Thiazide Diuretic-Induced Change in Fasting Plasma Glucose: a Meta-analysis of Randomized Clinical Trials.

BACKGROUND: Prior meta-analyses measuring thiazide-induced glycemic change have demonstrated an increased risk of incident diabetes; however, this measure's definition has changed over time. AIM: To determine the magnitude of change in fasting plasma glucose (FPG) for thiazide diuretics. DATA SOURCES: A research librarian designed and conducted searches in Medline®, EMBASE, and EBM Reviews-Cochrane Central Register of Controlled Trials (inception through July 2018) and International Pharmaceutical Abstracts (inception to December 2014). STUDY SELECTION: Randomized, controlled trials comparing a thiazide or thiazide-like diuretic to any comparator reporting FPG were identified. Trials enrolling < 50 participants, those with a follow-up period of < 4 weeks, and conference abstracts were excluded. DATA EXTRACTION: Independent duplicate screening of citations and full-text articles, data extraction, and assessment of risk of bias was conducted. DATA SYNTHESIS: Ninety-five studies were included (N = 76,608 participants), with thiazides compared with placebo, beta-blockers, calcium channel blockers, renin-angiotensin-aldosterone-system inhibitors, potassium-sparing diuretic, and others alone or in combination. Thiazide diuretics marginally increased FPG (weighted mean difference 0.20 mmol/L (95% CI 0.15-0.25); I2 = 84%) (1 mmol/L = 18 mg/dL). Results did not change substantially when considering dose or duration, comparing thiazides with placebo or an active comparator, or using thiazides as monotherapy or combination therapy, even when combined with a potassium-correcting agent. CONCLUSION: Thiazide diuretics have a small and clinically unimportant impact on FPG.

KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline.

Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality and reduction of elevated blood pressure (BP) remains an important intervention for slowing kidney disease progression. Over the past decade, the most appropriate BP target for initiation and titration of BP-lowering medications has been an area of intense research and debate within the clinical community. In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) in conjunction with several other professional societies released new hypertension guidelines based on data from a systematic review of clinical trials and observational data. While many of the recommendations in the ACC/AHA hypertension guideline are relevant to nephrology practice, BP targets and management strategies for patients receiving dialysis are not discussed. This Kidney Disease Outcomes Quality Initiative (KDOQI) commentary focuses largely on recommendations from the ACC/AHA hypertension guidelines that are pertinent to individuals at risk of chronic kidney disease or with non-dialysis-dependent chronic kidney disease. This KDOQI commentary also includes a brief discussion of the consensus statement regarding hypertension diagnosis and management for adults receiving maintenance dialysis published by the European Renal and Cardiovascular Medicine Working Group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension. Overall, we support the vast majority of the ACC/AHA recommendations and highlight select areas in which best diagnosis and treatment options remain controversial.

Joint Clinical Consensus Statement of the American College of Foot and Ankle Surgeons® and the American Association of Nurse Practitioners®: Etiology, Diagnosis, and Treatment Consensus for Gouty Arthritis of the Foot and Ankle.

Gout is a condition that commonly affects the foot and ankle, and practitioners who treat these structures should be aware of the methods to diagnose and treat this form of arthritis. Practitioners also need to recognize extra-articular manifestations of the disease. Although the acutely red, hot, swollen joint is a common presentation, chronic tophaceous gout can be associated with pain, nodule formation, and cutaneous compromise. Since the underlying causes that lead to excessive monosodium urate deposition may be treatable, early and accurate diagnosis can be very beneficial and may even prevent articular degeneration.

The Impact of Antihypertensive Medications on Bone Mineral Density and Fracture Risk.

