Int. Med J Vol 3 No 2 December 2004

EFFECTS OF IRBESARTAN, AN ANGIOTENSIN RECEPTOR BLOCKER, ON GLUCOSE TOLERANCE IN HYPERTENSIVE PATIENTS: PRELIMINARY FINDINGS

Azizi Ayob[1], Tariq Abdul Razak[2]

ABSTRACT

Hypertension is more common among diabetics than nondiabetic subjects. Irbesartan, an angiotensin II (AII) receptor blocker, is a newer class of antihypertensive agents that inhibit the renin-angiotensin system by selectively blocking the AT₁ subtype of AII receptors. A non-randomized, run-in placebo 3-month follow up clinical study was carried out to determine the effects of Irbesartan (150 mg daily) on glucose tolerance and insulin secretion in 7 subjects with uncomplicated mild to moderate essential hypertension. Glucose tolerance and insulin secretion were evaluated by applying the extended (3-hour) oral glucose tolerance test with administration of 75 gm of glucose. The patients were kept on placebo for 4 weeks, and the first glucose tolerance test (OGTT) was performed, followed by Irbesartan 150 mg daily for 12 weeks period. A second OGTT was performed at the final visit. Blood glucose was determined with a glucose hexokinase preparation and insulin levels were measured by immunometric assay. There was a significant difference in lowering both the systolic and diastolic blood pressures after Irbesartan therapy (P<0.05). Nevertheless, there were no significant differences in the percentage change in blood insulin levels and glucose at the various specific time points during OGTT when the subjects were on placebo or on Irbesartan 150 mg. It appears that Irbesartan is free from adverse metabolic effects on glucose as well as plasma insulin levels in hypertensive subjects. In conclusion, Irbesartan has no effect on the tolerance for oral glucose and do not influence the concomitant insulin response in hypertensive subjects.

Keywords: Irbesartan, oral glucose tolerance, plasma insulin, hypertension.

INTRODUCTION

Hypertension is more common among diabetic than nondiabetic subjects, however, the subjects with hypertension alone, treated with anti-hypertensive drugs, develop diabetes more frequently than diabetic subjects develop hypertension (1). When a person has both diabetes and hypertension, the risk of a heart attack and stroke is exceptionally high, and treatment to lower blood pressure is essential. Effects of hypertensive drugs on the development of diabetes further enhances risk by threefold for the subjects who were on treatment (2). This is further supported by a study on 12,550 non-diabetic adults who were followed for 6 years, resulting in a significant 28% increased risk of developing diabetes after treatment with beta blockers in contrast to diuretics, calcium antagonists and angiotensin converting enzyme inhibitors (ACEI) (3). Recent large outcome studies, when compare to placebo, ACEI and angiotensin II receptor blocker (ARB) therapy not given as antihypertensive agents could also beneficially reduce new diabetes (4,5), suggesting that these agents have specific benefits of renin-angiotensin inhibitors. Candesartan and lisinopril, were evaluated in hypertensive patients with type II diabetes mellitus. Both drugs were well tolerated and produced a renoprotective effect independent of their blood pressure lowering effect (6). In this study, however, the effect of drugs on plasma glucose and insulin levels were not reported.

ARB is a new class of antihypertensive drugs that inhibit the renin-angiotensin system by selectively blocking the angiotensin II (AII) receptor subtype (AT₁) of AII receptors for treatment of hypertension (7). Nevertheless, data on the ARB influence on glucose tolerance and concomitant plasma insulin in human are limited as compared to its effects on insulin sensitivity (8,9,12). Losartan, is the first specific and orally ARB, is metabolically neutral, without any significant adverse effect on insulin secretion and glucose tolerance in hyperinsulinemic (insulin-resistant) hypertensive subjects (8). Irbesartan is a member of ARB, blocks the vasoconstrictor and aldosterone-secreting effects of Ang II by selectively binding to the AT₁ receptors subtype (10). Several studies have shown that long-term Irbesartan therapy, with or without other antihypertensives, achieved and maintained normalized blood pressure in the majority of patients and was well tolerated (11). Study in the insulin-resistant obese Zucker rat, however, showed a contrast finding whereby Irbesartan improved the glucose tolerance and the whole-body insulin sensitivity (12). Data on the effect of Irbesartan on plasma glucose and insulin levels in hypertensive subjects by performing the oral glucose tolerance test (OGTT) particularly in the local hypertensive subjects are lacking. It is therefore, important to consider these metabolic actions of Irbesartan in the treatment of hypertension especially in the presence of other risk factors of cardiovascular disease. For that reason, this study was undertaken to determine the effects of Irbesartan on OGTT and concomitant insulin levels in hypertensive subjects.

