Comprehensive overview: efficacy, tolerability, and cost-effectiveness of irbesartan

Abstract

Background

Hypertension represents a major health problem, affecting more than one billion adults worldwide. Irbesartan, an angiotensin II receptor blocker, is considered to be a highly effective treatment in the management of hypertension. The purpose of this review is to evaluate the efficacy, safety and tolerability profile , and cost-effectiveness of treatment with irbesartan in hypertension.

Methods

A review of the literature was conducted using the electronic PubMed and Cochrane Library databases and the Health Economic Evaluations Database of search terms relating to irbesartan efficacy, tolerability, and cost-effectiveness, and the results were utilized.

Results

Findings from the present analysis show that irbesartan either as monotherapy or in combination with other antihypertensive agents can achieve significant reductions in blood pressure, both systolic and diastolic, compared with alternative treatment options. Irbesartan was also found to have a renoprotective effect independent of its blood pressure-lowering in patients with type 2 diabetes and nephropathy. Furthermore, irbesartan demonstrated an excellent safety and tolerability profile , with either lower or equal adverse events compared with placebo and other alternative treatments. In terms of economic analyses, compared with other antihypertensive therapy alternatives, irbesartan was found to be a preferred option, that is less costly and more effective.

Conclusion

The evidence indicates that treating patients with hypertension alone or with type 2 diabetes and nephropathy using irbesartan can control hypertension, prolong life, and reduce costs in relation to existing alternatives.

Introduction

According to the World Health Organization, hypertension, defined as a systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, affects more than one billion adults worldwide.¹ Hypertension is a major health problem and a prevalent risk factor for cardiovascular disease and related death.² The prevalence of hypertension varies among European countries, the US, and Canada based on the results of a systematic review. Notably, the prevalence of hypertension for Europe was 44.2% compared with 27.8% in the US and 27.4% in Canada.³ The main factors that contribute to the development of high blood pressure can be attributed to social determinants such as age, income, educational level, unhealthy diet, tobacco consumption, physical inactivity, and excess of alcohol, and also to metabolic risk conditions such as obesity, diabetes, and raised blood lipids, and finally to other cardiovascular diseases, such as myocardial infarction, stroke, and heart failure, and finally to kidney disease.¹

Antihypertensive therapy can effectively reduce BP, and therefore reduce the risk of coronary heart disease, heart failure, cerebrovascular disease, and may thus prevent mortality. Early on, management of hypertension was done with angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors interfere with the renin-angiotensin system by direct blockade of ACE, thereby reducing the circulating concentrations of angiotensin II. However, they do not block angiotensin II production completely, because angiotensin II can be generated by non-ACE pathways. Angiotensin II receptor antagonists/blockers represent a relative newer class of antihypertensive agents, developed to overcome some of the deficiencies of ACE inhibitors.^4–6 Angiotensin II receptor blockers selectively block AT₁ receptors, preventing binding of angiotensin II, inhibiting the renin angiotensin system, and lowering BP.

The antihypertensive efficacy of angiotensin II receptor antagonists in patients with mild-to-moderate hypertension has been evaluated and compared with ACE inhibitors, calcium antagonists, beta-blockers, and diuretics in several studies.^7–20 Angiotensin II receptor blockers also slow the progression of renal disease associated with hypertension, have excellent tolerability, in fact similar to that of placebo, and are associated with a significantly lower incidence of adverse events.

Irbesartan belongs to this group of drugs and is approved for the treatment of hypertension, and is indicated for lowering BP either alone or in combination with other antihypertensive agents. It is a long-acting angiotensin II receptor blocker compared with some of the other drugs in this class, (eg, losartan and valsartan), characterized by high selectivity and significant blockade of the AT₁ receptor. Numerous studies have evaluated the efficacy of irbesartan in reducing BP and establishing control in large patient populations with mild-to-moderate or severe hypertension. Irbesartan is also approved for the reduction of progression of renal disease in patients with type 2 diabetes and nephropathy. The objective of the present study was to review and synthesize the published evidence on the efficacy, tolerability, and cost-effectiveness of irbesartan.

Search methods

The electronic PubMed and Cochrane Library databases and the Health Economic Evaluations Database were searched using the term “irbesartan”. All the resulting citations were screened to find out whether they were concerned with the efficacy, tolerability, and cost-effectiveness of irbesartan. This approach generated 41 studies evaluating irbesartan as monotherapy or as combination therapy in patients with hypertension only and/or type 2 diabetes and nephropathy and in patients with left ventricular hypertrophy, and also 15 cost-effectiveness studies. Studies were included in the review only if they were published in full papers and in the English language.

Pharmacokinetics and pharmacodynamics

Irbesartan has a rapid and almost complete absorption after oral administration, with maximum plasma concentration after administration (C_max) occurring at approximately 20 minutes regardless of dose, ie, 50 mg or 150 mg, and an average bioavailability of 60%–80%, significantly higher than for losartan and valsartan, the oral bioavailability of which is approximately 33% and 23%, respectively.^21–23 Food does not affect the bioavailability of irbesartan in contrast with other angiotensin II receptor antagonists, such as losartan and valsartan, the bioavailability of which is shown to decrease or be slowed by food.^4,24 In addition, pharmacokinetic parameters such as C_max, time required to reach C_max (t_max), and area under the plasma concentration-time curve (AUC), increased in a dose-dependent, linear manner, after irbesartan doses of 150–600 mg in healthy subjects.²⁵ Analysis of trough concentrations of irbesartan indicated that a steady-state level of irbesartan was achieved within 3 days of single daily doses of 150 mg, 300 mg, 600 mg, and 900 mg.²⁵ The volume of distribution of irbesartan at steady state is approximately 53–93 L, showing that irbesartan distributes into the extravascular space.²² Finally, irbesartan has the highest degree of plasma protein binding at approximately 96%.

