Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects.
We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors.
After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c.
Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus.
Candesartan; Angiotensin receptor blockers; Type 2 diabetes mellitus; Inflammatory parameters; Pulse pressure
Background and Purpose
Infections are important causes of postoperative morbidity after gastric surgery; currently, no factors have been identified that can predict postoperative infection. Adiponectin (ADN) mediates energy metabolism and functions as an immunomodulator. Perioperative ADN levels and perioperative immune functioning could be mutually related. Here we evaluated a potential biological marker to reliably predict the incidence of postoperative infections to prevent such comorbidities.
We analyzed 150 consecutive patients who underwent elective gastric cancer surgery at the Shiga University of Medical Science Hospital (Shiga, Japan) from 1997 to 2009; of these, most surgeries (n = 100) were performed 2008 onwards. The patient characteristics and surgery-related factors between two groups (with and without infection) were compared by the paired t-test and χ2 test, including preoperative ADN levels, postoperative day 1 ADN levels, and ADN ratio (postoperative ADN levels/preoperative ADN levels) as baseline factors. Logistic regression analysis was performed to access the independent association between ADN ratio and postoperative infection. Finally, receiver operating curves (ROCs) were constructed to examine its clinical utility.
Sixty patients (40%) experienced postoperative infections. The baseline values of age, American Society of Anesthesiologists physical status, total operating time, blood loss, surgical procedure, C-reactive protein (CRP) levels, preoperative ADN levels, and ADN ratio were significantly different between groups. Logistic regression analysis using these factors indicated that type 2 diabetes mellitus (T2DM) and ADN ratio were significantly independent variables (*p<0.05, ** p<0.01, respectively). ROC analysis revealed that the useful cutoff values (sensitivity/specificity) for preoperative ADN levels, ADN ratio, blood loss, operating time, and CRP levels were 8.81(0.567/0.568), 0.76 (0.767/0.761), 405 g (0.717/0.693), 342 min (0.617/0.614), and 8.94 mg/dl (0.583/0.591), respectively.
T2DM and ADN ratio were independent predictors of postoperative infection and ADN ratio was the most useful predictor for postoperative infection.
Angiotensin II receptor blockers (ARBs), including olmesartan and candesartan, are widely used antihypertensive agents. Many clinical studies have demonstrated that ARBs have organ-protecting effects, e.g., cardioprotection, vasculoprotection and renoprotection. However, the effect of prolonged olmesartan monotherapy on lipid metabolism in patients with hypertension is less well studied. We performed a retrospective observational study to compare the effects of olmesartan with those of candesartan, focusing on lipid metabolism and renal function.
We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and Feb 28, 2011, to identify cohorts of new olmesartan users (n = 168) and candesartan users (n = 266). We used propensity-score weighting to adjust for differences in all covariates (age, sex, comorbid diseases, previous drugs) between olmesartan and candesartan users, and compared serum chemical data including serum triglyceride (TG), LDL-cholesterol (LDL-C), total cholesterol (TC), potassium, creatinine and urea nitrogen. The mean exposure of olmesartan and candesartan users was 126.1 and 122.8 days, respectively.
After adjustment, there were no statistically significant differences in all covariates between olmesartan and candesartan users. The mean age was 60.7 and 61.0 years, and 33.4% and 33.7% of olmesartan and candesartan users were women, respectively. There were no statistically significant differences in mean values for all laboratory tests between baseline and during the exposure period in both olmesartan and candesartan users. In olmesartan users, the reduction of serum TG level was significant in comparison with that in candesartan users. Other parameters of lipid profile and renal function showed no statistically significant difference in the change from baseline to during the exposure period between olmesartan and candesartan users.
In this study, we observed a more beneficial effect on lipid metabolism, a reduction of serum TG, with olmesartan monotherapy than with candesartan monotherapy. However, there were no clinically significant changes in the levels of all test parameters between baseline and during the exposure period with both drugs. These results suggest that the influence of olmesartan or candesartan monotherapy on lipid metabolism and renal function is small, and that they can be safely used in patients with hypertension.
angiotensin II receptor blocker (ARB); olmesartan; candesartan; lipid metabolism; renal function; retrospective observational study
Studies focusing on the add-on effects of angiotensin II type 1 receptor blockers (ARBs) other than their antihypertensive effect are receiving attention. However, the effects of prolonged administration of ARBs on lipid metabolism in clinical cases are unclear. Our aims were to survey the changes in plasma lipid profile in patients with hypertension over a one-year period, and to examine the correlations between these values and the time after the start of ARB monotherapy with candesartan.
