Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients: a double-blind controlled trial. Comparison of effects of exercise and diuretic on left ventricular geometry, mass, and insulin resistance in older hypertensive adults. Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects. The Eurevie Study: contrasting effect of piretanide and thiazides in mild to moderate hypertension. Antihypertensive Drug Therapy and the Initiation of Treatment for Diabetes Mellitus Glucose and insulin levels during diuretic therapy in hypertensive men. Reduction of salt intake during converting enzyme inhibitor treatment compared with addition of a thiazide. A double-blind study of tienilic acid with two year follow-up of patients with mild to moderate essential hypertension. Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. The effects of thiazide diuretics upon plasma lipoproteins. Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension Long-acting and short-acting diuretics in mild essential hypertension. The Combination of Chlorthalidone with Nifedipine Does Not Exert an Additive Antihypertensive Effect in Essential Hypertensives: A Crossover Multicenter Study Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension.
Blood pressure ( BP ) and metabolic variables were determined initially and after 1 , 2 , 4 , 6 and 10 years ' treatment in two groups of hypertensive men ( n = 53 each ) r and omized to bendroflumethiazide 2.5 - 5 mg/day or propranolol 160 - 320 mg daily . There was no significant differences in BP or metabolic variables between the two groups at entry . BP was reduced to the same degree by both treatments . Five men in the propranolol group and one man in the thiazide group developed clinical ly overt diabetes during follow-up . Fasting blood sugar increased slightly but significantly though equally in both groups . Oral glucose tolerance was initially impaired to the same degree in both groups but improved significantly during treatment with both drugs . Fasting insulin increased slightly but to the same degree . While serum potassium decreased significantly in the thiazide group , the total body potassium was unchanged in this group . In the propranolol group , serum potassium rose , while total body potassium decreased significantly . Serum urate increased in both groups , though slightly more during thiazide treatment . One case of gout was found in each group . There was no difference in serum lipids between the two groups . The finding in this long-term trial indicate that in middle-aged men with mild to moderate hypertension a low-dose thiazide diuretic like bendroflumethiazide is as effective and safe an antihypertensive agent as the beta-blocker propranolol is and that it does not induce diabetes . The total clinical picture favors the retention of thiazide diuretics as a first choice drug in hypertension A blood lipid-lipoprotein elevating effect of the diuretics hydrochlorothiazide and chlorthalidone in mildly hypertensive men has been established by a cross-over , r and omized controlled trial , confirming previous clinical observations . Compared to baseline , plasma total cholesterol increased 6 % and 8 % and triglycerides 17 % and 15 % under treatment with hydrochlorothiazide and chlorthalidone , respectively . A cholesterol-lowering diet largely prevents this increase . Because these effects may be long-lasting and may cancel part of the potential benefit of blood pressure control in mildly hypertensive patients , with thiazide diuretics attention should be given to prescription of a cholesterol-lowering diet and to periodic monitoring of blood lipid levels . Different antihypertensive agents might be considered in patients with elevated blood lipid levels . Other antihypertensive agents currently in use need to be studied for potential effects on lipid metabolism To compare the effects of exercise training and hydrochlorothiazide on left ventricular ( LV ) geometry and mass , blood pressure ( BP ) , and hyperinsulinemia in older hypertensive adults , we studied 28 patients r and omized either to a group ( age 66.4 + /- 1.3 yr ; n = 16 ) that exercised or to a group ( age 65.3 + /- 1.2 yr ; n = 12 ) that received hydrochlorothiazide for 6 mo .  