Semaglutide Lowers Risk of Major Kidney Outcomes, Cardiovascular Events, Death in Patients With Diabetes and CKD

In patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), semaglutide reduced the risk of clinically important kidney outcomes, major cardiovascular events, and death from any cause by 24%, according to a study published in The New England Journal of Medicine.¹

To come to these findings, researchers randomly assigned 3533 patients with T2D and CKD to receive either 1.0 mg of subcutaneous semaglutide weekly (n = 1767) or placebo (n = 1766). CKD was defined by an estimated glomerular filtration rate (eGFR) of 50 to 75 mL/min/1.73 m² with a urinary albumin-to-creatinine ratio of 300 to 5000 mg/g, or an eGFR of 25 to less than 50 mL/min/1.73 m² with a urinary albumin-to-creatinine ratio of 100 to 5000 mg/g.

The primary outcome measured was major kidney disease events, including the onset of kidney failure—defined as dialysis, transplantation, or an eGFR of less than 15 mL/min/1.73 m²—a reduction of eGFR by at least 50% from baseline, or death from kidney-related or cardiovascular causes. Hierarchical testing was used for prespecified confirmatory secondary outcomes. The median follow-up was 3.4 years, translating to about 177 weeks of semaglutide for the treatment group.

Semaglutide injections | Image credit: Patrick Bay Damsted – stock.adobe.com

Compared with placebo, patients who took the weekly glucagon-like peptide 1 (GLP-1) receptor agonist experienced a 24% lower risk of primary outcome events, with 331 events in the treatment group and 410 in the placebo group (HR, 0.76; 95% CI, 0.66-0.88; P = .0003).

Specifically, these patients were 21% less likely to experience the kidney-related primary outcomes (HR, 0.79; 95% CI, 0.66-0.94) and 29% less likely to die due to cardiovascular causes (HR, 0.71; 95% CI, 0.56-0.89).

All confirmatory secondary outcomes also favored semaglutide. The mean annual eGFR slope decline was slower by 1.16 mL/min/1.73 m² (P < .001), the risk of major cardiovascular events was 18% lower (HR, 0.82; 95% CI, 0.68-0.98; P = .029), and the risk of death from any cause was 20% lower (HR, 0.80; 95% CI, 0.67-0.95; P = .01) in the treatment arm.

“These benefits reflect important clinical effects on kidney, cardiovascular, and survival outcomes among high-risk patients, particularly given the reassuring safety findings, and support a therapeutic role for semaglutide in this population,” the researchers said.

Additionally, fewer participants in the semaglutide arm (49.6%) experienced serious adverse events compared with the placebo group (53.8%), although the researchers noted this was mainly because fewer participants in the semaglutide group were reported to have serious infections or infestations (17.9% vs 21.3%) or serious cardiovascular disorders (15.4% vs 18.1%). Serious eye disorders were more frequent in the semaglutide group compared with the placebo group (3.0% vs 1.7%), while the occurrence of diabetic retinopathy events was similar between the groups (22.8% vs 22.5%). Adverse events leading to the permanent discontinuation of treatment were more common with semaglutide (13.2%) than with placebo (11.9%), primarily due to gastrointestinal disorders (4.5% vs 1.1%).

Given the benefits of renin-angiotensin system (RAS) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid-receptor antagonism with finerenone for patients with T2D and CKD, clinicians and patients must carefully prioritize the use of semaglutide and other GLP-1 receptor agonists once studied, according to the researchers. While SGLT2 inhibitors have shown significant benefits for kidney outcomes, their effects on major cardiovascular events and mortality in this population have been mixed in prior research. With a favorable safety profile, the benefits demonstrated in the new study support the consideration of semaglutide as an initial therapeutic option alongside other proven therapies for patients with T2D and CKD.

“Combination therapy is likely to be important in the future, and we found no clear heterogeneity of effect among patients receiving SGLT2 inhibitors at baseline as compared with those who were not, although the statistical power of this analysis was limited,” the researchers added. “Further analyses of these data are planned, and studies assessing approaches to combination therapy should be a priority.”

This study was funded by Novo Nordisk, a manufacturer of Wegovy (semaglutide).

This news comes a few months after the FDA added another indication for semaglutide, expanding its use to reduce the risk of cardiovascular death, heart attack, or stroke in adults who have cardiovascular disease and overweight or obesity.² Also, recent research showed that semaglutide led to significant improvements in exercise capacity, weight loss, and a number of secondary end points in patients with heart failure with preserved ejection fraction and obesity.³ In that study, patients taking the GLP-1 receptor agonist for a year lost 2.9% more body weight compared with patients taking placebo.

Reference

1. Perkovic V, Tuttle KR, Rossing P, et al. 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
2. Mattina C. FDA approves semaglutide to prevent heart events in patients with CVD and excess weight. AJMC^®. March 8, 2024. Accessed May 24, 2024. https://www.ajmc.com/view/fda-approves-semaglutide-to-prevent-heart-events-in-patients-with-cvd-and-excess-weight
3. Klein HE. Semaglutide linked to improved exercise capacity, weight loss in patients with HFpEF and obesity. AJMC. May 20, 2024. Accessed May 24, 2024. https://www.ajmc.com/view/semaglutide-linked-to-improved-exercise-capacity-weight-loss-in-patients-with-hfpef-and-obesity