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A 52-week prospective, cohort study of the effects of losartan with or without hydrochlorothiazide (HCTZ) in hypertensive patients with metabolic syndrome
Abstract and Figures
The impact of an ARB, with or without hydrochlorothiazide (HCTZ), on glycaemic factors and the risk for developing diabetes in hypertensive patients with the metabolic syndrome have not been fully assessed. This was a 52-week multicentre, prospective, phase-IV, open-label, cohort study of losartan or losartan/HCTZ in hypertensive patients with metabolic syndrome. All subjects were treated initially with losartan 50 mg day(-1). Those not achieving target blood pressure (BP <140/90 mm Hg) were titrated sequentially to losartan 100 mg, losartan 100 mg/HCTZ 12.5 mg, losartan 100 mg/HCTZ 25 mg and finally to losartan 100 mg/HCTZ 25 mg and calcium-channel blocker (CCB), as required. The primary glycaemic outcome measure was change in fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c) at 52 weeks of treatment. Among the 1897 potentially eligible patients enrolled in the study, 1714 fulfilled the screening criteria. During the 52-week treatment period of the study, FBG and HbA1c did not change significantly. Clinically important and statistically significant changes were observed for both the systolic (SBP) and diastolic BP (DBP) during the study treatment period, with an overall mean decrease of 16.95 mm Hg in SBP (P=0.001) and 9.84 mm Hg in DBP (P=0.001). The majority of the patients (77.3%) achieved a target BP of <140/90 mm Hg. In conclusion, losartan, either alone or in combination with HCTZ, is effective in managing hypertension without inducing any change in glycaemic parameters or increasing the risk for developing diabetes in hypertensive patients with the metabolic syndrome.
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... The hydroxychlorothiazide (HCTZ)/losartan potassium (LOS-K) tablet was the first compound preparation comprised of an antagonist to angiotensin II receptor (AT1) and a diuretic, which was approved by the FDA in April 1995. The combination of HCTZ and LOS-K exhibited a synergistic effect on pharmacological activity, increased antihypertensive efficacy, and reduced adverse reactions [1,2]. ...
Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final parameters. The type and amount of lactose monohydrate (SuperTab®14SD, 19.53–26.91%), microcrystalline cellulose (MCC PH102, 32.86–43.31%), pre-gelatinized starch (Starch-1500, 10.96–15.91%), and magnesium stearate (0.7%) were determined according to the compressive work, stress relaxation curves, and Py value. Then, the compression mechanism of the mixed powder was investigated by the Kawakita equation, Shapiro equation, and Heckel analysis, and the mixed powder was classified as a Class-II powder. The compaction pressure (150–300 MPa) and tableting speed (1200–2400 Tab/h) were recommended. A D-optimal mixture experimental design was utilized to select the optimal formulation (No 1, 26.027% lactose monohydrate, 32.811% MCC PH102, and 15.462% pregelatinized starch) according to the drug dissolution rate, using Hyzaar® tablets as a control. Following oral administration in beagle dogs, there were no significant differences in bioavailability between the No. 1 tablet and the Hyzaar® tablet in HCTZ, losartan carboxylic acid (E-3174), and LOS-K (F < F0.05). Thus, formulation and preparation factors were determined according to the combination of the compression and mechanical properties of the mixed powder and quality of tablets, which was demonstrated to be a feasible method in direct powder compression.
... In contrast, β-blockers (BBs), a commonly used antihypertensive drug in uncomplicated hypertension, are not recommended in people with the metabolic syndrome, in whom there are concerns about unexpected off-target effects on glucose metabolism and lipid profile based on observational studies [5,6] and small clinical trial evidence [7]. However, the observed associations are inconsistent [8,9], and may be open to residual confounding by socioeconomic position and health status. Evidence from RCTs is not clearly established due to the relatively short follow-up in trials with diabetes as the primary outcome (such as for ACE inhibitors) [4] and ethical considerations precluding examination of expected harms as a primary outcome in large RCTs (such as for BBs). ...
