-to-head trials and meta-analyses comparing these agents have reported clinically meaningful improvements but small differences in glycemic control between both agents. In this study, we calculate and compare the cost-effectiveness implications of these alternative effectiveness outcomes.MethodsWe developed a decision model to evaluate the short-term cost-effectiveness of exenatide QW 2 mg versus liraglutide QD 1.8 mg in T2DM patients, with effectiveness measured as reduction in glycated hemoglobin (HbA1c). In the base case, the model tracks change in HbA1c and direct medical expenditure over a 6-month time horizon. We calculated and compared the cost per 1% reduction in HbA1c of models populated with clinical data from a head-to-head randomized, controlled trial (DURATION-6) and a network meta-analysis. Expenditure inputs were derived from wholesale acquisition costs and published sources.ResultsIn the base case, 6-month expenditure for the liraglutide and exenatide strategies were $3,509 and $2,618, respectively. Using clinical data from DURATION-6 and the network meta-analysis, the liraglutide strategy had an incremental cost per 1% reduction in HbA1c of $4,773 and $27,179, respectively. The most influential model parameters were drug costs, magnitude of HbA1c reduction in patients on treatment for >1 month, and liraglutide gastrointestinal adverse event rate. In probabilistic sensitivity analyses (PSA) using DURATION-6 data, the exenatide strategy was optimal at willingness-to-pay levels below $4,800 per 1% reduction in HbA1c. In a PSA using meta-analysis data, the exenatide strategy was dominant.ConclusionsOur modeled results demonstrate that the effectiveness and cost-effectiveness of liraglutide QD 1.8 mg relative to exenatide QW 2 mg depend largely on the chosen source of the clinical data.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets