Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide. Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects. Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension Primary prevention of sudden cardiovascular death in hypertensive patients. Mortality results from the MAPHY Study. The Combination of Chlorthalidone with Nifedipine Does Not Exert an Additive Antihypertensive Effect in Essential Hypertensives: A Crossover Multicenter Study Thiazide Diuretics and the Risk for Hip Fracture Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic. Decreased Coronary Heart Disease in Hypertensive Smokers Mortality Results From the MAPHY Study Reduction of salt intake during converting enzyme inhibitor treatment compared with addition of a thiazide. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Effects of monotherapy and combination therapy on blood pressure control and target organ damage: a randomized prospective intervention study in a large population of hypertensive patients. Antihypertensive actions of diuretics. Comparative study of an aldosterone antagonist and a thiazide, alone and together. Effect of allopurinol on blood pressure and aortic compliance in hypertensive patients Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) Study Group. Azilsartan Medoxomil Plus Chlorthalidone Reduces Blood Pressure More Effectively Than Olmesartan Plus Hydrochlorothiazide in Stage 2 Systolic Hypertension Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor. South African hypertension guideline 2011. The Eurevie Study: contrasting effect of piretanide and thiazides in mild to moderate hypertension. Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY study.
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 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 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 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 In a r and omized primary prevention trial including 3,234 men with mild to moderate uncomplicated hypertension , the effect of the beta-blocker metoprolol or a thiazide diuretic as an initial antihypertensive therapy was compared regarding the risk of sudden cardiovascular death during a follow-up ranging from 2.3 to 10.8 years ( median of 4.2 years ) . Only men aged 40 to 64 years were included in the study . The r and omization of patients into the metoprolol ( n = 1,609 ) or diuretic group ( n = 1,625 ) was performed after stratification for age , smoking habits , serum cholesterol , and systolic blood pressure . At baseline the two treatment groups were well matched . Metoprolol was given in a mean dose of 174 mg daily and the mean dose of thiazide diuretic was either 46 mg hydrochlorothiazide daily or 4.4 mg bendroflumethiazide daily . Identical blood pressure control was achieved using the fixed therapeutic schedule . Total and cardiovascular mortality were significantly lower for metoprolol than for diuretics , owing to fewer deaths from coronary heart disease and stroke . Of the cardiovascular deaths , 78 % were classified as sudden cardiovascular deaths ( occurred within 24 h after the onset of symptoms ) . There were significantly fewer sudden cardiovascular deaths in the metoprolol group compared to the diuretic group ( 32 v 45 , P = .017 ) . The present results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of sudden cardiovascular deaths than initial diuretic treatment in uncomplicated hypertension 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 Context Thiazide diuretics reduce urinary calcium excretion and increase bone mineral density , but do they prevent bone fractures ? Contribution In this population -based cohort study of 7891 older adults , patients taking thiazides for more than 1 year had a lower risk for hip fracture than those not taking thiazides  ( hazard ratio , 0.46 [ 95 % CI , 0.21 to 0.96 ] ) . Within 4 months of stopping thiazides , the risk for hip fracture returned to its pretreatment value . Implication s Thiazide diuretics may reduce hip fractures . Whether they have effects similar or additive to those of other bone protective agents merits study . The Editors Hip fractures are associated with substantial morbidity and mortality . The costs of surgery and rehabilitation are a burden on public health re sources , especially because the incidence of hip fracture increases as the population ages ( 1 , 2 ) . Most hip fractures are related to osteoporosis , and treating accelerated bone loss may therefore be an important strategy to prevent hip fractures ( 3 ) . Thiazide diuretics are widely used as antihypertensive agents . They are inexpensive and effective and have few important adverse effects ( 4 ) . Thiazides are thought to protect against age-related bone loss by reducing urinary calcium excretion ( 5 ) . This bone-sparing effect could lead to reduced fracture incidence in patients treated for hypertension . Several epidemiologic studies have examined the effect of thiazides on bone mineral density and fracture incidence . Although bone mineral density was found to be increased in thiazide users , the difference was