Effect of race on cardiometabolic responses to once-weekly exenatide: insights from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)

Abstract

Background To 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). Methods EXSCEL 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. Results Mean 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). Conclusions Short-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.

Antihypertensive Effect of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists

“…1.70 This meta-analysis showed that SGLT2 inhibitors provoked an average reduction of SBP/DBP 3.62/1.70 mmHg in the 24-hour ambulatory BP Teo et al [23] Meta-analysis − 104,304 − 3.5 − SGLT2 inhibitors and combined sodium-glucose cotransporter 1/2 inhibitors produced small reductions in BP in patients with DM Davis et al [24] Exenatide 2 14,752 6 months 1.8 0.2 There was no significant reduction in BP Grimm et al [25] Exenatide 2 1,379 24-30 weeks 2.8 0.8 Exenatide was associated with significant reductions in HbA1c levels, body weight, BP, and fasting lipid levels…”

“…[13][14][15][16] The effects of different SGLT2 inhibitors on BP are presented in Table 1. [11,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The effect of canagliflozin was investigated in 2 large trials-Canagliflozin Cardiovascular Assessment Study (CANVAS) and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE)-that included patients with type-2 DM and high cardiovascular risk [13] or chronic kidney disease with albuminuria. [14] Both trials used office BP, and reduction in systolic BP (SBP) after almost 4and 3-year follow-up was 3.9 and 3.3 mmHg, respectively.…”

“…After 6 months of therapy, the mean SBP reduced by 1.6 mmHg compared to the placebo, whereas DBP values were higher by 0.3 mmHg. [24] A post hoc analysis of 6 randomized trials of the Diabetes Therapy…”

“…After 6 months of therapy, the mean SBP reduced by 1.6 mmHg compared to the placebo, whereas DBP values were higher by 0.3 mmHg. [24] A post hoc analysis of 6 randomized trials of the Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program showed that treatment with exenatide once weekly for 24–30 weeks was associated with modest but significant SBP and DBP reductions (by 2.8 and 0.8 mmHg, respectively). [25] The effects on BP of exenatide were investigated in a pooled analysis of data from 4 trials involving 1,121 subjects that showed significant SBP reduction (−2.8 mmHg), but only minimal DBP reduction relative to baseline (difference of 0.5 mmHg).…”

Glucagon-like peptide-1 receptor agonists: new strategies and therapeutic targets to treat atherosclerotic cardiovascular disease

“…The EXSCEL study, a randomized, double-blind, placebo-controlled clinical trial ( Bethel et al, 2020 ), is the largest global clinical trial on GLP-1RAs. It was designed to evaluate the cardiovascular safety and efficacy of a weekly formulation of exenatide in patients with T2DM at all levels of CVD risk combined ( Davis et al, 2022 ). The study enrolled 14,752 T2DM patients with HbA 1C of 6.5%–10.0%, of whom 73.1% had a history of prior cardiovascular events, and 26.9% had no prior cardiovascular events.…”