Endurance exercise training induced a 15 % increase in peak aerobic power . The reduction in systolic BP was twofold greater with thiazide than with exercise ( 26.6 + /- 12.2 vs. 11.5 + /- 10.9 mmHg ) . Exercise and thiazide reduced LV wall thickness , LV mass index ( 14 % in each group ) , and the LV wall thickness-to-radius ratio ( h/r ) similarly ( exercise : before 0.48 + /- 0.2 , after 0.42 + /- 0.01 ; thiazide : before 0.47 + /- 0.04 , after 0.40 + /- 0.04 ; P = 0.017 ) . The reductions in systolic BP and h/r were correlated in the exercise group ( r = 0.70 , P = 0.005 ) but not in the thiazide group . Exercise training reduced glucose-stimulated hyperinsulinemia ( before : 13.65 + /- 2.6 vs. 9.84 + /- 1.5 mU.ml(-1).min ; P = 0.04 ) and insulin resistance . Thiazide did not affect plasma insulin levels . The results suggest that although exercise is less effective in reducing systolic BP than thiazide , it can induce regression of LV hypertrophy similar in magnitude to thiazide . Unlike hydrochlorothiazide , exercise training can improve insulin resistance and aerobic capacity in older hypertensive people Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ . To characterize the lower end of the dose-response curve a double-blind , parallel group trial was performed as multicentre study in Sc and inavia . One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension ( untreated diastolic blood pressure of 95 - 115 mmHg after 4 weeks placebo ) were r and omly allocated to various doses of hydrochlorothiazide ( 3 , 6 , 12.5 or 25 mg ) or placebo for 6 weeks . Blood pressure and biochemical variables ( plasma renin activity , serum potassium , magnesium , urate , fasting glucose , total cholesterol , HDL-cholesterol , triglycerides and apolipoproteins A1 and B were measured . 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect . Biochemical changes were seen in plasma renin activity , serum potassium and urate after the 12.5 and 25 mg dose . Three and 6 mg had no effect on blood pressure or metabolic parameters UNLABELLED This study compares the loop diuretic piretanide 6 mg in a slow-release formulation ( PIR ) with hydrochlorothiazide 25 mg ( HCT ) and the fixed combination altizide 15 mg-spironolactone 25 mg ( ALT-SP ) in hypertension . 1105 mild to moderate hypertensive patients entered a three-week placebo wash-out period ; 899 were r and omized in a 6-month , double-blind , parallel group treatment phase ; 800 completed the study . Primary end-points ; serum potassium concentration and quality of life at one month ; secondary end-points : ionic , renal and metabolic variables ; blood pressure ( BP ) measurements . HCT and ALT-SP were compared only to PIR using Dunnett 's or chi 2 tests . RESULTS No difference was found for the overall quality of life . No change of serum potassium concentration at one month was found in PIR while small decreases were detected with ALT-SP ( -0.1 mM ) and HCT ( -0.26 mM ) . Serum creatinine concentration increased significantly in ALT-SP when compared to PIR . All the drugs were effective in reducing BP : HCT had a higher rate of responders than PIR with similar mean BP falls and ALT-SP induced greater falls in blood pressure . CONCLUSION PIR proves to be a potent antihypertensive drug without significant effect on serum electrolytes , plasma glucose and lipids . HCT was slightly more potent but induced a fall in serum potassium concentration with a significant risk of hypokalaemia . The addition of SP to ALT led to a more potent diuretic with a higher level of serum potassium and plasma creatinine disturbances Although several antihypertensive medications have been associated with impaired glucose tolerance [ 1 ] , thiazide diuretics have received the most attention in this regard . Since the introduction of chlorothiazide in 1957 , several cases have been reported in which thiazide diuretics were associated with glucose intolerance [ 2 - 5 ] . In addition , many clinical studies have provided information on the effects of thiazide diuretics on glucose homeostasis . The Veterans Administration Cooperative Study Group on Antihypertensive Agents [ 6 ] found that hydrochlorothiazide increased the average fasting plasma glucose level by approximately 0.3 mmol/L after 10 weeks of treatment . In the Systolic Hypertension in the Elderly Program study [ 7 ] , the treatment group showed an increase of 0.4 mmol/L in mean serum glucose levels over the baseline level after 1 year of thiazide diuretic therapy , whereas the placebo group showed an increase of 0.1 mmol/L. In the study conducted by the European Working Party on Hypertension in the Elderly [ 8 ] , the thiazide treatment group showed an increase of 0.5 mmol/L in the fasting serum glucose level after 2 years , whereas the placebo group showed a decrease of 0.2 mmol/L ( P < 0.001 ) . In a r and omized , crossover study of 50 patients , Pollare and coworkers [ 9 ] found that , when compared with placebo , hydrochlorothiazide reduced insulin-stimulated glucose uptake in patients with essential hypertension after 18 weeks of treatment . In