Which trial showed cardiovascular benefits with dapagliflozin (SGLT2 inhibitor)?

Cardiovascular Benefits of Dapagliflozin: The DECLARE-TIMI 58 Trial

The DECLARE-TIMI 58 trial demonstrated cardiovascular benefits with dapagliflozin, showing a significant reduction in the composite endpoint of cardiovascular death or hospitalization for heart failure, primarily driven by a 27% reduction in heart failure hospitalizations. 1, 2

Overview of DECLARE-TIMI 58 Trial

• DECLARE-TIMI 58 was a large, international, multicenter, randomized, double-blind, placebo-controlled cardiovascular outcomes trial specifically designed to evaluate the cardiovascular safety and efficacy of dapagliflozin in patients with type 2 diabetes mellitus 1, 2
• The trial enrolled 17,160 patients with type 2 diabetes who either had established atherosclerotic cardiovascular disease (40.6%) or multiple risk factors for cardiovascular disease (59.4%) 1, 3
• Patients were randomized to receive either dapagliflozin 10 mg daily or placebo and were followed for a median of 4.2 years, making it the longest and largest cardiovascular outcomes trial of an SGLT2 inhibitor 1, 4

Primary Outcomes of DECLARE-TIMI 58

• The trial had two co-primary endpoints: 1) the composite of cardiovascular death, myocardial infarction, or ischemic stroke (MACE), and 2) the composite of cardiovascular death or hospitalization for heart failure 1, 2
• For the MACE endpoint, dapagliflozin was non-inferior to placebo (HR 0.93,95% CI 0.84-1.03), demonstrating cardiovascular safety 1, 5
• For the composite of cardiovascular death or hospitalization for heart failure, dapagliflozin was superior to placebo (HR 0.83,95% CI 0.73-0.95), showing a significant cardiovascular benefit 1, 5
• The treatment effect was primarily driven by a significant 27% reduction in the risk of hospitalization for heart failure (HR 0.73,95% CI 0.61-0.88) 1, 3

Distinguishing Features of DECLARE-TIMI 58

• Unlike other SGLT2 inhibitor trials that primarily enrolled patients with established cardiovascular disease, DECLARE-TIMI 58 included a broader population with nearly 60% of participants having multiple risk factors but without established cardiovascular disease 5, 4
• The cardiovascular benefits of dapagliflozin were consistent across baseline systolic blood pressure categories, including in normotensive patients 3
• The benefits were observed regardless of baseline cardiac biomarker levels (NT-proBNP and hsTnT), with greater absolute risk reductions in patients with higher baseline biomarker levels 6

Comparison with Other SGLT2 Inhibitor Trials

• While EMPA-REG OUTCOME (empagliflozin) and CANVAS (canagliflozin) showed significant reductions in MACE, DECLARE-TIMI 58 demonstrated non-inferiority but not superiority for this endpoint 5
• All three SGLT2 inhibitor trials (EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) consistently showed significant reductions in heart failure hospitalizations 5
• The findings from DECLARE-TIMI 58 led to further investigation of dapagliflozin in dedicated heart failure trials, such as DAPA-HF, which confirmed its benefits in patients with heart failure with reduced ejection fraction regardless of diabetes status 5, 7

Clinical Implications

• Based on the DECLARE-TIMI 58 results, dapagliflozin is recommended for cardiovascular risk reduction, particularly for reducing heart failure hospitalizations in patients with type 2 diabetes 5, 8
• The American Diabetes Association and American Heart Association recognize the cardiovascular benefits of dapagliflozin demonstrated in the DECLARE-TIMI 58 trial 5, 8
• The FDA label for dapagliflozin specifically cites the DECLARE-TIMI 58 trial as evidence for its indication to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors 1

Important Considerations

• While dapagliflozin did not significantly reduce MACE in DECLARE-TIMI 58 (unlike empagliflozin in EMPA-REG OUTCOME), this may be due to the lower-risk population enrolled, with about 60% of participants without prevalent cardiovascular disease 5
• The cardiovascular benefits of dapagliflozin appear to be primarily related to its effects on heart failure outcomes rather than atherosclerotic events 5, 7
• The DECLARE-TIMI 58 findings, along with subsequent heart failure trials like DAPA-HF, have expanded the use of dapagliflozin beyond glycemic control to cardiovascular risk reduction and heart failure management 5, 1