Aims/hypothesis
Diabetes and hyperlipidaemia are common comorbidities in people with hypertension. Despite similar protective effects on CVD, different classes of antihypertensive drugs have different effects on CVD risk factors, including diabetes, glucose metabolism and lipids. However, these pleiotropic effects have not been assessed in long-term, large randomised controlled trials, especially for East Asians.
Methods
We used Mendelian randomisation to obtain unconfounded associations of ACE inhibitors, β-blockers (BBs) and calcium channel blockers (CCBs). Specifically, we used genetic variants in drug target genes and related to systolic BP in Europeans and East Asians, and applied them to the largest available genome-wide association studies of diabetes (74,124 cases and 824,006 controls in Europeans, 77,418 cases and 356,122 controls in East Asians), blood glucose levels, HbA1c, and lipids (LDL-cholesterol, HDL-cholesterol and triacylglycerols) (approximately 0.5 million Europeans and 0.1 million East Asians). We used coronary artery disease (CAD) as a control outcome and used different genetic instruments and analysis methods as sensitivity analyses.
Results
As expected, genetically proxied ACE inhibition, BBs and CCBs were related to lower risk of CAD in both ancestries. Genetically proxied ACE inhibition was associated with a lower risk of diabetes (OR 0.85, 95% CI 0.78–0.93), and genetic proxies for BBs were associated with a higher risk of diabetes (OR 1.05, 95% CI 1.02–1.09). The estimates were similar in East Asians, and were corroborated by systematic review and meta-analyses of randomised controlled trials. In both ancestries, genetic proxies for BBs were associated with lower HDL-cholesterol and higher triacylglycerols, and genetic proxies for CCBs were associated with higher LDL-cholesterol. The estimates were robust to the use of different genetic instruments and analytical methods.
Conclusions/interpretation
Our findings suggest protective association of genetically proxied ACE inhibition with diabetes, while genetic proxies for BBs and CCBs possibly relate to an unfavourable metabolic profile. Developing a deeper understanding of the pathways underlying these diverse associations would be worthwhile, with implications for drug repositioning as well as optimal CVD prevention and treatment strategies in people with hypertension, diabetes and/or hyperlipidaemia.
Graphical abstract
... In addition, total cholesterol levels were not changed during the study period, a finding already reported by several investigators [Hirose et al. 2011;Racine et al. 2010;Ibuki et al. 2014]. ...
Objectives:
The guidelines for hypertension require the presence of compelling indications for pharmacological management of hypertension associated with various diseases. Data mainly obtained through randomized controlled trials have provided evidence supporting effectiveness of the combination of losartan (Lo) and hydrochlorothiazide (HCTZ) for management of hypertensive patients. However, there have been few reports discussing the effectiveness of Lo/HTCZ (losartan 50 mg/hydrochlorothizide 12.5 mg) in the 'real world' in the management of isolated systolic hypertension (ISH). This study was designed to investigate the 'real world' effectiveness of Lo/HTCZ-based treatment of ISH associated with various diseases.
Methods:
This was a retrospective, uncontrolled analysis of data derived from a large, cross-sectional web-based clinical database collected by physicians.
Results:
Of 24,825 eligible patients, 20,726 were followed during a 6-month period. Among these, subjects for analysis included those with systolic blood pressure (SBP) >140 mmHg and diastolic BP (DBP) <90 mmHg; patients with diabetes mellitus and chronic kidney disease were excluded. A total of 15,846 patients were analysed. Among the various complications, hypercholesterolemia was the most frequent concomitant cardiovascular (CV) risk factor (48.1%), followed by obesity (16.3%). Associated clinical conditions were cerebrovascular diseases (9.6%), ischemic heart disease (7.9%) and left ventricular hypertrophy (4.6%). Total numbers of patients exhibiting any type of complications were 62% (≤64 years old), 69% (65-74 years old) and 67% (≥75 years old) (stratification of age). Mean SBP/DBP measurements (mm Hg) were 156/78 at the start, 140/72 at 1 month and 134/72 at 6 months. Blood pressure (BP) reductions associated with various diseases were similar among patients. Laboratory data including serum levels of total cholesterol, uric acid, hemoglobin A1c and serum potassium did not change during the study. Adverse effects such as orthostatic hypotension and considerable reductions in BP (>30 mmHg SBP) were rare.
