Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: SGLT2 inhibitors
| . | EMPA-REG OUTCOME (8) (n = 7,020) . | CANVAS Program (9) (n = 10,142) . | DECLARE-TIMI 58 (196) (n = 17,160) . | CREDENCE (194) (n = 4,401) . | DAPA-CKD (197,239) (n = 4,304; 2,906 with diabetes) . | VERTIS CV (201,240) (n = 8,246) . | DAPA-HF (11) (n = 4,744; 1,983 with diabetes) . | EMPEROR-Reduced (200) (n = 3,730; 1,856 with diabetes) . | EMPEROR-Preserved (189,241) (n = 5,988; 2,938 with diabetes) . | DELIVER (199) (n = 6,263; 2,807 with diabetes) . |
|---|---|---|---|---|---|---|---|---|---|---|
| Intervention | Empagliflozin/placebo | Canagliflozin/placebo | Dapagliflozin/placebo | Canagliflozin/placebo | Dapagliflozin/placebo | Ertugliflozin/placebo | Dapagliflozin/placebo | Empagliflozin/placebo* | Empagliflozin/placebo | Dapagliflozin/placebo |
| Main inclusion criteria | Type 2 diabetes and preexisting CVD | Type 2 diabetes and preexisting CVD at ≥30 years of age or ≥2 CV risk factors at ≥50 years of age | Type 2 diabetes and established ASCVD or multiple risk factors for ASCVD | Type 2 diabetes and albuminuric kidney disease | Albuminuric kidney disease, with or without diabetes | Type 2 diabetes and ASCVD | NYHA class II, III, or IV heart failure and an ejection fraction ≤40%, with or without diabetes | NYHA class II, III, or IV heart failure and an ejection fraction ≤40%, with or without diabetes | NYHA class II, III, or IV heart failure and an ejection fraction >40% | NYHA class II, III, or IV heart failure and an ejection fraction >40% with or without diabetes |
| A1C inclusion criteria (%) | 7.0–10.0 | 7.0–10.5 | ≥6.5 | 6.5–12 | — | 7.0–10.5 | — | — | — | — |
| Age (years)† | 63.1 | 63.3 | 64.0 | 63 | 61.8 | 64.4 | 66 | 67.2, 66.5 | 71.8, 71.9 | 71.7 |
| Race (% White) | 72.4 | 78.3 | 79.6 | 66.6 | 53.2 | 87.8 | 70.3 | 71.1, 69.8 | 76.3, 75.4 | 71.2 |
| Sex (% male) | 71.5 | 64.2 | 62.6 | 66.1 | 66.9 | 70 | 76.6 | 76.5, 75.6 | 55.4, 55.3 | 56.1 |
| Diabetes duration (years)† | 57% >10 | 13.5 | 11.0 | 15.8 | 12.9 | |||||
| Median follow-up (years) | 3.1 | 3.6 | 4.2 | 2.6 | 2.4 | 3.5 | 1.5 | 1.3 | 2.2 | 2.3 |
| Statin use (%) | 77 | 75 | 75 (statin or ezetimibe use) | 69 | 64.9 | — | — | — | 68.1, 68.8 | — |
| Metformin use (%) | 74 | 77 | 82 | 57.8 | 29 | 51.2% (of people with diabetes) | — | — | — | |
| Prior CVD/CHF (%) | 99/10 | 65.6/14.4 | 40/10 | 50.4/14.8 | 37.4/10.9 | 99.9/23.1 | 100% with CHF | 100% with CHF | 100% with CHF | 100% with CHF |
| Mean baseline A1C (%) | 8.1 | 8.2 | 8.3 | 8.3 | 7.1% (7.8% in those with diabetes) | 8.2 | — | — | — | 6.6 |
| Mean difference in A1C between groups at end of treatment (%) | −0.3^ | −0.58‡ | −0.43‡ | −0.31 | — | −0.48 to −0.5 | — | — | — | — |
| Year started/reported | 2010/2015 | 2009/2017 | 2013/2018 | 2017/2019 | 2017/2020 | 2013/2020 | 2017/2019 | 2017/2020 | 2017/2020 | 2018/2022 |
