Tirzepatide slowed kidney function decline in SURPASS-4 analysis

A post hoc analysis of the SURPASS-4 trial found that tirzepatide slowed the loss of kidney function and kept urine albumin from rising in adults with type 2 diabetes and high cardiovascular risk, compared with insulin glargine. The analysis was published on September 21, 2022, in The Lancet Diabetes & Endocrinology ^[1][2].

SURPASS-4 was a randomized, open-label, phase 3 trial run at 187 sites in 14 countries. It enrolled adults 18 and older whose type 2 diabetes was not well controlled on metformin, a sulfonylurea, an SGLT2 inhibitor, or a combination of those, with HbA1c between 7.5% and 10.5%, a BMI of 25 or higher, and established cardiovascular disease or a high risk of cardiovascular events ^[2].

Of 3,045 people screened, 2,002 were randomly assigned, and 1,995 received at least one dose: 995 took once-weekly tirzepatide at 5, 10, or 15 mg, and 1,000 took once-daily titrated insulin glargine. Treatment ran up to 104 weeks, with a median of 85 weeks ^[2].

At the start, participants' average estimated glomerular filtration rate (eGFR), a standard measure of how well the kidneys filter blood, was 81.3 mL/min/1.73 m2. Their median urine albumin-to-creatinine ratio (UACR), a marker of kidney stress, was 15.0 mg/g ^[2].

Filtration fell by an average of 1.4 mL/min/1.73 m2 per year in the combined tirzepatide groups and 3.6 mL/min/1.73 m2 per year in the insulin group, a difference of 2.2 (95% CI 1.6 to 2.8) ^[2]. The gap was wider among participants who started with an eGFR below 60, a difference of 3.7 (95% CI 2.4 to 5.1) ^[2].

Urine albumin rose 36.9% (95% CI 26.0 to 48.7) with insulin glargine and did not rise with tirzepatide (-6.8%, 95% CI -14.1 to 1.1). The between-group difference was -31.9% (95% CI -37.7 to -25.7) ^[2].

The analysis also tracked a composite kidney endpoint: a first occurrence of eGFR falling at least 40% from baseline, end-stage kidney disease, death from kidney failure, or new-onset macroalbuminuria. That endpoint was 42% less common in the tirzepatide groups (hazard ratio 0.58, 95% CI 0.43 to 0.80) ^[2]. The authors wrote that the results suggest tirzepatide "slowed the rate of eGFR decline and reduced UACR in clinically meaningful ways compared with insulin glargine" in this population ^[2].

Several cautions apply. This was a post hoc analysis, so the kidney comparisons were not the trial's main question when it was designed. The trial was open-label, meaning participants and investigators knew which treatment was given. The study was funded by Eli Lilly and Company, and five of its authors are Lilly employees and shareholders; one serves on a data monitoring committee for tirzepatide ^[2]. A separate commentary in the same journal called the findings "an intriguing and promising observation" ^[2].

Whether these differences mean fewer people eventually need dialysis or a transplant has not been shown. The average participant had fairly preserved kidney function, and no trial designed specifically to test hard kidney outcomes with tirzepatide has reported results.

Why it matters for patients

Kidney filtration and urine albumin are the two measures this analysis used, and both moved in tirzepatide's favor. If differences of that size held up over years, they could mean a later start of kidney complications for some patients, but that has not been demonstrated. The analysis does not show that tirzepatide prevents kidney failure, that it changes the course of kidney disease in people whose eGFR is already low, or that the same effects appear in people without diabetes. The sources do not describe any kidney-related approval or labeling change for tirzepatide.

The comparison was tirzepatide versus insulin glargine. Semaglutide was not tested here, so this analysis does not show how tirzepatide compares with semaglutide on kidney measures. People taking either drug who want to know how their kidney numbers are tracked can ask their clinician which tests are being used and how often, since eGFR and UACR are the markers this trial followed. The trial registry number is NCT03730662 ^[2].