Results From the FLOW Trial Show Benefits of Semaglutide on Chronic Kidney Disease

Chronic kidney disease (CKD) is a major cause of complications for type 2 diabetes (T2D), which is continuing to rise and is predicted to be the fifth leading cause of death worldwide in 2040, explained Peter Rossing, MD, DMSc, head of complications research and chief physician from the Steno Diabetes Center Copenhagen, during a session at the American Diabetes Association 84th Scientific Sessions (ADA).

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“That’s why we have FLOW [NCT03819153], the first dedicated kidney outcome trial for GLP-1 receptor agonist, which we evaluated with cardiovascular outcomes and mortality with once weekly semaglutide in people with [T2D] and [CKD],” said Rossing during the ADA session.

FLOW is a randomized, double-blind, parallel-group, multinational, phase 3b trial, enrolling 30,533 patients across 187 investigative sites in 28 countries with a median follow-up of 3.4 years; enrolled patients had T2D and a hemoglobin A1c of less than 10%. Investigators compared once weekly subcutaneous semaglutide 1 mg plus the standard of care with the placebo and the standard of care. The trial was stopped early due to efficacy results.

The primary end point included time to first occurrence of major kidney outcomes consisting of onset of persistent 50% or greater reduction of estimated glomerular filtration rate (eGFR) compared with baseline, kidney failure, kidney death, and cardiovascular (CV) death. Confirmatory secondary end points included annual rate of change in eGFR, time to first occurrence of a composite major adverse cardiovascular event (MACE), including CV death, non-fatal myocardial infarction (MI), non-fatal stroke, and time to occurrence of all-cause death. Other secondary end points in the study included time to occurrence of each individual component of the primary end point and MACE outcomes, time to first occurrence of composite of acute limb ischemia hospitalization or chronic limb ischemia hospitalization, and the change in eGFR, UACR, bodyweight, HbA1c, and blood pressure.

The mean age of individuals was 66, 30% were women, and participants were predominately White and non-Hispanic or Latino. The population’s HbA1c was approximately 7.8 on average, with a BMI of 32. Their systolic and diastolic blood pressure were 138 and 76, respectively. They presented with high diabetes and CV burden, with patients experiencing diabetes for more than 15 years on average. Further, 23% had prior stoke and the baseline kidney function was 47 milliliters per minute for 1.73. Approximately 93% of the patients were at high or very high risk of progression to CKD and other outcomes. There were approximately 49.6% of individuals who experienced severe adverse events with semaglutide compared to 53.8% with the placebo.

The primary outcome of composite kidney outcomes included approximately 18.7% with semaglutide reaching this outcome compared with 23.2% with the placebo, meeting prespecified criteria. There was a 24% lower risk of the outcome. Furthermore, investigators found a consistent risk reduction for kidney disease components that included the primary outcome.

“When we look at the composite kidney outcome--excluding CV deaths at this time, kidney failure, 50% reduction of EGFR, or death due to kidney disease--and we see the curve of the placebo arm 14.7% of participants reached that outcome. In the semaglutide group again, we see early separation and a lower rate of this outcome” Vlado Perkovic, MBBS, PhD, FRACP, FASN, FAHMS, from the University of New South Wales, said in the session.

There was a consistent risk reduction across pre-specific subgroups, and a slower reduction of kidney function by a mean eGFR of 1.16 mL/min/1.73 m²/year, according to Perkovic.

For CV outcomes, 14.4% of the patients in the placebo group suffer CV death, nonfatal MI, or non-fatal stroke compared with the semaglutide group at 0.0% of participants who suffered the CV composite outcome, representing an absolute risk reduction of 2.4% for the 3.4 years of follow up, correlating to a 18% relative risk reduction, cardiovascular death, nonfatal MI or non-fatal stroke with semaglutide. Further, there was a 29% reduction in CV death. Approximately 15.8% of patients had a death from any cause compared with 12.8% in the placebo, resulting in a relative risk reduction of 20% with semaglutide. There were only 45 hospitalizations for acute or chronic limb ischemia events.

“Approximately 65% of patients who died [due to CV] died of sudden death, or fewer strokes, heart failure, or acute MI,” Kenneth W. Mahaffey, MD, PhD, from Stanford Center for Clinical Research, said in the session. "For participants who died of non-CV, non-kidney deaths, approximately 60% of those died of infectious causes [and] approximately 20% due to cancers."

For patients who used sodium-glucose cotransporter-2 (SGLT2) inhibitors, the primary outcome of events for those on the placebo was 13.8% compared with 14.8% with semaglutide. Without SGLT2, the primary outcome was 24.9% and 19.5%, respectively. In total eGFR slope, there was -2.17 with semaglutide and -2.92 with the placebo compared with -2.20 and -3.44, respectively. MACE events occurred at 11.7% with the placebo and 9% with semaglutide compared with 14.9% and 12.6%, respectively, and all-cause death occurred at 8.4% and 6.5%, respectively, compared with 17.1% and 14%, respectively.

However, the FLOW trial has limited power to test these effects for SGLT2 inhibitors, and there were no benefits found with semaglutide for kidney, CV, and mortality outcome. Concurrent use of semaglutide and SGLT2 inhibitors could be considered for patients with T2D and CKD.

Reference

Pratley RE, Perkovic V, Rossing P, Mahaffey KW, Mann JF, Tuttle KR, Rosas S. The First Dedicated Kidney Outcome Trial with a GLP-1 Receptor Agonist—Once-Weekly Semaglutide and the FLOW Trial Results. Presented At: ADA 84th Scientific Sessions; June 21-June 24, 2024; Orlando, Florida.