Table 1.
Overview of recent SGLT2-inhibitor clinical trials design and results
| Trial Name | Drug | Duration (median) |
Cohort | Primary outcome | Key secondary outcomes |
|---|---|---|---|---|---|
| Cardiovascular Outcome Trials | |||||
| EMPA-REG Outcome [18] | Empagliflozin vs. placebo | 3.1 years |
n = 7020; T2DM with established CVD |
3P-MACE (HR 0.86; 95% CI 0.74–0.99) |
- 3P-MACE + hospitalisation for UA (HR 0.89; 95% CI 0.78 to 1.01) - CV death (HR 0.62; 95% CI 0.49 to 0.77) - HHF (HR 0.65; 95% CI 0.50 to 0.85) - CV death/HHF (HR 0.66; 95% CI 0.55 to 0.79) - Death from any cause (HR 0.68; 95% CI 0.57 to 0.82) |
| CANVAS [22] | Canagliflozin vs. placebo | 2.4 years |
n = 9734; Poorly controlled T2DM plus i) age 30 + and history of symptomatic atherosclerotic CVD or ii) age 50 + and high risk of CVD |
3P-MACE (HR 0.86; 95% CI 0.75–0.97) |
- CV death (hazard ratio, 0.87; 95% CI 0.72 to 1.06) - Progression of albuminuria (30% increase) (HR 0.73; 95% CI 0.67 to 0.79) - CV death/HHF (HR 0.78; 95% CI 0.67 to 0.91) |
| DECLARE-TIMI 58 [23] | Dapagliflozin vs. placebo | 4.2 years |
n = 17,160; age 40 + with T2DM and either history or high risk of atherosclerotic CV events |
3P-MACE (HR 0.93; 95% CI 0.84–1.03) CV death/HHF (HR 0.83; 95% CI 0.73–0.95) |
- > 40% reduction in eGFR/new ESRD/renal death/CV death (HR 0.76; 95% CI 0.67–0.87) - Death from any cause (HR 0.93; 95% CI 0.82–1.04) |
| VERTIS CV [28] | Ertugliflozin vs. placebo | 6.1 years |
n = 8246; T2DM and established ASCVD |
3P-MACE (HR 0.97; 95% CI 0.85–1.11) |
- CV death/HHF (HR 0.88; 95% CI 0.75–1.03) - HHF (HR 0.70; 95% CI 0.54–0.90) - Progression of renal disease (HR 0.81; 95% CI 0.63–1.04) |
| Heart Failure Outcome Trials | |||||
| DAPA-HF [31] | Dapagliflozin vs. placebo | 1.5 years |
n = 4744; HFrEF (LVEF < 40%); NTproBNP > 400–600 (depending on criteria); with or without T2DM |
Time to first occurrence of CV death/ HHF/ urgent HF visit (HR 0.74; 95% CI 0.65–0.85) |
- CV Death/HHF (HR 0.75; 95% CI 0.65–0.85) - ≥ 50% sustained reduction in eGFR/ reaching ESRD/renal death (HR 0.71; 95% CI 0.44–1.16) - KCCQ (HR 1.18; 95% CI 1.11–1.26) - Death from any cause (HR 0.83; 95% CI 0.71–0.97) |
| EMPEROR-Reduced [32] | Empagliflozin vs. placebo | 16 months |
n = 3730; HFrEF (LVEF ≤ 40%; NYHA II-IV); NTproBNP > 600–5000 (specific criteria based on diagnosis of AF and EF); with or without diabetes |
Time to first occurrence of CV death/ HHF (HR 0.75; 95% CI 0.65–0.86) |
- CV death (HR 0.92; 95% CI 0.75–1.12) - First HHF (HR 0.69; 95% CI 0.59–0.81) - HHF (HR 0.70; 95% CI 0.58–0.85) - Decline in eGFR (1.73 ml/min/1.73m2/year slower decline in treatment arm; 95% CI 1.10–2.37 - Death from any cause (HR 0.92; 95% CI 0.77 to 1.10) |
|
DELIVER [65] (Currently recruiting – est completion June 2021) |
Dapagliflozin vs. placebo | 2.75 years |
n = 6100; HFpEF (LVEF > 40%); Elevated NT-proBNP; Ambulatory and hospitalised patients |
Time to first occurrence of CV death/ HHF/ urgent HF visit |
- KCCQ - Worsening NYHA class - Total number of CV death or HHF - Time to death from any cause |