often small ( 6 - 12 ) . Thiazides were found to have a protective effect on hip fracture in most studies ( 9 , 12 - 17 ) , but occasionally an increased risk was found ( 18 ) . Most of the studies , however , had limitations . Some studies included detailed drug-dispensing data but limited information on potential confounders and effect modifiers ( 15 , 18 , 19 ) . Other studies had small patient sample s or used only baseline interview data on thiazide use ( 9 , 12 , 16 , 20 ) without accounting for timing of thiazide use ( 14 , 20 , 21 ) . Detailed information on thiazide dose and duration of use was often absent or unreliable because no data on day-to-day use were available . Because of these limitations , it is still unclear how long thiazides have to be taken to affect fracture incidence and how long this effect persists after thiazide use is discontinued . We conducted a prospect i ve , population -based cohort study using detailed drug-dispensing information , as well as extensive information on potential risk factors , to examine the association between current and past use of thiazides and the incidence of hip fractures in men and women 55 years of age and older . We also studied the effect of discontinuing thiazide use on fracture risk . Methods Study Sample This study was conducted as part of the Rotterdam Study , a prospect i ve , population -based cohort study on the occurrence and determinants of disease and disability in elderly persons ( 22 ) . In 1990 , all inhabitants of Ommoord , a suburb of Rotterdam in the Netherl and s , who were 55 years of age or older and had lived in the district for at least 1 year were invited to participate in the study . Of the 10 275 eligible persons , 7983 ( 78 % ) participated . Participants gave informed consent and permission to retrieve information from medical records . At baseline , between 1990 and 1993 , trained interviewers administered an extensive question naire covering socioeconomic background and medical history , among other topics , during a home interview . During subsequent visits to the study center , additional interviewing , laboratory assessment s , and clinical examinations were performed . Information on vital status is obtained at regular time intervals from the municipal authorities in Rotterdam . The Medical Ethics Committee of the Erasmus MC , Rotterdam , the Netherl and s , approved the study . For the present study , all participants were followed from 1 June 1991 until they had an incident hip fracture , died , or reached the end of the study at 31 December 1999 , whichever came first . Exposure Definition In the research area , there are 7 fully computerized pharmacies that are linked to 1 network . During the study , all participants filled their prescriptions in 1 of these 7 pharmacies . Data on all dispensed drugs since 1 January 1991 are available in computerized format on a day-to-day basis . The data include the date of prescribing , the total amount of drug units per prescription , the prescribed daily number of units , product name , and the Anatomical Therapeutic Chemical ( ATC ) code ( 23 ) . The exposure of interest included plain thiazides and thiazides combined with potassium and potassium-sparing agents . Although formally not a thiazide , chlorthalidone was included because it has a similar effect on calcium excretion . In a previous study , these 2 diuretics did not differ ( 12 ) . Therefore , we did not distinguish between them . When a hip fracture occurred , the date was defined as the index date and the cumulative duration of use of thiazides on that date was calculated for each participant . Current use was defined as use of thiazides at the index date and was expressed as the number of consecutive days of use . Past use was defined as use of thiazides after baseline and before but not on the index date itself . Past use was expressed as the number of days since discontinuing use . To study the effect of duration of thiazide use , exposure at the index date was divided into 7 mutually exclusive categories , defined a priori : never use , current use for 1 to 42 days , current use for 43 to 365 days , current use for more than 365 days , discontinuation of use since 1 to 60 days , discontinuation of use since 61 to 120 days , and discontinuation of use since more than 120 days . We selected the first duration of 42 days because in the first 6 weeks of thiazide use , the decrease in circulating volume can cause dizziness and relative cerebral ischemia . We anticipated that this might be associated with a transiently increased risk for falls that should be distinguished from a potentially protective effect after prolonged use . After 42 days , the circulating volume in most patients is within normal limits ( 24 ) . The duration of more than 365 days was chosen because trials on incidence of nonvertebral fractures with use of antiosteoporotic agents , such as bisphosphonates , all had at least 1 year of follow-up as well . Finally , the duration of 60 days after discontinuing use was chosen because it was used in an earlier study ( 15 ) . We