Thiazide Users Research Articles

The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population.

Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2, and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. Prospective population-based cohort study (Rotterdam Study). General population. 2178 participants (65% female, age 64 ± 8 years). None. Serum sodium levels. Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each 2-fold higher PGE2 -0.19 mmol/L [95% confidence interval (CI) -0.31 to -0.06], PGEM -0.29 mmol/L (95% CI -0.41 to -0.17). This association was stronger in thiazide users (per 2-fold higher PGE2 -0.73 vs -0.12 mmol/L and PGEM -0.6 vs -0.25 mmol/L, P for interaction <.05 for both). A propensity score matching analysis of thiazide vs non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion, and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia specifically.

Abstract P107: High-throughput Screening Detects Thiazide-induced Prescribing Cascades.

Introduction: Thiazide diuretics are effective but can cause adverse effects that prompt the use of additional therapy, i.e., a prescribing cascade. We aimed to identify potential thiazide-induced prescribing cascades using high throughput sequence symmetry analysis. Methods: Using claims from 5% (2011-15) and 15% (2016-20) samples of Medicare fee-for-service beneficiaries we identified new thiazide users aged ≥66 years who had continuous enrollment for ≥360 days pre- and ≥180 days post-thiazide initiation. We screened for the initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within ±90 days of thiazide initiation, generating sequence ratios (SRs) representing the proportion of thiazide initiators starting the marker class after, compared to before, the thiazide. Adjusted SRs (aSRs), accounting for prescribing trends over time, were calculated with 95% CIs &gt;1 suggesting a prescribing cascade signal. Results: We identified unique 189,971 thiazide initiators (mean ± SD age 76.2 ± 7.4 years, 66% women, 90% with hypertension). Among 446 ‘marker’ classes analyzed, we identified 21 statistically significant prescribing cascade signals (Figure). The 2 strongest prescribing cascade signals were carbohydrates and electrolyte solutions. Conclusion: Among 446 classes, we identified 21 possible prescribing cascades in our Medicare population, which may impact patient care outcomes. Further investigation is required to determine the biological plausibility of these signals.

Association of Thiazide Diuretics With Diabetes Progression, Kidney Disease Progression, Cardiovascular Outcomes, and Death Among Patients With Diabetes Who Initiate Statins

Statins have been associated with diabetes mellitus (DM) progression but their cardiovascular benefit in patients with DM outweigh the harm. However, the effects of concurrent use of other medications that similarly increase blood glucose level, such as thiazide diuretics, are not well studied. This study aimed to evaluate the association of concurrent use of thiazide diuretics and statins on DM progression, cardiovascular and renal outcomes, and death in patients with DM. This is a retrospective cohort study of Veterans with DM who initiated statins between 2003 and 2015. The cohort comprised thiazide users (concomitantly used thiazides and statins for ≥6months) and active comparators (concomitantly used calciun channel blockers [CCB] but not thiazides and statins for ≥6months). We excluded patients who were <18 years old, with chronic kidney disease stage 4 or worse, or used loop diuretics. We propensity-score-matched comparison groups on 99 baseline characteristics including demographics, healthcare utilization, co-morbidities, cardiovascular and co-morbidity scores, vital signs, laboratory data, and medication class usage. Outcomes were: (1) DM progression (new insulin initiation, increase in the number of glucose-lowering medication classes, and hyperglycemic episodes); (2) kidney disease progression (doubling of serum creatinine, incidence of chronic kidney disease stage 5, initiation of renal replacement therapy, and incidence of diabetic nephropathy); (3) cardiovascular outcomes (acute myocardial infarction, stroke, cardiac arrest); and (4) total mortality. From 297,967 statin users (228,509 Thiazide-statin users and 69,458 active comparators), we successfully matched 67,614 pairs. In comparison to active comparators, thiazide-statin users had increased risk of DM progression (65.6% in CCB group vs 68.1% in thiazide group; odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.09 to 1.15), decreased risk of kidney progression (16.9% in CCB group vs 16.5 in thiazide group; OR: 0.97, 95% CI: 0.94 to 0.99), decreased risk of cardiovascular outcomes (15.7% in CCB group vs 14.6% in thiazide group; OR: 0.92, 95% CI: 0.89 to 0.95), and similar risk of total mortality (19.7% in each group; OR: 1.00, 95% CI: 0.98 to 1.03). This study attempted to answer an important clinical question whether thiazide diuretics should be discontinued or substituted upon statin initiation. Our results showed that concurrent use of statin and thiazides in patients with DM was associated with DM progression but with less kidney progression and cardiovascular outcomes and no difference in mortality. Clinicians should closely monitor DM control when thiazides and statins are used concurrently.

