Efficacy and safety of HRS-7535, an oral small-molecule GLP-1 receptor agonist, in patients with diabetic kidney disease (SOLID-DKD): a randomised, double-blind, placebo-controlled, phase 2 trial.

Abstract

The efficacy of non-peptide small-molecule glucagon-like peptide-1 (GLP-1) receptor agonists in diabetic kidney disease remains uncertain, particularly as add-on therapy to contemporary high-intensity treatments. We assessed HRS-7535, a novel oral small-molecule GLP-1 receptor agonist, in this population. SOLID-DKD was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial conducted at 72 clinical sites in China. Adults with diabetic kidney disease (urinary albumin-to-creatinine ratio [UACR] 300-<3000 mg/g; estimated glomerular filtration rate [eGFR] ≥30 mL/min per 1.73 m²) were randomly assigned (1:1:1) via a central interactive web-response system, stratified by baseline UACR, concomitant SGLT2 inhibitor use, and finerenone use to once-daily oral HRS-7535 (30 mg or 90 mg) or placebo for 16 weeks. The primary endpoint was the relative change in UACR from baseline to week 16. This trial is registered at ClinicalTrials.gov (NCT06415214) and is completed. Between June 21, 2024, and March 30, 2025, 281 participants were randomised; 280 received at least one dose (30 mg: n = 93; 90 mg: n = 94; placebo: n = 93). Baseline median UACR was 763 mg/g; 181 (64.6%) participants were receiving SGLT2 inhibitors and 68 (24.3%) were receiving finerenone. At week 16, the placebo-corrected reduction in UACR with 90 mg was -32% (95% CI -43 to -18; treatment-policy estimand [intention-to-treat]) and -38% (-49 to -24; efficacy estimand [on-treatment analysis]); with 30 mg, -14% (-29 to 4) and -19% (-34 to -2), respectively. Compared with placebo, the mean difference in glycated haemoglobin with HRS-7535 90 mg was -1.09% (-1.32 to -0.86) and in body weight was -2.95% (-3.94 to -1.95). Adverse events were primarily mild-to-moderate gastrointestinal events during dose escalation. Serious adverse events occurred in 5 (5.4%), 4 (4.3%), and 2 (2.2%) participants in the 30 mg, 90 mg, and placebo groups. Discontinuation due to adverse events occurred in 3 (3.2%), 1 (1.1%), and 0 participants, respectively. No deaths occurred. HRS-7535 dose-dependently reduced albuminuria in patients with diabetic kidney disease receiving intensive contemporary therapy, with a short-term safety profile consistent with the GLP-1 receptor agonist class, supporting its evaluation in phase 3 renal outcome trials. Jiangsu Hengrui Pharmaceuticals.