We carried out candesartan monotherapy in patients with mild to moderate hypertension and examined the longitudinal changes in plasma lipid profile. Data from 405 patients for triglyceride (TG), 440 for total cholesterol (TC), 313 for high density lipoprotein cholesterol (HDL-C) and 304 for low density lipoprotein cholesterol (LDL-C) were obtained from the electronic medical records (EMRs) in the Clinical Data Warehouse (CDW) of Nihon University School of Medicine (NUSM). The inverse probability of treatment weighting (IPTW) method (calculated from the inverse of the propensity score) was used to balance the covariates and reduce bias in each treatment duration. Linear mixed effects models were used to analyse the relationship between these longitudinal data of blood examinations and covariates of patient sex, age, diagnosis of diabetes mellitus (DM) and duration of candesartan monotherapy.
Plasma HDL-C level was associated with sex, duration of treatment, and interaction of sex and treatment duration, but not with age or diagnosis of DM. HDL-C level was significantly decreased during the 6~9 months period (p = 0.0218) compared with baseline. TG and TC levels were associated with sex, but not with age, diagnosis of DM or treatment duration. LDL-C level was not associated with any covariate. Analysis of the subjects divided by sex revealed a decrease in HDL-C in female subjects (during the 6~9 months period: p = 0.0054), but not in male subjects.
Our study revealed that administration of candesartan slightly decreased HDL-C in female subjects. However, TG, TC and LDL-C levels were not influenced by candesartan monotherapy. Candesartan may be safely used for patients with hypertension with respect to lipid metabolism, because the effect of candesartan on lipids may be small.
Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial.
Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders.
The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12-27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P=0.674]. The response rate (55.6% vs. 61.5%, P=0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups.
The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended.
Portal hypertension; Angiotensin receptor blocker; Non-selective beta blocker; Cirrhosis; Hepatic venous pressure gradient
Angiotensin II type 1 receptor blockers (ARB) are a frequently used class of antihypertensive drug. The ARB losartan is known to decrease the serum uric acid (SUA) level. However, there are very few clinical data comparing the effects of other ARBs on SUA level under the conditions of clinical practice. This study evaluated and compared the long-term effects of monotherapy with five ARBs on SUA level in Japanese hypertensive patients with type 2 diabetes mellitus (DM).
We identified hypertensive patients with type 2 DM who had been treated with monotherapy with losartan (n = 214), valsartan (n = 266), telmisartan (n = 185), candesartan (n = 458), or olmesartan (n = 192), in whom laboratory data of SUA between November 1, 2004 and July 31, 2011 were available, from the Nihon University School of Medicine’s Clinical Data Warehouse (NUSM’s CDW). We used a propensity-score weighting method and a multivariate regression model to adjust for differences in the background among ARB users, and compared the SUA level. The mean exposure of losartan was 264.7 days, valsartan 245.3 days, telmisartan 235.9 days, candesartan 248.9 days, and olmesartan 234.5 days.
In losartan users, mean SUA level was significantly decreased from baseline, while it was conversely increased in users of other ARBs; valsartan, telmisartan, candesartan, and olmesartan. The mean reduction of SUA level from baseline was significantly greater in losartan users compared with that in other ARB users. Comparison of ARBs other than losartan showed no significant difference in mean change in SUA level from baseline.
Our study showed that losartan had the most beneficial effect on SUA level among five ARBs, and that there was no significant difference in the unfavorable effects on SUA level among four ARBs other than losartan, at least during one year. These findings provide evidence of an effect of ARBs on SUA level, and support the benefit of the use of losartan in hypertensive patients with type 2 DM.
ARB monotherapy; Losartan; Valsartan; Telmisartan; Candesartan; Olmesartan; Serum uric acid; Hypertension; Type 2 diabetes mellitus
The raising prevalence of type-2 diabetes mellitus and obesity has been recognized as a major problem for public health, affecting both developed and developing countries. Impaired fasting plasma glucose has been previously associated with endothelial dysfunction, higher levels of inflammatory markers and increased risk of developing insulin resistance and cardiovascular events. Besides life-style changes, the blockade of the renin-angiotensin system has been proposed as a useful alternative intervention to improve insulin resistance and decrease the number of new type-2 diabetes cases. The aim of this clinical trial is to study the effect of the treatment with Candesartan, an angiotensin II receptor antagonist, on the insulin resistance, the plasma levels of adipoquines, oxidative stress and prothrombotic markers, in a group of non diabetic, non hypertensive, dysglycemic and obese subjects.
