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Randomized Controlled Trial
. 2025 Mar 24;46(12):1096-1108.
doi: 10.1093/eurheartj/ehae613.

Cardiovascular outcomes with semaglutide by severity of chronic kidney disease in type 2 diabetes: the FLOW trial

Kenneth W Mahaffey  1 , Katherine R Tuttle  2   3 , Mustafa Arici  4 , Florian M M Baeres  5 , George Bakris, David M Charytan  6 , David Z I Cherney  7 , Gil Chernin  8 , Ricardo Correa-Rotter  9 , Janusz Gumprecht  10 , Thomas Idorn  5 , Giuseppe Pugliese  11 , Ida Kirstine Bull Rasmussen  5 , Søren Rasmussen  5 , Peter Rossing  12   13 , Ekaterina Sokareva  5 , Johannes F E Mann  14   15 , Vlado Perkovic  16 , Richard Pratley  17
Affiliations
Randomized Controlled Trial

Cardiovascular outcomes with semaglutide by severity of chronic kidney disease in type 2 diabetes: the FLOW trial

Kenneth W Mahaffey et al. Eur Heart J. .

Abstract

Background and aims: In the FLOW trial, semaglutide reduced the risks of kidney and cardiovascular (CV) outcomes and death in participants with type 2 diabetes and chronic kidney disease (CKD). These prespecified analyses assessed the effects of semaglutide on CV outcomes and death by CKD severity.

Methods: Participants were randomized to subcutaneous semaglutide 1 mg or placebo weekly. The main outcome was a composite of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (CV death/MI/stroke) as well as death due to any cause by baseline CKD severity. CKD was categorized by estimated glomerular filtration rate < or ≥60 mL/min/1.73 m2, urine albumin-to-creatinine ratio < or ≥300 mg/g, or Kidney Disease Improving Global Outcomes (KDIGO) risk classification.

Results: Three thousand, five hundred and thirty-three participants were randomized with a median follow-up of 3.4 years. Low/moderate KDIGO risk was present in 242 (6.8%), while 878 (24.9%) had high and 2412 (68.3%) had very high KDIGO risk. Semaglutide reduced CV death/MI/stroke by 18% [hazard ratio (HR) 0.82 (95% confidence interval 0.68-0.98); P = .03], with consistency across estimated glomerular filtration rate categories, urine albumin-to-creatinine ratio levels, and KDIGO risk classification (all P-interaction > .13). Death due to any cause was reduced by 20% [HR 0.80 (0.67-0.95); P = .01], with consistency across estimated glomerular filtration rate categories and KDIGO risk class (P-interaction .21 and .23, respectively). The P-interaction treatment effect for death due to any cause by urine albumin-to-creatinine ratio was .01 [<300 mg/g HR 1.17 (0.83-1.65); ≥300 mg/g HR 0.70 (0.57-0.85)].

Conclusions: Semaglutide significantly reduced the risk of CV death/MI/stroke regardless of baseline CKD severity in participants with type 2 diabetes.

Keywords: Cardiovascular outcomes; Chronic kidney disease; Semaglutide; Type 2 diabetes.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
In a prespecified analysis of the FLOW trial, semaglutide 1.0 mg significantly reduced the risk of CV death/MI/stroke regardless of baseline CKD severity in participants with T2D. *KDIGO-defined risk classification: low, moderate, high, and very high risk based on albuminuria and eGFR. †Data are the HR and 95% CI for the composite major CV event outcome. CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; KDIGO, Kidney Disease Improving Global Outcomes; MI, myocardial infarction; R, randomization; T2D, type 2 diabetes; UACR, urine albumin-to-creatinine ratio.
Figure 1
Figure 1
Time from randomization to first cardiovascular death/myocardial infarction/stroke event by (A) KDIGO risk class and (B) KDIGO risk class and randomized treatment. The cumulative incidence rate is calculated using Aalen–Johansen method with non-cardiovascular death as a competing risk. KDIGO, Kidney Disease Improving Global Outcomes
Figure 2
Figure 2
Effect of semaglutide 1.0 mg on the composite of CV death, non-fatal MI, and non-fatal stroke by baseline chronic kidney disease status. CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; MI, myocardial infarction; UACR, urine albumin-to-creatinine ratio
Figure 3
Figure 3
Effect of semaglutide 1.0 mg on (A) CV death, (B) non-fatal MI, and (C) non-fatal stroke by baseline chronic kidney disease. CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; MI, myocardial infarction; UACR, urine albumin-to-creatinine ratio
Figure 4
Figure 4
Effect of semaglutide 1.0 mg on death due to any cause by baseline chronic kidney disease. CI, confidence interval; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; UACR, urine albumin-to-creatinine ratio
Figure 5
Figure 5
KDIGO heat map with composite cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke event rates (semaglutide 1.0 mg vs. placebo). CI, confidence interval; G, grade; GFR, glomerular filtration rate; HR, hazard ratio; KDIGO, Kidney Disease Improving Global Outcomes
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