Semaglutide Significantly Reduces Risk of Renal Events, MACE, Mortality in People with CKD, T2D in Final FLOW Trial Findings

Treatment with semaglutide 1.0 mg (Ozempic; Novo Nordisk) in adults with type 2 diabetes and (T2D) chronic kidney disease (CKD) significantly reduced the risk of a composite of renal outcomes and death from both kidney-specific and cardiovascular causes by 24%, according to a full readout of data from the landmark FLOW trial presented at the 61st European Renal Association (ERA) Congress, May 23-26, 2024, in Stockholm, Sweden.¹

Study participants treated with the pluripotent GLP-1 mimetic also experienced a reduction in progression of CKD, reflected by slower decline in eGFR, compared with placebo, as well as a 21% reduction in risk of renal-specific components of the primary composite outcome.²

Moreover, investigators reported an 18% lower risk of MACE in semaglutide-treated participants and a reduced risk of death from any cause of 20% vs placebo. The full findings were simultaneously published in the New England Journal of Medicine.²

The presentation of the full data from the FLOW trial follows a topline readout in March 2024,³ an announcement expedited given the early discontinuation of the trial in October 2023.⁴ That decision was based on recommendation from the trial’s independent Data Monitoring Committee that stated an interim analysis had met the prespecified criteria for stopping the trial early for efficacy.⁴

“These findings offer great promise in reshaping treatment strategies for individuals at high risk of diabetes-related complications, offering a new avenue for kidney and cardiovascular protection,” presenting author professor Vlado Perkovic, MBBS, PhD, provost of the University of New South Wales in Sydney, Australia, said in an ERA statement.¹

Inclusion criteria for the FLOW trial, initiated in 2019, required participants to have an eGFR of 50 to 75 ml/min/1.73m² of body-surface area and a urinary albumin-to-creatinine ratio (UACR) of greater than 300 and less than 5000 or an eGFR of 25 to less than 50 ml/min/1.73m² and a UACR greater than 100 and less than 5000.² The randomized, double-blind, parallel-group, placebo-controlled, superiority trial compared the effects of injectable semaglutide 1.0 mg against placebo, administered weekly, as an adjunct to standard of care on kidney outcomes in people with T2D and CKD.² The trial’s 5-point composite primary endpoint was²:

• Onset of persistent ≥50% reduction in eGFR
• Onset of persistent eGFR decline to <15 mL/min/1.73 m²
• Initiation of chronic kidney replacement therapy
• Death from kidney disease
• Death from cardiovascular disease

The confirmatory secondary endpoints were annual rate of change in eGFR, 3-point major adverse cardiovascular events (MACE), and all-cause death.

Perkovic and colleagues enrolled 3553 participants from 387 study sites in 28 countries for a final study cohort with a mean age of 66.6 years and comprised of 69.7% men. Approximately two-thirds (65.8%) of the participants identified as non-Hispanic White.

Half the cohort was randomly assigned to receive semaglutide 1.0 mg and half to receive placebo. The median follow-up period was 3.4 years.²

FINAL STUDY FINDINGS²

As noted, use of semaglutide was associated with a 24% relative risk reduction for the primary outcome of major kidney disease events compared to treatment with placebo (HR 0.76; 95% CI, 0.66 to 0.88; P = .003). Risk reductions relative to placebo for semaglutide were similar for a composite of the kidney-specific components of the primary outcome (HR, 0.79; 95% CI, 0.66 to 0.94) as well as for death from CV causes (HR, 0.71; 95% CI, 0.56 to 0.89).

Results of all the confirmatory secondary outcomes were also more favorable for participants who received semaglutide and included a less steep decline in mean annual eGFR (difference, 1.16 mL/min/1.73m²; P <.001) and a reduced risk of 3-point MACE (HR, 0.82; 95% CI, 0.68 to 0.98; P = .029) and all-cause mortality (HR, 0.80; 95% CI, 0.67 to 0.95; P = .01). Findings from the safety analyses demonstrated a lower rate of serious adverse events among semaglutide- vs placebo-treated FLOW participants (49.6% vs 53.8%).²

“The use of semaglutide in people with type 2 diabetes and chronic kidney disease can lower the risk of major kidney outcomes and reduce the risk of cardiovascular events, cardiovascular death and all-cause death," Perkovic said. "These benefits signify a profound clinical impact saving kidneys, hearts and lives, for patients with type 2 diabetes and chronic kidney disease. Additionally, the reassuring safety findings further support the strong potential value of semaglutide in this population.”¹

References

1. 61st ERA Congress: Semaglutide significantly reduces risk of major kidney disease events, cardiovascular outcomes and mortality in patients with type 2 diabetes and chronic kidney disease, groundbreaking study reveals. News release. European Renal Association. May 24, 2024. Accessed May 24, 2024. https://www.prnewswire.com/news-releases/61st-era-congress-semaglutide-significantly-reduces-risk-of-major-kidney-disease-events- cardiovascular-outcomes-and-mortality-in-patients-with-type-2-diabetes-and-chronic-kidney-disease-groundbreaking-study-reveals-302152720.html
2. Perkovic V, Tuttle KR, Rossing P, et al, for the FLOW Trial Committee and Investigators. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. Published online May 24, 2024. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2403347
3. Halsey G. Semaglutide reduces CKD-related Events by 24% in population with T2D and CKD: FLOW findings announced. Patient Care. March 5, 2024. https://www.patientcareonline.com/view/semaglutide-reduces-ckd-related-events-by-24-in-population-with-t2d-and-ckd-flow-findings-announced
4. Halsey G. Novo stops semaglutide kidney outcomes trial early for efficacy. Patient Care. October 11, 2023. https://www.patientcareonline.com/view/novo-stops-semaglutide-kidney-outcomes-trial-early-for-efficacy