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Changes in Heart Rate Associated with Exenatide Once Weekly: Pooled Analysis of Clinical Data in Patients with Type 2 Diabetes.

ABSTRACT: INTRODUCTION:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemia in patients with type 2 diabetes, but heart rate increases have been observed. METHODS:A pooled post hoc analysis of 11 randomized clinical trials (N = 4595) of 10-30 weeks' duration from the exenatide once-weekly (QW) development program evaluated heart rate with exenatide QW (intervention group) and exenatide twice daily (BID), liraglutide, and non-GLP-1RAs (insulin, metformin, pioglitazone, and sitagliptin) (comparison groups). The time course and size of heart rate changes from baseline and the relationship of heart rate change with baseline heart rate were studied. A multivariate analysis (9 studies; N = 3903) examined associations between patient characteristics or treatments and heart rate increases. RESULTS:Mean baseline heart rate ± standard deviation was 75.0 ± 8.5 beats per minute (bpm) with exenatide QW (n = 2096), 75.8 ± 8.7 bpm with exenatide BID (n = 606), 75.2 ± 8.9 bpm with liraglutide (n = 450), and 74.5 ± 8.6 bpm with non-GLP-1RAs (n = 1443). Least-squares mean ± standard error changes from baseline to final heart rate were + 2.7 ± 0.2, + 1.0 ± 0.3, and + 3.0 ± 0.4 bpm with exenatide QW, exenatide BID, and liraglutide, respectively, and - 0.8 ± 0.2 bpm with non-GLP-1RAs. The size and direction of heart rate changes in individual patients varied within each treatment group at all time points. At posttreatment follow-up, heart rate reverted to the baseline level after GLP-1RA discontinuation. Heart rate changes correlated negatively with baseline heart rate for all therapies (r = - 0.3 to - 0.4). Baseline heart rate was the strongest predictor of increased heart rate. CONCLUSIONS:Small increases in heart rate were associated with exenatide QW, exenatide BID, and liraglutide treatments but reverted to baseline after discontinuation. Increases were more likely in patients with a low baseline heart rate. The clinical relevance of these heart rate increases is unknown but will be clarified by several ongoing and recently completed cardiovascular outcome studies.

SUBMITTER: Marso SP

PROVIDER: S-EPMC6104267 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Project description:Overweight or obesity contributes to the development of type 2 diabetes mellitus (T2DM) and increases cardiovascular risk. Exenatide, a glucagon-like peptide-1 receptor agonist, significantly reduces glycated hemoglobin (A1C) and body weight and improves cardiovascular risk markers in patients with T2DM. As weight loss alone has been shown to reduce A1C and cardiovascular risk markers, this analysis explored whether weight loss contributed importantly to clinical responses to exenatide once weekly.A pooled analysis from eight studies of exenatide once weekly was conducted. Patients were distributed into quartiles from greatest weight loss (Quartile 1) to least loss or gain (Quartile 4). Parameters evaluated for each quartile included A1C, fasting plasma glucose (FPG), blood pressure (BP), heart rate, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).The median changes from baseline in body weight in Quartiles 1-4 were -6.0, -3.0, -1.0, and +1.0 kg, respectively. All quartiles had reductions in A1C (median changes -1.6, -1.4, -1.1, and -1.2%, respectively) and FPG (-41, -40, -31, and -25 mg/dL, respectively), with the greatest decreases in Quartiles 1 and 2. Most cardiovascular risk markers (except diastolic BP) and liver enzymes improved in Quartiles 1 through 3 and were relatively unchanged in Quartile 4. Higher rates of gastrointestinal adverse events and hypoglycemia were observed in Quartile 1 compared with Quartiles 2 through 4.Exenatide once weekly improved glycemic parameters independent of weight change, although the magnitude of improvement increased with increasing weight loss. The greatest trend of improvement in glycemic parameters, cardiovascular risk factors including systolic BP, LDL-C, total cholesterol, and triglycerides, and in liver enzymes, was seen in the patient quartiles with the greatest reductions in body weight.

Project description:This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n?=?231), exenatide once weekly alone (n?=?230), or dapagliflozin alone (n?=?233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28?weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1?mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55?kg for body weight. Potential treatment-by-subgroup interactions (P?<?.10) were found for HbA1c change by age (P?= .016) and eGFR (P?= .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ?65?years (n?=?74 vs n?=?499 for patients aged <65?years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ?90 vs ?60 to <90?mL/min/1.73?m2 (least-squares mean reductions of -23.6 vs -19.0?mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0?mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9?mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P?= .099), with greater weight loss for women vs men across all treatments (range?-2.56 to -3.98?kg vs -0.56 to -2.99?kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

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.

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Changes in Heart Rate Associated with Exenatide Once Weekly: Pooled Analysis of Clinical Data in Patients with Type 2 Diabetes.

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