Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease

Although the angiotensin receptor antagonist (ARB) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate (NO(x)) excretion in hypertensive (140 and/or 90 mmHg) patients with chronic renal disease (serum creatinine < 265 (range, 44-265) micromol/l or creatinine clearance > 30 (range, 30-121) ml/min). Patients with mild (<1 g/day; range, 0.4-1.0) and moderate proteinuria (>1 g/day; range, 1.1-6.9) were randomly assigned to ACE-I- and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44 +/- 6% reduction in proteinuria (from 2.7 +/- 0.5 to 1.5 +/- 0.4 g/day, n = 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 +/- 0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23 +/- 8%, n = 13), but a 41 +/- 6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NO(x) excretion were observed with ACE-I (from 257 +/- 70 to 1111 +/- 160 micromol/day) and ARB (from 280 +/- 82 to 723 +/- 86 micromol/day), the ARB-induced increase in NO(x) excretion was smaller than that by ACE-I (P < 0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuria-reducing effect was observed with ACE-I, which paralleled the increase in urinary NO(x) excretion. Conversely, ARB decreased proteinuria and increased urinary NO(x) excretion gradually. These time course-dependent changes in proteinuria and urinary NO(x) may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin.     

Differing anti-proteinuric action of candesartan and losartan in chronic renal disease.

It has becoming clear that angiotensin receptor blockers (ARBs) show varying levels of angiotensin II type 1 (AT1) receptor blocking activity. Although the duration of activity and the efficacy on blood pressure of ARB are reported to vary, depending on the agents used, it has not been examined whether the effects on proteinuria and urinary nitrite/nitrate (NOx) excretion differ in hypertensive patients with chronic renal disease. In the present study, patients with hypertension (> 140 and/or 90 mmHg) and chronic renal disease (proteinuria > 0.5g/day; serum creatinine < 265 micromol/l or creatinine clearance > 30 ml/min/1.72 m2) were randomly assigned to perindopril- (n = 15), trandolapril- (n = 15), candesartan- (n = 17), and losartan-treated groups (n = 15), and were followed up for 96 weeks. All agents decreased blood pressure to the same level, and none of them had any effect on creatinine clearance. Candesartan, perindopril, and trandolapril reduced proteinuria markedly (from 3.0 +/- 0.6 to 1.8 +/- 0.5 g/day, 2.7 +/- 0.5 to 1.6 +/- 0.4 g/day, and 2.7 +/- 0.5 to 1.7 +/- 0.4 g/day, respectively) at 12 weeks, and the beneficial effect persisted throughout the study. The effect of losartan, however, diminished over the study period. Whereas perindopril, trandolapril, and candesartan markedly increased urinary NOx excretion (from 257 +/- 23 to 1,011 +/- 150 micromol/day, 265 +/- 70 to 986 +/- 130 micromol/day, and 260 +/- 62 to 967 +/- 67 micromol/day at 12 weeks, respectively), a relatively blunted increase was observed with losartan (from 309 +/- 42 to 596 +/- 64 micromol/day). In conclusion, renal action of ARB varies, with relatively less proteinuria-sparing, as well as NOx-enhancing, effects observed with candesartan showing the greatest reduction of proteinuria and greatest enhancement of NOx. Furthermore, renal nitric oxide may contribute to the renal protective action of these agents when administered to patients with chronic renal disease.     

Efficacy of candesartan cilexetil alone or in combination with amlodipine and hydrochlorothiazide in moderate-to-severe hypertension. UK and Israel Candesartan Investigators

This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA, P:<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period.     

Efficacy of candesartan cilexetil in hypertensive patients with or without diabetes

OBJECTIVE: To assess the effect of an ARB, candesartan cilexetil (CC), on blood pressure (BP) from 5 double-blind, randomised, studies in hypertensive patients. METHODS: Similar design was used in the 5 selected studies. Following 2-4 weeks run-in period with placebo, patients were randomised to receive the double-blind treatment. BP were assessed at inclusion, after 4-6 weeks and at the end (8-12 weeks). Depending on the BP response, dosage of CC 8 mg was doubled at the follow-up visit if BP >or=140/90 mmHg. RESULTS: 702 patients were randomised in CC group of whom 22% (153) were diabetic. Mean BP was 160 +/- 13/94 +/- 10/65 +/- 14 mmHg for SBP/DBP/PP at inclusion and were significantly reduced to 141 +/- 15/83 +/- 10/58 +/- 13 mmHg (p<0.001) after 8-12 weeks. The results according to the diabetes status are presented in the table below: [table: see text] CONCLUSION: Results of this meta analysis analysis performed on individual data show that CC reduces significantly BP in hypertensive population with a significant decrease in the diabetic patients.     