Irbesartan is metabolized via glucuronide conjugation and oxidation. After either oral or intravenous administration of irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unmetabolized irbesartan.²⁶ The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). Remaining circulating metabolites do not add substantially to the pharmacologic activity of irbesartan. Irbesartan and its metabolites are excreted by both biliary and renal pathways. Following administration of an oral or intravenous dose of irbesartan, approximately 20% of the total radioactivity has been found to be recovered in the urine and the remainder in the feces.^4,26,27 The elimination half-life of irbesartan averages 11–15 hours. In vitro studies showed that irbesartan is oxidized mainly via the cytochrome P450 isoenzyme 2C9, with negligible metabolism by 3A4.²⁸

Two studies in hypertensive patients have evaluated the effect of gender on irbesartan pharmacokinetics. Results showed that there were no significant gender effects on C_max, AUC, or the terminal elimination half-life of irbesartan. Even though women generally had higher C_max, t_max, and AUC values compared with men, these differences were not statistically significant or clinically relevant.²⁹ Furthermore, no gender-related dosage adjustment was found to be necessary.³⁰ The evaluation of age on irbesartan pharmacokinetics was similarly of no statistical significance. Healthy elderly male and female subjects (aged 65–80 years) had approximately 20%–25% higher AUC and C_max values compared with healthy young (18–40 years) subjects.^29,30 Concerning the effects of race on irbesartan pharmacokinetics, data from two single-dose pharmacokinetic studies showed that there were no statistically significant differences in C_max, AUC, or terminal elimination half-life between healthy black and healthy white normotensive subjects, although the mean values for AUC and terminal elimination halflife were 25% and 21% higher, respectively, in blacks.^29,30 Studies in pediatric hypertensive patients are limited, but an open-label evaluation of the pharmacokinetics of irbesartan in children (aged 1–12 years) and adolescents (aged 13–16 years) showed that the plasma concentration-time profile s of irbesartan were comparable between children and adolescents.^29,31

Renal impairment, including end-stage renal disease requiring hemodialysis, did not influence the pharmacokinetics of irbesartan.³² In a open-label, parallel-group study comparing irbesartan pharmacokinetics between patients with hepatic cirrhosis and normotensive subjects, there were no statistically significant differences in C_max, AUC, or terminal elimination half-life between these groups after single or multiple doses of irbesartan.³³ Finally, an evaluation of the pharmacokinetics of irbesartan in an open-label, randomized, two-way, crossover study showed no significant differences in mean values of C_max between heart failure patients and control subjects after oral administration of irbesartan.³⁴

Studies reveal that there are no significant pharmacokinetic interactions between irbesartan and hydrochlorothiazide (HCTZ), warfarin, nifedipine, or simvastatin. More specifically, in a randomized, double-blind, placebo-controlled study evaluating the effects of oral irbesartan administration on the steady-state pharmacodynamics and pharmacokinetics of warfarin, results showed no clinically important effect of irbesartan on the pharmacokinetics or pharmacodynamics of warfarin during concomitant administration.³⁵ In an open-label crossover study assessing the effect of irbesartan on the pharmacokinetics of simvastatin in healthy subjects, irbesartan had no significant effect on the single-dose pharmacokinetics of total simvastatin acid.³⁶ In a randomized, double-blind, placebo-controlled study comparing the pharmacokinetics of irbesartan as monotherapy and in combination with HCTZ in patients with mild-to-moderate hypertension, results showed that the pharmacokinetics of irbesartan were not affected by addition of HCTZ.³⁷ Finally, irbesartan does not affect the pharmacokinetics and pharmacodynamics of nifedipine during concomitant administration, as shown in an open-label, crossover study in healthy subjects.³⁸

In terms of pharmacodynamics, irbesartan is a potent, orally active, selective angiotensin II receptor type AT₁ antagonist that blocks all actions of angiotensin II mediated by the AT₁ receptor, regardless of the source or route of synthesis of angiotensin II. Irbesartan has the ability to inhibit the pressor response to exogenously administered angiotensin II in normotensive subjects and had a dose-related BP response as shown in several studies.^39–41 Irbesartan inhibited the pressor response by up to 100% at peak after 4 hours of oral doses at 25–300 mg.^40,41 Compared with losartan and valsartan in a double-blind, placebo-controlled, randomized, four-way crossover study, the degree and duration of angiotensin II receptor blockade induced by 150 mg of irbesartan was significantly greater than with either 50 mg of losartan or 80 mg of valsartan.³⁹ Furthermore, in studies evaluating its efficacy in hypertensive patients, chronic doses of up to 300 mg had no effect of clinical importance on renal plasma flow, glomerular filtration rate, filtration fraction, or urinary excretion of sodium and potassium.^42–44 Also, irbesartan in multiple doses in hypertensive patients does not affect serum uric acid during chronic administration, fasting triglycerides, total cholesterol, or fasting glucose concentrations.¹⁹

Safety and tolerability

Concerning the tolerability and safety of irbesartan, the results from placebo-controlled studies show that irbesartan treatment is well tolerated in patients with mild-to-moderate hypertension. The overall incidence of adverse events with irbesartan was comparable with that of placebo; the most common adverse events experienced with irbesartan were weakness, headaches, dizziness, fatigue, and musculoskeletal pain.^16,45,46 There were no significant differences between irbesartan and enalapril in the overall incidence of adverse events. Adverse events were mild in general and occurred much less frequently in patients on irbesartan treatment.^19,47–49 Major adverse reactions were headache, malaise, and dizziness. The incidence of cough with irbesartan and enalapril was 10% and 17%, respectively.¹⁹ Results from another study concerning the incidence of drug-related cough though, show an even more significant difference between enalapril (18%) and irbesartan (0%).⁴⁷ Comparing irbesartan with atenolol, the incidence of overall adverse events was similar with both treatments; however, irbesartan had no negative impact on heart rate in contrast with atenolol, which significantly lowered mean heart rate. The most common adverse events were fatigue, cold sensation, upper respiratory tract infection, dizziness, headache, somnolence, and musculoskeletal pain.²⁰ Irbesartan compared with amlodipine and valsartan had a similar incidence of adverse events.^50,51

Finally, in two studies comparing irbesartan with losartan treatment, the percentage of patients experiencing adverse events was not significantly different between treatment groups. Also, there were no significant differences in mean change in heart rate from baseline at any time point.^45,52 Early discontinuations because of adverse events were not considerably different between irbesartan 300 mg and placebo.⁴⁵ Concerning the safety and tolerability of a combination antihypertensive therapy, the addition of irbesartan to HCTZ, a thiazide-type diuretic, was in general well tolerated, as evident from several studies. Compared with placebo/HCTZ, the frequency of adverse events reported within the first 24 hours after initiation of double-blind therapy was similar between the treatment groups.⁵³ The most common adverse events were headache, fatigue, and nausea/vomiting, and had slightly higher incidences with an irbesartan/HCTZ combination compared with placebo/HCTZ.⁵⁴ Long-term treatment with irbesartan/HCTZ did not have a negative effect on tolerability or safety.⁵⁵