PURPOSE OF REVIEW: This review summarizes the impact of thiazide diuretics on fracture risk in older hypertensive individuals. RECENT FINDINGS: We performed a post hoc evaluation of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a randomized, prospective, double blind hypertension study comparing a thiazide-like diuretic, a calcium channel blocker (CCB), and an angiotensin converting enzyme inhibitor (ACEi). We examined the risk of hip and pelvic fractures during the in-trial period (n = 22,180 participants; mean 4.9-year follow-up) and during the post-trial period using national data bases (n = 16,622 participants) (mean total follow-up 7.8 years). During the trial, participants randomized to the thiazide diuretic versus the CCB or the ACEi had a lower risk of fracture on adjusted analyses (HR 0.79 [95% CI, 0.63, 0.98], p = 0.04). Risk of fracture was significantly lower in participants randomized to the diuretic as compared to those randomized to the ACEi (HR 0.75 [95% CI, 0.58, 0.98]; p = 0.04), but not significantly different compared to the CCB (HR 0.87 [95% CI, 0.71, 1.09]; p = 0.17). Over the entire trial and post-trial period of follow-up, the cumulative incidence of fractures was non-significantly lower in participants assigned to the diuretic vs assignment to the ACEi or the CCB (HR 0.87 [0.74-1.03], p = 0.10) and versus each medication separately. These findings establish a benefit for thiazide diuretic treatment for the prevention of fractures versus other commonly used antihypertensive medications using prospective, randomized data. The effects of the thiazide diuretic on bone appear to be long lasting.

Diuretics in the treatment of hypertension.

Diuretics have long been used for the treatment of hypertension. Thiazide diuretics are the most commonly prescribed diuretics for hypertension, but other classes of diuretics may be useful in alternative circumstances. Although diuretics are no longer considered the preferred agent for treatment of hypertension in adults and children, they remain acceptable first-line options. Diuretics effectively decrease blood pressure in hypertensive patients, and in adults with hypertension reduce the risk of adverse cardiovascular outcomes. Because of varied pharmacokinetic and pharmacodynamic differences, chlorthalidone may be the preferred thiazide diuretic in the treatment of primary hypertension. Other types of diuretics (e.g., loop, potassium sparing) may be useful for the treatment of hypertension related to chronic kidney disease (CKD) and other varied conditions. Common side effects of thiazides are mostly dose-related and involve electrolyte and metabolic abnormalities.

Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in Renin-Angiotensin System (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) study.

OBJECTIVE: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). METHODS: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. RESULTS: Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). CONCLUSIONS: The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

Antihypertensive Use and the Risk of Cataract in Patients with Hypertension: A Nationwide Case-control Study.

PURPOSE: This study aims to investigate the association between antihypertensive use and the risk of cataract in a matched case-control study. METHODS: We analysed the Korean National Health Insurance Service-Health Screening Cohort database from 2002 to 2013. We defined 'cases' as patients prescribed antihypertensives and underwent their first eye cataract surgery between 2010 and 2013. 'Controls' were patients prescribed antihypertensives and no history of cataract surgery or diagnosis between 2002 and 2013. Four controls were matched to each case by several variables. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for cataract risk using a conditional logistic regression model after adjustment. RESULTS: The analyses comprised 12,166 cases and 48,664 controls. The adjusted ORs for cataracts were 1.18 (95% CI: 1.12-1.24) in thiazide diuretics, 1.12 (95% CI: 1.07-1.18) in beta-blockers, 0.94 (95% CI: 0.90-1.00) in calcium channel blockers, 1.22 (95% CI: 1.14-1.30) in angiotensin-converting enzyme (ACE) inhibitors, and 0.97 (95% CI: 0.91-1.03) in angiotensin II receptor blockers compared to 'non-use' of each antihypertensive. CONCLUSION: In a nationwide case-control study, the use of thiazide diuretics, beta-blockers, or ACE inhibitors do not represent minimal clinical important difference in the risk of cataract and the use of calcium channel blockers or angiotensin II receptor blockers is not associated with an increased risk of cataracts compared to non-use of each antihypertensive. Given the benefits of treating hypertension, such as the reduction in further complications, we suggest there is no need to change current clinical practice for antihypertensives.

Thiazide and the Thiazide-Like Diuretics: Review of Hydrochlorothiazide, Chlorthalidone, and Indapamide.

The term thiazide is universally understood to refer to diuretics that exert their principal action in the distal tubule. The thiazide class is heterogenous and can be further subdivided into compounds containing the benzothiadiazine ring structure-the thiazide-type (e.g., hydrochlorothiazide)-and those lacking the benzothiadiazine ring-the thiazide-like (e.g., chlorthalidone and indapamide) drugs. Thiazide-like agents are longer acting and constitute the diuretics used in most of the cardiovascular outcome trials that established benefits of treatment with diuretics, but pragmatic aspects, such as lack of availability in convenient formulations, limit their use. Regardless of class heterogeneity, thiazides have retained importance in the management of hypertension for over 60 years. They are reliably effective as monotherapy in a majority of hypertensive patients, and augment the efficacy of other classes of antihypertensives when used in combination. Importantly, a thiazide-based treatment regimen lowers cardiovascular events, and their sturdy effect reinforces their place among the recommended first-line agents to treat hypertension in major domestic and international hypertension guidelines. There are few head-to-head comparisons within the class, but potential differences have been explored indirectly as well as in non-blood pressure mechanisms and potential pleiotropic properties. Until proven otherwise, the importance of these differences remains speculative, and clinicians should assume that cardiovascular events will be lowered similarly across agents when equivalent blood pressure reduction occurs. Thiazides remain underutilized, with only about one-third of hypertensive patients receiving them. For many patients, however, a thiazide is an indispensable component of their regimen to achieve adequate blood pressure control.

