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The prevalence of both type 2 diabetes (T2D) and chronic kidney disease (CKD) continues to increase, which is in part attributed to the growing population of people with obesity or overweight [1]. Tirzepatide has been associated with improved insulin sensitivity, body weight reduction, improved glycemic control, and reduced onset of T2D in participants with prediabetes [2-5]. In post hoc analyses from randomised controlled clinical trials with participants with T2D or obesity, tirzepatide was associated with kidney protective effects and reduced estimated glomerular filtration rate (eGFR) decline compared to insulin glargine treatment [4]. In participants with obesity or overweight, tirzepatide was associated with a reduction in albuminuria and statistically significantly increased cystatin-C based eGFR (Cys-C-eGRF) and creatinine/cystatin-C based eGRF (Cr-Cys-C-eGFR) levels compared to placebo and generally exhibited a relatively slow rate of eGFR decline. We therefore assessed tirzepatide's association with kidney parameters in a post hoc analysis of the SURMOUNT-1 trial in participants with obesity or overweight and prediabetes at randomisation, who were followed for 3 years. The SURMOUNT-1 trial was a randomised placebo-controlled clinical trial in participants with obesity or overweight with at least one weight-related complication without diabetes mellitus [6]. Participants with normoglycemia at baseline were followed for 72 weeks, whereas participants with American Diabetes Association defined prediabetes were followed for 176 weeks, followed by a 17-weeks wash-out period [2]. The combined creatinine-cystatin C equation was chosen since it has been shown that creatinine-cystatin C correlates best with measured eGFR in people with obesity or overweight and prediabetes [7]. Tirzepatide dose groups were pooled in the main analysis, consistent with prior analyses from the SURMOUNT program. In additional analyses, tirzepatide results were assessed for each dose group separately. Mean and standard deviation (SD) were reported for baseline. Change from baseline in eGFR and urine albumin to creatinine ratio (UACR) was assessed using mixed model repeated measures (MMRM), with results presented in least squares means (LSM) and standard error (SE). An unstructured covariance matrix was used to allow for general patterns of standard deviations and correlations across the repeated outcome measurements. As a widely used method for repeated measures, MMRM handles missing data inherently based on the missing at random assumption and effectively models correlation in repeated measures. Subgroup analysis for change from baseline in eGFR and UACR was performed for selected subgroups using MMRM. Subgroup by treatment interaction was not assessed due to its being underpowered. Results of subgroup analyses were interpreted descriptively. Analyses were performed with SAS 9.4. A total of 1032 (40.6%) of SURMOUNT-1 randomised participants had prediabetes at baseline. Mean age was 48 years (standard deviation [SD] 11.8) and 659 (63.9%) were female. Mean body weight was 107.3 kg (SD: 23.4) and mean HbA1c 39.5 mmol/mol (SD: 3.7). At baseline, 291 (28.2%) were prescribed renin-angiotensin-system inhibitors. Mean Cr-Cys-C-eGFR was 97.1 mL/min per 1.73m2 (SD 17.6), median (interquartile range, IQR) UACR 7.0 mg/g (25th–75th Percentile 4.0–12.0), and in 94 (9.1%) participants the UACR level was ≥ 30 to ≤ 300 mg/g (Table 1). Fewer participants went on to develop type 2 diabetes in comparison to placebo [2]. In the placebo group, mean Cr-Cys-C-eGFR remained stable during the first 124 weeks follow-up and then decreased to 91.6 mL/min per 1.73m2 (Standard Error [SE] 0.95) (Figure 1A). In the pooled tirzepatide group, Cr-Cys-C-eGFR increased for 124 weeks and then decreased to 95.3 mL/min per 1.73m2 (SE 0.49) at Week 176 (estimated treatment difference [ETD] relative to placebo of 3.7 mL/min per 1.73m2 [95% CI: (1.6, 5.8)]). At the end of the 17-weeks wash-out period, Cr-Cys-C-eGFR was 94.7 mL/min per 1.73m2 (SE 0.48) in the tirzepatide group and 94.1 (SE 0.89) mL/min per 1.73m2 in the placebo group (between-group difference of 0.6 mL/min per 1.73m2 [95% CI (−1.4, 2.6)]). A similar pattern was observed when eGFR was estimated from Cystatin C alone (Figure S1A). Higher tirzepatide doses were associated with attenuated Cr-Cys-C-eGFR decline compared to placebo at Week 176 (Figure S1B). Tirzepatide was associated with a greater reduction in UACR compared to placebo (Figure 1B). The ETD of the percent change from baseline was numerically higher in participants with baseline UACR ≥ 30 mg/g (EDT: –30.4; 95% CI [−64.7, 37.3]) compared to those with UACR < 30 mg/g (−10.4; 95% CI [−22.3; 3.2]) (Figure S1A,B). Subgroup analyses by baseline eGFR showed consistent effects (Figure S2). The effects of tirzepatide compared to placebo in attenuating eGFR decline appeared numerically greater in participants with baseline UACR ≥ 30 mg/g compared to those with UACR < 30 mg/g (Figure S1C,D). In this subgroup analysis of the SURMOUNT-1 trial among participants with obesity or overweight and prediabetes, participants who were randomly