Tirzepatide Use Can Slow Progression of CKD in Type 2 Diabetes

Hiddo Heerspink, PhD, PharmD

A prespecified analysis of the SURPASS-4 trial suggests the effects of tirzepatide may go beyond weight loss and glucose control, indicating use of the novel GIP/GLP-1 receptor agonist was associated with a slower progression of chronic kidney disease in patients with type 2 diabetes and increased cardiovascular risk.

Presented at the American Diabetes Association (ADA) 82nd Scientific Sessions, results of the analysis suggest use of tirzepatide was associated with a 41% reduction in risk for a composite of a 40% or greater decline in eGFR, renal death, progression to end-stage renal disease (ESRD), and new onset macroalbuminuria compared against titrated daily insulin glargine therapy, with the risk of new-onset of macroalbuminuria decreased by reduced by nearly 60% compared to insulin.

“With these exploratory findings of SURPASS-4, we are seeing the results of combined GIP/GLP-1 receptor agonists on the kidney function of patients with type 2 diabetes for the very first time,” said study presented H.J. L. Heerspink, PhD, PharmD, of the University Medical Center Groningen, Netherlands, in a statement from the ADA. “The findings will be of interest to physicians treating people with diabetes who may have chronic kidney disease.”

A set of 5 trials, which were used as the basis for the FDA’s approval of tirzepatide, the SURPASS program demonstrated the ability of the first-in-class agent against placebo therapy, insulin regimens, and GLP-1 receptor agonists. SURPASS-4 represented the largest and longest clinical trial in the program.

An open-label global trial, SURPASS-4 was designed to compare the safety and efficacy of three tirzepatide in 5 mg, 10 mg, and 15 mg doses to titrated insulin glargine in 2,002 adults with type 2 diabetes with increased cardiovascular risk who were treated with at least 1 oral antihyperglycemic medicine, including metformin, a sulfonylurea, or an SGLT-2 inhibitor.

Of the 2002 adults who underwent randomization, 1995 received at least 1 dose of tirzepatide or insulin glargine and 1706 completed the 104-week study on treatment. Results of SURPASS-4 indicated all 3 doses of tirzepatide provided statistically significant and superior HbA1c and body weight reductions compared to insulin glargine at 52 weeks.

The 1995 patients who received at least 1 dose were considered the study cohort of interest for the prespecified analysis. At baseline, these patients had a mean age of 63.6 years, a mean HbA1c of 8.5%, and a mean eGFR of 81.3 mL/min/1.73m2. Investigators also pointed out 17% had eGFRbelow 60 mL/min/1.73m2, 28% microalbuminuria, and 8% macroalbuminuria. Of note, microalbuminuria was defined as an UACR of 30-300 mg/g and macroalbuminuria was defined as an UACR exceeding 300 mg/g.

In the ADA 2022 presentation, Heerspink detailed the prespecified exploratory analysis, which was aimed at assessing progression to prespecified kidney endpoints between tirzepatide and insulin glargine. The primary outcomes of interest for the analysis were composite outcomes that consisted of a decline of 40% or more in eGFR from baseline, renal death, and progression to ESRD analyzed with and without new-onset macroalbuminuria as an additional component.

The analysis also included plans to examine this association in multiple subgroups defined by baseline use of SGLT2 inhibitors, an UACR of 30 mg/g or greater, an eGFR of less than 60 mL/min/1.73m2, and those at high risk for kidney-related outcomes, which was defined as having an eGFR of less than 75 mL/min/1.73m2 and macroalbuminuria, or eGFR less than 45 mL/min/1.73m2.

When assessing 104-week outcomes, results indicated use of tirzepatide was associated with a 41% reduction in risk of the first composite endpoint (HR, 0.59 [95% CI, 0.43-0.80]), which included new-onset macroalbuminuria, and a 20% reduction in risk for the second composite outcome (HR, 0.80 [95% CI, 0.53-1.22]), which did not include new onset of macroalbuminuria. Subgroup analyses suggested the benefit of tirzepatide for reducing risk of either primary composite outcome was consistent across all subgroups, including those with moderate or severely reduced kidney function, those at high-risk for kidney-related outcomes, with or without baseline albuminuria at or exceeding 30 mg/g, and according to baseline SGLT2 inhibitor use.

This study, “Effects of Tirzepatide vs. Insulin Glargine 100 U/mL on Kidney Outcomes in Participants with Type 2 Diabetes in SURPASS-4,” was presented at ADA 2022.