Circulation.
2005 May 2; [Epub ahead of print]
Effect of Atorvastatin and Irbesartan, Alone and in Combination,
on Postprandial Endothelial Dysfunction, Oxidative Stress, and Inflammation
in Type 2 Diabetic Patients.
Ceriello A, Assaloni R, Da Ros R, Maier A, Piconi L, Quagliaro L,
Esposito K, Giugliano D.
Department of Pathology and Medicine, Experimental and Clinical,
Chair of Internal Medicine, University of Udine, Udine.
BACKGROUND: Postprandial hypertriglyceridemia and hyperglycemia are considered
risk factors for cardiovascular disease. Evidence suggests that postprandial
hypertriglyceridemia and hyperglycemia induce endothelial dysfunction
and inflammation through oxidative stress. Statins and angiotensin type
1 receptor blockers have been shown to reduce oxidative stress and inflammation,
improving endothelial function. METHODS AND RESULTS: Twenty type 2 diabetic
patients ate 3 different test meals: a high-fat meal, 75 g glucose alone,
and a high-fat meal plus glucose. Glycemia, triglyceridemia, endothelial
function, nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1,
and interleukin-6 were assayed during the tests. Subsequently, diabetics
took atorvastatin 40 mg/d, irbesartan 300 mg/d, both, or placebo for 1
week. The 3 tests were performed again between 5 and 7 days after the
start of each treatment. High-fat load and glucose alone produced a decrease
in endothelial function and increases in nitrotyrosine, C-reactive protein,
intercellular adhesion molecule-1, and interleukin-6. These effects were
more pronounced when high-fat load and glucose were combined. Short-term
atorvastatin and irbesartan treatments significantly counterbalanced these
phenomena, and their combination was more effective than either therapy
alone. CONCLUSIONS: This study confirms an independent and cumulative
effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial
function and inflammation, suggesting oxidative stress as a common mediator
of such an effect. Short-term treatment with atorvastatin and irbesartan
may counterbalance this phenomenon; the combination of the 2 compounds
is most effective.
Nephrol Dial Transplant. 2005 Apr 26; [Epub ahead of print]
Cost-effectiveness of irbesartan in diabetic nephropathy: a systematic
review of published studies.
Palmer AJ, Tucker DM, Valentine WJ, Roze S, Gabriel S, Cordonnier
DJ.
CORE - Center for Outcomes Research, Bundtenmattstrasse 40, 4102
Binningen, Switzerland. Tel: +41 61 383 0756; Fax: +41 61 383 0759.
BACKGROUND: To review published studies on the cost-effectiveness of
the use of irbesartan for treatment of advance overt nephropathy in patients
with type 2 diabetes and hypertension. METHODS: Articles were identified
based on a search of the PubMed databases using the keywords 'irbesartan',
'ESRD', 'cost-effectiveness', 'nephropathy' and 'costs', and by personal
communication with the authors. Only studies published in the last 10
years were included. All costs data from the cost-effectiveness studies
were inflated to 2003 Euros using published governmental conversion tables.
RESULTS: Seven published studies were identified, spanning the following
country settings: the US, Belgium and France, Germany, Hungary, Italy,
Spain, and the UK. In each, the same pharmacoeconomic model was adapted
using country-specific data to project and evaluate the clinical and cost
outcomes of the treatment arms of the Irbesartan in Diabetic Nephropathy
Trial (IDNT) (irbesartan, amlodipine or standard blood pressure control).
Mean time to onset of ESRD was 8.23 years for irbesartan, 6.82 years for
amlodipine and 6.88 years for the control (values were the same for Belgium,
France, Germany, Hungary, Italy and Spain as transition probabilities
for progression to ESRD were all derived from the IDNT). Mean cumulative
incidence of ESRD was 36% with irbesartan, 49% with amlodipine and 45%
with control treatment. Treatment with irbesartan was projected to improve
life expectancy compared to both amlodipine and control in all seven published
studies. Analysis of total lifetime costs showed that irbesartan treatment
was cost saving compared to the other two treatment regimens, due to the
associated reduction in ESRD cases. Cost savings with irbesartan became
evident very early; after 2-3 years of treatment in most settings. CONCLUSIONS:
Modelling studies based on the IDNT published to date suggest that irbesartan
treatment in patients with type 2 diabetes, hypertension and advanced
nephropathy is both life- and cost-saving compared to amlodipine or control.
J Hypertens. 2005 Mar;23(3):633-40.
Irbesartan and atenolol improve diastolic function in patients
with hypertensive left ventricular hypertrophy.
Muller-Brunotte R, Edner M, Malmqvist K, Kahan T.
Division of Internal Medicine, Karolinska Institutet Danderyd Hospital,
Stockholm, Sweden.
