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Table 3 Recent clinical trials of SGLT-2i agents with kidney outcomes

From: New strategies to improve clinical outcomes for diabetic kidney disease

Study

Inclusion criteria

Participants

Kidney outcome(s)

HR (95% CI) or other as specified

Studies with at least one primary kidney outcome

 CREDENCE [41]

Feb 2014–Oct 2018

695 sites in 34 countries [42]

Adults with T2D, HbA1c 6.5% to 12.0%, age ≥30 yrs, eGFR (CKD-EPI) 30 to ≤90 AND UACR 300-5000, taking stable dose of ACEi or ARB for ≥4 weeks prior to randomization

N=2202 100 mg canagliflozin once daily

N=2199 placebo once daily

BL: mean age 63 yrs, 66% male, 67% white, mean HbA1c 8.3%, mean duration T2D 16 yrs, mean eGFR 56, median UACR 927

A) Primary kidney composite outcome of ESKD (dialysis for ≥30 days or kidney transplantation or eGFR≤15), doubling of serum creatinine from BL sustained for ≥30 days, or death from kidney or CVD cause

B) Secondary kidney composite outcome of ESKD, doubling of serum creatinine, or kidney death

C) ESKD

D) Doubling of serum creatinine

E) Dialysis or kidney transplantation

F) Kidney death

G) ESKD, kidney- or CVD-related death

Dialysis, kidney transplantation, or kidney death

A) 0.70 (0.59–0.82)

B) 0.66 (0.53–0.81)

C) 0.68 (0.54–0.86)

D) 0.60 (0.48–0.76)

E) 0.74 (0.55–1.00)

F) –

G) 0.73 (0.61–0.87)

0.72 (0.54–0.97)

 DAPA-CKD [43]

Feb 2017–June 2020

386 sites in 21 countries

Adults with or without T2D, an eGFR of 25-75 AND a UACR of 200–5000, taking stable dose of ACEi or ARB >4 weeks prior to screening

N=2152 10mg dapagliflozin once daily

N=2152 placebo once daily

BL: mean age 62 yrs, 67% male, 53% white, 68% T2D, mean eGFR 43, 48% had UACR >1000

A) Primary kidney composite outcome of decline of at least 50% in eGFR or death from kidney or CV cause in participants overall;

B) Primary kidney composite outcome of decline of at least 50% in eGFR or death from kidney or CV cause in participants with T2D;

C) Primary kidney composite outcome of decline of at least 50% in eGFR or death from kidney or CV cause in participants without T2D

D) Secondary kidney outcomes: composite of sustained eGFR decline of at least 50%, ESKD, kidney death;

Between-group difference in LS mean slope of eGFR from BL to month 30

A) 0.61 (0.51–0.72)

B) 0.64 (0.52–0.79)

C) 0.50 (0.35–0.72)

D) 0.56 (0.45–0.68)

Difference = 0.93 mL/min/ 1.73m2/yr (0.61–1.25)

Studies with kidney outcomes as secondary outcome(s) only

 EMPA-REG OUTCOME [44]

July 2010–April 2015

590 sites in 42 countries

Adults with T2D, HbA1c 7.0 to 10% if on antidiabetic therapy or 7 to 9% for drug naïve, age ≥18 yrs, established CVD or high risk for CVD, eGFR (MDRD) ≥30

N=4685 empagliflozin (10 or 25 mg) once daily

N=2333 placebo once daily

BL: mean age 64.5 yrs, 70% male, 72% white, mean HbA1c 8.1% [45]

A) Incident or worsening nephropathy (UACR >300)

B) Doubling of serum creatinine AND eGFR ≤45

C) Initiation of kidney replacement

D) Composite outcome of incident or worsening nephropathy or CV-related death

E) Progression to macroalbuminuria

F) Composite of b + c + kidney-related death

G) Incident albuminuria (UACR≥30) in those with normal albuminuria at BL

A) 0.61 (0.53–0.70)

B) 0.56 (0.39–0.79)

C) 0.45 (0.21–0.97)

D) 0.61 (0.55–0.69)

E) 0.62 (0.54–0.72)

F) 0.54 (0.40–0.75)

G) 0.95 (0.87–1.04)

 CANVAS, CANVAS-R [46]