Association of Thiazide Use in Patients with Hypertension with Overall Fracture Risk: A Population-Based Cohort Study.

Thiazide diuretics have long been widely used as antihypertensive agents. In addition to reducing blood pressure, thiazides also control calcium homeostasis and increase bone density. We hypothesized that the use of thiazides in patients with hypertension would reduce overall fracture risk. We used the Taiwan National Health Insurance Research Database to find patients with a hypertension diagnosis who accepted antihypertensive treatment from 2000 to 2017. The patients were further classified into thiazide users and nonthiazide users. Multivariable Cox regression analysis and Kaplan–Meier survival analysis were performed to estimate the adjusted hazard ratios (aHRs) and cumulative probability of fractures. After 1:1 propensity score matching by sex, age, urbanization level of place of residence, income, comorbidities, and medications, there were 18,483 paired thiazide users and non-users, respectively. The incidence densities of fractures (per 1000 person-months) were 1.82 (95% CI: 1.76–1.89) and 1.99 (95% CI: 1.92–2.06) in the thiazide and nonthiazide groups, respectively. The results indicated a lower hazard ratio for fractures in thiazide users (aHR = 0.93, 95% CI: 0.88–0.98). Kaplan–Meier survival analysis revealed a significantly lower cumulative incidence of fractures in the thiazide group (log-rank test; p = 0.0012). In conclusion, our results reveal that thiazide use can reduce fracture risk. When antihypertensive agents are being considered, thiazide may be a better choice if the patient is at heightened risk of fracture.

Thiazide use and skeletal microstructure: Results from a multi-ethnic study

BackgroundThiazide diuretics, a commonly used class of anti-hypertensives, have been associated with increased areal bone mineral density (aBMD). Data regarding effects on fracture are conflicting and no information is available regarding effects on skeletal microstructure and mechanical competence. MethodsWe compared skeletal microstructure, volumetric BMD (vBMD), stiffness and prevalent fractures in current thiazide diuretic users and non-users from a population-based multiethnic cohort of elderly adults age ≥ 65 years (N = 599) with high resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis. ResultsFemale current thiazide diuretic users had higher weight and BMI and were more likely to be non-Caucasian compared to non-users. There were no differences in age, historical fractures or falls between female users and non-users. Female thiazide users tended to have lower calcium and vitamin d intake compared to non-users. After adjusting for age, weight, race and other covariates, 1/3-radius mean aBMD by dual energy x-ray absorptiometry (DXA) was 3.2% (p = 0.03) higher in female users vs. non-users. By HRpQCT, adjusted mean cortical vBMD was 2.4% (p = 0.03) higher at the radius in female users vs. non-users, but there was no difference in stiffness. DXA results were similar in the subset of Black females. There was no difference in any adjusted aBMD or cortical skeletal parameters by DXA or HRpQCT respectively in males. ConclusionsThiazide use was associated with a modestly higher aBMD at the predominantly cortical 1/3-radius site and radial cortical vBMD by HRpQCT in females. The effect on cortical bone may offer skeletal benefits in women taking thiazides for other indications such as hypertension, hypercalciuria or recurrent nephrolithiasis.

