What medications are recommended for a middle‑aged or older adult with grade 2 diastolic dysfunction (heart failure with preserved ejection fraction)?

Medications for Grade 2 Diastolic Dysfunction (HFpEF)

For a patient with grade 2 diastolic dysfunction (heart failure with preserved ejection fraction), initiate an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) as first-line disease-modifying therapy, add loop diuretics as needed for congestion, and aggressively control blood pressure to <130/80 mmHg using ACE inhibitors or ARBs. 1

First-Line Disease-Modifying Therapy: SGLT2 Inhibitors

SGLT2 inhibitors are the cornerstone of HFpEF treatment and should be started immediately at diagnosis, regardless of diabetes status. 1

• Dapagliflozin 10 mg daily (if eGFR >30 mL/min/1.73 m²) reduces the composite of worsening heart failure and cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) 1
• Empagliflozin 10 mg daily (if eGFR >60 mL/min/1.73 m²) reduces heart failure hospitalization or cardiovascular death by 21% (HR 0.79,95% CI 0.69-0.90) 1
• These agents require no dose titration, have minimal impact on blood pressure or heart rate, and provide benefits within weeks of initiation 2, 1
• The mortality benefit is driven primarily by reduction in heart failure hospitalizations rather than mortality alone 1

Symptom Management: Diuretics

Loop diuretics are essential for managing congestion but should be used at the lowest effective dose. 3, 1

• Start with furosemide 20-40 mg daily (or equivalent) and titrate based on volume status 1
• Diuretics relieve orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema 3, 1
• Avoid excessive diuresis, which can precipitate hypotension and worsening renal function 1
• If inadequate response, consider increasing the loop diuretic dose before adding a thiazide diuretic for sequential nephron blockade 1

Blood Pressure Control: ACE Inhibitors or ARBs

Target blood pressure <130/80 mmHg using ACE inhibitors or ARBs as first-line antihypertensive agents after volume optimization. 1

• ACE inhibitors and ARBs effectively lower blood pressure and modestly reduce heart failure hospitalizations, though they do not provide the mortality benefit seen in HFrEF 1
• Hypertension is present in 60-89% of HFpEF patients and represents the most important modifiable risk factor 1
• These agents are reasonable for additional blood pressure control if needed beyond SGLT2 inhibitors 1

Additional Pharmacological Options for Selected Patients

Mineralocorticoid Receptor Antagonists (MRAs)

Consider adding spironolactone 12.5-25 mg daily, particularly if LVEF is in the lower preserved range (40-50%). 1

• Spironolactone reduces heart failure hospitalizations (HR 0.83,95% CI 0.69-0.99) but did not significantly reduce the primary composite outcome in TOPCAT 1
• This is a Class 2b recommendation, indicating it "may be considered" 1
• Monitor potassium and renal function closely, with caution when potassium >5.0 mEq/L 2, 1

Sacubitril/Valsartan (ARNI)

Sacubitril/valsartan may be considered specifically for women and patients with LVEF 45-57%, as these subgroups showed benefit in post-hoc analyses. 1

• The PARAGON-HF trial did not achieve a significant reduction in the primary endpoint overall (rate ratio 0.87,95% CI 0.75-1.01, p=0.06) 1
• Subgroup analyses showed potential benefit in patients with LVEF 45-57% (rate ratio 0.78,95% CI 0.64-0.95) and women (rate ratio 0.73,95% CI 0.59-0.90) 1
• This is a Class 2b recommendation 1

Medications to Avoid

Certain medications are harmful or ineffective in HFpEF and should be avoided. 1

• Nondihydropyridine calcium channel blockers (diltiazem, verapamil) have negative inotropic effects and increase the risk of heart failure worsening and hospitalization 3, 1
• Nitrates are associated with a signal of harm in HFpEF 1
• Thiazolidinediones (pioglitazone, rosiglitazone) increase the risk of worsening heart failure symptoms and hospitalizations 3
• Saxagliptin and alogliptin (DPP-4 inhibitors) increase the risk of heart failure hospitalization and should be avoided 3

Management of Comorbidities

Systematic management of comorbid conditions is essential because they markedly influence outcomes in HFpEF. 1

Diabetes Management

• Prioritize SGLT2 inhibitors for glycemic control given their dual benefit on glucose and heart failure outcomes 3, 1
• GLP-1 receptor agonists have a neutral effect on heart failure hospitalization and may be considered if SGLT2 inhibitors are not tolerated 3

Atrial Fibrillation

• Use beta-blockers for rate control, with careful monitoring of exercise tolerance due to potential chronotropic incompetence 1
• Anticoagulation should follow standard guidelines based on CHA₂DS₂-VASc score 1

Non-Pharmacological Interventions

Prescribe supervised exercise training programs to improve functional capacity and quality of life. 1

• Exercise training involves 3 sessions per week for 1-8 months at 40-90% of exercise capacity 1
• This improves aerobic exercise capacity by 12-14% with clinically meaningful benefits 1
• Advise dietary sodium restriction <2-3 g per day to lessen congestive symptoms 1

Monitoring and Follow-Up

Regular monitoring of blood pressure, renal function, and electrolytes is essential, especially with MRA therapy. 1

• Monitor serum creatinine, eGFR, and potassium routinely, particularly when using aldosterone antagonists 2, 1
• Assess volume status, symptoms, and functional capacity to guide treatment adjustments 1
• Close follow-up within 1-2 weeks of medication changes is recommended 4

Common Pitfalls to Avoid

• Do not treat HFpEF patients the same as those with reduced ejection fraction, as response to therapies differs significantly 1
• Do not overlook the importance of managing comorbidities (hypertension, diabetes, obesity, atrial fibrillation), which significantly impact outcomes 1
• Avoid excessive diuresis, which may lead to hypotension and worsening renal function 1
• Do not use routine beta-blockers, digoxin (in sinus rhythm), ivabradine, or sildenafil, as these have not demonstrated clinical benefit in HFpEF 1

Evidence Gaps

No single pharmacologic agent has yet demonstrated a definitive mortality reduction as a standalone endpoint in HFpEF. 1

• The principal benefit of SGLT2 inhibitors is reduction in heart failure hospitalizations, which drives improvement in composite cardiovascular outcomes 1
• Multiple other agents (perindopril, irbesartan, beta-blockers, nitrates, digoxin, ivabradine, sildenafil, serelaxin) have failed to show any mortality benefit 1