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Irbesartan

A Review of its Use in Hypertension and in the Management of Diabetic Nephropathy

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Summary

Abstract

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.

Pharmacodynamic Properties

Irbesartan selectively binds to the angiotensin II receptor subtype 1 (AT1), inhibiting the activity of angiotensin II. Studies in normotensive volunteers indicate that irbesartan exerts a long-lasting inhibitory effect on the pressor response to exogenous angiotensin II. Irbesartan 5–300mg induced elevations in plasma renin activity and angiotensin II levels in volunteers with or without renal failure. In healthy volunteers, the AT1 blockade induced by irbesartan was generally significantly greater and of longer duration than that induced by losartan and valsartan. While irbesartan and candesartan demonstrated a similar extent of AT1 antagonistic activity in vivo, ex vivo/in vitro studies suggested higher antagonistic activity for irbesartan. A greater reduction in aldosterone levels and a greater increase in plasma renin activity occurred with irbesartan than with candesartan.

Systolic and diastolic blood pressure (BP) did not change significantly after single doses of irbesartan 5–300mg in salt-replete normotensive volunteers, but decreased following single doses of irbesartan 10–100mg in salt-depleted volunteers. Heart rate was unaltered.

In healthy volunteers and hypertensive patients, irbesartan 50mg and 100mg, respectively, increased renal blood flow and decreased renal vascular resistance without affecting the glomerular filtration rate. Irbesartan 50mg increased sodium excretion in normotensive volunteers, without altering potassium or uric acid excretion.

Pharmacokinetic Properties

The mean bioavailability of irbesartan is approximately 60–80% after oral administration and is not affected by food. After administration of single or multiple doses of irbesartan 150–300mg, maximum plasma drug concentrations (Cmax) were achieved within 1.5–2 hours. Values for Cmax and area under the concentration-time curve (AUC) are dose-related within this range and values are similar after single or multiple doses. Irbesartan is ≥90% bound to plasma proteins and has a steady-state volume of distribution of 53–93L.

The primary metabolic fate of irbesartan is oxidation via cytochrome P450 (CYP) isoform 2C9. Metabolism by CYP3A4 is negligible. The pharmacological activity of metabolites is minimal. After oral administration to healthy volunteers <10% and 30% of the parent drug was recovered in urine and faeces, respectively. Total plasma clearance of irbesartan was approximately 9–11 L/h, of which approximately 0.18 L/h was renal clearance. The elimination half-life of multiple doses of irbesartan 150 or 300mg was 11 hours.

No differences were noted in the pharmacokinetic properties of irbesartan between healthy men and women, but the AUC and Cmax were higher in elderly than younger volunteers. The pharmacokinetic parameters of irbesartan are not significantly altered by mild-to-moderate or severe renal impairment, mild-to-moderate hepatic impairment or heart failure.

No significant and clinically relevant drug interactions have been identified between irbesartan and hydrochlorothiazide, nifedipine, simvastatin, tolbutamide, warfarin, magnesium and aluminium hydroxides or digoxin. Fluconazole increased the irbesartan Cmax and AUC by 19% and 63%.

Therapeutic Efficacy in Hypertension

Monotherapy with irbesartan 150–300mg once daily was effective at reducing BP in patients with hypertension in double-blind, placebo- or active-controlled studies, leading to placebo-subtracted reductions in trough seated BP of approximately 8–10/5-6mm Hg. Reductions in BP were maintained over a 24-hour period with once-daily dosing. Irbesartan reduced BP by 11–19/7–13mm Hg in active-controlled clinical trials compared with reductions of 8–18/5–14mm Hg with the comparator drugs. Response rates with irbesartan were 36–72% compared with 43–68% for comparators.

Irbesartan 150mg once daily produced significantly greater reductions in diastolic and systolic BP and higher response and normalisation rates than valsartan 80mg once daily in the only study involving both these agents to include a statistical comparison. Reductions in diastolic BP with irbesartan 150–300mg once daily were greater than with losartan 50–100mg once daily, although the effect on systolic BP was significantly greater for irbesartan in only 1 of 2 studies, and there were no significant differences in response or normalisation rates between the drugs. Irbesartan 150mg once daily reduced diastolic BP to a lesser extent than olmesartan 20mg once daily, but produced similar changes in systolic BP and mean 24-hour ambulatory BP to olmesartan.

