Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER)
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In patients with heart failure and a mildly reduced or preserved ejection fraction (>40%), dapagliflozin significantly reduced the composite risk of cardiovascular death or worsening heart failure compared to placebo, regardless of diabetes status or baseline ejection fraction.
Key Findings
Study Design
Study Limitations
Clinical Significance
The DELIVER trial cemented the role of SGLT2 inhibitors as a foundational, guideline-directed medical therapy across the entire spectrum of heart failure. By proving efficacy not only in mildly reduced and preserved ejection fraction but also in those whose ejection fraction had improved, it demonstrated that dapagliflozin can be initiated safely and effectively in symptomatic heart failure patients irrespective of left ventricular ejection fraction.
Historical Context
Originally developed as oral hypoglycemics for type 2 diabetes, SGLT2 inhibitors unexpectedly demonstrated profound cardiovascular benefits. Trials like DAPA-HF and EMPEROR-Reduced established their role in heart failure with reduced ejection fraction (HFrEF). Later, EMPEROR-Preserved showed that empagliflozin was effective in mildly reduced (HFmrEF) and preserved (HFpEF) ejection fractions, but subgroup analyses suggested the benefit might wane at the highest ejection fractions (LVEF ≥65%). DELIVER was a landmark trial that definitively showed dapagliflozin's efficacy in HFmrEF and HFpEF, critically proving that the clinical benefits extended even to patients with the highest ejection fractions and those with previously reduced but improved ejection fractions (HFimpEF).
Guided Discussion
High-yield insights from every perspective
What is the proposed mechanism by which dapagliflozin, originally developed as an antidiabetic medication, provides cardiovascular benefits in patients with heart failure regardless of their diabetes status?
Key Response
SGLT2 inhibitors block glucose and sodium reabsorption in the proximal tubule. Cardiovascular benefits are independent of glucose lowering and involve osmotic diuresis, reduced preload and afterload, improved myocardial energetics via a shift to ketone utilization, reduction in sympathetic nervous system activity, and inhibition of the Na+/H+ exchanger in the myocardium.
A 72-year-old patient with an LVEF of 55%, NYHA class II symptoms, and no history of diabetes presents for a follow-up. Based on the DELIVER trial results, how does initiating dapagliflozin alter their management plan, and what baseline labs should be checked before starting?
Key Response
DELIVER showed dapagliflozin reduces cardiovascular death or worsening HF in HFpEF and HFmrEF regardless of diabetes status. Initiation requires checking baseline renal function (eGFR greater than 25 ml/min/1.73m2 in DELIVER) and assessing volume status. It provides a targeted disease-modifying pharmacologic option where previous therapies showed limited or mixed efficacy.
How does the DELIVER trial's inclusion of patients with heart failure with improved ejection fraction (HFimpEF) impact our understanding of the trajectory of heart failure, and how does dapagliflozin's efficacy in this specific subgroup compare to those with consistently preserved LVEF?
Key Response
DELIVER was unique in explicitly including patients whose LVEF had improved from less than 40% to greater than 40%. Dapagliflozin showed consistent benefit in this HFimpEF group. This emphasizes that HF with improved LVEF is a state of remission rather than a cure, and these patients still require and benefit from GDMT, specifically SGLT2 inhibition, similar to primary HFmrEF/HFpEF.
Previous heart failure trials in HFpEF, such as PARAGON-HF and TOPCAT, demonstrated an attenuation of benefit at the highest LVEF ranges (e.g., LVEF greater than 60%). Did the DELIVER trial show a similar attenuation of benefit with dapagliflozin at higher ejection fractions, and how does this influence your clinical phenotype approach?
Key Response
Unlike PARAGON-HF or TOPCAT, the DELIVER trial demonstrated that the benefit of dapagliflozin extended across the entire spectrum of LVEF, without attenuation even in patients with LVEF greater than 60%. This shifts the clinical paradigm to treating all patients with HFmrEF and HFpEF with an SGLT2 inhibitor as foundational therapy, without needing to withhold therapy based on high normal LVEF.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The DELIVER trial used a time-to-first-event analysis for its primary composite endpoint but also performed recurrent event analyses. What are the methodological advantages of using a win ratio or recurrent event analysis in a trial like DELIVER compared to traditional time-to-first-event Cox proportional hazards models?
Key Response
Time-to-first-event analyses ignore subsequent events, such as recurrent HF hospitalizations, which are highly prevalent and clinically meaningful in HFpEF. Recurrent event models provide a more comprehensive assessment of the total disease burden and treatment effect over time, capturing the full morbidity-reducing potential of the intervention.
While the primary composite endpoint in DELIVER was significantly reduced, this was primarily driven by a reduction in worsening heart failure rather than cardiovascular death alone. How does this component-driven significance affect the overall strength of the trial's conclusions, and what concerns might a peer reviewer raise regarding the mortality data?
Key Response
An editor would note that the composite endpoint success masks the lack of statistically significant reduction in cardiovascular death alone (HR 0.88, 95% CI 0.74-1.05). Reviewers often challenge the clinical impact of an intervention that primarily reduces hospitalizations rather than hard mortality outcomes, noting that pooled meta-analyses are often required to overcome power limitations for mortality in modern HFpEF trials.
Considering the results of the DELIVER trial alongside EMPEROR-Preserved, how should the AHA/ACC/HFSA guidelines for Heart Failure be updated regarding the strength of recommendation and level of evidence for SGLT2 inhibitors in patients with LVEF greater than 40%?
Key Response
Prior to these trials, guidelines had weak recommendations for HFpEF, mostly symptom management with diuretics. Post-DELIVER and EMPEROR-Preserved, the evidence justifies a Class 1 or 2a, Level of Evidence A recommendation for SGLT2 inhibitors to decrease hospitalizations and CV mortality in HFmrEF and HFpEF. The 2022 ACC/AHA/HFSA guidelines gave SGLT2is a Class 2a recommendation for HFpEF, which is strongly reinforced and supported for an upgrade to Class 1 based on the totality of reproducible, robust data from DELIVER.
Clinical Landscape
Noteworthy Related Trials
DAPA-HF
Tested
Dapagliflozin 10 mg once daily
Population
Patients with heart failure and reduced ejection fraction
Comparator
Placebo
Endpoint
Composite of worsening heart failure or cardiovascular death
PARAGON-HF
Tested
Sacubitril/valsartan
Population
Patients with heart failure and preserved ejection fraction
Comparator
Valsartan
Endpoint
Composite of total hospitalizations for heart failure and cardiovascular death
EMPEROR-Preserved
Tested
Empagliflozin 10 mg once daily
Population
Patients with heart failure and preserved ejection fraction
Comparator
Placebo
Endpoint
Composite of cardiovascular death or hospitalization for heart failure
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