How should I start and titrate an angiotensin‑converting enzyme (ACE) inhibitor for an adult with uncomplicated primary hypertension, considering diabetes, chronic kidney disease, or high cardiovascular risk?

Starting and Titrating ACE Inhibitors for Hypertension

For adults with uncomplicated primary hypertension, start with lisinopril 10 mg daily or enalapril 5 mg daily, then titrate upward every 2-4 weeks to target doses of 20-40 mg daily, aiming for blood pressure <130/80 mm Hg. 1

Patient Selection and Risk Stratification

ACE inhibitors are particularly indicated as first-line therapy in specific high-risk populations:

• Diabetes mellitus: ACE inhibitors should be started immediately for blood pressure ≥130/80 mm Hg, regardless of albuminuria status 1, 2
• Chronic kidney disease (CKD): Initiate ACE inhibitors for patients with CKD stage 3 or higher, especially with albuminuria ≥300 mg/g 3, 4
• High cardiovascular risk: For patients with 10-year ASCVD risk ≥10%, start ACE inhibitors at blood pressure ≥130/80 mm Hg 1, 4

For uncomplicated hypertension without these conditions, thiazide diuretics demonstrate superior cardiovascular outcomes compared to ACE inhibitors and should be considered first-line 1. However, ACE inhibitors remain appropriate alternatives, particularly when combined with diuretics 1.

Specific Starting Doses by Agent

The following starting and target doses are recommended 1:

• Lisinopril: Start 10 mg daily → target 20-40 mg daily
• Enalapril: Start 5 mg daily → target 10-40 mg daily (1-2 divided doses)
• Ramipril: Start 2.5 mg daily → target 10-20 mg daily 5
• Benazepril: Start 10 mg daily → target 20-40 mg daily
• Fosinopril: Start 10 mg daily → target 20-80 mg daily

Critical caveat: For patients with suspected volume depletion, renal artery stenosis, or concurrent diuretic use, start at half the usual dose (e.g., ramipril 1.25 mg daily, lisinopril 5 mg daily) to minimize first-dose hypotension 5, 6.

Titration Protocol

Titrate every 2-4 weeks based on blood pressure response and tolerability, aiming for the highest approved dose proven effective in clinical trials 3, 2:

1. Week 0: Start at recommended initial dose
2. Week 2-4: Check blood pressure, serum creatinine, and potassium 3, 4
3. Week 4-6: If blood pressure remains ≥130/80 mm Hg and creatinine increase <30%, double the dose 3, 2
4. Week 8-12: Repeat monitoring and continue titration to target dose
5. Ongoing: Reassess every 1-3 months until blood pressure stabilized at goal

Mandatory Monitoring Parameters

Check serum creatinine and potassium within 2-4 weeks after initiating or increasing ACE inhibitor dose 3, 2, 4:

• Continue therapy if creatinine rises <30% from baseline 3, 2
• Discontinue if creatinine rises >30% within 4 weeks, symptomatic hypotension occurs, or uncontrolled hyperkalemia develops despite medical management 3
• Reduce diuretic dose if hypotension occurs, then retry ACE inhibitor titration 5

Special Populations Requiring Dose Adjustment

Renal impairment (creatinine clearance <40 mL/min): Start at 25% of usual dose 5:

• Hypertension: Start ramipril 1.25 mg daily, maximum 5 mg daily
• Heart failure: Start ramipril 1.25 mg daily, maximum 2.5 mg twice daily

Elderly patients or those on diuretics: Use "start low, go slow" approach with initial doses of lisinopril 5 mg or enalapril 2.5 mg daily 6, 7

Blood Pressure Targets

• Diabetes or CKD: Target <130/80 mm Hg 1, 4
• Uncomplicated hypertension with high CV risk: Target <130/80 mm Hg 1, 4
• Lower-risk patients: Target <140/90 mm Hg acceptable, though <130/80 mm Hg preferred 1

Combination Therapy Strategy

If blood pressure remains uncontrolled on maximum tolerated ACE inhibitor dose:

• Add thiazide diuretic (preferred second agent) 1, 4
• Alternative: Add calcium channel blocker or beta-blocker 1
• Never combine ACE inhibitor with ARB or direct renin inhibitor—this increases hyperkalemia and acute kidney injury risk without benefit 3, 2

Common Pitfalls to Avoid

• Do not use suboptimal doses: Titrate to maximum tolerated doses as used in landmark trials 2
• Do not discontinue for creatinine rise <30%: This represents expected hemodynamic effect and predicts long-term renoprotection 3, 2, 7
• Do not withhold in advanced CKD: Continue ACE inhibitor even when eGFR falls below 30 mL/min/1.73 m² unless specific contraindications develop 3
• Screen for renal artery stenosis risk: Elderly patients with diabetes, coronary disease, or peripheral vascular disease require lower starting doses 6