Several trials have shown irbesartan to be as effective as enalapril 10–20mg once daily in patients with mild-to-moderate hypertension, including in patients aged ≥65 years. Single studies have shown irbesartan 75–150mg once daily to produce similar decreases in BP to atenolol 50–100mg once daily, and irbesartan 150mg once daily to be as effective as amlodipine 5mg once daily.

The combination of irbesartan 75–300mg once daily with hydrochlorothiazide 12.5–25mg once daily produced additive BP-lowering effects in patients with mild-to-moderate hypertension. Irbesartan 150mg combined with hydrochlorothiazide 12.5mg (both once daily) produced reductions in BP of 4–7/2–4mm Hg additional to those with the individual components. The combination reduced BP in patients whose BP was unresponsive to monotherapy with irbesartan or hydrochlorothiazide.

Irbesartan induced regression of left ventricular mass in patients with left ventricular hypertrophy in several trials. The reduction in left ventricular mass was significantly greater with irbesartan than with amlodipine or atenolol, despite reductions in BP being similar for irbesartan and the comparators.

Therapeutic Efficacy in Hypertensive Patients with Type 2 Diabetes Mellitus and Nephropathy

Data from two large randomised, double-blind, placebo-controlled studies [Irbesartan Microalbuminuria Type 2 Diabetes Mellitus in hypertensive patients (IRMA 2) and the Irbesartan Diabetic Nephropathy Trial (IDNT)] showed that irbesartan slowed the development of overt nephropathy and the progression of renal disease in hypertensive patients with type 2 diabetes, and suggested that the renoprotective effect of irbesartan is at least in part independent of its BP-lowering effect.

In the IRMA 2 trial in patients with microalbuminuria (20–200 μg/min) and normal kidney function, overt nephropathy developed in 5% of irbesartan 300mg once daily recipients (p < 0.001 vs placebo), 10% of irbesartan 150mg once daily recipients (not significant) and 15% of placebo recipients. The hazard ratio for diabetic nephropathy was 0.3 in recipients of irbesartan 300mg once daily but did not achieve statistical significance in recipients of irbesartan 150mg once daily. Normoalbuminuria was restored in significantly more patients receiving irbesartan 300mg, but not 150mg, once daily compared with placebo. The renoprotective effect of irbesartan 300mg once daily was sustained in patients for whom antihypertensive medication was withdrawn for 1 month after completing 2 years of treatment.

The average trough systolic but not diastolic BP was significantly lower for the combined irbesartan groups than placebo (by l–3mm Hg). Reductions in ambulatory BP, measured in a subset of patients, were similar between groups.

In patients with more advanced renal disease, including proteinuria and elevated serum creatinine levels (IDNT), the relative risk of reaching the primary endpoint (a composite measure of doubling of the serum creatinine level, end-stage renal disease [ESRD] or death) was significantly lower in recipients of irbesartan 300mg once daily than placebo (by 20%) and amlodipine 10mg once daily (by 23%). The relative risk of doubling of serum creatinine levels and the rate at which serum creatinine levels increased were significantly lower in patients receiving irbesartan than placebo or amlodipine recipients. The relative risk of progression to ESRD alone was 23% lower in irbesartan recipients than in placebo or amlodipine recipients (not significant). The mean arterial BP in irbesartan recipients was not significantly different to that in amlodipine recipients.

Simulations of the long-term cost consequences of treatment with irbesartan, based on the outcomes of the IDNT, predicted that compared with amlodipine over a 25-year (lifetime) horizon irbesartan would be associated with an increase in life expectancy of 0.34–0.71 years and per-patient cost savings of €21 163-27 044 in the Belgian or French settings (year of costing 2002), $US26 290 in the US (year of costing 2000) and $Can 19 976 in Canada (year of costing 2001).

Tolerabilitv

There was no clinically relevant difference between irbesartan ≤900mg/day and placebo in the overall incidence of adverse drug events (21% vs 20%) in a pooled analysis of nine placebo-controlled trials. The incidence of withdrawal because of adverse events was 3.3% in irbesartan recipients and 4.5% in placebo recipients. Musculoskeletal trauma was the only adverse event to occur significantly more requently in recipients of irbesartan than placebo (1.9% vs 0.5%, p < 0.05).

