FLOW Analysis Sheds Light on Effects of Combination Therapy with GLP-1 RA and SGLT2 Inhibitor

Richard Pratley, MD
Credit: Advent Health Diabetes Institute

Exactly 1 month after its original presentation at the 61st European Renal Association Congress, the FLOW trial and semaglutide (Ozempic) were back in the spotlight at the 84th American Diabetes Association Scientific Sessions.^1,2

At ADA 2024, the medical community was granted further insight into the effects of semaglutide 1.0 mg among patients with type 2 diabetes at risk for chronic kidney disease based on use of SGLT2 inhibitor therapy.^1,2

“This is a patient population at high-risk of severe kidney outcomes. Despite existing treatment options, there is still a clear unmet need for this group,” said study co-chair Richard E. Pratley, MD, Medical Director at the Advent Health Diabetes Institute.³

Since Novo Nordisk announced the early discontinuation of the FLOW trial in August 2023, the trial has been hailed as paradigm-shifting by endocrinologists, nephrologists, and the rest of the medical community as well. A double-blind, randomized, placebo-controlled trial FLOW enrolled 3553 patients with 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 primary outcome of interest for the trial was a composite of major kidney disease events, which included dialysis, transplantation, an eGFR decline to less than 15 ml/min/1.73m2, a reduction of 50% or greater in eGFR from baseline, or death from kidney-related or cardiovascular causes. Investigators also assessed multiple of secondary outcomes of interest, which were tested hierarchically.¹

Results of the trial suggested use of semaglutide was associated with a 24% relative risk reduction for the primary outcome relative to placebo therapy (Hazard Ratio [HR], 0.76; 95% Confidence Interval [CI], 0.66 to 0.88; P = .0003). Further analysis indicated semaglutide use was associated with a 21% reduction in risk relative to placebo therapy for kidney-specific components of the primary outcome (HR, 0.79; 95% CI, 0.66 to 0.94). Analysis of death from cardiovascular causes pointed to a 29% reduction in risk relative to placebo therapy (HR, 0.71; 95% CI, 0.56 to 0.89).¹

Since the trial was launched in 2019, another antihyperglycemic agent has seen its role expand as revelations of its own cardiorenal protective qualities were elucidated in phase 3 trials. With the role of SGLT2 inhibitors now recognized as guideline-directed medical therapy for reducing the risk of chronic kidney disease and heart failure in people with type 2 diabetes considered to be at elevated risk, the question of the benefit of combination therapy became chief among the inquiries from the medical community for FLOW investigators.²¹

Among the 3553 patients enrolled in the trial, 550 had baseline SGLT2 inhibitor use and 2983 did not. Of the 550 with baseline SGLT2 inhibitor use, 277 received semaglutide and 273 received placebo.²

Among those with baseline SGLT2 inhibitor use, investigators found the primary outcome occurred among 41 of the 277 patients receiving semaglutide and 38 of the 273 patients receiving semaglutide (HR, 1.07; 95% CI, 0.69 to 1.67). Among those without baseline SGLT2 inhibitor use, a primary outcome event occurred among 290 of the 1490 patients receiving semaglutide versus 372 of the 1493 participants receiving placebo (HR, 0.73; 95% CI, 0.63 to 0.85; P <.001; P for interaction = .109).²

Additional analysis suggested treatment differences for total eGFR of 0.75 ml/min/1.73m2 per year (95% CI, –0.01 to 1.5) in the SGLT2i subgroup and 1.25 ml/min/1.73m2 per year (95% CI, 0.91 to 1.58) in non-SGLT2i-subgroup (P for interaction = .237. Investigators also pointed out the effects of semaglutide on major adverse cardiovascular events (P for interaction =.741) and all-cause mortality (P for interaction =.901) were similar regardless of SGLT2 inhibitor use.²

“The findings from the FLOW trial have the potential to change the disease course of these high-risk patients and pave the way for new treatment strategies, offering hope to millions of patients globally,” Pratley added.³

References:

1. ^{Campbell P. Vlado Perkovic, MBBS, PhD: Semaglutide’s role in CKD based on flow results. HCPLive. May 24, 2024. Accessed June 24, 2024. https://www.hcplive.com/view/vlado-perkovic-mbbs-phd-semaglutide-s-role-in-ckd-based-on-flow-results.}
2. ^{Mann, J.F.E., Rossing, P., Bakris, G. et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03133-0}
3. ^{American Diabetes Association. Semaglutide reduced risk for major kidney disease events by 24% for patients with type 2 diabetes and kidney disease. American Diabetes Association Newsroom. June 24, 2024. Accessed June 24, 2024. https://diabetes.org/newsroom/press-releases/semaglutide-reduced-risk-major-kidney-disease-events-24-patients-type-2.}