In the I-ADD (Irbesartan/Amlodipine in Hypertensive Patients Uncontrolled on Irbesartan 150 mg Monotherapy) study comparing the efficacy and safety profile of irbesartan/amlodipine combination therapy with irbesartan monotherapy, most treatment emergent adverse events were of mild or moderate intensity and only a few were considered severe. The most frequent adverse events were peripheral edema and edema leading to treatment discontinuation; however, these were associated with amlodipine treatment only and appeared at the beginning of study treatment. Mean values for potassium, sodium, and creatinine were similar on both fixed-dose combination and monotherapy treatments.⁵⁶ The tolerability and safety profile was similar in the I-COMBINE (Irbesartan/Amlodipine in Hypertensive Patients Uncontrolled on Amlodipine 5 mg Monotherapy) study between the irbesartan/amlodipine fixed-dose combination versus amlodipine monotherapy treatments.⁵⁷ In COSIMA (the COmparative Study of Efficacy of Irbesartan/HCTZ with Valsartan/HCTZ Using Home Blood Pressure Monitoring in the TreAtment of Mild-to-Moderate Hypertension), which compared irbesartan/HCTZ with valsartan/HCTZ, overall safety was similar in the two groups.⁵⁸ The most common adverse events were infections, gastrointestinal disorders, and musculoskeletal disorders, mild-to-moderate in intensity, and in most cases not related to the study drug.

Finally, in a study comparing the efficacy of fixed combinations of irbesartan/HCTZ and losartan/HCTZ, no differences were observed between the two treatments with respect to adverse events or tolerability. The most common adverse events were cold symptoms and sore throat on the irbesartan/HCTZ regimen and headache in the losartan/HCTZ regimen. Also, for the irbesartan/HCTZ combination, heart rate was not considerably different from baseline based on 24-hour, daytime, and night-time pulse rate data, whereas with losartan/HCTZ heart rate was significant greater than baseline for the mean 24-hour and daytime values.⁵⁹

Efficacy in treatment of cardiovascular disease

Efficacy of irbesartan monotherapy in hypertension

Irbesartan is primarily indicated for the treatment of hypertension with proven efficacy in achieving significant BP reductions. There are several published studies (Table 1) demonstrating the efficacy of irbesartan for the treatment of patients with essential, mild-to-moderate and severe hypertension, both as monotherapy and in combination with HCTZ and other antihypertensive agents. The majority of the studies involved patients with seated diastolic BP of 95–110 mmHg,^{16,19,20,47,49–51,60,61} while others used limits of 95–100 mmHg,^17,45 90–110 mmHg,^46,48,62 95–115 mmHg,⁵² 90–120 mmHg,⁶³ or 115–130 mmHg.¹⁸ The primary efficacy outcome measure was reduction in trough seated BP in the majority of the included studies and reduction in trough 24-hour ambulatory BP in four studies.^16,48,50,60

Table 1.

Trial studies in hypertension: methodologic characteristics, results, and conclusions

