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Canagliflozin
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| CANVAS [9] |
Age ≥30 y with T2D and established CVD
OR
Age ≥50 y with T2D and ≥2 CVD risk factors
(n = 10,142) |
Any SAE (vs. placebo): HR, 0.93 (95% CI, 0.87–1.00); p = 0.04 AE leading to discontinuation (vs. placebo): HR, 1.13 (95% CI, 0.99–1.28); p = 0.07 Higher rate vs. placebo of amputation (p < 0.001), adjudicated fracture (p = 0.02), infection of male genitalia (p < 0.001), osmotic diuresis (p < 0.001), volume depletion (p = 0.009), and mycotic genital infection in women (p < 0.001)
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| CREDENCE [22] |
Age ≥30 y with T2D and CKD a (n = 4401) |
Any AE (vs. placebo): HR, 0.87 (95% CI, 0.82–0.93) Any SAE (vs. placebo): HR, 0.87 (95% CI, 0.79–0.97) Treatment-related SAEs (vs. placebo): HR, 1.45 (95% CI, 0.98–2.14) Higher risk vs. placebo of diabetic ketoacidosis (HR, 10.80 (95% CI, 1.39–83.65)) Similar risk vs. placebo of lower extremity amputation (HR, 1.11 (95% CI, 0.79–1.56)) and fracture (HR, 0.98 (95% CI, 0.70–1.37))
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Dapagliflozin
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| DECLARE–TIMI 58 [10] |
Age ≥40 y with T2D and established CVD
OR
Age ≥55 y (men) or ≥60 y (women) with T2D and ≥1 CVD risk factor (n = 17,160) |
Any SAE (vs. placebo): HR, 0.91 (95% CI, 0.87–0.96); p < 0.001 AE leading to discontinuation (vs. placebo): HR, 1.15 (95% CI, 1.03–1.28); p = 0.01 Lower risk vs. placebo of major hypoglycemic event (HR, 0.68; p = 0.02) and AKI (HR, 0.69; p = 0.002) Higher risk vs. placebo of diabetic ketoacidosis (HR, 2.18; p = 0.02) and genital infection (HR, 8.36; p < 0.001) Similar risk vs. placebo of amputation (HR, 1.09; p = 0.53), fracture (HR, 1.04; p = 0.59), volume depletion symptoms (HR, 1.00; p = 0.99), and UTI (HR, 0.93; p = 0.54)
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| DAPA-HF [23] |
Age ≥18 y with NYHA class II–IV HFrEF (EF ≤ 40%) with or without T2D (n = 4744) |
Any SAE (vs. placebo): 37.8% vs. 42.0% AE leading to discontinuation (vs. placebo): 4.7% vs. 4.9%; p = 0.79 Lower incidence vs. placebo of serious renal events (1.6% vs. 2.7%; p = 0.009) Similar incidence vs. placebo of SAEs related to volume depletion (1.2% vs. 1.7%; p = 0.23)
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| DAPA-CKD [21] |
Age ≥18 y with CKD b with or without T2D
(n = 4094) |
Any SAE (vs. placebo): 29.5% vs. 33.9%; p = 0.002 AE leading to discontinuation (vs. placebo): 5.5% vs. 5.7%; p = 0.79 Lower incidence vs. placebo of major hypoglycemia (0.7% vs. 1.3%; p = 0.04) Higher incidence vs. placebo of volume depletion (5.9% vs. 4.2%; p = 0.01) Similar incidence vs. placebo of amputation (1.6% vs. 1.8%; p = 0.73), definite or probable diabetic ketoacidosis (0% vs. <0.1%; p = 0.50), fracture (4.0% vs. 3.2%; p = 0.22), and renal-related AE (7.2% vs. 8.7%; p = 0.07)
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Empagliflozin
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| EMPA-REG OUTCOME [11] |
Age ≥18 y with T2D and established CVD
(n = 7020) |