Conclusions:
Lo/HTCZ is safe and effective in reducing and improving BP control in a 'real world' setting. Treatment with Lo/HTCZ enabled a substantial proportion of hypertensive patients with associated diseases to achieve the recommended goal of <140 mm Hg.
... For instance, studies exploring the effect of ARB/HCTZ repeatedly showed a reduction in eGFR in association with an increase in serum Cr concentration [7, 16, 17]. Decreased eGFR owing to the use of diuretics could be explained by the contraction of circulating plasma volume. ...
Achieving adequate blood pressure (BP) control often requires more than one antihypertensive agent. The purpose of this study was to determine whether a fixed-dose formulation of losartan (LOS) plus hydrochlorothiazide (HCTZ) (LOS/HCTZ) is effective in achieving a greater BP lowering in patients with uncontrolled hypertension.
The study was a prospective, multicenter, observational trial exploring the antihypertensive effect of a single tablet of LOS 50 mg/HCTZ 12.5 mg. A total of 228 patients whose BP had previously been treated with more than one antihypertensive agents without having achieved BP goal below 130/80 mmHg enrolled in the study.
A significant decrease in systolic and diastolic BP was observed in both clinic and home measurement after switching from the previous treatment to LOS/HCTZ. There was a significant decrease in both B-type natriuretic peptide (BNP) and urinary albumin creatinine (Cr) excretion ratio (ACR), especially in patients with elevated values. In contrast, there was a significant increase in serum Cr concentration in conjunction with a decrease in estimated glomerular filtration rate (eGFR). Overall serum uric acid (UA) concentration increased, whereas in patients with hyperuricemia there was a significant reduction in this value.
Switching to LOS/HCTZ provides a greater reduction in clinic and home BP in patients with uncontrolled hypertension. This combination therapy may lead to cardio-, reno protection and improve UA metabolism.
Background: Metabolic syndrome (MetS) is a chronic disease defined by a set of genetic and environmental factors that determine high cardiovascular risk, being highly prevalent in hypertensive patients. Aim: To identify the efficacy of the association of antihypertensive drugs in hypertensive individuals with MetS. Methods: The systematic review searching the electronic databases Medline/PubMed, Lilacs, BVS and Periódicos Capes with articles published from 2010 to 2020. The registration number of this review at PROSPERO is CRD42021235614. Original articles and clinical randomized trials were included in present review. To calculate the meta-analytic effect measure was used the absolute difference between means using the random effects model with 95% confidence interval. Results: Eight articles were included in this review totaling data from 2,625 patients. In six papers was performed meta-analysis. The selected studies suggest that most combinations of antihypertensive drug classes reduced blood pressure to satisfactory values, and some combinations reduced markers of inflammation, improved lipid and glycemic parameters and reduced the risk of developing diabetes mellitus. The combination therapies between angiotensin receptor blockers (ARB) and calcium channel blockers (CCB), as well as, the combination between CCB and angiotensin converting enzyme inhibitors (ACEI) were well-tolerated and showed satisfactory results in hypertensive patients with metabolic syndrome. Conclusion: based on the results of the present study, we would like to suggest that further studies be carried out to assess the efficacy of the combination between irbesartan and manidipine (ARB and CCB), manidipine and Lisinopril (CCB and ACEI), and between enalapril and lercadipine (ACEI and CCB). These drugs have shown satisfactory results for use in hypertensive patients with MetS.
The current approach to the management of hypertension has not provided us with the desired results. The use of combination therapy as frst line treatment, or much earlier treatment in the course of treating hypertension, appears to be much more effcient than the stepped care approach. The use of combination therapy will provide greater effcacy, fewer adverse effects and greater adherence than can be achieved with monotherapy and, most importantly, will signifcantly increase control rates. It would appear that a paradigm change in the treatment of hypertension may be the most signifcant change to make in order to improve worldwide control rates, which will ultimately impact cardiovascular disease.
