Tirzepatide slowed kidney function decline versus insulin glargine in SURPASS-4 analysis
A post-hoc look at the SURPASS-4 trial found slower kidney filtration decline and no rise in urine protein on tirzepatide compared with insulin glargine.
People with type 2 diabetes at high cardiovascular risk who received tirzepatide in the SURPASS-4 trial lost kidney filtration more slowly than those who received insulin glargine, according to a post-hoc analysis published in The Lancet Diabetes & Endocrinology [1].
Tirzepatide is the molecule in Mounjaro and Zepbound. It acts on two gut hormone receptors, GIP and GLP-1, and was given as a weekly injection; insulin glargine was given daily and adjusted to target [1]. SURPASS-4 was an open-label, phase 3 randomized trial at 187 sites in 14 countries, meaning participants and their doctors knew which treatment was being used [1].
Volunteers could join if they were 18 or older, had type 2 diabetes not adequately controlled on metformin, a sulfonylurea, an SGLT2 inhibitor, or some mix of those, and either already had cardiovascular disease or faced a high risk of a cardiovascular event [1]. Starting HbA1c ranged from 7.5% to 10.5%, and BMI was at least 25 [1]. Screening took place between Nov 20, 2018, and Dec 30, 2019 [1]. Of 3,045 people screened, 1,043 were ineligible and 2,002 were assigned to tirzepatide 5, 10, or 15 mg weekly or to insulin glargine [1]. A total of 1,995 received at least one dose: 995 on tirzepatide and 1,000 on insulin glargine [1]. Treatment ran as long as 104 weeks, with a median of 85 weeks [1].
At the start, average eGFR was 81.3 mL/min per 1.73 m2 and median urine albumin-to-creatinine ratio (UACR) was 15.0 mg/g [1]. eGFR fell by roughly 1.4 mL/min per 1.73 m2 each year across the combined tirzepatide groups and 3.6 in the insulin group, a difference of 2.2 (95% CI 1.6 to 2.8) [1]. That gap was wider among people who began with eGFR below 60, at 3.7 (95% CI 2.4 to 5.1) [1].
UACR, a sign of protein escaping into urine, rose 36.9% (95% CI 26.0 to 48.7) on insulin glargine while showing no increase on tirzepatide (-6.8%, 95% CI -14.1 to 1.1); the between-group difference was -31.9% (95% CI -37.7 to -25.7) [1]. A combined kidney measure — first occurrence of eGFR dropping at least 40%, end-stage kidney disease, death from kidney failure, or new-onset macroalbuminuria — was less frequent with tirzepatide (hazard ratio 0.58, 95% CI 0.43 to 0.80) [1]. How many people in each arm actually reached that endpoint has not been reported.
The authors wrote that their work "suggests that in people with type 2 diabetes and high cardiovascular risk, tirzepatide slowed the rate of eGFR decline and reduced UACR in clinically meaningful ways compared with insulin glargine" [1]. Because the kidney comparison was post-hoc, it was run after the trial ended using data gathered for other purposes, and the open-label design is a further limitation [1]. Eli Lilly funded SURPASS-4; several authors are Lilly employees and shareholders, and other authors report grants, consulting fees, or speaking fees from Lilly and other drugmakers [1].
Why it matters for patients
eGFR and UACR are standard blood and urine tests that many people with type 2 diabetes already get, and both track how kidneys are holding up over years [1]. In this trial, one group's filtration slipped about twice as fast as the other's, and the protein leak that signals kidney stress grew on insulin glargine but not on tirzepatide [1]. The combined kidney endpoint used here includes end-stage kidney disease and death from kidney failure, outcomes with direct consequences for patients [1].
What these results do not show is how any single person would fare. They are group averages from one analysis of one trial, event counts by group are not given, and the publication does not describe tirzepatide as a kidney disease treatment or report any regulatory decision on a kidney indication [1]. Whether the difference comes from tirzepatide itself, from better blood sugar and weight control, or from other effects has not been established here [1]. Comparisons with GLP-1 medications or SGLT2 inhibitors were not part of this analysis [1].
What happens next
SURPASS-4 is registered with ClinicalTrials.gov as NCT03730662 [1]. The same journal issue carried a commentary titled "Tirzepatide and kidney function: an intriguing and promising observation" [1]. A dedicated kidney-outcome trial of tirzepatide has not been disclosed in the publication [1].
Sources
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