Intensification of pharmacological decongestion but not the actual daily loop diuretic dose predicts worse chronic heart failure outcome: insights from TIME-CHF.

BACKGROUND: Both loop diuretics (LDs) and congestion have been related to worse heart failure (HF) outcome. The relationship between the cause and effect is unknown. The aim of this study was to investigate the interaction between congestion, diuretic use and HF outcome. METHODS: Six hundred and twenty-two chronic HF patients from TIME-CHF were studied. Congestion was measured by means of a clinical congestion index (CCI). Loop diuretic dose was considered at baseline and month 6. Treatment intensification was defined as the increase in LD dose over 6 months or loop diuretic and thiazide or thiazide-like diuretic co-administration. The end-points were survival and HF hospitalisation-free survival. RESULTS: High-LD dose at baseline and month 6 (≥ 80 mg of furosemide per day) was not identified as an independent predictor of outcome. CCI at baseline remained independently associated with impaired survival [hazard ratio (HR) 1.34, (95% confidence interval) (95% CI) (1.20-1.50), p < 0.001] and HF hospitalisation-free survival [HR 1.09, 95% CI (1.02-1.17), p = 0.015]. CCI at month 6 was independently associated with HF hospitalisation-free survival [HR 1.24, 95% CI (1.11-1.38), p < 0.001]. Treatment intensification was independently associated with survival [HR 1.75, 95% CI (1.19-1.38), p = 0.004] and HF hospitalisation-free survival [HR 1.69, 95% CI (1.22-2.35), p = 0.002]. Patients undergoing treatment intensification resulting in decongestion had better outcome than patients with persistent (worsening) congestion despite LD dose up-titration (p < 0.001). CONCLUSION: Intensification of pharmacological decongestion but not the actual LD dose was related to poor outcome in chronic HF. If treatment intensification translated into clinical decongestion, outcome was better than in case of persistent or worsening congestion.

Influence of Antihypertensive Treatment on RAAS Peptides in Newly Diagnosed Hypertensive Patients.

(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1-7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.

Reversal of an unfavorable effect of hydrochlorothiazide compared to angiotensin converting enzyme inhibitor on serum uric acid and oxypurine levels by estrogen-progestin therapy in hypertensive postmenopausal women.

Background: The aim was to assess the effect of estrogen-progestin therapy (EPT) on serum levels of uric acid (SUA) and its precursors xanthine (X) and hypoxanthine (HX), and on uric acid (UA) renal excretion in hypertensive postmenopausal women treated with an angiotensin-converting enzyme inhibitor (ACEI) or thiazide diuretic (HCTZ) (ClinicalTrials.gov identifier: NCT03921736, registered 19 April 2019). Methods: Postmenopausal women with untreated essential hypertension were recruited to the study. The control group consisted of 40 postmenopausal women with normal blood pressure. Hypertensive women were randomized to two groups: hydrochlorothiazide (n = 50) or perindopril (n = 50) and to a group receiving or not receiving EPT (EPT+/EPT-) due to vasomotor symptoms. The follow-up period was one year. Blood pressure measurements as well as blood tests for SUA and its precursors X and HX were performed at baseline and after 12 months. Results: In hypertensive women, baseline serum X and HX were significantly higher when compared to the group of normotensive women. Treatment with HCTZ led to a statistically significant increase in SUA in the subgroup of EPT- women. In this group concentrations of X and HX increased significantly after 12 months. UA/X significantly decreased after treatment with HCTZ. Lack of EPT resulted in a decrease of renal plasma flow in the HCTZ group. However, in the HCTZ and EPT + group, SUA decreased significantly when compared to baseline. None of these unfavorable effects was observed in the ACEI group regardless of EPT. Conclusions: 1) EPT prevents the development of hyperuricemia during antihypertensive treatment with thiazide diuretics. 2) Arterial hypertension and menopause cause impairment of UA excretion and increase the levels of SUA and its precursors X and HX. 3) EPT reduces the risk of hyperuricemia in postmenopausal women.