Methods and design
A randomized, double blind, cross-over, placebo-controlled, clinical trial was designed to assess the effects of Candesartan (up to 32 mg/day during 6 months) on the Homeostasis Model Assessment (HOMA) index, lipid profile, protrombotic state, oxidative stress and plasma levels of inflammatory markers. The participants will be recruited in the "Fundación Cardiovascular de Colombia". Subjects who fullfil selection criteria will receive permanent educational, nutritional and exercise support during their participation in the study. After a 15 days-run-in period with placebo and life-style recommendations, the patients who have a treatment compliance equal or greater than 80% will be randomlly assigned to one of the treatment groups. Group A will receive Candesartan during 6 months and placebo during 6 months. Group B will receive placebo during the first 6 months, and then, Candesartan during the last 6 months. Control visits will be programed monthly and all parameters of interest will be evaluated every 6 months.
Treatment with Candesartan, could improve the HOMA index, the response to the oral glucose tolerance test and reduce the plasma levels of adipoquines, oxidative stress and prothrombotic markers, in non diabetic, non hypertense subjects with dysglycemia and abdominal obesity, recruited from a population at high risk of developing insulin resistance. These effects are independent of the changes in arterial blood pressure. Trial registration: NCT00319202
Background: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness.
Objectives: The primary end point of this study was to assess whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness.
Methods: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as using antihypertensive drugs at screening, systolic blood pressure [SBP] > 140 mm Hg, or diastolic BP [DBP] >90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5–10 mg/d) or candesartan (8–12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment.
Results: Twenty patients (11 men, 9 women; mean [SD] age, 62  years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was not significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (14/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.93] vs 8.60 [1.50]; P = 0.017), whereas candesartan was not (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (−7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect.
Conclusion: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT.
arterial stiffness; amlodipne; candesartan; cardio-ankle vascular index
To study the effect of candesartan cilexetil (CC) in the management of blood pressure (BP) in diabetic and non-diabetic hypertensive patients.
A selection of five randomized double-blind clinical trials in which patients were treated for hypertension with CC was analyzed. All of these were similar in design: i) a 4-week placebo run-in period, ii) a 4-to 6-week period (V1) with CC 8 mg once daily (od), after which the dosage was doubled if BP was not normalized (BP >140/90 or BP >130/80 mmHg in diabetes), and iii) a 4- to 6-week period (V2) with CC 8 or 16 mg od. Efficacy was measured at V1 and V2.
702 patients were screened. The population consisted of 397 males (56.6%) with a mean age of 60 ± 11 years, with 153 diabetic (21.8%) and 549 non-diabetic (78.2%) patients. At baseline, mean BP values were 160/94/65 mmHg for SPB, DBP, and pulse pressure (PP) respectively, with differences between diabetic and non-diabetic patients. SBP, DBP, and PP values showed a significant reduction at V1 (p < 0.001) and V2 (p < 0.001) compared with baseline for all hypertensive patients. Mean changes at V2 in SBP and PP values were higher in diabetic than non-diabetic patients (p < 0.001), and to a lesser degree on DBP values (p = 0.034).
CC was effective in lowering BP in diabetic and non-diabetic hypertensive patients. CC is a promising therapy to manage hypertensive diabetic patients, as demonstrated by the significant BP reduction.
The effect of candesartan cilexetil (CC) on controlling blood pressure (BP) in hypertensive diabetic and non-diabetic patients was analyzed. Five randomized double-blind trials were pooled treating hypertension by CC (n = 702), including 153 diabetic (21.8%) and 549 non-diabetic (78.2%) patients. After treatment with CC (8–16 mg), significant reductions in SBP, DBP, and pulse pressure (PP) values were observed after 4–6 weeks (p < 0.001) and after 8–12 weeks (p < 0.001) compared with baseline for all hypertensive patients. Mean BP reductions after 8–12 weeks were higher in diabetic patients than non-diabetic (p < 0.001). CC is a promising therapy to treat hypertensive patients, both diabetic and non-diabetic.
candesartan cilexetil; hypertension; antihypertensive diabetes; blood pressure lowering; angiotensin II receptor antagonist
Angiotensin II receptor antagonists (ARBs) have a protective effect in patients with chronic kidney disease (CKD) by suppressing progression, possibly by controlling hypertension. One marker of progression in such patients is the degree of proteinuria.
We aimed to retrospectively examine the protective effect of ARBs (olmesartan, losartan, candesartan, and valsartan) on CKD patients without a history of diabetic nephropathy.
Data were retrieved from medical records of patients with a diagnosis of CKD (serum creatinine [Cre] <3.0 mg/dL [265.2 μmol/L] and urinary protein of 0.3–3.5 g/g Cre) who were treated with ARBs and those with diabetic nephropathy were excluded. Blood pressure, serum Cre, urinary protein, urinary Cre, and estimated glomerular filtration rate were measured before the research began and at 1, 3, 6, 12, and 24 months after the ARB treatment was started.
