The Pharmacogenomic and Metabolomic Predictors of ACE Inhibitor and Angiotensin II Receptor Blocker Effectiveness and Safety

Abstract

Hypertension (HTN) is the most common chronic disease in the USA. Hypertensive patients frequently require repeat primary care visits to find an effective drug or drug combination to control their disease. Currently, patients are prescribed drugs for HTN based on race, age, and comorbidities and although the current guidelines are reasonable starting points for prescribing, 50% of hypertensive patients still fail to achieve target blood pressures. Despite numerous strategies to improve compliance, drug effectiveness, and optimization of initial drug choice, effectiveness has remained largely unchanged over the past two decades. Therefore, it is important to pursue alternative strategies to more effectively treat patients and to decrease medical costs. Additional precision medicine work is needed to identify factors associated with effectiveness of commonly used antihypertensive medications. The objective of this manuscript is to present a comprehensive review of the pharmacogenomic and metabolomic factors associated with ACEI and ARB effectiveness and safety.

Keywords: ACE inhibitors; Angiotensin II receptor blockers; Metabolomics; Pharmacogenomics; Precision medicine.

Fig. 1

ACE inhibitor interaction with the renin-angiotensin-aldosterone system. Angiotensinogen is released from the liver (no. 1) into the blood where it is converted to angiotensin I by renin (no. 2). Angiotensin I is converted to angiotensin II (ang II) by angiotensin converting enzyme (ACE, no. 3). Ang II binds angiotensin receptors which results in increased blood pressure (no. 4). Ang II also stimulates the production and release of aldosterone (nos. 5 and 6) which leads to increased blood pressure (no. 7). ACE inhibitors prevent the conversion of angiotensin I to ang II (no. 8). Angiotensin receptor blockers (ARBs) compete with Ang II at angiotensin receptor binding sites and result in decreased blood pressure (no. 9). ACE is an important enzyme for the breakdown of bradykinin (no. 12). In the presence of ACE inhibition, bradykinin accumulates and can lead to adverse effects such as cough and angioedema (nos. 10 and 11)

Fig. 2

Vasoactive peptide breakdown by neprilysin. Neprilysin breaks down bradykinin, substance P, endothelin, and atrial natriuretic peptide (ANP). Mutations in MME gene which encodes neprilysin can lead to decreased neprilysin function and accumulation of vasoactive peptides, especially in the presence of ACE inhibition, thus increasing the risk of cough and angioedema

Fig. 3

XPNPEP2 gene which encodes aminopeptidase P (APP) is located on the long arm of the X chromosome, marked above. APP is an inactivator of bradykinin, and is part of an important alternative bradykinin breakdown pathway in the presence of ACE inhibition. Females have redundancy in the XPENPEP2 gene due to the possession of two X chromosomes, while males only have one copy of the X chromosome and thus one copy of the XPNPEP2 gene. Males are likely more susceptible to adverse events during ACE inhibition due to variation in XPNPEP2 gene than are females

Fig. 4

ACE cleavage of antidiabetogenic cholecystokinin (CCK-8) with by-product aspartylphenylalanine (Asp-Phe). ACEI therapy leads to decreased levels of Asp-Phe. Patients with major ACE allele AA at rs4329 have lower levels of Asp-Phe indicating ACEI therapy is more effective in patients with this variant