| Reference | Study type | Population | Intervention and comparison | Outcomes | Risk of bias |
|---|---|---|---|---|---|
| RCT=randomized controlled trial; eGFR = an estimated glomerular filtration rate; MI = myocardial infarction; TIA = transient ischemic attack. | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | RCT NCT03819153 |
Randomized 1:1, double-blind, placebo-controlled trial. Median follow-up period: 3.4 years (range, 0 to 4.5). Between June 2019 and May 2021, 5581 patients were screened and 3533 were randomized. Europe 26.7 %, North America 23.9 %, Asia 27.1 %, Other 22.3 %. Included patients were adults (mean age 66.6±9.0 years, female 30.3%) with type 2 diabetes with HbA1c ≤10% (86 mmol/mol) and chronic kidney disease defined as either eGFR of 50 - 75 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 300 to 5000 mg/g or an eGFR of 25 - 50 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 100 to 5000 mg/g, treated with a stable maximum labelled or tolerated dose of renin-angiotensin system blockade. The mean eGFR was 47.0 ml/min/1.73 m2, and the median urinary albumin-to-creatinine ratio was 567.6. mg/g. Excluded patients had congenital or hereditary kidney disease or autoimmune kidney disease, history of a recent MI, stroke, recent hospitalization for unstable angina or TIA, NYHA class IV heart failure, malignant neoplasm within 5 years, dialysis treatment or a kidney transplant. |
Intervention: Semaglutide Participants received subcutaneous semaglutide treated up to 1.0 mg per week. Comparison: Placebo Participants received matching placebo once in week in addition to standard of care therapy. |
The primary composite outcome, assessed in a time-to-first-event analysis, was 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 per minute
per 1.73 m2 sustained for ≥28 days), a sustained (for ≥28 days) 50% or greater reduction in eGFR
from baseline, or death from kidney-related or cardiovascular causes. Three confirmatory secondary outcomes were total eGFR slope (i.e., the annual rate of change in eGFR from randomization to the end of the trial); major cardiovascular events (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes), assessed in a time-to-first-event analysis; and death from any cause. |
Low |
| Reference | Comments |
|---|---|
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) study evaluated whether
treatment with once-weekly subcutaneous semaglutide delays the progression of kidney
disease and lowers the risk of kidney failure, as well as kidney and cardiovascular
disease mortality, compared with placebo in people with chronic kidney disease and
type 2 diabetes. The trial was stopped early for efficacy after the single planned formal interim analysis, so its treatment effect may be overestimated. Semaglutide or placebo was permanently discontinued by 26% of participants during the trial. Only 11.3% of patients had baseline eGFR <30 mL/min/1.73 m2, so, whether GLP-1 receptor agonists are safe and effective in patients with severe CKD is unknown. Only 15.6% of patients were treated with sodium–glucose cotransporter-2 (SGLT2) inhibitors at baseline, so the stydy was underpowered to assess the effects of combination therapy. |
Results
| Reference | Number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| I= intervention; C=comparison; CI=confidence interval | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | 1767/1766 | 3.4 | 331 (18.7%) | 410 (23.2%) | 0.76 (0.66-0.88) |
| Level of evidence: high | |||||
| Reference | Number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| I= intervention; C=comparison; CI=confidence interval | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | 1767/1766 | 3.4 | 165 (9.3%) | 213 (12.1%) | 0.73 (0.59-0.89) |
| Level of evidence: high | |||||
| Reference | Number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| I= intervention; C=comparison; CI=confidence interval | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | 1767/1766 | 3.4 | 123 (7.0%) | 169 (9.6%) | 0.71 (0.56-0.89) |
| Level of evidence: high | |||||
| Reference | Number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| I= intervention; C=comparison; CI=confidence interval | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | 1767/1766 | 3.4 | 218 (12.3%) | 260 (14.7%) | 0.79 (0.66-0.94) |
| Level of evidence: moderate | |||||
| Reference | Number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| I= intervention; C=comparison; CI=confidence interval | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | 1767/1766 | 3.4 | 212 (12.0%) | 254 (14.4%) | 0.82 (0.68-0.98) |
| Level of evidence: moderate | |||||
| Reference | Number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| I= intervention; C=comparison; CI=confidence interval. | |||||
| «Perkovic V, Tuttle KR, Rossing P, ym. Effects of S...»1 | 1767/1766 | 3.4 | 227 (12.8 %) | 279 (15.8%) | 0.80 (0.67-0.95) |
| Level of evidence: moderate | |||||
«Badve SV, Bilal A, Lee MMY, ym. Effects of GLP-1 r...»2: A meta-analysis including 11 RCTs and 85 373 participants assessed the effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes. Of these, ten trials enrolled 67 769 patients with type 2 diabetes, and the remaining trial enrolled 17 604 patients with pre-existing cardiovascular disease and a BMI ≥27 kg/m2 but no previous diagnosis of diabetes. Mean age of patients was 63.3 years and 34.4% were female. Apart from the FLOW trial (R1), no other trial specifically enrolled participants with high-risk kidney disease. The mean baseline eGFR was 77.2 ml/min/1.73 m2, and 22.7% of patients had an eGFR lower than 60 ml/min/1.73 m2. Only 8.8% of patients had a urinary albumin-to-creatinine ratio greater than 300 mg/g (33.8 mg/mmol).
The main kidney outcome was a composite outcome, consisting of kidney failure (kidney replacement therapy or a persistent eGFR <15 ml/min/1.73 m2), a sustained reduction in eGFR by at least 50%, or death from kidney failure. The main cardiovascular outcome was MACE, consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
Compared with placebo, treatment with GLP-1 receptor agonists reduced the composite kidney outcome by 18% (hazard ratio [HR] 0.82, 95% CI 0.73-0-93), kidney failure by 16% (HR 0.84, 0.72-0.99), MACE by 13% (HR 0.87, 0.81-0.93), and the risk of death due to any cause by 12% (HR 0.88, 0.83-0.93) in patients with type 2 diabetes. The number needed to treat to prevent one composite kidney outcome was 164 over 25.1 months.