METHODS

Patients

The study group consisted of 8 uncomplicated essential hypertensive (5 men, 3 women) subjects aged 45-64 years (56.0+1.0 years, mean+SEM). The study participants were recruited from the Medical Out Patient Department (MOPD), Kuantan General Hospital, Pahang. Eligible subjects had the following characteristics: men or women of non-child bearing potential, age 21 to 70 years, untreated or treated hypertension for at least 6 months,  sitting systolic blood pressure (sSBP) is > 140 mmHg and/or sitting diastolic blood pressure (sDBP) > 90mmHg after at least 4 to 6 weeks of placebo therapy (at baseline), stable body weight over the past 3 months, and having given written informed consent. Individuals with the following characteristics were excluded: sSBP > 180 mmHg and/or sDBP > 110mmHg, diabetes, a known sensitivity to Irbesartan, serious disease, myocardial infarction unstable angina or stroke within the past 3 months, impaired liver function tests, renal insufficiency, history of alcohol or drug abuse, AIDS or pregnancy.

Study design

The study was conducted according to the declaration of Helsinki. The protocol was approved by the Ethical Committee of the Faculty of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang and had a single-blind, run-in placebo and 3-month follow up design. The first visit took place 4 to 6 weeks before the active treatment was started. During this visit the subjects underwent a physical examination with full medical history and have a series of baseline measurements including blood pressure, heart rate, height and weight. All of them were normocalcemic and had normal renal and hepatic functions, based on the normal serum levels of creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Subjects eligible to participate were given placebo for 4 weeks before the first 3-hour OGTT was performed. It was then followed by the Irbesartan 150 mg daily for 4 weeks period. At week 4 or week 8, if the sSBP is > 140 mmHg and/or sDBP > 90mmHg, the dose of Irbesartan were titrated from 150 mg to two tablets of Irbesartan 150 mg per day (figure 1). The second OGTT was performed at the final visit at week 12 together with other assessments such as blood pressure, heart rate, weight, liver enzymes and serum creatinine.

Oral glucose tolerance test and Insulin level

Experiments started in the morning, after an overnight fast and without taking the morning dose. A cannula was placed in one of the antecubital veins. This cannula was used for sampling blood for insulin and glucose determinations. The patency of the cannula was maintained with a solution of 9% dextrose containing 10,000 units of heparin per liter. The morning dose of Irbesartan was given 15-30 minutes before the first blood sample (0 minute) was collected. A series of 9 ml of blood were collected (7 ml of blood into heparinised tubes for insulin analysis and 2 ml of blood into BD Vacutainer for glucose analysis) at 0 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours and 3 hours, after administering orally 75 gm of glucose dissolved in water. Freshly taken samples were centrifuged at 4000 rpm at 15°C. Plasma was then separated for the measurement of insulin and glucose which were performed on the same day. The balance samples were stored at a 2-8°C for repeat analysis. All samples were stable at 2-8°C for 14 days.

Analytic Procedures

Blood glucose was determined by the glucose hexokinase method (Bayer Diagnostic Glucose (HK) Reagent with the Express Plus Clinical Chemistry Analyzer). Plasma insulin concentrations were determined by enzyme immunoassay (EIA) by using the IMMULITE Insulin Kit with the IMMULITE Analyzer (Diagnostic Product Corporation, Los Angeles). Mean insulin and glucose values were calculated from duplicate determinations for each sample. 

Statistical Analysis

For the purpose of standardizing the base line values the percentage increase in plasma glucose and insulin values were used. The non–parametric Wilcoxon signed rank test was applied on the differences of patients’ characteristics, blood pressures and the differences of insulin and glucose values. The SPSS version 11.5 software was used for the data analysis.

RESULTS

Patients’ characteristics

Seven subjects were followed up until the study ended. One subject dropped out because he refused to continue the study. The characteristic of the hypertensive patients treated with Irbesartan is as shown in table 1. All patients required the same dose of 150 mg daily to control the blood pressure throughout the study. There was no difference between the placebo and Irbesartan treatment in the parameters measured such as weight, heart rate, serum creatinine levels, ALT and AST. The sSBP and sDBP were significantly reduced after 3-month of therapy.

