Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers.

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to ß-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.

Circulating microRNA Biomarkers of Thiazide Response in Hypertension.

BACKGROUND: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response. METHODS AND RESULTS: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, and hydrochlorothiazide-treated Black individuals. Different blood pressure phenotypes including categorical (responder versus nonresponder) and continuous diastolic blood pressure and systolic blood pressure were tested for association with the candidate miRNA expression using multivariate regression analyses adjusting for age, sex, and baseline blood pressure. After quality control, 74 miRNAs were available for screening, 19 of which were considered for validation. In the validation cohort, miR-193b-3p and 30d-5p showed significant associations with continuous SBP or diastolic blood pressure response or both, to hydrochlorothiazide in European Americans at Benjamini-Hochberg adjusted P<0.05. In the combined analysis of validation cohorts, let-7g (odds ratio, 0.6 [95% CI, 0.4-0.8]), miR-142-3p (odds ratio, 1.1 [95% CI, 1.0, 1.2]), and miR-423-5p (odds ratio, 0.7 [95% CI, 0.5-0.9]) associated with categorical diastolic blood pressure response at Benjamini-Hochberg adjusted P<0.05. Predicted target genes of the 5 miRNAs were mapped to key hypertension pathways: lysine degradation, fatty acid biosynthesis, and metabolism. CONCLUSIONS: The above identified circulating miRNAs may have a potential for clinical use as biomarkers for thiazide diuretic selection in hypertension. REGISTRATION: URL: ClinicalTrials.gov. Unique identifiers: NCT00246519, NCT01203852, NCT00005520.

Pairwise comparison of hydrochlorothiazide and chlorthalidone responses among hypertensive patients.

This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p < 1.0e-5 SBP, p = 0.002 DBP) and 11/8 versus 20/11 mmHg among AA patients (p = 0.03 SBP, p = 0.22 DBP). While CTD showed clinically meaningful benefit over HCTZ in two-thirds of participants with respect to SBP reduction and half of EA patients with respect to DBP reduction, a majority of AA patients (53%) showed similar DBP reduction with both thiazides. Sixty percent of AA patients and 29% of EA patients attained blood pressure (BP) <140/90 mmHg with both thiazides. Mean potassium (K+) reduction was greater with CTD compared to HCTZ both in EA patients (mean difference = 0.35, p = 0.0002) and AA patients (0.49, p = 0.043). While 31% of AA patients developed severe hypokalemia on CTD, <5% of others developed severe hypokalemia. Although 46% of AA patients on CTD required K+ supplementation, only 6%-11% of others required supplementation. Overall, in the majority of EA patients, CTD was superior to HCTZ, whereas among AA patients, it was superior in a minority, and was associated with significant potassium-related risk, suggesting that guideline preferences for CTD over HCTZ are reasonable in EA patients but may be less reasonable in AA patients, particularly if the target is <140/90 mmHg.

Influence of Genetic West African Ancestry on Metabolomics among Hypertensive Patients.

Patients with higher genetic West African ancestry (GWAA) have hypertension (HTN) that is more difficult to treat and have higher rates of cardiovascular diseases (CVD) and differential responses to antihypertensive drugs than those with lower GWAA. The mechanisms underlying these disparities are poorly understood. Using data from 84 ancestry-informative markers in US participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, the GWAA proportion was estimated. Using multivariable linear regression, the baseline levels of 886 metabolites were compared between PEAR participants with GWAA < 45% and those with GWAA ≥ 45% to identify differential metabolites and metabolic clusters. Metabolites with a false discovery rate (FDR) < 0.2 were used to create metabolic clusters, and a cluster analysis was conducted. Differential clusters were then tested for replication in PEAR-2 participants. We identified 353 differential metabolites (FDR < 0.2) between PEAR participants with GWAA < 45% (n = 383) and those with GWAA ≥ 45% (n = 250), which were used to create 24 metabolic clusters. Of those, 13 were significantly different between groups (Bonferroni p < 0.002). Four clusters, plasmalogen and lysoplasmalogen, sphingolipid metabolism and ceramide, cofactors and vitamins, and the urea cycle, were replicated in PEAR-2 (Bonferroni p < 0.0038) and have been previously linked to HTN and CVD. Our findings may give insights into the mechanisms underlying HTN racial disparities.

