Authors' Reply: Tirzepatide and Kidney Protection in Obesity: Unanswered Questions

We thank Drs. Zhu and Ren1 for their Letter and agree that racial/ethnic heterogeneity in obesity-related kidney disease and response to tirzepatide treatment and other incretin-based therapies is of clinical relevance. In our analysis of the SURMOUNT 1 and 2 trials,2 published in JASN, the majority of participants were White. The ongoing SURMOUNT MMO trial will enroll a more diverse and representative global population of approximately 15,000 participants from 27 countries around the world. This large outcome trial will provide more insight into the consistency of the potential cardiovascular and kidney protective effects of tirzepatide in adults with overweight or obesity but without diabetes across races and regions.3 We also agree that additional biomarker research will help to explore mechanisms of kidney protective effects in people with overweight or obesity. Experimental studies have shown that tirzepatide reduces kidney injury molecule-1 and markers of oxidative stress.4 Whether these results translate to the clinical setting is currently being investigated in the TREASURE-CKD trial. Whether the dual glucagon like peptide -1 (GLP-1)/glucose-dependent insulinotropic polypeptide agonism of tirzepatide provides additional benefit compared with GLP-1 agonism alone has been studied before. Two clinical trials compared tirzepatide with semaglutide in adults with type 2 diabetes and overweight or obesity (SURMOUNT-5).5,6 Both trials demonstrated superior effects of tirzepatide in improving glycemic and body weight control, which could translate into greater kidney protective effects. A registry study showed that tirzepatide compared with GLP-1 receptor agonists was associated with a lower risk of all-cause mortality, cardiovascular, and kidney outcomes in patients with type 2 diabetes.7 In summary, the field involving GLP-1–based therapies is rapidly evolving, yet many mechanistic and clinical questions remain unresolved. Fortunately, large trials enrolling diverse cohorts of patients and mechanistic studies are underway that will hopefully deliver some answers.