The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease

Abstract

Background: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.

Methods: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.

Results: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.

Conclusion: FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Keywords: albuminuria; cardiovascular disease; diabetic kidney disease; glomerular filtration rate; glucagon-like peptide-1 receptor agonist.

Graphical Abstract

Figure 1:

Results of exploratory kidney analyses from GLP-1RA CV outcomes trials. *P < .05. ^†Defined as doubling of serum creatinine in LEADER, SUSTAIN 6 and ELIXA and sustained eGFR decline of ≥30% in REWIND. Direct comparisons not possible due to differing study designs. Secondary kidney composite endpoints were new-onset persistent macroalbuminuria/very high albuminuria, persistent doubling of the serum creatinine or end-stage kidney disease in LEADER; first occurrence of new macroalbuminuria/very high albuminuria (UACR >33.9 mg/mmol), a sustained decline in eGFR of ≥30% or chronic KRT in REWIND; new or worsening nephropathy (defined as persistent macroalbuminuria/very high albuminuria, persistent doubling of serum creatinine and a creatinine clearance of <45 ml/min/1.73 m² or the need for continuous KRT) in SUSTAIN 6; a 40% decline in eGFR, KRT, kidney death or incident macroalbuminuria/very high albuminuria in EXSCEL; and incident macroalbuminuria (UACR >33.9 mg/mmol) plus an increase in UACR of ≥30% from baseline, sustained decrease in eGFR of ≥40% for ≥30 days, renal replacement therapy for ≥90 days and sustained eGFR <15 ml/min/1.73 m² for ≥30 days in AMPLITUDE-O [6, 7, 10, 13, 38, 43]. exenatide ER, exenatide extended release; KRT, kidney replacement therapy; NR, not reported.

Figure 2:

FLOW trial design. *Stratified by SGLT-2i use (yes/no). EOT, end of treatment; N, number of participants; W, week.

Figure 3:

Map of trial site locations.

Figure 4:

KDIGO risk categories among FLOW participants. Data are n (%) for each category. To facilitate recruitment to the FLOW trial and increase generalisability of the outcomes by reflecting typical clinical practice, eligibility in terms of laboratory results could be based on historical values. Adapted from the KDIGO Diabetes Work Group, 2020 [3].