BACKGROUND: Elevated blood pressure (BP) and excess body weight (BW) are common in type 2 diabetes (T2D). Weight loss (WL) is associated with a reduction in BP. Glucagon-like peptide-1 (GLP-1) receptor agonist class effects include reduction of blood glucose, BW and BP. Semaglutide, a GLP-1 analogue for the treatment of T2D, significantly reduced HbA1c, BW and systolic BP (SBP) vs comparators across the phase 3a SUSTAIN clinical trial programme.
PURPOSE: To investigate the contribution of WL to the reduction in SBP associated with semaglutide treatment across SUSTAIN 1–5.
METHODS: SUSTAIN 1–5 included subjects with inadequately controlled T2D, randomised to once-weekly, subcutaneous semaglutide 0.5 or 1.0 mg (1.0 mg in SUSTAIN 3), or comparator for 30 or 56 weeks. Comparators were placebo (SUSTAIN 1 and 5), sitagliptin (SUSTAIN 2), exenatide extended release (SUSTAIN 3) and insulin glargine (SUSTAIN 4). Mediation analyses were performed post hoc to quantify the relative contribution of WL (mediator) to the treatment effect of semaglutide on SBP; WL was considered an indirect effect (WL-mediated), the effect not mediated by WL was considered a direct effect of semaglutide on SBP (WL-independent). Reduction in SBP was also evaluated across weight-change categories. Analyses were conducted on individual trials, due to differences in populations, comparators and background therapy.
RESULTS: Across the SUSTAIN 1–5 trials (n=3,918), mean changes in SBP (baseline 128.8–134.8 mmHg) ranged from −2.6 to −5.1 mmHg and −2.7 to −7.3 mmHg, with semaglutide 0.5 and 1.0 mg, respectively, vs −1.0 to −2.3 mmHg with comparators (p<0.02 vs comparator for all trials except SUSTAIN 1 [both doses] and SUSTAIN 5 [lower dose]). Mean changes in BW (baseline 89.5–95.8 kg) ranged from −3.5 to −4.3 kg and −4.5 to −6.4 kg with semaglutide 0.5 and 1.0 mg, respectively, vs −1.9 to +1.2 kg with comparators (p<0.0001 vs comparator for all trials). WL-mediated and WL-independent effects of semaglutide on SBP reduction for each trial are shown in the Figure. There were greater reductions in SBP with semaglutide (vs comparators) across all weight-change categories evaluated. In the >4.0 kg WL category, mean change in SBP was −3.0 to −6.8 and −4.4 to −9.3 mmHg with semaglutide 0.5 and 1.0 mg, respectively, vs −4.0 to +1.1 mmHg with comparators. In the 0–4.0 kg WL category, mean change in SBP was −2.0 to −4.8 mmHg and −0.7 to −5.2 mmHg with semaglutide 0.5 and 1.0 mg, respectively, vs -2.1 to -4.2 mmHg with comparators. For subjects with no WL/BW gain, mean change in SBP was −1.5 to +1.5 mmHg and −5.4 to +1.0 mmHg with semaglutide 0.5 and 1.0 mg, respectively, vs −1.0 to +1.1 mmHg with comparators.
CONCLUSIONS: With semaglutide, greater WL was generally associated with greater reductions in SBP. However, the SBP reduction observed with semaglutide was driven by both WL-mediated and WL-independent mechanisms.