|
EMPEROR-Preserved [66] (est completion Nov 2020) |
Empagliflozin vs. placebo | 3.2 years |
n≈5988; HFpEF (LVEF > 40%) + structural heart disease; NTproBNP > 300; with or without diabetes |
Time to first occurrence of CV death/ HHF |
- CV death - HHF - All-cause hospitalisation - Change in KCCQ - RRT or sustained reduction of ≥ 40% eGFR - All-cause mortality - Onset of DM |
| Mechanistic / Biomarker Trials | |||||
| REFORM [61] | Dapagliflozin vs. placebo | 12 months |
n = 58; T2DM; stable HFrEF (LVEF ≤ 45%) NYHA class I-III; on furosemide ≤ 80 mg or other loop diuretics; eGFR ≥ 45 |
Change in indexed LVESV (2.49 mL/m2; 95% CI -6.30 to 11.28) |
- LVMi (2.5 g/m2; 95% CI -3.95 to 8.95) - LVEF (0.69%; 95% CI -3.32 to 4.69) -LVEDV (indexed; 3.9 mL/m2; 95% CI -7.05 to 14.85) - Weight (-2.26 kg; 95% CI -4.83 to 0.31) - SBP (-4.7 mmHg; 95% CI -14.51 to 5.11) - Haematocrit (2.89%; 95% Cl 1.14 to 4.64) - Loop diuretic dose (-29.06 mg; 95% CI -42.17 to -15.95) |
| RECEDE-CHF [17] | Empagliflozin vs. placebo | 6 weeks |
n = 23; T2DM and HF (NYHA II-III; LVEF < 50%); eGFR ≥ 45 ml/min/1.73m2; median NT-proBNP 2381; on furosemide or equivalent loop diuretic therapy |
Mean change in 24-h urinary volume at 6 weeks (545 ml, 95% CI 136–954) |
- 24-h urinary sodium excretion (7.85 mmol/L; 95% CI -2.43 to 6.73) - Electrolyte-free water clearance (312 ml; 95% CI 26–598) - Fractional clearance of sodium (0.11%; 95% CI -0.22 to 0.44) - Change in urine creatinine (-1.66 mmol/L; 95% CI -3.07 to -0.25) - Change in NTproBNP (283.4 pg/ml; 95% CI -835.8 to 1402.3) |
| DAPA-LVH [67] | Dapagliflozin vs. placebo | 12 months |
n = 66; T2DM; BMI ≥ 23; BP < 145/90 mmHg; LV hypertrophy |
Change in indexed LVM (-2.82 g; 95% CI -5.13 to -0.51) |
- LVMi (-0.20 g/m2; 95% CI -1.21 to 0.80) - LVEF (0.79%; 95% CI − 1.14 to 2.72) - EDV (-1.59mLS; 95% CI -7.06 to 3.87) - ESV (-1.12mLs; 95% CI -3.50 to 1.25) - Ambulatory SBP (-3.63 mmHg; 95% CI -6.44 to -0.82) - Abdominal obesity (-609.76cm3; 95% CI -948.13 to -271.28) - Weight (-3.77 kg; 95% CI -4.92 to -2.61) - Haematocrit (2.90%; 95% CI 1.84 to 3.96) - NT-proBNP (-103.68 pg/mL; 95% CI -326.90 to 119.54) |
| EMPA HEART Cardio-Link 6 [64] | Empagliflozin vs. placebo | 6 months |
n = 97; T2DM; established CVD (MI ≥ 6 months, or coronary revascularization ≥ 2 months) |
Change in indexed LVM (-3.35 g/m2; 95% CI -5.9 to -0.81) |
- LVEDV (− 0.9 mL/m2; 95% CI -8.5 to − 6.7) - ESV (− 2.2 mL/m2; 95% CI -7.3 to 2.8) - LVEF (2.2%; 95% CI -0.2 to 4.7) - NT-proBNP (7.4 pg/mL; 95% CI − 10.3, 25.1) |
| DEFINE-HF [62] | Dapagliflozin vs. placebo | 12 weeks |
n = 263; HFrEF (LVEF ≤ 40%, and NYHA class II-III) with or without T2DM |
i) average of 6- and 12-week mean NT-proBNP (HR 0.95; 95% CI 0.84 to 1.08) ii) ≥ 5-point increase in average of 6- and 12-week KCCQ-OS or ≥ 20% reduction in average of 6- and 12-week NT-proBNP (OR 1.8, 95% CI 1.03 to 3.06) |
