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

Many people take ACE inhibitors or ARBs to manage high blood pressure, heart failure, or kidney disease. These drugs work in similar ways-both target the renin-angiotensin system-but they’re not the same. Mixing them together sounds like it should make things better, right? More power to fight high blood pressure. But here’s the truth: combining ACE inhibitors and ARBs is dangerous for most people. It doesn’t give you better results. It just ups your risk of serious side effects.

How ACE Inhibitors and ARBs Work

ACE inhibitors like lisinopril, enalapril, and ramipril stop your body from making angiotensin II, a chemical that tightens blood vessels and raises blood pressure. They do this by blocking the enzyme that turns angiotensin I into angiotensin II. Less angiotensin II means relaxed blood vessels, lower blood pressure, and less strain on your heart and kidneys.

ARBs-like losartan, valsartan, and irbesartan-work differently. Instead of stopping angiotensin II from being made, they block its receptors. Think of it like putting a lock on the door angiotensin II tries to open. Even if angiotensin II is still around, it can’t do its job. This is why ARBs are often used when someone can’t tolerate ACE inhibitors.

One big difference? ACE inhibitors cause a buildup of bradykinin, a substance that can trigger a dry, hacking cough in 10-15% of users. ARBs don’t do this. That’s why about 1 in 6 people switch from an ACE inhibitor to an ARB-not because the first one didn’t work, but because they couldn’t stand the cough.

Why You Shouldn’t Mix Them

The idea of combining ACE inhibitors and ARBs seems logical: double the blockade, better results. But studies have shown this doesn’t work that way. The ONTARGET trial in 2008 followed over 25,000 high-risk patients. Half got ramipril (an ACE inhibitor). Half got telmisartan (an ARB). A third group got both. The combo group had no fewer heart attacks, strokes, or deaths. But they had way more problems.

Here’s what happened:

• Renal failure requiring dialysis went from 1% to 2.3%
• Hyperkalemia (dangerously high potassium) jumped from 2.5% to 5.5%
• Low blood pressure, dizziness, and kidney injury increased by nearly 80%

The VA NEPHRON-D trial in 2018 confirmed this. In diabetic patients with kidney disease, adding an ARB to an ACE inhibitor didn’t slow kidney decline. Instead, it increased serious side effects by 27%. That’s not a trade-off worth making.

Today, the American Heart Association, the American College of Cardiology, and the European Society of Cardiology all say: don’t combine ACE inhibitors and ARBs. Not for hypertension. Not for diabetic kidney disease. Not unless you’re in a research study.

When Cross-Reactivity Matters

Even if you’re not taking both drugs at once, cross-reactivity can still be a problem. About 1 in 100 people who get angioedema (swelling of the face, lips, or throat) on an ACE inhibitor will also get it on an ARB. It’s rare-0.1% to 0.2%-but it’s real. If you’ve had angioedema on lisinopril, switching to losartan isn’t a safe fix.

Also, if you’ve had a severe cough on an ACE inhibitor, you’re more likely to switch to an ARB. But don’t assume the ARB is a perfect replacement. Some people still feel off-fatigue, dizziness, or even mild kidney changes. That’s because both drugs affect the same system. Your body doesn’t suddenly forget how to react.

Side Effects You Can’t Ignore

Both classes of drugs can raise potassium and hurt kidney function, especially in older adults or those with existing kidney disease. Here’s what you need to watch for:

• High potassium (hyperkalemia): Both drugs reduce aldosterone, which tells your kidneys to dump potassium. Without it, potassium builds up. Levels above 5.5 mmol/L can cause dangerous heart rhythms.
• Acute kidney injury: Especially if you’re dehydrated, on diuretics, or have narrowed kidney arteries. Your kidneys rely on angiotensin II to keep blood flowing through them. Block that, and filtration drops fast.
• Low blood pressure: Dizziness, fainting, or falls-especially when standing up. This is common when starting or increasing the dose.

That’s why doctors check your blood work 1-2 weeks after starting or changing the dose. Then every 3 months. If your creatinine jumps more than 30% or your potassium goes above 5.0, you need to adjust the treatment.

What to Do Instead

If your blood pressure isn’t controlled on one drug, don’t add the other. Here’s what works better:

• Add a diuretic: Hydrochlorothiazide or chlorthalidone helps flush out extra fluid and lowers potassium slightly.
• Add a calcium channel blocker: Amlodipine is often paired with an ACE inhibitor or ARB for better control.
• Try a mineralocorticoid receptor antagonist: Spironolactone (12.5-25 mg daily) reduces proteinuria and protects the heart without the risks of dual RAS blockade.
• Switch to an ARNI: Sacubitril/valsartan (Entresto) is now first-line for heart failure with reduced ejection fraction. It blocks the bad effects of angiotensin II while boosting protective peptides. It’s not a combo of ACE + ARB-it’s a new kind of drug.

For people with heavy proteinuria (>1 gram/day) who aren’t diabetic, some nephrologists still consider adding an ARB to an ACE inhibitor. But this is rare. It requires weekly blood tests, no NSAIDs, and no salt substitutes. Most doctors won’t touch it unless everything else has failed.

Real-World Experience

Dr. Lisa Chen, a nephrologist at Massachusetts General Hospital, stopped combination therapy in 87% of her 215 diabetic kidney disease patients. Why? Their potassium levels rose an average of 0.8 mmol/L. Their kidney function dropped by 15% in just a few months. No one got better. Some got worse.

On Reddit, medical students report seeing hyperkalemia hospitalizations from this combo more than once during rotations. One resident wrote: “I saw a 62-year-old man on lisinopril and losartan come in with a potassium of 6.8. He needed emergency dialysis. He didn’t know he was on both.”

Meanwhile, the few cases where the combo seemed to help-like in rare kidney diseases such as focal segmental glomerulosclerosis-require extreme monitoring. Weekly labs. No NSAIDs. No potassium-rich foods. It’s not a lifestyle you want.

Switching Safely

If you need to switch from an ACE inhibitor to an ARB, don’t just swap them on the same day. The Cleveland Clinic recommends a 4-week washout period. Why? Because ACE inhibitors can linger in your system, and their effects on angiotensin II levels take time to reverse. Jumping straight to an ARB can cause a sudden drop in blood pressure or kidney function.

But here’s the catch: only 42% of doctors follow this rule. That’s a problem. If you’re switching, ask your doctor for a clear plan. Don’t assume it’s automatic.

What’s Next?

The future of RAS blockade isn’t in combining ACE inhibitors and ARBs. It’s in newer drugs. ARNIs like Entresto are already replacing them in heart failure. SGLT2 inhibitors like dapagliflozin and empagliflozin-originally diabetes drugs-are now proven to protect kidneys and hearts in people with or without diabetes. They’re safer, easier to use, and don’t raise potassium.

The FINE-REWIND trial, running from 2024 to 2028, is testing ultra-low-dose ACE + ARB combinations. But even the researchers don’t expect this to become standard. They’re just exploring if tiny doses might help without the risks.

By 2028, experts predict less than 1% of RAS blocker prescriptions will involve combining ACE inhibitors and ARBs. That’s because the data is clear: the risks outweigh the benefits. Every major guideline says so. Every real-world study confirms it.

If you’re on one of these drugs and your blood pressure isn’t where it should be, talk to your doctor about safer ways to adjust. Don’t assume adding another RAS blocker is the answer. It’s not. It’s a trap.