Top four gene-drug pairs in cardiovascular pharmacogenomics

Medicine and pharmacy are evolving. They are moving away from a one-size-fits-all model to individualized care models powered by genomic, big data, AI algorithms (machine learning, deep learning, large language models, etc), digital health, and soon quantum computing.

Pharmacogenomics, one of the most used tools of individualized medicine, is also evolving. As we navigate through this transformative era, the role of pharmacogenomics will continue to grow. Especially in cardiovascular medicine: tailoring treatments based on individual’s genetics to minimize side effects and optimize efficacy.

Although, I am excited about the promising future, let’s look at what we can currently do to improve lives through pharmacogenomics. Suppose you are bringing PGx into your practice or developing tools to help others do so. In that case, you will need to consider the four most valuable pharmaco-genes that are reshaping how we individualize cardiovascular treatments.

1. CYP2C19 -CLOPIDOGREL:  THE POSTER CHILD

What: Clopidogrel is an antiplatelet that prevents stroke, heart attacks, and other CV problems. But there is a catch. In order to work, it has to be metabolized in the liver to an active drug. The key enzyme is CYP2C19.

Why: Clopidogrel is a prodrug, activated by CYP2C19 into an antiplatelet. Genetic variants can greatly alter a drug’s pharmacokinetics and its levels. These variants, common in a population, either rev up metabolism aka activation (rapid and ultrarapid metabolizers), or slow it down (intermediate and poor metabolizers). This is an elegant example of pharmacogenetics where variants of one gene/enzyme, directly impact drug levels and clinical outcomes.

Who: identify non-responders such as intermediate to poor metabolizers because the drug may not work for them.

When: best to do it pre-emptively and up to 3 months post stent replacement (time of highest platelet reactivity).

Current guidelines: https://cpicpgx.org/guidelines/guideline-for-clopidogrel-and-cyp2c19/

2. VKORC1 + CYP2C9 – WARFARIN:  THE POWER DUO

What: Warfarin is an anticoagulant that prevents blood clots. It was supposed to be a poster child of CV PGx but things got complicated with the discovery of other genes from various ancestry groups that also contributed to warfarin’s dosing. Story for another time…

Why: Due to its narrow therapeutic index, significant interindividual variability in dosing requirements can be challenging. The VKORC1 and CYP2C9 genetic variants are critical in warfarin metabolism and sensitivity.

Who: identify those at increased risk of warfarin-induced bleeding AND those who may be warfarin-resistant (need higher doses).

When: I see best results when this is done pre-emptively but have seen some insightful findings in individuals who were “warfarin resistant” (needed higher than standard dose)

Current guidelines and warfarin calculator: https://cpicpgx.org/guidelines/guideline-for-warfarin-and-cyp2c9-and-vkorc1/

3. SLCO1B1 – STATINS:  A MUSCLE THING

What: statins are HMG-CoA reductase inhibitors aka cholesterol-reducing drugs. They reduce the amount of cholesterol in the liver and help the liver get rid of cholesterol from the blood. But they are more than liver helpers. Statins may reduce inflammation in blood vessels and damage to the heart, brain, etc. This makes them a powerful ally in combating CV risks (halves the risk of a heart attack and strokes). But they come with side effects, especially statin-induced myopathy (muscle pain, weakness, etc). I see at least two patients a week who are referred for PGx due to this. Drug genetics plays an important role. SLCO1B1 is one such contributor. The gene encodes for the same named enzyme found in liver cells. It transports bilirubin, hormones, toxins, and drugs from the blood into the liver for metabolism

Why: Genetic variants of a drug transporter, SLCO1B1 (solute carrier organic anion transporter family member 1B1) can increase the risk of statin myopathy. They alter the enzyme’s function so that statins are not taken up efficiently from the blood into the liver. Mutations in the SLCO1B1 gene also cause Rotor syndrome (elevated bilirubin).

Who: identify those at risk of statin-induced myopathy. Here is where it gets tricky: I have seen many of my patients who have this mutation and they do well on either hydrophilic statins (pravastatin, rosuvastatin) or low to medium-dose statins. I have also seen many patients without SLC01B1 variants who continue to experience muscle side effects regardless of statin type, dose, and frequency. Meaning: other genes and clinical factors contribute.

Guidelines: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/

Pharmacogenetic and pharmacogenomics testing is not without challenges, including cost, accessibility, emerging evidence and guidelines, and the need for education, to name a few. However, they have the potential to meaningfully improve patient safety and efficacy by personalizing therapy. Together we can do this!

Best,

Adrijana

p.s.

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