References	Study design	Comparator	Population	Duration of therapy and treatment dose (mg)	Baseline mean SBP/DBP (mmHg)	Mean reduction in SBP/DBP (mmHg)	Conclusion
Monotherapy				8-week;			All irbesartan regimens significantly reduced mean 24-hour ambulatory DBP and SBP and were well tolerated
Fogari et al16	Multicenter, randomized, double-blind, placebo-controlled	Placebo	Patients aged ≥18 years with mild-to-moderate hypertension (n = 215)	Irbesartan 75	143.8/91.6	5.2/2.8
Larochelle et al18	Randomized, double-blind	Enalapril	Patients with severe hypertension (n = 182)	Irbesartan 75 twice daily	144.4/91.0	10.9/9.2
Kassler-Taub et al45	Multicenter, randomized, double-blind, placebo-controlled	Placebo, losartan	Patients with mild-to-moderate hypertension (n = 567)	Irbesartan 150	143.0/91.0	7.3/5.7
Pool et al17	Multicenter, randomized, double-blind, placebo-controlled	Placebo	Patients with mild-to-moderate hypertension (n = 319)	Placebo	145.2/91.3	0.1/1.2
Oparil et al52	Multicenter, randomized, double-blind, elective-titration	Losartan	Patients with mild-to-moderate hypertension (n = 432)	12-week;			Irbesartan effectively and safely reduced SBP and DBP in patients with severe hypertension in a manner comparable to that of enalapril
Stumpe et al20	Multicenter, randomized, double-blind	Atenolol	Patients aged ≥18 years with mild-to-moderate hypertension (n = 231)	Irbesartan 150–300	119.2/176.7	40.1/29.6
Mimran et al19	Multicenter, randomized, double-blind	Enalapril	Patients with mild-to-moderate hypertension (n = 191)	Enalapril 20–40	119.0/175.4	39.3/30.5
Lacourciere et al49	Multicenter, randomized, double-blind	Enalapril	Patients aged ≥65 years, with mild-to-moderate hypertension (n = 141)	8-week;			Antihypertensive effect of 300 mg irbesartan was significantly greater than that of 100 mg losartan
Chiou et al47	Multicenter, double-blind, randomized, parallel-group	Enalapril	Patients aged 24–75 years with mild-to-moderate hypertension (n = 54)	Irbesartan 150	155.3/101.1	12.1/9.7
Oparil et al63	Multicenter, randomized, double-blind	Olmesartan, losartan, valsartan	Patients aged ≥18 years with essential hypertension (n = 588)	Irbesartan 300	155.4/100.4	16.4/11.7
Coca et al48	Multicenter, randomized, double-blind	Enalapril	Patients with mild-to-moderate hypertension (n = 238)	Losartan 100	153.3/100.6	11.3/8.7
Mancia et al50	Multicenter, randomized, double-blind, parallel-group	Valsartan	Patients aged ≥18–75 years, with mild-to-moderate hypertension (n = 426)	Placebo	152.4/100.3	3.7/4.9
Hwang and Lu60	Open-label, uncontrolled		Patients with mild-to-moderate hypertension (n = 25)	8-week;			Irbesartan reduced BP in a dose-related manner; significant reductions over placebo were observed
Morales-Olivas et al46	Observational, open-label, uncontrolled, longitudinal, prospective		Patients aged ≥18 years, with mild-to-moderate hypertension (n = 4,612)	Irbesartan 100–300	159.8/100.7	13.0/11.6
Neutel et al51	Multicenter, randomized, double-blind, parallel-group	Amlodipine	Patients with mild-to-moderate hypertension (n = 181)	Placebo		5.0/5.5
Coronel et al62	Longitudinal, nonrandomized, prospective	(ACEI) Enalapril, captopril, perindopril	Patients with hypertension (nondiabetic advanced chronic kidney disease) (n = 43)	12-week;			Reductions in trough seated DBP and seated SBP were greater with irbesartan than with losartan treatment
				Irbesartan 150–300	155.3/100.9	18.0/13.8
				Losartan 50	154.2/100.7	10.8/13.9
				12-week;			Both treatments significantly lowered BP from baseline; irbesartan demonstrated an excellent safety and tolerability profile
				Irbesartan 75–150	158.0/101.9	15.0/12.3
				Atenolol 50–100	158.4/101.3	13.2/11.6
				12-week;			Irbesartan was as effective as the full dose range of enalapril and demonstrated an excellent tolerability profile
				Irbesartan 75–300	164/101	19/13
				Enalapril 10–40	165/102	18/14
				8-week;			Irbesartan is an effective and well tolerated antihypertensive treatment for elderly patients with mild-to-moderate hypertension
				Irbesartan 150–300	164.4/99.7	10.1/9.6
				Enalapril 10–20	161.5/98.3	11.6/9.8
				8-week;			Irbesartan was as effective in lowering BP as enalapril; both treatments were well tolerated, while there was a significantly
				Irbesartan 150–300	155/102	16.5/7.2
				Enalapril 10–20	155/101	10.6/5.0	lower incidence of cough with irbesartan compared with enalapril
				8-week;			Irbesartan compared with olmesartan showed similar reductions in ambulatory BP and seated SBP; however it was found to be less effective at reducing diastolic BP
				Irbesartan 150	156/104	11.0/9.9
				Losartan 50	157/104	9.5/8.2
				Valsartan 80	155/104	8.4/7.9
				Olmesartan 20	157/104	11.3/11.5
				12-week;			Irbesartan was as effective as enalapril up to 20 mg/day; irbesartan though, was better tolerated than enalapril
				Irbesartan 150–300	160.3/101.6	19.0/12.7
				Enalapril 10–20	158.2/102.0	17.512.4
				8-week;
				Irbesartan 150	159.3/100.7	19.0/12.7	Irbesartan was more effective than valsartan in reducing DBP and SBP at trough and in providing greater overall 24-hour BP-lowering efficacy
				Valsartan 80	158/100.8	17.5/12.4
				8-week;		After treatment:	Irbesartan monotherapy once daily provided effective BP control
				Irbesartan 150–300	143/91	128/82
				6-month;		After treatment:	Irbesartan produced significant reductions in BP and was well tolerated
				Irbesartan 150–300	165.0/96.7	140.0/82.5
				4-week;			Irbesartan 150 mg demonstrated comparable efficacy to amlodipine 5 mg, thereby confirming its value as an antihypertensive treatment option
				Irbesartan 150	150.7/99.7	12.2/9.4
				Amlodipine 5	149.6/99.8	12.0/9.6
				12-months;		After treatment:	Irbesartan compared with ACEI showed similar blood pressure control
				Irbesartan 150–300	153.76/85.24	138/77
				ACEI	145.68/85.23	133/77
Kawano et al61	Randomized, double-blind, placebo-controlled	Placebo	Patients with essential hypertension (n = 76)	6-week;			Irbesartan significantly reduced 24-hour daytime and night-time BPs compared with placebo; overall safety was even greater for irbesartan than placebo
Combination therapy				Irbesartan 100	145.0/95.0	5.8/3.4
Rosenstock et al53	Multicenter, randomized, double-blind, placebo-controlled	Placebo/HCTZ	Patients aged ≥28 years to 76 years, with mild-to-moderate essential hypertension (n = 238)	Placebo	142.9/92.0	1.7/0.5
Kochar et al71	Matrix	Placebo HCTZ	Patients with mild-to-moderate hypertension (n = 683)	12-week;			Irbesartan/HCTZ produced clinically and statistically significant mean reductions over placebo in both trough seated SBP and DBP and a significant antihypertensive response
Raskin et al55	Randomized, double-blind, placebo-controlled	Irbesartan HCTZ	Patients aged ≥18 years with mild-to-moderate essential hypertension (n = 1098)	Irbesartan/HCTZ 75–150/25	145.8/98.6	20.2/18.4
Howe et al54	Randomized, double-blind, placebo-controlled	Placebo	Patients aged ≥21 years with mild-to-moderate essential hypertension (n = 178)	Placebo/HCTZ 25	147.8/99.0	6.0/7.4