Triple Combination Therapies Based on Olmesartan: A Personalized Therapeutic Approach to Improve Blood Pressure Control.

Recent epidemiological surveys have demonstrated that effective and sustained blood pressure (BP) control is achieved in a relatively small proportion of treated hypertensive patients. Indeed, treatment of hypertension represents a key strategy for preventing coronary artery disease, stroke, congestive heart failure and cardiovascular death. Several interventions have been proposed by international guidelines for ameliorating hypertension management and control, mostly including integrated and multi-dimensional pharmacological and non-pharmacological strategies. In particular, numerous evidence demonstrated that a more extensive use of combination therapy may represent a valid therapeutic option for treating hypertensive patients at different risk profile. This strategy has been definitely strengthened by the availability of single pill fixed-dose combinations. Among potential combination therapies, those based on the association of renin-angiotensin system antagonists, thiazide diuretics and calcium channel blockers are very effective in lowering BP levels and well tolerated. We will provide here an overview of clinical evidence supporting the use of triple combination therapy, with a focus on that based on olmesartan medoxomil, a thiazide diuretic (hydrochlorothiazide) and a calcium channel blocker (amlodipine besylate), which is available in multiple dosages. Finally, in view of the recognised importance of single-pill combination therapy for treating hypertension, we will examine the potential benefits of dual (fixed) combination therapy based on olmesartan medoxomil with either thiazide diuretic hydrochlorothiazide or calcium channel blocker amlodipine in terms of efficacy, safety and tolerability profile.

Monotherapy and Dual Combination Therapies Based on Olmesartan: A Comprehensive Strategy to Improve Blood Pressure Control.

Olmesartan medoxomil is an antihypertensive drug of the class of angiotensin II type 1 (AT1) receptor antagonists (or blockers), characterized by tight and prolonged binding to AT1 receptor compared to other molecules within the same class. These characteristics produce effective and sustained blood pressure reductions in hypertensive patients at different cardiovascular risk profile with a good tolerability profile. After a brief description of the pharmacological characteristics of olmesartan, we will provide a thorough overview of the clinical studies that investigated its efficacy and safety in the clinical management of hypertensive patients both in monotherapy and in dual combination therapies with either thiazide diuretics or calcium channel blockers. These studies demonstrated that olmesartan-based antihypertensive strategy may indeed provide sustained BP control over the 24-h period in a wide proportion of hypertensive patients, thus contributing to a substantial progress in hypertension management. Finally, since growing evidence suggest that olmesartan may also exert potential favourable effects at vascular level, thereby antagonizing the vascular inflammatory process involved in the development and progression of atherosclerosis, the main clinical studies addressing this issue will be also discussed.

Diuretic Use and Risk of Vertebral Fracture in Women.

BACKGROUND: Vertebral fracture is the most common type of osteoporotic fracture. While thiazide diuretics, which are commonly prescribed for the treatment of hypertension, decrease calciuria, they may also induce hyponatremia, which has been associated with increased vertebral fracture risk. Loop diuretics increase calciuria, which would reduce bone mineral density and increase vertebral fracture risk, but they rarely cause hyponatremia. Recent studies on diuretics and fractures did not include or specifically examine vertebral fracture. The few studies of diuretics and vertebral fracture have been limited by cases defined by self-report or administrative data, relatively small number of cases, study design that was not prospective, and lack of long-term follow-up with updated information on diuretic use. METHODS: We conducted a prospective cohort study of thiazide diuretic use, loop diuretic use, and risk of incident clinical vertebral fracture in 55,780 women, 55-82 years of age, participating in the Nurses' Health Study, without a prior history of any fracture. Diuretic use was assessed by questionnaire every 4 years. Self-reported vertebral fracture was confirmed by medical record review. Cox proportional-hazards models were used to simultaneously adjust for potential confounders. RESULTS: Our analysis included 420 incident vertebral fracture cases documented between 2002 and 2012. The multivariate-adjusted relative risk of clinical vertebral fracture for women taking thiazides compared with women not taking thiazides was 1.47 (95% confidence interval, 1.18-1.85). The multivariate adjusted relative risk of vertebral fracture for women taking loop diuretics compared with women not taking loop diuretics was 1.59 (95% confidence interval, 1.12-2.25). CONCLUSION: Thiazide diuretics and loop diuretics are each independently associated with increased risk of vertebral fracture in women.