contrast , patients treated with captopril showed improved carbohydrate metabolism , including an increase in insulin-stimulated glucose uptake , when compared with placebo recipients . Previous efforts to quantify the clinical risk for development of hyperglycemia requiring treatment in patients taking various antihypertensive regimens have been limited by the relative infrequency of this event and the limited range of antihypertensive agents used in large clinical trials [ 10 ] . For the same reasons , the risks of different agents have not been adequately compared . To address these issues , we conducted a casecontrol study of 11 855 New Jersey Medicaid enrollees newly started on hypoglycemic therapy . Methods Sources of Data The study sample was drawn from the state of New Jersey 's Medicaid program for the years 1981 to 1990 . Enrollment in the program was ascertained through the Medicaid eligibility file , which identifies all program participants , their date s of coverage , and demographic characteristics including age , gender , and race . Data on medication use were taken from the Medicaid pharmacy cl aims file , which contains information on all prescriptions filled by Medicaid recipients , including the National Drug Code and the date dispensed . Medications of interest were identified using the National Drug Code specific for each agent . Hospitalization data for all Medicaid recipients were also ascertained . Medicaid recipients who were eligible to receive Medicare benefits ( crossover enrollees ) were identified to acquire full information on utilization of hospital services . Medicaid covers payment for medications for these Medicare recipients , which enabled us to ascertain all prescription information for this group . Case Patients Case patients were Medicaid enrollees 35 to 99 years of age who filled a first prescription for a hypoglycemic agent between 1981 and 1990 . All oral hypoglycemic medications and insulin preparations were included . The date of the first prescription for a hypoglycemic medication was defined as the index date . To ensure that study patients were active users of the Medicaid system , each case patient was required to be continuously eligible in the program for at least 120 days before the index date and to have filled a prescription for at least one drug of any kind during this period . No cl aims for a hypoglycemic agent could be made before the index date . Drug cl aims were search ed back to 1981 to ensure that case patients and controls had not previously filled a prescription for a hypoglycemic agent .  Of the 35 202 patients who filled a first prescription for a hypoglycemic agent during the defined study period , 443 had deficient eligibility records , and 4753 did not meet the specified age criteria . The additional requirement that case patients be continuously enrolled in Medicaid during the 120 days before the index date eliminated 9292 persons . Another 8859 patients were excluded from the case group because they had not filled a prescription for any other drug during the 120 days preceding the index date . The final case group included 11 855 patients . Controls We identified controls by selecting a r and om sample of Medicaid enrollees who met the same criteria for eligibility and use of the health care system as did case patients but who had not filled a prescription for a hypoglycemic agent on or before a r and omly assigned index date . One control was r and omly selected for each case . Definitions of Antihypertensive Drug Use To characterize current exposure to antihypertensive agents , all prescriptions filled during the 120 days before the index date were review ed for both case patients and controls . Medications of principal interest included thiazide diuretics ; angiotensin-converting enzyme inhibitors ; central ly acting antiadrenergic agents ; peripherally acting antiadrenergic agents ; -blockers ; calcium-channel blockers ; and vasodilators . Categorization of patients taking multiple-agent regimens representing more than one category of antihypertensive agent was based on whether the regimen did or did not contain a thiazide diuretic . Drug-exposure categories were mutually exclusive so that patients were either characterized as exposed to a single category of antihypertensive therapy or placed in one of the multiple-category groups , but not both . Three time windows of exposure before the index date were created : 1 to 45 days , 1 to 90 days , and 91 to 120 days . A patient was considered to be currently exposed to an agent if he or she filled a prescription for a medication of interest in the 45 days before the index date . This