| Reference | Study type | Population | Intervention and comparison | Outcomes | Risk of bias |
|---|---|---|---|---|---|
| «Perkovic V, Jardine MJ, Neal B, ym. Canagliflozin ...»1 | RCT NCT02065791 |
Randomized 1:1, double-blind, placebo-controlled trial. Median follow-up period: 2.6 years (range, 0.02-4.53 years). Between March 2014 and May 2017, 12 900 patients were screened and 4401 were randomized and included in the full analysis set. Europe 19.6 %, North America 26.9 %, Central/South America 21.4 %, Rest of the world 32.1 %. Included patients were ≥ 30 years with type 2 diabetes and glycated hemoglobin level 6.5-12.0% and chronic kidney disease defined as an estimated glomerular filtration rate ≥ 30 to < 90 mL per min per 1.73 m2 and urine albumin-to-creatinine ratio >300 to 5000 mg/g, treated with optimized renin-angiotensin system blockade. 50.4 % of patients had CVD at baseline. All patients had chronic kidney disease and type 2 diabetes. Excluded patients had a non-diabetic kidney disease, type 1 diabetes, had been treated with immunosuppression for kidney disease, or had a history of dialysis or kidney transplantation. |
Intervention: Canagliflozin (JNJ 28431754) Participants received canagliflozin 100 mg in addition to standard of care therapy. Comparison: Placebo Participants received matching placebo once daily in addition to standard of care therapy. |
The primary outcome was a composite of end-stage kidney disease (dialysis for at least 30 days, kidney transplantation, or an estimated GFR of <15 ml per minute per 1.73 m2 sustained for at least 30 days according to central laboratory assessment), doubling of the serum creatinine level from baseline (average of randomization and prerandomization value) sustained for at least 30 days according to central laboratory assessment, or death from renal or cardiovascular disease. | Low |
| «The EMPA-KIDNEY Collaborative Group, Herrington WG...»2 | RCT NCT03594110 |
Randomized 1:1, double-blind, placebo-controlled trial. Median follow-up period: 2.0 (interquartile range 1.5-2.4) years. Between February 2019 and April 2021, 8544 patients were screened and 6609 were randomized and included in the full analysis set. Europe 40.0 %, North America 26.0 %, Asia 34.0 %. Included patients were ≥ 18 years with race-adjusted eGFR (calculated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula16) of at least 20 but less than 45 ml per minute per 1.73 m2, regardless of the level of albuminuria, or with an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio of at least 200. Patients were required to be taking a clinically appropriate dose of a single-agent RAS inhibitor, but patients could be included, as specified in the protocol, if an investigator judged that a RAS inhibitor was not indicated or would not be not tolerated. Patients with or without diabetes were eligible. All patients had chronic kidney disease and 46.0 % had type 2 diabetes. Excluded patients had polycystic kidney disease, uncontrolled hypertension or symptomatic hypotension, ketoacidosis in the past 5 years, previous or scheduled bariatric surgery, or were undergoing maintenance dialysis or had a functioning kidney transplant. |
Intervention: Empagliflozin (BI 10773) Participants received empagliflozin 10 mg once daily in addition to standard of care therapy. Comparison: Placebo Participants received matching placebo once daily in addition to standard of care therapy. |
The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease (initiation of maintenance dialysis or receipt of a kidney transplant), a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. | Low |
| «Heerspink HJL, Stefánsson BV, Correa-Rotter R, ym....»3 | RCT NCT03036150 |
Randomized 1:1, double-blind, placebo-controlled trial. Median follow-up period: 2.4 (interquartile range 2.0-2.7) years. Between February 2017 and October 2018, 7517 patients were screened and 4304 were randomized and included in the full analysis set. Regional distribution of the study patients was not disclosed. Included patients were ≥ 18 years with or without type 2 diabetes who had an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 were eligible for participation. All the participants were required to be receiving a stable dose of an ACE inhibitor or ARB for at least 4 weeks before screening. However, participants who were documented to be unable to take ACE inhibitors or ARBs were allowed to participate. All patients had chronic kidney disease and 67.5 % had type 2 diabetes. Excluded patients a had documented diagnosis of type 1 diabetes, polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody–associated vasculitis or history of kidney transplantation. Participants who had received immunotherapy for primary or secondary kidney disease within 6 months before enrollment were also excluded. |
