Rationale, design and baseline characteristics of REMODEL, a mechanism-of-action trial with semaglutide in people with type 2 diabetes and chronic kidney disease.

Background: Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD) and kidney failure globally. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces the risk of major kidney, cardiovascular, and mortality outcomes in people with T2D and CKD, but the mechanism-of-action (MoA) remains unclear.

Methods: REMODEL (NCT04865770) is a 52-week placebo-controlled, double-blind, parallel-group, randomized trial in adults with T2D and CKD. Inclusion criteria include HbA1c ≤ 9%, estimated glomerular filtration rate (eGFR) ≥ 30 to ≤75 mL/min per 1.73m2 and urine albumin-creatinine ratio (UACR) ≥ 20 to < 5,000 mg/g. The co-primary outcome is magnetic resonance imaging (MRI) based, including change in kidney oxygenation, perfusion and inflammation. Secondary outcomes include change from baseline in creatine clearance rate, urinary sodium excretion, albumin excretion rate and kidney fibrosis and blood flow parameters measured by MRI. A subgroup had kidney biopsies at baseline and at end of the treatment for tissue-based interrogation including single nucleus and spatial transcriptomics, pathology, and advanced histological assessment.

Results: Across 8 countries, 106 participants (N = 33, biopsy subgroup) were enrolled. The mean age was 65.3 years [SD 9.9] at baseline with hemoglobin A1c of 7.1% [SD 0.9], creatinine-based eGFR of 51.1 mL/min per 1.73m2 [SD 10.4] and median UACR of 187.3 mg/gram (IQR 60.5-546.4). Renin-angiotensin-system (RAS) inhibitor use was 98.1% and sodium glucose cotransporter 2 inhibitor (SGLT2i) use was 38.7%. In the kidney biopsy subgroup, baseline characteristics were like the full population. Histological analysis of kidney tissues revealed 17 participants with primarily diabetic nephropathy, 6 participants with primarily vascular features, 9 with mixed diabetic nephropathy and vascular characteristics, and 1 with membranous nephropathy.

Conclusion: The REMODEL trial leverages multi-pronged approaches to investigate the kidney-specific effects and underlying mechanisms of semaglutide in a representative population of people with T2D and CKD, which supports the generalizability and clinical relevance of the findings.