Pharmacogenomics is a rapidly expanding field with new evidence and implications for cardiology practice, experts said during the ASHP 2023 Midyear Clinical Meeting & Exhibition, in Anaheim, Calif.
Pharmacogenomics (also known as pharmacogenetics) explores how a person’s genes metabolize medications. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has compiled information about nearly 200 drug–gene associations, many in common cardiology drug classes such as antiarrhythmics, antiplatelet/anticoagulants, beta-blockers and statins, said Jordan Baye, PharmD, MA, BCPS, an assistant professor of pharmacy practice at South Dakota State University, in Brookings.
Statins
Statins represent one area of importance to note, said Natasha Petry, PharmD, MPH, BCACP, an associate professor of practice at North Dakota State University, in Fargo. Atorvastatin is the most prescribed medication in the United States, and four additional statins rank among the top 100 (Pharmacy [Basel] 2018; 6[2]:43). Concerns about statin-associated musculoskeletal symptoms (SAMS), including pain, are a leading reason that patients refuse or discontinue the medications, Dr. Petry said. However, pharmacogenomics can help predict these side effects.
In 2022, CPIC published updated prescribing guidance for all statins (Clin Pharmacol Ther 2022;111[5]:1007-1021) and clinically relevant genes that could affect a patient’s risk for muscle symptoms. Decreased function of the gene SLCO1B1, for example, results in increased systemic exposure to statins—a causative factor of SAMS—and can be used to guide statin selection and dosing, Dr. Petry said.
The CPIC guidance also provides recommendations relating to ABCG2 (which is expressed in the liver, blood–brain barrier and intestines) before prescribing rosuvastatin, and for cytochrome P450 2C9 (CYP2C9) enzyme function (a contributor to metabolism of many drugs) before prescribing fluvastatin, she said. Dosing recommendations for each statin are based on individual test results. For example, intermediate metabolizers of CYP2C9 should receive a maximum starting dose of fluvastatin of 40 mg per day, while poor metabolizers should receive a maximum starting dose of 20 mg per day.
The guidance also contains a table with recommended dosing of statins for people with alterations in both SLCO1B1 and CYP2C9.
Beta-Blockers
Pharmacogenomics also can help pharmacists optimize beta-blocker therapy, said Jasmine Luzum, PharmD, PhD, BCPS, an assistant professor of clinical pharmacy at the University of Michigan, in Ann Arbor. Metoprolol is the eighth most prescribed drug in the United States, with six beta-blockers on the list of the top 200 prescribed drugs (Pharmacy [Basel] 2018;6[2]:43). Dr. Luzum noted that over 117 million prescriptions for beta-blockers were written for more than 26 million Americans in 2020. “So if we can make even small improvements in beta-blocker therapy, it could still have a huge public health impact.”
Individual patient responses to this class of drugs can vary widely, she said, with side effects sometimes including low blood pressure or fatigue. Multiple genetic variants can affect a patient’s beta-blocker response.
Pharmacogenomics Resources
Guidelines:
- Association for Molecular Pathology (AWP)
www.amp.org - Clinical Pharmacogenetics Implementation Consortium (CPIC)
cpicpgx.org/guidelines - Dutch Pharmacogenetics Working Group (DPWG)
www.knmp.nl
Data repositories:
- Pharmacogenomics Knowledgebase (PharmGKB)
www.pharmgkb.org
Regulatory:
- FDA table of pharmacogenetic associations
www.fda.gov/medical-devices/ precision-medicine/ table-pharmacogenetic-associations
On the pharmacokinetic side, many beta-blockers are metabolized by the protein encoded by the gene CYP2D6, which can perform differently across individuals. “There’s lots of genetic variants in CPY2D6, and we still haven’t figured out what all of them do yet,” Dr. Luzum said. She is co-authoring a CPIC guideline that addresses beta-blockers and CYP2D6, plus a few other genes, that is expected to be released early this year.
Dr. Luzum and her colleagues believe metoprolol is the only beta-blocker significantly affected by CYP2D6 genetic variants. “If you have a patient who is a poor CYP2D6 metabolizer, don’t use metoprolol—use a different beta-blocker,” she advised. Those who still wish to use metoprolol should start at the lowest possible dose and take precautions when up-titrating, such as checking heart rate and blood pressure at every dose increase.
Regarding pharmacodynamics, two common genetic variants in ADRB1 (the beta-1 adrenergic receptor) may decrease beta-blocker response across a variety of patient populations. However, the forthcoming CPIC drug-gene guideline notes that while there is good experimental evidence noting this issue, clinical data were inconsistent, and the authors were “not convinced” that the issue should mandate a change in beta-blocker prescribing at this time, Dr. Luzum said.
In some cases, beta-blocker response can result from alterations in multiple genes. Dr. Luzum and her colleagues recently identified 44 genetic variants that could affect beta-blocker response and compiled those into a polygenic response predictor (PRP) score. This score predicted whether beta-blocker exposure was associated with improved survival in two studies. One looked at nearly 1,200 patients with heart failure accompanied by reduced ejection fraction (<50%) who had European ancestry (Circ Heart Fail 2020;13[12]:e007012); the other studied 7,141 heart failure patients with European ancestry (Circ Genom Precis Med 2023;16[2]:e003835). Specifically, greater beta-blocker exposure was associated with reduced all-cause mortality in patients with low PRP scores (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; P=0.0075) but not high PRP scores (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; P=0.448). The difference between the two groups was statistically significant (P interaction, 0.0235).
Part 1:
Making the case for adding pharmacogenomics to routine clinical care. Click the URL to access.
The CPIC guideline mentions the PRP score, she said, but does not yet include a formalized process making clinical recommendations.
Dr. Baye added that clopidogrel is another drug that can be metabolized differently by people with variations in the CYP2C19 gene and possibly others. CPIC guidance from 2013 (Clin Pharmacol Ther 2013;94[3]:317-323) recommends alternative antiplatelet agents for intermediate or poor metabolizers of CYP2C19, he said, who have an increased risk for major adverse cardiac events such as myocardial infarction and stroke.
Dr. Petry reported owning stocks/options in Teva Pharmaceuticals. The other speakers reported no relevant financial disclosures.
This article is from the February 2024 print issue.