Objective:
The aim of the present study was to assess changes in blood pressure and metabolism after switching treatment from maximum-dose angiotensin II receptor blocker (ARB) therapy to a mixture of conventional-dose ARBs and low-dose diuretics.
Methods:
This study was conducted among 43 Japanese patients with type 2 diabetes complicated with hypertension in whom continuous treatment with high doses of ARBs did not reduce their blood pressure to the target level (a systolic blood pressure of 130 mmHg or lower and a diastolic blood pressure of 80 mmHg or lower). The antihypertensive and metabolic effects of switching from high-dose ARBs to a combination of losartan (50 mg/day) plus hydrochlorothiazide (12.5 mg/day) were examined. The primary endpoint was a decrease in blood pressure at 24 weeks.
Results:
The combination treatment significantly decreased both systolic (baseline: 147±11; 24 weeks: 133±13 mmHg) and diastolic (baseline: 79±8; 24 weeks: 72±10 mmHg) blood pressure. This treatment was also associated with a significant increase in the HbA1c level (baseline: 7.0±0.8%; 24 weeks: 7.2±0.9%) and a significant decrease in the urinary albumin-creatinine ratio (baseline: 280±590; 24 weeks: 110±253 mg/g creatinine). However, the combination treatment had no effect on lipid metabolism or the serum uric acid or potassium levels.
Conclusion:
In patients with diabetes, sodium reabsorption in the renal tubules is enhanced, which leads to the development of salt-sensitive hypertension. Therefore, the concurrent use of a diuretic that promotes sodium excretion can increase the antihypertensive effects of other drugs. This study demonstrated that switching from high-dose ARB treatment to losartan/hydrochlorothiazide combination therapy results in significant control of blood pressure.
This study is a meta-analysis of the metabolic profile (fasting plasma glucose and serum potassium) of low-dose thiazide and thiazide-like diuretics. The meta-analysis involved 10 randomized controlled clinical trials with a total sample size of 17,636 and 17,947 for the potassium and glucose arms respectively. The random effect model was used to calculate the odds ratio with 95 percent confidence interval. The cumulative mean change of fasting plasma glucose was +0.20 mmol/L (+3.6 mg/dL) for the diuretic arm versus +0.12 mmol/L (+2.2 mg/dL) for the comparator arm. The cumulative mean change of serum potassium was -0.22 mmol/L (-0.22 mEq/L) for the diuretic arm versus +0.05 mmol/L (+0.05 mEq/L) for the comparator arm. The aggregate odds ratio for having higher fasting plasma glucose in subjects on low-dose thiazide versus non-thiazide antihypertensive was 1.22 (1.11 to 1.33; P < .01). The odds ratio for having a lower serum potassium in subjects on low-dose thiazide versus non-thiazide antihypertensive was 0.36 (0.27 to 0.49; P < .01). The magnitude of the observed change in fasting plasma glucose associated with low-dose thiazide diuretic use, while statistically significant, does not appear to place patients at clinically significant risk. On the other hand, the observed change in serum potassium was also statistically significant, and may be clinically significant in patients whose baseline potassium concentration is low or low-normal, and could predispose at-risk patients, such as those with ischemic heart disease, to ventricular arrhythmias.
Aim:
The concomitant use of angiotensin II receptor blocker (ARB) with low doses of hydrochlorothiazide (HCTZ) may provide additional antihypertensive activity. HCTZ induces hypokalemia and hyperglycemia, while ARB slightly induces hyperkalemia. Recently, it has been reported that ARB/ HCTZ did not worsen fasting blood sugar levels; however, the detailed glucose tolerance change effect with combination therapy of ARB/HCTZ compared to ARB alone therapy remains to be investigated.
Methods:
Treated non-diabetes mellitus (DM) hypertensive patients taking a common dose of ARB regimens, not achieving blood pressure (BP) goals, were switched to 50 mg Losartan/12.5 mg HCTZ combinations, and the 75 g oral glucose tolerance test (75 g OGTT) was performed before switching and after switching at 3 months.
