Consistent Renal Benefits of Semaglutide in CKD and T2DM Patients With or Without SGLT2 Inhibitors Use. FLOW Trial

By M Cecilia Bahit, MD on
  • The FLOW trial showed that among patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), once-weekly subcutaneous semaglutide was superior to placebo in improving renal and CV outcomes over a median follow-up of 3.4 years.
  • In this analysis, the benefits of semaglutide in improving  renal outcomes were consistent in patients with/without baseline SGLT2i use

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) (Funded by Novo Nordisk; FLOW number, NCT03819153.) trial assessed the efficacy and safety of subcutaneous semaglutide at a dose of 1.0 mg once weekly for the prevention of kidney failure, substantial loss of kidney function, and death from kidney-related or cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. Among the 3,533 participants who underwent randomization (1,767 in the semaglutide group and 1,766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group compared to the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P=0.0003). Similar results were observed for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94), and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P=0.01). Serious adverse events were lower in the semaglutide group compared to the placebo group (49.6% vs. 53.8%).New data presented at a symposium at the American Diabetes Association’s® (ADA) 84th Scientific Sessions in Orlando, FL, highlighted the benefits of combined therapy with SGLT2 inhibitors, and were simultaneously published in Nature Medicine.

People with type-2-diabetes (T2D) and chronic kidney disease (CKD), have a high risk for kidney and cardiovascular (CV) complications. Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce cardiovascular and kidney events independently. Whether combining both will be beneficial is unknown. FLOW trial participants with T2D and CKD were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% eGFR reduction, kidney or cardiovascular death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide vs placebo (95% confidence interval [CI] 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (HR 1.07; 95% CI 0.69, 1.67; P=0.755), and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (HR 0.73; 0.63, 0.85; P<0.001; P-interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total eGFR slope (ml/min/1.73m2/year) were 0.75 (–0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in non-SGLT2i-subgroup, P-interaction 0.237. There were also similar benefits of semaglutide on major cardiovascular events and all-cause death regardless of SGLT2i use (P-interaction 0.741 and 0.901, respectively). In this analysis, the benefits of semaglutide in reducing kidney outcomes were consistent in patients with chronic kidney disease and type 2 diabetes with/without baseline SGLT2i use; however, power was limited to detect smaller but clinically relevant effects.

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 Richard E. Pratley, MD, Medical Director at the AdventHealth Diabetes Institute Orlando, FL, and co-chair of the FLOW trial. “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.”

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