Carvedilol and your genes: what CYP2D6 testing can and cannot tell you

Carvedilol (Coreg) is a beta-blocker that slows the heart rate and lowers blood pressure. It is mainly used to treat heart failure, to protect the heart after a heart attack, and sometimes to treat high blood pressure. Finding the right dose can take time, and side effects such as dizziness and tiredness are common while the dose is being increased. This article explains how your genes affect carvedilol, what genetic testing can and cannot tell you today, and how a pharmacogenetic medication review can help you and your doctor.

What is carvedilol used for?

Carvedilol blocks the effects of adrenaline on the heart and blood vessels. It is one of the beta-blockers proven to help people with heart failure live longer and stay out of hospital, and it is also used after a heart attack. For uncomplicated high blood pressure, beta-blockers are usually not the first choice. Hypertension Canada recommends against using them as first-line treatment in people aged 60 and older, although they can be useful for people with other heart conditions or in combination with other medications. Learn more in What is the best blood pressure medication? Part I.

What are the common side effects of carvedilol?

The most common side effects are dizziness or light-headedness, especially when standing up, tiredness, a slow heart rate and low blood pressure. They are most likely in the first weeks and after each dose increase. This is why carvedilol is always started at a low dose and increased gradually, usually every two weeks, while your doctor checks your heart rate, blood pressure and symptoms.

How do genes affect carvedilol?

Carvedilol is broken down in the liver mainly by two enzymes, CYP2D6 and CYP2C9. The CYP2D6 gene varies a lot from person to person. Based on their CYP2D6 genes, people can be poor, intermediate, normal or ultrarapid metabolizers.

• Poor and intermediate metabolizers break down carvedilol more slowly and have higher levels of the drug in their blood. The US Food and Drug Administration (FDA) notes that CYP2D6 poor metabolizers may be at higher risk of dizziness while the carvedilol dose is being increased.
• Ultrarapid metabolizers break down carvedilol faster, but there is no clear evidence that this makes standard doses less effective.

Higher blood levels do not always mean a stronger effect. CYP2D6 turns carvedilol into both active and inactive forms, and carvedilol is usually increased slowly, which protects most people from large drops in heart rate. For these reasons, the 2024 CPIC guideline for beta-blockers concluded that there is not yet enough evidence to recommend a different carvedilol dose based on CYP2D6 genes. Genetic results should never be used to stop a doctor from increasing the dose to the target recommended for heart failure.

How is carvedilol different from metoprolol?

Metoprolol is another commonly used beta-blocker, and it depends even more on CYP2D6. People who are CYP2D6 poor metabolizers have about five times more metoprolol in their blood than normal metabolizers given the same dose, and their heart rate and blood pressure drop more. For metoprolol, CPIC recommends that poor metabolizers start at the lowest recommended dose, increase the dose carefully while being monitored for a slow heart rate, or consider a different beta-blocker. For intermediate and normal metabolizers, standard dosing is recommended.

Can other medications change how carvedilol works?

Yes. Some medications block CYP2D6, including fluoxetine, paroxetine and bupropion. A person with normal CYP2D6 genes who takes one of them can process carvedilol and metoprolol like a poor metabolizer. In the same way, a person who inherited low CYP2D6 activity is expected to respond as if they were already taking a CYP2D6 blocker. Medications that also slow the heart, such as some calcium channel blockers (verapamil, diltiazem) and digoxin, can add to the effect of carvedilol. Always tell your doctor and pharmacist about all of your medications.

How can a genetic test help? A tale of two treatment strategies

Consider Adam, a 62-year-old grandfather of three who was recently diagnosed with heart failure. His doctor prescribes carvedilol.

Usual approach:

• Adam starts carvedilol at a low dose, and the dose is increased every two weeks.
• After the second increase, Adam feels dizzy when he stands up and almost falls. His doctor lowers the dose and increases it more slowly.
• Adam reaches his target dose after several extra visits and a fall scare.

Approach informed by pharmacogenetics:

• Adam already has a Pillcheck report. It shows that he is a CYP2D6 poor metabolizer.
• The pharmacist notes that Adam is likely to have higher carvedilol levels and a higher risk of dizziness while the dose is increased, and that he is also taking paroxetine, which blocks CYP2D6.
• Adam's doctor starts carvedilol at the usual low dose but plans smaller, slower dose increases, asks Adam to check his blood pressure and heart rate at home, and reviews whether paroxetine is the best antidepressant for him.
• Adam reaches his target dose without a fall, and his doctor knows which other medications to watch in the future.

In both cases, Adam gets back to his life. The genetic result did not change the target dose, but it helped his care team anticipate side effects, plan the dose increases and spot a drug interaction.

How can Pillcheck help?

Pillcheck reports your CYP2D6 and CYP2C9 genes, along with many others, and a Pillcheck pharmacist reviews your results together with all of your current medications. For beta-blockers, the report highlights when guideline-based dose advice applies, as for metoprolol, and flags medications such as carvedilol for closer monitoring when your genes or other medications are likely to raise drug levels. You can share these recommendations with your doctor.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• Carvedilol is mainly used for heart failure and after a heart attack. For uncomplicated high blood pressure in people aged 60 and older, beta-blockers are not a first choice.
• Dizziness and tiredness are common while the dose is increased, so carvedilol is always started low and increased slowly.
• CYP2D6 poor metabolizers have higher carvedilol levels and may have more dizziness, but there is no gene-based carvedilol dose recommendation yet.
• For metoprolol, CPIC recommends a low starting dose and careful increases, or another beta-blocker, for CYP2D6 poor metabolizers.
• Medications that block CYP2D6 can have the same effect as poor metabolism, so genes and other medications should be reviewed together.

Frequently asked questions

Should I take a lower dose of carvedilol if I am a CYP2D6 poor metabolizer?

Not necessarily. Current guidelines do not recommend a different carvedilol dose based on genes. Your doctor may increase the dose more slowly and watch for dizziness, but you should still aim for the dose that is right for your heart condition. Never change your dose without talking to your doctor.

Is metoprolol affected by genes more than carvedilol?

Yes. Metoprolol depends more on CYP2D6, and CPIC recommends a lower starting dose and careful increases, or a different beta-blocker, for CYP2D6 poor metabolizers.

What should I do if I feel dizzy on carvedilol?

Stand up slowly, sit down if you feel light-headed, and tell your doctor, who may adjust the dose or the schedule of increases. Seek urgent care if you faint, have chest pain or have a very slow or irregular heartbeat. Do not stop carvedilol suddenly, as this can be dangerous.

Can I take carvedilol with antidepressants?

Often yes, but some antidepressants, such as fluoxetine, paroxetine and bupropion, block CYP2D6 and can raise carvedilol levels. Ask your pharmacist to check your combination.

References

1. Duarte JD, Thomas CD, Lee CR, et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 genotypes and beta-blocker therapy. Clin Pharmacol Ther. 2024;116(4):939-947. doi:10.1002/cpt.3351
2. Hypertension Canada. Choice of therapy for adults with hypertension without compelling indications for specific agents.
3. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5(1):6-13. doi:10.1038/sj.tpj.6500285

Image used under the Creative Commons 2.0 License, photo taken by Bernard Goldbach.