In an adult with hypertension, heart failure with reduced ejection fraction (EF ≤40%), and type 2 diabetes, what are the recommended first‑line agents, dosing, and titration for angiotensin‑converting‑enzyme inhibitors (ACE inhibitors), angiotensin‑receptor blockers (ARBs), angiotensin‑receptor‑neprilysin inhibitors (ARNIs), and glucagon‑like peptide‑1 (GLP‑1) receptor agonists?

Guideline-Directed Medical Therapy for HFrEF with Hypertension and Type 2 Diabetes

All patients with HFrEF (EF ≤40%), hypertension, and type 2 diabetes should receive simultaneous quadruple therapy: ARNI (preferred over ACE inhibitor/ARB), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor, initiated together at low doses and titrated to target doses proven in clinical trials. 1, 2

First-Line Agent Selection and Dosing

ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - PREFERRED FIRST CHOICE

Sacubitril/valsartan is the preferred renin-angiotensin system inhibitor over ACE inhibitors or ARBs for all ambulatory patients with symptomatic HFrEF. 1, 2, 3

• Starting dose: Sacubitril/valsartan 24/26 mg twice daily (or 49/51 mg twice daily if previously on moderate-dose ACE inhibitor/ARB) 3
• Target dose: Sacubitril/valsartan 97/103 mg twice daily 3
• Titration schedule: Double the dose every 2-4 weeks as tolerated, monitoring blood pressure and renal function 2
• Critical requirement: Must discontinue ACE inhibitor at least 36 hours before initiating ARNI to avoid angioedema 3

ACE Inhibitors (if ARNI not available or not tolerated)

Use evidence-based ACE inhibitors at target doses proven to reduce mortality: 1

• Enalapril: Start 2.5 mg twice daily, target 10-20 mg twice daily 1
• Lisinopril: Start 2.5-5 mg once daily, target 20-40 mg once daily 1
• Ramipril: Start 1.25-2.5 mg once daily, target 5 mg twice daily or 10 mg once daily 1

Titration: Increase dose every 1-2 weeks, monitoring blood pressure, renal function (creatinine, potassium) at baseline, 1-2 weeks after each adjustment, then every 3-6 months 1, 2

ARBs (ONLY if ACE inhibitor intolerant due to cough or angioedema)

ARBs are alternatives to ACE inhibitors, NOT additions: 1

• Candesartan: Start 4-8 mg once daily, target 32 mg once daily 2
• Valsartan: Start 40 mg twice daily, target 160 mg twice daily 2

Critical warning: Never combine ACE inhibitor + ARB + mineralocorticoid receptor antagonist—this causes life-threatening hyperkalemia and renal dysfunction 1, 2

Beta-Blockers (one of three evidence-based agents ONLY)

Use ONLY bisoprolol, carvedilol, or metoprolol succinate (sustained-release), which reduce cardiovascular death and hospitalization: 1, 2

• Carvedilol: Start 3.125 mg twice daily, target 25 mg twice daily (50 mg twice daily if >85 kg) 2
• Metoprolol succinate: Start 12.5-25 mg once daily, target 200 mg once daily 2
• Bisoprolol: Start 1.25 mg once daily, target 10 mg once daily 2

Titration: Start simultaneously with ARNI/ACE inhibitor (not sequentially), increase every 2-4 weeks to target doses 2

Mineralocorticoid Receptor Antagonists (MRAs)

All eligible HFrEF patients should receive MRAs with careful potassium and renal monitoring: 1, 2

• Spironolactone: Start 12.5-25 mg once daily, target 25-50 mg once daily 1
• Eplerenone: Start 25 mg once daily, target 50 mg once daily 2

Monitoring requirements: Check potassium and creatinine at baseline, 1 week, 4 weeks, then every 3-6 months; hold if potassium >5.5 mEq/L or creatinine significantly elevated 2

SGLT2 Inhibitors (for ALL HFrEF patients regardless of diabetes status)

SGLT2 inhibitors are Class I, Level A recommendation for all HFrEF patients, reducing cardiovascular death and HF hospitalization by 32-35%: 1, 4, 2

• Empagliflozin: 10 mg once daily 1, 4
• Dapagliflozin: 10 mg once daily 1, 4
• Canagliflozin: 100 mg once daily 1, 4

Critical caution: When initiating SGLT2 inhibitors in patients already on ARNI, start at lower dose (dapagliflozin 5 mg) if euvolemic, as combination increases diuretic effect and hypotension risk 5

GLP-1 Receptor Agonists for Type 2 Diabetes Management

GLP-1 receptor agonists have neutral effect on HF hospitalization and may be considered for glycemic control in HFrEF patients with type 2 diabetes: 1, 4

• Semaglutide: 0.25 mg subcutaneous weekly, titrate to 0.5-1 mg weekly 1
• Liraglutide: 0.6 mg subcutaneous daily, titrate to 1.2-1.8 mg daily 1
• Dulaglutide: 0.75 mg subcutaneous weekly, titrate to 1.5 mg weekly 1

For obesity (BMI ≥30 kg/m²) with HFmrEF/HFpEF (EF ≥45%), GLP-1 RAs provide additional cardiovascular benefit: 1

Blood Pressure Targets

Target systolic BP <130 mm Hg and diastolic BP <80 mm Hg in patients with diabetes, hypertension, and HFrEF: 1

• This target applies to patients with 10-year ASCVD risk ≥10% or known cardiovascular disease 1
• Minimum acceptable control (audit standard): <140/90 mm Hg 1

Critical Monitoring Schedule

Monitor at each medication adjustment: 2

• Blood pressure (watch for symptomatic hypotension, especially with ARNI + SGLT2i combination) 5
• Renal function (serum creatinine, eGFR)
• Electrolytes (potassium, sodium)
• Timing: Baseline, 1-2 weeks after each dose change, at 3 months, then every 6 months 2

Medications to AVOID in HFrEF

Thiazolidinediones (pioglitazone, rosiglitazone) are Class III contraindicated—they increase HF hospitalization risk: 1, 4

Saxagliptin (DPP-4 inhibitor) increases HF hospitalization and is contraindicated: 1, 4

Calcium channel blockers (diltiazem, verapamil) worsen HF and increase hospitalization: 1, 2

NSAIDs should be avoided as they cause fluid retention and reduce ACE inhibitor/diuretic efficacy: 1

Additional Diabetes Management

Metformin should be considered as second-line diabetes therapy if eGFR stable and >30 mL/min/1.73 m²: 1, 4

Insulin may be considered in advanced HFrEF but use cautiously to avoid hypoglycemia, which triggers arrhythmias: 1, 4

Common Pitfalls to Avoid

• Sequential rather than simultaneous initiation: Start all four pillars (ARNI, beta-blocker, MRA, SGLT2i) together at low doses 2
• Undertitration: Must titrate to target doses proven in trials, not just symptomatic improvement 1
• Volume depletion with ARNI + SGLT2i: Educate patients on signs of dehydration; consider lower SGLT2i starting dose if euvolemic 5
• Combining ACE inhibitor + ARB: Never use together—increases hyperkalemia and renal dysfunction without benefit 1
• Using non-evidence-based beta-blockers: Only bisoprolol, carvedilol, or metoprolol succinate reduce mortality 1, 2