Rationale, Design, and Baseline Characteristics of the TRANSCEND-CKD trial of Retatrutide in Patients with Chronic Kidney Disease.

BACKGROUND AND HYPOTHESIS: Retatrutide is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors that reduced weight and HbA1c in individuals with obesity and type 2 diabetes (T2D). Retatrutide may also address key chronic kidney disease (CKD)-related pathophysiological pathways. Mechanism-of-action studies are needed to understand its effects on kidney function. METHODS: TRANSCEND-CKD is a double-blind, placebo-controlled, Phase 2b mechanistic study evaluating the efficacy of retatrutide in adults with overweight/obesity and CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2, with and without T2D. Participants were randomized 1:1 to once-weekly retatrutide maximum tolerated dose up to 12 mg or matched placebo. The primary objective is to evaluate the effect of retatrutide versus placebo on change in measured glomerular filtration rate (mGFR) by iohexol clearance from baseline to Week 24. Additional objectives include changes in MRI-assessed kidney hemodynamic and volumetric measurements, including perirenal and renal sinus fat. RESULTS: Of 367 participants screened, 146 were randomized to study interventions. The mean age was 65.1 years [SD 10.6], 45.2% were female, and 69.9% were White. The mean weight was 101.1 kg (SD 20.6) and BMI 35.7 kg/m2 (SD 6.1). Participants with T2D (37.7%) had a mean HbA1c of 7.1% (SD 1.1%), while HbA1c was 5.7% (SD 0.3%) in participants without T2D. The mean mGFR was 49.3 mL/min/1.73 m2 (SD 19.0), cystatin C-based eGFR was 49.6 mL/min/1.73 m2 (SD 13.2), and creatinine-based eGFR was 64.2 mL/min/1.73 m2 (SD 17.8). The median baseline urine albumin-to-creatinine ratio was 14.0 mg/g (IQR 6.0-69.0). A total of 21.8% of participants were treated with sodium-glucose co-transporter-2 inhibitors at baseline. CONCLUSIONS: TRANSCEND-CKD is designed to provide mechanistic insights on the effects of retatrutide on kidney function and structure, and to inform clinical findings in the ongoing cardio-kidney outcome trial TRIUMPH-Outcomes (NCT06383390).