What is the recommended use and dosage of Angiotensin-Converting Enzyme (ACE) inhibitors, such as lisinopril (Zestril) or enalapril (Vasotec), for treating hypertension, heart failure, and protecting the kidneys in people with diabetes?

ACE Inhibitors: Recommended Use and Dosing

ACE inhibitors are first-line therapy for hypertension in patients with diabetes, particularly when albuminuria is present, and should be titrated to maximum tolerated doses used in clinical trials rather than stopping at initial response. 1, 2

Blood Pressure Targets in Diabetes

• Target BP <130/80 mmHg for patients with diabetes and hypertension 1
• Patients with systolic BP 130-139 mmHg or diastolic BP 80-89 mmHg should receive lifestyle modification for maximum 3 months, then add pharmacologic therapy if targets not achieved 1
• Patients with BP ≥140/90 mmHg require immediate drug therapy plus lifestyle modification 1

First-Line Agent Selection

ACE inhibitors are the preferred initial antihypertensive agent in patients with diabetes, based on superior cardiovascular outcomes compared to other drug classes 1. The evidence supporting this recommendation includes:

• ACE inhibitors reduce cardiovascular events more effectively than dihydropyridine calcium channel blockers in patients with diabetes 1
• They provide cardiovascular benefits beyond blood pressure reduction alone 1
• If ACE inhibitors are not tolerated (typically due to cough), ARBs should be substituted 1

Renal Protection in Diabetes

When to Initiate ACE Inhibitors for Kidney Protection

ACE inhibitors are mandatory first-line therapy for patients with:

• Established CKD (eGFR <60 mL/min/1.73 m²) AND macroalbuminuria (UACR ≥300 mg/g) 1
• Microalbuminuria (UACR 30-299 mg/g) with hypertension to prevent progression to macroalbuminuria 1

Do NOT use ACE inhibitors in patients without hypertension to prevent CKD development, as clinical trials showed no benefit and potential harm 1

ACE Inhibitors vs ARBs for Renal Protection

• Both ACE inhibitors and ARBs are equally effective for renal protection in patients with albuminuria 3
• Choose based on tolerability rather than efficacy differences 3
• ACE inhibitors are preferred for type 1 diabetes with nephropathy; both are appropriate for type 2 diabetes 1

Specific Dosing Recommendations

Lisinopril (Zestril)

For Hypertension:

• Initial dose: 10 mg once daily (or 5 mg if on diuretics) 4
• Titrate to maximum 40 mg once daily 4
• Pediatric patients ≥6 years: Start 0.07 mg/kg once daily (max 5 mg), titrate to max 0.61 mg/kg (up to 40 mg) 4

For Heart Failure:

• Initial dose: 5 mg once daily (2.5 mg if hyponatremic with sodium <130 mEq/L) 4
• Titrate to maximum 40 mg once daily as tolerated 4

For Post-MI:

• Day 1: 5 mg, then 5 mg at 24 hours 4
• Day 3: 10 mg, then 10 mg daily for at least 6 weeks 4
• Use 2.5 mg initial dose if systolic BP 100-120 mmHg 4

Enalapril (Vasotec)

For Hypertension:

• Initial dose: 5 mg once daily (2.5 mg if on diuretics or under close supervision) 5
• Usual range: 10-40 mg daily in single or divided doses 5

For Heart Failure:

• Initial dose: 2.5 mg twice daily 5
• Titrate to 2.5-20 mg twice daily (maximum 40 mg daily in divided doses) 5

Critical Dosing Principles

Titrate to maximum tolerated doses demonstrated in clinical trials, not just to blood pressure control 2, 6. The ATLAS study showed that high-dose lisinopril (32.5-35 mg daily) reduced mortality and hospitalizations by 12-24% compared to low-dose (2.5-5 mg daily) in heart failure 7.

Renal Dose Adjustments

For Creatinine Clearance:

• >30 mL/min: No adjustment needed 4, 5
• 10-30 mL/min: Reduce initial dose by 50% (lisinopril 5 mg, enalapril 2.5 mg) 4, 5
• <10 mL/min or hemodialysis: Start 2.5 mg 4, 5

Monitoring Requirements

Within 1-2 weeks of initiation or dose change, check:

• Serum creatinine/eGFR 1, 2
• Serum potassium 1, 2

Accept up to 30% increase in serum creatinine as expected hemodynamic effect 2, 8. This initial decline in GFR correlates with better long-term renal protection 8.

Continue monitoring at least annually thereafter 3

Critical Pitfalls to Avoid

Never Combine ACE Inhibitors with ARBs

Dual RAAS blockade increases adverse events (hyperkalemia, acute kidney injury) without cardiovascular or renal benefit 1, 3. Multiple clinical trials definitively demonstrated harm from this combination 1.

Do Not Underdose

Most patients receive subtherapeutic doses in clinical practice 2, 6. The mortality and morbidity benefits demonstrated in trials used maximum tolerated doses, not the doses that merely control blood pressure 6, 7.

Monitor for Hyperkalemia Risk

Higher risk with:

• eGFR <60 mL/min/1.73 m² 3, 2
• Concurrent potassium-sparing diuretics, NSAIDs, or mineralocorticoid receptor antagonists 3, 2
• Diabetes mellitus 8

If hyperkalemia develops, use potassium-wasting diuretics or potassium binders rather than stopping the ACE inhibitor 2

Counsel Patients to Hold During Volume Depletion

Instruct patients to temporarily discontinue ACE inhibitors during acute illness with vomiting, diarrhea, or dehydration to prevent acute kidney injury 2, 8

Combination Therapy

Most patients with diabetes require ≥3 antihypertensive agents to achieve BP <130/80 mmHg 1. When adding agents:

• Add low-dose thiazide diuretic as second agent (e.g., hydrochlorothiazide 12.5 mg) 1, 4
• Consider β-blockers for post-MI patients 1
• Calcium channel blockers are appropriate as third-line agents, not replacements for ACE inhibitors 1

Special Populations

Heart Failure with Reduced Ejection Fraction

ACE inhibitors reduce mortality and should be used in all patients unless contraindicated 6, 7. However, angiotensin receptor/neprilysin inhibitors (ARNIs) are now first choice, with ACE inhibitors as second choice 9.

Post-Myocardial Infarction

Initiate ACE inhibitor within 24 hours in hemodynamically stable patients with HF, left ventricular dysfunction, or diabetes 9. Continue long-term 9.

Contraindications

• History of angioedema 2
• Pregnancy or women planning pregnancy 2
• Bilateral renal artery stenosis 2
• Systolic BP <80 mmHg 2

Managing ACE Inhibitor-Induced Cough

If intolerable cough develops, switch to an ARB 2, 9. The incidence of cough is often overestimated and can be reduced by using lipophilic ACE inhibitors or combining with calcium channel blockers 9.