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1.
Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
Seyerle, AA, Sitlani, CM, Noordam, R, Gogarten, SM, Li, J, Li, X, Evans, DS, Sun, F, Laaksonen, MA, Isaacs, A, et al
The pharmacogenomics journal. 2018;(2):215-226
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Abstract
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.
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Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies.
Xiao, X, Xu, Y, Wu, Q
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018;(7):1515-1524
Abstract
UNLABELLED Inconsistent findings in regard to association between thiazide diuretic use and the risk of fracture have been reported during the past decade. This updated meta-analysis, which pooled data from 11 qualified prospective designed studies, found that thiazides have a significant protective effect on fracture risk. INTRODUCTION An updated comprehensive meta-analysis examine the association between thiazide diuretic use and therisk of fracture is needed. METHODS Cohort studies regarding thiazide diuretic exposure and the risk of fracture, published from inception to May 1 2017, were identified through MEDLINE, EMBASE, SCOPUS, and the Cochrane Database of Systematic Reviews. The literature search, study selection, study appraisal, and data extraction were pre-defined in the protocol and were independently conducted by two investigators. Due to the heterogeneity of the original studies, a random effects model was used to pool the confounder-adjusted relative risk (RR). RESULTS Eleven eligible cohort studies involving 2,193,160 participants were included for analysis. Overall, thiazide diuretic users, as compared with non-users, had a significant 14% reduction in the risk of all fractures (relative risk [RR], 0.86; 95% confidence interval [CI], 0.80-0.93; p = 0.009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95%CI, 0.80-0.93; p = 0.009). However, the effect size associated with thiazide use became slightly weaker when the analysis was limited to only high-quality original studies (quality score > 8) (RR, 0.89; 95%CI, 0.80-0.99; p = 0.005), studies with a larger sample size (> 10,000) (RR, 0.90; 95%CI, 0.80-1.00; p = 0.002), and studies published after 2007 (RR, 0.92; 95%CI, 0.82-1.02; p = 0.001). CONCLUSION Our findings indicate that thiazide diuretic use may convey a decreased risk of fracture and as such, the protective effect of this class of medicine should be considered when prescribing thiazide diuretics in clinical practice.
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Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients.
Singh, S, McDonough, CW, Gong, Y, Alghamdi, WA, Arwood, MJ, Bargal, SA, Dumeny, L, Li, WY, Mehanna, M, Stockard, B, et al
Journal of the American Heart Association. 2018;(6)
Abstract
BACKGROUND Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change. METHODS AND RESULTS Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with P<5×10-8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10-8). G-allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (ß=5.54; P=0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis P value of 3.71×10-8. HMGCS2, a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. CONCLUSIONS These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
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Urolithiasis: evaluation, dietary factors, and medical management: an update of the 2014 SIU-ICUD international consultation on stone disease.
Jung, H, Andonian, S, Assimos, D, Averch, T, Geavlete, P, Kohjimoto, Y, Neisius, A, Philip, J, Saita, A, Shah, H, et al
World journal of urology. 2017;(9):1331-1340
Abstract
PURPOSE The aim of this review was to provide current best evidence for evaluation, dietary, and medical management of patients with urolithiasis. METHODS Literature addressing evaluation, dietary, and medical management of urolithiasis was searched. Papers were analyzed and rated according to level of evidence (LOE), whereupon a synthesis of the evidence was made. Grade of recommendation (GOR) was judged from individual clinical experience and knowledge of the evidence according to the Oxford Centre for Evidence-based Medicine. RESULTS It is obvious that different stone diseases influence the life of stone-forming individuals very differently, and that evaluation and medical management should be personalized according to risk of recurrence, severity of stone disease, presence of associated medical conditions, and patient's motivation. With regard to evaluation, dietary and medical management of patients with urolithiasis evidence from the literature suggest that selective metabolic evaluation may lead to rational dietary and medical management. Statements based on LOE and GOR are provided to guide clinical practice. CONCLUSION The provided evidence for evaluation of patients with urolithiasis aims at defining patients at high risk for recurrent/complicated stone disease. Based on this approach, evidence-based dietary and medical management regimes are suggested.
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Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients.
Pathare, G, Tutakhel, OAZ, van der Wel, MC, Shelton, LM, Deinum, J, Lenders, JWM, Hoenderop, JGJ, Bindels, RJM
American journal of physiology. Renal physiology. 2017;(6):F1063-F1072
Abstract
The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide.
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Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response.
Shahin, MH, Sá, AC, Webb, A, Gong, Y, Langaee, T, McDonough, CW, Riva, A, Beitleshees, AL, Chapman, AB, Gums, JG, et al
Circulation. Cardiovascular genetics. 2017;(1)
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Abstract
BACKGROUND Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response. METHODS AND RESULTS Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10-5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (Δ systolic BP/Δ diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mm Hg, respectively, Δ systolic BP P=3×10-4, Δ diastolic BP P=5×10-5). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r2=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. CONCLUSIONS This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
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[Not Available].
Muheim, L
Praxis. 2017;(5):271-272
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Thiazide diuretics and the risk of osteoporotic fractures in hypertensive patients. Results from the Swedish Primary Care Cardiovascular Database.
