Effects of Semaglutide With or Without Concomitant Mineralocorticoid Receptor Antagonist Use in Participants With Type 2 Diabetes and Chronic Kidney Disease: A FLOW Trial Prespecified Secondary Analysis

Abstract

Objective: In the Evaluate Renal Function With Semaglutide Once Weekly (FLOW) trial, semaglutide reduced the risk of major kidney and cardiovascular (CV) outcomes and all-cause mortality in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). This prespecified analysis assessed the effects of semaglutide on kidney, CV, and mortality outcomes by baseline mineralocorticoid receptor antagonist (MRA) use.

Research design and methods: Participants were randomized to once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary kidney outcome was a composite of time to first persistent ≥50% eGFR reduction from baseline, kidney failure, or death from kidney/CV causes. Baseline MRA was predominantly spironolactone; finerenone was only available after recruitment ended.

Results: Effects were analyzed by baseline MRA use (n = 257 [136 in the semaglutide group and 121 in the placebo group]) and nonuse (n = 3,276 [1,631 in the semaglutide group and 1,645 in the placebo group]). Semaglutide reduced the risk of the primary kidney outcome by 49% (59 events; hazard ratio [HR] 0.51 [95% CI 0.30, 0.86]) and 21% (682 events; HR 0.79 [95% CI 0.68, 0.92]; P-interaction = 0.12) versus placebo in MRA and non-MRA subgroups, respectively. There was no heterogeneity, favoring the effects of semaglutide on major adverse CV events (MACE) and all-cause mortality in both MRA subgroups (P-interaction > 0.7). Albuminuria at 104 weeks was reduced from baseline with semaglutide by 15% (95% CI -41, 31) in MRA users and 33% (26, 39) in nonusers versus placebo (P-interaction = 0.22). Estimated glomerular filtration rate decline was similarly reduced with semaglutide (P-interaction = 0.71). The safety profile of semaglutide was comparable between subgroups.

Conclusions: In participants with T2D and CKD, consistent benefits of semaglutide on major kidney outcomes, MACE, and all-cause mortality were observed regardless of baseline MRA use.

Graphical abstract

Figure 1

Time from randomization to first primary kidney outcome event without (A) and with (B) MRA use at baseline and time to first secondary four-component composite outcome event without (C) and with (D) MRA use at baseline. The cumulative incidence rate was calculated using the Aalen-Johansen method with nonkidney and non-CV death (A and B) and nonkidney death (C and D) as a competing risk.

Figure 2

Major kidney outcomes, all-cause mortality, and CV outcomes by MRA use at baseline. Data from the in-trial period (full analysis set). Time from randomization to each outcome was analyzed using a stratified Cox proportional hazards model with treatment as a categorical fixed factor and two-sided P values. Participants without events of interest were censored at the end of their in-trial period. For the subgroup analyses, estimated HRs and corresponding CIs were calculated in a Cox proportional hazards model with interaction between treatment groups and subgroup as a fixed factor. P values for the test of no interaction effect between MRA use and treatment using a score test are shown. There was no kidney death in the MRA use subgroup, which is not displayed here. Renal replacement therapy includes dialysis initiation or kidney transplant.

Figure 3

eGFR over time based on serum creatinine in participants without (A) and with (B) MRA use at baseline and based on serum cystatin C in participants without (C) and with (D) MRA use at baseline. Observed data from the in-trial period are shown. Error bars are SEM. Numbers shown under the plots represent the number of participants contributing to the means.