Effects of up-titration of candesartan versus candesartan plus amlodipine on kidney function in type 2 diabetic patients with albuminuria

In the present study, we tested the hypothesis that up-titrating the dose of an angiotensin receptor blocker (ARB) is superior to combined treatment with an ARB and a calcium channel blocker for the same degree of blood pressure (BP) reduction, with respect to urinary albumin excretion in diabetic patients treated with a standard dose of the ARB. Hypertensive patients with type 2 diabetes mellitus and albuminuria (≥30?mg?g(-1) creatinine) were enroled in the study, and were either started on or switched to candesartan (8?mg per day) monotherapy. After a 12-week run-in period, baseline evaluations were performed and patients with BP ≥130/80?mm?Hg were randomly assigned to receive either candesartan (12?mg per day) or candesartan (8?mg per day) plus amlodipine (2.5?mg per day) for a further 12 weeks. The primary end-point was a reduction in urinary albumin levels. Although there was no significant difference in the BP reduction between the two groups, the reduction in urinary albumin was greater in the up-titrated than the combination therapy group (-40±14% vs -9±38%, respectively; P<0.0001). Thus, up-titration of candesartan more effectively reduces urinary albumin excretion than combined candesartan plus amlodipine in hypertensive patients with diabetes for the same degree of BP reduction.     

The use of ACE inhibitors on diabetic patients without renal disease

Strategies that interrupt the renin-angiotensin system, especially with angiotensin-converting enzyme (ACE) inhibition, reduce cardiovascular disease mortality and morbidity in high-risk persons such as those with the insulin resistance syndrome and diabetes mellitus. In the 1980s emphasis was placed on the renal protective effects of ACE inhibitors in patients with diabetes and proteinuria. During the past several years controlled clinical trials have demonstrated that ACE inhibition reduces cardiovascular disease (CVD) mortality and morbidity. This is especially important in patients in the United States, where 80% of excess mortality for diabetes mellitus is attributed to CVD. This article reviews the clinical trials in high-risk patients, especially those with diabetes, that shown beneficial CVD risk reduction with ACE inhibitors.     

Switching from ACE inhibitors,beta-blockers,calcium antagonists or diuretics to candesartan improves efficacy and tolerability

OBJECTIVE: To evaluate the efficacy and safety of candesartan in patients previously treated with, but displaying adverse reactions to, ACE inhibitors, beta-blockers, calcium antagonists or thiazide diuretics. METHODS: 968 mild to moderate essential hypertensive patients (aged 18-74 years) entered an 8-week treatment period with candesartan 8 or 16 mg according to a multicenter, randomized, open-label, parallel-group design. After the first 4 weeks of treatment, candesartan was doubled in 33.6% of patients taking the 8-mg dose, in whom blood pressure was > 140/90 mmHg. RESULTS: Sitting diastolic and systolic blood pressures were significantly reduced (mean and 95% confidence interval) after 4 [3.7 (3.2-4.2)/8.9 (8.0-9.9) mmHg; n = 930] and even more after 8 [5.8 (5.4-6.3)/12.1 (11.1-13.0) mmHg; n = 890] weeks of treatment. The rate of improvement in the tolerability profile (success) was always greater than the rate of failure (93.3 vs 6.7% at the end of treatment). Adverse reactions amounted to 1125 at baseline, 129 at 4 weeks and 46 at 8 weeks of treatment. Adverse events to candesartan were reported in 2.7% of patients. Efficacy and safety were similar when data were analyzed taking into account the type of previous antihypertensive treatment. CONCLUSION: Candesartan is an effective and safe alternative to common antihypertensive drugs when they are not tolerated by patients.     

