Tulane University School of Medicine, New Orleans, LA, USA.
Eli Lilly and Company, Indianapolis, IN, USA.
Cardiovasc Diabetol. 2023 Mar 9;22(1):49. doi: 10.1186/s12933-023-01775-x.
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.
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.
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.
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.
接受胰高血糖素样肽-1 受体激动剂（GLP-1RA）治疗的 2 型糖尿病（T2D）患者可能会减轻体重和血压。本研究的主要目的是确定在 T2D 患者中，使用利拉鲁肽 1.5mg 治疗 6 个月时，体重依赖性和非体重依赖性作用。
对五项利拉鲁肽 1.5mg 的随机、安慰剂对照试验进行中介分析，以估计利拉鲁肽与安慰剂相比，在收缩压（SBP）、舒张压（DBP）和脉压的基线变化方面的体重依赖性（即通过体重介导）和非体重依赖性作用。采用随机效应荟萃分析合并这些结果。为了研究利拉鲁肽 4.5mg 与安慰剂之间的剂量反应，首先在 AWARD-11 中进行利拉鲁肽 4.5mg 与 1.5mg 的中介分析，以估计利拉鲁肽 4.5mg 与 1.5mg 相比的体重依赖性和非体重依赖性作用，然后与利拉鲁肽 1.5mg 与安慰剂相比的中介结果进行间接比较。
试验的基线特征基本相似。在安慰剂对照试验的中介荟萃分析中，利拉鲁肽 1.5mg 治疗后经安慰剂校正的 SBP 总治疗效果为-2.6mmHg（95%CI：-3.8，-1.5；p<0.001），归因于体重依赖性效应（-0.9mmHg；95%CI：-1.4，-0.5；p<0.001）和非体重依赖性效应（-1.5mmHg；95%CI：-2.6，-0.3；p=0.01），分别占总效应的 36%和 64%。对于脉压，利拉鲁肽的总治疗效果为-2.5mmHg（95%CI：-3.5，-1.5；p<0.001），其中 14%是体重依赖性的，86%是体重非依赖性的。对于 DBP，利拉鲁肽治疗的影响有限，仅有很小的体重介导作用。利拉鲁肽 4.5mg 对 SBP 和脉压的降低作用超过了利拉鲁肽 1.5mg，主要是通过体重介导的。
在 AWARD 项目的安慰剂对照试验中，利拉鲁肽 1.5mg 降低了 T2D 患者的 SBP 和脉压。虽然利拉鲁肽 1.5mg 对 SBP 和脉压的影响有三分之一归因于体重减轻，但大部分是与体重无关的。更深入地了解 GLP-1RA 对降低血压的多效性作用，可能有助于开发治疗高血压的新方法。临床试验注册（clinicaltrials.gov）NCT01064687、NCT00734474、NCT01769378、NCT02597049、NCT01149421、NCT03495102。