Forty-four patients completed the research protocol. Of these, 10 took olmesartan, 13 took losartan, 9 took candesartan, 9 took valsartan, and 3 took telmisartan. Systolic blood pressure was decreased in all cases. The extent of this decrease 1 month after starting ARB treatment was greater for olmesartan than for candesartan (P < 0.05), and after 2 years, it was greater than for losartan (P < 0.05). Diastolic blood pressure decreased in all patients; this decrease was significantly greater with olmesartan 1 month after treatment started than with candesartan (P < 0.05). Olmesartan significantly decreased daily urinary protein compared with that with the other ARBs during follow-up. This decrease 1 month after starting ARB treatment was greater for olmesartan than losartan, valsartan, and candesartan (P < 0.01, P < 0.01, and P < 0.05, respectively), and after 2 years, this effect was still significant (P < 0.05, P < 0.01, and P < 0.01, respectively).
Olmesartan is more effective in reducing urinary protein than other ARBs, suggesting that the renal protective effects of olmesartan may be better than those of other ARBs.
angiotensin II receptor antagonist; nondiabetic chronic kidney disease; olmesartan; proteinuria
The reduction of blood pressure alone does not eliminate the increased risk of arterial hypertension. Whilst concomitant metabolic risk factors have been shown to be responsible, the available pharmacotherapy has differential effects on these metabolic risk factors. For example, diuretics and betablockers worsen glucose metabolism, hence the starting point of the current subanalysis of the CHILI (Candesartan in patients with HIgher cardiovascuLar rIsk) study was the assumption that an angiotensin receptor blocker may counterbalance the metabolic effects of a low dose diuretic in patients with several metabolic risk factors.
The present study was performed as a non-interventional observational study in Germany. Patients with previously uncontrolled hypertension with at least one further risk factor in which physicians deemed a treatment with 16 mg Candesartan/12.5 mg HCTZ to be necessary were included. The risk factors were calculated in patient subgroups with diabetes, the metabolic syndrome (MetSyn) and neither condition (control). The risk of cardiovascular mortality within the next 10 years was calculated using the SCORE algorithm of the ESC.
Between August 2006 and February 2007 a total of 3,787 patients were included into the non-interventional trial. Patients were 62.2 ± 11.3 years old, 48.1% were female, 97.5% had at least one additional risk factor. Blood pressure was reduced by -27.2/-13.4 mmHg with only minor non significant variations between patient groups. Waist circumference was reduced (P < 0.0001) and HDL-C elevated (P < 0.05) in every subgroup except the control subgroup. Fasting blood glucose was reduced by -5.6 ± 21.6% (P < 0.0001 vs. baseline and vs. control) as well as triglycerides (-4.9 ± 29.4%; P < 0.0001 vs. baseline and vs. control). The SCORE value was reduced substantially (-8.7, -3.2 and -2.7% in patients with diabetes, the metabolic syndrome or neither).
The present study demonstrates that a 16 mg candesartan/12.5 mg HCTZ based treatment results in a pronounced blood pressure reduction and was associated with a favourable change in metabolic risk factors such as HDL cholesterol, triglycerides and blood glucose. These data indicate that metabolic effects observed in clinical trials like ALPINE, SCOPE or CHARM can also be observed in an unselected patient population in primary care.
Candesartan cilexetil has been shown to effectively reduce blood pressure and cardiovascular risk. Whether it is advantageous to combine candesartan cilexetil with low-dose hydrochlorothiazide (HCTZ) or uptitrate it in cases of insufficient blood pressure control has not been fully investigated under routine clinical conditions.
CHILI Triple T is a prospective, noninterventional, observational study. Patients with uncontrolled hypertension and added cardiovascular risk received a fixed-dose combination of candesartan cilexetil 16 mg and HCTZ 12.5 mg (combination therapy group) or high-dose monotherapy with candesartan cilexetil 32 mg (high-dose monotherapy group).
A total of 4600 patients with a mean age of 63.1 ± 11.0 years, of which 44.7% were female, was included. The combination therapy group had 3337 patients, and the high-dose monotherapy group 1263 patients. Patients in both treatment groups were comparable with respect to age and gender, but patients receiving high-dose monotherapy had a slightly higher mean systolic blood pressure, more prior revascularizations, renal insufficiency, diabetic nephropathy, peripheral artery disease, and a lower ankle brachial index. The use of combination therapy resulted in a blood pressure reduction of −28.5 ± 13.8/−14.2 ± 9.4 mm Hg (P < 0.001 vs 160.2 ± 13.3/94.5 ± 8.2 mm Hg at baseline). The use of high-dose monotherapy reduced blood pressure by −29.73 ±15.3/−14.1 ± 9.6 mm Hg (P < 0.001 vs 162.4 ± 14.7/94.7 ±8.7 mm Hg at baseline). Differences in subgroups of patients defined by age, gender, body mass index, dyslipidemia, waist circumference, smoking, prior cardiovascular event, glomerular filtration rate, and microalbuminuria were minor, although partially significant. Tolerability was excellent, with only 28 out of 3358 patients (0.8%) in the combination therapy group and 15 out of 1273 patients (1.2%) in the high-dose monotherapy group experiencing any adverse event, of which one in each group was considered to be serious (<0.1%).