Risk of Electrolyte Disorders, Syncope, and Falls in Patients Taking Thiazide Diuretics: Results of a Cross-Sectional Study

BackgroundThiazide diuretics are a mainstay in the management of hypertension and often associated with dyselectrolytemias. We investigated the prevalence of and risk factors for hyponatremia and hypokalemia in thiazide users, substance-specific differences, and the association of thiazides with syncope and falls. MethodsIn this cross-sectional analysis all patients admitted to an interdisciplinary emergency department in Switzerland between January 1, 2017, and December 31, 2018, with measurements of serum sodium and potassium were included. Data regarding serum electrolytes and creatinine were analyzed to classify for dysnatremias, dyskalemias, and acute kidney injury. Chart reviews were performed to screen for syncope or falls. ResultsA total of 1604 patients (7.9%) took thiazides. Acute kidney injury was significantly more common in thiazide users (22.1 vs 7%, P < .0001). Hyponatremia (22.1 vs 9.8%, P < .0001) and hypokalemia (19 vs 11%, P < .0001) were more frequent with thiazides. Thiazide use together with higher age and female sex were independent predictors of hyponatremia and hypokalemia. A dose-dependent effect was found for electrolyte disorders, and there was a variance in risk between the investigated substances with chlorthalidone bearing the highest and hydrochlorothiazide the lowest risk. Patients taking thiazide diuretics had significantly more episodes of syncope and falls. ConclusionsThiazide use is a clear risk factor for hyponatremia and hypokalemia. The effect appears to be dose-dependent and highly variable depending on the substance. Syncope and falls seem to be causally related to thiazide use. Especially in patients who are elderly, female, and prone to falls, the use of thiazide diuretics should be thoroughly questioned.

Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease: an observational study

BackgroundIn autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin–angiotensin–aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions.MethodsWe analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death.ResultsA total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference −0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) −0.83 to –0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5–4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI −0.46 to –0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05–2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50–1.29), P = 0.4].ConclusionsThese data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Do Hyponatremia or Its Underlying Mechanisms Associate With Mortality Risk in Observational Data?

Whether unaccounted determinants of hyponatremia, rather than water excess per se, primarily associate with mortality in observational studies has not been explicitly examined. Retrospective cohort study of the association between hyponatremia and mortality, stratified by outpatient diuretic use in three strata. An inception cohort of 13,661 critically ill patients from a tertiary medical center. Admission serum sodium concentrations, obtained within 12 hours of admission to the ICU, were the primary exposure. Hyponatremia was associated with 1.82 (95% CI, 1.56-2.11; p < 0.001) higher odds of mortality, yet differed according to outpatient diuretic use (multiplicative interaction between thiazide and serum sodium < 133 mEq/L; p = 0.002). Although hyponatremia was associated with a three-fold higher (odds ratio, 3.11; 95% CI, 2.32-4.17; p < 0.001) odds of mortality among those prescribed loop diuretics, no increase of risk was observed among thiazide diuretic users (odds ratio, 0.87; 95% CI, 0.47-1.51; p = 0.63). When examined as a continuous variable, each one mEq/L higher serum sodium was associated with 8% (odds ratio, 0.92; 95% CI, 0.90-0.94; p < 0.001) lower odds of mortality in loop diuretic patients and 5% (odds ratio, 0.95; 95% CI, 0.93-0.96, p < 0.001) lower in diuretic naïve patients, but was not associated with mortality risk among thiazide users (odds ratio, 0.99; 95% CI, 0.95-1.02; p = 0.45). Hyponatremia is not uniformly associated with increased mortality, but differs according to diuretic exposure. Our results suggest that the underlying pathophysiologic factors that lead to water excess, rather water excess itself, account in part for the association between hyponatremia and poor outcomes. More accurate estimations about the association between hyponatremia and outcomes might influence clinical decision-making.

33Can anti-hypertensive thiazide diuretics also reduce fragility fracture risk?

