Is it safe to combine Lisinopril (Angiotensin-Converting Enzyme Inhibitor) and Irbesartan (Angiotensin II Receptor Blocker) for a patient with difficult-to-control hypertension and no significant kidney disease or heart failure?

Do Not Combine Lisinopril and Irbesartan

Combining lisinopril (an ACE inhibitor) with irbesartan (an ARB) is explicitly contraindicated and should not be done, even in difficult-to-control hypertension. This dual renin-angiotensin system (RAS) blockade increases serious risks—including hyperkalemia, hypotension, and acute renal failure—without providing additional cardiovascular or renal protection 1, 2, 3, 4, 5.

Why This Combination Is Harmful

Evidence from Major Trials

• The ONTARGET trial demonstrated that combining an ACE inhibitor with an ARB resulted in a significant excess of end-stage renal disease (ESRD) cases compared to monotherapy 1.
• The ALTITUDE trial, which tested dual RAS blockade in diabetic patients, was prematurely terminated due to increased rates of ESRD and stroke in the combination therapy arm 1.
• These findings led all major guideline organizations to explicitly recommend against this combination 1, 2, 3.

Specific Risks

• Hyperkalemia: Both drugs raise serum potassium; combined use creates additive risk of severe, potentially life-threatening hyperkalemia 4, 5.
• Hypotension: Dual blockade causes excessive blood pressure reduction beyond therapeutic benefit 3, 4, 5.
• Acute kidney injury: The combination significantly increases risk of acute renal failure and progression to ESRD 1, 2, 3.
• No mortality benefit: Despite theoretical advantages, dual RAS blockade does not reduce all-cause mortality, cardiovascular mortality, or slow progression to ESRD compared to optimized monotherapy 6, 7.

What to Do Instead for Resistant Hypertension

Preferred Combination Strategies

If a single RAS blocker (either lisinopril OR irbesartan, not both) fails to control blood pressure, add a medication from a different class 1:

1. First choice: RAS blocker + dihydropyridine calcium channel blocker (e.g., amlodipine) 1, 8
2. Second choice: RAS blocker + thiazide diuretic (e.g., hydrochlorothiazide or chlorthalidone) 1

Escalation for Triple Therapy

If two drugs are insufficient 1:

• Add a third agent: RAS blocker + calcium channel blocker + thiazide diuretic 1
• This triple combination is the recommended approach before considering additional agents 1

Fourth-Line Options

For truly resistant hypertension requiring four drugs 1, 3:

• Add spironolactone (aldosterone antagonist) to the triple therapy above 1, 3
• Beta-blockers or alpha-blockers may be considered as fifth-line agents if compelling indications exist 1, 9

Clinical Management If Already Prescribed

If a patient is currently taking both lisinopril and irbesartan, discontinue one agent immediately 3:

• Choose to continue either the ACE inhibitor OR the ARB (not both) based on patient tolerance and prior response 2, 3
• Monitor serum creatinine and potassium within 2-4 weeks after discontinuation 3
• Check blood pressure closely to ensure adequate control with monotherapy 3
• Add agents from different drug classes (calcium channel blocker or thiazide diuretic) if blood pressure remains uncontrolled 1, 3

Important Caveats

FDA Drug Label Warnings

Both the lisinopril and irbesartan FDA labels explicitly state: "Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors" 4, 5.

No Exception for Diabetic Nephropathy

Even in patients with diabetic kidney disease and proteinuria—where RAS blockade is particularly beneficial—dual therapy with ACE inhibitor plus ARB does not provide additional renoprotection and increases adverse events 2, 6, 7. A randomized trial specifically comparing lisinopril plus irbesartan combination versus high-dose monotherapy of either agent showed no benefit of combination therapy on progression of type 2 diabetic nephropathy (HR 0.96,95% CI 0.44-2.05, P=0.9) 7.

Single-Pill Combinations Are Available

For patients requiring multiple agents, single-pill combinations improve adherence and are strongly favored 1. However, no fixed-dose combination of ACE inhibitor plus ARB exists or should be used 1, 2. Available and appropriate combinations include irbesartan/amlodipine and irbesartan/hydrochlorothiazide 8.