Both the fixed-dose combination of candesartan cilexetil 16 mg and HCTZ 12.5 mg and high-dose monotherapy with candesartan 32 mg were highly effective in lowering blood pressure in patients at increased cardiovascular risk. Tolerability was excellent. The choice of either strategy therefore largely depends on the principal aim: blood pressure reduction with pronounced volume restriction or pronounced additional end-organ protection.
essential hypertension; combination therapy; high-dose monotherapy; candesartan cilexetil; noninterventional study; diuretics; Phase IV
Background: Diabetes mellitus and hypertension are aggravated by activation of the renin-angiotensin system caused by increased oxygen stress and local inflammatory responses. Several studies have suggested that angiotensin II type 1 receptors can reduce inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, IL-18, soluble vascular cell adhesion molecule [VCAM]-I, and l-selectin) and oxidative stress markers (urinary 8-hydroxy-7,8-dihydro-2'-deoxyguanosine [8-OHdG] and 8-epi-prostaglandin F2α [8-isoprostane]) in hypertensive patients.
Objective: The aim of this study was to assess the effects of valsartan, an angiotensin II receptor blocker, on inflammatory and oxidative stress markers in hypertensive patients with mild diabetes or impaired glucose tolerance.
Methods: In this open-label, prospective study, hypertensive patients aged >20 years with mild diabetes (requiring treatment by diet alone or an oral hypoglycemic), seen on an outpatient basis at the Division of Diabetes, Metabolism, and Endocrinology, Omori Hospital, Toyko, Japan, who were receiving a therapeutic dietary regimen for ≥1 month in the treatment of diabetes or hypertension, were eligible for enrollment. Blood pressure, inflammatory markers (hs-CRP, IL-6, IL-18, VCAM-1, and L-selectin), and oxidative stress markers (urinary 8-OHdG and 8-isoprostane) were monitored before treatment commencement with valsartan (40-80 mg/d) and after 3 months of treatment.
Results: A total of 26 patients (18 men, 8 women; mean [SD] age, 57.7 [11.3] years; mean [SD] weight, 65.3 [13.1] kg) were enrolled in the study. After 3 months of treatment, patients' mean (SD) blood pressure had significantly decreased from 153.1 (11.2)/88.3 (11.4) to 143.7 (13.7)/85.2 (9.0) mm Hg (P < 0.05). Among the inflammatory and oxidative stress markers, hs-CRP, VCAM-1, and urinary 8-OHdG concentrations decreased significantly from 0.231 (0.199) to 0.134 (0.111) mg/dL (P = 0.043), 471.1 (193.9) to 403.2 (135.2) ng/mL (P = 0.012), and 12.12 (5.99) to 8.07 (3.36) ng/mg · creatinine (P = 0.001), respectively. The reductions in these markers were observed in patients regardless of whether or not their glycosylated hemoglobin (HbA1c) concentration improved (defined as a decrease of ≥1% in HbA1c).
Conclusion: This small, open-label, prospective study found that a 3-month treatment with valsartan was associated with a significant reduction of hs-CRP, VCAM-1, and urinary 8-OHdG concentrations independent of improvement in HbA1c concentration in these hypertensive patients with hyperglycemia.
valsartan; hypertension; diabetes; inflammatory marker; oxidative stress marker
Angiotensin receptor blockers (ARBs) are known to reduce the cardiovascular risk in hypertensive patients. This study was designed to examine the effect of an ARB candesartan on subclinical atherosclerosis assessed by cardio-ankle vascular index (CAVI) in comparison with calcium channel blockers (CCBs) alone in hypertensive patients with metabolic syndrome (MetS). A total of 53 consecutive hypertensive patients with MetS were randomly assigned to the candesartan group, in which candesartan was added on, or the CCBs group, in which CCBs were added on. Clinical and biological parameters were obtained before and after the 12-month treatment period. The primary measure of efficacy was the %change in CAVI. When treated with candesartan, but not CCBs, CAVI significantly decreased from 8.7 to 7.7 by 11%. Blood pressure (BP) significantly decreased with both treatments, but the differences between groups were not significant. The changes in other parameters remained unchanged in both the groups. Analysis of covariance found that both the BP reduction and the therapy difference contributed to the decrease in CAVI, but the BP reduction was not involved in the decrease in CAVI caused by the difference in the therapy. Candesartan may be a better antihypertensive drug than CCBs to improve subclinical atherosclerosis of patients with MetS.