Meaney-Mendiolea et al72	Multicenter, nonblinded	Irbesartan	Patients (female) with mild-to-moderate hypertension (n = 188)	8-week;		Range	The combination of HCTZ in doses up to 25 mg with irbesartan in doses up to 300 mg is safe and produces dose-dependent reductions in BP
Bobrie et al58	Randomized, prospective, open-label, blinded endpoint	Valsartan/HCTZ	Patients >18 years and <80 years with untreated or uncontrolled hypertension (n = 414)	Irbesartan 37.5, 100, and 300	151/100	7.5–14.9/7.1–10.2
Neutel et al59	Randomized, parallel-group, open-label	Losartan/HCTZ	Patients with mild-to-moderate hypertension (n = 16)	HCTZ 6.25, 12.5, and 25		4.6–11.5/5.1–15.0
Neutel et al75	Multicenter, prospective, open-label, single-arm (INCLUSIVE)	Placebo HCTZ	Patients aged ≥18 years with hypertension and uncontrolled systolic BP (n = 736)	irbesartan/HCTZ 37.5–300/6.25–25		10.2–23.1/8.1–15.0 2.3/3.5
Neutel et al73	Multicenter, randomized, double-blind, active-controlled	Irbesartan	Patients with uncontrolled hypertension (n = 697)	Placebo
Franklin et al68	Multicenter, randomized, double-blind, active-controlled, forced-titration	Irbesartan HCTZ	Patients with moderate and severe hypertension (n = 1235)	12-month;			Long-term therapy with irbesartan/HCTZ is safe, well tolerated, and maintains normalized BP in >80% of patients
Cushman et al64	Prospective, open-label, single-arm	Placebo HCTZ	Patients aged ≥18 years with hypertension (n = 844)	Irbesartan/HCTZ 75–300/12.5–25	151.6/100.4	20.6/15.6
Neutel et al76	Randomized, double-blind, active-controlled, parallel-group	Irbesartan HCTZ	Patients with moderate hypertension (n = 538)	8-week;			Irbesartan/HCTZ produced clinically and statistically significant mean reductions in 24-hour ABP compared with placebo
Ofili et al74	Multicenter, prospective, open-label, single-arm (INCLUSIVE1)		Patients (women) aged ≥18 years with hypertension (n = 436)	Irbesartan/HCTZ 75/12.5	150.2/93.4	21.6/12.0
Fogari et al67	Prospective, randomized, open-label, blinded, end-point (PROBE)	Valsartan/amlodipine	Very elderly patients with hypertension (n = 94)	Irbesartan/HCTZ 150/12.5	152.6/93.5	22.1/13.5
				Placebo	148.3/93.2	6.4/3.5
				24-week;			Irbesartan alone or combined with HCTZ showed excellent antihypertensive efficacy with a low incidence of adverse events
				Irbesartan/HCTZ 150–300/12.5–25	136.5/84.8	28.1/ 20.0
				8-week;	153/91	14.8/8.2	Irbesartan/HCTZ is more effective than valsartan/HCTZ in hypertensive patients
				Irbesartan/HCTZ 150/12.5	153/90	11.6/6.8
				Valsartan/HCTZ 80/12.5
				4-week;			Irbesartan 50 mg/HCTZ 12.5 mg resulted in greater reductions in ambulatory BP than losartan 50 mg/HCTZ 12.5 mg
				Irbesartan/HCTZ 150/12.5	149.2/92.6	16.0/10.5
				Losartan/HCTZ 50/12.5	142.7/89.0	11.1/6.1
				18-week;			Irbesartan/HCTZ treatment achieved SBP goals in more than 75% of patients uncontrolled on monotherapy
				Irbesartan/HCTZ 150–300/12.5–25	154.0/91.3	21.5/ 10.4
				7-week;			In patients with severe hypertension, irbesartan/HCTZ combination therapy lowered BP more rapidly and to a greater extent than maximum-dose irbesartan monotherapy
				Irbesartan 150–300	171.6/113.3	31.7/24.5
				Irbesartan/HCTZ 150–300/12.5–25	171.5/113.4
				12-week;			Irbesartan/HCTZ combination therapy was well tolerated and more effective than irbesartan or HCTZ monotherapy in lowering BP in patients with moderate-to-severe hypertension
				Irbesartan 300	168.4/108.4	21.7/17.3
				HCTZ 25	162.0/97.6	15.7/7.2
				Irbesartan/HCTZ 300/25	167.5/106.8	29.9/20.4
				8-week;			Irbesartan/HCTZ combination therapy allowed SBP goal attainment in 73% of patients aged >65 years whose hypertension was previously uncontrolled with monotherapy
				HCTZ 12.5	156.5/85.6	31.7/24.5
				Irbesartan/HCTZ 150–300/12.5–25
				12-week;			Irbesartan/HCTZ is well tolerated and achieves rapid and sustained reductions in SBP/DBP in patients with moderate hypertension
				Irbesartan/HCTZ 150–300/12.5–25	161.7/97.5	28.3/15.2
				Irbesartan 150–300	161.4/97.9	19.5/11.1
				HCTZ 12.5–25	162/97.6	16.5/7.8
				8-week;			Irbesartan/HCTZ treatment was effective and well tolerated in a diverse population of women whose BP was previously uncontrolled on monotherapy
				Irbesartan/HCTZ 300/25	153.9/90.3	22.9/10.3
				4-week;			In very elderly hypertensive patients, treatment with both valsartan/amlodipine combination and irbesartan/HCTZ combination was similarly effective in reducing clinical as well as ambulatory BP levels
				Valsartan/amlodipine 160/5	163.2/89.8	22.9/15.6
				Irbesartan/HCTZ 300/12.5	162.7/90.1	29.6/15.4
Chrysant et al66	Multicenter, prospective, open-label, single-arm (INCLUSIVE trial)	Placebo HCTZ	Patients aged ≥18 years with isolated systolic hypertension (n = 443)	16-week;			Once-daily fixed-dose irbesartan/HCTZ combination treatment provided effective and well tolerated BP-lowering
Franklin and Neutel69	Randomized double-blind trial	No comparator	Patients with severe uncontrolled hypertension (n = 468)	HCTZ 12.5	156.2/88.7	21.4/10.1
Bobrie et al57	Multicenter, parallel-group, prospective, randomized, open-label, blinded endpoint (I-COMBINE)	Amlodipine	Patients with essential, uncontrolled hypertension (n = 287)	Irbesartan/HCTZ 150–300/12.5–25
Bobrie et al56	Multicenter, parallel-group, prospective, randomized, parallel-group, open-label, blinded-end point (I-AAD)	Irbesartan	Patients with essential, uncontrolled hypertension (n = 320)	7-week;		Range	Irbesartan/HCTZ was rapidly effective regardless of age, obesity, T2DM, and baseline SBP; treatment was well tolerated
Al Balushi et al65	Retrospective, observational	Valsartan/HCTZ	Patients with mild-to-moderate hypertension (n = 232)	Irbesartan/HCTZ 300/25	191.2/115.1	28.0–42.9/22.9–27.2
Huang et al70	Multicenter, single-arm, prospective	No comparator	Patients with moderate-to-severe hypertension (n = 501)	10-week;			Fixed-dose combination irbesartan/amlodipine suggests greater efficacy over monotherapy in lowering SBP
				Irbesartan/amlodipine 150/5	148.5/84.8	12.4/5.6
				Amlodipine 5	149.2/85.1	6.3/3.0
				10-week;			There was a greater antihypertensive efficacy of the fixed-dose combination of irbesartan 300/amlodipine 5 mg over irbesartan 300 alone in lowering systolic BP; both treatments were well tolerated
				Irbesartan/amlodipine 300/5	152.7/86.6	18.7/8.6
				Irbesartan 300	150.4/86.0	9.9/3.9
				3-month;			The irbesartan/HCTZ combination was associated with significant reductions in both SBP and DBP when compared with valsartan/HCTZ combinations; reductions were noted more in diabetics than nondiabetics
				Irbesartan/HCTZ 150/12.5	153/81	9.0/5.0
				Valsartan/HCTZ 80–160/12.5	144/77	2.0/0.0
				12-week;			The fixed irbesartan/HCTZ combination may control BP to the target level in about 60% of Chinese patients with moderate-to-severe hypertension, with an acceptable safety profile