OBJECTIVES AND DESIGN: An abnormal diastolic filling is common in hypertensive
left ventricular (LV) hypertrophy, a condition that may lead to heart
failure and death. The renin-angiotensin-aldosterone system has been implicated
in the development of LV hypertrophy. This study examines the effects
of 48 weeks of double-blind treatment with the AT1 receptor blocker irbesartan
and the beta-blocker atenolol on diastolic function. METHODS: Diastolic
function was evaluated in 115 hypertensive patients with LV hypertrophy
by Doppler echocardiography mitral inflow velocities calculated from the
peak of early (E) and peak of late (A) diastolic velocities (E/A ratio),
the E-wave deceleration time, the isovolumic relaxation time, the pulmonary
venous flow velocity, and by the atrioventricular valve plane displacement
method. RESULTS: By similar reductions in blood pressure both groups progressively
reduced the LV mass index, with a greater reduction in the irbesartan
group (P = 0.024). Diastolic function was improved similarly by irbesartan
and atenolol; for example, the E/A ratio by 12 and 14% (P = 0.022 and
P < 0.001), and the pulmonary venous flow velocity by 10 and 7% (P
= 0.036 and P = 0.001), respectively. The isovolumic relaxation time was
improved by irbesartan (P = 0.040) only, and was related to changes in
LV geometry (P < 0.001). For atenolol, improvement in diastolic function
was associated only with the reduction in blood pressure (P = 0.048).
An improvement in diastolic function appeared greater in concentric LV
hypertrophy than in eccentric LV hypertrophy. CONCLUSIONS: Treatment based
on atenolol or irbesartan improves diastolic function in patients with
hypertensive LV hypertrophy to the same degree, but through different
mechanisms.
Circulation. 2005 Jan 25;111(3):343-8. Epub 2005 Jan 17.
Irbesartan and lipoic acid improve endothelial function and reduce
markers of inflammation in the metabolic syndrome: results of the Irbesartan
and Lipoic Acid in Endothelial Dysfunction (ISLAND) study.
Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S,
Khan BV.
Division of Cardiology, Emory University School of Medicine, Atlanta,
Ga 30303, USA.
BACKGROUND: The metabolic syndrome is associated with increased angiotensin
II activity, induction of a proinflammatory and oxidative state, and endothelial
dysfunction. We evaluated the ability of irbesartan, an angiotensin receptor
blocker, and lipoic acid, an antioxidant, to affect endothelial function
and inflammation in patients with the metabolic syndrome. METHODS AND
RESULTS: We randomized 58 subjects with the metabolic syndrome in a double-blinded
manner to irbesartan 150 mg/d (n=14), lipoic acid 300 mg/d (n=15), both
irbesartan and lipoic acid (n=15), or matching placebo (n=14) for 4 weeks.
Endothelium-dependent and -independent flow-mediated vasodilation was
determined under standard conditions. Plasma levels of interleukin-6,
plasminogen activator-1, and 8-isoprostane were measured. After 4 weeks
of therapy, endothelium-dependent flow-mediated vasodilation of the brachial
artery was increased by 67%, 44%, and 75% in the irbesartan, lipoic acid,
and irbesartan plus lipoic acid groups, respectively, compared with the
placebo group. Treatment with irbesartan and/or lipoic acid was associated
with statistically significant reductions in plasma levels of interleukin-6
and plasminogen activator-1. In addition, treatment with irbesartan or
irbesartan plus lipoic acid decreased 8-isoprostane levels. No significant
changes in blood pressure were noted in any of the study groups. CONCLUSIONS:
Administration of irbesartan and/or lipoic acid to patients with the metabolic
syndrome improves endothelial function and reduces proinflammatory markers,
factors that are implicated in the pathogenesis of atherosclerosis.
Kidney Int Suppl. 2004 Nov;(92):S99-S101.
Impact of irbesartan, blood pressure control, and proteinuria
on renal outcomes in the Irbesartan Diabetic Nephropathy Trial.
Hunsicker LG, Atkins RC, Lewis JB, Braden G, de Crespigny PJ,
Deferrari G, Drury P, Locatelli F, Wiegmann TB, Lewis EJ; for the Collaborative
Study Group.
Department of Internal Medicine, University of Iowa College of Medicine,
Iowa City, Iowa.
Impact of irbesartan, blood pressure control, and proteinuria on renal outcomes in the Irbesartan Diabetic Nephropathy Trial. Background. It is important to know the reliability of early changes in proteinuria in predicting late renal outcomes. The IDNT was a trial in which treatment assignment, baseline and follow-up blood pressure determinations, and albumin/creatinine ratios (ACR), and renal outcomes were recorded. Methods. Risk of renal outcomes in the IDNT was assessed by proportional hazards modeling as a function of treatment assignment, and achieved systolic blood pressure (SBP) both without, and then with, inclusion of values for baseline proteinuria and early changes in proteinuria. Results. In models without ACR variables, both treatment with irbesartan and achieved SBP during follow-up were significantly predictive of the risk of renal outcomes. Addition of ACR variables to the models reduced the apparent impact of assignment to irbesartan by 52% to 81%, and irbesartan was no longer a significant predictor of renal outcomes. Conversely, addition of ACR variables to the models attenuated the effect of achieved follow-up SBP by only 32% to 46%, and follow-up BP remained a highly significant predictor of renal outcomes. Conclusion. The ability of early changes in proteinuria to predict the impact of treatment on renal outcomes is a function of the specific treatment. One must use caution in using early changes in proteinuria as a surrogate for longer-term renal outcomes.
Kidney Int Suppl. 2004 Nov;(92):S118-20.
Health economics studies assessing irbesartan use in patients
with hypertension, type 2 diabetes, and microalbuminuria.
Palmer AJ, Rodby RA.
CORE-Center for Outcomes Research, Binningen/Basel, Switzerland; and
Rush University Medical Center, Chicago, Illinois.