was the exposure window of primary interest . In addition , we examined records of patients who filled a prescription for a medication of interest 1 to 90 days before the index date and 91 to 120 days before the index date to study people with evidence of a more prolonged duration of exposure . Covariates Because other medications can also directly and indirectly affect glucose metabolism , we measured exposure to potassium supplements , potassium-sparing diuretics , oral glucocorticoids , estrogen-containing compounds , and niacin . In addition , exposure status for these agents was characterized according to the previously defined exposure windows . Other covariates included demographic variables ( age , gender , race , residence in a nursing home ) the number of days hospitalized , and the number of prescriptions filled in the 120-day period before the index date . Statistical Analysis Differences in categorical variables between case patients and controls were assessed with chi-square tests . Relative risks for new use of a hypoglycemic agent within each exposure category were estimated from odds ratios calculated by unconditional logistic regression [ 11 ] using the SAS CATMOD program [ 12 ] . For these analyses , the reference category was the absence of exposure to any antihypertensive medication . Models were constructed with patients characterized according to the study definitions of duration of exposure ( current exposure or exposure of more prolonged duration ) . Covariates in the models included age , gender , race , nursing home residency , number of days in the hospital , number of drug cl aims , glucocorticoid exposure , potassium supplementation , estrogen exposure , and niacin exposure . Because of temporal trends in the pattern of antihypertensive drug prescribing [ 13 ] , the study sample was stratified according to index date ( pre-1985 or 1985 to 1990 ) , and models were constructed for each sub sample . Confidence intervals ( CIs ) for the estimated odds ratios and significance tests for differences between individual odds ratios were calculated using the estimated st and ard errors . To control for potential surveillance bias ( that is , the possibility that patients receiving antihypertensive agents may have had closer medical supervision and may have had more laboratory tests than patients not receiving antihypertensive therapy ) and to make the case and control groups more comparable , we did a separate analysis of the 8005 current users of antihypertensive medications ( 4794 case patients and 3211 controls ) . In these models , current exposure to thiazide diuretics was the reference exposure . This model also included the same potential confounding variables mentioned above . Results We found no consistent trend when examining the relation between age and the likelihood of starting a hypoglycemic medication ( Table 1 ) in the age range studied . Patients 55 to 74 years of age were more likely to be started on a hypoglycemic agent than patients 35 to 54 years of age , although no significant difference was found between patients 75 years of age or older and patients 35 to 54 years of age . No significant differences in gender distribution were observed between case patients and controls . Blacks and other non-whites were more likely to be started on hypoglycemic therapy than whites . Patients in nursing homes were less likely to start hypoglycemic therapy than noninstitutionalized patients . Patients who had a greater number of hospital days or who filled more prescriptions were more likely to be started on a hypoglycemic medication . No relation was found between index date ( pre-1985 or 1985 to 1990 ) and the likelihood of being started on hypoglycemic therapy . Table 1 . Characteristics of the Study Sample and Their Relation to Starting a Hypoglycemic Medication The relative risk for the initiation of hypoglycemic therapy  was significantly increased among patients who were current We investigated serum glucose and insulin levels result ing from thiazide or thiazide-like diuretic administration and determined whether they were associated with serum or intracellular potassium or magnesium values . We also explored the role of obesity both alone and with thiazides on serum insulin and glucose . Hypertensive men were withdrawn from  diuretics  and repleted with oral potassium and magnesium and then r and omized to 2 months of treatment with ( 1 ) hydrochlorothiazide , ( 2 ) hydrochlorothiazide with oral potassium , ( 3 ) hydrochlorothiazide with oral potassium and magnesium ( 4 ) hydrochlorothiazide and triamterene , ( 5 ) chlorthalidone , or ( 6 ) placebo . Serum was