SURPASS-4: Tirzepatide slows kidney disease in adults with type 2 diabetes, CV risk
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NEW ORLEANS — Tirzepatide, a novel glucose-lowering therapy, reduced urinary albumin secretion and slowed kidney function decline for adults with type 2 diabetes and high cardiovascular risk, according to data from the SURPASS-4 trial.
Tirzepatide (Mounjaro, Eli Lilly), a first-in-class glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist, was approved by the FDA in May to improve glucose response in adults with type 2 diabetes. In a prespecified exploratory analysis of SURPASS-4 data, the drug also showed benefit for patients with chronic kidney disease.
“Tirzepatide ... reduces albuminuria and slows progressive loss of kidney function in patients with type 2 diabetes at high cardiovascular risk,” presenter Hiddo J. L. Heerspink, PhD, professor of clinical trials and personalized medicine and a clinical pharmacologist/trialist in the department of clinical pharmacy and pharmacology at the University Medical Center Groningen in the Netherlands, told Healio. “These 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.”
The open-label SURPASS 4 trial compared the safety and efficacy of three doses of tirzepatide with titrated insulin glargine among adults with type 2 diabetes at high risk for CV events. Participants were on background therapy with one to three oral diabetes medications (metformin, a sulfonylurea or an SGLT2 inhibitor).
Heerspink and colleagues analyzed data from 1,995 participants (mean age, 63.6 years; mean HbA1c, 8.5%; mean estimated glomerular filtration rate, 81.3 mL/min/1.73 m2) who were followed for up to 104 weeks (median 85 weeks). At baseline, 17% of participants had an eGFR below 60 mL/min/1.73 m2; 28% had microalbuminuria with a urine albumin-to-creatinine ratio (UACR) of 30 mg/g to 300 mg/g, and 8% had a UACR greater than 300 mg/g. 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; the same composite without macroalbuminuria was a secondary outcome.
In the entire study population, participants assigned tirzepatide (n = 995) had significantly lower risk for renal outcomes vs. those assigned insulin glargine (n = 1,000), for an HR of 0.59 (95% CI, 0.43-0.8), and for new-onset macroalbuminuria (HR = 0.41; 95% CI, 0.26-0.66). Results were similar among the subgroup of participants who were not using SGLT2 inhibitors at baseline (HR = 0.57; 95% CI, 0.4-0.81). Furthermore, tirzepatide significantly reduced risk for renal outcomes vs. insulin glargine among participants with UARC of at least 30 mg/g (HR = 0.47; 95% CI, 0.31-0.71) and with eGFR less than 60 mL/min/1.73 m2 (HR = 0.46; 95% CI, 0.23-0.93).
“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,” Heerspink said.
“Since many patients with type 2 diabetes and CKD remain at high risk of kidney failure despite optimal guideline therapy, the development of new therapies has to continue. Tirzepatide is a novel drug which may be a promising addition to the current guideline-recommended treatment for CKD,” Heerspink said.
Perspective
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Microalbuminuria is an inflammatory maker reflecting generalized inflammation not just in the kidney, but throughout the body. Obesity in general is associated with increased inflammation and is even more intensified by presence of diabetes. Agents associated with significant weight loss have been demonstrated to reduce albuminuria, as in the case of the GLP-1 receptor agonists semaglutide (Wegovy, Novo Nordisk) and liraglutide (Saxenda, Novo Nordisk). Now we have tirzepatide, a dual receptor agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1.
Thus, the consistent data from this and previous trials suggest real promise in the possibility of reducing the metabolic contribution to inflammation and further reduce risk for cardiorenal outcomes. What would be interesting is to see if blood pressure was also reduced by at least 3 mm Hg to 4 mm Hg with the weight reduction.
I am very optimistic that these data coupled with what we already know about the combinations of RAS blockers, SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists will be a welcome partner to the armamentarium to reduce cardiorenal risk. The question is whether they will be better than GLP-1 receptor agonists given their additional mechanism.
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Heerspink H, et al. 17-OR. Presented at: American Diabetes Association Scientific Sessions; June 3-7, 2022; New Orleans (hybrid meeting).
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