Metolazone Associated Stevens Johnson Syndrome-Toxic Epidermal Necrolysis Overlap.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe mucocutaneous disease with high mortality rate. It is characterised by severe necrosis and detachment of the epidermis. Drugs are the most common triggering agent for SJS/TEN. These are commonly reported with the use of aromatic antiepileptics, antiretrovirals, allopurinol, NSAID'S and sulfonamide antibiotics. Non antibiotic sulfonamides rarely cause SJS/TEN. Metolazone is a well known diuretic and is extensively used by clinicians. Although this drug is in market for last several decades, no case of SJS/TEN has been reported till date. We report a rare case of metolazone induced SJS/TEN overlap in a 55-year-old lady.

Comparison of Blood Pressure Control Rates Among Recommended Drug Selection Strategies for Initial Therapy of Hypertension.

BACKGROUND: Several approaches to initiation of antihypertensive therapy have been suggested. These include thiazide diuretics (TDs) as the first drug in all patients, initial drug selection based on age and race criteria, or therapy selection based on measures of plasma renin activity (PRA). It is uncertain which of these strategies achieves the highest control rate with monotherapy in Stage-I hypertension. We sought to compare control rates among these strategies. METHODS: We used data from the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR) to estimate control rates for each strategy: (i) TD for all, (ii) age- and race-based strategy: Hydrochlorothiazide (HCTZ) for all blacks and for whites ≥50 years and a renin-angiotensin system inhibitor (atenolol) for whites <50 years) or (iii) a PRA based strategy: HCTZ for suppressed PRA (<0.6ng/ml/h) and atenolol for non-suppressed PRA (≥0.6ng/ml/h) despite age or race. Hypertension was confirmed prior to treatment with HCTZ (148 blacks and 218 whites) or with atenolol (146 blacks and 221 whites). RESULTS: In the overall sample, using clinic blood pressure (BP) response, the renin-based strategy was associated with the greatest control rate (48.9% vs. 40.8% with the age and race-based strategy (P = 0.0004) and 31.7% with the TD for all strategy (P < 0.0001)). The findings were similar using home or by 24-hour ambulatory BP responses and within each racial subgroup. CONCLUSIONS: A strategy for selection of initial antihypertensive drug therapy based on PRA was associated with greater BP control rates compared to a thiazide-for-all or an age and race-based strategy.

SFE/SFHTA/AFCE consensus on primary aldosteronism, part 7: Medical treatment of primary aldosteronism.

Spironolactone, which is a potent mineralocorticoid receptor antagonist, represents the first line medical treatment of primary aldosteronism (PA). As spironolactone is also an antagonist of the androgen and progesterone receptor, it may present side effects, especially in male patients. In case of intolerance to spironolactone, amiloride may be used to control hypokaliemia and we suggest that eplerenone, which is a more selective but less powerful antagonist of the mineralocorticoid receptor, be used in case of intolerance to spironolactone and insufficient control of hypertension by amiloride. Specific calcic inhibitors and thiazide diuretics may be used as second or third line therapy. Medical treatment of bilateral forms of PA seem to be as efficient as surgical treatment of lateralized PA for the control of hypertension and the prevention of cardiovascular and renal morbidities. This allows to propose medical treatment of PA to patients with lateralized forms of PA who refuse surgery or to patients with PA who do not want to be explored by adrenal venous sampling to determine whether they have a bilateral or lateralized form.

Central integration and neural control of blood pressure during the cold pressor test: a comparison between hydrochlorothiazide and aliskiren.