Health economics studies assessing irbesartan use in patients with hypertension, type 2 diabetes, and microalbuminuria. Two studies comparing the cost-effectiveness of irbesartan to similar blood pressure control with standard antihypertensive medications (excluding angiotensin-converting enzyme inhibitors and other angiotensin receptor blockers) in treatment of patients with hypertension, type 2 diabetes, and microalbuminuria have been published to date; one in a United States setting, the other in a Spanish setting. Both studies were based on a Markov-based Monte Carlo simulation model, with the effects of irbesartan or standard blood pressure control taken from the Irbesartan Reduction of Microalbuminuria-2 (IRMA-2) and the Irbesartan in Diabetic Nephropathy Trial (IDNT) clinical trials. In both Spanish and U.S. settings, irbesartan was projected to delay the onset of end-stage renal disease (ESRD), reduce the cumulative incidence of ESRD, increase life expectancy, and reduce overall direct medical costs. Irbesartan treatment of patients with type 2 diabetes, hypertension, and microalbuminuria may lead to major improvements in long-term patient outcomes, with substantial cost savings as an added bonus to third party payers.
Curr Med Res Opin. 2004 Oct;20(10):1625-31.
The effect of irbesartan in reducing cardiovascular risk in hypertensive
type 2 diabetic patients: an observational study in 16,600 patients in
primary care.
Bramlage P, Pittrow D, Kirch W.
Institute of Clinical Pharmacology, Medical Faculty Carl Gustav Carus,
Technical University, Dresden, Germany.
OBJECTIVES: As arterial hypertension substantially increases the risk of premature death, cardiovascular disease and renal insufficiency in patients with type 2 diabetes, effective and safe antihypertensive therapy is of importance. Therefore, the effect of irbesartan as monotherapy, or in fixed combination with hydrochlorothiazide, on blood pressure, metabolic parameters and microalbuminuria and the safety and tolerability of the drug were assessed. RESEARCH DESIGN AND METHODS: Multicentric, prospective, open phase IV study over 3 months in 16,600 patients with the clinical diagnoses of hypertension and type 2 diabetes. Blood pressure was measured sphygmometrically and albuminuria was assessed with semi-quantitative urine dipsticks. MAIN OUTCOME MEASURES: Systolic (SBP) and diastolic (DBP) blood pressure reduction, proportion of patients with microalbuminuria and cardiovascular risk calculated based on the SCORE score, each after a follow-up of 3 months compared to baseline. Number and nature of adverse events (AEs). RESULTS: The sample consisted of 51.3% men, mean age was 62.2+/-10.7 years, 53.9% of patients were overweight and 26.4% were obese. Mean SBP/DBP decrease after 3 months was 22.3/11.2 mmHg. The BP lowering effect was similar in the analyses of various subgroups (according to age group, sex, presence of micro- or macrovascular complications). Irbesartan treatment reduced the percentage of patients with microalbuminuria from 45.6% to 30.6% at 3 months (32.9% relative reduction). Metabolic parameters (lipids, blood glucose, HbA1c) and weight were improved significantly or showed trends for improvement, respectively. The mean 10-year cardiovascular risk as calculated with the SCORE score was decreased from a baseline value of 9.8% to 5.7% (-58% relative reduction). Tolerability was excellent: only 0.3% experienced an AE. CONCLUSIONS: Treatment with irbesartan in patients with concomitant hypertension and type 2 diabetes led to large blood pressure reductions. In view of the renoprotective effect documented by the reduced rate of patients with albuminuria, and the improvement of further metabolic parameters, these changes translate into a reduction of cardiovascular risk.
Ren Fail. 2004 Jul;26(4):399-404.
Comparative effects of fosinopril and irbesartan on hematopoiesis
in essential hypertensives
Robles NR, Angulo E, Grois J, Barquero A.
Unidad de Hipertension Arterial, Hospital Infanta Cristina, Badajoz,
Spain.
OBJECTIVE: To compare the response of erythropoiesis to an angiotensin receptor blocker, irbesartan with an angiotensin conversing enzyme inhibitor, fosinopril, in essential hypertensive patients with normal renal function. DESIGN AND METHODS: Thirty patients were randomized to receive either irbesartan (150 mg once daily) (n = 15, mean age 65.2+/-8.7 years) or fosinopril (20 mg once daily) (n = 15, mean age 57.4+/-11.5 years, difference is not significant) during 12 weeks. Plasma erythropoietin, hemoglobin (Hb) and hematocrit (Hc) levels were measured at start and monthly after receiving the treatment. All values are expressed as mean+/-1SD. RESULTS: Irbesartan decreased erythropoietin levels (baseline 20.7+/-1.3 vs. 18.1+/-3.7 mU/mL, p=0.019), but they remained unchanged with fosinopril (baseline 18.8+/-1.3 vs. 18.6+/-1.6 mU/mL). Hb levels lowered in irbesartan group (baseline 13.8+/-1.2 vs. 13.5+/-1.1 g/dL, p=0.029), but they did not change in fosinopril-treated patients (baseline 14.6+/-1.3 vs. 14.5+/-1.3 g/dL). Hc did not show any change neither in irbesartan group (baseline 40.9+/-3.7 vs. 40.8+/-3.3 %) nor in fosinopril group (baseline 14.6+/-1.3 vs. 14.5+/-1.3 %). CONCLUSIONS: Irbesartan lowered erythropoietin secretion and hemoglobin levels in essential hypertensives. Fosinopril can neither influence erythropoietin secretion nor decrease hemoglobin levels. Angiotensin receptor blockers seem to get higher efficacy for antagonism angiotensin effects. Safety of angiotensin receptor blockers in anemic hypertensive patients should be studied.