| Primary outcome§ | 3-point MACE 0.86 (0.74–0.99) | 3-point MACE 0.86 (0.75–0.97) | 3-point MACE 0.93 (0.84–1.03) CV death or HF hospitalization 0.83 (0.73–0.95) | ESRD, doubling of creatinine, or death from renal or CV cause 0.70 (0.59–0.82) | ≥50% decline in eGFR, ESKD, or death from renal or CV cause 0.61 (0.51–0.72) | 3-point MACE 0.97 (0.85–1.11) | Worsening heart failure or death from CV causes 0.74 (0.65–0.85) Results did not differ by diabetes status | CV death or HF hospitalization 0.75 (0.65–0.86) | CV death or HF hospitalization 0.79 (0.69–0.90) | Worsening HF or CV death 0.82 (0.73–0.92) |
| Key secondary outcome§ | 4-point MACE 0.89 (0.78–1.01) | All-cause and CV mortality (see below) | Death from any cause 0.93 (0.82–1.04) Renal composite (≥40% decrease in eGFR rate to <60 mL/min/1.73 m2, new ESRD, or death from renal or CV causes 0.76 (0.67–0.87) | CV death or HF hospitalization 0.69 (0.57–0.83) 3-point MACE 0.80 (0.67–0.95) | ≥50% decline in eGFR, ESKD, or death from renal cause 0.56 (0.45–0.68) CV death or HF hospitalization 0.71 (0.55–0.92) Death from any cause 0.69 (0.53–0.88) | CV death or HF hospitalization 0.88 (0.75–1.03) CV death 0.92 (0.77–1.11) Renal death, renal replacement therapy, or doubling of creatinine 0.81 (0.63–1.04) | CV death or HF hospitalization 0.75 (0.65–0.85) | Total HF hospitalizations 0.70 (0.58–0.85) Mean slope of change in eGFR 1.73 (1.10–2.37) | All HF hospitalizations (first and recurrent) 0.73 (0.61–0.88) Rate of decline in eGFR (−1.25 vs. −2.62 mL/min/1.73 m2; P < 0.001) | Total number worsening HF and CV deaths 0.77 (0.67–0.89) Change in KCCQ TSS at month 8 1.11 (1.03–1.21) Mean change in KCCQ TSS 2.4 (1.5–3.4) All-cause mortality 0.94 (0.83–1.07) |
| Cardiovascular death§ | 0.62 (0.49–0.77) | 0.87 (0.72–1.06) | 0.98 (0.82–1.17) | 0.78 (0.61–1.00) | 0.81 (0.58–1.12) | 0.92 (0.77–1.11) | 0.82 (0.69–0.98) | 0.92 (0.75–1.12) | 0.91 (0.76–1.09) | 0.88 (0.74–1.05) |
| MI§ | 0.87 (0.70–1.09) | 0.89 (0.73–1.09) | 0.89 (0.77–1.01) | — | — | 1.04 (0.86–1.26) | — | — | — | — |
| Stroke§ | 1.18 (0.89–1.56) | 87 (0.69–1.09) | 1.01 (0.84–1.21) | — | — | 1.06 (0.82–1.37) | — | — | — | — |
| HF hospitalization§ | 0.65 (0.50–0.85) | 67 (0.52–0.87) | 0.73 (0.61–0.88) | 0.61 (0.47–0.80) | — | 0.70 (0.54–0.90) | 0.70 (0.59–0.83) | 0.69 (0.59–0.81) | 0.73 (0.61–0.88) | 0.77 (0.67–0.89) |
| Unstable angina hospitalization§ | 0.99 (0.74–1.34) | — | — | — | — | — | — | — | — | — |
| All-cause mortality§ | 0.68 (0.57–0.82) | 87 (0.74–1.01) | 0.93 (0.82–1.04) | 0.83 (0.68–1.02) | 0.69 (0.53–0.88) | 0.93 (0.80–1.08) | 0.83 (0.71–0.97) | 0.92 (0.77–1.10) | 1.00 (0.87–1.15) | 0.94 (0.83–1.07) |
| Worsening nephropathy§ǁ | 0.61 (0.53–0.70) | 0.60 (0.47–0.77) | 0.53 (0.43–0.66) | (See primary outcome) | (See primary outcome) | (See secondary outcomes) | 0.71 (0.44–1.16) | Composite renal outcome 0.50 (0.32–0.77) | Composite renal outcome** 0.95 (0.73–1.24) | — |
| . | EMPA-REG OUTCOME (8) (n = 7,020) . | CANVAS Program (9) (n = 10,142) . | DECLARE-TIMI 58 (196) (n = 17,160) . | CREDENCE (194) (n = 4,401) . | DAPA-CKD (197,239) (n = 4,304; 2,906 with diabetes) . | VERTIS CV (201,240) (n = 8,246) . | DAPA-HF (11) (n = 4,744; 1,983 with diabetes) . | EMPEROR-Reduced (200) (n = 3,730; 1,856 with diabetes) . | EMPEROR-Preserved (189,241) (n = 5,988; 2,938 with diabetes) . | DELIVER (199) (n = 6,263; 2,807 with diabetes) . |
|---|---|---|---|---|---|---|---|---|---|---|
