Tirzepatide vs Dulaglutide May Reduce Major Kidney Events in High-Risk CKD With T2DM

Among patients with high-risk chronic kidney disease (CKD), type 2 diabetes, and atherosclerotic cardiovascular disease (ASCVD), tirzepatide may reduce risks for kidney function decline, albuminuria increases, and composite major kidney events compared with dulaglutide. Sophia Zoungas, MBBS, PhD, academic director of the Monash University Clinical Trials Centre and head of the School of Public Health and Preventive Medicine in Melbourne, Australia, presented data on these most vulnerable patients in prespecified post hoc analyses of the SURPASS-CVOT trial at the American Society of Nephrology’s Kidney Week 2025 in Houston, Texas.

Tirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor, whereas dulaglutide targets the GLP-1 receptor only. “Tirzepatide has been shown to improve glycemic control and weight loss compared with GLP-1 receptor agonists,” Dr Zoungas said. “Benefits have also been observed for atherogenic lipoproteins, improvements in blood pressure, highly sensitive C-reactive protein, albuminuria, and kidney function.” 

The SURPASS-CVOT trial (Clinicaltrials.gov, NCT04255433) was designed to test the efficacy of tirzepatide. Among the 13,165 trial participants, 1241 patients had very high-risk CKD:

• an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m² or 
• an eGFR of 30 to less than 45 mL/min/1.73m² plus any albuminuria or 
• an eGFR of 45 to less than 60 mL/min/1.73 m² and macroalbuminuria.

Mean patient age was 68.5 years. Mean body mass index was 33.0 kg/m². Mean hemoglobin A1c was 8.5%, and diabetes duration was 19.2 years. A quarter of patients took an SGLT2 inhibitor, which was newly approved during the trial. Patients were otherwise well treated with statins (86.5%), angiotensin-converting enzyme inhibitors (30.9%), and angiotensin receptor blockers (52.1%), mineralocorticoid receptor antagonist (13.6%), and insulin (68.8%). 

Over 36 months, eGFR declined more slowly with tirzepatide compared with dulaglutide: -3.0 vs -7.2 mL/min per 1.73m² — a significant difference of 4.1 mL/min per 1.73m². 

UACR decreased significantly more with tirzepatide: -45.6 vs -28.0 g/kg. 

The composite kidney events outcome included onset of macroalbuminuria, a 50% or greater decline in eGFR, end-stage kidney disease, or kidney-related death. Risk for the composite kidney outcome was 33% lower (HR 0.67, 95% CI 0.52 to 0.87, P=0.002) with tirzepatide than dulaglutide: 16.7% vs 23.0%. By individual component, tirzepatide appeared to significantly reduce the risks for persistent macroalbuminuria and halving of eGFR. 

Drug discontinuation was 30.0% in the tirzepatide group compared with 28.2% in the dulaglutide group. The investigators found comparable rates of any treatment emergent adverse events (TEAEs: 95.7% vs 94.7%) and serious AEs (60.8% vs 63.5%). However, tirzepatide use led to more gastrointestinal AEs (64.6% vs 58.5%) and severe gastrointestinal events (7.5% vs 5.3%). Nausea, vomiting, and diarrhea were more frequent in the tirzepatide group. 

“We think that this data adds to the growing body of evidence that these agents are kidney protective and really should be part of the contemporary management and prevention of CKD,” Dr Zoungas said. “Within that [GLP1-RA] class, dual agonists are likely to have greater effects.” 

Dr Zoungas added that investigators are now looking at triple agonists and newer agents that might have greater, broader, and/or additive effects. Beyond Hb1Ac reduction and weight loss, there may be indirect effects such as on inflammation.

Disclosure: This research was supported by Eli Lilly and Company. Please see the original reference for a full list of disclosures.