Abbreviations: HCTZ, hydrochlorothiazide; ACEI, angiotensin-converting enzyme inhibitor; BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus.

The main exclusion criteria in general concerned patients with secondary or malignant hypertension, cardiovascular diseases such as stroke, myocardial infarction, and heart failure, renal failure or liver dysfunction, other concomitant diseases presenting safety hazards, and medications that could interface with the assessment of efficacy or safety.

Results from placebo-controlled studies show that irbesartan treatment, at doses ranging from 75 mg to 300 mg, achieves a statistically significant reduction in both systolic and diastolic BP in patients with mild-to-moderate hypertension.^16,17,46 BP reductions were evident within 2 weeks with irbesartan treatment, although even greater reductions appeared in week 4 and thereafter, and were dose-related up to 300 mg per day. In comparative studies, irbesartan 300 mg in patients with mild-to-moderate hypertension resulted in greater reductions in trough seated diastolic BP and systolic BP compared with losartan.^45,52 Further, irbesartan demonstrated significant greater reductions in mean systolic ambulatory BP, at trough, mean 24-hour diastolic and systolic ambulatory BP, as well as office-measured diastolic BP and systolic BP compared with valsartan.⁵⁰ Compared with enalapril, atenolol, and amlodipine, irbesartan demonstrated comparable efficacy in reducing both diastolic and systolic blood pressure and normalized seated diastolic BP at dosages up to 300 mg.^{19,20,47–49,51} Finally, in a study by Oparil et al, irbesartan compared with the newest angiotensin II antagonist, olmesartan, showed similar reductions in ambulatory BP, as well as in seated systolic BP. However olmesartan achieved significant greater reductions in seated diastolic BP than irbesartan.⁶³

Efficacy of irbesartan in combination therapy for hypertension

In many cases, hypertensive patients require the addition of a second drug to achieve adequate BP control. The literature search identified several studies evaluating the efficacy of irbesartan combined with HCTZ for the treatment of patients with mild-to-moderate or severe hypertension. Primary efficacy outcomes and exclusion criteria for patients were similar to the ones mentioned above. Patients’ seated diastolic BP in the majority of the studies was 95–110 mmHg,^{53–58,64–74} while others used limits of 70–109 mmHg,⁷⁵ 95–114 mmHg,⁵⁹ or 100–109 mmHg.⁷⁶

Results from three placebo-controlled studies showed that reductions from baseline trough seated diastolic BP and systolic BP with irbesartan/HCTZ combination were greater compared with placebo/HCTZ. Results were obvious within 2 weeks of treatment with irbesartan/HCTZ.^53–55 Similarly, the INCLUSIVE (IrbesartaN/HCTZ bLood pressUre reductionS in dIVErse patient populations) trial as well as subgroup analyses of this trial showed that irbesartan/HCTZ combination therapy leads to substantial reductions in both systolic BP (in more than 75% of patients uncontrolled on monotherapy) and diastolic BP.^66,74,75

In comparative studies, the fixed combination of irbesartan/HCTZ had a superior BP-lowering effect compared with valsartan/HCTZ, and there was a significant difference in adjusted mean changes from baseline 24-hour ambulatory diastolic BP and systolic BP compared with losartan/HCTZ.^58,59 Further, in patients with severe hypertension (ie, seated diastolic BP ≥ 110 mmHg), irbesartan/HCTZ resulted in greater and more rapid reductions in BP, compared with irbesartan 150 mg or 300 mg and HCTZ 12.5 mg or 25 mg monotherapies.^68–70,73 Finally, results from the I-ADD and the I-COMBINE studies, which evaluated the efficacy of irbesartan/amlodipine combination therapy, suggest greater efficacy with the fixed-dose combination of irbesartan 150 mg/amlodipine 5 mg over amlodipine 5 mg and irbesartan 150 mg monotherapies.^56,57

Efficacy in hypertensive patients with type 2 diabetes and nephropathy

Irbesartan is also indicated for the treatment of renal disease in adult hypertensive patients with type 2 diabetes mellitus. Results from the IDNT (Irbesartan in Diabetic Nephropathy Trial) and IRMA (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria) trials show that irbesartan was associated with better renal outcomes compared with amlodipine, placebo, and other antihypertensive agents. Further, irbesartan provided a significantly slower increase in serum creatinine concentration and decrease in creatinine clearance and reduced the rate of progression to albuminuria (by 38% and 24% with irbesartan 300 mg and 150 mg, respectively).^77,78

Irbesartan was also found to reduce microalbuminuria both in diabetic and nondiabetic patients, resulting in an increase in the percentage of patients with normoalbuminuria from 17.1% at baseline to 40.9% and in a decrease in patients with microalbuminuria from 49.2% to 23.2%.^79,80 Finally, irbesartan was found to reduce significantly the albumin excretion rate in both microalbuminuric normotensive and hypertensive patients as well as 24-hour mean systolic and diastolic BP.⁸¹

Effects of irbesartan on left ventricular hypertrophy

Left ventricular hypertrophy increases the risk of cardiovascular disease in patients with hypertension, and there are several studies investigating the potential effects of irbesartan in patients with left ventricular hypertrophy.^82–85 In the SILVHIA (Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol) trial, patients treated with irbesartan showed a greater reduction in left ventricular mass and BP than those treated with atenolol. Irbesartan decreased QT dispersion from 56 ± 24 msec to 45 ± 20 msec at 48 weeks and QTc dispersion from 57 ± 24 msec to 44 ± 19 msec.⁸³ Similarly, the effect of irbesartan 150 mg once daily in patients with essential arterial hypertension and echocardiographically determined left ventricular hypertrophy showed a decrease by 23.2% and 24.7% in left ventricular mass index compared with a decrease of 11.4% and 11.6% with amlodipine (after 3 months and 6 months, respectively).⁸²

Cost-effectiveness

The literature review identified 15 papers eligible for inclusion in the review concerning the cost-effectiveness of irbesartan. More specifically, 13 studies compared the cost-effectiveness of irbesartan with standard antihypertensive medications (amlodipine, valsartan, losartan), while the other two assessed the cost-effectiveness of irbesartan in combination with HCTZ. The studies are presented in Table 2 and the results are summarized under the following headings: study reference, analysis perspective, methods, population, time horizon, discounting rate, costs, outcomes, and study conclusions. The majority of the studies based their efficacy data on two clinical trials, ie, IDNT and IRMA-2. All studies were modeling ones, using a Markov model, with the majority being cost-effectiveness analyses^86–94 or cost-consequence analyses,^95–99 while one was a cost utility analysis.¹⁰⁰ Studies were done either from a third party payer perspective or from a health care payer perspective. The population under consideration included patients with hypertension, type 2 diabetes, microalbuminuria, and nephropathy. The majority of the studies were conducted in a European setting (France, Belgium, the UK, Spain, Hungary, Italy, Greece, Switzerland, and Sweden), while two were conducted in the US, two in Canada, and another one in Asia.

Table 2.

