ACE Inhibitors and ARBs: What You Need to Know About Interactions and Cross-Reactivity

When your doctor prescribes an ACE inhibitor or an ARB for high blood pressure, heart failure, or kidney protection, you’re getting one of the most studied and effective classes of heart meds available. But here’s the thing: ACE inhibitors and ARBs aren’t interchangeable, and mixing them can be dangerous-even if it seems like doubling down should help more.

How ACE Inhibitors and ARBs Work (And Why It Matters)

Both ACE inhibitors and ARBs target the same system in your body-the renin-angiotensin system (RAS)-but they hit different spots. ACE inhibitors like lisinopril and enalapril block the enzyme that turns angiotensin I into angiotensin II, the molecule that tightens blood vessels and raises blood pressure. ARBs like losartan and valsartan don’t stop angiotensin II from being made; they just block its receptors so it can’t do its job.

This small difference has big consequences. ACE inhibitors cause bradykinin to build up, which is why about 1 in 10 people on these drugs get a dry, annoying cough. ARBs don’t do that. That’s why if you can’t tolerate an ACE inhibitor, your doctor will switch you to an ARB-not add it.

And here’s something most people don’t realize: even if your ACE inhibitor seems to stop working after a few months, it’s not because your body got used to it. It’s because your body found another way to make angiotensin II. About two-thirds of long-term users experience this ‘escape effect,’ where angiotensin II levels bounce back up by 25-30%. That’s why some patients need higher doses or different meds-not more RAS blockers.

The Real Risk: Combining ACE Inhibitors and ARBs

It’s tempting. If one drug lowers blood pressure, two must be better, right? Wrong. Multiple large studies-like the ONTARGET trial and the VA NEPHRON-D trial-showed that combining an ACE inhibitor with an ARB doesn’t save lives, doesn’t prevent heart attacks, and doesn’t slow kidney disease any better than one drug alone.

But it does make you sicker.

Here’s what happens when you mix them:

• Hyperkalemia (high potassium): Your potassium level jumps by an average of 0.8 mmol/L. Normal is 3.5-5.0. Above 5.5, you risk dangerous heart rhythms. In studies, the risk of dangerous hyperkalemia doubled-from 5% to 10%.
• Acute kidney injury: Your kidneys can’t handle the double hit. Risk goes up by 80%. In diabetic patients, this can mean sudden dialysis.
• Low blood pressure and fainting: You’re more likely to feel dizzy, fall, or end up in the ER.

The FDA and major guidelines from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology all say: Don’t combine them. Not for hypertension. Not for kidney disease. Not unless you’re in a research study-and even then, only under strict supervision.

When Might a Doctor Still Consider It?

There’s one tiny gray area: non-diabetic kidney disease with heavy proteinuria (over 1 gram per day) that doesn’t respond to maximum ACE inhibitor doses. A handful of nephrologists, like Dr. Srinivasan Beddhu, have reported cases where adding an ARB cut protein loss by 40-60%. But these are rare. And they come with a catch.

If you’re one of those rare cases, you’ll need weekly blood tests for potassium and kidney function. You’ll need to avoid salt substitutes, potassium-rich foods like bananas and spinach, and NSAIDs like ibuprofen. And you’ll need to stop the combo immediately if your creatinine rises more than 30% or your potassium hits 5.5.

Even then, most doctors won’t do it. A 2023 survey of 317 primary care doctors found only 11% still used the combo-and only in patients they monitored monthly. The rest stopped after the VA NEPHRON-D trial showed 27% more serious side effects with no benefit.

What to Do Instead

If your blood pressure isn’t controlled on an ACE inhibitor or ARB, here’s what actually works:

• Add a diuretic: Hydrochlorothiazide or chlorthalidone helps flush out extra fluid and sodium. This is the most common next step.
• Add a calcium channel blocker: Amlodipine is often paired with RAS blockers and works well together.
• Switch to an ARNI: Sacubitril/valsartan (Entresto) is now first-line for heart failure with reduced ejection fraction. It combines an ARB with a neprilysin inhibitor and has better outcomes than ACE inhibitors alone.
• Add a mineralocorticoid receptor antagonist: Spironolactone or eplerenone can reduce proteinuria by 30-40% without the hyperkalemia risk of ARB+ACE combos.

One big mistake I see? Doctors switch from an ACE inhibitor to an ARB and start the new drug the next day. That’s risky. The drugs linger in your system. The American College of Cardiology recommends a 4-week washout period before switching. Only 42% of prescribers follow this, according to a 2022 JAMA study. If you’re switching, ask your doctor about this.

Side Effects: ACE Inhibitors vs. ARBs

Both can raise potassium and hurt kidney function, especially if you’re older, have diabetes, or already have kidney disease. But their side effect profiles are very different.

That 1.8% difference in discontinuation might not sound like much, but over 4 years, it means 1 in every 55 patients avoids a side effect serious enough to quit the drug. That’s meaningful.

Monitoring: What You Need to Watch

Whether you’re on an ACE inhibitor or ARB, you need regular blood tests. Here’s the standard schedule:

1. Check potassium and creatinine 1-2 weeks after starting or changing dose.
2. If stable, repeat every 3 months.
3. If you have diabetes or kidney disease, check every 2 months.
4. If you’re sick, dehydrated, or start a new med (like NSAIDs), check immediately.

And don’t ignore symptoms: unusual fatigue, muscle weakness, irregular heartbeat, or swelling in your legs could mean your potassium is too high. Call your doctor right away.

Market Trends and New Developments

In 2023, ACE inhibitors were still the most prescribed RAS blockers in the U.S.-over 32 million prescriptions, led by lisinopril. ARBs came in second at 23.6 million, with losartan as the top choice. But the trend is shifting. More patients are being switched to ARBs because of the cough issue.

There’s also been progress in safety. Between 2018 and 2020, several ARBs were recalled due to cancer-causing impurities. That’s mostly fixed now. New manufacturing standards have restored confidence.

And the future? The FINE-REWIND trial is testing ultra-low-dose combinations in diabetic kidney disease, with results expected in 2026. But don’t hold your breath-analysts predict less than 1% of prescriptions will ever involve this combo. The real winners are newer drugs like ARNIs and SGLT2 inhibitors, which are now preferred for heart and kidney protection.

Bottom Line

ACE inhibitors and ARBs are powerful tools. But they’re not meant to be used together. The added blood pressure drop isn’t worth the risk of kidney failure or life-threatening high potassium. If your current med isn’t working, talk to your doctor about adding a diuretic, switching to an ARNI, or using a mineralocorticoid blocker-not another RAS drug.

And if you’re on both? Ask your doctor why. Most of the time, it’s an accident from years ago. It’s not too late to stop.