ACE Inhibitors and ARBs: Understanding Interactions and Cross-Reactivity Risks

When you're managing high blood pressure, heart failure, or kidney disease, your doctor might prescribe an ACE inhibitor or an ARB. These drugs are common, effective, and often lifesaving. But what happens when you take both? Or switch from one to the other? The answer isn’t as simple as it seems.

How ACE Inhibitors and ARBs Work

Both ACE inhibitors and ARBs target the same system in your body-the renin-angiotensin system (RAS)-but they do it in different ways. ACE inhibitors, like lisinopril and enalapril, stop your body from making angiotensin II, a chemical that narrows blood vessels and raises blood pressure. By blocking the enzyme that turns angiotensin I into angiotensin II, these drugs help relax arteries and reduce fluid buildup.

ARBs, such as losartan and valsartan, work downstream. Instead of stopping angiotensin II from being made, they block its receptors. This means angiotensin II is still present, but it can’t bind to the receptors that cause blood vessels to tighten. This difference might sound small, but it leads to real-world differences in side effects and safety.

One key point: ACE inhibitors cause bradykinin to build up in your system. That’s why about 1 in 10 people on these drugs get a dry, persistent cough. ARBs don’t affect bradykinin, so cough happens in only 3-5% of users. That’s why ARBs are often the go-to alternative when someone can’t tolerate an ACE inhibitor.

Why Combining Them Is Risky

You might think: if one drug lowers blood pressure, two must be better. That’s a logical assumption-but it’s wrong here. 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 chance of serious side effects.

The ONTARGET trial in 2008 followed over 25,000 high-risk patients. Half got ramipril (an ACE inhibitor), half got telmisartan (an ARB), and half got both. The combination group had no improvement in heart attacks, strokes, or death. But their risk of needing dialysis jumped from 1% to 2.3%. Hyperkalemia-dangerously high potassium-rose from 2.5% to 5.5%. That’s more than double.

Other studies, like the VA NEPHRON-D trial in 2018, confirmed this pattern. In diabetic patients with kidney disease, adding an ARB to an ACE inhibitor increased serious adverse events by 27% without protecting kidney function. The FDA and major medical societies now say: do not combine ACE inhibitors and ARBs outside of rare, tightly monitored cases.

When Cross-Reactivity Matters

Even switching from one class to the other isn’t risk-free. If you stop an ACE inhibitor and start an ARB right away, you’re not giving your body time to reset. The renin-angiotensin system can go into overdrive during the transition, causing a sudden drop in blood pressure or worsening kidney function.

Guidelines recommend a 4-week washout period between switching classes. But in practice, only about 4 in 10 doctors follow this. That’s dangerous. Patients who switch too quickly are more likely to end up in the ER with low blood pressure, dizziness, or acute kidney injury.

Also, if you’ve had angioedema (swelling of the face, tongue, or throat) on an ACE inhibitor, you’re at higher risk of getting it again on an ARB-even though the risk is lower. About 0.1-0.7% of ACE inhibitor users get angioedema. For ARBs, it’s 0.1-0.2%. Still, if you’ve had it once, most doctors will avoid ARBs entirely and choose a different class of blood pressure medication.

Who Might Still Get Both?

There’s a small group of patients where doctors might consider combining these drugs-but only as a last resort. These are people with non-diabetic kidney disease, like focal segmental glomerulosclerosis (FSGS), who still have protein loss in their urine (over 1 gram per day) despite being on the highest tolerated dose of an ACE inhibitor.

In these rare cases, adding an ARB might cut proteinuria by 25-40%. But it’s not a decision made lightly. Patients need weekly blood tests for potassium and kidney function. They’re watched like hawks. And even then, many doctors still avoid it.

One nephrologist at Massachusetts General Hospital reported discontinuing combination therapy in 87% of her patients with diabetic kidney disease because of rising potassium or dropping kidney function. That’s not an outlier. A 2023 survey of 317 primary care doctors found that only 11% still use the combination, and only with monthly lab checks.

What to Do Instead

If your blood pressure isn’t controlled on one RAS blocker, don’t reach for the other. There are safer, proven options.

• For extra blood pressure control: Add a low-dose thiazide diuretic like hydrochlorothiazide.
• For kidney protection with proteinuria: Add a mineralocorticoid receptor antagonist like spironolactone (12.5 mg daily). Studies show it cuts proteinuria by 30-40% with a better safety profile than ARB-ACE combos.
• For heart failure: Consider an ARNI (angiotensin receptor-neprilysin inhibitor), like sacubitril/valsartan. It’s been shown to outperform ACE inhibitors in survival and hospitalization rates.

These alternatives don’t carry the same risks. They’re backed by solid evidence. And they’re recommended in the 2023 ACC/AHA and ESC guidelines.

Monitoring Is Non-Negotiable

Even when you’re on just one of these drugs, you need regular blood tests. Both ACE inhibitors and ARBs can raise potassium and lower kidney function-especially in older adults, diabetics, or those with existing kidney disease.

Check your potassium and creatinine:

• 1-2 weeks after starting or changing the dose
• Every 3 months once you’re stable

If your potassium goes above 5.5 mmol/L or your creatinine rises more than 30% from baseline, your doctor needs to act. That’s not just a lab result-it’s a warning sign. Left unchecked, high potassium can cause dangerous heart rhythms. A sudden drop in kidney function could mean you’re at risk of needing dialysis.

People with diabetes, heart failure, or chronic kidney disease are at highest risk. But even healthy adults on long-term therapy can develop these issues over time. That’s why ongoing monitoring isn’t optional-it’s essential.

Real-World Problems

Behind the numbers are real people. On Reddit’s r/medicalschool, 78% of residents said they’ve seen a patient hospitalized for hyperkalemia after being put on both an ACE inhibitor and ARB. One 68-year-old man with diabetes was prescribed lisinopril and losartan together after his blood pressure didn’t drop. Two weeks later, he was in the ER with a potassium level of 6.8. He needed emergency treatment and spent five days in the hospital.

On the flip side, a few patients with rare kidney diseases have seen big improvements with combination therapy. But these are exceptions-not the rule. And they’re managed under strict supervision.

The takeaway? Don’t assume more drugs = better results. Sometimes, less is more.

What’s Next?

Research is still evolving. The FINE-REWIND trial, running from 2024 to 2028, is testing whether very low doses of both drugs might offer kidney protection without the usual risks. Results won’t be out until late 2026.

Meanwhile, the market is shifting. ACE inhibitors still dominate prescriptions-58% in the U.S. in 2023. But ARBs are catching up, especially because they’re better tolerated. And new drugs like ARNIs are replacing both in heart failure treatment.

One thing won’t change: the warning against combining ACE inhibitors and ARBs. The data is too clear. The risks are too high. The benefits? Nonexistent.