Evaluate Renal Function With Semaglutide Once Weekly - FLOW
Contribution To Literature:
The FLOW trial showed that among patients with CKD and DM2, once weekly subcutaneous semaglutide was superior to placebo in improving renal and CV outcomes over a median follow-up of 3.4 years.
Description:
The goal of the trial was to compare the safety and efficacy of semaglutide among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (DM2).
Study Design
Patients were randomized in 1:1 fashion to once weekly subcutaneous semaglutide (n = 1,767) or matching placebo (n = 1,766). An 8-week dose-escalation regimen was used, with dose escalation (as long as unacceptable side effects did not occur) from 0.25 mg per week for 4 weeks and 0.5 mg per week for another 4 weeks, followed by a maintenance dose of 1.0 mg per week throughout the remainder of the treatment period.
- Total screened: 5,581
- Total randomized participants: 3,533
- Median duration of follow-up: 3.4 years
- Median patient age: 66.6 years
- Percentage female: 30.3%
Inclusion criteria:
- DM2 with glycated hemoglobin (HbA1c) ≤10%
- High-risk CKD (estimated glomerular filtration rate [eGFR] 25-75 mL/min/1.73 m2 with a urinary albumin-to-creatinine ratio of >300 and <5000 if the eGFR was ≥50 mL/min/1.73 m2 or a urinary albumin-to-creatinine ratio of >100 and <5000 if the eGFR was 25 to <50)
- Receiving a stable maximal labeled dose (or the maximal dose without unacceptable side effects) of renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitor [ACEi]/angiotensin receptor blocker [ARB])
Other salient features/characteristics:
- White race: 65.8%, Asian: 23.9%
- Median body weight: 89.6 kg
- Median body mass index: 32 kg/m2
- Mean HbA1c: 7.8%
- Mean blood pressure (BP): 138.6/76.4 mm Hg
- Baseline mean eGFR: 47 mL/min/1.73 m2
- Previous myocardial infarction (MI)/stroke: 22.9%
- Baseline medications: ACEi, 35.1%; ARB, 60.2%; diuretic, 50.4%; lipid-lowering therapy, 80.2%; sodium–glucose cotransporter 2 (SGLT2) inhibitor, 15.6%
Principal Findings:
The trial was terminated early due to efficacy. The primary endpoint, major kidney disease events (a composite of onset of kidney failure; initiation of long-term dialysis, kidney transplantation, or a reduction in the eGFR to <15 mL/min/1.73 m2 sustained for ≥28 days), a sustained (for ≥28 days) ≥50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular [CV] cause, for semaglutide vs. placebo, was: 18.7% vs. 23.2% (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.66-0.88, p = 0.0003).
Key secondary outcomes for semaglutide vs. placebo:
- All-cause mortality: 12.8% vs. 15.8%, HR 0.80, 95% CI 0.67-0.95
- CV mortality: 7.0% vs. 9.6%, HR 0.71, 95% CI 0.56-0.89
- Nonfatal MI: 2.9% vs. 3.6%, HR 0.80, 95% CI 0.55-1.15
- Change in HbA1c from baseline to week 104: -0.87 vs. -0.06 (p < 0.05)
- Change in body weight from baseline to week 104: -5.55 kg vs. -1.45 kg (p < 0.05)
- Mean change in systolic BP: -3.79 vs. -1.55 mm Hg (p < 0.05)
- Mean change in diastolic BP: -0.23 vs. -1.01 mm Hg (p < 0.05)
Interpretation:
The results of this trial show that among patients with CKD and DM2, once weekly subcutaneous semaglutide was superior to placebo in improving renal and CV outcomes over a median follow-up of 3.4 years. Reductions in all-cause and CV mortality were also noted. A modest reduction in body weight (4.1 kg greater weight loss), HbA1c (0.81% greater reduction), and systolic BP (~2.2 mm Hg greater reduction) was observed between baseline and 104 weeks. Semaglutide slowed eGFR loss by 1.16 mL/min/m2. These are landmark findings and are likely to have a major impact on the management of CKD and DM2.
A similar improvement in renal outcomes with SGLT2 inhibitors has been reported before. In this trial, approximately 15% of patients were on these agents at baseline. Although the p-value for interaction was negative and the sample size small (n = 550), patients on SGLT2 inhibitors did not appear to have the same benefit for the primary endpoint numerically. Head-to-head comparisons between these agents as well as potential combination use will need to be explored in future trials.
References:
Perkovic V, Tuttle KR, Rossing P, et al., on behalf of the FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients With Type 2 Diabetes. N Engl J Med 2024;May 24:[Epub ahead of print].
Clinical Topics: Diabetes and Cardiometabolic Disease
Keywords: Cardiometabolic Diseases, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors
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