Olanzapine/Samidorphan: New Drug Approved for Treating Bipolar I Disorder and Schizophrenia.

OBJECTIVE: To describe the approval of olanzapine/samidorphan, compare the clinical trial data, and summarize key findings, with a focus on impact to clinical practice. DATA SOURCES: A literature search of PubMed was performed (March 2006 to November 2021) using the following search terms: Lybalvi, olanzapine/samidorphan, olanzapine, antipsychotic, bipolar disorder, and schizophrenia. Product monographs, review articles, and randomized control trials were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies conducted in humans were considered. Primary use of Phase III clinical drug approval trials preferred; supplementary trial analysis evaluated to provide context. DATA SYNTHESIS: In June 2021, the Food and Drug Administration (FDA) approved Lybalvi® (olanzapine/samidorphan) for indications including treatment of adults with schizophrenia and/or bipolar I disorder (acute manic episodes or acute episodes with mixed features) through the multi-stage ENLIGHTEN clinical trials. Participants were enrolled in 4-week, 24-week, and 52-week studies to evaluate the safety and efficacy of olanzapine/samidorphan. Subsequent secondary analysis evaluated metabolic effects. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review details the pharmacologic, pharmacokinetic, associated dosing and indications, and adverse effects for the drug combination olanzapine/samidorphan. Better understanding of novel drug mechanisms will help to expand on the potential role and place for use in clinical practice. CONCLUSION: When treating complex patients with schizophrenia, the olanzapine/samidorphan combination has limited effect on medication-induced weight gain often associated with antipsychotic olanzapine monotherapy. Additional studies are needed to further define the role of olanzapine/samidorphan in bipolar I disorder and clinical practice.

Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients.

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European-American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to ß-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European-American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European-American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (ß = -1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (ß = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.

Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone.

BACKGROUND: Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. METHODS: We compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17-65-year-old mild-moderate uncomplicated hypertensive whites and blacks. RESULTS: Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P < 10-6 SBP and DBP); 12 ± 10/7 ± 6 vs 15 ± 10/9 ± 6 in blacks (P = .008 SBP, P = .054 DBP). Treatment with HCTZ vs chlorthalidone in whites resulted in significantly fewer patients achieving target BP (<140/90 mm Hg) (44% vs 57%, P = .018) and clinical response rate (≥10 mm Hg DBP reduction); and significantly higher nonresponse rate (<6 mm Hg DBP reduction); but no significant differences in rates among blacks (eg, target-BP rate: 56% vs 63%, P = .31). HCTZ treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs chlorthalidone, and significantly lower odds of requiring potassium supplementation among blacks (odds ratio 0.16; 95% confidence interval, 0.07-0.37; P = 3.4e-7). CONCLUSION: Compared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.

Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.

Design and Early Implementation Successes and Challenges of a Pharmacogenetics Consult Clinic.

Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered CYP2C19 and/or CYP2D6 testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist's effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist-physician collaboration.

Sorting nexin 1 loss results in increased oxidative stress and hypertension.

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1-/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1 R), NADPH oxidase (NOX) subunits, D5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5 R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response.

Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1) was significantly associated with better DBP response to CTD (p = 5.76 × 10-6, ß = -15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, ß = -9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10-9. This variant was further validated for opposite association in two ß-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10-3, ß = 7.47) and PEAR atenolol (p = 0.04, ß = 4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to ß-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.

Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers.

BACKGROUND: Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease. METHODS: AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4-9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation. RESULTS: Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1-2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10-7) in those with 1-2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10-7) in those with 0 risk alleles. CONCLUSIONS: Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required.

