What is the role of Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors in the management of pulmonary hypertension?

SGLT2 Inhibitors in Pulmonary Hypertension

SGLT2 inhibitors show promising therapeutic potential in pulmonary hypertension and should be considered as an adjunctive treatment option, particularly in patients with PH due to left heart disease (Group 2 PH), based on emerging evidence demonstrating reduced mortality, improved hemodynamics, and attenuated pulmonary vascular remodeling.

Evidence for Clinical Benefit

Mortality and Composite Outcomes

• A large multicenter database analysis of 771,490 PH patients found that SGLT2 inhibitor treatment significantly reduced the composite endpoint of all-cause mortality, right heart failure, and hospital admissions (HR 0.71,95% CI: 0.707-0.729) over 365 days 1
• These beneficial effects were observed across all five PH groups, not limited to patients with left heart disease 1
• Individual secondary outcomes including all-cause mortality, hospitalization rates, and intubation frequency were all significantly lower in SGLT2 inhibitor-treated patients 1

Hemodynamic Improvements

• In experimental monocrotaline-induced pulmonary arterial hypertension, empagliflozin significantly reduced mean pulmonary artery pressure, right ventricular systolic pressure, and increased pulmonary acceleration time 2
• Tofogliflozin improved right ventricular systolic pressure in two distinct murine models of PH due to left heart disease (transverse aortic constriction and high-fat diet models) 3

Structural and Vascular Benefits

• SGLT2 inhibition resulted in reduced right ventricular hypertrophy and fibrosis in experimental PAH 2
• Histological assessments revealed significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles with empagliflozin treatment 2
• Tofogliflozin ameliorated pulmonary vascular remodeling and suppressed pulmonary artery smooth muscle cell migration 3

Mechanisms of Action in Pulmonary Hypertension

Metabolic Effects

• SGLT2 inhibitors reduce aerobic glycolysis, improve mitochondrial function, and enhance fatty acid oxidation—all relevant to PH pathophysiology 1
• These agents act independently of insulin signaling, making them suitable across the spectrum of metabolic dysfunction seen in PH 4

Hemodynamic and Diuretic Properties

• SGLT2 inhibitors combine proximal tubule diuretic and osmotic diuretic action, leading to mild natriuretic effects that can reduce preload and pulmonary congestion 5
• Blood pressure reduction of 3-5 mmHg systolic has been consistently demonstrated, which may benefit pulmonary vascular afterload 6

Clinical Application Algorithm

Patient Selection

• Prioritize SGLT2 inhibitors in Group 2 PH (PH due to left heart disease), where the strongest mechanistic rationale and experimental evidence exist 3
• Consider in all PH groups given the broad benefit observed in the large database analysis 1
• Particularly valuable in patients with concurrent heart failure with reduced or preserved ejection fraction, where SGLT2 inhibitors are already guideline-recommended 4

Renal Function Considerations

• Initiate SGLT2 inhibitors when eGFR ≥30 mL/min/1.73 m² for both glycemic and cardiorenal benefits 7
• Continue therapy even as eGFR declines below 45 mL/min/1.73 m², as cardiovascular and kidney benefits persist despite reduced glucose-lowering efficacy 7
• Can be continued down to eGFR 20 mL/min/1.73 m² if well-tolerated and kidney replacement therapy is not imminent 7

Agent Selection

• Empagliflozin, dapagliflozin, or canagliflozin are preferred given their proven cardiovascular and renal benefits in heart failure populations 7
• All three agents demonstrate high SGLT2 selectivity, which is mechanistically relevant for PH benefits 7

Critical Safety Considerations and Monitoring

Acute Illness Management

• Immediately discontinue SGLT2 inhibitors during acute decompensation, severe illness, or hospitalization for PH exacerbation due to euglycemic diabetic ketoacidosis risk 8
• The glycosuric effects persist for 3-4 days after discontinuation, prolonging ketoacidosis risk 8
• Check both glucose AND ketone levels during acute illness—normal glucose does not exclude ketoacidosis 8

Restart Criteria After Acute Illness

• Patient must be eating and drinking normally for at least 24-48 hours 8
• Capillary ketones must be <0.6 mmol/L before restarting 8
• Clinical stability with improving hemodynamics and stable renal function required 8

Volume Status Monitoring

• Monitor for volume depletion, particularly in patients already on aggressive diuretic regimens for right heart failure 5
• The osmotic diuretic effect can compound existing volume depletion from loop diuretics 8
• Adjust loop diuretic doses as needed when initiating SGLT2 inhibitors to avoid excessive diuresis 4

Integration with Existing PH Therapies

Group 2 PH (Left Heart Disease)

• SGLT2 inhibitors are recommended in heart failure with preserved ejection fraction (HFpEF) to improve outcomes in the context of their modest BP-lowering properties 4
• In symptomatic HFrEF/HFmrEF, SGLT2 inhibitors are recommended alongside ACE inhibitors/ARBs/ARNi, beta-blockers, and MRAs 4
• Do not discontinue SGLT2 inhibitors solely because glucose-lowering efficacy has declined—the cardiorenal benefits are out of proportion to glycemic effects 7

Pulmonary Arterial Hypertension (Group 1)

• While no specific guidelines exist for PAH, the experimental evidence showing reduced mortality and improved hemodynamics supports consideration as adjunctive therapy 2
• SGLT2 inhibitors should complement, not replace, PAH-specific therapies (endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostacyclins) 9

Common Pitfalls to Avoid

Discontinuation Errors

• Do not stop SGLT2 inhibitors when eGFR falls below 45 mL/min/1.73 m² thinking they are no longer effective—cardiorenal protection persists 7
• Do not continue SGLT2 inhibitors "for cardioprotection" during acute PH decompensation or pneumonia—the immediate ketoacidosis risk outweighs theoretical benefits 8

Monitoring Gaps

• Do not assume normal glucose excludes ketoacidosis in acutely ill patients on SGLT2 inhibitors—always check ketones 8
• Do not mistake the initial reversible eGFR dip (hemodynamic effect) as a reason to discontinue therapy 7

Infection Risk

• Counsel patients about increased risk of genital mycotic infections and rare urinary tract infections 6
• These are generally manageable and should not preclude use in appropriate candidates 6

Future Directions

The convergence of experimental data showing improved survival and pulmonary vascular remodeling 2, 3, combined with large-scale clinical database evidence of reduced mortality and hospitalizations 1, provides compelling rationale for randomized controlled trials specifically evaluating SGLT2 inhibitors in pulmonary hypertension populations 2, 9. Until such trials are completed, clinicians should strongly consider SGLT2 inhibitors in PH patients with concurrent indications (diabetes, heart failure, chronic kidney disease) and may reasonably extend use to other PH groups given the favorable safety profile and broad mechanistic benefits 1.