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

When you’re taking medication for high blood pressure, heart failure, or kidney disease, you expect it to help - not hurt. But when it comes to ACE inhibitors and ARBs, mixing them can be dangerous. Even though both drugs target the same system in your body, combining them doesn’t make them work better. It just makes side effects worse.

How ACE Inhibitors and ARBs Work

ACE inhibitors and ARBs both calm down the renin-angiotensin system (RAS), a hormone pathway that tightens blood vessels and raises blood pressure. But they do it in different ways.

ACE inhibitors - like lisinopril, enalapril, and ramipril - block the enzyme that turns angiotensin I into angiotensin II. Less angiotensin II means relaxed blood vessels and less fluid retention. That’s why they lower blood pressure and protect the kidneys in people with diabetes.

ARBs - such as losartan, valsartan, and irbesartan - work downstream. Instead of stopping angiotensin II from forming, they block its receptors. Think of it like shutting the door so angiotensin II can’t get in, even if it’s still floating around.

This difference matters. ACE inhibitors cause bradykinin to build up, which leads to a dry cough in 10-15% of users. ARBs don’t do that, so only 3-5% of people on ARBs get coughing. That’s why ARBs are often used when someone can’t tolerate ACE inhibitors.

The Real Risk: Combining Them

You might think, “If one is good, two must be better.” But that’s not true here. Studies show combining an ACE inhibitor with an ARB doesn’t improve survival, reduce heart attacks, or prevent kidney failure any more than using one alone.

What it does do is double the risk of dangerous side effects.

The ONTARGET trial in 2008 followed over 25,000 high-risk patients. Those on both drugs had a 2.3% chance of needing dialysis - more than double the 1% risk in those taking just ramipril (an ACE inhibitor). Hyperkalemia - dangerously high potassium - jumped from 2.5% to 5.5%. Acute kidney injury rose by 80%.

The VA NEPHRON-D trial in 2018 confirmed this. In diabetic patients with kidney disease, adding an ARB to an ACE inhibitor increased serious side effects by 27% - without helping kidney function at all.

Because of this, 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 heart failure. Not even for proteinuria - unless you’re in a research study.

When Is It Ever Okay?

There’s one tiny gray area. A small group of nephrologists, like Dr. Srinivasan Beddhu, say that in rare cases - like non-diabetic patients with proteinuria over 1 gram per day - adding an ARB to a maximum-dose ACE inhibitor might help reduce protein loss in the urine. But even then, it’s not standard. It requires weekly blood tests, close monitoring, and only after all other options are exhausted.

Most doctors won’t do it. Dr. Lisa Chen, a nephrologist at Massachusetts General, says she stopped combination therapy in 87% of her 215 diabetic kidney patients because of high potassium or sudden drops in kidney function. On Reddit, 78% of medical residents reported seeing someone hospitalized from this combo during their rotations.

Bottom line: if your doctor suggests combining them, ask why. And ask for the evidence. The odds are they’re going against current guidelines.

Switching Between ACE Inhibitors and ARBs

Some people switch from one to the other because of side effects - usually a cough from an ACE inhibitor. But you can’t just swap them like light bulbs.

There’s a risk of additive effects. Your blood pressure could drop too low. Your kidneys might react badly. That’s why guidelines recommend a 4-week washout period before switching. But here’s the problem: only 42% of doctors actually follow this.

If you’re switching, make sure your doctor checks your potassium and kidney function before and after. Don’t assume it’s safe just because both drugs are “blood pressure meds.”

Other Drug Interactions to Watch For

Even if you’re only on one of these drugs, other medications can make things worse.

• Potassium supplements or salt substitutes with potassium can push your levels into the danger zone. Both ACE inhibitors and ARBs raise potassium by 0.3-0.5 mmol/L on average.
• NSAIDs like ibuprofen or naproxen reduce kidney blood flow. When taken with RAS blockers, they increase the risk of sudden kidney injury by up to 40%.
• Diuretics like hydrochlorothiazide are often paired with these drugs - but they need careful dosing. Too much can cause low blood pressure, especially when you first start.
• Spironolactone, a potassium-sparing diuretic, should be used with extreme caution. Combining it with an ACE inhibitor or ARB can lead to life-threatening hyperkalemia.

Always tell your doctor about every supplement, OTC pill, or herb you take. Even something as simple as licorice root can interfere with potassium levels.

Monitoring: What You Need to Check

If you’re on an ACE inhibitor or ARB, regular blood tests aren’t optional - they’re essential.

• Check serum potassium and creatinine 1-2 weeks after starting or changing the dose.
• Then every 3 months during stable therapy.
• More often if you’re older, have kidney disease, or are taking other risk-increasing drugs.

Normal potassium is 3.5-5.0 mmol/L. Anything above 5.5 is dangerous. Creatinine tells you how well your kidneys are filtering. A sudden rise of 30% or more could mean acute kidney injury.

Don’t wait for symptoms. High potassium doesn’t always cause weakness or palpitations - it can sneak up silently until it causes a heart rhythm problem.

Why Do Doctors Still Prescribe Them?

Despite the risks, these drugs are still widely used - and for good reason.

ACE inhibitors are first-line for hypertension and heart failure. They’ve been shown to reduce death by 23% in heart failure patients with reduced ejection fraction. ARBs aren’t quite as strong on mortality, but they’re better tolerated.

In 2023, lisinopril was the 6th most prescribed drug in the U.S., with over 22 million prescriptions. Losartan wasn’t far behind at 14.8 million. The market for both classes is still growing - not because people are combining them, but because they’re being used correctly.

And now, newer drugs like ARNIs (angiotensin receptor-neprilysin inhibitors) are replacing the need for combinations. Sacubitril/valsartan (Entresto) has proven better than ACE inhibitors alone in heart failure, with fewer side effects.

What’s Next?

Research is still ongoing. The FINE-REWIND trial (NCT05192641), running from 2024 to 2028, is testing whether very low doses of both drugs - half the usual amount - might offer kidney protection without the same risks. Results won’t come until 2026.

But for now, the message is clear: don’t mix ACE inhibitors and ARBs. The small drop in blood pressure or proteinuria isn’t worth the risk of kidney failure, dialysis, or cardiac arrest from high potassium.

If you’re on one of these drugs and feel fine, keep taking it. But if your doctor suggests adding the other, ask: “What’s the evidence? What are the risks? Are there safer alternatives?”

There are better ways to control blood pressure and protect your kidneys - without putting your life on the line.