Evaluate Renal Function With Semaglutide Once Weekly - FLOW

Oct 09, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Novo Nordisk
Date Published:
08/30/2024
Date Updated:
10/09/2024
Original Posted Date:
05/29/2024
References

Contribution To Literature:

Highlighted text has been updated as of October 9, 2024.

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)

Impact on CV outcomes by CKD severity: Participants with lower eGFR, higher urine albumin-to-creatinine ratio (UACR), or Kidney Disease Improving Global Outcomes (KDIGO) risk class also had a higher incidence of CV outcomes and all-cause mortality. In the overall population, semaglutide reduced rates of the composite of CV death/MI/stroke compared with placebo (HR 0.82 [95% CI 0.68-0.98]). Number needed to treat (NNT) to prevent one composite endpoint at 156 weeks was 45. Consistent treatment effects were observed across all CKD categories, defined by eGFR, UACR, or KDIGO risk class (p for interaction > 0.05). All-cause mortality was similarly reduced by semaglutide compared with placebo with similar consistent effects across subgroups of CKD. NNT at 156 weeks to prevent one death was 39.

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. These improvements were noted across a broad range of CKD severity. 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:

Mahaffey KW, Tuttle KR, Arici M, et al., on behalf of the FLOW Trial Committees and Investigators. Cardiovascular Outcomes With Semaglutide by Severity of Chronic Kidney Disease in Type 2 Diabetes: The FLOW Trial. Eur Heart J 2024;Aug 30:[Epub ahead of print].

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;391:109-21.

Clinical Topics: Diabetes and Cardiometabolic Disease

Keywords: Cardiometabolic Diseases, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors


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