Survodutide, a glucagon receptor/glucagon-like peptide-1 receptor dual agonist, improves blood pressure in adults with obesity: A post hoc analysis from a randomized, placebo-controlled, dose-finding, phase 2 trial

Abstract

Obesity is a major risk factor for hypertension and increases the risk of cardiovascular disease.¹ Sustained weight loss is associated with improved blood pressure (BP) control, with systolic BP (SBP) reductions of 5–20 mmHg per 10 kg weight loss.² Survodutide (BI 456906) is a glucagon receptor/GLP-1 receptor dual agonist in clinical development for the treatment of obesity,³ and metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis.⁴ In a phase 2 clinical trial in adults with a BMI ≥27 kg/m² without diabetes (ClinicalTrials.gov, number NCT04667377), survodutide therapy led to significant and dose-dependent reductions in body weight versus placebo (survodutide: 0.6 mg, p = 0.026; ≥2.4 mg, p < 0.001).⁵ Mean changes in body weight reached −14.9% and − 18.7% at week 46 for planned (all data) and actual treatment (on-treatment data), respectively, with survodutide 4.8 mg, versus −2.8% and − 2.3% with placebo.⁵ Mean reductions in BP at week 46 with survodutide 4.8 mg by planned treatment were 8.6 mmHg for SBP and 4.8 mmHg for diastolic BP (DBP), versus 2.5 mmHg for SBP and 1.9 mmHg for DBP with placebo; and similar reductions occurred by actual treatment, with reductions of 8.3 mmHg for SBP and 4.7 mmHg for DBP with survodutide, versus 2.5 mmHg for SBP and 1.9 mmHg for DBP with placebo.⁵ The tolerability profile of survodutide was similar to that of GLP-1 receptor mono-agonists; gastrointestinal disorders were the most frequent treatment-emergent adverse events (AEs).⁵

Here, we report a post hoc analysis to investigate the efficacy of survodutide on BP parameters in subgroups with or without hypertension at baseline in people with a BMI ≥27 kg/m².

Data were derived from a 46-week, randomized, double-blind, placebo-controlled, dose-finding phase 2 trial of survodutide (ClinicalTrials.gov, number NCT04667377, EudraCT, number 2020-002479-37).⁵ Briefly, 387 adults (aged ≥18 to <75 years) with a BMI ≥27 kg/m² and without diabetes were randomized 1:1:1:1:1 to receive once-weekly subcutaneous survodutide (0.6, 2.4, 3.6, or 4.8 mg) or placebo for 46 weeks, comprising an initial 20-week dose-escalation period (dose adjusted for gastrointestinal tolerability), followed by a 26-week dose-maintenance period.⁵ The primary end-point was the percentage change in body weight from baseline to week 46. In this post hoc analysis, changes from baseline to week 46 in SBP and DBP (via office BP measurement) were evaluated by the presence or absence of hypertension at baseline, defined as investigator-reported before and at screening. Data were analysed descriptively for the full analysis set (FAS), defined as all randomized participants receiving ≥1 dose of study drug with data for ≥1 efficacy end-point, according to doses received during the maintenance period (actual treatment) or those assigned at randomization (planned treatment) using on-treatment data.⁵

In total, 387 participants were randomized (withdrawal, n = 1); 386 participants received survodutide or matched placebo during the dose-escalation phase and 286 during the dose-maintenance phase. The FAS consisted of 384 participants (lack of post-baseline efficacy data, n = 2).⁵ Baseline demographic and clinical characteristics were similar across treatment groups.⁵ In the FAS, the majority of participants were female (262; 68.2%) and White (301; 78.4%). At baseline, 133 (34.6%) participants had hypertension and 108 (28.1%) had dyslipidaemia.

At week 46, reductions in SBP and DBP were observed in all survodutide dose groups tested when participants were analysed according to the presence or absence of hypertension at baseline (Figure 1). The largest mean reductions in SBP and DBP occurred in the survodutide 2.4 and 3.6 mg dose groups, and were slightly larger in participants who were normotensive at baseline: SBP decreases were 9.9 and 11.8 mmHg by planned treatment, and 9.7 and 12.0 mmHg by actual treatment, respectively; and DBP decreases were 5.6 and 4.5 mmHg by planned treatment, and 5.4 and 4.5 mmHg by actual treatment, respectively. The most common concomitant antihypertensive agents taken during the treatment period were angiotensin II receptor blockers (52; 13.5%), angiotensin-converting enzyme inhibitors (39; 10.1%), beta blockers (31; 8.0%) and calcium channel blockers (31; 8.0%). No important changes from baseline in the use of antihypertensive medications were observed across treatment groups to week 46.

