Pharmacists’ Role Expands in Pharmacogenomics and Personalized Cardiometabolic Treatment

Cardiometabolic diseases encompass a variety of interrelated disorders, including hypertension, dyslipidemia, obesity, type 2 diabetes (T2D), and cardiovascular diseases. Cardiovascular diseases are the leading cause of death globally,¹ and an estimated 11.6% of the US population has diabetes.² These conditions account for a substantial proportion of the morbidity and mortality globally.

Despite well-established treatment guidelines, patients often fail to achieve treatment goals due to multiple factors, including variation in drug response, adverse effects (AEs), and complex comorbidities. Pharmacogenomics (PGx) may provide additional insights into patients’ medication responses, enabling the personalized selection and dosing of medications based on a patient’s genetic profile. Given pharmacists’ expertise in medications and their vital role in managing cardiometabolic diseases, pharmacists are uniquely positioned to implement PGx-guided care for cardiometabolic diseases.

Current Guidance

PGx is the study of how genetic variation impacts medication safety and efficacy.³ The Clinical Pharmacogenetics Implementation Consortium (CPIC) is an international association of experts who create evidence-based, peer-reviewed guidelines on how to utilize PGx results for clinical application. Within the CPIC guidelines, several drug-gene associations have a significant impact on the safety and efficacy of medications used in cardiometabolic diseases. Examples of these include clopidogrel, warfarin, statins, metoprolol, and certain antihypertensive medications.

One of the most significant drug-gene associations is that of clopidogrel (Plavix) and CYP2C19. Clopidogrel is bioactivated by CYP2C19 into its active metabolite. Individuals may have genetic variations in CYP2C19 that result in reduced or no function of the enzyme; these patients are referred to as intermediate or poor metabolizers, respectively. CYP2C19 intermediate and poor metabolizers taking clopidogrel have reduced platelet inhibition and increased risk of major adverse cardiovascular and cerebrovascular events; CPIC recommends avoiding clopidogrel in these patients.⁴ PGx testing can identify these patients, enabling clinicians to select alternative antiplatelet agents such as prasugrel (Effient) or ticagrelor (Brilinta).

CPIC provides additional PGx guidance on the statin medication class and SLCO1B1, ABCG2, and CYP2C9. The presence of genetic variants in these genes affects systemic concentrations, and the genes may increase the risk of statin-associated musculoskeletal symptoms (SAMS). SAMS can lead to poor adherence, ultimately limiting the long-term benefits of statin therapy. CPIC guidance is most robust for simvastatin and, to a lesser extent, atorvastatin and rosuvastatin. No dose adjustments are needed for fluvastatin or pravastatin.⁵ Routine genetic testing is not standard of care, as the clinical impact outside of simvastatin is limited.⁵

A classic and one of the earliest PGx associations is the warfarin and VKORC1, CYP2C9, CYP4F2, and CYP2C cluster. Genetic variations in these genes can influence the dose requirements of warfarin. CPIC recommends utilization of genetic variation in conjunction with other clinical factors to guide warfarin dosing.6 Genetic testing prior to initiation may reduce the time to stable international normalized ratio and lower the risk of bleeding.

Additional guidance from CPIC includes CYP2D6 and metoprolol. CPIC guidance focuses mainly on reducing the risk of AEs in CYP2D6 poor metabolizers, who have increased systemic exposure to metoprolol and a greater reduction in heart rate and blood pressure than CYP2D6 normal metabolizers. CYP2D6 has a moderate strength recommendation of initiating therapy at the lowest recommended starting dose with close monitoring and careful titration; an alternative β-blocker may be considered.⁷ Lastly, CPIC provides guidance for hydralazine (Apresoline) based on the NAT2 phenotype, with specific dosing recommendations based on systemic concentrations.⁸

Clinical Trials and Investigations

Large-scale, prospective clinical trials and meta-analyses have begun to evaluate PGx-guided therapy in patients with T2D. However, most evidence to date suggests associations between genetic variants and drug response, rather than direct improvements in clinical outcomes resulting from genotype-guided prescribing. The 2020 American Diabetes Association consensus report and systematic reviews confirm that genetic variants (eg, CYP2C9 for sulfonylureas, SLC2A2 for metformin) can influence drug response, though no large trials have shown PGx-guided therapy improves glycemic control or cardiovascular outcomes. For glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors, variants in GLP1R and SLC5A2 have been linked to differences in glycemic response.^9-12

Expanding beyond isolated drug-gene associations, there is emerging research on the polygenic risk score (PRS), which integrates the cumulative impact of multiple genetic variants to assess an individual’s genetic predisposition to cardiometabolic diseases. PRS may enhance cardiometabolic risk prediction by integrating genetic data with traditional patient-specific clinical factors. PRS has shown utility in identifying individuals at higher risk for conditions, particularly coronary heart disease. PRS may help to guide preventive and therapeutic decisions. However, there is considerable variability across various PRS tools and limited validation, particularly among ancestrally diverse populations.

The variability and limited validation impose challenges for its clinical implementation. PRS is still evolving and may have a potential role in complementing PGx data by helping pharmacists identify patients who may benefit from earlier or more intensive preventive therapies, such as the earlier initiation of statins in genetically high-risk individuals. PRS is a developing area of precision medicine, and pharmacists must be aware of PRS’ potential and current limitations.^13,14

The Pharmacist’s Role

Pharmacists are uniquely positioned to lead the integration of PGx in cardiometabolic management. Pharmacists can utilize their strong knowledge of medications and pharmacokinetics to identify patients for PGx testing, interpret PGx results, and collaborate with providers to optimize and personalize therapy. Although limitations exist in terms of PGx implementation within institutions, such as limited reimbursement/cost and accessibility of testing, as well as integration with electronic health records, pharmacists are increasingly initiating and expanding these services to improve outcomes and prevent adverse drug events, while also working as precision medicine specialists. Continuing education and certification programs in PGx are expanding, equipping pharmacists to interpret genetic data and advocate for safe, individualized treatment plans.

As the health care landscape evolves toward precision medicine, pharmacists’ expertise in pharmacotherapy positions them to lead implementation efforts, ensuring that every patient receives therapy tailored to their unique genetic and clinical profiles. Embracing PGx is not just an expansion of pharmacy practice; it is a fundamental step toward the future of individualized health care.

REFERENCES

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