Semaglutide Provides Cardiorenal Benefits in CKD With or Without Diabetes

Semaglutide, a glucagon-like peptide-1 receptor agonist, is linked with significant cardiorenal improvements and a favorable safety profile in adults with chronic kidney disease (CKD), with or without type 2 diabetes mellitus (T2DM).1

Findings from a meta-analysis of 5 randomized controlled trials showed semaglutide significantly reduced the risk of major cardiovascular adverse events (MACE), kidney-related complications, and cardiovascular mortality, additionally pointing to the need to address gaps in the literature and enhance generalizability.1

“Our findings advocate for semaglutide's role as a valuable therapeutic option for patients with CKD due to its demonstrated cardiovascular and renal benefits,” wrote study investigator, Mahir Tesfaye from Addis Ababa University in Ethiopia, and colleagues.1 “The observed reduction in cardiovascular medication usage also means that semaglutide may decrease the need for intensive pharmacological interventions. This might improve patient quality of life, adherence, and healthcare costs.”

Standard treatment strategies for CKD include medication management of associated risk factors, such as hyperglycemia, dyslipidemia, and blood pressure. Recent cardiovascular outcome trials have highlighted renoprotective benefits and glucose-lowering effects in glucagon-like peptide-1 receptor agonists, but have been limited in sample size.2,3

To address this gap in research, investigators conducted a systematic review of MEDLINE, Embase, and Cochrane CENTRAL databases to find studies comparing semaglutide with placebo or standard care in adults 18 ≥ years of age with CKD, regardless of comorbidity of type 2 diabetes mellitus status.1

Primary outcomes included major kidney-related adverse events, MACE, cardiovascular mortality, nonfatal myocardial infarction (MI), and nonfatal stroke.

All-cause mortality, serious adverse events, hospitalization due to unstable angina or heart failure, and the use of cardiovascular medications were the secondary outcomes.1

Investigators leveraged data from 12,785 participants with comorbid T2DM and CKD from 5 randomized controlled trials. The patient population had a mean age of 64-67 years, was predominantly male, with elevated body weight (~90–109 kg) and body mass index (~32–37 kg/m²), consistent blood pressure (systolic blood pressure ~135–138 mmHg; diastolic blood pressure ~76–78 mmHg) and glycemic control (Hemoglobin A1c ~5.6–8.7%).1

An outlier study, Apperloo, had a younger cohort, with a mean age of 55 years, and was the only trial with a completely non-diabetic CKD population, while the remaining studies enrolled 100% patients with T2DM.1

Analysis of the pooled trial data revealed a significantly reduced risk of cardiovascular mortality compared with placebo, with a 26% relative risk reduction (Relative Risk [RR], 0.74; 95% Confidence Interval [CI], 0.62–0.88; I² = 36%).

Investigators observed a 22% reduced incidence of MACE (RR, 0.78; 95% CI, 0.70–0.87; I² = 0%), highlighting consistent cardiovascular benefit. While there was a trend toward reduction in nonfatal myocardial infarction and nonfatal stroke, these outcomes were not statistically significant (MI: RR, 0.86; 95% CI, 0.66–1.12; I² = 24%; stroke: RR, 0.86; 95% CI, 0.53–1.40; I² = 64%).

Kidney outcomes were similarly improved, with a 20% decrease in major kidney adverse events among patients receiving semaglutide (RR, 0.79; 95% CI, 0.71–0.87; I² = 0%).1

For secondary outcomes, semaglutide showed a non-significant trend toward reduced all-cause mortality (RR, 0.80; 95% CI, 0.68–0.93; I² = 44%), and was associated with fewer serious adverse events (RR, 0.86; 95% CI, 0.74–0.99; I² = 87%). Sensitivity analysis further strengthened the effect on serious adverse events (RR, 0.92; 95% CI, 0.87–0.98; I² = 14%).1

Investigators noted no significant differences in hospitalizations for unstable angina (RR, 1.01; 95% CI, 0.55–1.84; I² = 27%) or heart failure (RR, 1.03; 95% CI, 0.76–1.40; I² = 0%). The need for cardiovascular medications was modestly reduced, corresponding to a 14% relative risk reduction, with low heterogeneity.1

“These findings are collectively supportive of its use as a therapeutic strategy for CKD management, with or without diabetes,” investigators concluded.1 “Long-term studies, however, are needed to confirm its role in reducing rates of hospitalization and mortality in broader populations of patients.”

References:

1. Abdullah A, Sagreeka FNU, Aniket GA, et al. Safety and Efficacy of Semaglutide in Patients With Chronic Kidney Disease, With or Without Type 2 Diabetes: A Systematic Review and Meta‐Analysis. Endocrinology, Diabetes & Metabolism. 2025;8(6). doi:https://doi.org/10.1002/edm2.70136

2. ‌Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nature Reviews Nephrology. 2020;17(4):227-244. doi:https://doi.org/10.1038/s41581-020-00367-2

3. Caruso I, Giorgino F. SGLT2 inhibitors as cardio-renal protective agents. Metabolism. Published online November 2021:154937. doi:https://doi.org/10.1016/j.metabol.2021.154937