available from 202 participants for insulin and glucose determinations . Mean fasting serum glucose and insulin did not change significantly after 2 months of r and omized therapy with the exception of participants r and omized to chlorthalidone , who had significant increases in both serum insulin and glucose ( P < .05 and P < .01 , respectively ) . As body mass index increased , there was a corresponding increase in serum insulin and to a lesser degree in serum glucose . Also , as body mass index increased , participants taking hydrochlorothiazide had a corresponding increase of serum insulin ( P < .05 ) . After treatment , intracellular potassium and magnesium were both associated with higher serum insulin ( P < .001 for each ) , and serum potassium was associated with higher and serum magnesium with lower serum glucose ( P < .01 for each ) . In most hypertensive men , treatment with 50 mg chlorthalidone increases glucose and insulin levels , whereas administration of 50 mg hydrochlorothiazide , with or without potassium and /or magnesium conserving strategies , does not . ( ABSTRACT TRUNCATED AT 250 WORDS A moderate reduction in salt intake lowers blood pressure in individuals with hypertension and improves blood pressure control in those taking a converting enzyme inhibitor . However , it is unclear how effective reduction of salt intake is compared with addition of other drugs , in particular , thiazide diuretics . We directly compared the separate effects on blood pressure of reducing sodium intake or adding a thiazide diuretic in the pressure of a converting enzyme inhibitor in a double-blind , r and omized , crossover study . We studied 11 subjects with essential hypertension who had been taking 25 mg captopril twice daily for at least 1 month . In the double-blind study , after 1 month of captopril alone , supine blood pressure was 151 + /- 5/95 + /- 4 ( SEM ) mm Hg . With the addition of 25 mg hydrochlorothiazide once daily for 1 month , blood pressure fell to 137 + /- 5/87 + /- 3 mm Hg . When a moderate reduction in salt intake ( from 206 + /- 26 to 109 + /- 20 mmol urinary sodium/24 h ) was added to captopril for 1 month , blood pressure was reduced by a similar amount ( to 137 + /- 4/90 + /- 3 mm Hg ) . Plasma potassium fell during the diuretic treatment ( 3.9 + /- 0.1 to 3.7 + /- 0.1 mmol/L , P < .05 ) but increased nonsignificantly during salt reduction ( 3.9 + /- 0.1 to 4.1 + /- 0.2 mmol/L ) . These results clearly demonstrate that moderate salt reduction , which can be easily achieved , is as effective as a thiazide diuretic in lowering blood pressure in the presence of a converting enzyme inhibitor and has the particular advantage that plasma potassium does not decrease . ( ABSTRACT TRUNCATED AT 250 WORDS In a double-blind study , thirty patients having mild to moderate essential hypertension were r and omly assigned to a six week regimen of either tienilic acid , hydrochlorothiazide , or placebo .  Blood pressure was significantly reduced with tienilic acid and hydrochlorothiazide although more so with tienilic acid .  Serum uric acid declined strikingly with tienilic acid and increased significantly with hydrochlorothiazide .  Serum potassium declined slightly with tienilic acid but more so with hydrochlorothiazide .  Serum creatinine and blood urea nitrogen increased slightly more with tienilic acid than with hydrochlorothiazide . There were no clinical adverse effects to any of the medications during this study . Twenty-four months of continuous administration of tienilic acid revealed maintenance of blood pressure effect , but with slight increases in blood urea nitrogen , serum creatinine and uric acid and slight decreases in serum potassium as compared to six weeks administration . Tienilic acid appears to be a useful new antihypertensive agent . The hypouricaemic effect is profound and strongly suggests the need for continuing evaluation of this compound because of its unique combination of diuretic , antihypertensive and hypouricaemic properties BACKGROUND To attain goal blood pressure ( BP ) , many hypertensive patients require combination antihypertensive therapy . Thiazide diuretic/beta-blocker regimens lower BP , and clinical studies indicate that they reduce the risk for cardiovascular consequences of hypertension . Fixed-dose combination tablets can simplify multidrug treatment regimens . METHODS This multicenter , r and omized , double-blind , placebo-controlled , unbalanced factorial study ( N = 1571 ) was design ed to determine whether hydrochlorothiazide ( HCT ) and extended release ( ER ) metoprolol both contribute to an antihypertensive effect .  