Abstract Introduction A great deal of fractures are related to osteoporosis. Thiazide diuretics have been associated with reduced age-related bone loss, by decreasing urinary calcium excretion. On the other hand, they can also induce hyponatremia, which is a risk factor for fracture occurrence, potentially jeopardizing hypocalciuric protective effects. Recently, a secondary analysis of the ALLHAT trial found that chlorthalidone may reduce hip and pelvic fractures, when compared to lisinopril. Purpose To compare fracture outcomes of hypertensive thiazide users with those of hypertensive patients not treated with thiazides. Methods MEDLINE, EMBASE, Cochrane and SCOPUS databases were comprehensively searched, from inception to the first of February of 2019, for cohort studies mentioning thiazide diuretic usage and fracture rates. Literature search, study eligibility, including methodological quality assessment, and data extraction were independently conducted by two investigators. Meta-analysis was performed using generic inverse variance outcome and, due to heterogeneity of the original studies, a random effects model. Confounder-adjusted relative risk (RR) was pooled. Primary outcome was total fracture rate, whereas hip and women-specific fracture risk were regarded as secondary endpoints. Results Fourteen eligible studies were identified. Overall, 3,601,779 patients were included and 290,885 incidental fractures were recorded. Prototype patient was middle-aged to old and three studies only enrolled females. Clinical follow-up was documented at a median of five years. Thiazide diuretic users, as compared with non-users, had a significant 11% reduction in total fractures (RR=0.86, 95% confidence interval [CI]=0.82–0.97, p=0.008, i2=77%). Seven studies, encompassing 553,614 patients and 5,005 cases, allowed for estimation of hip fracture risk, with thiazides demonstrating an even larger effect (RR=0.78, 95% CI=0.68–0.89, p=0.0004, i2=45%). Likewise, four studies, incorporating 149,024 patients and 150.998 cases, were able to provide insight into women fracture risk, in whom thiazides seem to exert no significant protective effect (RR=1.00, 95% CI=0.78–1.27, p=0.98, i2=77%). Conclusion Thiazide diuretics may convey a decreased risk of fracture, particularly in the potentially lethal hip location. This protective secondary effect of thiazides should be considered in hypertension clinic, with osteoporotic men seeming the best candidates for this therapy.

P1589Thiazides and skin cancer risk: should we be worried?

Abstract Introduction Diuretic thiazides represent a first-line therapeutic option for arterial hypertension. However, this drug class is regarded as having photosensitizing properties, and, as such, may act as a carcinogen, by triggering phototoxic reactions. Whether or not its long-term use increases skin malignancy risk remains unclear. Purpose To examine a possible association between thiazide usage and the risk of skin cancer, namely basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Methods MEDLINE, EMBASE, Cochrane Library and Google Scholar databases were comprehensively searched, from inception to the first of February of 2019, for observational studies mentioning thiazide diuretic usage and incidence or prevalence of cutaneous basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Literature review, study selection and appraisal, including methodological quality assessment, and data extraction were independently led by two investigators. Meta-analysis was conducted using generic inverse variance outcome and, due to heterogeneity of the original studies, a random effects model. Confounder-adjusted summary relative risk (RR), with 95% confidence interval (CI), was pooled. Results Ten studies met eligibility criteria. Of these, six had a case-control design and the remaining were cohort studies. Overall, 7,079,530 patients were included; 125,946 were diagnosed with basal cell carcinoma, 21,775 with squamous cell carcinoma and 31,191 with malignant melanoma. One study encompassed only squamous cell carcinoma of the lip. In five articles, individual thiazides employed were not addressed, whereas three embraced solely hydrochlorothiazide and other two exclusively bendroflumethiazide. Thiazides were found to be associated with increased risk of basal cell carcinoma (six studies, RR=1.05, 95% CI=1.01–1.10, p=0.02, i2=62%), squamous cell carcinoma (seven studies, RR=1.35, 95% CI=1.05–1.74, p=0.02, i2=92%) and malignant melanoma (six studies, RR=1.17, 95% CI 1.11–1.23, p&lt;0.ehz748.03491, i2=0%). Conclusion Risk of all three major forms of skin malignancy is heightened in thiazide diuretic users. Increased awareness and education, especially for those who are at high risk and under the form of intense solar irradiation avoidance, are warranted for both patients and healthcare providers.

Association between diuretic use and the risk of vertebral fracture after stroke: a population-based retrospective cohort study

