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1.  Effects of co-administration of candesartan with pioglitazone on inflammatory parameters in hypertensive patients with type 2 diabetes mellitus: a preliminary report 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Trial registration
UMIN-CTR: UMIN000010142
doi:10.1186/1475-2840-12-71
PMCID: PMC3663745  PMID: 23635096
Candesartan; Angiotensin receptor blockers; Type 2 diabetes mellitus; Inflammatory parameters; Pulse pressure
2.  Association between Reduction of Plasma Adiponectin Levels and Risk of Bacterial Infection after Gastric Cancer Surgery 
PLoS ONE  2013;8(3):e56129.
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.
Methods
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.
Results
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.
Conclusion
T2DM and ADN ratio were independent predictors of postoperative infection and ADN ratio was the most useful predictor for postoperative infection.
doi:10.1371/journal.pone.0056129
PMCID: PMC3592855  PMID: 23520452
3.  Comparative effect of olmesartan and candesartan on lipid metabolism and renal function in patients with hypertension: a retrospective observational study 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1475-2840-10-74
PMCID: PMC3163179  PMID: 21827713
angiotensin II receptor blocker (ARB); olmesartan; candesartan; lipid metabolism; renal function; retrospective observational study
4.  Effect of candesartan monotherapy on lipid metabolism in patients with hypertension: a retrospective longitudinal survey using data from electronic medical records 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1475-2840-9-38
PMCID: PMC2933671  PMID: 20712859
5.  Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension 
Clinical and Molecular Hepatology  2014;20(4):376-383.
Background/Aims
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3350/cmh.2014.20.4.376
PMCID: PMC4278069  PMID: 25548744
Portal hypertension; Angiotensin receptor blocker; Non-selective beta blocker; Cirrhosis; Hepatic venous pressure gradient
6.  A randomized, double blind, cross-over, placebo-controlled clinical trial to assess the effects of Candesartan on the insulin sensitivity on non diabetic, non hypertense subjects with dysglyce mia and abdominal obesity. "ARAMIA" 
Trials  2006;7:28.
Background
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.
Hypothesis
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
doi:10.1186/1745-6215-7-28
PMCID: PMC1594582  PMID: 16959033
7.  Comparative effect of angiotensin II type I receptor blockers on serum uric acid in hypertensive patients with type 2 diabetes mellitus: a retrospective observational study 
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1475-2840-12-159
PMCID: PMC4176752  PMID: 24180232
ARB monotherapy; Losartan; Valsartan; Telmisartan; Candesartan; Olmesartan; Serum uric acid; Hypertension; Type 2 diabetes mellitus
8.  A study about the relevance of adding acetylsalicylic acid in primary prevention in subjects with type 2 diabetes mellitus: effects on some new emerging biomarkers of cardiovascular risk 
Aim
To evaluate the relevance of adding acetylsalicylic acid (ASA) in primary prevention in subjects with type 2 diabetes mellitus.
Methods
213 patients with type 2 diabetes mellitus and hypertension were randomized to amlodipine 5 mg, or amlodipine 5 mg + ASA 100 mg for 3 months (Phase A); then, if adequate blood pressure control was reached patients terminated the study; otherwise, amlodipine was up-titrated to 10 mg/day for further 3 months and compared to amlodipine 10 mg + ASA 100 mg (Phase B). We assessed at baseline, at the end of Phase A, and at the end of Phase B the levels of some new emerging biomarkers of cardiovascular risk including: high sensitivity C-reactive protein (Hs-CRP), adiponectin (ADN), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), myeloperoxidase (MPO), soluble CD40 ligand (sCDL40).
Results
Compared to baseline, at the end of Phase A, patients treated with amlodipine 5 mg + ASA 100 mg showed a statistically significant reduction of Hs-CRP (−15.0%), TNF-α (−21.7%), MPO (−9.7%), and sCDL40 (−15.7%), and a statistically significant increase of ADN (+15.0%). These values were significantly better than the ones obtained with amlodipine alone. Similarly, at the end of Phase B, amlodipine 10 mg + ASA significantly lowered Hs-CRP (−18.8%), TNF-α (−15.0%), MPO (−9.2%), and sCDL40 (−20.0%) and increased ADN (+11.8%), with a better effect compared to amlodipine alone.
Conclusion
All biomarkers considered were significantly improved by ASA addition. These data suggest that the use of ASA in primary prevention could be useful in patients with type 2 diabetes mellitus and hypertension.