albuminuria; ambulatory blood pressure; calcium channel blockers; carotid intima-media thickness
Morning blood pressure (BP) surge is reported as a risk factor for cardiovascular events and end-organ damage independent of the 24-h BP level. Controlling morning BP surge is therefore important to help prevent onset of cardiovascular disease. We compared the efficacy of azilsartan and candesartan in controlling morning systolic BP (SBP) surges by analyzing relevant ambulatory BP monitoring data in patients with/without baseline BP surges. As part of a 16-week randomized, double-blind study of azilsartan (20–40 mg once daily) and candesartan (8–12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was carried out using ambulatory BP monitoring at baseline and week 14. The effects of study drugs on morning BP surges, including sleep trough surge (early morning SBP minus the lowest night-time SBP) and prewaking surge (early morning SBP minus SBP before awakening), were evaluated. Patients with sleep trough surge of at least 35 mmHg were defined by the presence of a morning BP surge (the ‘surge group’). Sleep trough surge and prewaking surge data were available at both baseline and week 14 in 548 patients, 147 of whom (azilsartan 76; candesartan 71) had a baseline morning BP surge. In surge group patients, azilsartan significantly reduced both the sleep trough surge and the prewaking surge at week 14 compared with candesartan (least squares means of the between-group differences −5.8 mmHg, P=0.0395; and −5.7 mmHg, P=0.0228, respectively). Once-daily azilsartan improved sleep trough surge and prewaking surge to a greater extent than candesartan in Japanese patients with grade I–II essential hypertension.
azilsartan; candesartan; hypertension; morning blood pressure surge
To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension.
Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs) for treatment of adult hypertension (DBP: 90–115 mmHg). Random-effects meta-regression adjusting for baseline blood pressure (BP) was used to analyse the data. Mean change in SBP and DBP was estimated for each individual drug and dose combination.
In all, 31 RCTs (n = 13,110 patients) were included in the analysis. Six studies include trial arms with candesartan, six irbesartan, 13 losartan, two olmesartan, five telmisartan and 12 valsartan. The weighted average reduction in mean SBP and DBP for valsartan 160 mg was −15.32 mmHg (95% CI: −17.09, −13.63) and −11.3 mmHg (95% CI: −12.15, −10.52) and for 320 mg was −15.85 mmHg (95% CI: −17.60, −14.12) and −11.97 mmHg (95% CI: −12.81, −11.16); these are statistically significantly greater reductions compared with losartan 100 mg, which was −12.01 mmHg (95% CI: −13.78, −10.25) and −9.37 mmHg (95% CI: −10.18, −8.54) for SBP and DBP respectively. There is evidence that valsartan 160 mg reduces SBP and DBP more than irbesartan 150 mg and reduced DBP more than candesartan 16 mg. No other statistically significant difference in efficacy is demonstrated.
Valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg and shows comparable efficacy to other ARBs in patients with essential hypertension.
The prevalence of heart failure is ever increasing around the world, particularly due to aging populations. Despite improvements in treatment over the last 20 years, the prognosis for heart failure remains poor. Among the treatments recommended for chronic heart failure, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers are crucial, provided of course that they are not contraindicated. However, angiotensin II receptor blockers (ARBs) can also be a beneficial treatment option. Candesartan is a particular ARB, characterized by a strong binding affinity to the angiotensin II type 1 receptor and slow dissociation. The benefits of candesartan have been demonstrated by the CHARM programme, which showed that candesartan significantly reduces the incidence of cardiovascular death, hospital admissions for decompensated heart failure, and all-cause mortality in chronic heart failure patients with altered left ventricular systolic function, when added to standard therapies or as an alternative to ACE inhibitors when these are poorly tolerated. Furthermore, candesartan can protect against myocardial infarction, atrial fibrillation and diabetes. Tolerance to candesartan is good, but blood pressure and serum potassium and creatinine levels must be monitored.
chronic heart failure; angiotensin II receptor blockers; candesartan; left ventricular systolic function
Visceral adipose tissue (VAT) predicts incipient diabetes mellitus and cardiovascular disease. Human data is mixed regarding the benefits of selective VAT reduction.
We investigated omentectomy added to laparoscopic Roux-en-Y gastric bypass (LRYGB) on glucose homeostasis and lipids, inflammatory markers and adipokines after 90-days in non-diabetic patients.
Legacy Good Samaritan Hospital and Oregon Health & Science University in Portland, Oregon.
A single-blinded, randomized study of LRYGB plus omentectomy vs. LYRGB alone in 28 subjects (7 male, 21 female). Groups were matched at baseline for gender, age, and body mass index (BMI). Eligibility included age ≥ 18 years old, a body mass index (BMI) ≥ 40 and < 50 kg/m2 without co-morbid conditions or BMI ≥ 35 and < 50 kg/m2 with co-morbid conditions. The primary outcome measures were changes in fasting plasma glucose, insulin and HOMA-IR. Secondary measures were BMI and levels of hs-CRP, TNF-α, interleukins, total and HMW adiponectin, fibrinogen, and PAI-1.