Results:
This study included 30 patients aged 66.5±8.7 years, 67% women. Pre-switching BP 146.6±17.0/ 88.4±10.4 mmHg decreased and was maintained at a steady state, reaching 131.4±1.0/73.8±8.8 mmHg (p<0.001) 3 months later. After switching, blood glucose levels on the 75 g OGTT at fasting, 30, 60 and 120 minutes were significantly decreased. Homeostasis model assessment as an index of insulin resistance and the whole body insulin sensitivity index were significantly ameliorated.
Conclusions:
On the 75 g OGTT, 50 mg Losartan with 12.5 mg HCTZ combinations did not worsen glucose tolerance; moreover, they improved BP, insulin resistance and sensitivity in non-DM Japanese patients with essential hypertension uncontrolled with ARBs alone.
To evaluate the effect of CYP11B2 gene -344T/C polymorphism on renin-angiotensin-aldosterone system (RAAS) activity and blood pressure in response to hydrochlorothiazide (HCTZ) treatment in Han Chinese patients with essential hypertension.
Eight hundred and twenty-nine patients with mild/moderate essential hypertensive were enrolled. All subjects had their antihypertensive medications withdrawn. After two weeks of wash-out period with placebo, each patient was given 12.5 mg of HCTZ per day for the next six weeks. Physical, biochemical measurements, and the activity of RAAS were taken at the end of the wash-out period (baseline) and 6-week diuretic therapy period. Changes in systolic and diastolic blood pressure were analyzed for association with interaction between genotypes at CYP11B2 -344T/C polymorphism and gender.
A total of 776 patients completed the study. 17.5% of subjects have achieved blood pressure normalization after six weeks treatment. For male patients, the aldosterone level with CC genotype was significantly higher than that of those with TT or TC genotype. Following the HCTZ treatment, the blood pressure response in patients with CC genotype was less obvious than that in others, whilst the increase of aldosterone level was greater. For female patients, no association was found between CYP11B2 -344T/C polymorphism and aldosterone level. Following the HCTZ treatment, the blood pressure response in patients with CC genotype was greater than others, whilst the increase of aldosterone activity was less apparent.
In males, the -344T/C polymorphism of CYP11B2 gene is associated with aldosterone level, and the change of aldosterone level was greater, the blood pressure response was weaker after HCTZ treatment. In females, there was no association between this polymorphism and aldosterone level. The change of aldosterone level and blood pressure response to HCTZ were different from that in males.
Scientific Section of the Canadian Diabetes Association. The process was facilitated by funding from Bayer Canada, Eli Lilly/Boehringer Mannheim Alliance, Servier, Parke-Davis, Medisense and Novo-Nordisk Canada. None of the funding sources had a role in the collection, analysis or interpretation of the data or in the decision to publish this report.
Losartan/hydrochlorothiazide (HCTZ) [Hyzaar®] is a fixed-dose combination of the angiotensin II receptor antagonist (angiotensin receptor blocker [ARB]) losartan and the thiazide diuretic HCTZ. It is indicated for the treatment of hypertension (including as initial therapy in severe hypertension) and for stroke risk reduction in patients with hypertension and left ventricular hypertrophy (LVH).
Losartan/HCTZ is an effective combination therapy, lowering blood pressure (BP) to a greater extent than losartan or HCTZ alone in patients with hypertension. Other ARB/HCTZ fixed-dose combinations generally lowered BP to a greater extent than losartan/HCTZ in patients with hypertension, although whether this translates into improvements in cardiovascular outcomes is not known. In the LIFE study, losartan-based therapy was associated with a lower incidence of cardiovascular morbidity and mortality than atenolol-based therapy, mainly as a result of a reduced risk of stroke; the incidence of new-onset diabetes mellitus was also lower with losartan- based therapy. Losartan/HCTZ is a well tolerated combination therapy. Thus, losartan/HCTZ remains an important option in the treatment of hypertension, as well as being indicated to reduce stroke risk in patients with hypertension and LVH.
