Tirzepatide Reduced Albuminuria in T2D Patients With Heart Risk

Tirzepatide (Mounjaro) cut the risk for renal events among patients with type 2 diabetes, according to a prespecified exploratory analysis of the SURPASS-4 trial.

Compared with patients on daily insulin glargine 100 U/mL (iGlar), patients on this glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GLP-1/GIP) agonist had a 41% reduced risk for a composite kidney outcome, which included an eGFR decline of 40% or more, renal death, progression to end-stage renal disease (ESRD), or new-onset macroalbuminuria during a maximum 104-week follow-up (HR 0.59, 95% CI 0.43-0.80), reported Hiddo Heerspink, PhD, of the University Medical Center Groningen in the Netherlands.

However when broken down, tirzepatide only appeared to significantly reduce the risk for new-onset macroalbuminuria -- defined as a urine albumin-creatinine ratio (UACR) above 300 mg/g -- cutting it by 59% (HR 0.41, 95% CI 0.26-0.66). Individually, the risks for renal death or an eGFR decline of 40% or more from baseline weren't significantly reduced, Heerspink explained at the American Diabetes Association (ADA) annual meeting.

By week 104, albuminuria increased by 56.7% in insulin glargine-treated patients, while it decreased by 4.4% in tirzepatide-treated patients. Of note, albuminuria decreased by about 20% during the initial 42 weeks of treatment in the tirzepatide group before stabilizing.

"When we look at the effects during the wash-out period, we can see that from the last on-treatment visit to the last visit off-treatment, there was an increase in albuminuria in the tirzepatide arm of about 31%," Heerspink said, noting that the albuminuria levels continued to steadily increase in the insulin arm.

"This tells me that the initial reduction in albuminuria is a real pharmacological effect," he added.

Baseline use of an SGLT2 inhibitor also appeared to play a role in the reno-protective benefits of tirzepatide. More specifically, patients who were using an SGLT2 inhibitor at baseline didn't see a significant renal benefit over insulin glargine for any of the three kidney outcomes. But, in patients not on an SGLT2 inhibitor at baseline, they saw a 63% lower risk for new-onset macroalbuminuria with tirzepatide versus insulin glargine (HR 0.37, 95% CI 0.21-0.65).

As for albuminuria at baseline, tirzepatide significantly reduced the risk for new-onset macroalbuminuria in patients with a UACR of 30 mg/g or higher, as well as those below 30 mg/g, versus insulin.

However, patients with moderate or severely reduced kidney function or those at high risk for kidney-related outcomes didn't see this effect with tirzepatide.

"Collectively, these results indicate that tirzepatide may provide kidney protection," Heerspink said, "and support future research to further evaluate the efficacy of tirzepatide in reducing kidney failure in patients with chronic kidney disease [CKD] and type 2 diabetes."

According to ADA guidelines, GLP-1 receptor agonist treatment is recommended for patients with diabetes and CKD with an eGFR rate less than 60 mL/min/1.73 m² who are also at risk for cardiovascular disease. This class of agents has also been deemed safe for use in patients with late-stage CKD or ESRD.

Tirzepatide was greenlit by the FDA only a few weeks ago, indicated for patients with type 2 diabetes based on the SURPASS clinical program. It is available at three dose levels (5 mg, 10 mg, and 15 mg), should be administered via injection once weekly, and is indicated as an adjunct to diet and exercise.

Another milestone trial also presented at the ADA meeting -- SURMOUNT-1 -- looked at tirzepatide as a potential treatment option for people with overweight or obesity.

For this open-label trial, a total of 1,995 participants with type 2 diabetes were included. This cohort had an average age of 63.6, an HbA1c of 8.5%, and an eGFR of 81.3 mL/min/1.73 m². At baseline, 17% had an eGFR less than 60 mL/min/1.73 m², 28% had microalbuminuria (defined as a UACR of 30-300 mg/g), and 8% had macroalbuminuria.

Half of patients received 5 mg, 10 mg or 15 mg/week of injectable tirzepatide compared with the other half of patients on titrated daily insulin glargine. All participants were considered inadequately controlled on oral diabetes treatments and were at high cardiovascular risk.

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