Trial registration: ClinicalTrials.gov: NCT02064218
doi:10.1186/s12933-015-0254-8
PMCID: PMC4518654  PMID: 26223257
Acetylsalicylic acid; Amlodipine; Cardiovascular risk; Hypertension; New emerging biomarkers; Primary prevention
9.  Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: A 24-week study 
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 [10] 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.
doi:10.1016/j.curtheres.2008.10.002
PMCID: PMC3969957  PMID: 24692816
arterial stiffness; amlodipne; candesartan; cardio-ankle vascular index
10.  Effect of candesartan cilexetil on diabetic and non-diabetic hypertensive patients: meta-analysis of five randomized double-blind clinical trials 
Objective
To study the effect of candesartan cilexetil (CC) in the management of blood pressure (BP) in diabetic and non-diabetic hypertensive patients.
Methods
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.
Results
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).
Conclusions
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.
Short abstract
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.
PMCID: PMC1994048  PMID: 17583187
candesartan cilexetil; hypertension; antihypertensive diabetes; blood pressure lowering; angiotensin II receptor antagonist
11.  Olmesartan is More Effective Than Other Angiotensin Receptor Antagonists in Reducing Proteinuria in Patients With Chronic Kidney Disease Other Than Diabetic Nephropathy☆ 
Background
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.
Objective
We aimed to retrospectively examine the protective effect of ARBs (olmesartan, losartan, candesartan, and valsartan) on CKD patients without a history of diabetic nephropathy.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.curtheres.2013.02.002
PMCID: PMC3862195  PMID: 24384547
angiotensin II receptor antagonist; nondiabetic chronic kidney disease; olmesartan; proteinuria
12.  Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats 
The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes.
doi:10.1293/tox.2015-0033
PMCID: PMC4766525  PMID: 26989296
diabetes; neuropathy; hypertension; rat
13.  Metabolic effects of an AT1-receptor blockade combined with HCTZ in cardiac risk patients: a non interventional study in primary care 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1471-2261-8-30
PMCID: PMC2588554  PMID: 19000308
14.  Candesartan cilexetil/hydrochlorothiazide combination treatment versus high-dose candesartan cilexetil monotherapy in patients with mild to moderate cardiovascular risk (CHILI Triple T) 
Background:
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.
Methods:
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).
Results:
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%).
Conclusions:
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.
doi:10.2147/VHRM.S17004
PMCID: PMC3049544  PMID: 21415922
essential hypertension; combination therapy; high-dose monotherapy; candesartan cilexetil; noninterventional study; diuretics; Phase IV
15.  Effects of Valsartan on Inflammatory and Oxidative Stress Markers in Hypertensive, Hyperglycemic Patients: An Open-Label, Prospective Study 
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.
doi:10.1016/j.curtheres.2007.10.008
PMCID: PMC3969933  PMID: 24692765
valsartan; hypertension; diabetes; inflammatory marker; oxidative stress marker
16.  Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome 
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.
PMCID: PMC2922318  PMID: 20730073
albuminuria; ambulatory blood pressure; calcium channel blockers; carotid intima-media thickness
17.  Effect of azilsartan versus candesartan on morning blood pressure surges in Japanese patients with essential hypertension 
Blood Pressure Monitoring  2014;19(3):164-169.
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.
doi:10.1097/MBP.0000000000000042
PMCID: PMC4011626  PMID: 24710336
azilsartan; candesartan; hypertension; morning blood pressure surge
18.  Candesartan cilexetil in the treatment of chronic heart failure 
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.
PMCID: PMC2672439  PMID: 19436650
chronic heart failure; angiotensin II receptor blockers; candesartan; left ventricular systolic function
19.  Omentectomy added to Roux-en-Y gastric bypass surgery: A randomized, controlled trial 
BACKGROUND
Visceral adipose tissue (VAT) predicts incipient diabetes mellitus and cardiovascular disease. Human data is mixed regarding the benefits of selective VAT reduction.
OBJECTIVES
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.
SETTING
Legacy Good Samaritan Hospital and Oregon Health & Science University in Portland, Oregon.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1016/j.soard.2011.09.027
PMCID: PMC3883565  PMID: 22118842
omentectomy; omentum; obesity; bariatric surgery; Roux-en-Y; gastric bypass surgery; visceral adipose; intra-abdominal adipose; adiponectin; high-molecular weight adiponectin
20.  Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach 
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
doi:10.1111/j.1742-1241.2009.02028.x
PMCID: PMC2779985  PMID: 19392925
21.  Neurorestoration after traumatic brain injury through angiotensin II receptor blockage 
Brain  2015;138(11):3299-3315.