Pharmacological Properties
Losartan is a reversible, selective, competitive inhibitor of the angiotensin II type 1 (AT1) receptor; E3174, the active metabolite of losartan, is more potent than the parent drug. HCTZ acts directly on the kidney, ultimately increasing the urinary excretion of sodium and reducing the extracellular fluid volume and peripheral resistance, which leads to activation of the renin-angiotensin and sympathetic nervous systems, thereby increasing the sensitivity of the AT1 receptor and enhancing the response to ARBs.
Combination therapy with losartan and HCTZ achieved greater reductions in BP than those seen with either drug alone. Losartan alone and in combination with HCTZ maintained BP control over the entire 24-hour period in patients with essential hypertension, with no significant change in heart rate.
Significantly greater regression of electrocardiographic (ECG) LVH occurred with losartan-than with atenolol-based therapy in patients with hypertension and LVH in the LIFE study. Losartan ameliorated structural abnormalities and endothelial dysfunction in resistance arteries in patients with essential hypertension. In LIFE substudies, regression of carotid artery hypertrophy was seen with losartan- but not atenolol-based therapy, although there was no significant between-group difference in carotid artery plaque development. Losartan-based therapy reduced albuminuria to a significantly greater extent than atenolol-based therapy in patients with hypertension and LVH in a LIFE substudy. Losartan may ameliorate some of the deleterious metabolic effects of HCTZ. For example, losartan attenuated the increase in serum uric acid levels and the potassium loss associated with HCTZ therapy. In addition, losartan reduced serum levels of natriuretic peptides and inhibited platelet aggregation.
Oral losartan tablets have a bioavailability of 33% and oral HCTZ has a bioavailability of ≈60–80%. Losartan undergoes extensive first-pass metabolism by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2C9, whereas HCTZ is not metabolized and is mainly eliminated unchanged in the urine.
Therapeutic Efficacy
Three dose-ranging trials revealed that once-daily losartan 50 mg in combination with HCTZ 12.5 or 25 mg once daily (but not 6.25 mg once daily) was consistently more effective than losartan or HCTZ alone in patients with essential hypertension. The fixed-dose combination of losartan/HCTZ was effective in patients with essential hypertension in another three trials, reducing trough sitting systolic BP (SiSBP)/sitting diastolic BP (SiDBP) to a significantly greater extent than placebo or losartan monotherapy, and achieving significantly higher response rates. In four trials in Black, Chinese, Japanese and obese patients with hypertension, losartan/HCTZ consistently showed significantly greater antihypertensive efficacy than monotherapy with losartan or HCTZ or than placebo.
Comparisons of losartan/HCTZ with other ARB/HCTZ combination therapies in patients with essential hypertension revealed significantly greater BP reductions with telmisartan/HCTZ than with losartan/HCTZ in two trials assessing the reduction in ambulatory BP during the last 6 hours of the dosing interval, with candesartan cilexetil/HCTZ than with losartan/HCTZ in two trials assessing trough SiSBP/SiDBP, and with irbesartan/HCTZ than with losartan/HCTZ in one trial assessing 24-hour ambulatory mean DBP. In terms of response rates, significant between-group differences favouring the comparator ARB/HCTZ were seen in the candesartan/cilexetil trials and in patients receiving the higher telmisartan/HCTZ dosage in one of the telmisartan/HCTZ trials. The reduction in trough SiDBP did not significantly differ between losartan/HCTZ and olmesartan medoxomil/HCTZ recipients in one trial, although the reduction in trough SiSBP and the response rate significantly favoured olmesartan medoxomil/HCTZ.
In two trials, losartan/HCTZ had similar efficacy to captopril/HCTZ or enalapril/HCTZ in patients with essential hypertension, in terms of reductions from baseline in trough SiSBP/SiDBP and response rates.
In the LIFE study in patients with hypertension and LVH, recipients of losartan-based therapy were significantly less likely than those receiving atenolol-based therapy to experience cardiovascular mortality, stroke or myocardial infarction (MI) [primary composite endpoint]. When considered separately, the risk of stroke was significantly lower with losartan- than with atenolol-based therapy, although there were no significant between-group differences in the risk of cardiovascular mortality or MI. The significant effect of losartan-based therapy on stroke was found to be independent of its effects on regression of ECG LVH or BP. New-onset diabetes occurred in significantly fewer patients receiving losartan- versus atenolol-based therapy.