Diabetologia. 2004 Sep;47(9):1535-40.
Effect of irbesartan on nitrotyrosine generation in non-hypertensive
diabetic patients.
Ceriello A, Assaloni R, Da Ros R, Maier A, Quagliaro L, Piconi
L, Esposito K, Giugliano D.
Department of Experimental and Clinical Pathology and Medicine, University
of Udine, P. le S. Maria della Misericordia, 33100, Udine, Italy.
AIMS/HYPOTHESIS. Oxidative stress is involved in the pathogenesis of microangiopathic and macroangiopathic diabetic complications. The results of recent trials suggest that type 1 angiotensin II (AT-1) receptor blockers may prevent or delay nephropathy and cardiovascular disease in diabetic patients, independently of their anti-hypertensive action. There is evidence that AT-1 receptor blockers can work as intracellular antioxidants. This study investigated whether the AT-1 receptor blocker irbesartan is able to reduce nitrotyrosine formation in non-hypertensive diabetic patients under fasting conditions and during acute hyperglycaemia. METHODS. A total of 40 non-hypertensive, non-microalbuminuric Type 2 diabetic patients and 20 healthy, normotensive subjects were recruited for this study. Diabetic patients followed a randomised, double-blind, placebo-controlled, crossover protocol, taking either irbesartan (150 mg orally, twice daily) or placebo for 60 days. Fasting glucose and nitrotyrosine were measured at baseline and at the end of each treatment period. An OGTT was also performed at the same time intervals, during which plasma glucose and nitrotyrosine levels were monitored. RESULTS. Compared with baseline measurements, treatment with irbesartan (0.57+/-0.4 vs 0.35+/-0.3 micromol/l, p<0.01) but not placebo (0.58+/-0.3 vs 0.59+/-0.2 micromol/l) significantly reduced fasting nitrotyrosine levels. Irbesartan also significantly reduced nitrotyrosine formation during the OGTT. CONCLUSIONS/INTERPRETATION. This study demonstrates that irbesartan reduces plasma levels of nitrotyrosine in diabetic patients and is effective in counterbalancing nitrotyrosine formation during acute hyperglycaemia. Our results may help to elucidate how AT-1 receptor blockers exert their beneficial effect independently of their BP-lowering activity.
Diabetes Care. 2004 Aug;27(8):1897-903.
Cost-effectiveness of early irbesartan treatment versus control
(standard antihypertensive medications excluding ACE inhibitors, other
angiotensin-2 receptor antagonists, and dihydropyridine calcium channel
blockers) or late irbesartan treatment in patients with type 2 diabetes,
hypertension, and renal disease.
Palmer AJ, Annemans L, Roze S, Lamotte M, Lapuerta P, Chen R,
Gabriel S, Carita P, Rodby RA, de Zeeuw D, Parving HH.
CORE-Center for Outcomes Research, Buendtenmattstrasse 40, 4102 Binningen/Basel,
Switzerland.
OBJECTIVE: The aim of this study was to determine the most cost-effective
time point for initiation of irbesartan treatment in hypertensive patients
with type 2 diabetes and renal disease. RESEARCH DESIGN AND METHODS: This
study was a Markov model-simulated progression from microalbuminuria to
overt nephropathy, doubling of serum creatinine, end-stage renal disease,
and death in hypertensive patients with type 2 diabetes. Two irbesartan
strategies were created: early irbesartan 300 mg daily (initiated with
microalbuminuria) and late irbesartan (initiated with overt nephropathy).
These strategies were compared with control, which consisted of antihypertensive
therapy with standard medications (excluding ACE inhibitors, other angiotensin-2
receptor antagonists, and dihydropyridine calcium channel blockers) with
comparable blood pressure control, initiated at microalbuminuria. Transition
probabilities were taken from the Irbesartan in Reduction of Microalbuminuria-2
study, Irbesartan in Diabetic Nephropathy Trial, and other published sources.
Costs and life expectancy, discounted at 3% yearly, were projected over
25 years for 1,000 simulated patients using a third-party payer perspective
in a U.S. setting. RESULTS: Compared with control, early and late irbesartan
treatment in 1,000 patients were projected to save (mean +/- SD) 11.9
+/- 3.3 million dollars and 3.3 +/- 2.7 million dollars, respectively.
Early use of irbesartan added 1,550 +/- 270 undiscounted life-years (discounted
960 +/- 180), whereas late irbesartan added 71 +/- 40 life-years (discounted
48 +/- 27) in 1,000 patients. Early irbesartan treatment was superior
under a wide-range of plausible assumptions. CONCLUSIONS: Early irbesartan
treatment was projected to improve life expectancy and reduce costs in
hypertensive patients with type 2 diabetes and microalbuminuria. Later
use of irbesartan in overt nephropathy is also superior to standard care,
but irbesartan should be started earlier and continued long term.
Br J Pharmacol. 2004 Jul;142(6):933-42.
Irbesartan inhibits human T-lymphocyte activation through downregulation
of activator protein-1.
