The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity.

INTRODUCTION: 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. METHODS: A analysis of 2 retatrutide studies (dose range: 0.5-12 mg) was performed in participants (estimated glomerular filtration rate [eGFR] ≥ 45 ml/min per 1.73 m) with T2D ( = 281) and with overweight or obesity without T2D ( = 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. RESULTS: At baseline, mean eGFR derived from creatinine and median UACR were 91 ml/min per 1.73 m and 13 mg/g, respectively in the T2D study, and 90 ml/min per 1.73 m 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 m (95% CI: 1.9-8.7) and 8.5 ml/min per 1.73 m (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. CONCLUSION: 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.