BackgroundStroke is a major risk factor for osteoporosis and fractures. No study has evaluated the association between diuretic use and risk of vertebral fracture in stroke patients, although a considerable proportion of stroke patients are prescribed diuretics for hypertension. Our study aimed to investigate whether treatment with thiazides or loop diuretics affects the risk of vertebral fracture after stroke.MethodsA population-based propensity score-matched retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database. Patients with a new diagnosis of stroke between 2000 and 2011 were included. After propensity score matching, 9468 patients were included in the analysis of the effect of thiazides, of who 4734 received thiazides within 2 years after stroke. To analyze the loop diuretic effect, 4728 patients were included, of who 2364 received loop diuretics. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) of vertebral fractures among patients according to thiazide or loop diuretic use within 2 years following stroke. Sensitivity analyses based on the duration of thiazide or loop diuretic use were further conducted.ResultsThere was no significant difference in vertebral fracture risk between thiazide users and non-users (adjusted HR [aHR] = 1.14, 95% confidence interval [CI] = 0.88–1.47, p = 0.316). Loop diuretic users had a significantly higher vertebral fracture risk than non-users (aHR = 1.45, 95% CI = 1.06–1.98, p = 0.019). However, the sensitivity analysis revealed that short-term thiazide use (exposure duration < 90 days within 2 years after stroke) significantly increased the risk of vertebral fracture versus non-use (aHR = 1.38, 95% CI = 1.02–1.88, p = 0.039). Only short-term loop diuretic users had significantly higher risk of vertebral fracture (aHR = 1.56, 95% CI = 1.11–2.20, p = 0.011). The other two subgroups with longer exposure duration in analyses for both thiazides and loop diuretics revealed no significant effect.ConclusionsShort-term thiazide or loop diuretic use was associated with an increased risk of vertebral fracture after stroke. Further prospective clinical trials are required to confirm this finding.

Thiazide-associated hyponatremia attenuates the fracture-protective effect of thiazide: A population-based study.

BackgroundThiazide, a first-line therapy for hypertension, lowers blood pressure, increases bone mineral density, and reduces the risk of fractures. However, hyponatremia, an adverse effect of thiazide, is associated with increased risk of osteoporosis and fractures. It is currently unclear whether thiazide-associated hyponatremia (TAH) outweighs the protective effects of thiazide.MethodsUsing data from Taiwan’s National Health Insurance Research Database, we identified patients who were prescribed thiazide between 1998 and 2010. Those diagnosed with hyponatremia within three years after initiation of thiazide were selected for the TAH group. Thiazide users without hyponatremia were selected for the control group. The association between TAH and fracture risk was further evaluated using multivariable Cox regression models adjusted for comorbidities and medications. Subjects were followed up from the index date until the appearance of a fracture, death, or the end of a 3-year period.ResultsA total of 1212 patients were included in the TAH group, matched with 4848 patients in the control group. The incidence rate of fracture was higher in the TAH group than in the control group (31.4 versus 20.6 per 1000 person-years). TAH was associated with a higher risk of total fractures (adjusted hazard ratio [aHR]: 1.47, 95% confidence interval [CI] = 1.15–1.88), vertebra fractures (aHR: 1.84, 95% CI = 1.12–3.01), and hip fractures (aHR: 1.66, 95% CI = 1.12–2.46) after controlling for comorbidities and other medications.ConclusionsThiazide users with hyponatremia have a higher risk of fracture than thiazide users without hyponatremia. The fracture-protective effect of thiazide is attenuated by TAH.

Abstract TP185: Diuretic Use and the Risk of Vertebral Fracture After Stroke: A Population-based Cohort Study

Introduction: Stroke is a major risk factor for vertebral fracture. Hypertension is a very common comorbidity observed in stroke patients, and diuretics have been widely used for the treatment of hypertension. Our study investigated whether treatment with thiazides or loop diuretics affects the risk of vertebral fracture after stroke. Methods: A population-based propensity-matched cohort study was conducted using the Taiwan National Health Insurance Research Database. Patients with a new diagnosis of stroke between 2000 and 2011 were included. After propensity score matching, 9468 patients were included in the analysis of the effect of thiazides, of who 4734 received thiazides within 2 years after stroke. To analyze the loop diuretic effect, 4728 patients were included, of who 2364 received loop diuretics. A Cox proportional hazards regression model was used to calculate the hazard ratios (HRs) of vertebral fractures among patients according to thiazide or loop diuretic use within 2 years following stroke. Sensitivity analyses based on the duration of thiazide or loop diuretic use were further conducted. Results: There was no significant difference in vertebral fracture risk between thiazide users and non-users (adjusted HR [aHR] = 1.14, 95% confidence interval [CI] = 0.88–1.47, p = 0.316). Loop diuretic users had a significantly higher vertebral fracture risk than non-users (aHR = 1.45, 95% CI = 1.06–1.98, p = 0.019). However, the sensitivity analysis revealed that short-term thiazide use (exposure duration &lt;90 days within 2 years after stroke) significantly increased the risk of vertebral fracture versus non-use (aHR = 1.38, 95% CI = 1.02–1.88, p = 0.039). Only short-term loop diuretic users had significantly higher risk of vertebral fracture (aHR = 1.56, 95% CI = 1.11–2.20, p = 0.011). The other two subgroups with longer exposure duration in analyses for both thiazides and loop diuretics revealed no significant effect. Conclusions: Short-term thiazide or loop diuretic use was associated with an increased risk of vertebral fracture after stroke. We believe that physicians should be aware of this potential association.

