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General Study Overview

Citation for this article

Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.  N Engl J Med. Published online May 24, 2024. doi:10.1056/NEJMoa2403347

Background

Title

· Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes

· New England Journal of Medicine

· Published May 24, 2024

Background

· Over time, uncontrolled type 2 diabetes mellitus (T2DM) can cause chronic kidney disease (CKD) and affects over half a billion people worldwide. As fibrosis continues, proteinuria will cause further damage.

· Although there are drugs that have shown to be renal protective and decrease the risk of cardiovascular disease, such as RAS inhibitors and SGLT2 inhibitors, many people continue to lose kidney function.

· This study was conducted to find the efficacy and safety of using a glucagon-like peptide 1 (GLP-1) receptor agonist, semaglutide 1.0 mg SUBQ once weekly, to prevent kidney failure and damage to those with T2DM and CKD.

Previous Trials

· LEADER (2016): multicenter, double blind, placebo-controlled trial to show the impact of liraglutide on death from CV events, nonfatal MI, or nonfatal stroke. Prespecified outcomes included composite renal microvascular outcomes (nephropathy, the need for continuous renal replacement therapy, or death from renal disease). The incidence was lower in the liraglutide group than in the placebo group with:

· Hazard ratio: 0.78; 95% CI: 0.67 to 0.92; P=0.003

· SUSTAIN-6 (2016): randomized, double blind, placebo controlled, parallel group trial to show the impact of semaglutide on death from CV events, nonfatal MI, or nonfatal stroke. Prespecified secondary outcomes included new or worsening nephropathy occurred in 3.8% in the semaglutide group vs 6.1% in the placebo group.

· Hazard ratio: 0.64; 95% CI: 0.46 to 0.88; P=0.005

Funding

· Sponsored, managed trial operations, and analysis by Novo Nordisk

Objective

Study Objective

· To evaluate if semaglutide 1.0 mg SUBQ once weekly will delay the progression of renal damage compared to placebo in patients with T2DM and CKD.

Methods

Study Design

· International, double blinded, randomized, placebo controlled

· Intention to treat protocol

Enrollment

· N = 3533, with a 1:1 randomization to receive semaglutide (N=1767) or placebo (N=1766)

· Performed at 387 sites in 28 countries (recruitment from June 2019-May 2021)

Inclusion Criteria

· Informed consent obtained

· Age ≥18 years

· Diagnosed with T2DM

· HbA1c ≤ 10%

· Serum creatinine based eGFR between 50-75 mL/min/1.73 m2 using 2009 CKD-EPI and UACR between 300–5000 mg/g or serum creatinine based eGFR between 25 - 50 mL/min/1.73 m2 using 2009 CKD-EPI and UACR between 100 – 5000 mg/g

· Treated with maximum tolerated dose of RAAS inhibitor (ACE inhibitor or ARB), unless contraindicated, for ≥4 weeks before lab assessments measured for inclusion criteria and kept stable until screening

Exclusion Criteria

· Congenital or hereditary kidney disease

· Use of GLP-1 receptor agonist within 30 days before screening

· MI, stroke, hospitalization for unstable angina pectoris or TIA within 60 days before screening

· NYHA Class IV heart failure

· Planned coronary, carotid, or peripheral artery revascularization

· Current or within 90 days of chronic or intermittent hemodialysis or peritoneal dialysis

· Uncontrolled and unstable diabetic retinopathy or maculopathy

Interventions

· Two arms: semaglutide at an 8 week dose-escalation regimen given that unacceptable side effects did not occur from 0.25 mg SUBQ weekly x 4 weeks, then 0.5 mg SUBQ weekly x 4 weeks, then 1.0 mg SUBQ weekly for the remaining treatment period

