The SGLT-2 inhibitor class drugs were initially developed as diabetic medications. The FDA required all diabetic drugs to showcase CV safety before their approval. This led to the design and implmentation of three trials that tested different SGLT-2 inhibitors safety profile. Namely, CANVAS, EMPA REG OUTCOME, and DECLARE-TIMI 58. These three trials tested the CV safety of canagliflozin, empagliflozin and dapagliflozin respectively. EMPA REG OUTCOME and CANVAS trials not only showed safety of these drugs but also showed HF and CV survival benefit of these agents. This led to the development of DAPA HF trial.
Clinical Question of the VERTIS CV trial:
To evaluate the efficacy of dapagliflozin in patients with heart failure with reduced ejection fraction (NYHA II-IV, LVEF ≤40%) with or without diabetes, in terms of cardiovascular and heart failure outcomes?
Among patients with HFrEF with or without DM2, dapagliflozin showed to significantly reduce all cause, cardiovascular mortality as well as HF exacerbations and outcomes.
Multicenter, double-blind, parallel-group, randomized, controlled trial
- Dapagliflozin (n=2,373)
- Placebo (n=2,371)
- Age of at least 18 years
- Ejection fraction of ≤40%
- NYHA Class II, III, or IV symptoms
- Plasma NT-proBNP level of:
- ≥ 600pg/mL OR
- ≥ 400pg/mL if they were hospitalized for HF within the past 12 months OR
- ≥ 900pg/mL if patient had atrial fibrillation/flutter on baseline ECG.
- Type 1 Diabetes
- Hypotension/ sBP <95 mm HG
- eGFR ≤30 ml/m/1.73m2
- Current decompensated HF or HF hospitalization <4 weeks prior
- MI, unstable angina, stroke, or TIA within 3 months to enrolment
- Worsening heart failure (hospitalization or urgent visit resulting in IV therapy for HF) or CV mortality %
16.3% (dapagliflozin) vs. 21.2% (placebo)
HR 0.74; 95% CI 0.65-0.85; P<0.001
Key Secondary Outcomes:
1. Cardiovascular death or heart-failure hospitalization %
16.1% (dapagliflozin) vs 20.9% (placebo)
HR 0.75; 95% CI 0.65-0.85; P<0.001
2. Worsening renal function
1.2% (dapagliflozin) vs 1.6% (placebo)
HR 0.71; 95% CI 0.44-1.16
3. All cause mortality
11.6% (dapagliflozin) vs 13.9% (placebo)
HR 0.83; 95% CI 0.71-0.97
Take Home Point:
Dapagliflozin and other SGLT2 inhibitors except the newer ertugliflozin have now joined the ranks of drugs that reduced CV mortality in patients with heart failure. Based on the DAPA HF trial and multiple other trials on other SGLT2 inhibitors, the FDA has now approved these agents for HF with or without diabetes.