GLP-1RA reduces kidney events in dedicated kidney outcomes trial in patients with CKD and T2D

ERA 2024 – Previous analyses of CVOTs have suggested that GLP-1RAs reduce kidney-related outcomes in patients with T2D, but data of dedicated kidney outcomes trial were lacking. At the ERA Congress 2024 findings of the FLOW trial with semaglutide were presented.

This summary is based on the presentation of Peter Rossing, MD (Copenhagen, Denmark), Richard Pratley, MD (Orlando, FL, USA), Vlado Perkovic, PhD (Syndey, Australia), Kenneth Mahaffey, MD (Palo Alto, CA, USA), Johannes Mann, MD (Erlangen, Germany), Katherine Tuttle, MD (Seattle, WA, USA) and Christoph Wanner, MD (Würzburg, Germany) at the ERA Congress 2024 – FLOW scientific session.

Introduction and methods

Despite improvements in kidney-related outcomes with available treatments, risk of kidney failure and CVD remains high in patients with CKD and T2D. Findings of CV outcomes trials have suggested benefit on kidney-related outcomes with GLP-1RAs in patients with T2D. Therefore, the effect of semaglutide on kidney and CV outcomes and mortality were evaluated in patients with CKD and T2D in a dedicated kidney outcomes trial – the FLOW trial.

The FLOW trial was a multinational, randomized controlled clinical trial in which adults with T2D on a RAAS blocker and an eGFR ≥50 and ≤75 ml/min/1.73m² and UACR >300 and <5000 mg/g OR eGFR ≥20 and <50 ml/min/1.73m² and UACR >100 and <5000 mg/g were eligible for participation. A total of 3533 participants were randomized in a 1:1 ratio to once-weekly semaglutide 1 mg on top of standard care or to placebo on top of standard care. FLOW was an event-driven trial with ≥854 first primary outcome events, but was stopped early for efficacy at ~570 events. Mean follow-up was 3.4 years.

The primary outcome of the trial was time to first occurrence of major kidney events consisting of onset of persistent ≥50% reduction in eGFR compared with baseline, kidney failure, kidney death or CV death.

Main results

• The composite primary kidney outcome was reduced in the semaglutide group (event rate 18.7%) compared with the placebo group (23.2%) (HR 0.76, 95%CI: 0.66-0.88, P=0.0003). This translated to a NTT of 37 at 2 years, and NTT of 20 at 3 years.
• There was a trend of reductions in the individual outcomes of the primary outcome with semaglutide compared with placebo, but findings were non-significant (except for onset of persistent ≥50% reduction in eGFR).
• Subgroup analyses show no clear heterogeneity by sex, age, BMI, diabetes duration, HbA1c, region, race or ethnicity. Also, consistency in the findings was seen by eGFR level, UACR level, presence or absence of CVD, or chronic heart failure.
• Annual rate of change in eGFR was reduced in the semaglutide group (-2.19 ml/min/1.73m²/year) compared with the placebo group (-3.36 ml/min/1.73m²/year), resulting in a between group difference of 1.16 ml/min/1.73m²/year (95%CI:0.86-1.47), P<0.001). 
• Estimated treatment difference in change in eGFR (calculated by cystatin C) at week 104 was 3.39 ml/min/1.73m²/year (95%CI: 2.63-4.15) with less change in the semaglutide group; and this was 3.30 ml/min/1.73m²/year (95%CI: 2.43-4.17) when calculated by serum creatinine.
• In the semaglutide group, the UACR ratio to baseline at week 104 was 0.60 and this was 0.88 in the placebo group, resulting in an estimated treatment ration of 0.68 (95%CI:0.62-0.75).
• The outcome of MACE -consisting of CV death, non-fatal MI or non-fatal stroke- was reduced in the semaglutide group (12.0%) compared with the placebo group (14.4%) (HR 0.82, 95%CI: 0.68-0.98, P=0.029).
• All-cause death was reduced in the semaglutide group (12.8%) compared with the placebo group (15.8%) (HR 0.80, 95%CI: 0.67-0.95, P=0.010).
• Safety adverse events were reported fewer in the semaglutide group (49.6%) than in the placebo group (53.8%), which was driven by infections and infestations, or cardiac disorders. Adverse events leading to permanent treatment discontinuation were more common in the semaglutide group (13.2%) than in the placebo group (11.9%), driven mainly by discontinuations due to gastrointestinal disorders.

Conclusion

In the FLOW trial, treatment with semaglutide resulted in a 24% lower risk of the composite primary kidney outcome, slower reduction of kidney function by a mean eGFR of 1.16 ml/min/1.73m²/year, 18% of lower risk of MACE and 20% lower risk of all-cause death compared with placebo in patients with CKD and T2D.

- Our reporting is based on the information provided at the ERA Congress 2024 -

The findings of this study were simultaneously published in New Engl J Med