Tirzepatide slowed kidney function decline in SURPASS-4 analysis of adults with type 2 diabetes

At the American Diabetes Association's 82nd Scientific Sessions in New Orleans, researchers presented a prespecified analysis of the SURPASS-4 trial showing that tirzepatide (Mounjaro) slowed loss of kidney function and reduced new or worsening albuminuria compared with insulin glargine in adults with type 2 diabetes at high cardiovascular risk ^[1][2]. Tirzepatide, a dual GIP/GLP-1 receptor agonist, was approved by the FDA in May 2022 to improve blood sugar in adults with type 2 diabetes ^[1].

SURPASS-4 compared three doses of tirzepatide (5 mg, 10 mg and 15 mg) with titrated insulin glargine in an open-label trial ^[2]. The 2,002 adults enrolled were taking at least one oral diabetes medicine — metformin, a sulfonylurea or an SGLT2 inhibitor — and were at high risk for cardiovascular events ^[1][2]. Of those, 1,995 received at least one dose and formed the analysis group, with a mean age of 63.6 years, a mean HbA1c of 8.5% and a mean estimated glomerular filtration rate (eGFR) of 81.3 mL/min/1.73 m2 ^[1]. At the start, 17% had an eGFR below 60 mL/min/1.73 m2, 28% had microalbuminuria (a urine albumin-to-creatinine ratio, or UACR, of 30 to 300 mg/g), and 8% had a UACR above 300 mg/g ^[1]. Participants were followed for up to 104 weeks, with a median of 85 weeks ^[1].

The primary composite kidney outcome was a decline in eGFR of at least 40% from baseline, renal death, progression to end-stage renal disease, or new-onset macroalbuminuria ^[1]. Participants assigned tirzepatide (n = 995) had a 41% lower risk of that outcome than those assigned insulin glargine (n = 1,000), a hazard ratio of 0.59 (95% CI, 0.43-0.8) ^[1][2]. Risk of new-onset macroalbuminuria fell by nearly 60% (HR = 0.41; 95% CI, 0.26-0.66) ^[1][2]. A second composite that excluded macroalbuminuria showed a 20% risk reduction (HR = 0.80; 95% CI, 0.53-1.22), a range that crosses 1.0 ^[2].

Subgroup results pointed in the same direction: HR 0.57 (95% CI, 0.4-0.81) among participants not taking an SGLT2 inhibitor at baseline; HR 0.47 (95% CI, 0.31-0.71) among those with a UACR of at least 30 mg/g; and HR 0.46 (95% CI, 0.23-0.93) among those with an eGFR below 60 mL/min/1.73 m2 ^[1]. A separate account of the presentation described the benefit as consistent across subgroups, including people with moderate or severely reduced kidney function and those at high risk for kidney-related outcomes ^[2].

"The most surprising finding is the profound effect of tirzepatide to slow eGFR decline even when given on top of SGLT2 inhibitors and/or RAAS inhibition," presenter Hiddo J.L. Heerspink, PhD, a clinical pharmacologist and trialist at the University Medical Center Groningen in the Netherlands, said ^[1]. He said the data "support the potential of tirzepatide to reduce the risk of clinically meaningful kidney endpoints and encourage future trials in patients with type 2 diabetes and CKD" ^[1].

In a separate commentary, George L. Bakris, MD, of University of Chicago Medicine, wrote that albuminuria reflects inflammation throughout the body, not only in the kidney, and that drugs producing significant weight loss — including semaglutide (Wegovy) and liraglutide (Saxenda) — have been shown to reduce albuminuria. He said the open question is whether tirzepatide will prove better than GLP-1 receptor agonists given its additional mechanism ^[1]. Bakris reported receiving honoraria from AstraZeneca, Merck, Novo Nordisk and Relypsa ^[1].

Why it matters for patients

Kidney function in diabetes is tracked mainly through blood and urine tests such as eGFR and a urine albumin-to-creatinine ratio ^[1]. In this analysis, the group taking tirzepatide had fewer of those warning signs than the group taking insulin glargine.

Several limits are worth knowing. This was a prespecified exploratory analysis of a trial built mainly to compare blood sugar control and safety, not a trial designed around kidney outcomes ^[1][2]. The sources do not report how many individual participants reached end-stage renal disease or died from kidney causes. Whether the difference comes from better blood sugar control, from weight loss, or from a direct effect of the drug on the kidney has not been reported. The comparison was against insulin glargine; a head-to-head comparison with a GLP-1 receptor agonist such as semaglutide has not been reported, and Bakris raised that as an open question ^[1].

Participants in SURPASS-4 all had type 2 diabetes and high cardiovascular risk, and the sources do not report kidney results in people without those characteristics.

What happens next

The kidney analysis was presented at the ADA Scientific Sessions, held June 3-7, 2022, in New Orleans as a hybrid meeting ^[1]. Heerspink said the findings encourage future trials in patients with type 2 diabetes and chronic kidney disease ^[1]; whether such a trial is planned has not been disclosed. The FDA's May 2022 approval of tirzepatide covered improvement of blood sugar in adults with type 2 diabetes ^[1], and the sources do not say whether the kidney findings have been added to the drug's label.