FLOW trial stopped early due to evidence of renal protection with semaglutide

Abstract

On 10 October 2023, Novo Nordisk1 announced the decision to stop the kidney outcome trial FLOW (Effect of semaglutide versus placebo on the progression of renal impairment in people with type 2 diabetes and chronic kidney disease; NCT03819153). The decision to terminate the trial prematurely was based on the recommendation of the independent Data Monitoring Committee, which concluded that the results of a pre-specified interim analysis met the criteria to stop the trial early for efficacy. Full results from the FLOW trial are expected to be released in the first half of 2024. This announcement by the Danish company comes on the eve of the presentation of the SELECT2 cardiovascular outcome trial at the American Heart Association (AHA) Scientific Sessions 2023, in which subcutaneous semaglutide 2.4 mg once weekly was associated with a significant 20% relative risk reduction in major adverse cardiovascular events (MACEs) compared with placebo in 17 604 patients aged ≥45 years with overweight or obesity and established cardiovascular disease without a history of diabetes.2 Recent evidence suggests a potential protective effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal function in patients with type 2 diabetes mellitus (T2DM).3–6 However, most of this evidence has been derived indirectly from cardiovascular outcome trials that included patients with and without chronic kidney disease (CKD), with renal adverse events reported only as secondary exploratory outcomes.3–6 Dedicated renal outcomes trials, such as FLOW, are needed to confirm the renoprotective effects of GLP-1RAs.7 FLOW is a randomized, double-blind, parallel-group, event-driven, phase 3b superiority trial comparing subcutaneous semaglutide 1.0 mg vs. a visually identical placebo as an adjunct to standard of care on renal outcomes in patients with T2DM and CKD (Figure 1).7 An 8-week dose-escalation regimen was used to initiate treatment, with dose escalation (if tolerated) from 0.25 mg/week for 4 weeks to 0.5 mg for 4 weeks, followed by a maintenance dose of 1.0 mg/week for the remainder of the trial.7 A total of 3534 patients were enrolled at 418 study sites across 28 countries. The eligibility criteria were chosen to select a broad population of patients at high risk of CKD progression.7 Design and main characteristics of the FLOW trial. CV: cardiovascular; KDIGO: kidney disease: improving global outcomes; UACR: urine albumin creatinine ratio; HbA1c: glycosylated haemoglobin; BMI: body-mass-index; SGLT2-I: sodium-glucose cotransporter-2 inhibitors; RAAS: renin-angiotensin-aldosterone system; OW: once weekly; CKRT: chronic kidney replacement therapy; s.c.: subcutaneous. Other abbreviations as in the text. The primary objective of the FLOW trial was to demonstrate a delay in the progression of CKD and a reduction in the risk of renal and cardiovascular mortality using a composite primary endpoint consisting of (i) onset of kidney failure, defined as the initiation of chronic kidney replacement therapy (i.e. dialysis or renal transplantation) or persistent estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 for at least 4 weeks; (ii) death from kidney failure; (iii) cardiovascular death; and (iv) onset of a persistent ≥50% reduction in eGFR from baseline. Key secondary endpoints included the annual rate of change in eGFR, MACEs (a composite of myocardial infarction, stroke, or cardiovascular death), and all-cause death.7 In conclusion, the FLOW trial has the potential to expand the pharmacotherapy options for patients with T2DM and CKD to prevent clinically relevant renal outcomes with semaglutide. The study results are potentially practice-changing and are eagerly awaited by the cardiology community. Conflict of interest: Relationships with Industry and Other Entities: Drs. Gragnano, De Sio, and Calabrò have no relationships relevant to the contents of this paper to disclose. There are no new data associated with this article.