Is lisinopril (angiotensin-converting enzyme inhibitor) ever dosed twice daily in patients with hypertension or heart failure?

Is Lisinopril Ever Dosed Twice Per Day?

Lisinopril is predominantly dosed once daily for both hypertension and heart failure, but twice-daily dosing can be considered when once-daily dosing fails to achieve adequate blood pressure control. 1

Standard Dosing Recommendations

Heart Failure

• Lisinopril is dosed once daily for heart failure, with a target dose of 30-35 mg once daily. 2, 3
• The ATLAS trial demonstrated that high doses (32.5-35 mg daily) administered once daily significantly reduced mortality and hospitalizations compared to low doses (2.5-5 mg daily). 2, 4, 5
• Starting dose is 2.5-5 mg once daily, titrated upward every 2 weeks as tolerated. 2, 1

Hypertension

• The FDA-approved dosing for hypertension is 10-40 mg once daily, with doses up to 80 mg studied but not providing greater effect. 1
• The recommended initial dose is 10 mg once daily, adjusted according to blood pressure response. 1
• The usual maintenance range is 20-40 mg per day administered as a single daily dose. 1

When Twice-Daily Dosing May Be Considered

Evidence for Twice-Daily Dosing

• A 2017 retrospective cohort study found that lisinopril 20 mg twice daily (total 40 mg/day) produced significantly greater systolic blood pressure reductions than 40 mg once daily—a 10.2 mmHg greater reduction in systolic blood pressure (p=0.016). 6
• This suggests that when once-daily dosing at maximum recommended doses fails to control blood pressure, splitting the same total daily dose into twice-daily administration may be more effective. 6

Clinical Context

• The pharmacodynamic effects of lisinopril persist for 12-24 hours after administration, with maximum effects occurring 6-8 hours post-dose. 5
• While lisinopril's long half-life (12.6 hours) supports once-daily dosing, some patients may experience end-of-dose waning of effect. 7, 8

Important Caveats

Guideline-Based Practice

• European Society of Cardiology guidelines consistently recommend once-daily dosing for lisinopril in both hypertension and heart failure. 2
• No major clinical trials have evaluated twice-daily lisinopril dosing for heart failure or post-MI management. 2

When to Consider Twice-Daily Dosing

• If blood pressure remains uncontrolled on lisinopril 40 mg once daily, consider either:
  • Splitting to 20 mg twice daily (based on the 2017 study showing superior efficacy) 6
  • Adding a low-dose diuretic (e.g., hydrochlorothiazide 12.5 mg) to once-daily lisinopril 1

Monitoring Requirements

• When initiating or titrating lisinopril, check blood pressure, renal function (creatinine), and potassium at 1-2 weeks after each dose change, then at 3 months, and every 6 months thereafter. 2, 4
• Creatinine increases up to 50% above baseline or to 3 mg/dL (whichever is greater) are acceptable. 3, 4

Practical Algorithm

For hypertension:

1. Start lisinopril 10 mg once daily 1
2. Titrate to 20-40 mg once daily at 2-week intervals 2, 1
3. If inadequate control on 40 mg once daily, either add hydrochlorothiazide 12.5 mg 1 OR consider splitting to 20 mg twice daily 6

For heart failure:

• Always use once-daily dosing, targeting 30-35 mg daily 2, 3, 4
• Twice-daily dosing has not been studied in heart failure and should not be used 2