Abstract
BACKGROUND: Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D. METHODS: Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo. RESULTS: Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was - 2.6 mmHg (95% CI - 3.8, - 1.5; p < 0.001) and was attributed to both a weight-dependent effect (- 0.9 mmHg; 95% CI: - 1.4, - 0.5; p < 0.001) and a weight-independent effect (- 1.5 mmHg; 95% CI: - 2.6, - 0.3; p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (- 2.5 mmHg; 95% CI: - 3.5, - 1.5; p < 0.001) was 14% weight-dependent and 86% weight-independent. For DBP there was limited impact of dulaglutide treatment, with only a small weight-mediated effect. Dulaglutide 4.5 mg demonstrated an effect on reduction in SBP and pulse pressure beyond that of dulaglutide 1.5 mg which was primarily weight mediated. CONCLUSIONS: Dulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension. Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102.