See Moon (doi:10.1093/awv239) for a scientific commentary on this article.
Angiotensin II type 1 receptor (AT1R) blockers, or ‘sartans’, are neuroprotective and neurorestorative. Villapol et al. show that the FDA-approved drugs candesartan and telmisartan promote morphological and functional recovery in a mouse model of traumatic brain injury. Sartans with dual AT1R-blocking and PPARγ-activating properties have therapeutic potential in patients.
See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Angiotensin II type 1 receptor (AT1R) blockers, or ‘sartans’, are neuroprotective and neurorestorative. Villapol et al. show that the FDA-approved drugs candesartan and telmisartan promote morphological and functional recovery in a mouse model of traumatic brain injury. Sartans with dual AT1R-blocking and PPARγ-activating properties have therapeutic potential in patients.
See Moon (doi:10.1093/awv239) for a scientific commentary on this article.
Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan’s blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking and PPARγ activating properties have therapeutic potential for traumatic brain injury.
doi:10.1093/brain/awv172
PMCID: PMC4731413  PMID: 26115674
candesartan; telmisartan; inflammation; apoptosis; recovery
22.  Introducing candesartan 32 mg plus hydrochlorothiazide 25 mg in previously untreated patients with severe essential hypertension 
Purpose
To investigate the efficacy of candesartan 32 mg and hydrochlorothiazide (HCTZ) 25 mg combination in patients with severe essential hypertension.
Patients and methods
In this prospective, open-label, single-group study, 106 previously untreated patients with a baseline systolic blood pressure (SBP) of 150–200 mmHg, and a diastolic blood pressure (DBP) of 110 to 120 mmHg, started with candesartan 16 mg during the first week. HCTZ 12.5 mg was added at week 2 and from fourth week onwards candesartan 32 mg plus HCTZ 25 mg was given over 6 weeks. The primary efficacy endpoint was mean reduction in SBP and DBP after 9 weeks. Response was defined as a decrease in SBP to <140 mmHg and/or by ≥20 mmHg and in DBP to <90 mmHg and/or by ≥10 mmHg. A second response criterion defined blood pressure reduction below 140/90 mmHg.
Results
Blood pressure was lowered from 180.0 ± 11.7/114.7 ± 3.1 mmHg by SBP 44.4 ± 16.8 and DBP 32.0 ± 11.3 mmHg (P < 0.0001). Response was 92.4% and 64.8% achieved <140/90 mmHg. Each titration step produced a statistically significant and clinically relevant decrease in SBP and DBP, but a level below 140/90 mmHg was achieved by >50% of the patients only after the third titration step. Adverse reactions were reported by 3.8% of the patients. The disorders were in line with the known safety profile of the study drugs.
Conclusion
A stepped treatment approach with candesartan/HCTZ combinations is effective and safe to achieve a swift blood pressure reduction in newly diagnosed, severe hypertension. The target of <140/90 mmHg was reached by >50% of the patients only after taking the full dose of candesartan 32 mg and HCTZ 25 mg.
doi:10.2147/POR.S18303
PMCID: PMC5045001  PMID: 27774009
primary therapy of newly diagnosed hypertension; fixed combination; decrease in blood pressure; response rates; candesartan
23.  Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis 
Bioscience Reports  2016;36(5):e00398.
High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes.
doi:10.1042/BSR20160344
PMCID: PMC5091470  PMID: 27612496
albuminuria; candesartan; nephropathy; RAS; type 2 diabetes
24.  Effects of Angiotensin II Type 1 receptor blocker and adiponectin on adipocyte dysfunction in stroke-prone spontaneously hypertensive rats 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1476-511X-12-108
PMCID: PMC3750705  PMID: 23876211
Stroke-prone spontaneously hypertensive rats; Adipose tissue; Renin–angiotensin system; Angiotensin II type I receptor blocker; Lipoatrophy; Adipokines
25.  An overview of candesartan in clinical practice 
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.
doi:10.1586/erc.11.90
PMCID: PMC3202428  PMID: 21878042
candesartan; heart failure; hypertension

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