expressed the prescribed daily dosage during current use at the index date as a proportion of the defined daily dosage ( 25 ) . The defined daily dosage of thiazide diuretics is the st and ard recommended adult daily dosage for treating patients with hypertension in the Netherl and s. To avoid potential misclassification of exposure at baseline , we ensured that all participants had potential pharmacy data for at least 5 months before baseline . Outcome Definition The study participants ' general practitioners report all fatal and nonfatal events , such as fractures , through a computerized system . These data cover about 80 % of the study sample . For participants who were not covered in this system , research physicians performed annual checks on the complete medical records of all general practitioners in the Rotterdam Study . Two research physicians independently coded all fractures that occurred during the study period using the International Classification of Diseases , 10th revision ( ICD-10 ) ( 26 ) . A medical expert in the field who was unaware of patients ' history and medication use ( including thiazides )  review ed all coded events for a final classification . Fractures with ICD-10 codes S72.0 , S72.1 , and S72.2 were included , but pathologic hip fractures ( M84.4 ) and fractures in prosthetic hips ( M96.6 ) were excluded . Cofactors The following baseline patient characteristics , all determined by interview , were individually assessed as potential confounders : age , sex , score on the Mini-Mental State Examination ( < 26 points ) ( 27 ) , use of a walking aid , any fracture in the past 5 years , history of hysterectomy , thyroid disease , frequency of falling ( once per month ) , current smoking , intake of alcohol ( > 2 g/d ) , and dizziness . Participants were interviewed about a previous diagnosis of Parkinson disease or use of antiparkinsonian drugs and were screened for symptoms of Parkinson disease by study physicians at the research center . Diabetes mellitus was defined as the use of glucose-lowering medication  or a r and om or postload serum glucose level of 11.1 mmol/L ( 200 mg/dL ) or greater . Hypertension ( systolic blood pressure > 160 mm Hg , diastolic blood pressure > 95 mm Hg , or use of any antihypertensive drug ) , visual impairment in 1 or both eyes , and body mass index ( kg/m2 ) were measured at the research center . Presence of peripheral arterial disease was measured ( as described elsewhere [ 28 ] ) by using a single measurement of systolic blood pressure taken at both the left and the right posterior tibial artery . The ratio of the systolic blood pressure at the ankle to the systolic blood pressure at the arm was calculated for each leg . Peripheral arterial disease was considered present when the blood pressure at the arm was lower than 0.9 mm Hg on at least 1 side . Lower-limb disability was assessed by using a modified version of the Stanford Health Assessment Question naire ( 29 ) and by calculating the mean score of answers to questions about rising , walking , bending , and getting in and out of a car ( 30 ) . A score of 0 indicates no disability , a score between 0 and 1 indicates mild disability , and a score of more than 1 indicates severe disability . Intake of calcium was adjusted for the total caloric intake according to the method of Willett and associates ( 31 ) . Bone mineral density of the femoral neck was measured by using dual-energy x-ray absorptiometry ( DPX-L densitometer , Lunar 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 We tested the hypothesis that xanthine oxidase inhibition among African Americans receiving the thiazide-type diuretic chlorthalidone  may improve blood pressure control with fewer hyperuricemia-related side effects . We performed a r and omized , double-blind , placebo-controlled study of African Americans with Stage 1 hypertension without clinical ly significant renal disease . One hundred fifty African American men or women between the ages of 18 and 65 years who met the exclusion/ inclusion criteria with untreated or treated hypertension were started on chlorthalidone ( 25 mg/d ) and potassium chloride . After a 5-week run-in on chlorthalidone , baseline testing was performed and they were r and omized to allopurinol ( 300 mg/dL ) or placebo with doses adjusted based on uric acid levels and followed for 8 weeks . One hundred ten subjects completed the study . Baseline systolic blood pressures after the 5-week chlorthalidone run-in were 119.9 ± 13.6 in the allopurinol group and 117 ± 11.2 in the placebo group indicating excellent blood pressure control with the single agent . After at least 4 week postr and omization , the difference in mean change in systolic blood pressure  in allopurinol less placebo from visits 5 to 3 was 4.3 mm Hg ( 95 % confidence interval , -0.2 to 8.7 ; P = .059 ) . The difference in mean change in uric acid levels over the same period was 2.1 mg/dL ( 95 % confidence interval , 1.7 - 2.6 ; P < .001 ) . The use of chlorthalidone with or without allopurinol result ed in excellent blood pressure control . The addition of