| Intervention | Empagliflozin/placebo | Canagliflozin/placebo | Dapagliflozin/placebo | Canagliflozin/placebo | Dapagliflozin/placebo | Ertugliflozin/placebo | Dapagliflozin/placebo | Empagliflozin/placebo* | Empagliflozin/placebo | Dapagliflozin/placebo |
| Main inclusion criteria | Type 2 diabetes and preexisting CVD | Type 2 diabetes and preexisting CVD at ≥30 years of age or ≥2 CV risk factors at ≥50 years of age | Type 2 diabetes and established ASCVD or multiple risk factors for ASCVD | Type 2 diabetes and albuminuric kidney disease | Albuminuric kidney disease, with or without diabetes | Type 2 diabetes and ASCVD | NYHA class II, III, or IV heart failure and an ejection fraction ≤40%, with or without diabetes | NYHA class II, III, or IV heart failure and an ejection fraction ≤40%, with or without diabetes | NYHA class II, III, or IV heart failure and an ejection fraction >40% | NYHA class II, III, or IV heart failure and an ejection fraction >40% with or without diabetes |
| A1C inclusion criteria (%) | 7.0–10.0 | 7.0–10.5 | ≥6.5 | 6.5–12 | — | 7.0–10.5 | — | — | — | — |
| Age (years)† | 63.1 | 63.3 | 64.0 | 63 | 61.8 | 64.4 | 66 | 67.2, 66.5 | 71.8, 71.9 | 71.7 |
| Race (% White) | 72.4 | 78.3 | 79.6 | 66.6 | 53.2 | 87.8 | 70.3 | 71.1, 69.8 | 76.3, 75.4 | 71.2 |
| Sex (% male) | 71.5 | 64.2 | 62.6 | 66.1 | 66.9 | 70 | 76.6 | 76.5, 75.6 | 55.4, 55.3 | 56.1 |
| Diabetes duration (years)† | 57% >10 | 13.5 | 11.0 | 15.8 | 12.9 | |||||
| Median follow-up (years) | 3.1 | 3.6 | 4.2 | 2.6 | 2.4 | 3.5 | 1.5 | 1.3 | 2.2 | 2.3 |
| Statin use (%) | 77 | 75 | 75 (statin or ezetimibe use) | 69 | 64.9 | — | — | — | 68.1, 68.8 | — |
| Metformin use (%) | 74 | 77 | 82 | 57.8 | 29 | 51.2% (of people with diabetes) | — | — | — | |
| Prior CVD/CHF (%) | 99/10 | 65.6/14.4 | 40/10 | 50.4/14.8 | 37.4/10.9 | 99.9/23.1 | 100% with CHF | 100% with CHF | 100% with CHF | 100% with CHF |
| Mean baseline A1C (%) | 8.1 | 8.2 | 8.3 | 8.3 | 7.1% (7.8% in those with diabetes) | 8.2 | — | — | — | 6.6 |
| Mean difference in A1C between groups at end of treatment (%) | −0.3^ | −0.58‡ | −0.43‡ | −0.31 | — | −0.48 to −0.5 | — | — | — | — |
| Year started/reported | 2010/2015 | 2009/2017 | 2013/2018 | 2017/2019 | 2017/2020 | 2013/2020 | 2017/2019 | 2017/2020 | 2017/2020 | 2018/2022 |
| Primary outcome§ | 3-point MACE 0.86 (0.74–0.99) | 3-point MACE 0.86 (0.75–0.97) | 3-point MACE 0.93 (0.84–1.03) CV death or HF hospitalization 0.83 (0.73–0.95) | ESRD, doubling of creatinine, or death from renal or CV cause 0.70 (0.59–0.82) | ≥50% decline in eGFR, ESKD, or death from renal or CV cause 0.61 (0.51–0.72) | 3-point MACE 0.97 (0.85–1.11) | Worsening heart failure or death from CV causes 0.74 (0.65–0.85) Results did not differ by diabetes status | CV death or HF hospitalization 0.75 (0.65–0.86) | CV death or HF hospitalization 0.79 (0.69–0.90) | Worsening HF or CV death 0.82 (0.73–0.92) |