Cheng SM, Yang SP, Ho LJ, Tsao TP, Chang DM, Lai JH.
Division of Cardiology, Department of Medicine, Tri-Service General
Hospital, National Defense Medical Center, No 325, Section 2, Cheng-Kung
Road, Neihu 114, Taipei, Taiwan, ROC.
1 Irbesartan is a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atherosclerosis, human T-lymphocytes play an important role, but it is not yet known how irbesartan modulates human T-lymphocytes activation. To gain insight into the mechanisms by which irbesartan acts, we investigated its effects on human T-lymphocytes. 2 Primary human T-lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. Activator protein-1 (AP-1) and related protein activities were determined by electrophoretic mobility shift assays, kinase assays, Western blotting and transfection assays. 3 Irbesartan inhibited the production of both tumor necrosis factor-alpha and interferon-gamma by activated T-cells, especially at therapeutic concentrations. Further investigation at the molecular level indicated that the inhibition of activated human T-lymphocytes specifically correlated with the downregulation of AP-1 DNA-binding activity. In the Jurkat T-cell line, irbesartan also inhibited AP-1 transcriptional activity. Finally, we revealed that irbesartan is unique in its ability to inhibit the activation of both c-Jun NH2-terminal protein kinase and p38 MAPK. 4 Our studies show that irbesartan may modulate inflammation-based atherosclerotic diseases through a cell-mediated mechanism involving suppression of human T-lymphocytes activation via downregulation of AP-1 activity.
Hypertension. 2004 Jul;44(1):61-6.
Effect of irbesartan versus atenolol on left ventricular mass
and voltage: results of the CardioVascular Irbesartan Project.
Schneider MP, Klingbeil AU, Delles C, Ludwig M, Kolloch RE, Krekler
M, Stumpe KO, Schmieder RE.
Department of Medicine IV/Nephrology,University of Erlangen-Nurnberg,
Germany.
Regression of hypertensive left ventricular hypertrophy (LVH) is associated with improved prognosis. The aim of this trial was to compare the effects of irbesartan versus atenolol on LVH in subjects with essential hypertension. Because electrocardiographic and echocardiographic parameters of LVH carry disparate prognostic information, both methods were applied in this trial. In the randomized, double-blind, multicenter trial CardioVascular Irbesartan Project, 240 patients with essential hypertension were treated with irbesartan or atenolol for 18 months. Voltage criteria used for LVH were Sokolow index, Cornell index, Cornell voltage x QRS duration product and Lewis index. In parallel, left ventricular mass (LVM) was determined by 2-dimensional guided M-mode echocardiography. After 6 and 18 months, reductions of LVM and voltage criteria for LVH were only found in subjects treated with irbesartan. However, a reduction of LVM was only detectable in subjects within the highest quartile of baseline LVM but not overall. In contrast, reductions of voltage criteria for LVH were detectable after 6 and 18 months even within commonly used normal limits. In conclusion, treatment of hypertension with irbesartan resulted in a significant reduction in the voltage criteria for LVH, although an effect on LVM was only seen in subjects with high baseline LVM. In contrast, atenolol did not lead to reductions in electrocardiographic or echocardiographic parameters of LVH. Because voltage criteria for LVH have been shown to predict cardiovascular outcome independently from LVM, we suggest that both methods should be used to accurately assess the benefits of antihypertensive treatment.
Am J Cardiol. 2004 Jun 1;93(11):1432-5, A10.
Comparison of effects of losartan, irbesartan, and candesartan
on flow-mediated brachial artery dilation and on inflammatory and thrombolytic
markers in patients with systemic hypertension.
Koh KK, Han SH, Chung WJ, Ahn JY, Jin DK, Kim HS, Park GS, Kang
WC, Ahn TH, Shin EK.
Department of Cardiology, Vascular Medicine and Atherosclerosis Unit,
Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu,
Incheon 405-760, Korea.
We administered placebo, losartan 100 mg/day, irbesartan 300 mg/day, and candesartan 16 mg/day during 2 months to 122 patients with mild to moderate hypertension. Compared with placebo, angiotensin II type-1 receptor blockers significantly improved the percent flow-mediated dilator response to hyperemia (p = 0.019 by analysis of variance [ANOVA]) and reduced plasma levels of malondialdehyde (p = 0.005 by ANOVA). However, only irbesartan and candesartan therapies significantly lowered plasma levels of plasminogen activator inhibitor type-1 antigen (p <0.001 by ANOVA) with no differences between the 2, and only candesartan therapy significantly lowered plasma levels of monocyte chemoattractant protein-1 (p = 0.004 by ANOVA).
Related Articles, Links Life Sci. 2004 Jun 11;75(4):407-20.
Diverse effects of long-term treatment with imidapril and irbesartan
on cell growth signal, apoptosis and collagen type I expression in the
left ventricle of spontaneously hypertensive rats.
Wang JM, Wang Y, Zhu ZS, Zhang MC, Zou Y, Li JJ, Li MJ, Jiang
XJ, Li XY.
Department of Cardiology, Renmin Hospital, Wuhan University School
of Medicine, Wuhan 430060, People's Republic of China.
To compare diverse effects of angiotensin II type 1 receptor antagonists
(irbesartan) and angiotensin converting enzyme inhibitors (imidapril)
on left ventricular remodeling in spontaneously hypertensive rats (SHR).