The risk of cardiovascular mortality, stroke or MI was significantly lower in most patient subgroups, including patients with no clinically evident vascular disease, patients with isolated systolic hypertension, patients with diabetes, women, patients with a history of atrial fibrillation and patients considered higher risk. However, Black patients who received losartan-based therapy were significantly more likely than those receiving atenolol-based therapy to experience the composite endpoint of cardiovascular mortality, stroke or MI.
Losartan-based therapy was a cost-effective alternative to atenolol-based therapy in patients with hypertension and LVH, according to the results of cost-effectiveness analyses that were conducted from healthcare payer and/or societal perspectives (and based on the findings of the LIFE study).
Tolerability
Losartan/HCTZ was well tolerated in patients with essential hypertension or hypertension and LVH; adverse events were usually transient and of mild severity. According to a pooled analysis of data from patients with essential hypertension, adverse events reported in >1% of losartan/HCTZ recipients and in numerically more losartan/HCTZ than placebo recipients included upper respiratory tract infection, dizziness, cough, back pain, rash, palpitations, oedema/swelling, abdominal pain and sinusitis. The adverse events seen with losartan/HCTZ were consistent with those seen with losartan or HCTZ monotherapy, and losartan/HCTZ and other ARB/HCTZ combination therapies had generally similar tolerability profiles. In general, losartan/HCTZ was better tolerated than captopril/HCTZ or enalapril/HCTZ in patients with essential hypertension (e.g. a lower incidence of cough).
Losartan-based therapy was generally better tolerated than atenolol-based therapy in patients with hypertension and LVH in the LIFE study. For example, hypotension was the only prespecified adverse event that occurred in significantly more recipients of losartan- versus atenolol-based therapy, whereas bradycardia, cold extremities and sexual dysfunction occurred in significantly more patients receiving atenolol-than losartan-based therapy.
Introduction: Apolipoprotein (apo) C-II is considered as an important activator of lipoprotein lipase (LPL) and is required for efficient lipolysis of triglyceride (TG)-rich lipoproteins. In contrast, excess apo C-II inhibits LPL-mediated hydrolysis of TGs. Apo C-III is an inhibitor of LPL activity. These effects may influence the plasma levels of atherogenic small dense low-density lipoprotein cholesterol (sdLDL-C), since TG concentrations are markers of this subfraction. Material and methods: We examined the possible influence of apo C-II and C-III plasma levels on sdLDL-C concentration in obese patients with metabolic syndrome (MetS). Plasma apo C-II and C-III were determined by an immunoturbidimetric assay. Obese subjects (n=73) with MetS but without any clinically evident cardiovascular disease were enrolled. Results: TG, apo C-II and C-III plasma levels progressively increased when study participants were divided according to sdLDL-C tertiles (P<0.001 for all 3 trends). The apo C-III/C-II ratio was relatively constant (i.e. 2.5) for all tertiles of sdLDL-C. Stepwise multiple linear regression analyses showed that apo C-III levels independently correlated with TG levels, while TG and apo B levels were independently associated with sdLDL-C concentrations. Apo C-II and C-III significantly correlated with sdLDL-C in univariate analysis, but not in multivariate analysis. Conclusions: Apo C-II and C-III levels are not independent predictors of sdLDL-C levels in obese subjects with MetS.