| Key secondary outcome§ | 4-point MACE 0.89 (0.78–1.01) | All-cause and CV mortality (see below) | Death from any cause 0.93 (0.82–1.04) Renal composite (≥40% decrease in eGFR rate to <60 mL/min/1.73 m2, new ESRD, or death from renal or CV causes 0.76 (0.67–0.87) | CV death or HF hospitalization 0.69 (0.57–0.83) 3-point MACE 0.80 (0.67–0.95) | ≥50% decline in eGFR, ESKD, or death from renal cause 0.56 (0.45–0.68) CV death or HF hospitalization 0.71 (0.55–0.92) Death from any cause 0.69 (0.53–0.88) | CV death or HF hospitalization 0.88 (0.75–1.03) CV death 0.92 (0.77–1.11) Renal death, renal replacement therapy, or doubling of creatinine 0.81 (0.63–1.04) | CV death or HF hospitalization 0.75 (0.65–0.85) | Total HF hospitalizations 0.70 (0.58–0.85) Mean slope of change in eGFR 1.73 (1.10–2.37) | All HF hospitalizations (first and recurrent) 0.73 (0.61–0.88) Rate of decline in eGFR (−1.25 vs. −2.62 mL/min/1.73 m2; P < 0.001) | Total number worsening HF and CV deaths 0.77 (0.67–0.89) Change in KCCQ TSS at month 8 1.11 (1.03–1.21) Mean change in KCCQ TSS 2.4 (1.5–3.4) All-cause mortality 0.94 (0.83–1.07) |
| Cardiovascular death§ | 0.62 (0.49–0.77) | 0.87 (0.72–1.06) | 0.98 (0.82–1.17) | 0.78 (0.61–1.00) | 0.81 (0.58–1.12) | 0.92 (0.77–1.11) | 0.82 (0.69–0.98) | 0.92 (0.75–1.12) | 0.91 (0.76–1.09) | 0.88 (0.74–1.05) |
| MI§ | 0.87 (0.70–1.09) | 0.89 (0.73–1.09) | 0.89 (0.77–1.01) | — | — | 1.04 (0.86–1.26) | — | — | — | — |
| Stroke§ | 1.18 (0.89–1.56) | 87 (0.69–1.09) | 1.01 (0.84–1.21) | — | — | 1.06 (0.82–1.37) | — | — | — | — |
| HF hospitalization§ | 0.65 (0.50–0.85) | 67 (0.52–0.87) | 0.73 (0.61–0.88) | 0.61 (0.47–0.80) | — | 0.70 (0.54–0.90) | 0.70 (0.59–0.83) | 0.69 (0.59–0.81) | 0.73 (0.61–0.88) | 0.77 (0.67–0.89) |
| Unstable angina hospitalization§ | 0.99 (0.74–1.34) | — | — | — | — | — | — | — | — | — |
| All-cause mortality§ | 0.68 (0.57–0.82) | 87 (0.74–1.01) | 0.93 (0.82–1.04) | 0.83 (0.68–1.02) | 0.69 (0.53–0.88) | 0.93 (0.80–1.08) | 0.83 (0.71–0.97) | 0.92 (0.77–1.10) | 1.00 (0.87–1.15) | 0.94 (0.83–1.07) |
| Worsening nephropathy§ǁ | 0.61 (0.53–0.70) | 0.60 (0.47–0.77) | 0.53 (0.43–0.66) | (See primary outcome) | (See primary outcome) | (See secondary outcomes) | 0.71 (0.44–1.16) | Composite renal outcome 0.50 (0.32–0.77) | Composite renal outcome** 0.95 (0.73–1.24) | — |
—, not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; KCCQ TSS, Kansas City Cardiomyopathy Questionnaire Total Symptom Score; MACE, major adverse cardiovascular event; Ml, myocardial infarction; SGLT2, sodium–glucose cotransporter 2; NYFIA, New York Fleart Association. Data from this table was adapted from Cefalu et al. (238) in the January 2018 issue of Diabetes Care.
Baseline characteristics for EMPEROR-Reduced displayed as empagliflozin, placebo.
Age was reported as means in all trials; diabetes duration was reported as means in all trials except EMPA-REG OUTCOME, which reported as percentage of population with diabetes duration >10 years, and DECLARE-TIMI 58, which reported median.
Significant difference in A1C between groups (P < 0.05).
AIC change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin).
Outcomes reported as hazard ratio (95% Cl).
Definitions of worsening nephropathy differed between trials.
Composite outcome in EMPEROR-Preserved: time to first occurrence of chronic dialysis, renal transplantation; sustained reduction of ≥40% in eGFR, sustained eGFR <15 mL/min/1.73 m2 for individuals with baseline eGFR ≥30 mL/min/1.73 m2.