Dec 2009–Feb 2017

667 sites in 30 countries

Adults with T2D, HbA1c 7% to 10.5%, eGFR ≥30, age ≥30 yrs with symptomatic history of CVD, or age ≥50 yrs with 2+ risk factors for CVD

N=5795 canagliflozin (100 or 300 mg)

N=4347 placebo

BL: mean age 63.3 yrs, 64% male, 78% white, mean duration T2D=14 yrs, mean HbA1c 8.2%

A) Composite of progression of albuminuria (more than 30% increase in albuminuria), change from either normoalbuminuria to microalbuminuria or micro- to macroalbuminuria

B) Regression of albuminuria

C) Composite of 40% reduction in eGFR for at least 2 consecutive measures, need for kidney replacement therapy, and kidney-related death

A) 0.73 (0.67–0.79)

B) 1.70 (1.51–1.91)

C) 0.60 (0.47–0.77)

 DECLARE-TIMI 58 [47]

April 2013–Sept 2018

882 sites, 33 countries

Adults with T2D, HbA1c 6.5% to 11.9%, age ≥40 yrs, creatinine clearance ≥60 ml/min, with multiple CVD risk factors or established CVD

N=8582 dapagliflozin (10 mg once daily)

N=8578 placebo (once daily)

BL: mean age 64 yrs, 63% male, 80% white, mean HbA1c 8.3%, median duration T2D 10.5 yrs, mean eGFR 85

A) Composite of sustained decrease in eGFR (per CKD-EPI) of 40% or more to less than 60, new ESKD, or death from kidney or CV cause

B) Sustained decrease in eGFR (per CKD-EPI) of 40% or more to less than 60, new ESKD, or death from kidney cause

A) 0.76 (0.67–0.87)

B) 0.53 (0.43–0.66)

 VERTIS-CV [48]

Nov 2013–Dec 2019

567 sites in 34 countries

Adults, with T2D and established atherosclerotic CVD, age ≥40 yrs, HbA1c 7.0% to 10.5%, BMI≥18 kg/m2, eGFR ≥30

N=5499 5 or 15 mg ertugliflozin once daily

N=2747 placebo once daily

BL: mean age 64 yrs, 70% male, 88% white, mean HbA1c 8.2%, mean duration T2D 13 yrs, mean eGFR 76

Composite of kidney death, kidney replacement therapy, or doubling of serum creatinine

0.81 (0.63–1.04)

 EMPEROR REDUCED [49]

March 2017–May 2020

520 sites in 20 countries

Adults with chronic heart failure and left ventricular ejection fraction <40%, age ≥18 yrs

Note: Roughly 7 in 10 participants were taking MRAs at BL

N=1863 10 mg empagliflozin once daily

N=1867 placebo once daily

BL: mean age 67 yrs, 76% male, 70% white, 50% DM, mean eGFR 62

A) Rate of decline in eGFR calculated per CKD-EPI equation

B) Composite kidney outcome of chronic dialysis or kidney transplantation, profound & sustained reduction in eGFR

A) Between group difference=1.73 ml/min/1.73m2 (1.10–2.37)

B) 0.50 (0.32–0.77)

  1. Abbreviations: SGLT-2i, sodium glucose transport protein 2 inhibitor; HR, hazard ratio; CI, confidence interval; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients, T2D type 2 diabetes, HbA1c glycated hemoglobin, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, in mL/min/1.73 m2 body surface area, MDRD Modification of Diet in Renal Disease, BL baseline, yrs years, UACR urine albumin to creatinine ratio, in mg albumin to g creatinine, CV cardiovascular, CANVAS, CANVAS-R Canagliflozin Cardiovascular Assessment Study, DECLARE-TIMI 58 Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58, CKD-EPI chronic kidney disease epidemiology collaboration, ESKD end-stage kidney disease, VERTIS-CV EValuation of ERTugliflozin effIcacy and safety – CardioVascular outcomes, BMI body mass index, EMPEROR REDUCED Empagliflozin Outcome Trial in Patients with Chronic Heart Failure, Reduced Ejection Fraction. MRA mineralocorticoid receptor antagonist, DM diabetes mellitus, CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, ACEi angiotensin-converting enzyme inhibitor(s), ARB angiotensin II receptor blocker(s), DAPA-CKD Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease, LS least-square, BL baseline