Are sodium‑glucose cotransporter‑2 (SGLT‑2) inhibitors safe for an adult with Group 1 pulmonary arterial hypertension, particularly when they have type 2 diabetes or right‑sided heart failure and risk of hypotension, volume depletion, or impaired renal function?

SGLT2 Inhibitors in Group 1 Pulmonary Arterial Hypertension

Direct Answer

SGLT2 inhibitors can be used cautiously in patients with Group 1 pulmonary arterial hypertension (PAH), but require careful volume status monitoring and patient selection, particularly avoiding initiation during acute decompensation or in patients with severe hypotension.

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Evidence Base and Safety Profile

Emerging Evidence in Pulmonary Hypertension

• A large multicenter database study of 771,490 patients with pulmonary hypertension (all groups) demonstrated that SGLT2 inhibitor treatment reduced the composite endpoint of all-cause mortality, right heart failure, and hospital admissions by 29% (HR 0.71,95% CI 0.707-0.729) over 365 days. 1
• Beneficial effects were observed across all five WHO pulmonary hypertension groups, including Group 1 PAH, with significant reductions in all-cause mortality, hospitalization, and intubations. 1
• A systematic review of six studies (462 participants) found that SGLT2 inhibitors, particularly dapagliflozin and empagliflozin, significantly reduced pulmonary arterial pressure and improved cardiac indices including left ventricular parameters and E/e' ratios. 2

Guideline Recognition of Right Heart Failure Benefits

• The 2024 multispecialty consensus explicitly lists pulmonary hypertension as a condition where SGLT2 inhibitors may provide benefit through treatment of right heart failure. 3
• SGLT2 inhibitors reduce heart failure hospitalization by 26-29% in patients with both reduced and preserved ejection fraction, benefits that extend to right-sided heart failure. 3

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Critical Safety Considerations in Group 1 PAH

Volume Depletion Risk

• SGLT2 inhibitors cause osmotic diuresis and natriuresis, leading to plasma volume contraction. 4
• Patients with Group 1 PAH often have compromised right ventricular preload dependence, making them particularly vulnerable to volume depletion. 4
• The American Heart Association/Heart Failure Society of America guidelines specifically warn that SGLT2 inhibitors "should be used with caution in acute decompensation." 3

Pre-Initiation Assessment Algorithm

Before starting an SGLT2 inhibitor in Group 1 PAH:

1. Assess volume status carefully and correct any existing volume depletion. 3
2. Evaluate baseline blood pressure—use caution if systolic BP <100 mmHg or patient has symptomatic hypotension. 3
3. Check renal function—initiate only if eGFR ≥25 mL/min/1.73 m² (≥20 mL/min/1.73 m² per 2024 ADA guidelines). 5, 6
4. Review concurrent diuretics—consider reducing loop or thiazide diuretic doses by 25-50% when starting SGLT2 inhibitor. 3, 6
5. Confirm patient is not in acute right heart failure decompensation—defer initiation until clinically stable. 3

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Dosing and Monitoring Protocol

Standard Dosing

• Initiate dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily for cardiovascular and renal protection in stable Group 1 PAH patients with type 2 diabetes or right heart failure. 5, 6, 7
• No dose titration is required; 10 mg daily is the evidence-based dose for all cardiovascular indications. 5, 6

Intensive Monitoring Schedule

• Week 1-2: Recheck eGFR, electrolytes, and blood pressure; expect a transient eGFR dip of 2-5 mL/min/1.73 m² (hemodynamic, not harmful). 5, 6
• Weeks 2-4: Monitor for symptoms of volume depletion (lightheadedness, orthostasis, weakness) and adjust diuretics accordingly. 3
• Monthly for 3 months: Reassess volume status, blood pressure, and renal function, then every 3-6 months if eGFR <60 mL/min/1.73 m². 5, 7

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Specific Contraindications in PAH Population

Absolute Contraindications

• Active acute decompensated right heart failure with hypotension or requiring IV inotropes. 3
• Severe volume depletion or symptomatic hypotension (systolic BP <90 mmHg). 3
• eGFR <20-25 mL/min/1.73 m² for new initiation (can continue if already established). 5, 6, 7
• Pregnancy or breastfeeding. 3

