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Do Thiazide Diuretics Increase the Risk of Skin Cancer? A Critical Review of the Scientific Evidence and Updated Meta-Analysis.
Bendinelli, B, Masala, G, Garamella, G, Palli, D, Caini, S
Current cardiology reports. 2019;(9):92
Abstract
PURPOSE OF REVIEW We reviewed the hypothesised mechanisms of skin cancerogenesis for thiazide diuretics; conducted an updated meta-analysis of studies focusing on their association with skin cancer risk; critically appraised the quality of available studies and identified knowledge gaps; and discussed implications for health professionals and patients. RECENT FINDINGS Thiazide diuretics possess well-described photosensitizing properties and a causal association with skin cancer is biologically plausible. The epidemiological evidence is stronger for squamous cell cancer; however, diversity in design among studies, methodological concerns potentially affecting the validity of results, and scarcity of data on dose-relation relationship suggest caution in drawing conclusions. Only few, unbalanced, and/or heterogeneous data exist to date for melanoma and basal cell cancer. Patients effectively treated with thiazide diuretics are currently not advised to stop treatment, but encouraged to limit exposure to sunlight and regularly check their skin. While endorsing these recommendations, we believe that well-designed studies are urgently needed to overcome persistent knowledge gaps.
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Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.
Irvin, MR, Sitlani, CM, Noordam, R, Avery, CL, Bis, JC, Floyd, JS, Li, J, Limdi, NA, Srinivasasainagendra, V, Stewart, J, et al
The pharmacogenomics journal. 2019;(1):97-108
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Abstract
We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
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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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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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Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.
Olde Engberink, RH, Frenkel, WJ, van den Bogaard, B, Brewster, LM, Vogt, L, van den Born, BJ
Hypertension (Dallas, Tex. : 1979). 2015;(5):1033-40
Abstract
Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide-like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had ≥1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes (P<0.001). Corrected for differences in office blood pressure reductions among trials, TL diuretics resulted in a 12% additional risk reduction for cardiovascular events (P=0.049) and a 21% additional risk reduction for heart failure (P=0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension.
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Thiazide diuretics and the risk of hip fracture.
Aung, K, Htay, T
The Cochrane database of systematic reviews. 2011;(10):CD005185
Abstract
BACKGROUND Thiazide diuretics are one of the most commonly prescribed antihypertensive agents worldwide. Thiazides reduce urinary calcium excretion. Chronic ingestion of thiazides is associated with higher bone mineral density. It has been suggested that thiazides may prevent hip fracture. However, there are concerns that diuretics, by increasing the risk of fall in elderly, could potentially negate its beneficial effects on hip fracture. OBJECTIVES To assess any association between the use of thiazide diuretics and the risk of hip fracture in adults. SEARCH STRATEGY We searched eligible studies up to December 2008 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), International Pharmaceutical Abstracts, the Database of Abstracts of Review of Effects (DARE) and reference lists of previous reviews and included studies. SELECTION CRITERIA All randomized controlled trials and observational studies, which assessed the association between thiazide diuretic use and hip fracture. DATA COLLECTION AND ANALYSIS Two review authors independently applied the selection criteria, extracted data and assessed risk of bias of each study selected. The results were summarized descriptively and quantitatively. Cohort studies and case control studies were analysed separately. MAIN RESULTS No randomized control trials were found. Twenty-one observational studies with nearly four hundred thousand participants were included. Six of them were cohort studies and 15 were case-control studies. Two cohort studies appear to involve the same cohort so there were only 5 unique ones. The risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). Five cohort studies had low risk of bias and one had moderate risk of bias. Seven case control studies had low risk of bias and 8 had moderate risk of bias. Meta-analysis of cohort studies showed that thiazide use was associated with a reduction in risk of hip fracture by 24%, pooled RR 0.76 (95% CI 0.64-0.89; p = 0.0009). We chose not to provide a pooled summary statistics for case-control studies because of high heterogeneity (Tau(2) = 0.03, I(2) = 62%, p = 0.0008). AUTHORS' CONCLUSIONS Thiazides appear to reduce the risk of hip fracture based on observational studies. Randomized controlled trials are needed to confirm these findings.
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Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension.
Chen, JM, Heran, BS, Wright, JM
The Cochrane database of systematic reviews. 2009;(4):CD007187
Abstract
BACKGROUND Diuretics are widely prescribed for hypertension not only as a first-line drug but also as a second-line drug. Therefore, it is essential to determine the effects of diuretics on blood pressure (BP), heart rate and withdrawals due to adverse effects (WDAEs) when given as a second-line drug. OBJECTIVES To quantify the additional reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of diuretic therapy as a second-line drug in patients with primary hypertension SEARCH STRATEGY CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE (1966-July 2008), EMBASE (1988-July 2008) and bibliographic citations of articles and reviews were searched. SELECTION CRITERIA Double-blind, randomized, controlled trials evaluating the BP lowering efficacy of a diuretic in combination therapy with another class of anti-hypertensive drugs compared with the respective monotherapy (without a diuretic) for a duration of 3 to 12 weeks in patients with primary hypertension. DATA COLLECTION AND ANALYSIS Two review authors independently extracted the data and assessed trial quality. MAIN RESULTS Fifty-three double-blind RCTs evaluating a thiazide in 15129 hypertensive patients (baseline BP of 156/101 mmHg) were included. Hydrochlorothiazide was the thiazide used in 49/53 (92%) of the included studies. The additional BP reduction caused by the thiazide as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. Thiazides as a second-line drug reduced BP by 6/3 and 8/4 mmHg at doses of 1 and 2 times the manufacturer's recommended starting dose respectively. The BP lowering effect was dose related. The effect was similar to that obtained when thiazides are used as a single agent. Only 3 double-blind RCTs evaluating loop diuretics were identified. These RCTs showed a BP lowering effect of a starting dose of about 6/3 mmHg. AUTHORS' CONCLUSIONS Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug. This means that the BP lowering effect of thiazides is additive. Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose. Because of the short duration of the trials and lack of reporting of adverse events, this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug.