Lipid Luminations: Risk Reduction: DECLARE-TIMI 58 Outcomes

Results from multiple trials prompted the Food and Drug Administration’s (FDA) approval of empagliflozin (Jardiance) for reducing cardiovascular (CV) death and canagliflozin (Invokana) for reducing CV death and CV events, in patients with cardiovascular disease and type II diabetes (T2D).(1-6) The FDA’s expanded approval of empagliflozin and canagliflozin led to the American College of Cardiology (ACC) and the American Diabetes Association
(ADA) incorporating sodium–glucose cotransporter 2 (SGLT2) inhibitors into decision pathways for patients with T2D and atherosclerotic cardiovascular disease (ASCVD).(7,8) These pathways create a renewed focus on clinicians utilizing all available comprehensive CV risk reduction strategies.

Wiviott et al. (2019) questioned the CV benefits of the third SGLT2 inhibitor, dapagliflozin, in the randomized, double-blinded, placebo-controlled trial, dapagliflozin (Farxiga) Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58).(9) We review the findings of DECLARE-TIMI 58 and its implications in clinical practice.

DECLARE-TIMI 58 included 17,160 patients with T2D, of which, 10,186 (59.4%) were without established ASCVD.(9) Patients with T2D and a creatinine clearance (CrCl) of 60 mL or more per minute, who also had multiple risk factors for ASCVD or established ASCVD, were eligible and followed for a median of 4.2 years. The primary safety outcome was a composite of major adverse CV events (MACE), defined as CV death, myocardial infarction or ischemic stroke. Researchers added two efficacy outcomes after results of another SGLT2 inhibitor trial were released: MACE and a composite of CV death or hospitalization from heart failure (HF).(1) Secondary efficacy outcomes were death from any cause and a renal composite (≥ 40% decrease in estimated glomerular filtration rate to < 60 mL per minute, new end-stage renal disease, or death from renal or CV causes).

DECLARE-TIMI 58 did not show a significant reduction in MACE between treatment (dapagliflozin 10 mg daily) and placebo groups (8.8% and 9.4%, respectively; P = 0.17) but did in reduction of the composite end point of CV death or hospitalization for HF (4.9% vs. 5.8%, respectively; P = 0.005).(9) The significant reduction of the latter was attributed to a lowered hospitalization rate for HF in the treatment group (hazard ratio [HR], 0.73; 95% CI, 0.61 to 0.88). No difference between groups was found for CV death alone (HR, 0.98; 95% CI, 0.82 to 1.17).

The primary safety outcome reported noninferiority of the treatment group to placebo (P <0.001).(9) Safety results include no evidence of a higher risk of stroke, amputations, Fournier’s gangrene or fractures with dapagliflozin than with placebo. As previously reported with SGLT2 inhibitors, a higher incidence of ketoacidosis and genital infections with dapagliflozin was noted.(2,10)

Secondary outcomes showed no significant difference in rate of death from any cause (HR, 0.93; 95% CI, 0.82 to 1.04) but renal composite outcome was significant with 4.3% in the dapagliflozin group and 5.6% in the placebo group (HR, 0.76; 95% CI, 0.67 to 0.87).(9)

With other SGLT2 inhibitor trials reporting reductions in MACE and CV death, one could point to differences between drugs within the class, but differences in eligibility criteria between trials (i.e. DECLARE-TIMI 58 excluded patients with CrCl < 60 mL per minute and majority were without clinical ASCVD) and the change in primary outcome without increase in sample size (possibly reducing statistical power) may account for the lack of reduction in MACE and CV death.(1,2,9)

The ACC’s “Expert Consensus Decision Pathway” pushes us out of our comfort zone and into shared decision making to tackle residual risk.(7) Despite DECLARE-TIMI 58 CV results inconsistency with other SGLT2 inhibitor trials, SGLT2 inhibitors are now part of our toolbox and how integral they become is still unclear.(1-6) This trial and others have created a drive for knowledge and pursuit of new FDA approvals as six trials are currently evaluating safety and efficacy in HF and chronic kidney disease in patients with and without T2D.(7,11)

Disclosure statement: Dr. Peterson has no financial disclosures to report.

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