Relative Contraindications Requiring Extra Caution

• Recurrent genital mycotic infections—occur in ~6% of SGLT2 inhibitor users vs 1% placebo. 3, 6
• History of diabetic ketoacidosis—SGLT2 inhibitors can cause euglycemic DKA even with normal glucose. 3, 8, 9
• Concurrent high-dose loop diuretics (furosemide >80 mg/day)—requires diuretic dose reduction before SGLT2 inhibitor initiation. 3, 6

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Sick Day Management Rules (Critical for PAH Patients)

When to Hold SGLT2 Inhibitor

• Immediately discontinue during any acute illness with reduced oral intake, fever, vomiting, or diarrhea. 6, 9
• Stop at least 3 days before major surgery or procedures requiring prolonged fasting. 3, 6
• Hold during acute PAH exacerbations requiring hospitalization or IV diuretics. 6, 9

Patient Education Essentials

• Instruct patients to stop the medication and contact provider if they develop malaise, nausea, vomiting, or abdominal pain—even with normal blood glucose—as these may signal euglycemic DKA. 3, 6, 9
• Educate about genital hygiene to reduce mycotic infection risk. 3
• Warn about symptoms of volume depletion and when to reduce fluid restriction temporarily. 3

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Integration with PAH-Specific Therapies

Safe Combinations

• SGLT2 inhibitors can be safely combined with:

  • Phosphodiesterase-5 inhibitors (sildenafil, tadalafil)
  • Endothelin receptor antagonists (bosentan, ambrisentan, macitentan)
  • Prostacyclin analogs (epoprostenol, treprostinil)
  • Soluble guanylate cyclase stimulators (riociguat) 1, 2

• Continue ACE inhibitors or ARBs unchanged when adding SGLT2 inhibitor—the combination provides additive cardiovascular protection. 5, 6

Diuretic Management

• Reduce loop diuretic dose by 25-50% when initiating SGLT2 inhibitor in patients on furosemide ≥40 mg/day or equivalent. 3, 6
• Monitor daily weights and adjust diuretics based on volume status rather than stopping SGLT2 inhibitor. 6

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Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitor solely because eGFR falls below 45 mL/min/1.73 m²—cardiovascular and renal benefits persist. 5, 6, 7
• Do not stop the drug because of the expected initial eGFR dip of 2-5 mL/min/1.73 m² in weeks 1-4. 5, 6
• Do not initiate during acute PAH crisis or right heart failure decompensation—wait until patient is euvolemic and stable. 3
• Do not combine with sulfonylureas in diabetic PAH patients—increases hypoglycemia risk without cardiovascular benefit. 5, 6
• Do not reduce SGLT2 inhibitor dose below 10 mg for cardiovascular indications, even at lower eGFR. 5, 6

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Special Population: Non-Diabetic Group 1 PAH

• SGLT2 inhibitors provide cardiovascular and renal protection independent of diabetes status—67.5% of DAPA-CKD participants had diabetes, 32.5% did not, with similar benefits. 5, 6
• For non-diabetic Group 1 PAH patients with right heart failure, initiate SGLT2 inhibitor at 10 mg daily if eGFR ≥25 mL/min/1.73 m² and patient is euvolemic. 5, 7
• The 2020 Canadian Cardiovascular Society guidelines explicitly recommend SGLT2 inhibitors "in patients with mild to moderate HF attributable to reduced ejection fraction, and without concomitant T2DM." 3

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Bottom Line Clinical Algorithm

For a stable Group 1 PAH patient with type 2 diabetes or right heart failure:

1. ✓ Confirm eGFR ≥25 mL/min/1.73 m² and patient is euvolemic
2. ✓ Reduce concurrent diuretics by 25-50% if on high doses
3. ✓ Start dapagliflozin 10 mg or empagliflozin 10 mg once daily
4. ✓ Recheck eGFR and BP at 1-2 weeks
5. ✓ Continue therapy even if eGFR dips 2-5 mL/min/1.73 m²
6. ✓ Hold during acute illness or before surgery
7. ✓ Monitor for genital infections and euglycemic DKA symptoms

The key is patient selection and volume status management—SGLT2 inhibitors are not contraindicated in Group 1 PAH, but require more vigilant monitoring than in other populations.