Once-weekly injection of tirzepatide, a dual GIP and GLP-1 receptor antagonist, slowed eGFR* decline and reduced UACR** in patients with type 2 diabetes (T2D) who are at high risk of cardiovascular (CV) disease compared with once-daily insulin glargine (iGlar), according to a prespecified post hoc analysis of the SURPASS-4*** trial presented at EASD 2022.
“People with T2D at high CV risk frequently have chronic kidney disease and are at risk for deterioration of kidney function and related complications … In this kidney-specific exploratory analysis, … [our] findings suggest that tirzepatide has kidney-protective effects [in this patient population],” said Professor Hiddo Heerspink from the Department of Clinical Pharmacy and Pharmacology at University Medical Center Groningen in Groningen, Netherlands.
This open-label, phase III trial involved 1,995 adults (mean age 63.6 years, 62.0 percent male) with T2D (mean HbA1c 8.52 percent) who were treated with any combination of metformin, sulfonylurea, or SGLT2+ inhibitor. Baseline mean eGFR was 81.3 mL/min/1.73 m2 and median UACR was 15.0 mg/g. Participants were randomly assigned to receive either subcutaneous injection of tirzepatide at a dose of 5, 10, or 15 mg once weekly (n=995) or titrated iGlar 100 U/mL once daily (n=1,000) for up to 104 weeks. Twenty-eight percent of participants had microalbuminuria (UACR 30–300 mg/g) and 8 percent had macroalbuminuria (UACR >300 mg/g) in each group. [EASD 2022, abstract 167; Lancet Diabetes Endocrinol 2022:doi:10.1016/S2213-8587(22)00243-1]
At week 104, annual eGFR decline was slower among participants receiving tirzepatide than those receiving iGlar (mean, -1.4 vs -3.6 mL/min/1.73 m2 per year), yielding a between-group difference of 2.2 mL/min/1.73 m2 per year.
The reduction in eGFR decline per year was even more pronounced among tirzepatide-treated patients with an eGFR of <60 vs ≥60 mL/min/1.73 m2 (mean, 0.5 vs -1.4 mL/min/1.73 m2).
UACR among tirzepatide recipients dropped from baseline to week 104 (mean percentage change, -4.4 percent), whereas those on iGlar had an increase of 56.7 percent (between-group difference, -39.0 percent; p<0.0001).
The advantage of tirzepatide over iGlar remained regardless of SGLT2 inhibitor use (mean, -1.2 vs -3.2 mL/min/1.73 m2 [reduction in eGFR decline] and -7.9 percent vs 55.2 percent [percentage change in UACR]) or nonuse (mean, -1.5 vs -3.8 mL/min/1.73 m2 and -10.4 percent vs 26.6 percent, respectively) at baseline.
“[This] is clinically important, as SGLT2 inhibitors are recommended by clinical practice guidelines and are part of the standard of care for kidney protection in addition to renin-angiotensin system inhibition,” said the researchers.
Furthermore, the incidence of the composite kidney endpoint (new-onset of macroalbuminuria, ≥40 percent decline in eGFR, end-stage kidney disease, or renal death) was significantly lower among patients treated with tirzepatide compared with those receiving iGlar (63 vs 104 events; hazard ratio, 0.58; p=0.00075). “[T]his effect appears to be largely driven by a reduction in new-onset macroalbuminuria,” the researchers noted.
“[Overall,] these data suggest that in people with T2D and high CV risk, tirzepatide slowed the progression of diabetic kidney disease compared with iGlar,” said Heerspink.
“These data support doing long-term clinical trials to assess the effect of dual GIP and GLP-1 receptor agonist therapies on kidney protection in people at risk of progressive kidney function loss, including those with T2D,” they added.
*eGFR: Estimated glomerular filtration rate
**UACR: Urine albumin-creatinine ratio
***SURPASS-4: A study of tirzepatide (LY3298176) once a week versus insulin glargine once a day in participants with type 2 diabetes and increased cardiovascular risk
+SGLT2: Sodium-glucose cotransporter 2