Should dapagliflozin be added for a patient with heart failure with preserved ejection fraction, NYHA class I–II, and severe mitral and tricuspid regurgitation, assuming adequate renal function and no contraindications?

Dapagliflozin for HFpEF with Severe Valvular Regurgitation

Dapagliflozin 10 mg daily is recommended for patients with HFpEF NYHA class I-II, including those with severe mitral and tricuspid regurgitation, as the major clinical trials (DELIVER and DAPA-HF) did not exclude patients with significant valvular disease and demonstrated consistent cardiovascular benefits across diverse heart failure populations. 1, 2, 3

Evidence Supporting Use in This Population

Trial Data and Guideline Recommendations

• The American College of Cardiology and American Diabetes Association provide strong recommendations (Class I) for SGLT2 inhibitors in all patients with symptomatic heart failure regardless of ejection fraction or diabetes status, based on robust evidence from the DELIVER trial which enrolled 6,263 patients with LVEF >40%. 1, 2

• Dapagliflozin reduced the primary composite outcome of worsening heart failure (hospitalization or urgent visit) or cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92; P<0.001) in the DELIVER trial, with benefits consistent across the entire ejection fraction spectrum including patients with LVEF ≥50%. 2, 3

• The FDA label specifically indicates dapagliflozin for heart failure with LVEF >40%, demonstrating efficacy in reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure visits. 2

Applicability to Severe Valvular Disease

• The DELIVER trial enrolled patients with "evidence of structural heart disease," which encompasses valvular pathology, and did not exclude patients with significant valvular regurgitation. 3, 4

• Treatment effects remained consistent across all prespecified subgroups examined in DELIVER, with no interaction by baseline structural heart disease characteristics. 3

• Among patients with severe heart failure (including NYHA class III-IV, recent hospitalization, and poor symptom burden), dapagliflozin demonstrated consistent benefit regardless of LVEF category (HR for primary endpoint: 0.82 across LVEF spectrum, 3-way P-interaction = 0.52). 5

Clinical Implementation Algorithm

Initiation Criteria (All Must Be Met)

• NYHA class I-II symptoms with HFpEF (LVEF >40%) 2, 3
• Elevated natriuretic peptides (NT-proBNP ≥300 pg/mL or ≥600 pg/mL if atrial fibrillation) 3, 4
• eGFR ≥25 mL/min/1.73 m² 2, 6
• No contraindications (history of serious hypersensitivity to dapagliflozin) 7

Dosing and Monitoring

• Initiate dapagliflozin 10 mg once daily—no dose titration required, unlike ACE inhibitors or beta-blockers. 1, 8

• The American College of Cardiology recommends initiating during hospitalization in stabilized patients or as outpatient, as benefits occur within weeks of initiation. 1, 8

• Continue all existing guideline-directed medical therapy (ACE inhibitors/ARBs, beta-blockers, MRAs) as dapagliflozin provides additive benefit. 1

Safety Considerations in Valvular Disease

• Dapagliflozin has minimal blood pressure effects with symptomatic hypotension occurring in only 0.3% vs 0.5% with placebo in DAPA-HF, making it safe even in patients with hemodynamic concerns from valvular regurgitation. 1

• Monitor for volume depletion, particularly when combined with loop diuretics, as dapagliflozin enhances natriuresis through SGLT2 inhibition. 1

• A mild, transient eGFR decline (typically 2-4 mL/min/1.73 m²) may occur after initiation but represents hemodynamic adjustment and provides long-term kidney protection—do not discontinue for this reason. 1, 6

• Dapagliflozin actually slowed eGFR decline by 1.4 mL/min/1.73 m² per year (95% CI 1.0-1.8; P<0.001) from month 1 to 36 in DELIVER. 6

Specific Benefits in This Clinical Context

Hemodynamic Advantages

• Dapagliflozin shifts cardiac metabolism toward ketone utilization, improving myocardial energetics with less oxygen consumption—particularly beneficial in patients with volume overload from severe regurgitant lesions. 1

• The natriuretic effect through proximal tubular sodium-glucose inhibition enhances diuretic efficacy and reduces cardiac preload, potentially mitigating the hemodynamic burden of severe mitral and tricuspid regurgitation. 1

Outcomes Data

• Cardiovascular death was reduced by 12% (HR 0.88,95% CI 0.74-1.05) and worsening heart failure events by 21% (HR 0.79,95% CI 0.69-0.91) in DELIVER. 2

• All-cause mortality was reduced by 31% (HR 0.69,95% CI 0.53-0.88) in the DAPA-CKD trial, with cardiovascular death or heart failure hospitalization reduced by 29% (HR 0.71,95% CI 0.55-0.92). 2

• Benefits were consistent regardless of diabetes status, with similar efficacy in normoglycemia (HR 0.77), prediabetes (HR 0.87), and type 2 diabetes (HR 0.81) subgroups (P-interaction = 0.82). 9

Critical Clinical Caveats

• The presence of severe valvular regurgitation does not contraindicate dapagliflozin use—the drug's benefits on heart failure outcomes are independent of the underlying structural heart disease etiology. 5, 3

• For NYHA class I patients, ensure documentation of elevated natriuretic peptides and structural heart disease (which severe mitral and tricuspid regurgitation clearly provides) to meet trial enrollment criteria. 3, 4

• Do not delay initiation pending valve intervention—dapagliflozin provides immediate symptomatic and prognostic benefit while surgical or transcatheter valve repair is being considered. 1, 8

• Genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%) are manageable adverse effects that should not preclude use in appropriate candidates. 7