Thirty male SHR were randomly divided into three groups: SHR-IR (treated
with irbesartan, 50 mg/kg), SHR-IM (imidapril, 3 mg/kg), SHR-C (placebo).
Ten male Wistar Kyoto rats (WKY) treated with placebo acted as the control.
All treatments were administered once daily from 14 to 27 weeks of age.
Imidapril and irbesartan have the similar inhibitor effects on blood pressure
and left ventricular mass indexes in SHR. Despite both drugs suppressed
ERK-1 protein expression, decreased cardiomyocytes apoptosis index, blocked
collagen type I deposition, reduced TGF-beta(1) gene expression in SHR,
imidapril elicits a stronger inhibitory effect. Irbesartan had little
effect on MKP-1 protein expression, but imidapril decreased it significantly.
As a result, the ERK-1/MKP-1 ratio in SHR-IR was significantly greater
than that in SHR-IM (P < 0.05). These results suggest that the balance
between MKP-1 and ERKs in myocardial tissue is important for cardiac cell
proliferation and growth. They also indicate that the similar efficacy
of antihypertensive treatment in reducing blood pressure does not predict
the similar capacity to control the individual facet of left ventricular
remodeling. Irbesartan is more effective in regressing the homeostasis
between ERK-1 and MKP-1, however imidapril is superior in suppressing
apoptosis and collagen synthesis in cardiac tissue.
J Hum Hypertens. 2004 Oct;18(10):733-8.
An economic evaluation of the Irbesartan in Diabetic Nephropathy
Trial (IDNT) in a UK setting.
Palmer AJ, Annemans L, Roze S, Lamotte M, Rodby RA, Bilous RW.
Center for Outcomes Research, Basel, Switzerland.
There are substantial healthcare costs associated with the provision of renal replacement therapy. Patients with diabetes mellitus are the largest and fastest growing group developing end-stage renal disease (ESRD) in the United Kingdom (UK). Treatment leading to a slowing of progression to ESRD in diabetic patients could lead to considerable cost savings. Using treatment-specific probabilities derived from the Irbesartan in Diabetic Nephropathy Trial (IDNT), the cost effectiveness of treating patients with hypertension, type II diabetes and nephropathy with irbesartan, amlodipine or control was calculated using a Markov model. UK-specific ESRD-related data were retrieved from published sources to reflect local management practices, ESRD outcomes and costs. Mean 10-year costs and changes in life expectancy due to ESRD delayed or avoided were calculated. Future costs and clinical benefits were discounted at 6.0 and 1.5% per annum and extensive sensitivity analyses were performed. Delay in the onset of ESRD with irbesartan led to cost savings of pound sterling 5125 and pound sterling 2919/patient and improvements in projected discounted life expectancy of 0.07 and 0.21 years over 10 years vs amlodipine and control, respectively. The costs of treatment of ESRD were the main contributor to the total costs. The cost of trial medications had only a minor impact. These results were robust in a wide range of plausible assumptions. Given that the IDNT efficacy results could be translated to a UK setting, treating patients with hypertension, type II diabetes and overt nephropathy with irbesartan was cost saving over a 10-year period compared to amlodipine and control.
Chin Med J (Engl). 2004 Apr;117(4):547-51.
Effect of irbesartan on angiotensin II-induced hypertrophy of
human proximal tubular cells.
Liu BC, Sun J, Chen Q, Luo DD, Ma KL, Ruan XZ.
Institute of Nephrology, Zhongda Hospital, Southeast University School
of Medicine, Nanjing 210009, China.
BACKGROUND: Intrarenal activation of the renin angiotensin system (RAS) plays an important role in mediating renal fibrosis. Both angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II (AngII) receptor antagonists have been shown to exert a protective role against diabetic and non-diabetic nephropathy. However, the exact mechanism of how blocking local RAS prevents renal fibrosis is unclear. The present study was to investigate the influence of a new AngII receptor antagonist, irbesartan (Irb), on AngII-induced hypertrophy in human proximal tubular cell line (HK-2). METHODS: The cell line, HK-2, was grown in Dulbeccos's Modified Eagle's Medium containing 10% heat-inactivated fetal calf serum. After rested in serum-free medium for 24 hours, the effects of Irb on AngII (10(-7) mol/L)-induced [(3)H]-leucine incorporation, total protein content (measured by the Coomassie brilliant blue G250 method), and change in cell size (determined by scanning electron microscopy) were observed. The influence of Irb on the cell cycle was analyzed by fluorescence activated cell sorter (FACS) flow cytometry. RESULTS: AngII induced cell hypertrophy in a time and dose dependent manner. Stimulation of cells with AngII for 48 hours resulted in a increase in [(3)H]-leucine incorporation [0 hour: (5584 +/- 1016) cpm/10(5) cells vs 48 hours: (10741 +/- 802) cpm/10(5) cells, P < 0.05], which was significantly attenuated by treatment with Irb. AngII significantly increased the total protein content in HK-2 cells [control: (0.169 +/- 0.011) mg/10(5) cells vs AngII group: (0.202 +/- 0.010) mg/10(5) cells, P < 0.05], which was also markedly inhibited by cotreatment with Irb (P < 0.01). Scanning electron microscopy showed that AngII induced an increase in average physical cell size, which was significantly inhibited by Irb [control: (11.92 +/- 1.62) microm; AngII group: (20.63 +/- 3.83) micro m; AngII + Irb group: (13.59 +/- 3.15) micro m; P < 0.01 vs control, respectively]. Furthermore, flow cytometry revealed that AngII arrested cells in the G(0)-G(1) phase, which was significantly reversed by treatment with Irb [G(0)-G(1) cells in AngII group: (76.09 +/- 1.82)%, in AngII + Irb group: (67.00 +/- 2.52)%, P < 0.05]. CONCLUSION: Irb can inhibit AngII-induced hypertrophy in HK-2 cells.