allopurinol tended to improve clinic blood pressure , but the difference from the group receiving chlorthalidone alone was not statistically significant The present primary prevention study aim ed at investigating whether metoprolol given as initial antihypertensive treatment would lower cardiovascular complications of high blood pressure to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1,609 , 8,110 patient-years ) or a thiazide diuretic ( n = 1,625 , 8,070 patient-years ) . At r and omization , 535 patients in the metoprolol group and 524 patients in the diuretic group were classified as smokers . Blood pressure control during follow-up was equally effective regardless of smoking habits at r and omization . Cardiovascular and coronary heart disease mortality was three to four times higher in smokers than in nonsmokers , underlining the importance of smoking as a risk factor . Total and cardiovascular mortality were significantly lower for the metoprolol group than for the thiazide diuretic group in the whole study population ( p = 0.028 and p = 0.012 ) , as well as in smokers ( p = 0.013 and p = 0.016 ) . Coronary heart disease mortality was significantly lower for patients on metoprolol  than for patients on diuretics  in the whole study population ( p = 0.048 ) as well as in smokers ( p = 0.02l ) . The results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of total , cardiovascular , and coronary heart disease mortality as compared with initial diuretic treatment , both in the whole study population and in smokers . The favorable effect of metoprolol must be mediated via mechanisms other than the blood pressure-lowering effect of metoprolol because equal blood pressure control was achieved with both types of medication , irrespective of smoking habits at r and omization 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 BACKGROUND Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors . METHODS The Systolic Hypertension in the Elderly Program was a community-based , multicenter , r and omized , double-blind , placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older . This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program , including changes in serum chemistry test results in a subgroup for 3 years . Patients were r and omized to receive placebo or treatment with active drugs , with the dose increased in stepwise fashion if blood pressure control goals were not attained : step 1 , 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone ; and step 2 , the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo . RESULTS After 3 years , the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group ( both groups , P<.001 ) . New cases of diabetes were reported by 8.6 % of the participants in the active treatment group and 7.5 % of the participants in the placebo group ( P=.25 ) . Small effects of active treatment compared with placebo were observed with fasting levels of glucose ( + 0.20 mmol/L [ + 3.6 mg/dL ] ; P<.01 ) , total cholesterol ( + 0.09 mmol/L [ + 3.5 mg/dL ] ; P<.01 ) , high-density lipoprotein cholesterol ( -0.02 mmol/L [ -0.77 mg/dL ] ; P<.01 ) and creatinine ( + 2.8 micromol/L [ + 0.03 mg/dL ] ; P<.001 ) . Larger effects were seen with fasting levels of triglycerides ( + 0.9 mmol/L [ + 17 mg/dL ] ; P<.001 ) , uric acid ( + 35 micromol/L [ + .06 mg/dL ] ; P<.001 ) , and potassium ( -0.3 mmol/L ; P<.001 ) . No evidence was found for a subgroup at higher risk of risk factor changes with active treatment . CONCLUSIONS Antihypertensive therapy with low-dose chlorthalidone ( supplemented if necessary ) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels This prospect i ve , r and omized trial evaluated the effect of monotherapy and different combination therapies on cardiovascular target organ damage and metabolic profile in 520 hypertensive patients . Patients were allocated to a single agent : carvedilol 25 mg , amlodipine 10 mg , enalapril 20 mg , or losartan 50 mg ( groups C , A , E , and L , respectively ) . After 2 months ( level 2 ) , nonresponders received a low-dose thiazide diuretic , and after 4 months ( level 3 ) , amlodipine ( groups E , C , and L ) and carvedilol ( group A ) . Twenty-four-hour blood pressure was significantly lowered in all treatment groups . Blood pressure control was more pronounced in patients receiving two or three drugs . At the end of the study , the carotid intima-media thickness decreased in group L ( P<.01 ) , left ventricular mass index in groups E and L ( P<.05 and P<.001 , respectively ) , with a concomitant reduction in cholesterol in group L ( P<.03 ) . Diastolic function improved significantly in group L ( P<.05 ) . This study describes the need to control blood pressure with two or more drugs in most hypertensive patients and illustrates good clinical outcomes , independent of blood pressure lowering , using combination therapy with losartan , low-dose thiazide , and amlodipine Hydrochlorothiazide in a daily dose of 150 mg and spironolactone in a daily dose of 400 mg ( 100 mg of the currently available preparation ) were found to have equivalent antihypertensive