Oral HRS-7535 90 mg Cut UACR by 32% in Diabetic Kidney Disease Patients
Background
Managing diabetic kidney disease (DKD) remains a significant challenge, with a persistent need for therapies that effectively reduce albuminuria and preserve renal function. While injectable GLP-1 receptor agonists (GLP-1 RAs) have shown renal benefits, their use can be limited by administration route and patient adherence. The efficacy of novel non-peptide small-molecule GLP-1 RAs, particularly as add-on therapy to contemporary high-intensity treatments like SGLT2 inhibitors and finerenone, has been uncertain. This study aimed to evaluate a new oral small-molecule GLP-1 RA, HRS-7535, in this specific patient population to address these gaps.
Study Design
The SOLID-DKD trial was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study conducted across 72 sites in China. 281 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 randomized (1:1:1). Participants received once-daily oral HRS-7535 30 mg, HRS-7535 90 mg, or placebo for 16 weeks. Randomization was stratified by baseline UACR, concomitant SGLT2 inhibitor use, and finerenone use. The primary endpoint was the relative change in UACR from baseline to week 16.
Results
Of the 281 randomized participants, 280 received at least one dose (93 in 30 mg, 94 in 90 mg, 93 in placebo). Baseline median UACR was 763 mg/g. Notably, 64.6% (181) were on SGLT2 inhibitors and 24.3% (68) on finerenone. At week 16, the higher dose of HRS-7535 demonstrated significant UACR reduction: > The placebo-corrected reduction in UACR with HRS-7535 90 mg was -32% (95% CI -43 to -18; treatment-policy estimand). For HRS-7535 30 mg, the reduction was -14% (95% CI -29 to 4). Beyond renal effects, HRS-7535 90 mg significantly improved glycemic control, with a mean difference in glycated hemoglobin of -1.09% (95% CI -1.32 to -0.86) compared to placebo. Body weight also decreased by -2.95% (95% CI -3.94 to -1.95) with the 90 mg dose. Adverse events were primarily mild-to-moderate gastrointestinal issues 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, respectively.
Key Findings
- Oral HRS-7535 90 mg reduced urinary albumin-to-creatinine ratio (UACR) by -32% (95% CI -43 to -18) compared to placebo.
- HRS-7535 90 mg lowered glycated hemoglobin by -1.09% (95% CI -1.32 to -0.86) vs. placebo.
- Body weight decreased by -2.95% (95% CI -3.94 to -1.95) with HRS-7535 90 mg.
- Adverse events were primarily mild-to-moderate gastrointestinal issues during dose escalation.
- Efficacy was observed as an add-on to SGLT2 inhibitors and finerenone in a significant proportion of patients.
Why It Matters
An oral small-molecule GLP-1 receptor agonist like HRS-7535 represents a significant advancement, offering a convenient alternative to injectable GLP-1 RAs for diabetic kidney disease management. Its efficacy in reducing albuminuria, even when added to existing high-intensity therapies, suggests a powerful synergistic effect. This study provides compelling evidence for an oral GLP-1 RA as a viable add-on therapy for DKD, potentially improving patient adherence and expanding treatment options. The observed reductions in glycated hemoglobin and body weight further underscore its broad metabolic benefits. While a phase 2 trial, these results pave the way for larger studies to confirm long-term renal protection and cardiovascular outcomes, bringing an oral protocol closer to clinical reality.