Drugs. 2004;64(9):999-1028.
Irbesartan: a review of its use in hypertension and in the management
of diabetic nephropathy.
Croom KF, Curran MP, Goa KL, Perry CM.
Adis International Limited, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, Auckland 1311, New Zealand.
Irbesartan (Avapro, Aprovel) is a potent and selective angiotensin II subtype 1 receptor antagonist indicated for use in patients with hypertension, including those with type 2 diabetes mellitus and nephropathy. Once-daily administration of irbesartan provided 24-hour control of blood pressure (BP). In patients with mild-to-moderate hypertension irbesartan was as effective as enalapril, atenolol and amlodipine, and more effective than valsartan in terms of absolute reduction in BP and response rates. Irbesartan produced a greater reduction in diastolic BP at trough than once-daily losartan, but had a smaller effect than olmesartan; the reduction in systolic BP achieved with irbesartan was similar or greater than that with losartan and similar to that seen with olmesartan. The combination of irbesartan with hydrochlorothiazide produced additive effects on BP reduction. Irbesartan also induced regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy. In two large studies (IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients [IRMA 2] and the Irbesartan Diabetic Nephropathy Trial [IDNT]) irbesartan exerted a renoprotective effect in hypertensive patients with type 2 diabetes at both the early and later stages of diabetic nephropathy. The renoprotective effect was at least partly independent of the BP-lowering effect. In the IRMA 2 trial, the proportion of patients progressing to overt nephropathy was significantly lower for recipients of irbesartan 300mg once daily than placebo. In patients with overt nephropathy in the IDNT, irbesartan 300mg once daily provided significantly greater renoprotection than amlodipine 10mg once daily or placebo. The relative risk of doubling of serum creatinine was significantly lower with irbesartan than amlodipine or placebo. Irbesartan is well tolerated in hypertensive patients, including those with type 2 diabetes and incipient or overt nephropathy. The overall incidence of adverse events with irbesartan was similar to that with placebo. Irbesartan was associated with a lower incidence of cough than enalapril and was not associated with ankle oedema or with any clinically significant drug interactions. In conclusion, irbesartan is a well tolerated and effective antihypertensive agent. It also slows the progression of renal disease in hypertensive patients with type 2 diabetes at both the early and later stages of diabetic nephropathy. Thus, irbesartan is a valuable agent in the management of patients with these indications.
J Hum Hypertens. 2004 Oct;18(10):687-91.
Effect of delapril-manidipine combination vs irbesartan-hydrochlorothiazide
combination on fibrinolytic function in hypertensive patients with type
II diabetes mellitus.
Mugellini A, Preti P, Zoppi A, Corradi L, Fogari E, Derosa G,
Fogari R.
Department of Internal Medicine and Therapeutics, Clinica Medica II,
IRCCS Policlinico S Matteo, University of Pavia, Pavia, Italy.
The aim of this double-blind, double-dummy, parallel group study was to compare the effects of delapril-manidipine combination vs a irbesartan-hydrochlorothiazide combination on plasma tissue plasminogen activator (t-PA) and plasmogen activator inhibitor type I (PAI-l) activities in hypertensive patients with type II diabetes mellitus. After a 4-week run-in placebo period, 80 patients (37 male and 43 female), aged 41-65 years, were randomly allocated to an 8-week treatment with delapril 30 mg once daily or irbesartan 150 mg once daily. Thereafter, manidipine l0 mg once daily was added to delapril treatment and hydrochlorothiazide 12.5 mg to irbesartan treatment for a further 8 weeks. Blood pressure (BP), plasma t-PA and PAI-l activities were evaluated at the end of the run-in period, after 4-week monotherapy treatments, and at the end of the combination treatment periods. Both combination treatments, delapril-manidipine and irbesartan-hydrochlorothiazide, produced a greater reduction in systolic BP/diastolic BP (SBP/DBP) values (-27.6/21.8 mmHg and -26.4/20.2 mmHg, respectively) than the respective monotherapies (-15.2/11.7 mmHg with delapril and -16.3/11.3 mmHg with irbesartan). Delapril monotherapy significantly decreased plasma PAI-l activity (-10.4 IU/mI; P<0.05). The addition of manidipine produced a significant increase in t-PA activity (+0.27 IU/mI); P<0.05). Irbesartan monotherapy did not significantly affect the fibrinolytic balance, whereas the addition of hydrochlorothiazide worsened it, producing a significant increase in PAI-l activity (+9.5 IU/ml; P<0.05). In hypertensive patients with type II diabetes mellitus, the combination delapril-manidipine may determine a greater improvement of the fibrinolytic function than the respective monotherapy, while the association irbesartan-hydrochlorothiazide may worsen it.
Circulation. 2004 Mar 30;109(12):1536-42.
Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.
