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

When it comes to managing high blood pressure, heart failure, or kidney damage from diabetes, doctors often turn to two types of medications: ACE inhibitors and ARBs. They both target the same system in your body-the renin-angiotensin system-but they do it in different ways. Many patients are prescribed one, then switched to the other if they have side effects. But what happens when someone tries to take both at the same time? And why do so many doctors avoid this combo?

How ACE Inhibitors and ARBs Work

ACE inhibitors like lisinopril, enalapril, and ramipril block an enzyme called angiotensin-converting enzyme. This enzyme normally turns angiotensin I into angiotensin II, a powerful chemical that tightens blood vessels and raises blood pressure. By stopping this conversion, ACE inhibitors help relax arteries and reduce fluid buildup in the body.

ARBs-like losartan, valsartan, and irbesartan-work differently. Instead of blocking the enzyme, they block the receptors that angiotensin II binds to. Think of it like putting a lock on the door so angiotensin II can’t get in and cause trouble. This means ARBs don’t interfere with the enzyme itself, which is why they don’t cause the same side effects as ACE inhibitors in many people.

Both classes lower blood pressure and protect the kidneys in people with diabetes. But here’s the catch: ACE inhibitors reduce angiotensin II levels overall, while ARBs leave those levels unchanged-they just prevent them from acting on one type of receptor (AT1). That difference matters more than it sounds.

The Big Problem: Combining Them

It might seem logical to use both drugs together-double the power, better results. But that’s not how it works in real life. Multiple large studies have shown that combining ACE inhibitors and ARBs doesn’t give you better survival rates, fewer heart attacks, or slower kidney decline. What it does give you is a much higher risk of serious side effects.

The ONTARGET trial in 2008, which followed over 25,000 high-risk patients for more than five years, found that those on both drugs had a 2.3% chance of needing dialysis due to kidney failure-almost double the 1.0% risk for those on just an ACE inhibitor. The same group also saw their risk of dangerously high potassium levels (hyperkalemia) jump from 2.5% to 5.5%. That’s not a small increase-it’s life-threatening.

More recent studies, like the 2018 VA NEPHRON-D trial, confirmed these findings. In diabetic patients with kidney disease, adding an ARB to an ACE inhibitor increased serious adverse events by 27% without improving kidney outcomes. As a result, major guidelines from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology now say: don’t combine them.

Why Do Some Doctors Still Consider It?

There’s one narrow exception. A small group of nephrologists-like Dr. Srinivasan Beddhu at the University of Utah-say that in rare cases of non-diabetic kidney disease, such as focal segmental glomerulosclerosis, where protein loss in urine stays above 1 gram per day despite maximum ACE inhibitor therapy, adding an ARB might help. These patients often have no other options.

But even then, it’s not done lightly. These patients need weekly blood tests for potassium and kidney function. One 2023 survey of primary care doctors found that only 11% still used this combo-and only in patients they monitored closely. Most have stopped entirely since the 2018 trial results came out.

On Reddit’s medical student forums, 78% of residents reported seeing someone hospitalized for hyperkalemia after being put on both drugs. In real-world clinics, Dr. Lisa Chen at Massachusetts General Hospital discontinued the combo in 87% of her 215 diabetic kidney patients because their potassium levels rose too high or their kidney function dropped.

Side Effects: Why ARBs Are Often Preferred

One of the biggest reasons patients switch from ACE inhibitors to ARBs is a dry, nagging cough. About 10-15% of people on ACE inhibitors get it. That’s because ACE inhibitors cause bradykinin to build up in the lungs. ARBs don’t affect bradykinin, so only 3-5% of users report coughing.

Another rare but dangerous side effect is angioedema-swelling of the face, tongue, or throat. It happens in about 0.1-0.7% of ACE inhibitor users, but only 0.1-0.2% of ARB users. If it happens, you need emergency care. That’s why if a patient develops angioedema on an ACE inhibitor, they’re switched to an ARB and never put back on the original drug.

Both classes can raise potassium and harm kidney function, especially in older adults or those with existing kidney disease. That’s why your doctor checks your blood work 1-2 weeks after starting either drug, then every 3 months. If your potassium goes above 5.5 mmol/L or your creatinine rises more than 30%, the dose is lowered or stopped.

Switching Between Them: What You Need to Know

If you’re switching from an ACE inhibitor to an ARB-or vice versa-don’t just stop one and start the other the next day. There’s a risk of additive effects, especially on blood pressure and kidney function.

The Cleveland Clinic recommends a 4-week washout period between switching. But in practice, only 42% of doctors follow this. Many patients are switched immediately, especially if they’re having a cough. That’s usually fine if they’re stable, but it’s risky if they’re elderly or have poor kidney function.

Always tell your doctor if you’ve ever had swelling, a cough, or high potassium on either drug. That history helps them choose the safest option for you.

What to Do Instead of Combining Them

If your blood pressure isn’t controlled on one drug, don’t add the other class. Instead, try adding a different type of medication:

• A calcium channel blocker like amlodipine
• A diuretic like hydrochlorothiazide
• A mineralocorticoid receptor antagonist like spironolactone (12.5 mg daily)

Spironolactone, for example, can reduce proteinuria by 30-40% in kidney disease patients-similar to adding an ARB-but with fewer risks. It’s also cheaper and has been used safely for decades.

For heart failure patients who still have symptoms on an ACE inhibitor, doctors now often switch them to an ARNI (angiotensin receptor-neprilysin inhibitor), like sacubitril/valsartan (Entresto). This new class has shown better survival rates than ACE inhibitors alone and doesn’t carry the same interaction risks.

What’s Changing in 2026?

The field is still evolving. A new trial called FINE-REWIND, which started in 2024, is testing whether very low doses of both drugs-half the usual amount-could offer kidney protection without the usual risks. Results won’t be out until 2026.

Also, in Europe, a fixed-dose combination of perindopril (an ACE inhibitor) and indapamide (a diuretic) is now approved for heart failure. But in the U.S., no combination of ACE inhibitor + ARB is approved for any use.

Market data shows ACE inhibitors still dominate-58% of first prescriptions in the U.S.-but ARBs are growing. Lisinopril and losartan remain the top two drugs in both classes. The 2018-2020 ARB recalls due to nitrosamine impurities have mostly been resolved, and new manufacturing standards are in place.

By 2028, experts predict ACE inhibitor-ARB combinations will be used in less than 1% of cases. The focus is shifting to safer, more effective alternatives.

What Patients Should Remember

• ACE inhibitors and ARBs are both effective for blood pressure and kidney protection-but they’re not interchangeable in all cases.
• Never take both together unless your specialist says so-and even then, only with strict monitoring.
• If you get a dry cough on an ACE inhibitor, switching to an ARB often fixes it.
• High potassium and kidney changes are real risks with either drug. Get your blood tested regularly.
• There are safer ways to boost treatment than combining these two drugs.

If you’re on either of these medications, keep your appointments. Don’t stop or change your dose without talking to your doctor. And if you’ve ever had swelling, a persistent cough, or an abnormal blood test-tell them. That information could save your life.