Renal and Cardiovascular Benefits of Semaglutide in Type 2 Diabetes With CKD

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The glucagon-like peptide-1 receptor agonist semaglutide improves renal outcomes and reduces cardiovascular mortality in patients with type 2 diabetes and chronic kidney disease (CKD), reports a clinical trial in The New England Journal of Medicine.

A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW), an international, multicenter trial, enrolled 3533 patients (mean age, 67 years) with type 2 diabetes and CKD. Eligible patients had an estimated glomerular filtration rate (eGFR) of 50 to 75 mL/min/1.73 m2 with a urinary albumin to creatinine ratio of >300 and <5000 or an eGFR of 25 to <50 mL/min/1.73 m2 with a urinary albumin to creatinine ratio of >100 and <5000.

Participants were randomly assigned to receive subcutaneous semaglutide (1.0 mg weekly) or placebo. Primary outcomes were major kidney disease events, a composite of kidney failure, 50% or greater reduction in eGFR, or death from renal or cardiovascular causes.

The trial was halted at a median follow-up of 3.4 years based on the results of a prespecified interim analysis of efficacy. At that time, the primary outcome event rate was 5.8 per 100 patient-years with semaglutide versus 7.5 per 100 patient-years with placebo (hazard ratio [HR], 0.76). Similar patterns were shown for a composite of kidney-specific components of the primary outcome (HR, 0.79) and for death from cardiovascular causes (HR, 0.71).

Semaglutide also improved secondary outcomes, including a 1.16-mL/min/1.73 m2 decrease in the mean annual eGFR slope. Major cardiovascular events (HR, 0.82) and all-cause mortality (HR, 0.80) also decreased. Numbers needed to treat were 45 to prevent one major cardiovascular event and 39 to prevent one death.

Patients in the semaglutide group had greater reductions in body weight (mean difference, 4.10 kg), glycated hemoglobin, and systolic blood pressure. Semaglutide was also associated with a lower rate of serious adverse events, mainly reflecting fewer events related to infections or cardiovascular disorders.

Previous studies of glucagon-like peptide-1 receptor agonists in type 2 diabetes have not addressed clinically important kidney outcomes. The FLOW trial “provides confidence that the use of semaglutide in patients with type 2 diabetes and chronic kidney disease will reduce the risk of kidney failure and slow the decline in the eGFR, as well as reduce the risk of cardiovascular events and death,” the researchers write. They discuss the mechanisms of semaglutide's kidney-protective effects, which are likely multifactorial [Perkovic V, et al.; FLOW Trial Committees and Investigators. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med, published online May 24, 2024. doi: 10.1056/NEJMoa2403347].

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