What is the initial treatment approach for a patient with heart failure with preserved ejection fraction (HFpEF) and diabetes?

Treatment for Heart Failure with Preserved Ejection Fraction and Diabetes

Start an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) immediately as first-line disease-modifying therapy, regardless of glycemic control needs, combined with loop diuretics titrated to relieve congestion. 1, 2, 3

First-Line Disease-Modifying Therapy

SGLT2 inhibitors are the cornerstone of treatment for HFpEF with diabetes, providing dual benefits for both conditions. 1, 2

• Dapagliflozin 10 mg once daily reduced the composite endpoint of worsening heart failure and cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) and heart failure hospitalizations by 23% (HR 0.77,95% CI 0.67-0.89) in the DELIVER trial. 2, 3

• Empagliflozin 10 mg once daily reduced heart failure hospitalization or cardiovascular death by 21% (HR 0.79,95% CI 0.69-0.90) in EMPEROR-PRESERVED. 1, 2, 3

• These benefits occur independent of glucose-lowering effects and are seen in patients with and without diabetes, representing a class effect for cardiovascular protection. 1

• The 2022 American Diabetes Association guidelines explicitly state that SGLT2 inhibitors should be included irrespective of the need for additional glucose lowering and irrespective of metformin use. 1

Symptom Management with Diuretics

Loop diuretics are essential for managing congestion but should be used at the lowest effective dose to avoid complications. 1, 2, 3

• Start furosemide 20-40 mg daily (or bumetanide 0.5-1.0 mg, or torsemide 5-10 mg) and titrate based on symptoms, weight, and volume status. 1

• Train patients to self-adjust diuretic doses based on daily weight monitoring and symptoms of congestion to maintain euvolemia ("dry weight"). 1

• Avoid excessive diuresis, which can lead to hypotension, renal dysfunction, and reduced cardiac output—particularly problematic in HFpEF where cardiac output is already compromised. 1, 3

• If inadequate response occurs despite dose increases, consider switching to a different loop diuretic or adding a thiazide diuretic (hydrochlorothiazide 12.5-100 mg or metolazone 2.5-10 mg) for sequential nephron blockade, but do not use thiazides if eGFR <30 mL/min. 1

Additional Pharmacological Options

Mineralocorticoid Receptor Antagonists (MRAs)

Consider adding spironolactone 12.5-25 mg daily (titrating to 50 mg) particularly if LVEF is in the lower preserved range (40-50%). 1, 2

• Spironolactone has a Class 2b recommendation based on TOPCAT trial showing reduction in heart failure hospitalizations (HR 0.83,95% CI 0.69-0.99) but no significant mortality benefit. 2

• Monitor potassium and renal function closely—check within 1 week of initiation and after dose changes, as hyperkalemia is a significant risk, especially with concurrent ACE inhibitor or ARB use. 1

• Consider potassium binders if hyperkalemia (K+ >5.0 mEq/L) develops to facilitate ongoing use of evidence-based therapies. 1

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

Sacubitril/valsartan may be considered (Class 2b recommendation) for selected patients, particularly women and those with LVEF 45-57%. 2

• The PARAGON-HF trial showed no significant reduction in the primary endpoint overall (rate ratio 0.87,95% CI 0.75-1.01, p=0.06), but subgroup analyses suggested benefit in women (rate ratio 0.73,95% CI 0.59-0.90) and those with LVEF below the median. 2

• This is a lower priority than SGLT2 inhibitors given the weaker evidence base. 2

Blood Pressure Management

Target blood pressure <130/80 mmHg using the medications already prescribed for heart failure. 1, 3

• The SGLT2 inhibitor, loop diuretic, and potentially MRA will contribute to blood pressure control. 1

• ACE inhibitors or ARBs are reasonable for additional blood pressure control if needed, though they have not shown mortality benefit in HFpEF specifically. 1

• Beta-blockers may be used for blood pressure control and are reasonable in HFpEF, particularly if atrial fibrillation is present for rate control. 1

• Avoid non-dihydropyridine calcium channel blockers (diltiazem, verapamil) as they increase risk of heart failure worsening and hospitalization in HFpEF. 3

• Amlodipine or felodipine are safe if additional blood pressure control is needed beyond other agents. 1

Glycemic Management Beyond SGLT2 Inhibitors

If additional glucose lowering is needed after starting an SGLT2 inhibitor, prioritize agents with cardiovascular benefits. 1

• GLP-1 receptor agonists (such as semaglutide, dulaglutide, or liraglutide) provide additional cardiovascular protection and can be added for glycemic control. 1

• Metformin can be continued or added for glycemic control but does not provide specific heart failure benefits. 1

• Avoid or use pioglitazone with extreme caution as thiazolidinediones cause fluid retention and can worsen heart failure. 1

Non-Pharmacological Interventions

Prescribe supervised exercise training (Class 1 recommendation) as it improves functional capacity and quality of life with clinically meaningful benefits. 2, 3, 4

• Exercise training produced significant improvements in functional capacity in randomized trials of HFpEF patients. 4

Recommend dietary sodium restriction to <2-3 g/day to help control volume status and reduce congestion. 3

Encourage weight loss if BMI ≥30 kg/m² through diet and exercise, as obesity is a major contributor to HFpEF pathophysiology and diet-induced weight loss improved functional capacity in trials. 4, 5

Provide education in heart failure self-care, including medication adherence, dietary sodium restriction, daily weight monitoring, and recognition of worsening symptoms. 4

Monitoring and Follow-Up

Assess the following at each visit: 2, 3

• Volume status: weight, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, jugular venous pressure
• Vital signs: blood pressure, heart rate
• Renal function: serum creatinine, eGFR (tolerate acute eGFR decreases ≤30% from baseline with SGLT2 inhibitors and MRAs)
• Electrolytes: potassium (especially with MRA use), sodium
• Symptoms: dyspnea, exercise tolerance, NYHA functional class

Adjust diuretic doses based on congestion status to avoid overdiuresis leading to hypotension and renal dysfunction. 3

Common Pitfalls to Avoid

Do not treat HFpEF patients identically to those with reduced ejection fraction—the response to therapies differs significantly between these populations. 2, 3

Do not overlook comorbidity management—hypertension, diabetes, obesity, and atrial fibrillation significantly impact outcomes and must be aggressively treated. 1, 3

Do not use excessive diuretic doses—this leads to hypotension, renal dysfunction, and may prevent achievement of target doses of disease-modifying therapies. 1

Do not prescribe non-dihydropyridine calcium channel blockers (diltiazem, verapamil) as they worsen outcomes in HFpEF. 3

Do not delay SGLT2 inhibitor initiation—these should be started immediately upon diagnosis regardless of glycemic control status. 1, 2

Treatment Algorithm Summary

1. Immediately start SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10 mg daily) 1, 2
2. Initiate loop diuretic (furosemide 20-40 mg daily) and titrate to relieve congestion 1, 2
3. Optimize blood pressure to <130/80 mmHg using existing medications ± ACE inhibitor/ARB or beta-blocker 1, 3
4. Consider adding spironolactone 12.5-25 mg daily if LVEF 40-50% and potassium/renal function permit 2
5. Add GLP-1 receptor agonist if additional glycemic control needed 1
6. Prescribe supervised exercise training and sodium restriction <2-3 g/day 2, 3, 4
7. Monitor closely for volume status, renal function, electrolytes, and symptoms 2, 3