Metabolic syndrome (MS), typified by hypertension, abdominal obesity, dyslipidaemia and impaired glucose metabolism, is a precursor of type 2 diabetes. Thiazide diuretics (TD) and beta-blockers are associated with increased risk of diabetes in patients with hypertension; however, the role of these agents in development of diabetes in MS patients is unknown. We reviewed the literature regarding risk factors for diabetes development and compared this with data from the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR), which investigated the effects of two fixed-dose combinations (FDCs) [trandolapril/verapamil SR and losartan/hydrochlorothiazide (L/H)] on glucose control and new diabetes in MS patients. In STAR, logistic regression modelling identified haemoglobin A1c [odds ratio (OR) 4.21 per 1% increment; p = 0.003), L/H treatment (OR 4.04; p = 0.002) and 2-h oral glucose tolerance test glucose levels (OR 1.39 per 10 mg/dl increments; p < 0.001) as baseline predictors of diabetes. These data support prior analyses and suggest that choice of antihypertensive agent is important. Patients with MS may be at lower risk of diabetes when using a FDC calcium channel blocker + angiotensin-converting enzyme inhibitor compared with an angiotensin receptor blocker + TD.
Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor-1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.
Hypertension in metabolic syndrome is common. Basic principles of therapeutic approach like decrease of body weight are discussed. Goal blood pressure levels are < or = 130/80mm Hg. ACE-inhibitors/AT1-blockers are considered drugs of choice. In most cases it is necessary to combine at least two drugs. Preferred combination is ACE-inhibitor/AT1-blocker + calcium channel blocker.
Combination therapy with angiotensin II Type I receptor blocker 50 mg of losartan and a fixed combination of losartan (50 mg)/hydrochlorothiazide (12.5 mg) was administered to hypertensive patients with Stage 3 - 4 chronic kidney disease to investigate its renoprotective effect.
Subjects already being administered the angiotensin I-converting enzyme inhibitor enalapril and losartan 100 mg daily were enrolled in this open-labeled trial (n = 40). Administration of 100 mg losartan twice daily was replaced with losartan (50 mg)/hydrochlorothiazide (12.5 mg) once daily after the morning meal and losartan at 50 mg once daily after the evening meal for the 24-week study period.
The mixture of losartan/hydrochlorothiazide significantly reduced systolic and diastolic blood pressures by 14.7 and 7.4 mmHg, respectively, compared with the baseline values. No significant changes were observed in the serum creatinine levels and estimated glomerular filtration rate. The urinary protein/creatinine ratio was, however, significantly decreased. Similarly, the regression line of 1/serum creatinine level was significantly increased after administration of losartan/hydrochlorothiazide. None of the patients exhibited a significant increase in the occurrence of adverse effects.
Our results demonstrated that a low dose of hydrochlorothiazide had a renoprotective effect due to its blood pressure-lowering effect. We accordingly propose that a low dose of hydrochlorothiazide should be administered to those patients in whom the blood pressure is not well controlled by intensive renin-angiotensin system inhibition therapy using the maximum recommended doses of angiotensin II Type I receptor blockers and angiotensin I-converting enzyme inhibitors.
The aim of this retrospective cohort study is to assess the cumulative development incidence and predictive factors for type 2 diabetes (T2DM) in HCV positive and hypertensive patients treated with losartan. Eighty Japanese patients were given 50 mg of losartan per day after diagnosis of hypertension (losartan group). Another 160 treated with spironolactone were selected as control (spironolactone group). Patients in spironolactone group were matched 1:2 with losartan group for age and sex. The mean observation period was 5.2 years in losartan group and 5.4 years in spironolactone group. An overnight (12 hr) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal is the onset of T2DM. Evaluation was performed by using the Kaplan-Meier method and the cox proportional hazards analysis. Three patients in losartan group and 20 in spironolactone group developed T2DM. The 5th year cumulative appearance rates of T2DM were 5.4% in losartan group and 14.4% in spironolactone group. Multivariate cox proportional hazards analysis showed that T2DM development after the initiation of anti-hypertensive drugs occurred when anti-hypertensive drug was spironolactone (hazard ratio: 6.10; 95% confidence interval = 1.78-20.84; P = 0.004), histological staging was advanced (hazard ratio: 4.31; 95% confidence interval = 1.94-9.60; P < 0.001), fatty liver was present (hazard ratio: 3.28; 95% confidence interval = 1.47-7.27; P = 0.004), and patient had pre-diabetes (hazard ratio: 2.47; 95% confidence interval = 1.08-5.63; P = 0.032). Our results indicate losartan causes about 60% reduction of the onset of T2DM compared to patients treated with spironolactone.