Intervention: Dapagliflozin (BMS-512148) Participants received dapagliflozin 10 mg once daily in addition to standard of care therapy. Comparison: Placebo Participants received matching placebo once daily in addition to standard of care therapy. |
The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease (defined as maintenance dialysis for ≥28 days, kidney transplantation, or an estimated GFR of <15 ml per minute per 1.73 m2), or death from renal or cardiovascular causes. | Low |
RCT=randomized controlled trial
| Reference | Comments |
|---|---|
| «Perkovic V, Jardine MJ, Neal B, ym. Canagliflozin ...»1 | The CREDENCE trial (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) evaluated the effect of the Sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin on kidney outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease and with optimized renin-angiotensin system blockade. |
| «The EMPA-KIDNEY Collaborative Group, Herrington WG...»2 | The EMPA-KIDNEY trial (The study of heart and kidney protection with empagliflozin) was designed to assess the effect of once-daily empagliflozin treatment on the progression of kidney disease and cardiovascular disease and to examine the safety profile of the drug in a wide range of patients with CKD. The trial aimed to include large numbers of patients without diabetes, patients with an eGFR of less than 30 ml per minute per 1.73 m2, and patients with low levels of proteinuria, as measured by the urinary albumin-to-creatinine ratio.14 |
| «Heerspink HJL, Stefánsson BV, Correa-Rotter R, ym....»3 | The DAPA-CKD trial (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular
Mortality in Patients With Chronic Kidney Disease) was designed to assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes |
Results
| Reference | Number of studies and number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Hazard ratio (95% CI) |
|---|---|---|---|---|---|
| «Perkovic V, Jardine MJ, Neal B, ym. Canagliflozin ...»1 | 4401 | 2.6 | 245/2022 (12.1 %) | 340/2199 (15.5 %) | 0.70 (0.59-0.82); P=0.00001 |
| «The EMPA-KIDNEY Collaborative Group, Herrington WG...»2 | 6609 | 2.0 | 432/3304 (13.1 %) | 558/3305 (16.9 %) | 0.72 (0.64-.82); p<0.001 |
| «Heerspink HJL, Stefánsson BV, Correa-Rotter R, ym....»3 | 4304 | 2.4 | 197/2152 (9.2 %) | 312/2152 (14.5 %) | 0.61 (0.51-0.72); p<0.001 |
| Level of evidence: high Assess the risk of bias and delete irrelevant sources of bias: The quality of evidence is downgraded due to variation. |
|||||
I= intervention; C=comparison; CI=confidence interval
| Reference | Number of studies and number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Relative effect (95% CI) |
|---|---|---|---|---|---|
| «Perkovic V, Jardine MJ, Neal B, ym. Canagliflozin ...»1 | 4401 | 2.6 | 118/2022 (5.8 %) | 188/2199 (8.5 %) | 0.60 (0.48-0.76); p<0.001 |
| «The EMPA-KIDNEY Collaborative Group, Herrington WG...»2 | 6609 | 2.0 | 359/3304 (10.9 %) | 474/3305 (14.3 %) | 0.70 (0.61-.81); NA |
| «Heerspink HJL, Stefánsson BV, Correa-Rotter R, ym....»3 | 4304 | 2.4 | 112/2152 (5.2 %) | 201/2152 (9.3 %) | 0.53 (0.42-0.67); NA |
| Level of evidence: high Assess the risk of bias and delete irrelevant sources of bias: The quality of evidence is downgraded due to variation. |
|||||
I= intervention; C=comparison; CI=confidence interval
«Nuffield Department of Population Health Renal Stu...»4: A meta-analysis of SGLT2 inhibitor trials including 13 RCTs and 90 413 participants. The prevalence of type 2 diabetes was over 99%, mean age ranged from 61.9 years to 71.8 years and 35.7% were female. Furthermore, four trials included 19 552 patients with chronic kidney disease and type 2 diabetes and were analysed also in a separate subcohort. The primary composite outcome was kidney disease progression (standardised to a definition of a sustained ≥50% decrease in eGFR from randomisation, a sustained low eGFR, ESKD (start of maintenance dialysis or receipt of a kidney transplant), or death from kidney failure).
Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0.63, 95% CI 0.58–0.69). In the subcohort of four RCTs including chronic kidney disease patients with type 2 diabetes, an SGLT2 inhibitor reduced the risk of kidney disease progression by 40% (relative risk [RR] 0.60, 95% CI 0.53–0.69).