Bone mineral density changes among women initiating blood pressure lowering drugs: a SWAN cohort study.

We examined the effect of blood pressure lowering drugs on BMD using data from the Study of Women's Health Across the Nation. Thiazide users had a slower decline in BMD compared to nonusers, while decline among ACE inhibitor and beta blocker users were similar to rates in nonusers. Several blood pressure lowering drugs may affect bone mineral density (BMD), leading to altered fracture risk. We examined the effect of blood pressure lowering drugs on BMD using data from the Study of Women's Health Across the Nation. We conducted a propensity score matched cohort study. Women were initiators of ACE inhibitors (ACEi), beta-blockers (BB), or thiazide diuretics (THZD). Their annualized BMD changes during the 14 years of observation were compared with nonusers. Among the 2312 eligible women, we found 69 ACEi, 71 BB, and 74 THZD users who were matched by a propensity score with the same number of nonusers. THZD users had a slower annual percent decline in BMD compared to nonusers at the femoral neck (FN) (-0.28% vs -0.88%; p = 0.008) and the spine (-0.74% vs -1.0%; p = 0.34), albeit not statistically significant. Annual percent changes in BMD among ACEi and BB users were similar to rates in nonusers. In comparison with BB, THZD use was associated with a trend toward less annualized BMD loss at the spine (-0.35% vs -0.60%; p = 0.08) and a similar trend at the FN (-0.39% vs -0.64%; p = 0.08); in comparisons with ACEi, THZD was also associated with less loss at the FN (-0.48% vs -0.82%; p = 0.02), but not at the spine (-0.40% vs -0.56%; p = 0.23). Neither ACEi nor BB was associated with improvements in BMD. THZD use was associated with less annualized loss of BMD compared with nonusers, as well as compared with ACEi and BB.

Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk.

Data from observational studies have suggested that thiazide diuretics protect against fractures. Few studies have investigated time frames from initiation of treatment to fracture occurrence. To evaluate the time to spinal, hip, femur, wrist and upper extremity fracture occurrence before and after thiazide exposure. A matched retrospective cohort study of patient information from national Danish patient databases was conducted. Patients with reimbursed prescriptions for noncompounded thiazide diuretics with potassium supplementation (Anatomical Therapeutic Chemical classification system code C03AB) between 1996 and 2011 were matched with nonexposed control subjects by date of birth and gender. Weekly odds ratios (ORs) of fracture occurrence and total incidence rates (IRs) and incidence rate ratios (IRRs) of fracture risk were calculated for the periods before treatment initiation, weeks 1-42 and weeks 43-780. A total of 1,602,141 'thiazide exposure periods' (46,8271 individuals) and 1,530,233 'nonexposure periods' (655,399 individuals) were included in the analysis. Thiazide use was associated with factors of increased de novo fracture risk. Weekly adjusted fracture risk between exposure and nonexposure was increased prior to commencing thiazide therapy, further increasing from weeks 1-42 weeks and then decreasing gradually from weeks 43-780. There was a decreasing trend in total age-adjusted risk during these periods: IRR [95% confidence interval 1.44 [1.42; 1.47], 1.27 [1.24; 1.29] and 1.14 [1.11; 1.18], respectively. Prescription patterns showed several treatment breaks amongst thiazide users. It appears that thiazides reduce the background risk of fracture that is increased prior to commencing therapy. Long duration and continuity of thiazide exposure seems to be important to obtain this protective effect on fracture risk, but we have found in this study that this approach is not always used in clinical practice.

