Is a combination of Angiotensin-Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) recommended as a first-line treatment for hypertension?

ACEI and ARB Combination Therapy is Not Recommended for Hypertension

The combination of ACE inhibitors and ARBs is not recommended for the treatment of hypertension due to increased risks of hyperkalemia and acute kidney injury without additional cardiovascular benefits. 1

Evidence Against ACEI-ARB Combination

Guidelines Consensus

Multiple high-quality guidelines explicitly recommend against dual RAAS blockade:

• The 2019 KDOQI US Commentary on ACC/AHA Hypertension Guidelines states: "Simultaneous use of an ACE inhibitor, ARB, and/or renin inhibitor is potentially harmful and is not recommended to treat adults with hypertension." (Class III: Harm, Level of Evidence A) 1

• The 2021 American Diabetes Association guidelines clearly state: "Combinations of ACE inhibitors and angiotensin receptor blockers and combinations of ACE inhibitors or angiotensin receptor blockers with direct renin inhibitors should not be used." 1

• The 2022 Mayo Clinic Proceedings guideline on diabetic kidney disease management explicitly states that combination ACEI plus ARB therapy is "not recommended due to lack of additive benefit and increased risks for hyperkalemia and acute kidney injury." 1

• The 2024 ESC guidelines for hypertension management clearly state: "Combining two RAS blockers (ACE inhibitor and an ARB) is not recommended." 1

Documented Risks

The FDA drug labels for both lisinopril (ACEI) and losartan (ARB) highlight specific warnings:

• Dual blockade of the RAS is associated with "increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy" 2, 3

• The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial showed that patients receiving the combination of losartan and lisinopril "did not obtain any additional benefit compared to monotherapy" but experienced "increased incidence of hyperkalemia and acute kidney injury" 2

First-Line Treatment Recommendations for Hypertension

Instead of combination ACEI-ARB therapy, guidelines recommend:

1. First-line agents for hypertension include:

   • ACE inhibitors OR ARBs (not both together)
   • Thiazide/thiazide-like diuretics
   • Calcium channel blockers (CCBs) 1

2. For patients requiring multiple medications:

   • Preferred two-drug combinations include a RAS blocker (either ACEI or ARB, not both) with either a dihydropyridine CCB or a diuretic 1, 4
   • For three-drug combinations, use a RAS blocker + dihydropyridine CCB + thiazide/thiazide-like diuretic 1

Special Considerations

For Patients with Proteinuria/Albuminuria

While the combination of ACEI and ARB may reduce proteinuria, this potential benefit does not outweigh the risks when used solely for hypertension treatment 1. For patients with albuminuria:

• Either an ACEI or ARB (not both) should be used as first-line therapy and titrated to maximally tolerated doses 1
• In stages 1-3 CKD with severely increased urine albumin excretion, ACEIs or ARBs reduce the risk of kidney endpoints 1

For Resistant Hypertension

Rather than combining ACEI and ARB, consider:

• Adding a mineralocorticoid receptor antagonist (such as spironolactone or eplerenone) 1, 4
• The recently approved nonsteroidal mineralocorticoid receptor antagonist finerenone has lower rates of hyperkalemia 1

Monitoring Requirements

When using a single RAAS blocker (either ACEI or ARB):

• Monitor serum creatinine/eGFR and potassium levels at least annually 1
• More frequent monitoring is needed when initiating therapy, increasing doses, or in patients with reduced kidney function 2, 3
• Be particularly vigilant in patients with inadequate dialysis, low solute transporters, or dietary noncompliance 5

Despite some theoretical benefits suggested in older research 6, 7, the most recent and highest quality evidence clearly demonstrates that the risks of ACEI-ARB combination therapy outweigh any potential benefits for hypertension management.