ß2 -Adrenergic Receptor Gene Affects the Heart Rate Response of ß-Blockers: Evidence From 3 Clinical Studies.

ß-Blockers' heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among ß-blocker-treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to ß-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to ß-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following ß-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both ß-blockers in whites (rs1042714 C-allele carriers, meta-analysis ß = -0.95 beats per minute [bpm], meta-analysis P = 3×10-4 ; rs1042713 A-allele carriers, meta-analysis ß = -1.15 bpm, meta-analysis P = 2×10-3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective ß-blockade in hypertensive patient cohorts.

Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans.

European Americans (EA) have a better antihypertensive response to ß-blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post-metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and tested for replication in the atenolol-treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to ß-blockers in the PEAR-2 study (P = 3.41 × 10-6 , ß = -2.70) and replicated (P = 0.01, ß = -1.17) in the PEAR study. Post-meta-analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to ß-blockers (P = 3.43 × 10-6 , ß = 4.57) and was replicated in the atenolol add-on cohort (P = 0.007, ß = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a ß-blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to ß-blockers.

Erenumab: A First-in-Class Monoclonal Antibody for Migraine Prevention.

Objective: To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy. Data Sources: A MEDLINE/PubMed search (January 2000 to January 2019) was conducted using the keywords erenumab-aooe, erenumab, migraine, migraine prophylaxis, migraine prevention, and chronic migraine. Additional articles were identified by hand from references. Study Selection and Data Extraction: We included English-language articles (excluding poster presentations) evaluating erenumab pharmacology, efficacy, or safety in humans for migraine prevention. Data Synthesis: Erenumab is a CGRP inhibitor that inhibits vasodilation in response to acute migraines, which decreases pain perception during the migraine. Erenumab efficacy and safety has only been compared with placebo, but its reduction in monthly migraine days (MMDs) and medication response (≥50% reduction in MMDs) are comparable to current recommended off-label therapies for migraine prevention in short-term treatment studies. Additionally, erenumab is associated with low adverse event burden with no difference found compared with placebo per published clinical trials. Relevance to Patient Care and Clinical Practice: Erenumab is the first medication approved in the United States for the prevention of migraines in adults. No head-to-head data are available, but existing data suggest that erenumab is at least as effective as current off-label products and with reduced adverse effects. Conclusion: Erenumab is an effective once-monthly injectable agent for migraine prevention in patients with chronic or episodic migraine. It is also effective for patients who have previously failed migraine preventive therapy. Erenumab has a favorable adverse effect profile, which may improve patient adherence.

Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension.

BACKGROUND: Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS: Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS: EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS: PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION: NCT01203852, NCT00246519, NCT00005520.

Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies.

ß-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to ß-blockers. Expression of 22 ß-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and ß-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate ß1-adrenergic receptor and other ß-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to ß-blockers.

Incident-to Billing for Pharmacists.

The inclusion of pharmacists on care teams has been shown to improve clinical and economic health outcomes. However, a significant barrier to the widespread incorporation of pharmacists into care teams is the ability to financially support the salary of the pharmacist. A mechanism to improve the ability of pharmacists to generate clinical revenue already exists in the form of incident-to billing, although there remains considerable uncertainty regarding the criteria for incident-to billing and specifically how pharmacists can use this model to capture revenue for clinical services. In this article, we discuss incident-to billing criteria as it pertains to outpatient clinics, common misconceptions related to incident-to billing, and how clinical pharmacists may use this mechanism to generate revenue for the clinical services they provide. DISCLOSURES: This work was not supported by any funding source. The authors have no relevant conflicts of interest to disclose.

Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, ß=-1.60, ΔDBP: P=0.023, ß=-1.08) and GERA (ΔSBP: P=0.028, ß=-1.95, ΔDBP: P=0.032, ß=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.