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SURPASS-4 trial: Tirzepatide slows rate of eGFR decline and reduces UACR in T2DM patients

Updated: Sep 29, 2022

An analysis of the SURPASS-4 trial has reported that type 2 diabetics with high cardiovascular risk who took resulted in a slowed the rate of estimated Glomerular Filtration Rate (eGFR) decline and a reduced urine albumin-creatinine ratio (uACR) in clinically meaningful ways, compared with insulin glargine. The findings were featured in the paper, Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial’, published in The Lancet Diabetes & Endocrinology.

tirzepatide (Mounjaro)

In the SURPASS-4 trial the dual GIP and GLP-1 receptor agonist tirzepatide reduced HbA1c concentrations, bodyweight, and blood pressure more than titrated daily insulin glargine in people with type 2 diabetes inadequately controlled on oral diabetes treatments and with high cardiovascular risk. In this latest analysis, the researchers sought to compare the effects of tirzepatide and insulin glargine on kidney parameters and outcomes in type 2 diabetics.

In this post-hoc analysis of data from SURPASS-4 - a randomised, open-label, parallel-group, phase 3 study at 187 sites (including private practice, research institutes, and hospitals) in 14 countries - eligible participants were adults (age ≥18 years), with type 2 diabetes treated with any combination of metformin, sulfonylurea, or SGLT2 inhibitor, and with baseline HbA1c of 7·5–10·5% (58–91 mmol/mol), BMI of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Randomisation via an interactive web-response system was 1:1:1:3 to a once-weekly subcutaneous injection of tirzepatide (5mg, 10mg, or 15mg) or a once-daily subcutaneous injection of titrated insulin glargine (100U/mL).

The study included up to 104 weeks of treatment, with a median treatment duration of 85 weeks. The research then examined the rates of eGFR decline and the urine albumin–creatinine ratio (UACR) between the combined tirzepatide groups and the insulin glargine group in the modified intention-to-treat population. The kidney composite outcome was time to first occurrence of eGFR decline of at least 40% from baseline, end-stage kidney disease, death owing to kidney failure, or new-onset macroalbuminuria.

In total, 2,002 (66%) were randomly assigned to a study drug (997 to tirzepatide and 1005 to insulin glargine). Of those, 1,995 (>99%) of 2002 received at least one dose of tirzepatide (n=995) or insulin glargine (n=1000). At baseline, participants had a mean eGFR of 81.3 (SD 21·11) mL/min per 1.73m2 and a median UACR of 15.0mg/g (IQR 5·0–55·8). The mean rate of eGFR decline was –1.4 (SE 0.2)mL/min per 1.73m2 per year in the combined tirzepatide groups and –3.6 (0·2) mL/min per 1.73m2 per year in the insulin group (between-group difference 2.2 [95% CI 1.6 to 2.8]).

Compared with insulin glargine, the reduction in the annual rate of eGFR decline induced by tirzepatide was more pronounced in participants with eGFR less than 60 mL/min per 1.73m2 than in those with eGFR 60mL/min per 1.73 m2 or higher (between-group difference 3.7 [95% CI 2.4 to 5.1]). UACR increased from baseline to follow-up with insulin glargine (36.9% [95% CI 26.0 to 48.7]) but not with tirzepatide (–6.8% [–14.1 to 1.1]; between-group difference –31.9% [–37.7 to –25.7]). Participants who received tirzepatide showed a significantly lower occurrence of the composite kidney endpoint, compared with those who received insulin glargine (hazard ratio 0.58 [95% CI 0.43 to 0.80]).

The SURPASS-4 trial was funded by Eli Lilly and Company.

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