Methodologic characteristics of economic evaluation studies

Reference	Analysis perspective	Methods	Population	Time horizon discount rate	Costs	Outcomes	Study conclusion
Rodby et al94	Third party payer (Medicare)	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and nephropathy	25 years, 5%	TC/patient (25 years):	LE (25 years):	Irbesartan was both the least costly and most effective strategy
Palmer et al96	Third party payer (Medicare)	CCA based on a Markov model	Patients with type 2 diabetes, hypertension, and nephropathy	10 years, 3%	Irbesartan $111,647 versus amlodipine $137,937 versus control $127,254	Irbesartan 8.225 versus amlodipine 7.601 versus placebo 7.484
Palmer et al92	Third party payer	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and microalbuminuria	25 years, 3%	Cost savings (25 years):
Palmer et al95	NHS payer	CCA based on a Markov model	Patients with type 2 diabetes, hypertension, and nephropathy	10 years, 6%	Irbesartan versus amlodipine $26,290 versus control $15,607
Palmer et al93	Third party payer	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and microalbuminuria	25 years, 3%	Lifetime TC/patient:	Mean time to ESRD (years):	Irbesartan was both cost-saving and life-saving compared with amlodipine and control therapy
Palmer et al91	Health care payer	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and nephropathy	25 years, 5%	Belgium: Irbesartan €76,777 versus amlodipine €97,940 versus control €88,662	Irbesartan 8.23 versus amlodipine 6.82 versus control 7.88
Palmer et al97	Third party payer	CCA based on a Markov model	Patients with type 2 diabetes, hypertension, and microalbuminuria	25 years, 5%	France: Irbesartan €93,204 versus amlodipine €120,284 versus control €109,585	LE (years):
Palmer et al100	Third party payer	CUA based on a Markov model	Patients with type 2 diabetes, and hypertension	25 years, 3%		Belgium: Irbesartan 8.57 versus amlodipine 8.11 versus control 7.95
					Cost savings/patient:	France: Irbesartan 8.58 versus amlodipine 8.13 versus control 7.97
					Belgium: Irbesartan versus amlodipine: €14,949 versus control: €9,205
					France: Irbesartan versus amlodipine: €20,128 versus control: €13,337
					TC/patient (25 years):	Years free of ESRD:	Early irbesartan treatment reduces costs in hypertensive patients with type 2 diabetes and microalbuminuria; late irbesartan is also superior in overt nephropathy but should start earlier and continued long term
					Early irbesartan: $16,859	Early irbesartan: 14.4
					Late irbesartan: $25,529	Late irbesartan: 12.7
					Control: $28,782	Control: 12.4
					Cost savings/patient:	LYG/patient:
					Early irbesartan versus control: $11,922	Early versus control 0.96;
					Late irbesartan versus control: $3,252	late versus control 0.05;
					Early versus late irbesartan: $8,670	early versus late 0.92
					Mean TC/patient (10 years):	LE (years):	Treating patients with hypertension, type 2 diabetes, and overt nephropathy with irbesartan was cost-saving over a 10-year period compared with amlodipine and control
					Irbesartan £20,884 versus amlodipine £27,417 versus control £24,642	Irbesartan versus amlodipine 0.07 versus control 0.21
					Cost savings/patient (ESRD delay):
					Irbesartan versus amlodipine £5,125 versus control £2,919
					TC/patient (25 years):	Years free of ESRD:	Treating patients with hypertension, microalbuminuria and type 2 diabetes with irbesartan was projected to reduce the incidence of ESRD, extend life, and reduce costs
					Irbesartan: €14,038	Irbesartan 15.66 versus control 13.44
					Control: €25,119	LE (years):
					Cost savings/patient (25 years):	Irbesartan 12.37 versus control 11.53
					Irbesartan versus control €11,082
					TC/patient (10 years):	Mean time to ESRD (years):	Irbesartan is a life-saving and cost-saving drug in patient with type 2 diabetes compared with amlodipine and standard blood pressure treatment
					Irbesartan €41,692 versus amlodipine €55,222 versus placebo €49,825	Irbesartan 8.23 versus amlodipine 6.82 versus placebo 6.88
					Cost saving/patient (10 years):	Increase in LE (10 years):
					Irbesartan versus amlodipine €13,530; versus placebo €8,133	Irbesartan 0.15 versus amlodipine 0.31 versus placebo 0.31
					TC/patient (25 years):	Mean LE (years):	Irbesartan treatment of type 2 diabetes patients with hypertension and microalbuminuria is both cost and life-saving
					Irbesartan CHF 25,469 versus control CHF 46,956	Irbesartan 10.37 versus control 9.80
					Cost savings/patient (25 years):	Years free of ESRD:
					Irbesartan versus control CHF 21,487	Irbesartan 15.04 versus control 12.90
					TC/patient (25 years):	LYG:	Early irbesartan treatment improved quality of life and reduced costs compared with late irbesartan treatment
					Early irbesartan €17,689 versus late irbesartan €33,383 versus control €40,003	Early irbesartan 12.17 versus late irbesartan 11.27 versus control 11.23
						QALY:
						Early irbesartan 10.55 versus late irbesartan 9.58 versus control 9.52
Palmer et al98	NHS payer	CCA based on a Markov model	Patients with type 2 diabetes, hypertension, and nephropathy	25 years, 3.5%	TC/patient (25 years):	Years free of ESRD:	Treatment with irbesartan was projected to improve life expectancy and reduce costs in patients with type 2 diabetes and hypertension at risk of developing ESRD
Palmer et al99	Third party payer (health insurance)	CCA based on a Markov model	Patients with type 2 diabetes and hypertension	25 years, 5%	Early irbesartan £6,735 versus late irbesartan £9,045 versus control £10,536	Early irbesartan 14.29 versus late irbesartan 12.47 versus control 12.25
Coyle and Rodby88	Third party payer	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and proteinuria	25 years, 5%	Cost savings/patient (25 years):	LE (years):
Coyle et al87	NHS payer	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and microalbuminuria	25 years, Not stated	Early irbesartan versus control £3,801	Early 11.00 versus late 10.20 versus control 10.18
Annemans et al86	Third party payer	CEA based on a Markov model	Patients with type 2 diabetes, hypertension, and nephropathy	25 years, 3%	Late irbesartan versus control £1,491
Ekman et al89	Health care payer	CEA based on a Markov model	Patients with hypertension	Not stated		LYG:
Maniadakis et al90	Third party payer	CEA based on a Markov model	Patients with hypertension	5 years, 6%		Early versus control 0.83
						Late versus control 0.02
					TC/patient (25 years):	LE (years):	Irbesartan was projected to be a dominant treatment compared with placebo in the Hungarian setting when treating hypertensive patients with type 2 diabetes and microalbuminuria
					Irbesartan HUF 1,250,204 versus placebo HUF 1,770,197	Irbesartan 8.16 versus placebo 7.62
					Cost saving/patient (25 years):	LYG:
					Irbesartan versus placebo HUF 519,993	Irbesartan versus placebo 0.54
					TC/patient (CAN$):	LYG:	Irbesartan compared with amlodipine and standard care, led to reduction in medical costs and an increase in life expectancy
					Irbesartan 89,304 versus amlodipine 109,280 versus control 101,688	Irbesartan 6.82 versus Amlodipine 6.48 versus control 6.40
					TC/patient (CAN$):	LYG:	Early use of irbesartan for patients with hypertension and type 2 diabetes is both more effective and less costly
					Early irbesartan $67,300 versus late irbesartan $121,400 versus control $135,700	Early versus late irbesartan 0.45
						Early irbesartan versus control 0.62
					Cost saving/patient (CAN$):
					Early irbesartan versus late irbesartan $54,100
					Early irbesartan versus control $68,400
					Late irbesartan versus control $14,300
					TC/patient (25 years):	Late irbesartan,	Increase in LE (years):	Early irbesartan treatment was a cost-effective alternative in the Asian settings
					Early irbesartan	standard treatment:	Early versus late: 0.31 to 0.48
					Malaysia $8,455	$2,980 to $13,484,
					South Korea $12,961	$6,189 to $21,148
					Thailand $29,737	$8,200 to $29,732
					Taiwan $25,790	Higher than costs
					People’s Republic of China $42,990	of early irbesartan
					Men:	Men:	Irbesartan/HCTZ is a cost-effective antihypertensive treatment strategy compared with placebo, valsartan, and losartan
					Irbesartan/HCTZ (150/12.5 mg): €17,107	Irbesartan/HCTZ (150/12.5 mg):
					Irbesartan/HCTZ (300/25 mg): €17,371	13.067 QALY
					C/E ratio: €18,964	Irbesartan/HCTZ (300/25 mg):
					Women:	13.081 QALY
					Irbesartan/HCTZ (150/12.5 mg): €13,610	Women:
					Irbesartan/HCTZ (300/25 mg): €13,912	Irbesartan/HCTZ (150/12.5 mg):
					C/E ratio: €44,552	14.113 QALY
						Irbesartan/HCTZ (300/25 mg):
						14.120 QALY
					Mild-to-moderate hypertension	QALY
					Men:	Men:
					Irbesartan €15,146 versus losartan €15,696 versus valsartan €15,613	Irbesartan 1.67 versus losartan 12.63 versus valsartan 12.64
					Women:	Women:
					Irbesartan €12,945 versus losartan €14,424 versus valsartan €13,397	Irbesartan 14.29 versus losartan 14.27 versus valsartan 14.27
					Severe hypertension
					Men:	Men:
					Irbesartan €18,697 versus losartan €21,488	Irbesartan 12.47 versus losartan 12.37
					Women:	Women:
					Irbesartan €16,202 versus losartan €19,099	Irbesartan 14.16 versus losartan 14.09