The incidence of cancer deaths among hypertensive patients in a large Chinese population: A cohort study

Current evidence is mixed regarding the association between antihypertensive prescriptions and cancer mortality. We evaluated this association in a large Chinese hypertensive population.We followed for five years all patients who were prescribed their first-ever antihypertensive agents between 2001 and 2005 in a public healthcare sector of Hong Kong. The association between antihypertensive drug class and cancer mortality was evaluated by Cox proportional hazard models with propensity score matching. Age, gender, socioeconomic status, service settings, district of residence, proportion of days covered reflecting medication adherence, and the number of comorbidities were adjusted.From 217,910 eligible patients, 9500 (4.4%) died from cancer within five years after their first-ever antihypertensive prescription. Most cancer deaths occurred in the digestive (38.9%) and respiratory system (30.4%); the breast (6.2%); and the lympho-hematopoietic tissues (5.3%). The proportion of patients who died from cancer was the highest in the calcium channel blocker (CCB) group (6.5%), followed by thiazide diuretics (4.4%), angiotensin converting enzyme inhibitors (4.2%) and β-blockers (2.6%). When compared with β-blockers, patients prescribed CCBs (Adjusted Hazard Ratio [AHR]=1.406, 95% C.I. 1.334–1.482, p<0.001) were more likely to die from cancer. Thiazide users were also more likely to suffer from cancer deaths (AHR=1.364, 95% C.I. 1.255–1.483, p<0.001), but became insignificant in stratified analysis.The association between cancer mortality and use of CCB, and perhaps thaizide, may alert physicians to the need for more meticulous and comprehensive care of these patients in clinical practice. We recommend prospective studies to evaluate cause-and-effect relationships of these associations.

Thiazides and the risk of hypokalemia in the general population.

Hypokalemia is a frequent adverse reaction to thiazide diuretics, but is often asymptomatic. However, even asymptomatic hypokalemia may contribute to chronic disabilities and mortality. The aim of this study was to assess the risk of thiazide-induced hypokalemia in men and women in the general population. Within the Rotterdam study, which is a population-based cohort study, the association between thiazide exposure and hypokalemia (serum potassium level <3.5 mmol/l; moderate to severe ≤3.0 mmol/l) was studied using Cox proportional-hazard regression analysis over a 10-year period, with thiazide use as a time-varying exposure. During follow-up, 507 cases of hypokalemia occurred in 13, 328 patients. Thiazide use was associated with an 11 times higher risk of hypokalemia than no use [relative risk (RR) 11.18, 95% confidence interval (CI) 8.95, 13.96] after adjustment for sex, age, and use of a renin-angiotensin system (RAS) inhibitor or separate potassium-sparing diuretic. In users of a thiazide in combination with triamterene, the risk was still six times higher (RR 5.93, 95% CI 4.65, 7.55) than in nonusers. The risk of thiazide-induced hypokalemia was significantly higher in men than in women and changed significantly with age and dosage. The risk of moderate to severe hypokalemia was almost five times higher in thiazide users (RR 4.80, 95% CI 2.61, 8.84) than in nonusers. The risk of thiazide-induced hypokalemia is high, and more than twice as high in men as in women. Hypokalemia risk is influenced by age and dosage, and is still increased if used in combination with triamterene.

Hypertensive Patients Using Thiazide Diuretics as Primary Stroke Prevention Make Better Functional Outcome after Ischemic Stroke

Thiazides have been used for the control of blood pressure and primary prevention of ischemic stroke. No previous studies have assessed the influence of thiazides on functional prognosis after ischemic stroke. Demographics, prestroke conditions, poststroke National Institutes of Health Stroke Scale score, and clinical and laboratory parameters were prospectively registered in 216 Taiwanese patients. One hundred forty patients who completed follow-up 3 months after experiencing ischemic stroke were assessed with the modified Rankin scale as functional prognoses. Twenty-one patients used thiazide to control hypertension before experiencing ischemic stroke. No differences of stroke subtypes and comorbidities before stroke were observed between the 2 groups. The emergency department National Institutes of Health Stroke Scale was lesser among thiazide users (4 [2-7] versus 6 [4-16], P = .02). Among 140 patients who completed follow-up in 90 days, thiazide users had more favorable functional status (modified Rankin scale ≤2: 42.4% versus 26.9%, P = .02, odds ratio 3.34, 95%, confidence interval .130-.862). Hypertensive patients treated with thiazides long term had a lesser severity of stroke and better functional outcomes after ischemic stroke.