Candido R, Allen TJ, Lassila M, Cao Z, Thallas V, Cooper ME,
Jandeleit-Dahm KA.
Vascular Division, Baker Heart Research Institute, PO Box 6492, Melbourne
8008, Victoria, Australia.
BACKGROUND: It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection. METHODS AND RESULTS: Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT1 receptor expression, cellular proliferation, collagen content, macrophage- and alpha-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments. CONCLUSIONS: Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.
Card Electrophysiol Rev. 2003 Sep;7(3):243-6.
Angiotensin receptor blocker as adjunctive therapy for rhythm
control in atrial fibrillation: results of the irbesartan-amiodarone trial.
Madrid AH, Escobar C, Rebollo JM, Marin I, Bernal E, Nannini
S, Limon L, Peng J, Moro C.
Arrhythmia Unit, Ramon y Cajal Hospital, Department of Medicine, Alcala
University, Madrid, Spain.
Atrial fibrillation (AF) is a common arrhythmia associated with increased risk of stroke and mortality. The early appearance of electrical remodeling is followed by structural remodeling of the atrial tissue. Direct current cardioversion of persistent AF is the most effective treatment for the restoration of sinus rhythm, but it is hampered by a high percentage of recurrences. Recurrences may be the consequence of both electrical and structural remodeling. A study on the use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent AF showed that this angiotensin II receptor blocker combined with amiodarone prolonged sinus rhythm after cardioversion. Irbesartan may have antifibrotic effects due not only to the ability to diminish the synthesis of collagen type I molecules but also to its capacity to stimulate the degradation of collagen type I fibers, as has been demonstrated with losartan, another angiotensin II receptor blocker. This suggests that efforts to reduce the structural changes that occur during AF may be more useful in preventing recurrences than efforts designed to minimize the electrical changes alone. The AFFIRM trial compared two approaches to the treatment of AF: cardioversion with antiarrhythmic drugs to maintain sinus rhythm and the use of rate-controlling drugs. The results show that management of AF with the rhythm-control strategy offers no survival advantage over the rate-control strategy. However, non-antiarrhythmic drugs to prevent recurrences, like irbesartan, were not controlled and amiodarone was used in a low percentage of the patients. The treatment strategies proposed in both AFFIRM and RACE, in our opinion, may not be the optimal. The modern clinical approach to AF involves an early intervention to restore sinus rhythm, therefore preventing atrial remodeling. The pretreatment of patients with AF who undergo electrical cardioversion is very important and will be the subject for continuous improvement.
Diabetes Care. 2003 Dec;26(12):3296-302.
Kidney function during and after withdrawal of long-term irbesartan
treatment in patients with type 2 diabetes and microalbuminuria.
Andersen S, Brochner-Mortensen J, Parving HH; Irbesartan in Patients
With Type 2 Diabetes and Microalbuminuria Study Group.
Steno Diabetes Center, Gentofte, Denmark.
OBJECTIVE: Irbesartan is renoprotective in patients with type 2 diabetes and microalbuminuria. Whether the observed reduction in microalbuminuria is reversible (hemodynamic) or persistent (glomerular structural/biochemical normalization) after prolonged antihypertensive treatment is unknown. Therefore, the present substudy of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study (IRMA-2) investigated the reversibility of kidney function changes after withdrawal of 2 years' antihypertensive treatment. RESEARCH DESIGN AND METHODS: The substudy included 133 hypertensive type 2 diabetic patients with persistent microalbuminuria in IRMA-2, randomized to double-masked treatment with either placebo, irbesartan 150 mg, or irbesartan 300 mg o.d. for 2 years. Arterial blood pressure, overnight urinary albumin excretion rate, and glomerular filtration rate (GFR) were determined repeatedly. RESULTS: Baseline characteristics were similar in the placebo, irbesartan 150-mg, and irbesartan 300-mg groups. At the end of the study, mean arterial blood pressure (MABP) was similarly lowered to 105 +/- 2 (mean +/- SE), 103 +/- 2, and 102 +/- 2 mmHg, respectively (P < 0.05 versus baseline), and urinary albumin excretion rate reduced by 8% (-16 to 27) (NS), 34% (95% CI 8-53), and 60% (46-70) (P < 0.05). Rates of decline in GFR were 1.3 +/- 0.7, 1.2 +/- 0.7, and 1.0 +/- 0.8 ml. min(-1). 1.73 m(-2) per month, respectively, during the initial 3 months of the study and 0.3 +/- 0.1, 0.3 +/- 0.1, and 0.4 +/- 0.1 ml. min(-1). 1.73 m(-2) per month in the remaining study period. One month after withdrawal of all antihypertensive medication, MABP remained unchanged in the placebo group, 105 +/- 2 mmHg, but increased significantly in the irbesartan groups, to 109 +/- 2 and 108 +/- 2 mmHg, respectively. Compared with baseline, urinary albumin excretion rate was increased by 14% (-17 to 54) in the placebo group and by 11% (-26 to 65) in the irbesartan 150-mg group but was persistently reduced by 47% (24-73) in the irbesartan 300-mg group (P < 0.05). GFR levels increased to baseline values in the placebo group and approached initial levels in irbesartan groups. CONCLUSIONS: Persistent reduction of microalbuminuria after withdrawal of all antihypertensive treatment suggests that high-dose irbesartan treatment confers long-term renoprotective effects.