After surgery, BMI decreased significantly in both groups and was not different at follow-up. While many outcome parameters improved with weight loss in both groups post-operatively, only the omentectomy group experienced statistically significant decreases in fasting glucose (p<0.05), total (p=0.004) and VLDL (p=0.001) cholesterol, and an increase in the HMW:total adiponectin ratio (p=0.013).
Omentectomy added to a LRYGB results in favorable changes in glucose homeostasis, lipid levels, and adipokine profile at 90-days. These data support the hypothesis that selective ablation of VAT conveys metabolic benefit in non-diabetic humans.
omentectomy; omentum; obesity; bariatric surgery; Roux-en-Y; gastric bypass surgery; visceral adipose; intra-abdominal adipose; adiponectin; high-molecular weight adiponectin
Hypoadiponectinemia in lipoatrophy may be related to worsening of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). One of the beneficial effects of candesartan (Angiotensin II Type 1 receptor blocker) for preventing hypertension may be increasing of adiponectin due to improvement of adipocyte dysfunction. In this study, we determined the effects of candesartan or adiponectin on pathophysiologic features and adipocyte dysfunction in SHRSP.
Candesartan was administered to male SHRSP from 16 to 20 weeks of age (2 mg/kg/day). Adiponectin was cloned and intravenously administered to male SHRSP from 16 to 20 weeks of age. We examined biological parameters, as well as the expression and release of adipokines.
The SHRSP exhibited severe atrophy of visceral fat and progression of severe hypertension. The expression and release of leptin and adiponectin were impaired at 6 and 20 weeks of age. Candesartan suppressed the development of lipoatrophy and reduced the incidence of stroke at 20 weeks of age. Candesartan also enhanced the expression of adiponectin and leptin by inducing the overexpression of peroxisome proliferator activated receptor γ. Circulating level of leptin was significantly higher in candesartan group than in the control group, whereas adiponectin was similar in both groups. Intravenous administration of adiponectin resulted in enhancement of adiponectin expression in adipose tissue, but no remarkable effects were found in pathophysiology in SHRSP.
Our results indicate that candesartan protects against hypertension and adipocyte dysfunction in SHRSP. The induction of leptin expression appeared to be important factor in the inhibition of stroke lesions, whereas adiponectin was not a major regulator of blood pressure in SHRSP with genetic hypertension. Further studies are needed to elucidate the role of the renin–angiotensin system in adipose tissue dysfunction in relation to hypertensive end-organ damage.
Stroke-prone spontaneously hypertensive rats; Adipose tissue; Renin–angiotensin system; Angiotensin II type I receptor blocker; Lipoatrophy; Adipokines
Hypertension is a major risk factor for coronary heart disease, stroke, heart failure and renal disease. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure 7 defined hypertension as a blood pressure of more than 140/90 mmHg and recommended to initiate treatment with a two-drug combination for stage 2 hypertension (blood pressure of 160-179/100-109 mmHg). The need for drug combinations is clear from a patient and physician perspective as they provide more effective blood pressure lowering, reduce pill burden, improve compliance and decrease hypertension-related morbidity and mortality. Angiotensin II receptor blocker therapy has been proven to be well tolerated and effective in the management of hypertension, chronic heart failure with left ventricular dysfunction and the prevention and progression of diabetic renal disease. Blockers of the renin-angiotensin system are an important component of antihypertensive combination therapy. Thiazide-type diuretics are usually added to increase the blood pressure lowering efficacy. Fixed drug-drug combinations of both principles, such as candesartan/hydrochlorothiazide, are highly effective in lowering blood pressure while providing improved compliance, a good tolerability and largely neutral metabolic profile. In this article, we review the literature for the role of candesartan-based therapy for hypertension, stroke, diabetes mellitus and heart failure.
candesartan; heart failure; hypertension
Angiotensin II AT1 receptor blockers (ARBs) are commonly used in the clinical treatment of hypertension. Subcutaneous or oral administration of the ARB candesartan inhibits brain as well as peripheral AT1 receptors, indicating transport across the blood brain barrier. Pretreatment with candesartan profoundly modifies the response to stress. The ARB prevents the peripheral and central sympathetic activation characteristic of isolation stress and abolishes the activation of the hypothalamic-pituitary-adrenal axis during isolation. In addition, candesartan prevents the isolation-induced decrease in cortical corticotropin-releasing factor 1 and benzodiazepine receptors induced by isolation. When administered before cold-restraint stress, candesartan totally prevents the production of gastric ulcerations. This preventive effect of candesartan is the consequence of profound anti-inflammatory effects, reduction of sympathetic stimulation, and preservation of blood flow to the gastric mucosa. The ARB does not reduce the hypothalamic-pituitary-adrenal axis stimulation during cold-restraint. Preservation of the effects of endogenous glucocorticoids is essential for protection of the gastric mucosa during cold-restraint. Administration of the ARB to non-stressed rats decreases anxiety in the elevated plus-maze. Our results demonstrate that Angiotensin II, through AT1 receptor stimulation, is a major stress hormone, and that ARBs, in addition to their anti-hypertensive effects, may be considered for the treatment of stress-related disorders.