Hypertensive adults with sitting diastolic BP ( SiDBP ) 95 to 114 mm Hg and systolic BP ( SiSBP ) < 180 mm Hg received one of three hydrochlorothiazide doses ( 6.25 mg , 12.5 mg , or 25 mg ) , one of four ER-metoprolol doses ( 25 mg , 50 mg , 100 mg , 200 mg ) , or one of nine of the combinations or placebo for 8 weeks . RESULTS Blood pressure decreased with all combinations ( P < .001 v placebo ) ; reductions were dose related , ranging from 8.7 to 15.7 mm Hg ( SiDBP ) and 9.7 to 18.9 mm Hg ( SiSBP ) ( model-derived values ) . Reductions with placebo were 5.3 ( SiDBP ) and 4.2 mm Hg ( SiSBP ) . Both active agents contributed to the combination effect ( P = .0015 for SiDBP ; P = .0006 for SiSBP ) . Several low-dose combinations were approximately as effective as high doses of the individual agents ( differences within 1 to 2.5 mm Hg ) . The adverse event discontinuation rate was 2.9 % . Serum potassium decreased and uric acid increased with increasing doses of HCT . CONCLUSIONS Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components In a double-blind , placebo-controlled , crossover study in 16 hypertensives , 4 weeks of 50 mg  hydrochlorothiazide twice daily , caused significant elevations in total plasma cholesterol , high density lipoprotein (HDL)-cholesterol , low density lipoprotein (LDL)-cholesterol , very low density lipoprotein (VLDL)-cholesterol and triglycerides . Significant elevations in fasting plasma glucose and in plasma insulin were observed , but no correlation between individual lipid elevations and either glucose or insulin elevations was apparent . The metabolic effects developed within 2 weeks , and dissipated within 4 weeks . Changes induced within 4 weeks of treatment with hydrochlorothiazide were unaltered at 6 months . Hydrochlorothiazide induces elevation of all lipoprotein cholesterol fractions and VLDL-triglyceride . However , as the important ratio between LDL- and HDL-cholesterol is unchanged , coronary risk may be unchanged BACKGROUND No reduction in either coronary mortality or sudden cardiac death ( SCD ) has been demonstrated in overviews of r and omized trials of treatment of hypertension with diuretics . METHODS An overview was conducted of coronary mortality and SCD in r and omized controlled antihypertensive trials in which an  epithelial sodium channel ( ENaC ) inhibitor/ hydrochlorthiazide ( HCTZ ) combination was used . Secondarily , an analogous overview in which thiazide diuretic was used alone was performed . R and omized trials that used an ENaC inhibitor/ HCTZ combination ( or , alternatively , thiazide diuretic alone ) were identified from previous meta-analyses , search es of PubMed , search of the Cochrane Clinical Trials data base , and review of publications that addressed the consequences of treating hypertension . Trials in which participants were r and omized to either an ENaC inhibitor combined with a thiazide diuretic ( or to a thiazide diuretic alone ) or to control treatment for at least one year and in which coronary mortality was reported were included . Numbers of events in individual trials were abstract ed independently by 2 authors . RESULTS Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/ HCTZ combination . The odds ratio ( OR ) for coronary mortality was 0.59 ( 95 % confidence interval [ CI ] 0.44 , 0.78 ) and for SCD was 0.60 ( 95 % CI 0.38 , 0.94 ) . In contrast , an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality ( OR 0.94 ; 95 % CI 0.81 , 1.09 ) or SCD ( OR 1.27 ; 95 % CI 0.93 , 1.75 ) . CONCLUSIONS Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD To achieve the target blood pressure recommended by the latest guidelines , multiple antihypertensive drugs are needed in most patients . In this study , the efficacy of treatment using an angiotensin II receptor antagonist ( ARB ) combined with a calcium channel blocker ( CCB ) or a diuretic was compared from multiple perspectives in patients with hypertension . Twenty-nine patients with essential hypertension , who had failed to achieve their target blood pressure ( < 130/85 mm Hg for patients < 65 years old and < 140/90 mm Hg for those ⩾65 years ) when treated with the ARB olmesartan at 20 mg day−1 , were additionally given 8–16 mg day−1 of the CCB azelnidipine or 1–2 mg day−1 of trichlormethiazide ( a thiazide diuretic ) in a r and omized crossover manner for 4 months each . At the end of each combination therapy period , blood and urine sample s were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity . Compared with monotherapy , the blood pressure was reduced similarly by adding azelnidipine ( −12/−10 mm Hg ) or trichlormethiazide ( −14/−9 mm Hg ) . The heart rate was