Any SAE (vs. placebo): 38.2% vs. 42.3%; p < 0.001 AE leading to discontinuation (vs. placebo): 17.3% vs. 19.4%; p < 0.01 Lower incidence vs. placebo of UTI in women (36.4% vs. 40.6%; p < 0.05), AKI (1.0% vs. 1.6%; p < 0.05), and acute renal failure (5.2% vs. 6.6%; p < 0.01) Higher incidence vs. placebo of genital infection in men (5.0% vs. 1.5%; p < 0.001) and women (10.0% vs. 2.6%; p < 0.001) Similar incidence vs. placebo of hypoglycemia requiring assistance (1.3% vs. 1.5%), UTI (18.0% vs. 18.1%), complicated UTI (1.7% vs. 1.8%), volume depletion (5.1% vs. 4.9%), fracture (3.8% vs. 3.9%), thromboembolic event (0.6% vs. 0.9%), and diabetic ketoacidosis (0.1% vs. <0.1%)
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| EMPEROR-Reduced [25] |
Age ≥18 y with NYHA class II–IV HFrEF (EF ≤40%) with or without T2D (n = 3730) |
Any SAE (vs. placebo): 41.4% vs. 48.1% Higher incidence vs. placebo of genital infections (1.7% vs. 0.6%) Similar incidence vs. placebo of volume depletion (10.6% vs. 9.9%), hypotension (9.4% vs. 8.7%), symptomatic hypotension (5.7% vs. 5.5%), UTI (4.9% vs. 4.5%), fracture (2.4% vs. 2.3%), hypoglycemic event (1.4% vs. 1.5%), complicated UTI (1.0% vs. 0.8%), lower extremity amputation (0.7% vs. 0.5%), complicated genital infection (0.3% vs. 0.3%), and ketoacidosis (0% vs. 0%)
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| EMPEROR-Preserved [26] |
Age ≥18 y with NYHA class II–IV HFpEF
(EF >40%) with or without T2D (n = 5988) |
Any SAE (vs. placebo): 47.9% vs. 51.6% AE leading to discontinuation (vs. placebo): 19.1% vs. 18.4% Higher incidence vs. placebo of hypotension (10.4% vs. 8.6%), UTI (9.9% vs. 8.1%), and genital infection (2.2% vs. 0.7%) Similar incidence vs. placebo of acute renal failure (12.1% vs. 12.8%), symptomatic hypotension (6.6% vs. 5.2%), fracture (4.5% vs. 4.2%), hypoglycemic event (2.4% vs. 2.6%), ketoacidosis (0.1% vs. 0.2%), complicated UTI (1.9% vs. 1.5%), lower extremity amputation (0.5% vs. 0.8%), and complicated genital infection (0.3% vs. 0.3%)
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Ertugliflozin
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| VERTIS CV [8] |
Age ≥40 y with T2D and established CVD
(n = 8246) |
Any SAE (vs. placebo): risk difference, 1.2 (95% CI, −3.7, 1.4) (5 mg); −2.0 (95% CI, −4.5, 0.6) (15 mg) AE leading to discontinuation (vs. placebo): risk difference, 0.7 (95% CI, −0.7, 2.1) (5 mg); 0.5 (95% CI −0.9, 1.8) (15 mg) Higher risk vs. placebo of UTI (risk difference, 2.1 (p = 0.02; 5 mg); 1.8 (p = 0.03; 15 mg)), genital mycotic infection in women (risk difference, 3.6 (p < 0.001; 5 mg); 5.4 (p < 0.001; 15 mg)) and men (risk difference, 3.3 (p < 0.001; 5 mg); 4.0 (p < 0.001; 15 mg)) Similar risk vs. placebo of symptomatic hypoglycemia (risk difference, −0.8 (5 mg); −2.3 (15 mg)), severe hypoglycemia (risk difference, −0.9 (5 mg); −0.5 (15 mg)), hypovolemia (risk difference, 0.4 (5 mg); 0.4 (15 mg)), AKI (risk difference −0.4 (5 mg); −0.3 (15 mg)), and amputation (pooled risk difference, 0.1) Similar incidence vs. placebo of fractures (3.6% (5 mg) and 3.7% (15 mg) vs. 3.6%), serious AKI (0.9% (5 mg) and 0.7% (15 mg) vs. 0.8%), and serious UTI (0.9% (5 mg) and 0.4% (15 mg) vs. 0.8%)
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