effects — reducing basal blood pressure , decreasing the pressor response to levarterenol bitartrate ( norepinephrine ) and angiotensin amide , and increasing the depressor response to a ganglion-blocking agent , trimethaphan camsylate — in a double-blind study of 11 hypertensive patients . The two diuretics , when given together , appear to act independently and additively in their antihypertensive effects . Serum potassium level , lowered by hydrochlorothiazide , was in the normal range during administration of spironolactone alone or in combination with hydrochlorothiazide . Spironolactone can thus be a useful substitute for a benzothiadiazine derivative in the treatment of hypertension . The administration of a combination of these diuretics , a thiazide and an aldosterone antagonist , can render hypertension more readily manageable Abstract Background . Arterial hypertension is commonly associated with hyperuricemia . Several studies have shown that allopurinol reduces arterial blood pressure in animal models and in adolescent patients with newly diagnosed hypertension . Moreover , allopurinol has shown beneficial effects on endothelial function and arterial wave reflection in contrast to uricosuric agents . Antihypertensive drugs produce different effects on serum uric acid levels . Objective . The aim of the study was to evaluate the influence of allopurinol on blood pressure and aortic compliance in patients with arterial hypertension depending on hypotensive therapy with angiotensin-converting enzyme inhibitor ( ACE-I ) or thiazide diuretic , hypotensive drugs with distinct effects on serum uric acid levels and conversely , a positive influence on pulse wave velocity ( PWV ) in the aorta . Material and Methods . Sixty-six patients aged 25–70 ( mean age 46.17 ± 10.89 ) with mild and moderate arterial hypertension diagnosed on the basis of office blood pressure , were studied . They were r and omized to antihypertensive therapy on either perindopril ( n = 35 ) or hydrochlorothiazide ( n = 31 ) . After 8 weeks of antihypertensive therapy , 150 mg of allopurinol daily was added for the next 8 weeks . Measurement of the serum uric acid level , PWV and 24-h ambulatory blood pressure monitoring ( ABPM ) were performed at baseline , after 8 weeks antihypertensive therapy and again after the final 8 weeks with the additional allopurinol . Results . No significant changes in systolic ( SBP ) and diastolic blood pressure ( DBP ) or ABPM were observed after allopurinol treatment in either of the subgroups receiving ACE-I or thiazide-based antihypertensive therapy . The mean PWV decreased from 10.7 ± 1.4 m/s to 10.0 ± 1.2 m/s ( p = 0.00008 ) in the ACE-I-based therapy subgroup and from 11.5 ±1.7 m/s to 10.4 ± 1.5 m/s ( p = 0.00002 ) in the thiazide-based therapy subgroup after treatment with allopurinol . However , significant correlations were found between PWV changes and the basic PWV ( r = −0.52 ; p < 0.001 ) or SBP changes ( r = 0.29 ; p < 0.019 ) after allopurinol treatment . Conclusions . Allopurinol does not produce additional antihypertensive effects in patients with treated arterial hypertension . Allopurinol increases aortic compliance independently of ACE-I or thiazide-based , antihypertensive therapy . However , this effect is significantly dependent on the initial PWV in the aorta and on SBP changes during allopurinol therapy Because obesity-associated hypertension has unique hemodynamic and hormonal profiles , certain classes of antihypertensive agents may be more effective than others as monotherapy . Thus , we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week , multicenter , double-blind trial in 232 obese patients with hypertension . Patients with an office diastolic pressure between 90 and 109 mm Hg were r and omized to treatment with daily doses of lisinopril ( 10 , 20 , or 40 mg ) ,  hydrochlorothiazide  ( 12.5 , 25 , or 50 mg ) , or  placebo . Mean body mass indexes were similar for all patients . At week 12 , lisinopril and hydrochlorothiazide effectively lowered office diastolic ( -8.3 and -7.7 versus -3.3 mm Hg , respectively ; P<.005 ) and systolic ( -9.2 and -10.0 versus -4.6 mm Hg , respectively ; P<.05 ) pressures compared with placebo .  Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo ( P<.001 ) . Significant dose-response differences were observed between treatments . Sixty percent of patients treated with lisinopril had an office diastolic pressure < 90 mm Hg compared with 43 % of patients treated with hydrochlorothiazide ( P<.05 ) . Responses to therapies differed with both race and age . Neither treatment significantly affected insulin or lipid profiles ; however , plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril ( + 0.31 versus -0.21 mmol/L ; P<.001 ) . Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline . In conclusion , lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension . Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics , may have a more rapid rate of response , and may offer advantages in patients at high risk of metabolic disorders Azilsartan medoxomil , an effective , long-acting angiotensin II receptor blocker , is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone , a potent , long-acting thiazide-like diuretic . We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg . The design was a r and omized , 3-arm , double-blind , 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ⩽119 mm Hg . Patients had a mean age of 57 years ; 59 % were men , 73 % were white , and 22 % were black . At  baseline , mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg . Changes in clinic ( primary end point ) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm ( P<0.001 ) . Changes in clinic systolic blood pressure ( mean±SE ) were −42.5±0.8 , −44.0±0.8 , and −37.1±0.8 mm Hg , respectively . Changes in 24-hour ambulatory systolic blood pressure were −33.9±0.8 , −36.3±0.8 , and −27.5±0.8 mm Hg , respectively . Adverse events leading to permanent drug discontinuation occurred in 7.9 % , 14.5 % , and 7.1 % of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg , azilsartan medoxomil/chlorthalidone 80/25 mg , and olmesartan/hydrochlorothiazide 40/25 mg , respectively . This large , forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide BACKGROUND Losartan , an angiotensin II receptor antagonist , has been shown to decrease serum uric acid and to increase urinary excretion of uric acid . METHODS To determine if this effect can increase the risk of acute urate nephropathy , 63 hypertensive patients with thiazide-induced asymptomatic hyperuricemia ( serum uric acid 7.0 to 12.0 mg/dl ) were r and omized double-blind to losartan 50 mg every day ( q.d . ) , losartan 50 mg plus hydrochlorothiazide ( HCTZ ) 50 mg q.d . , HCTZ 50 mg q.d . , or placebo for three weeks . To potentiate the risk of crystal formation , patients received a 2 g/kg protein diet one day prior to each clinic visit on days 0 ( baseline ) , 1 , 7 , and 21 . RESULTS Adverse events typically associated with acute urate nephropathy , for example , flank pain , hematuria , or increased blood urea nitrogen/creatinine , were not reported . Uric acid excretion and urine pH increased four and six hours after losartan on day 1 compared with day 0 . Dihydrogen urate , the primary risk factor for crystal formation , decreased at four and six hours on day 1 compared with day 0 associated with the concurrent rise in urine pH. Day 7 and 21 changes , compared with day 0 , in uric acid excretion rate , urine pH , and dihydrogen urate with losartan were comparable to day 1 results but were not statistically significant . Serum uric acid was significantly reduced after 21 days of therapy with losartan . CONCLUSION Losartan decreased serum uric acid and increased uric acid excretion without increasing urinary dihydrogen urate , the primary risk factor for acute urate nephropathy , during 21 days of dosing in hypertensive patients with thiazide-induced hyperuricemia Men aged 40 - 64 years with mild to moderate hypertension [ diastolic blood pressure ( DBP ) 100 - 130 mmHg ] were r and omized to treatment with a  diuretic ( n = 3272 ) or a  beta-blocker ( n = 3297 ) , with additional drugs if necessary , to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease ( CHD ) events and death .  Patients with previous CHD , stroke or other serious diseases , or with contraindications to diuretics or beta-blockers were excluded . If normotension ( DBP less than 95 mmHg ) was not achieved by monotherapy , other antihypertensive drugs were added , but the two basic drugs were not crossed over . Patients were assessed at 6-monthly intervals . The mean follow-up for end-points was 45.1 months . Blood pressure ( BP ) side effects and end-points were recorded in a st and ardized manner . Entry characteristics and the BP reduction achieved were very similar in both treatment groups . All analyses were made on an intention-to-treat basis . The incidence of CHD did not differ between the two treatment groups . The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group . Total mortality and the total number of end-points were similar in both groups . The percentage of patients withdrawn due to side effects was similar , whereas the number of reported symptoms , according to a question naire , was higher for patients on beta-blockers . The incidence of diabetes did not differ between the two groups . Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers , and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD . Beta-blockers and thiazide diuretics were approximately equally well tolerated . The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group . Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications , including CHD , to a different extent The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated . A total of 127 adult out patients with diastolic blood pressure between 100 and 114 mmHg were r and omized into this double-blind , parallel group study . After a 2-week wash-out period and a subsequent 2-week placebo run-in period , they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide ( R/C ) , or 5 mg enalapril . If diastolic blood pressure was not normalized after 3 weeks of therapy ( i.e. DBP < 90 mmHg ) , the dosage was doubled from week 4 to 6 . The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure ( DBP/SBP ) after 3 weeks of therapy . Secondary variables included the change in DBP and SBP after 6 weeks of therapy , the BP normalization rates at 3 and 6 weeks and , concerning tolerability , the rates of adverse events after 6 weeks of therapy . An intent-to-treat analysis was performed . The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics ( mean age 57 or 58 years , respectively ; 63 % or 56 % males , respectively ; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups ) . After 3 weeks of treatment with one capsule daily , mean SBP/DBP reduction from baseline ( 24 h after last medication intake ) in the R/C combination group was -19.6/ -17.0 mmHg , in the enalapril group -6.1/ -9.5 mmHg ( between-group comparison : 2p < 0.01 for both parameters ) . The normalization rates for DBP ( < 90 mmHg ) were 64.1 % ( R/C ) and 28.6 % ( enalapril ) ( 2p < 0.01 ) . Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients ( 17.2 % ) in the R/C group and in 9 patients ( 14.3 % ) in the enalapril group ( NS ) . Two patients in the enalapril group discontinued the study prematurely due to adverse events ( cough ; skin eruption ) . In the treatment of mild-to-moderate hypertension , a low-dose combination of reserpine and clopamide once a day is considerably more effective than , and as tolerable as , 5 - 10 mg of enalapril once a day . These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension . Besides , the " old " reserpine-diuretic regimen also in these days appears to be a rational alternative to " modern " monotherapies OUTCOMES Extensive data from r and omised controlled trials have shown the benefit of treating hypertension . The target blood pressure ( BP ) for antihypertensive management is systolic < 140 mmHg and diastolic < 90 mmHg with minimal or no drug side-effects ; however , stricter BP control is required for patients with end-organ damage , co-existing risk factors and co-morbidity , e.g. diabetes mellitus . The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 1 month . Co-existent risk factors should also be controlled . BENEFITS Benefits of management include reduced risks of stroke , cardiac failure , chronic kidney disease and coronary heart disease . RECOMMENDATIONS The correct BP measurement procedure is described , and evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated . The total cardiovascular disease risk profile should be determined for all patients to inform management strategies . Lifestyle modification and patient education are cornerstones in the management of every patient . Major indications , pre caution s and contra-indications to each recommended antihypertensive drug are listed . Combination therapy should be considered ab initio if the BP is ≥ 20/10 mmHg . First-line drug therapy for uncomplicated hypertension includes low-dose thiazide-like diuretics , calcium channel blockers ( CCBs ) or angiotensin-converting enzyme inhibitors ( ACE-Is ) ( or ARBs - angiotensin II receptor blockers ) . If the target BP is not obtained , a second antihypertensive should be added from the aforementioned list . If the target BP is still not met , the third remaining antihypertensive agent should be used . In black patients  either thiazide-like diuretics or CCBs can be used initially , because response rates are better than with ACE-Is or β-blockers . In treating resistant hypertension , a central ly acting drug , vasodilator , α-blocker , spironolactone or β-locker should be added . This guideline includes management of specific situations , i.e. hypertensive emergency and urgency , severe hypertension with target organ damage , hypertension in diabetes mellitus , resistant hypertension , fixed drug combinations , new trials in hypertension , and interactions of antihypertensive agents with other drugs . VALIDITY The guideline was developed by the Southern African Hypertension Society 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 The present study of primary prevention in white men aged 40 to 64 years attempts to investigate whether a beta-blocker given as initial antihypertensive treatment would lower total mortality to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1609 , 8110 patient-years ) or a thiazide diuretic ( n = 1625 , 8070 patient-years ) . The median follow-up time was 4.2 years . The mean dose of metoprolol was 174 mg/d , and of thiazide diuretics , 46 mg/d of hydrochlorothiazide or 4.4 mg/d of bendroflumethiazide . Identical control of blood pressure was achieved using a fixed therapeutic schedule . Total mortality was significantly lower for metoprolol than for thiazide diuretics because of fewer deaths from coronary heart disease and stroke . Total mortality was also significantly lower in smokers r and omized to metoprolol .  The benefit demonstrated in patients treated with metoprolol seems to have important implication s for clinical practice
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 .