decreased with the CCB by 4 b.p.m . ( P<0.05 ) , whereas it was unchanged with the thiazide . Serum K , lipids and blood glucose were not significantly changed with either combination , whereas serum uric acid was increased with the thiazide ( P<0.01 ) but was unchanged with azelnidipine  . Plasma levels of renin , angiotensin II and aldosterone were also increased with the thiazide period , whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine . In addition , the cardio-ankle vascular index , a parameter of arterial stiffness , was decreased with the azelnidipine period but was unchanged with the thiazide period ( P<0.01 ) . It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia , sympathetic activation , renin – angiotensin-aldosterone system stimulation , inflammation , oxidative stress , and increased arterial stiffness in patients with moderate hypertension . These properties may provide cardiovascular protection in addition to the hypotensive effect Objective : To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses . Design : Double blind r and omised crossover study of two 12 week treatment periods with either low dose ( 1.25 mg ) or conventional dose ( 5.0 mg ) bendrofluazide given after a six week placebo run in period . Setting : Outpatient clinics serving the greater Belfast area . Subjects : 16 white non-diabetic patients ( 9 male ) under 65 with essential hypertension recruited from general practice s within the greater Belfast area . Main outcome measures : Systolic and diastolic blood pressure and peripheral and hepatic insulin action . Results : One man failed to complete the study . There were no differences between doses in their effects on systolic and diastolic blood pressure .  Bendrofluazide 1.25 mg had substantially less effect20on serum potassium concentration than the 5.0 mg dose . There were no intertreatment differences in fasting glucose , insulin , cholesterol , and triglyceride concentrations .  Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline ( mean 10.9 ( SD 1.2 ) v 10.0 ( 0.8 ) μmol/kg/min ) , whereas bendrofluazide 1.25 mg did not . Postabsorptive endogenous glucose20production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg ( 10.9 ( 1.2 ) v 9.9 ( 0.8 ) μmol/kg/min ) but was suppressed to a similar extent after insulin ( bendrofluazide 5.0 mg202.8 ( 1.5 ) μmol/kg/min v bendrofluazide 1.25 mg 2.2 ( 1.5 ) μmol/kg/min ) . Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were20similar to baseline . Conclusions : Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect . In contrast with conventional doses , how dose bendrofluazide has no effect on hepatic insulin action . There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity A r and omised , placebo-controlled , double-blind crossover study was conducted in 14 patients with mild essential hypertension comparing different regimens of administration of the " short-acting " diuretic , chlorothiazide and the " long-acting " diuretic , chlorthalidone . There were 6 r and omised treatment phases each of 5 weeks duration . For blood pressure recorded both at the Clinic and at home the most prominent effects were seen with st and ing blood pressure , for which significant reductions of mean blood pressure compared to the placebo phase were observed with chlorthalidone 25 mg once daily ( -5 + /- 1 ( SE ) mm Hg - p less than 0.05 ) , chlorthalidone 50 mg once daily ( -7 + /- 1 mm Hg - p less than 0.01 ) and chlorothiazide 500 mg twice daily ( -4 + /- 1 mm Hg - p less than 0.05 ) . Blood pressure reductions with chlorothiazide 500 mg once daily and 1000 mg once daily were not significant . About half of the patients completing the trial could be described as " non-responders " . The observed biochemical changes ( reduced plasma potassium and chloride concentrations and increased plasma bicarbonate and urate concentrations ) were most marked in the phases with the most prominent blood pressure effects . The result support the suggestion that a sustained diuretic effect is desirable when diuretics are used in the treatment of hypertension . This can be obtained by selection of the appropriate dosage regimen for a particular diuretic , such as once daily administration for " long-acting " and twice daily for " short-acting " thiazide-type diuretics To evaluate whether the combination of nifedipine with chlorthalidone exerts an additive antihypertensive effect when compared to single-drug treatment , 66 uncomplicated essential hypertensives , whose diastolic blood pressure was > 100 and < 115 mm Hg at the end of a 1-month washout placebo period , received , according to a r and omized , double-blind , crossover design , nifedipine ( 20 mg b.i.d . ) , chlorthalidone ( 25 mg o.d . ) , the two drugs combined at the same doses , and the corresponding placebo . When compared to the r and omized placebo the three active treatments significantly ( p < 0.001 ) reduced blood pressure without changing heart rate and body weight . However , blood prssure values were similarly reduced under nifedipine and the combination and were significantly lower ( p < 0.05 ) than those under chlorthalidone . Moreover , the percentage of responders and normalized patients under nifedipine and the two drugs combined were similar and significantly ( normalized , p < 0.001 ; responders , p < 0.02 ) greater than those under chlorthalidone . Under chlorthalidone and its combination with nifedipine , plasma potassium tended to decrease and blood glucose and serum uric acid were significantly ( p < 0.05 ) increased . These data show that the combination of nifedipine with chlorthalidone does not exert any additive antihypertensive effect when compared to nifedipine alone and that this combination increases both blood glucose and serum uric acid . Taken together these findings indicate that the combination of a dihydropyridine calcium antagonist with a thiazide diuretic is devoid of any clinical significance in the treatment of uncomplicated essential hypertensives The purpose of this study was to evaluate the long-term safety and efficacy of moexipril , a non-sulphydryl angiotensin converting enzyme inhibitor , alone or in combination with hydrochlorothiazide in older patients with hypertension . One hundred and seventy two hypertensive men and women , 65 - 80 years old , with seated DBP between 95 and 114 mm Hg were studied . The study was a 2 year , multicentre ( 12 centres ) , open-label protocol of moexipril monotherapy or combination therapy ( with hydrochlorothiazide ) .  Blood pressure , pulse rate , weight , adverse effects and laboratory studies were assessed following moexipril at 7.5 or 15 mg once daily or 7.5 or 15 mg daily in combination with 25 mg of hydrochlorothiazide if the seated DBP remained > or = 90 mm Hg on moexipril monotherapy . The primary measure of efficacy was a change from baseline in seated DBP . Secondary outcome measures included changes in seated DBP , pulse rate , laboratory parameters and adverse side-effects . Following 1 year of therapy in 135 patients , the BP fell 16/14 mm Hg among patients receiving moexipril monotherapy and 27/17 mm Hg for those receiving combined therapy compared with baseline ( P < 0.001 for both ) . After 2 years of treatment , reductions were similar in 120 patients . Nineteen patients ( 11 % ) were prematurely withdrawn from the study because of inadequate therapeutic response and 28 ( 16 % ) because of adverse experiences . There were no significant changes in pulse rate or postural reductions in BP on either moexipril monotherapy or combination treatment . Three adverse side-effects occurred at a frequency exceeding 2 % that were possibly or probably attributable to moexipril or combination therapy : hypotension ( 2 % ) , dizziness ( 6 % ) and increased cough ( 12 % ) . There were no clinical ly relevant mean group changes from baseline laboratory values in the treatment groups . In conclusion , these long-term data demonstrate that moexipril , either alone or in combination with hydrochlorothiazide , has long-term anti-hypertensive efficacy and is generally well tolerated in elderly patients with hypertension
Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available : bendrofluazide , chlorthalidone , cyclopenthiazide , metolazone or indapamide .
This is based on an informal indirect comparison of results observed in other Cochrane review s on ACE inhibitors , ARBs and renin inhibitors compared with placebo , which used similar inclusion /exclusion criteria to the present review .Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides .
These effects were dose-related and were least for hydrochlorothiazide .
Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides .
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect .
Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides
BACKGROUND Hypertension is a modifiable cardiovascular risk factor .
Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity , the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review .
It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects .
OBJECTIVES To determine the dose-related decrease in systolic and /or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension .
Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium , uric acid , creatinine , glucose and lipids .