· The trial ended with a final participant visit on January 9, 2024

Primary endpoint

· Major kidney disease events

· Initiation of long-term dialysis

· Kidney transplant

· eGFR reduction to <15 ml/min/1.73m2 for ≥28 days

· ≥50% reduction in eGFR compared to baseline

· Renal or CV death

· Calculated a minimum of 854 primary events needed to provide 90% power to detect a 20% relative risk in the semaglutide group than placebo at an overall one-sided significance level of 2.5%

Secondary endpoints

· Annual rate of eGFR change using CKD-EPI

· Time to first occurrence of major CV events (non-fatal MI, non-fatal stroke, CV death)

· Time to occurrence of all cause death

Other efficacy endpoints

· UACR

· Body weight

Safety endpoints

· CV, eye, or GI disorders

· Infections or infestations

Key definitions

· Kidney disease – eGFR 50-75 ml/min/1.73m2 using 2009 CKD-EPI equation with UACR 300-5000 mg/g or eGFR 25-50 ml/min/1.73m2 with UACR 100-5000mg/g

· Type 2 diabetes – glycated hemoglobin level ≤ 10%

Statistics

· The trial was event driven, with time-to-first-event outcomes analyzed using a stratified Cox proportional hazards model with randomization as a fixed factor and grouped according to SGLT2 inhibitor use at baseline

· P values obtained using a score test

· Pre-specified subgroups for primary endpoint analysis included baseline eGFR, UACR, and SGLT2 inhibitor use

· Secondary outcomes analyzed with two sided CI’s and an alpha value of < 0.05 considered significant

Results

Baseline Characteristics

See Table 1, pages 4-5 in article

· Mean age of 66.6 years with ~30% women

· Mean eGFR was 47 ml/min/1.73m2 with mean UACR being 567.6 mg/g

· 68% of participants at high risk for kidney disease progression, kidney failure, CV events, or death

· Patient demographic characteristics were matched with no significant difference between the treatment and placebo group

Primary endpoint results

See Table 2, pages 8-9 in article

· 331 first events(18.7%) in semaglutide arm vs. 410 first events (23.2%) in placebo arm

· Hazard ratio 0.76; 95% confidence interval [CI] 0.66 to 0.88; P=0.0003

· NTT over 3 years to prevent one primary outcome event was 20 (95% CI 14-40)

· Results were consistent across range of prespecified sensitivity analysis and participant subgroups

Secondary endpoint results

See Table 2, pages 8-9 in article

· Mean annual slope of eGFR was less steep in semaglutide vs placebo

· Risk of major CV events was lower in semaglutide vs placebo (individual components of MI and death from CV events were consistent with primary analysis but fewer stroke in placebo vs semaglutide)

· Risk of death from any cause was lower in semaglutide vs placebo

· NNT = 45 persons over 3 years to prevent one major CV event

· NNT = 39 persons over 3 years to prevent once death from any cause

Author’s Conclusions

Author’s Conclusions

”Semaglutide at a dose of 1.0 mg once weekly significantly reduced the risk of major kidney disease events (the primary outcome), by 24%. Semaglutide also reduced the risk of major cardiovascular events and death from any cause while slowing the annual loss of kidney function by a mean of 1.16 ml/minute/1.73 m2”

Discussion

Strengths

· Large, international, multicenter population

· double blinded, randomized, placebo-controlled trial

Patient demographic characteristics were matched with no significant difference between the treatment and placebo group

Limitations

· Did not assess effects of combination therapy of SGLT2 inhibitors or nonsteroidal MRAs

· No generalizable to marginalized populations such as Black and Indigenous persons or persons with lower risk of kidney disease progression

· Novo Nordisk sponsored, maintained the clinical database, conducted statistical analysis, and reviewed the manuscript to provide suggested revisions

Overall Assessment

Although the FLOW trial has limitations, it has showed statistically and clinically significant results in reducing the risk of major kidney disease compared to placebo for those with T2DM and CKD. Future studies need to be done to access combination therapy, especially since SGLT2 inhibitors and nonsteroidal MRAs have been approved for kidney protection and affect more patients.