Risk of thiazide-induced metabolic adverse events in older adults.

To evaluate the risk and predictors of thiazide-induced adverse events (AEs) in multimorbid older adults in real-world clinical settings. Observational cohort study. National Veterans Affairs data from 2007 to 2008. Veterans aged 65 and older newly prescribed a thiazide (N = 1,060) compared with propensity-matched nonusers of antihypertensive medications (N = 1,060). The primary outcome was a composite of metabolic AEs defined as sodium less than 135 mEq/L, potassium less than 3.5 mEq/L, or a decrease in the estimated glomerular filtration rate (eGFR) of more than 25% from the baseline rate. Secondary outcomes included sev-ere AEs (sodium <130 mEq/L, potassium <3.0 mEq/L, or a decrease in eGFR of more than 50%). Over 9 months of follow-up, 14.3% of new thiazide users developed an AE, compared with 6.0% of nonusers (number needed to harm (NNH) 12, 95% confidence interval (CI) = 9-17, P < .001); 1.8% of new users developed a severe AE, compared with 0.6% of nonusers (NNH = 82, P = .008), and 3.8% of new users had an emergency department visit or hospitalization with an AE, compared with 2.0% of nonusers (NNH = 56, P = .02). Risk of AEs did not vary according to age, but having five or more comorbidities was associated with 3.0 times the odds (95% CI = 1.4-6.2) of developing an AE as having one comorbidity (hypertension). Low-normal and unmeasured baseline sodium and potassium values were among the strongest predictors of hyponatremia and hypokalemia, respectively. Only 42% of thiazide users had laboratory monitoring within 90 days after initiation. Thiazide-induced AEs are common in older adults. Greater attention should be paid to potential complications in prescribing thiazides to older adults, including closer laboratory monitoring before and after initiation of thiazides.

Sex differences in bone mineral density of the STE20/SPS1‐related proline/alanine‐rich kinase (SPAK) targeted hypotensive mouse model of Gitelman syndrome (1083.4)

Increased bone mineral density (BMD), hypocalciuria and hypophosphatemia have been reported in hypertensive patients with chronic thiazide treatment and in Gitelman syndrome; a salt-wasting hypotensive disease caused by reduced renal thiazide-sensitive Na+-Cl- cotransporter (NCC) activity. SPAK phosphorylates NCC increasing activity and our SPAK T243A loss-of-function knock-in (SPAK-KI) mice recapitulate the human Gitelman syndrome by reducing phospho-NCC. We hypothesised that SPAK-KI mice would have increased BMD. Earlier work in our lab showed hypophosphatemia is specific to male SPAK-KI (Table 1). Therefore, our aim was to investigate potential sex differences in BMD. Whole body (excluding skull) areal BMD of age matched SPAK-KI and wildtype (WT) littermates were measured by dual energy x-ray absorptiometry in vivo. In a subset of mice, tibiae were excised and the mid- and proximal-shafts used as markers of cortical and trabecular bone, respectively. Compared to WT males (n=11), SPAK-KI (n=11) had significantly higher whole body [3.7%] and cortical BMDs [11.9%] (p<0.05), but trabecular BMD [7.9%] was not significant. No significant BMD differences were found between WT (n=12) and SPAK-KI (n=10) females (Fig 1). In conclusion, only SPAK-KI males have increased BMD with hypophosphatemia. We postulate this could be a compensatory response to hypocalciuria, maintaining the Ca2+ X PO43- product to prevent calciphylaxis. In light of these results, the implications of sex differences should be investigated in Gitelman syndrome and chronic thiazide users. Table 1. Plasma PO43- (mMol/L) WT SPAK-KI Male 2.19 ± 0.06(n=16) 2.02 ± 0.04*(n=10) Female 2.00 ± 0.07(n=9) 2.06 ± 0.15(n=13) Data are mean ± SEM. * P<0.05 Grant Funding Source: Supported by the British Heart Foundation