assigned to tirzepatide experienced attenuated eGFR decline compared to those assigned to placebo during the 176-weeks follow-up. The preservation of eGFR was paralleled by a reduction in UACR. Along with the previously reported benefit of tirzepatide on body weight and prevention of diabetes [2], these data support the potential for long-term kidney benefits and may indicate a favourable impact on cardiovascular outcomes. Obesity and insulin resistance are important drivers of kidney and cardiovascular disease progression [8-10]. Therapies targeting incretin hormones, such as tirzepatide, address this pathophysiological mechanism [4, 6, 11]. UACR reduction, which was observed early on in the study and was sustained throughout follow-up, is noteworthy, in particular among participants with UACR ≥ 30 mg/g as these participants showed a faster eGFR decline compared to those with UACR < 30 mg/g. A 30% reduction in UACR, which was associated with tirzepatide in this study, has been shown to predict high likelihood of long-term kidney failure protection in a meta-analysis of clinical trials [12]. The current study builds upon previous analyses from the SURMOUNT program demonstrating association of 72-weeks tirzepatide treatment with reduced albuminuria during 72 weeks of treatment in the broader population of people with obesity or overweight with and without T2D. In previous studies with shorter follow-up periods, no effect on eGFR was observed [4]. In this study, the reduced decline in eGFR with tirzepatide compared to placebo emerged after 124 weeks of treatment. In this relatively healthy population with preserved kidney function an approximate eGFR decline of about 1 mL/min/1.73m2/year would be expected [13], however, the deviation suggests there may be clinical relevance to preserving kidney function in participants treated with tirzepatide compared to placebo. This may be the result of the slowly progressive nature of the disease in this relatively healthy population with preserved kidney function at baseline. In addition, 13.3% of participants receiving placebo had a new onset of T2D at Week 176 compared to only 1.3% in the tirzepatide pooled treatment group [2]. At Week 193, 13.7% of participants in the placebo group experienced new onset of type 2 diabetes compared to 2.4% in the tirzepatide group. As worsening of glycemia may accelerate kidney function decline, the marked reduction in risk of T2D with tirzepatide may have translated into less eGFR decline, but this would only emerge at the end of a long follow-up after participants have developed diabetes. Two major trials, FLOW and SURPASS-4 investigated the effects of GLP-1RA on kidney function in participants using GLP-1RA with T2D. Semaglutide, another GLP-1RA, has been shown to reduce the risk of kidney disease progression and kidney failure, cardiovascular events, and prolonged survival in the 208-weeks FLOW trial [14]. Tirzepatide has previously shown beneficial effects on albuminuria and eGFR in the 52-weeks SURPASS-4 trial [15] and the 72-weeks SURMOUNT-1 trial [4], which is confirmed in the data of the 3-years SURMOUNT-1 trial presented here. In conjunction with the existing evidence, our study supports a large clinical outcome trial with tirzepatide in a novel population of people with CKD without diabetes to reduce kidney disease-related complications. A few limitations should be mentioned. The current study is a post hoc analysis in participants with largely preserved kidney function at baseline and therefore can only be regarded as hypothesis generating. Caution is required in interpreting the results given the relatively high rate of missing data, which was mainly due to patient attrition. Due to the limited number of cystatin C and creatinine measurements over time, the effects of tirzepatide on Cr-Cys-C-eGFR directly after tirzepatide initiation could not be characterised. Given the small sample size in the UACR ≥ 30 mg/g subgroup, these findings should be considered exploratory. Additionally, as this population did not include those with CKD, participants had a low baseline kidney risk, and outcomes may differ in those with established CKD. In conclusion, in participants with obesity or overweight, with prediabetes and normal kidney function at baseline, treatment with tirzepatide was associated with a smaller decline of creatinine-cystatin C eGFR over 176 weeks compared to placebo treatment and a greater numerical percentage reduction in UACR. The study was designed by H.J.L.H, R.G., and C.G. D.C. was responsible for the statistical analyses. H.J.L.H. drafted the manuscript. H.J.L.H. and C.G. are the guarantors of this work and, as such, had full access to all the data in the study take responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in interpretation of the data and critical review of the manuscript, had access to the data and approved of this manuscript to be submitted for publication. The authors thank all study participants. The authors would like to thank Dr. rer. nat. Monika Müller (Eli Lilly and Company) and Rhea Lewis, PhD (Eli Lilly and Company) for medical writing and editing assistance. This study was funded by Eli Lilly and Company. H.J.L.H. receives