A comparison of the effects of tirzepatide and dulaglutide on major kidney events in people with type 2 diabetes: pre-specified exploratory analyses of the SURPASS-CVOT trial

Background In the SURPASS-CVOT trial, tirzepatide, a dual incretin agonist that targets the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, was shown to be non-inferior to dulaglutide for the primary composite cardiovascular outcome in people with type 2 diabetes and atherosclerotic cardiovascular disease. Here, we report the results of a pre-specified exploratory analysis of SURPASS-CVOT that aimed to assess major kidney events in the overall population, low-to-moderate-risk chronic kidney disease population, and high-risk chronic kidney disease population. Methods SURPASS-CVOT was a randomised, active comparator-controlled, double-blind trial that enrolled people with type 2 diabetes and atherosclerotic cardiovascular disease at 640 sites in 30 countries. Participants aged 40 years or older with type 2 diabetes and atherosclerotic cardiovascular disease, HbA 1c between 7% and 10·5%, and a BMI of 25 kg/m 2 or greater were randomly assigned 1:1 to once-weekly blinded subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1·5 mg. Annual visits included assessment of serum creatinine, cystatin C, and urine albumin-to-creatinine ratio (UACR). High-risk chronic kidney disease was defined by an estimated glomerular filtration rate (eGFR) of 60 mL/min per 1·73 m 2 or greater and UACR greater than 300 mg/g; eGFR 45 mL/min per 1·73 m 2 to less than 60 mL/min per 1·73 m 2 and UACR greater than 30 mg/g; or eGFR less than 45 mL/min per 1·73 m 2 , with eGFR calculated with the CKD-Epidemiology Collaboration serum creatinine-cystatin C equation. The primary composite kidney outcome was time to first occurrence of persistent macroalbuminuria, persistent reduction in eGFR of 50% or greater, end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 or initiation of chronic kidney replacement therapy), or death from kidney disease. Findings Between May 29, 2020, and June 27, 2022, 16 979 participants were screened and 13 299 (2948 with high-risk chronic kidney disease) were randomly assigned. After excluding 134 participants randomly assigned in error, 6586 were assigned to tirzepatide and 6579 were assigned to dulaglutide. At baseline, 4142 (32·0%) of 12 954 participants had microalbuminuria and 1491 (11·5%) of 12 954 had macroalbuminuria, and 2928 (22·5%) of 13 004 had an eGFR less than 60 mL/min per 1·73 m 2 . After a median follow-up of 4·0 (IQR 3·7–4·4) years, the risk of the primary composite kidney outcome in the overall population was 23% lower with tirzepatide than with dulaglutide (396 [6·0%] vs 498 [7·6%] events, hazard ratio 0·77 [95% CI 0·68 to 0·88], p=0·0002) and was similarly reduced in those with low-to-moderate-risk chronic kidney disease (195 [4·0%] vs 283 [5·6%], 0·70 [0·58 to 0·84], p=0·0001) and those with high-risk chronic kidney disease (185 [12·2%] vs 203 [14·5%], 0·79 [95% CI 0·64 to 0·96], p=0·018). This was primarily driven by a lower rate of new-onset persistent macroalbuminuria in those with low-to-moderate-risk chronic kidney disease and a lower rate of eGFR decline in those with high-risk chronic kidney disease. Observations were consistent in all other subgroups examined. The annual rate of decline in eGFR was lower with tirzepatide than with dulaglutide in the overall population (between-group difference 0·29 mL/min per 1·73 m 2 [95% CI 0·17 to 0·41]; p<0·0001) and in those with high-risk chronic kidney disease (0·93 mL/min per 1·73 m 2 [0·65 to 1·22], p<0·0001). Nausea, vomiting, and diarrhoea were all more common in those receiving tirzepatide than in those receiving dulaglutide. Interpretation Among people with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was associated with a reduced risk of major kidney events compared with dulaglutide, primarily driven by a reduction in new-onset macroalbuminuria in people with low-to-moderate-risk chronic kidney disease, and slowed decline in kidney function in people with high-risk chronic kidney disease. Funding Eli Lilly and Company.