Semaglutide’s Impact on Cardiovascular Outcomes Across Chronic Kidney Disease Stages in Type 2 Diabetes: Insights from the FLOW Trial

Highlight

• Semaglutide reduces the risk of cardiovascular death, myocardial infarction, and stroke by 18% in type 2 diabetes patients with chronic kidney disease.
• The beneficial cardiovascular effects were consistent regardless of chronic kidney disease severity, as defined by eGFR, urine albumin-to-creatinine ratio, or KDIGO risk classification.
• Overall mortality decreased by 20%, with a significant reduction particularly noted in patients with higher albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g).

Study Background and Disease Burden

Chronic kidney disease (CKD) is a frequent and severe complication among individuals with type 2 diabetes, significantly elevating risks for cardiovascular morbidity and mortality. Cardiovascular disease remains the leading cause of death in this population. Current therapeutic strategies target glycemic control, blood pressure, and renal protection, but residual cardiovascular risk persists.

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has shown promise in improving cardiovascular outcomes and slowing CKD progression. The FLOW trial specifically investigated semaglutide’s efficacy in reducing risks of cardiovascular events and mortality in patients with type 2 diabetes complicated by CKD.

Study Design

The FLOW trial was a randomized, double-blind, placebo-controlled study enrolling 3,533 participants with type 2 diabetes and chronic kidney disease. Participants were randomized to receive weekly subcutaneous semaglutide 1 mg or placebo and followed for a median of 3.4 years.

CKD severity was classified by estimated glomerular filtration rate (eGFR) categories (< or ≥60 mL/min/1.73 m2) and urine albumin-to-creatinine ratio (UACR) levels (< or ≥300 mg/g), as well as by the Kidney Disease Improving Global Outcomes (KDIGO) risk classification into low/moderate, high, or very high risk groups.

The primary composite cardiovascular outcome comprised cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Secondary endpoints included all-cause mortality.

Key Findings

Over the study period, 6.8% of participants were classified as low/moderate KDIGO risk, 24.9% high risk, and 68.3% very high risk, reflecting a population with substantial cardiovascular and renal risk burdens.

Semaglutide treatment led to an 18% relative risk reduction in the primary composite cardiovascular endpoint compared with placebo (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.68-0.98; P = .03). Importantly, this benefit was consistent across all CKD subgroups stratified by eGFR categories, UACR strata, and KDIGO risk classes (all P-interaction > 0.13), indicating uniform efficacy irrespective of baseline kidney disease severity.

For all-cause mortality, semaglutide reduced the risk by 20% (HR 0.80; 95% CI 0.67-0.95; P = .01). This effect also appeared consistent across eGFR and KDIGO risk categories, with P-interactions of 0.21 and 0.23, respectively. However, the treatment effect differed significantly by UACR subgroup (P-interaction = .01): no significant mortality benefit was observed in patients with UACR <300 mg/g (HR 1.17; 95% CI 0.83-1.65), whereas a substantial 30% mortality reduction occurred in those with UACR ≥300 mg/g (HR 0.70; 95% CI 0.57-0.85).

These results underscore semaglutide's dual renal and cardiovascular protective effects, especially in patients with albuminuria, a strong marker of kidney and cardiovascular risk.

Expert Commentary

The FLOW trial adds compelling data supporting the addition of semaglutide to treatment regimens for patients with type 2 diabetes and concomitant CKD. The lack of interaction by kidney function categories suggests semaglutide’s cardiovascular benefits do not diminish even in advanced CKD stages, an important consideration given limited data for many therapies in this high-risk group.

The pronounced mortality benefit in individuals with significant albuminuria aligns with the pathophysiologic role of albuminuria in vascular and renal disease progression, suggesting that patients with higher UACR derive greater clinical advantage from semaglutide.

One limitation is the relatively small subset of patients with low/moderate KDIGO risk, which may warrant further research to confirm effects in early CKD.

Mechanistically, semaglutide might improve cardiovascular outcomes through multiple pathways beyond glycemic control, including effects on blood pressure, inflammation, and endothelial function, although these require further elucidation.

Conclusion

Semaglutide significantly reduces major adverse cardiovascular events and all-cause mortality in type 2 diabetes patients with chronic kidney disease, with consistent benefits across varying CKD severities. These findings reinforce the importance of GLP-1 receptor agonists in managing cardiovascular risk in this vulnerable population, especially among those with high albuminuria.

Future studies should explore long-term renal outcomes and investigate mechanistic insights to optimize personalized treatment strategies.

References

1. Heerspink HJL, et al. Cardiovascular and renal outcomes with semaglutide in patients with type 2 diabetes and chronic kidney disease: The FLOW trial. [Journal Name]. [Year];[Volume](Issue):[Pages].
2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):1–150.
3. Gerstein HC, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776-785.
4. American Diabetes Association. Standards of Medical Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1-S276.