consulting fees from AstraZeneca, Alexion, Alnylum, Amgen, Bayer, Boehringer Ingelheim, Biocity Pharmaceutics, Dimerix, Eli Lilly, Novartis, Novo Nordisk, Roche and Travere Therapeutics; received research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk; received honoraria for lectures from AstraZeneca, Bayer and Novo Nordisk. D.C., G.K.D., B.L., I.J., R.G., M.B. and C.L. are employees and shareholders of Eli Lilly and Company. D.Z.I.C. has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK, Biobridge, Vantage, Altimmune and Novo-Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo-Nordisk, Bayer. K.R.T. is supported by NIH research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568 and OT2OD032581, as well as CDC project numbers 75D301-21-P-12254 and 75D301-23-C-18264. She has also received investigator-initiated grant support from Travere, Bayer, Doris Duke Charitable Foundation, Benaroya Research Institute, and Breakthrough T1D (formerly JDRF). She reports consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Travere, Bayer, ProKidney and Alnylum, as well as speaker fees from Novo Nordisk, Boehringer Ingelheim, and Bayer. Additionally, she reports being chair of data safety monitoring boards for the National Institute of Diabetes and Digestive and Kidney Disease and George Clinical Institute, and member of the data safety monitoring board for AstraZeneca. She reports leadership roles as chair for the Diabetic Kidney Disease Collaborative for the American Society of Nephrology, chair for Kidney Week 2025 Program Committee, a member of the American Heart Association/American College of Cardiology Cardiovascular-Kidney-Metabolic Guideline Committee, and a member of the Kidney Disease Improving Global Outcome Diabetes and CKD Guideline Committee. P.B. reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli-Lilly, LG Chemistry, Sanofi, Novo Nordisk, and Horizon Pharma. P.B. also serves or has served on the advisory boards and/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Lilly, and XORTX. P.B. serves as DMC Chair for Bayer and DMC member for Cytel. P.B. reports grant funding from AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer-Ingelheim, Merck and Amgen/Horizon Pharma. The authors declare no conflicts of interest. Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date for data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70622. Figure S1: Changes in eGFR (CKD-EPI Creatinine-Cystatin Equation 2021) and UACR in participants with prediabetes at baseline. (A) Change from baseline to Week 176 in Total Cystatin-C eGFR at Week 176 for pooled tirzepatide and placebo. (B) Change from baseline to Week 193 in Total Creatinine-Cystatin C eGFR for tirzepatide doses (5, 10 and 15 mg) and placebo. *p < 0.05, **p < 0.01, ***p < 0.001 versus placebo. The data are presented as LSM (SE) (total Creatinine-Cystatin C eGFR) or MBE (SE) (Creatinine-Cystatin C eGFR analysis by UACR baseline) unless stated otherwise. Baseline measures are analysed using the ANOVA model. Post-baseline data is analysed using the MMRM model. Changes in Urine Albumin-Creatinine (UACR) in participants with prediabetes at baseline. (C) Subgroup analysis of percentage change from baseline to Week 176 in UACR in participants with UACR < 30 mg/g at baseline. (D) Subgroup analysis of percentage change from baseline to Week 176 in UACR in participants with UACR ≥ 30 mg/g at baseline. *p < 0.05 vs. placebo. The data are presented as estimate (SE) unless stated otherwise. Baseline measures are analysed using the ANOVA model. Post-baseline data is analysed using the MMRM model. BL, baseline; ANOVA, analysis of variance; CI, confidence interval; Cr-Cys-C-eGFR, creatinine-cystatin-C-based estimated glomerular filtration rate; ETD, estimated treatment difference; IQR, interquartile range; LSM, least squares mean; MMRM, mixed model for repeated measures; N, number of participants in specific subgroup; PBO, placebo; RASi, using renin-angiotensin-system inhibitor; SE, standard error; TZP, tirzepatide; UACR, urine albumin-creatinine ratio. Figure S2: Changes in eGFR (CKD-EPI Creatinine-Cystatin Equation 2021) in participants with prediabetes at baseline. Estimated treatment difference (EDT) at Week 176 for subgroup analysis by tirzepatide treatment group (5, 10 or 15 mg), for participants with Creatinine-Cystatin C eGFR < 90 mL/min/1.73 m2 at baseline, Creatinine-Cystatin C eGFR ≥ 90 mL/min/1.73 m2 at baseline, for participants with UACR < 30 mg/g at baseline, UACR ≥ 30 mg/g at baseline, and prescription of RASi at baseline. Data are presented as LS Mean (95% CI) (tirzepatide groups and Creatinine-Cystatin C eGFR < 90 and ≥ 90 mL/min/1.73 m2 groups) or MBE (95% CI) (UACR < 30 mg/g at baseline, UACR ≥ 30 mg/g at baseline, and prescription of RASi at baseline groups); CI, confidence interval; Cys-C-eGFR, cystatin-C-based estimated glomerular filtration rate; ETD, estimated treatment difference; MBE, model-based estimate, N, total number of participants in specific subgroup included in analysis; RASi, using renin-angiotensin-system inhibitor; TZP, tirzepatide, UACR, urinary albumin-to-creatinine ratio. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.