Retatrutide, a triple‑receptor agonist, lowered urine albumin (a kidney stress marker) and boosted estimated kidney filtration rates in people with obesity (and in those with diabetes at high doses for albumin). The biggest kidney benefits were seen at the 8‑12 mg doses, especially in non‑diabetic overweight/obese participants.

Obesity and type 2 diabetes mellitus (T2D) increase the risk of kidney disease. This study assessed changes in kidney parameters with retatrutide, an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. A <i>post hoc</i> analysis of 2 retatrutide studies (dose range: 0.5-12 mg) was performed in participants (estimated glomerular filtration rate [eGFR] &#x2265; 45 ml/min per 1.73 m²) with T2D (<i>n</i> = 281) and with overweight or obesity without T2D (<i>n</i> = 338). Both studies were placebo-controlled; the T2D study included dulaglutide 1.5 mg as an active comparator. We assessed change from baseline at week 36 (T2D) and week 48 (overweight/obesity) in urine albumin-to-creatinine ratio (UACR) and eGFR derived from creatinine, cystatin C, or both. At baseline, mean eGFR derived from creatinine and median UACR were 91 ml/min per 1.73 m² and 13 mg/g, respectively in the T2D study, and 90 ml/min per 1.73 m² and 7 mg/g, respectively in the obesity study. In participants with T2D, retatrutide 12 mg was associated with reduced UACR compared with placebo at 36 weeks by -37.0% (95% CI: -57.3 to -7.0); eGFR was unchanged compared with placebo. In participants with overweight or obesity, retatrutide 8 mg and 12 mg, compared with placebo at 48 weeks, was associated with decreased UACR by -28.0% (95% CI: -46.0 to -4.1) and -31.5% (95% CI: -49.3 to -7.4), respectively, and with increased eGFR derived from creatinine by 5.3 ml/min per 1.73 m² (95% CI: 1.9-8.7) and 8.5 ml/min per 1.73 m² (95% CI: 4.9-12.1), respectively. Similar increases in eGFR derived from cystatin C and combined creatinine-cystatin C eGFR were observed. Because most patients had normal albuminuria, the absolute reduction in UACR was modest. Higher doses of retatrutide were associated with reduced UACR in participants with T2D and obesity, and with increased eGFR in participants with obesity but not in those with T2D.