Analysis of tolerability data from five nonblind trials (mean duration 276 days) involving 1006 patients with hypertension indicated that irbesartan monotherapy (≤300mg once daily) was well tolerated. In this analysis, the incidence of adverse drug experiences was 20% in recipients of irbesartan monotherapy, with 6% of recipients of irbesartan monotherapy discontinuing because of adverse events.

The overall incidence of adverse events with irbesartan was similar to that of most comparator agents. However, irbesartan was associated with a significantly lower incidence of cough than enalapril and was not associated with ankle oedema. The combination of irbesartan and hydrochlorothiazide was also well tolerated in patients with hypertension, with the overall incidence of adverse events being similar to that for placebo.

In the IRMA 2 trial, serious adverse events occurred in fewer irbesartan than placebo recipients (15% vs 23%). In the IDNT, the rate of adverse events per 1000 treatment days was significantly lower in recipients of irbesartan than placebo or amlodipine. The number of patients experiencing at least one serious adverse event did not differ significantly between the treatment groups. Significantly more irbesartan patients (1.9%) withdrew because of hyperkalaemia than amlodipine (0.5%) or placebo (0.4%) recipients. Patients treated with irbesartan reported more orthostatic symptoms than those receiving placebo.

Dosaae and Administration

Irbesartan is approved for the treatment of hypertension in many countries worldwide. In a number of countries, including the US, Canada, Australia and in Europe, it has also been approved for the treatment of nephropathy in patients with type 2 diabetes and hypertension.

Irbesartan may be used alone or in combination with other antihypertensive agents. The usual starting dosage is 150mg administered once daily, and the maximum recommended dosage for both indications is 300mg once daily, which is also the recommended maintenance dosage for patients with diabetic nephropathy. Irbesartan may be administered with or without food. No dosage adjustments are necessary in patients with hepatic or renal impairment. Dosage adjustments are not usually necessary in elderly patients, but consideration may be given to starting treatment at 75mg once daily in those aged >75 years. Irbesartan should not be administered during the second and third trimesters of pregnancy.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Katherine F. Croom, Monique P. Curran, Karen L. Goa & Caroline M. Perry

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  1. Katherine F. Croom
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  2. Monique P. Curran
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  4. Caroline M. Perry
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Correspondence to Katherine F. Croom.

Additional information

Various sections of the manuscript reviewed by: N.H. Andersen, Department of Diabetes and Endocrinology, Aarhus Kommunehospital, Aarhus, Denmark; M. Burnier, Polyclinique Medicale Universitaire, Lausanne, Switzerland; A. Coca, Department of Hypertension, Hospital Clinic, University of Barcelona, Barcelona, Spain; M.E. Cooper, Danielle Alberti Memorial Centre for Diabetes Complications, Heart Research Institute, Melbourne, Australia; G. Jerums, Endocrine Unit, Austin Hospital, Heidelberg, Australia; C.E. Mogensen, Department of Diabetes and Endocrinology, Aarhus Kommunehospital, Aarhus, Denmark; L.M. Ruilope, Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; A. Salvetti, Department of Medicine, University of Pisa, Pisa, Italy; G.L. Schwartz, Division of Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on irbesartan, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘irbesartan’ and ‘diabetic nephropath*’. EMBASE search terms were ‘irbesartan’ and (‘diabetic nephropath*’ or ‘hypertension’). AdisBase search terms were ‘irbesartan’ or ‘BMS-186295’ or ‘SR 47436’ and (‘diabetic-nephropathies’ or ‘hypertension’). Searches were last updated 25 March 2004.

Selection: Studies in patients with hypertension or those with hypertension and type 2 diabetes mellitus with microalbuminuria or diabetic nephropathy who received irbesartan. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Diabetic nephropathy, hypertension, irbesartan, pharmacodynamics, pharmacokinetics, therapeutic use, type 2 diabetes mellitus.

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Croom, K.F., Curran, M.P., Goa, K.L. et al. Irbesartan. Drugs 64, 999–1028 (2004). https://doi.org/10.2165/00003495-200464090-00011

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