Five participants receiving survodutide reported AEs of hypotension (two of whom had underlying hypertension), and one AE in a participant receiving placebo (with underlying hypertension); in addition, two AEs of orthostatic hypotension were reported in participants receiving survodutide (none with underlying hypertension). None of these AEs were serious, but one case was graded as severe (survodutide 4.8 mg dose group in the participant with underlying hypertension). Reductions in SBP in participants without hypertension at baseline (i.e., normotensive) were not associated with any severe or serious hypotensive episodes.

All tested doses of survodutide were associated with clinically meaningful decreases in SBP and DBP. Reductions in BP occurred regardless of the presence or absence of hypertension at baseline. Our results are consistent with preliminary analyses showing beneficial effects of incretin-based mono- and dual-agonists in BP-lowering in people with a BMI ≥27 kg/m² without diabetes.^6-8 However, incretin-based agents with regulatory approval to treat obesity are not yet approved to treat hypertension.

Anti-hypertension medications need to be monitored in patients receiving survodutide, as hypotension may occur if doses of these agents are not adjusted. However, caution is needed, because stopping all antihypertensives, especially agents with known cardiovascular benefits, may offset the benefits observed with survodutide.

This analysis has limitations: it was exploratory in nature, the trial population was predominantly female and White and the trial duration was relatively short. These points will be addressed in phase 3 trials currently in progress (SYNCHRONIZE™-1, NCT06066515; SYNCHRONIZE™-2, NCT06066528; and SYNCHRONIZE™-CVOT, NCT06077864). Inflammatory markers will also be evaluated in phase 3 trials, as improvements in inflammation may underpin many of the potential benefits of survodutide on end-organ damage.

As there did not appear to be a dose–response relationship, it is possible that the observed reductions in BP could be secondary to weight loss and increased activity/exercise. Hypertension reduction strategies based on lifestyle changes have been shown to improve BP control,⁹ including short-term intensive diet and exercise programmes,¹⁰ and longer-term e-counselling approaches.¹¹

In conclusion, survodutide was associated with clinically meaningful improvements in BP, regardless of hypertension status at baseline. These results complement published phase 2 efficacy data, which demonstrated a dose-dependent reduction in body weight with survodutide,⁵ and suggest that survodutide may help to alleviate cardiovascular risk.

Design: Carel W. le Roux and Anita M. Hennige. Conduct/data collection: Oren Steen, Kathryn J. Lucas and Elif I. Ekinci. Analysis: Carel W. le Roux, Elena Startseva, Anna Unseld, Samina Ajaz Hussain and Anita M. Hennige. Writing manuscript: All authors contributed to manuscript writing (assisted by a medical writer paid for by the funder), approved the final version of the manuscript and vouched for data accuracy and fidelity to the protocol.

This study was supported by Boehringer Ingelheim.

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of this manuscript. Carel W. le Roux has received personal fees from Boehringer Ingelheim, Eli Lilly, GI Dynamics, Gila Pharmaceuticals, Herbalife, Johnson & Johnson, Keyron, Novo Nordisk and Zealand Pharma outside the submitted work. Oren Steen has received research support from Alnylam, Anji, AstraZeneca, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Gilead Sciences, Janssen, Kowa, Medicago, Moderna, Novartis, Novo Nordisk, Pfizer, Sanofi, ViaCyte and Zucara Therapeutics; speaker bureau fees from Abbott, Amgen, AstraZeneca, Bausch Health, Boehringer Ingelheim, Eli Lilly, Janssen, LMC, Novo Nordisk and Sanofi; and consultancy fees from Amgen, Bayer, Eli Lilly, Novo Nordisk and Sanofi. Kathryn J. Lucas has nothing to disclose. Elif I. Ekinci is a consultant for Eli Lilly Australia, and her institute receives research funding support from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly Australia and Versanis. Elena Startseva, Anna Unseld, Samina Ajaz Hussain and Anita M. Hennige are employees of Boehringer Ingelheim.