Bokrantz, T, Ljungman, C, Kahan, T, Boström, KB, Hasselström, J, Hjerpe, P, Mellström, D, Schiöler, L, Manhem, K
Journal of hypertension. 2017;(1):188-197
Abstract
OBJECTIVE The objective is to investigate if treatment with thiazides reduces the risk of osteoporotic fractures in hypertensive patients in primary healthcare. Further we aimed to examine the impact of duration of thiazide use, the consequences of discontinuation of treatment, and the possible difference in effect between men and women. METHOD This retrospective cohort study includes 57 822 individuals, 45 years and older, diagnosed with hypertension during 2001-2008 in the Swedish Primary Care Cardiovascular Database. Patients were followed from 1 January 2006 (or the date of their first diagnosis of hypertension if that date came later), until they had an incident osteoporotic fracture, died, or reached the end of the study at 31 December 2012. Patients exposed to thiazides were compared with patients never exposed to thiazides. RESULTS Current use of thiazides was associated with significantly reduced risk of osteoporotic fractures [hazards ratio 0.89; 95% confidence interval (CI) 0.81-0.98], and increased with longer treatment periods (hazards ratio 0.87; 95% CI 0.78-0.97 after 2 years). However, discontinuation of thiazides increased the risk of osteoporotic fractures (hazards ratio 1.18; 95% CI 1.04-1.33), but attenuated with longer duration past treatment period. When analyzing men and women separately, similar results were seen, although only significant in men. CONCLUSION This large observational study confirms that thiazide therapy in hypertensive patients is associated with a reduced risk of osteoporotic fractures. The protective effect increased with longer treatment periods. However, discontinuation of treatment increased the risk of fractures, which emphasizes the importance of continuous treatment.
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A theory-based process evaluation alongside a randomised controlled trial of printed educational messages to increase primary care physicians' prescription of thiazide diuretics for hypertension [ISRCTN72772651].
Presseau, J, Grimshaw, JM, Tetroe, JM, Eccles, MP, Francis, JJ, Godin, G, Graham, ID, Hux, JE, Johnston, M, Légaré, F, et al
Implementation science : IS. 2016;(1):121
Abstract
BACKGROUND Pragmatic trials of implementation interventions focus on evaluating whether an intervention changes professional behaviour under real-world conditions rather than investigating the mechanism through which change occurs. Theory-based process evaluations conducted alongside pragmatic randomised trials address this by assessing whether the intervention changes theoretical constructs proposed to mediate change. The Ontario Printed Educational Materials (PEM) cluster trial was designed to increase family physicians' guideline-recommended prescription of thiazide diuretics. The trial found no intervention effect. Using the theory of planned behaviour (TPB), we hypothesised that changes in thiazide prescribing would be reflected in changes in intention, consistent with changes in attitude and subjective norm, with no change to their perceived behavioural control (PBC), and tested this alongside the RCT. METHODS We developed and sent TPB postal questionnaires to a random sub-sample of family physicians in each trial arm 2 months before and 6 months after dissemination of the PEMs. We used analysis of covariance to test for group differences using a 2 × 3 factorial design. We content-analysed an open-ended question about perceived barriers to thiazide prescription. Using control group data, we tested whether baseline measures of TPB constructs predicted self-reported thiazide prescribing at follow-up. RESULTS Four hundred twenty-six physicians completed pre- and post-intervention questionnaires. Baseline scores on measures of TPB constructs were high: intention mean = 5.9 out of 7 (SD = 1.4), attitude mean = 5.8 (SD = 1.1), subjective norm mean = 5.8 (SD = 1.1) and PBC mean = 6.2 (SD = 1.0). The arms did not significantly differ post-intervention on any of the theory-based constructs, suggesting a possible ceiling effect. Content analysis of perceived barriers suggested post-intentional barriers to prescribing thiazides most often focused on specific patient clinical characteristics and potential side effects. Baseline intention (β = 0.63, p < 0.01) but not PBC (β = 0.04, p = 0.78) predicted 42.6 % of the variance in self-reported behaviour at follow-up in the control group. CONCLUSIONS Congruent with the Ontario Printed Educational Messages trial results and aligned with the TPB, we saw no impact of the intervention on any TPB constructs. The theoretical basis of this evaluation suggests possible explanations for the failure of the PEM intervention to change professional behaviour, which can directly inform the design and content of future theory-based PEM interventions to change professional behaviour. TRIAL REGISTRATION ISRCTN, Canada ISRCTN72772651.
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The Combined Effect of High Ambient Temperature and Antihypertensive Treatment on Renal Function in Hospitalized Elderly Patients.
Sagy, I, Vodonos, A, Novack, V, Rogachev, B, Haviv, YS, Barski, L
PloS one. 2016;(12):e0168504
Abstract
BACKGROUND The aging kidney manifests structural, functional as well as pharmacological changes, rendering elderly patients more susceptible to adverse environmental influences on their health, dehydration in particular. HYPOTHESIS Higher temperature is associated with renal function impairment in patients 65 years and older who routinely take thiazide and/or ACE-inhibitors/ARBs. METHODS We obtained health data of patients older than 65 who were admitted to a large tertiary center during the years 2006-2011, with a previous diagnosis of hypertension, and treated with thiazide, ACE-inhibitors/ARBs or both. We collected environmental data of daily temperature, available from collaborative public and governmental institutions. In order to estimate the effect of daily temperature on renal function we performed linear mixed models, separately for each treatment group and creatinine change during hospital admission. RESULTS We identified 26,286 admissions for 14, 268 patients with a mean age of 75.6 (±6.9) years, of whom 53.6% were men. Increment in daily temperature on admission of 5°C had significant effect on creatinine increase in the no treatment (baseline creatinine adjusted 0.824 mg/dL, % change 1.212, % change 95% C.I 0.082-2.354) and dual treatment groups (baseline creatinine adjusted 1.032mg/dL, % change 3.440, % change 95% C.I 1.227-5.700). Sub-analysis stratified by advanced age, chronic kidney disease and primary diagnosis on hospital admission, revealed a significant association within patients admitted due to acute infection and treated with dual therapy. CONCLUSION Whereas previous studies analyzed sporadic climate effects during heat waves and/or excluded older population taking anti-hypertensive medications, the present study is novel by showing a durable association of temperature and decreased renal function specifically in elderly patients taking anti-hypertensive medications.