Effects of candesartan cilexetil on oxidative state and renal function in 5/6 nephrectomized rats

We have investigated the influence of a novel angiotensin II type 1 receptor antagonist, candesartan cilexetil, on the oxidative state of renal tissue and renal function in 5/6 nephrectomized rats, and compared its effects with those of an angiotensin-converting enzyme inhibitor, enalapril. Candesartan cilexetil (1 and 5 mg/kg per day), enalapril (5 mg/kg per day) and vehicle were orally administered once daily for 16 weeks after 5/6 nephrectomy. There was a marked degree of proteinuria evident prior to treatment, an average of 5.69 mg/mg creatinine in the nephrectomized rats, vs 1 to 2 mg/mg creatinine in the control group matched for species and body weight. Inhibition of development of proteinuria by candesartan cilexetil was dose dependent. Enalapril also significantly blunted the rise in urinary protein. Malondi-aldehyde content in the homogenate from the renal cortex increased significantly in the nephrectomized rats compared to control animals. This elevation of malondi-aldehyde content was unaffected by administration of either candesartan cilexetil or enalapril. Antioxidative enzyme (glutathione peroxidase, superoxide dismutase, and catalase) activities in the renal tissue were not affected by any active treatment. Elevation of lipid peroxide in remnant renal tissue suggests that oxidative stress may contribute to the progression of renal injury in the nephrectomized rats. Neither candesartan cilexetil nor enalapril affected antioxidant defenses in renal tissue in nephrectomized rats, indicating that mechanisms other than alteration in oxidative stress are involved in the renoprotective effects of candesartan cilexetil and enalapril.     

Beneficial cardiometabolic actions of telmisartan plus amlodipine therapy in elderly patients with poorly controlled hypertension

Background

There is a growing body of evidence that blood pressure (BP) level is one of the major determinants of cardiovascular morbidity and mortality in individuals, including elderly people. However, to achieve a target BP level in the elderly is more difficult compared with patients aged <65 years. Current guidelines recommend combination drug therapy with different modes of action for the treatment of elderly patients with moderate hypertension (HT). However, the optimal combination regimen is not well established in elderly HT.

Hypothesis

We hypothesized that combination therapy of telmisartan plus amlodipine would exert favorable cardiometabolic actions in elderly HT.

Methods

Seventeen elderly patients with essential HT who failed to achieve a target home BP level with treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Then the patients were assigned to replace their valsartan or candesartan with 40 mg telmisartan. The subjects were instructed to measure their own BP at home every day during the study periods.

Results

Replacement of valsartan or candesartan by telmisartan in amlodipine‐treated elderly hypertensive patients showed a significant reduction in morning home systolic BP and evening home systolic and diastolic BP at 12 weeks. Switching to telmisartan significantly increased serum adiponectin level.

Conclusions

Our present study suggests that combination therapy with telmisartan plus amlodipine may exert more beneficial cardiometabolic effects in elderly patients with HT compared with valsartan or candesartan plus amlodipine treatment. © 2011 Wiley Periodicals, Inc. This work was supported in part by Grants of Collaboration with Venture Companies Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to S.Y.). The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.

PURPOSE: To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease. DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease. STUDY SELECTION: Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997. DATA EXTRACTION: Data on 1860 nondiabetic patients were analyzed. DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 and P = 0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d. CONCLUSION: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.     

Calcium channel blocker inhibition of AGE and RAGE axis limits renal injury in nondiabetic patients with stage I or II chronic kidney disease

Background:

There is a growing body of evidence that advanced glycation end products (AGE) and their receptor (RAGE) system are implicated in chronic kidney disease (CKD). We have previously found that a long‐acting calcium channel blocker, azelnidipine, but not amlodipine, improves renal injury in CKD patients. However, little is known about the effect of azelnidipine on the AGE‐RAGE axis in humans. In this study, we examined whether azelnidipine addition could have renoprotective properties in hypertensive CKD patients by reducing serum levels of AGE and soluble form of RAGE (sRAGE). Thirty nondiabetic stage I or II CKD patients who had already been treated with angiotensin II receptor blockers were enrolled in this study.

Hypothesis:

We hypothesized that azelnidipine treatment could limit renal injury partly by blocking the AGE‐RAGE axis.

Methods:

Patients were randomly divided into 2 groups; one group was treated with 16 mg azelnidipine and the other with 5 mg amlodipine once daily. They were followed up for 6 months.

Results:

Proteinuria was positively correlated with circulating AGE and sRAGE levels in our subjects. Both drugs exhibited comparable and significant blood pressure (BP)‐lowering effects. Although neither of them affected glucose, glycated hemoglobin, lipid levels, and estimated glomerular filtration rate, treatment with azelnidipine, but not amlodipine, decreased circulating AGE, sRAGE, proteinuria, and urinary levels of liver‐type fatty acid binding protein, a marker of tubular injury, in a BP‐lowering–independent manner.

Conclusions:

Our present results suggest that azelnidipine may exert renoprotective properties in nondiabetic hypertensive CKD patients via its unique inhibitory effects on the AGE‐RAGE axis. © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.