Abbreviations: ESRD, end-stage renal disease; CEA, cost-effectiveness analysis; CCA, cost-consequence analysis; CHF, congestive heart failure; CUA, cost-utility analysis; C/E, cost-effectiveness; TC, total cost; LYG, life years gained; LE, life expectancy; NHS, National Health System; HUF, Hungarian Forint; CAN, Canadian; QALY, quality-adjusted life years; HCTZ, hydrochlorothiazide.

In many of the studies, there are extrapolations on the long-term life years gained and quality-adjusted years with irbesartan. In four studies comparing irbesartan with amlodipine treatment, results concerning effectiveness showed that life expectancy improved with irbesartan compared with amlodipine. Life expectancy for irbesartan was 8.58 life years in a 25-year time horizon versus 8.13 life years with amlodipine.^{88,91,94–96} Five studies comparing early versus late irbesartan treatment showed that early irbesartan is more effective than late irbesartan.^{86,87,92,98,100} Life years gained with irbesartan were 12.17 versus 11.27 with late irbesartan treatment. The quality-adjusted life years gained were 10.55 and 9.58, respectively.¹⁰⁰ Further, several studies indicated an association between irbesartan treatment and delayed onset of end-stage renal disease (ESRD). Results showed that use of irbesartan delayed the onset of ESRD and reduced the cumulative incidence of ESRD apart from increasing life expectancy. The cumulative incidence of ESRD after 25 years for irbesartan compared with control therapy was 10.7%–26.6%, respectively. Irbesartan was estimated to delay the onset of ESRD by 2.14 years.⁹⁷

Results concerning the cost-effectiveness of irbesartan monotherapy compared with conventional antihypertensive therapy reveal that treatment of hypertensive patients with type 2 diabetes, microalbuminuria, and nephropathy with irbesartan lead to significant cost savings. More specifically, total per patient costs with irbesartan ranged from approximately €14,000 to €93,000. Corresponding costs per patient with the comparison treatment ranged from approximately €20,000 to €120,000, resulting to substantial cost savings of up to about €20,000 with irbesartan treatment.

Four studies evaluated the cost-effectiveness of three alternative strategies for the management of hypertensive patients with type 2 diabetes and microalbuminuria; these alternative strategies were early irbesartan treatment, late irbesartan treatment, and conventional antihypertensive treatment.^86,87,92,98 Results from these studies showed that early irbesartan treatment is cost-effective compared with late irbesartan treatment and conventional antihypertensive therapy, resulting to cost savings per patient of up to approximately €40,000 versus late irbesartan treatment and up to approximately €50,000 versus standard treatment.^86,87,92,98

Two studies evaluating irbesartan in combination with HCTZ for the treatment of patients with hypertension showed that irbesartan is a cost-effective antihypertensive treatment strategy compared with alternative hypertension therapies, losartan and valsartan.^89,90 More specifically, the combination of irbesartan 150 mg/HCTZ 12.5 mg was a dominant strategy (ie, better health effects at lower costs) compared with losartan 50 mg/HCTZ 12.5 mg and valsartan 80 mg/HCTZ 12.5 mg.⁸⁹

Conclusion

Evidence from this review suggests that irbesartan represents not only an effective and well tolerated treatment for patients with hypertension and those with type 2 diabetes and nephropathy, but also a cost-saving and cost-effective treatment compared with other conventional treatment options.