Individuals with hypertension and sympathetic overactivity are at risk for cardiovascular events. Renin inhibitors are new while thiazide diuretics are first-class drugs used for treatment of hypertension. The purpose of this study was to determine whether 6 months of treatment with aliskiren (ALSK) or hydrochlorothiazide (HCTZ) would alter blood pressure (BP) and muscle sympathetic nerve activity (MSNA) indices in older mild hypertensives during a cold pressor test (CPT). We hypothesized that the ALSK group would demonstrate a blunted response compared to HCTZ. Nineteen (9 men, 10 women) subjects performed a CPT pre- and post treatment where heart rate (HR), systolic BP (SBP) and diastolic BP (DBP), and MSNA were measured. Blood samples were withdrawn for assessment of renal-adrenal hormones. Both medications lowered ambulatory SBP and DBP (P < 0.05). Direct renin tended to be higher in the ALSK group after treatment (P = 0.081). Aldosterone was higher in the HCTZ group after treatment (P < 0.001). As expected, both groups showed increases in HR, SBP, DBP, and MSNA during the CPT (all P < 0.05). All cardiovascular and MSNA responses were similar pre- and post treatment in both groups (peak CPT SBP: 26 ± 10 vs. 17 ± 21 and 21 ± 20 vs. 29 ± 15 mmHg for pre vs. post for HCTZ and ALSK, respectively; peak CPT MSNA burst frequency: 13 ± 8 vs. 11 ± 11 and 11 ± 17 vs. 6 ± 13 bursts/min; all P > 0.05). Treatment with these antihypertensive medications lowered BP but was not successful in lowering the responsiveness to the CPT.

Comparison of effects of azelnidipine and trichlormethiazide in combination with olmesartan on blood pressure and metabolic parameters in hypertensive type 2 diabetic patients.

UNLABELLED: Aims/Introduction: Angiotensin II type 1 receptor blockers (ARB) are regarded as first-line treatment for type 2 diabetes with hypertension. However, lowering blood pressure to the target level often requires more than one antihypertensive agent as recommended by the guideline. In this open-label, prospective, crossover clinical trial, we compared the effects of combination treatment of ARB with a calcium channel blocker (CCB) or with a low-dose thiazide diuretic on blood pressure (BP) and various metabolic parameters in hypertensive patients with type 2 diabetes. MATERIALS AND METHODS: A total of 39 Japanese type 2 diabetics with hypertension treated with olmesartan (20 mg/day) for at least 8 weeks were recruited to this study. At study entry, treatment was switched to either olmesartan (20 mg/day)/azelnidipine (16 mg/day) or olmesartan (20 mg/day)/trichlormethiazide (1 mg/day) and continued for 12 weeks. Then, the drugs were switched and treatment was continued for another 12 weeks. We measured clinical blood pressure and various metabolic parameters before and at the end of each study arm. RESULTS: Compared with the olmesartan/trichlormethiazide treatment, treatment with olmesartan/azelnidipine achieved superior clinical blood pressure and pulse rate control. In contrast, the treatment with olmesartan/trichlormethiazide resulted in increased HbA1c, serum uric acid and worsening of estimated glomerular filtration rate, though there were no differences in other metabolic parameters including urine 8-hydroxy-2'-deoxyguanosine, C-reactive protein and adiponectin between the two treatments. CONCLUSIONS: Our results show that the combination of ARB with azelnidipine is more beneficial with regard to blood pressure control and metabolic outcome than the combination of olmesartan with low dose trichlormethiazide. This trial was registered with UMIN clinical trial registry (no. UMIN000005064). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00135.x, 2011).

Clinical efficacy and safety of olmesartan/hydrochlorothiazide combination therapy in patients with essential hypertension.

Hypertension is a major risk factor for cardiovascular disease that contributes to the premature death of millions of people each year, and identification and treatment of hypertension continues to be a challenge. Guidelines recommend that many patients will require two or more antihypertensive agents from different classes. Combining an angiotensin II receptor blocker (ARB) with hydrochlorothiazide (HCTZ) has been shown in clinical studies to increase the antihypertensive efficacy of both agents compared with either agent alone. This review covers several clinical trials and aims to examine several aspects of the efficacy of the combination of olmesartan and HCTZ, including dose-responsiveness, long-term efficacy, goal rate achievement, and efficacy in patients with moderate to severe hypertension. The results presented here demonstrate that olmesartan is effective when added to HCTZ monotherapy or when HCTZ is added to olmesartan monotherapy, both over the short and long term. Moderate to severe hypertension responds well to olmesartan/HCTZ combination therapy, and the great majority of patients are able to achieve recommended blood pressure targets. Thus olmesartan/HCTZ is a well-tolerated option for patients who fail to respond to monotherapy and as initial therapy in those who require large reductions in diastolic blood pressure or systolic blood pressure to achieve goal blood pressure.