Renin Angiotensin System; inflammation; brain; gastric ulcers; Corticotropin releasing hormone; GABAA; sympathetic system
Hypertensive patients have an increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure and the risk of new-onset diabetes in high-risk Japanese hypertensive patients.
RESEARCH DESIGN AND METHODS
The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between pulse pressure at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male 1,471; mean age 63.7 years; mean BMI 24.8 kg/m2) as a subanalysis of the CASE-J trial.
During 3.3 ± 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, pulse pressure was an independent predictor for new-onset diabetes (hazard ratio [HR] per 1 SD increase 1.44 [95% CI 1.15–1.79]) as were male sex, BMI, and additional use of diuretics, whereas age and heart rate were not. Plots of HRs for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher pulse pressure with a lower DBP, indicating that the increased pulse pressure was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes.
Pulse pressure is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.
The advantages of blood pressure (BP) control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8–32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.
angiotensin receptor blockers; candesartan; candesartan cilexetil; clinical trials; efficacy studies; safety; blood pressure
Hypertension treatment and control is largely unsatisfactory when guideline-defined blood pressure goal achievement and maintenance are considered. Patient- and physician-related factors leading to non-adherence interfere in this respect with the efficacy, tolerability, and convenient use of pharmacological treatment options. Blockers of the renin–angiotensin system (RAS) are an important component of antihypertensive combination therapy. Thiazide-type diuretics are usually added to increase the blood pressure lowering efficacy. Fixed drug–drug combinations of both principles like candesartan/hydrochlorothiazide (HCTZ) are highly effective in lowering blood pressure while providing improved compliance, a good tolerability, and largely neutral metabolic profile. Comparative studies with losartan/HCTZ have consistently shown a higher clinical efficacy with the candesartan/HCTZ combination. Data on the reduction of cardiovascular endpoints with fixed dose combinations of antihypertensive drugs are however scarce, as are the data for candesartan/HCTZ. But many trials have tested candesartan versus a non-RAS blocking comparator based on a standard therapy including thiazide diuretics. The indications tested were heart failure and stroke and particular emphasis was put on elderly patients or those with diabetes. In patients with heart failure, for example, the fixed dose combination might be applied in patients in whom individual titration resulted in a dose of 32 mg candesartan and 25 mg HCTZ which can then be combined into one tablet to increase compliance with treatment. Also in patients with stroke the fixed dose combination might be used in patients in whom maintenance therapy with both components is considered. Taken together candesartan/HCTZ assist both physicians and patients in achieving long-term blood pressure goal achievement and maintenance.
chronic heart failure; stroke; diabetes; angiotensin receptor blocker; patients; physicians; persistence; compliance
To demonstrate that the administration of an angiotensin (Ang) II type 1 receptor (AT1R) blocker (ARB) inhibits the vicious cycle of high glucose (HG)-reactive oxygen species (ROS)-angiotensinogen (AGT)-Ang II-AT1R-ROS by suppressing ROSs and inflammation, thus ameliorating diabetic nephropathy (DN).
Research Design and Methods
Thirteen hypertensive DN patients were administered ARBs, and the following parameters were evaluated before and 16 weeks after the treatment: urinary AGT (UAGT), albumin (albumin-creatinine ratio: ACR), 8-hydroxyde-oxyguanosine (8-OHdG), 8-epi-prostaglandin F2α(8-epi-PGF2α), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, and IL-10.
ARB treatment reduced the blood pressure and urinary levels of AGT, ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 but increased the urinary levels of IL-10. The reduction rate of UAGT correlated with the reduction rate of blood pressure; the reduction rates of the urinary ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 levels; and the increase rate of the urinary IL-10 levels. Moreover, subjects who had high UAGT values at baseline exhibited higher reduction rates of urinary albumin excretion.
ARB-induced blockade of the abovementioned vicious cycle contributes to the renoprotective effects of ARBs in DN. The urinary levels of AGT could represent a predictive factor for reduced ACR in patients receiving ARB treatment.
angiotensin II type 1; receptor blockers; diabetic nephropathy