- KCCQ 6 weeks (OR 1.8; 95% CI 1.04 to 3.12) and 12 weeks (OR 1.7; 95% CI 0.98 to 3.1) - ≥ 20% reduction NT-proBNP at 6 weeks (OR 1.1; 95% CI 0.6 to 1.9) and 12 weeks (OR 1.9; 95% CI 1.09 to 3.31) - ≥ 20% reduction in BNP at 6 weeks (OR 1.5; 95% CI 0.9 to 2.7) and 12 weeks (OR 2.0; 95% CI 1.1 to 3.4) - 6MWT—adjusted distance at week 12 (304 m vs 301 m) - Mean weight reduction of -1.33 kg without T2DM Dapa vs. placebo (95% CI -2.41 to -0.23 kg) - HHF or urgent HF visits (HR 0.84; 95% CI 0.35 to 1.97) |
|
EMPA-TROPISM [68] (est completion Dec 2020) |
Empagliflozin vs. placebo | 6 months |
n = 84; stable HFrEF (LVEF < 50%) NYHA II-III); with or without T2DM |
Changes in LVESV/LVEDV |
- LVEF index - VO2 Consumption - 6MWT - KCCQ-12 |
| Renal Outcome Trials | |||||
| CREDENCE [52] | Canagliflozin vs. placebo | 2.6 years |
n = 4401; T2DM; CKD (eGFR 30 to < 90 ml/minute/1.73 m2); albuminuria (UACR > 300 to 5000); on ACEi/ARB therapy |
ESRD/ serum creatinine × 2 baseline (30 + days)/ renal or CV death (HR 0.70; 95% CI 0.59 to 0.82) |
- CV death/HHF (HR 0.69; 95% CI 0.57 to 0.83) - CV death/ MI/ stroke (HR 0.80; 95% CI 0.67 to 0.95) - HHF (HR 0.61; 95% CI 0.47 to 0.80) - CV death (HR 0.78; 95% CI 0.61 to 1.00) - Death from any cause (HR 0.83; 95% CI 0.68 to 1.02) - CV death/ MI/ stroke/ hospitalization for HF or UA (HR 0.74; 95% CI 0.63 to 0.86) |
| DAPA-CKD [69] | Dapagliflozin vs. placebo | 2.4 years |
n = 4304; with or without diabetes; eGFR ≥ 25 and ≤ 75 ml/min/1.73m2; UACR ≥ 200 or ≤ 5000 mg/g; maximum tolerated daily dose of ACEi or ARB |
≥ 50% decline in eGFR/reaching ESRD/CV death/renal death (HR 0.61; 95% CI 0.51–0.72) |
- HHF/ CV death (HR 0.71; 95% CI 0.55–0.92) - Death from any cause (HR 0.69; 95% CI 0.53–0.88) - ≥ 50% decline in eGFR/reaching ESRD/renal death (HR 0.56; 95% CI 0.45–0.68) |
|
EMPA-Kidney [70] (est completion June 2022) |
Empagliflozin vs. placebo | 3.1 years |
n≈6000; CKD + risk of kidney disease progression (depending on criteria); g on ACEi or ARB therapy |
Time to first occurrence of: (i) Kidney disease progression (ESRD, sustained decline in eGFR to < 10 mL/min/1.73m2, renal death, decline of ≥ 40% in eGFR) or (ii) Cardiovascular death |
Time to: - HHF or CV death - All-cause hospitalisations - Death from any cause - First occurrence of kidney disease progression - CV death - CV death or ESRD |
3P-MACE, Composite of: CV Death; non-fatal MI; non-fatal Stroke); ASCVD, atherosclerotic cardiovascular disease; UA, unstable angina; LVEF, left ventricle ejection fraction; ESRD, end Stage Renal Disease; KCCQ, Kansas City Cardiomyopathy Questionnaire; 6MWT, 6-min walk test; ITT, intention to treat analysis; LVSD, left ventricular systolic dysfunction; LV, left ventricle; CVD, cardiovascular disease; LVEDV, LV end-diastolic volume; ESV, End-systolic volume; EDV, end diastolic volume; BIA, Bioelectrical impedence Analysis; CPET, Cardio-pulmonary Exercise Testing; LVM, LV mass; CMRI, cardiac magnetic resonance imaging; LVMi, BSA indexed LVM; CKD, chronic kidney disease; ACEi, angiotensin-converting–enzyme inhibitor; ARB, angiotensin-receptor blocker; UACR, urine albumin-to-creatinine ratio; RRT, renal replacement therapy