Table 3.
Clinical trials investigating the cardiovascular outcomes of individuals treated with sodium–glucose cotransporter-2 inhibitors.
| Clinical Trial | Type of Trial | Study Information | Duration | Outcomes |
|---|---|---|---|---|
| DECLARE-TIMI 58 [163] |
Double-blind, placebo-controlled RCT (phase 3) | 17,160 T2DM patients at high risk for CV events (only 7% of patients had an eGFR < 60 mL/min/1.73 m2) Dapagliflozin 10 mg vs. placebo |
Up to 6 years | Cardiovascular death, nonfatal MI, nonfatal ischemic stroke; cardiovascular death, hospitalization because of HF Renal composite end point (≥40% decrease in eGFR to <60 and ESRD and renal or cardiovascular death, all-cause mortality) |
| DAPA-HF [9] |
Double-blind, placebo-controlled RCT (phase 3) | 4304 diabetic (68%) or non-diabetic patients with class II-IV HF Dapagliflozin 10 mg vs. placebo |
36 months | Time to cardiovascular death or hospitalization for HF or an urgent HF visit Time to ≥50% sustained decline in eGFR or ESRD QoL score by questionnaire Time to death by any cause |
| DEFINE HF [181] |
Double-blind, placebo-controlled RCT (phase 4) | 263 diabetic or nondiabetic patients with class II and III HF Dapagliflozin 10 mg vs. placebo |
12 weeks | Change in NTproBNP Change in SBP, weight, HbA1c, BNP, and QoL score by questionnaire |
| EMPA-REG OUTCOME [8] |
Double-blind, placebo-controlled RCT (phase 3) | 7020 T2DM patients at high risk for CV events and an eGFR ≥ 30 mL/min/1.73 m2 Empagliflozin 10 mg vs. Empagliflozin 25 mg vs. placebo |
Up to 4.6 years | 14% reduction in 3-point MACE (cardiovascular death, nonfatal MI, nonfatal stroke) pooled from 10 mg and 25 mg empagliflozin doses 35% reduction in hospitalization for HF, 39% reduction in the composite renal end point (new macroalbuminuria, doubling of serum creatinine and a GFR ≤ 45, renal replacement therapy, renal death) |
| EMPEROR-Reduced [10] |
Double-blind, placebo-controlled RCT (phase 3) | 3730 diabetic or non-diabetic patients with class II, III, or IV HF and an EF ≤ 40% Empagliflozin 10 mg vs. placebo (additionally to recommended treatment) |
38 months | Cardiovascular death or adjudicated hospitalization for HF Change in eGFR Time to sustained reduction in eGFR Time to all-cause mortality Time to DM. |
| EMPEROR-Preserved [11] |
Double-blind, placebo-controlled RCT (phase 3) | 5988 diabetic or not diabetic patients with class II-IV HF and EF > 40% Empagliflozin 10 mg vs. placebo (in addition to usual therapy) |
38 months | Cardiovascular death or adjudicated hospitalization for HF Change in eGFR Time to sustained reduction in eGFR Time to all-cause mortality Time to DM. |
| CANVAS [182] |
Double-blind, placebo-controlled RCT (phase 3) | 10,142 participants with T2DM and high CV risk Canagliflozin 100 mg (with an increase to 300 mg) vs. placebo |
3.6 years | 14% reduction in 3-point MACE (cardiovascular death, nonfatal MI, nonfatal stroke) 27% reduction in progression of albuminuria, 70% increase in regression of albuminuria, 40% reduction in the composite renal end point (40% reduction in eGFR, renal replacement therapy, renal death) |
| CREDENCE [183] |
Double-blind, placebo-controlled RCT (phase 3) | 3627 T2DM patients with stage 2 or 3 CKD and macroalbuminuria and on ACEIs/ARB (>30 y) Canagliflozin 100 mg daily vs placebo |
4 years | ESRD, S-creatinine doubling, renal/cardiovascular death Cardiovascular death, nonfatal MI, nonfatal stroke, hospitalized UAP, hospitalized CHF, composite renal end point (ESRD, doubling of serum creatinine renal death) |
| VERTIS CV [184] |
Double-blind, placebo-controlled RCT (phase 3) | 8246 T2DM patients with established CV disease and an eGFR ≥ 30 mL/min/ 1.73 m2 Ertugliflozin 5 or 15 mg vs. placebo |
Up to 6 years | Cardiovascular death, nonfatal MI, nonfatal stroke Cardiovascular death, nonfatal MI, nonfatal stroke and hospitalized UAP |
Abbreviations: RCT—randomized controlled trial; CV—cardiovascular; eGFR—estimated glomerular filtration rate; MI—myocardial infarction; HF—heart failure; ESRD—end-stage renal disease/failure; QoL—quality of life; NTproBNP—N-terminal prohormone of brain natriuretic peptide; SBP—systolic blood pressure; HbA1c—hemoglobin A1c/glycohemoglobin; BNP—brain natriuretic peptide; GFR—glomerular filtration rate; EF—ejection fraction; DM—diabetes mellitus; ACEIs—angiotensin-converting enzyme inhibitors; ARBS—angiotensin receptor blockers; S-creatinine—serum creatinine; UAP—unstable angina pectoris; CHF—congestive heart failure; DECLARE-TIMI 58—dapagliflozin effect on cardiovascular events—thrombolysis in MI 58; DAPA-HF—dapagliflozin and prevention of adverse outcomes in HF; DEFINE-HF—dapagliflozin effects on biomarkers, symptoms and functional status in patients with HFrEF (heart failure with reduced ejection fraction); EMPA-REG OUTCOME—empagliflozin cardiovascular outcome event trial in T2DM; EMPEROR-Reduced—empagliflozin outcome trial in patients with chronic HFrEF; EMPEROR-Preserved—empagliflozin outcome trial in patients with chronic HFpEF (heart failure with preserved ejection fraction); CANVAS—canagliflozin cardiovascular assessment study; CREDENCE—canagliflozin and renal events in diabetes with established nephropathy clinical evaluation; VERTIS CV—evaluation of ertugliflozin efficacy and safety cardiovascular outcomes trial.