Effects of Irbesartan on blood glucose and insulin levels during OGTT

The effects of Irbesartan on the percentage rise of glucose levels at specific time points during the OGTT are as shown in figure 2. There was no significant difference in the blood glucose at the various specific time points during OGTT when the subjects were at baseline or after Irbesartan therapy. There were no glucose intolerance cases reported in the subjects after completed the treatment (Table 2). The effects of Irbesartan on the percentage rise in blood insulin levels during OGTT are as shown in figure 3. There were no significant differences in the blood insulin levels at the various specific time points during OGTT when the subjects were at baseline or after Irbesartan therapy.

DISCUSSION

The success of ARB in the treatment of hypertension is mainly attributed to an anti-Ang II effect of this drug. Clinical experience with ARB indicates that this new class of drugs is safe, efficacious and well tolerated (11,14,16). The future prospect and clinical relevance of ARB in the management of hypertension, however, are based on the several factors. One of them is the potential role of ARB in improving concomitant metabolic risk factors of CHD, which include plasma glucose and insulin levels. The short-term benefit of the treatment of hypertension must be balanced against its effect on these parameters. The present findings are consistent with that of Laakso Markku et al. (8). The authors reported that losartan, an ARB, had no effect on insulin sensitivity, glucose tolerance, and lipid metabolism in hyperinsulinemic (insulin-resistant) hypertensive subjects. Study in neonatal non-insulin dependent diabetes mellitus (NIDDM) rats, however, showed a different finding whereby losartan reduced the insulin levels and also led to reduction in elevated fasting and fed glucose levels (13). These findings were also consistent to that of Henriksen et al. (12), who reported that Irbesartan had improved the glucose tolerance and the whole-body insulin sensitivity on insulin-resistant obese Zucker rats. There are at least two possibilities which may explain these contradictory findings. Firstly, it may due to the factor of species difference in insulin response of rat and man. Secondly, the potential of ARB’s  (i.e. Losartan and Irbesartan) effects in improving insulin sensitivity would be maximized in the hyperinsulinemic (insulin resistant) rats as compared to insulin-sensitive hypertensive rats. The issue can probably be clarified if we study the irbesartan effect on both parameters by performing OGTT in insulin-sensitive hypertensive rats. In addition, none of the hypertensive patients showed glucose intolerance when on Irbesartan. It appeared that Irbesartan is free from adverse metabolic effects on glucose. Similarly, there were no significant changes noted in the concomitant insulin levels at the various time points during the procedure. All hypertensive subjects were treated with Irbesartan at a daily dose of 150 mg throughout the 12 weeks treatment. There was significant lowering of both the sSBP and sDBP after Irbesartan therapy. These findings are consistent with previous studies (14,15,16). It appears that a single dose is adequate to lower the blood pressure after 3-month therapy. With adequate blood pressure control, Irbesartan did not affect the tolerance for oral glucose and did not influence concomitant insulin response in hypertensive subjects.

Of particular interest are the recently published data showing that administration of irbesartan appears to be protective against target organ damage. Substantial benefits in prevention of major cardiovascular morbidity and mortality in high-risk populations have been reported. Malmqvist, et al. found that irbesartan induced a progressive reduction in left ventricular mass in hypertensive patients with LVH (17). The Irbesartan Diabetic Nephropathy Trial (IDNT) showed a beneficial effect of irbesartan on development of diabetic nephropathy in hypertensive patients with type II diabetes mellitus (Parving, et al. 2001)(18). In the recent report, when compared with placebo, ACEI by ramipril or by the ARB, candesartan, both decrease the incidence of new diabetes (19). Based on this report, the hypothesis that these agents actually prevent the changes leading to insulin resistance or may improve insulin sensitivity has been speculated.

In conclusion, Irbesartan decreased sSBP and sDBP but did not affect the plasma glucose and insulin levels as shown by the OGTT study. Irbesartan seem to be well suited drug in hypertensive subjects for the treatment of hypertension.

ACKNOWLEDGEMENT

This study was supported by the Research Centre and the Faculty of Medicine, International Islamic University of Malaysia (IIUM), Kuantan, Pahang, Malaysia. 

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 Section 6: TABLES

Table 1: The characteristics of patients.

NS: Not significant

Table 2: The plasma glucose and insulin responses during OGTT in hypertensive patients after treated with Irbesartan (Week 12) and at baseline (Week 0). Mean + SEM (n=7).

Note: There was no significant difference on the plasma glucose and insulin levels at various time points.
 

Section 7: FIGURES

Figure 1: Study design

Figure 2: Percentage change in glucose response during an OGTT at baseline (after placebo) and after Irbesartan treatment.

Figure 3: Plasma insulin in response to OGTT at baseline (after placebo) and after Irbesartan treatment.