What is the role of Dapagliflozin (SGLT2 inhibitor) in treating right ventricular (RV) failure, particularly in patients with concomitant type 2 diabetes?

Dapagliflozin for Right Ventricular Failure

Dapagliflozin should be used in patients with right ventricular failure, particularly when associated with heart failure with preserved or reduced ejection fraction, as it significantly improves RV-pulmonary vascular coupling, reduces pulsatile RV afterload, and decreases pulmonary artery stiffness during exercise. 1

Evidence for RV-Specific Benefits

The most compelling and recent evidence comes from the CAMEO-DAPA trial, which specifically evaluated dapagliflozin's effects on right ventricular performance using simultaneous echocardiography and invasive hemodynamic testing. 1

Key RV Hemodynamic Improvements

• Dapagliflozin improved pulmonary artery compliance during exercise by 0.57 mL/mm Hg (95% CI, 0.11-1.03; P = .02), directly reducing the pulsatile load on the right ventricle. 1

• Pulmonary artery elastance (stiffness) decreased by -0.17 mm Hg/mL (95% CI, -0.28 to -0.07; P = .001) with exercise, indicating reduced RV afterload. 1

• RV-PA coupling improved during exercise, demonstrated by increased PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and improved RV systolic velocity indexed to PA pressure (0.09 cm·s-1/mm Hg; 95% CI, 0.02-0.16; P = .01). 1

Mechanism of RV Benefit

The improvements in RV function are mechanistically linked to reductions in both right atrial pressure and pulmonary capillary wedge pressure. 1 Specifically:

• PA elastance reduction correlated with RA pressure reduction (Pearson r = 0.55; P = .008) and PCWP reduction (Pearson r = 0.58; P <.001). 1

• Dapagliflozin increased resistance-compliance time (median change 0.06 seconds vs 0.01 seconds with placebo; P = .046), resulting in higher PA compliance for any given pulmonary vascular resistance during exercise. 1

Broader Heart Failure Evidence Supporting Use

Heart Failure with Reduced Ejection Fraction (HFrEF)

The 2022 ACC/AHA/HFSA guidelines strongly recommend SGLT2 inhibitors for all patients with symptomatic HFrEF (LVEF ≤40%, NYHA class II-IV), regardless of diabetes status. 2

• Dapagliflozin reduced cardiovascular death or HF hospitalization by 26% (HR 0.74; 95% CI 0.65-0.85) in the DAPA-HF trial. 3

• HF hospitalizations specifically decreased by 30% in both DAPA-HF and EMPEROR-Reduced trials. 2

• Cardiovascular death was reduced by 18% with dapagliflozin, along with a 17% reduction in all-cause mortality. 2

Heart Failure with Preserved Ejection Fraction (HFpEF)

• The DELIVER trial demonstrated dapagliflozin reduced worsening HF or cardiovascular death by 18% in 6,263 patients with LVEF >40%. 3, 4

• Benefits were consistent across the spectrum of LVEF >40%, including both mildly reduced and preserved ejection fraction. 4

Clinical Implementation Algorithm

Patient Selection

1. Identify RV failure patients with:

   • HFrEF (LVEF ≤40%) with NYHA class II-IV symptoms 2
   • HFpEF (LVEF >40%) with NYHA class II-IV symptoms 3
   • Elevated natriuretic peptides and structural heart disease 4
   • eGFR ≥25-30 mL/min/1.73 m² 2, 3

2. Exclude patients with:

   • eGFR <20-30 mL/min/1.73 m² (varies by guideline) 2
   • Type 1 diabetes 2
   • Systolic blood pressure <95-100 mm Hg 2

Dosing and Initiation

• Start dapagliflozin 10 mg once daily without need for titration. 3

• Initiate during hospitalization in stabilized patients rather than deferring to outpatient setting, as delay results in many eligible patients never receiving therapy. 3

• Benefits occur within weeks of initiation and are maintained long-term. 3

Monitoring

• Monitor renal function periodically, though mild transient eGFR decrease does not indicate kidney injury and should not prompt discontinuation. 3

• Assess for volume depletion signs (hypotension occurs in ~5.7% of patients), especially in those already volume depleted. 3

• Watch for genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%), which are generally manageable. 3

Independence from Diabetes Status

The RV and overall cardiovascular benefits of dapagliflozin are independent of diabetes status and baseline glycemic control. 2

• In DAPA-HF, benefits were equivalent in patients with and without diabetes (non-diabetic HR 0.73; 95% CI 0.60-0.88). 3

• Treatment effects are consistent regardless of background glucose-lowering therapy, including number and class of medications. 5

• The 2019 ADA/EASD consensus recommends considering SGLT2 inhibitor use independently of baseline HbA1c or individualized HbA1c target in appropriate high-risk individuals. 2

Critical Pitfalls to Avoid

• Do not withhold dapagliflozin due to mild eGFR decline after initiation—this is expected and does not represent kidney injury. 3

• Do not delay initiation to outpatient setting in hospitalized patients once stabilized, as this significantly reduces likelihood of ever receiving therapy. 3

• Do not restrict use to diabetic patients—the RV and cardiovascular benefits are independent of diabetes status. 2, 3, 1

• Do not discontinue for mild urinary symptoms—cardiovascular benefits should be prioritized. 3