SURPASS-4 post hoc analysis shows slower kidney decline with tirzepatide than insulin

Researchers reanalyzing data from the SURPASS-4 trial reported that people with type 2 diabetes who took tirzepatide lost kidney filtering capacity more slowly than those treated with titrated insulin glargine, and did not show the rise in urine protein seen in the insulin group ^[1]. The analysis was published in The Lancet Diabetes & Endocrinology and funded by Eli Lilly and Company ^[1].

What the trial tested

SURPASS-4 was a randomized, open-label, phase 3 study run at 187 sites in 14 countries, including private practices, research institutes and hospitals ^[1]. Participants were adults with type 2 diabetes that was not adequately controlled on metformin, a sulfonylurea, an SGLT2 inhibitor, or some combination of those drugs, with a baseline HbA1c of 7.5–10.5% (58–91 mmol/mol), a BMI of 25 kg/m2 or higher, and either established cardiovascular disease or a high risk of cardiovascular events ^[1].

Between Nov 20, 2018, and Dec 30, 2019, investigators screened 3,045 people; 1,043 (34%) were ineligible and 2,002 (66%) were randomly assigned in a 1:1:1:3 ratio to once-weekly tirzepatide at 5 mg, 10 mg or 15 mg, or to once-daily titrated insulin glargine 100 U/mL ^[1]. Of those, 1,995 (more than 99%) received at least one dose — 995 on tirzepatide and 1,000 on insulin glargine ^[1]. Treatment ran up to 104 weeks, with a median duration of 85 weeks ^[1]. The trial is registered as NCT03730662 ^[1].

The kidney findings

At the start, participants had a mean estimated glomerular filtration rate (eGFR) of 81.3 mL/min per 1.73 m2 (SD 21.11) and a median urine albumin-to-creatinine ratio (UACR) of 15.0 mg/g (IQR 5.0–55.8) ^[1].

Over the study, eGFR fell by an average of 1.4 mL/min per 1.73 m2 per year (SE 0.2) in the combined tirzepatide groups versus 3.6 (SE 0.2) with insulin glargine — a between-group difference of 2.2 (95% CI 1.6 to 2.8) ^[1]. The gap was wider among participants who started with an eGFR below 60 mL/min per 1.73 m2, where the between-group difference was 3.7 (95% CI 2.4 to 5.1) ^[1].

Urine albumin, a marker of kidney damage, rose 36.9% from baseline in the insulin glargine group (95% CI 26.0 to 48.7) but did not rise with tirzepatide (−6.8%, 95% CI −14.1 to 1.1), for a between-group difference of −31.9% (95% CI −37.7 to −25.7) ^[1].

The analysis also looked at a composite kidney endpoint: time to the first occurrence of an eGFR drop of at least 40% from baseline, end-stage kidney disease, death from kidney failure, or new-onset macroalbuminuria ^[1]. Tirzepatide was associated with a significantly lower rate of that composite, with a hazard ratio of 0.58 (95% CI 0.43 to 0.80) ^[1].

The authors concluded that in people with type 2 diabetes and high cardiovascular risk, tirzepatide slowed eGFR decline and reduced UACR "in clinically meaningful ways" compared with insulin glargine ^[1]. SURPASS-4 had earlier shown that tirzepatide lowered HbA1c, body weight and blood pressure more than titrated daily insulin glargine in this population ^[1].

Why it matters for patients

Kidney disease is one of the most common long-term complications of type 2 diabetes, and eGFR and urine albumin are the two measures doctors track most often. This analysis suggests the choice between adding a weekly tirzepatide injection and adding daily basal insulin may have consequences for those numbers, not just for blood sugar and weight ^[1].

Several limits are worth keeping in mind. This was a post hoc analysis, meaning the kidney comparisons were not the trial's original main question ^[1]. The study was open-label, so participants and clinicians knew which drug was being used ^[1]. Everyone enrolled had high cardiovascular risk and fairly high starting HbA1c, so results may not carry over to people with different profiles ^[1]. The trial was funded by tirzepatide's maker, and several authors are Eli Lilly employees and shareholders ^[1]. An accompanying commentary in the journal called the finding "intriguing and promising" — language that signals the result is suggestive rather than settled ^[1].

The sources do not report whether these kidney differences translate into fewer dialysis starts or deaths over longer follow-up, nor do they address tirzepatide's effects in people without diabetes. Those questions are not yet answered here.

What happens next

The analysis was published online ahead of the November 2022 print issue of The Lancet Diabetes & Endocrinology, along with the commentary ^[1]. Confirming whether tirzepatide protects kidneys would require a trial designed with kidney outcomes as the primary goal; no such trial results appear in these sources.