Can amlodipine and lisinopril be used together to treat hypertension?

Combination Therapy with Amlodipine and Lisinopril for Hypertension

Yes, amlodipine and lisinopril can and should be used together for hypertension management—this combination is explicitly recommended by major guidelines as a preferred first-line strategy, particularly for patients with stage 2 hypertension or those not controlled on monotherapy. 1, 2

Guideline-Based Recommendations

Primary Combination Strategy

The combination of an ACE inhibitor (lisinopril) with a calcium channel blocker (amlodipine) represents one of the preferred two-drug combinations for initial or escalation therapy in hypertension. 1, 2

• The 2024 ESC guidelines explicitly list a RAS blocker (ACE inhibitor or ARB) combined with a dihydropyridine calcium channel blocker as a preferred combination for most patients with confirmed hypertension (BP ≥140/90 mmHg). 1

• The 2017 ACC/AHA guidelines recommend initiating therapy with two first-line agents of different classes for stage 2 hypertension (BP >20/10 mmHg above target), and both ACE inhibitors and calcium channel blockers are designated as first-line agents. 1

• Fixed-dose single-pill combinations are specifically recommended over separate pills to improve adherence. 1

When to Use This Combination

Initiate combination therapy when:

• Stage 2 hypertension is present (BP ≥160/100 mmHg or >20/10 mmHg above target). 1
• Monotherapy with either agent fails to achieve BP <130/80 mmHg after appropriate titration. 1, 2
• Total cardiovascular risk is high or very high, regardless of BP stage. 1, 2

Consider monotherapy first when:

• Stage 1 hypertension (130-139/80-89 mmHg) with low-to-moderate cardiovascular risk. 1
• Age ≥85 years, symptomatic orthostatic hypotension, or moderate-to-severe frailty. 1

Mechanistic Rationale and Efficacy

Complementary Mechanisms

The combination produces additive BP lowering through complementary mechanisms of action. 1, 2

• Amlodipine causes vasodilation through calcium channel blockade, which may stimulate compensatory activation of the renin-angiotensin system. 1
• Lisinopril blocks this compensatory response by inhibiting ACE, preventing conversion of angiotensin I to angiotensin II. 1, 3
• This complementary activity results in greater BP reduction than either agent alone without increasing adverse effects proportionally. 4, 5

Clinical Trial Evidence

Studies demonstrate superior efficacy of the combination compared to monotherapy:

• In a randomized trial of 24 patients with essential hypertension, the combination of amlodipine 2.5 mg plus lisinopril 5 mg achieved target BP in a higher percentage of patients than either 5 mg amlodipine (71% control rate) or 10 mg lisinopril (72% control rate) alone. 5

• A study comparing amlodipine/valsartan versus lisinopril/HCTZ in stage 2 hypertension showed both ACE inhibitor-based and calcium channel blocker-based combinations achieved significant BP reductions (MSSBP/MSDBP: -35.8/-28.6 mmHg and -31.8/-27.6 mmHg respectively), with response rates of 100% and 95.5%. 4

Special Population Considerations

Black Patients

The combination of ACE inhibitor plus calcium channel blocker is particularly appropriate for Black patients, as it overcomes the reduced efficacy of ACE inhibitor monotherapy in this population. 1, 6, 2

• ACE inhibitors are notably less effective than calcium channel blockers in Black patients for preventing stroke and heart failure when used as monotherapy. 1, 6
• However, the combination produces similar BP lowering in Black patients as in other racial groups. 2
• The 2017 ACC/AHA guidelines note that lisinopril was less effective than amlodipine in Black patients in the ALLHAT trial, but combination therapy eliminates these racial differences. 1, 3

Patients with Diabetes

Both agents are appropriate for diabetic patients, though BP reduction itself may be more important than the specific agent selected. 6

• The UKPDS found no significant differences in macrovascular events between ACE inhibitors and other agents in diabetic patients when BP control was equivalent. 6
• For diabetic nephropathy specifically, ACE inhibitors like lisinopril have established renoprotective benefits. 1, 6

Heart Failure Patients

In patients with heart failure and persistent hypertension, amlodipine can be added as a third-line agent after ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. 1, 6

• Amlodipine neither improves nor worsens survival in heart failure patients, making it safe for BP control when other agents are insufficient. 1
• The combination of ACE inhibitor, calcium channel blocker, and thiazide diuretic is effective and well-tolerated in heart failure patients requiring multiple agents. 1

Practical Implementation Algorithm

Dosing Strategy

Start with standard doses and titrate based on response:

1. Initial combination: Amlodipine 5 mg + lisinopril 10 mg once daily. 7, 3
2. If BP not controlled after 2-4 weeks: Increase to amlodipine 10 mg + lisinopril 20 mg. 7, 3
3. If still uncontrolled: Add a thiazide diuretic as third agent (preferably chlorthalidone or indapamide over hydrochlorothiazide). 1

When Combination Fails

If BP remains uncontrolled on amlodipine plus lisinopril, add a thiazide diuretic rather than a beta-blocker. 8

• A randomized crossover study demonstrated that adding bendrofluazide 5 mg to amlodipine/lisinopril produced significantly greater BP reduction than adding atenolol 100 mg. 8
• The preferred three-drug combination is RAS blocker + calcium channel blocker + thiazide/thiazide-like diuretic, preferably as a single-pill combination. 1

Common Pitfalls and Monitoring

Adverse Effects to Monitor

Key safety considerations specific to this combination:

• ACE inhibitor-related cough: Occurs in 5-20% of patients; if intolerable, substitute an ARB (valsartan or losartan) for lisinopril. 1, 2
• Angioedema risk: Higher in Black patients and Asian Americans; requires immediate discontinuation if occurs. 2
• Peripheral edema: More common with amlodipine monotherapy (10-30%); the addition of an ACE inhibitor may reduce this through venodilation. 7
• Hyperkalemia: Monitor potassium, especially in patients with renal impairment or those taking potassium supplements. 3
• Hypotension: Particularly in volume-depleted patients; ensure adequate hydration before initiating combination therapy. 3

Dosing Errors to Avoid

Do not combine two RAS blockers (ACE inhibitor plus ARB)—this increases cardiovascular and renal risk without additional benefit. 1

Do not use suboptimal doses of thiazide diuretics in triple therapy—many fixed-dose triple combinations contain inadequate diuretic doses. 1

Timing of Administration

Administer at the most convenient time for the patient to establish a habitual pattern and improve adherence—there is no evidence that evening dosing is superior to morning dosing. 1

Renal Function Considerations

Adjust lisinopril dosing when glomerular filtration rate is <30 mL/min:

• GFR 10-30 mL/min: Initial dose 5 mg daily, maximum 40 mg daily. 3
• GFR <10 mL/min: Initial dose 2.5 mg daily. 3
• Amlodipine requires no dose adjustment in renal impairment. 7