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Effect of Three Months' Treatment With Irbesartan on Blood and Pulse Pressure of Hypertensive Type 2 Diabetic Patients: Open, Observational Study in 31793 Patients

Posted on: Saturday, 15 October 2005, 03:00 CDT

By Strutz, F; Bramlage, P; Paar, W D

Key words: Cardiovascular risk * Hypertension * Irbesartan * Microalbuminuria * Pulse pressure * Type 2 diabetes

ABSTRACT

Objectives: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-ll- receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability.

Methods: 8714 general practitioners included 31793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300 mg as monotherapy or in combination with hydrochlorothiazide 12.5mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP ≥ 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability.

Results: Thirty-eight per cent of patients received irbesartan 300 mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5 mmHg, diastolic blood pressure by 10.7 mmHg (baseline values: 160.2 and 93.2 mmHg). Pulse pressure fell on average by 11.6 mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140 mmHg and DBP < 90 mmHg), respectively 73.8% (DBP < 90 mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7 mg/L. Only 0.3% of patients experienced adverse events.

Conclusions: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.

Introduction

Hypertension and diabetes mellitus are frequently seen in combination. Thus, arterial hypertension is present in more than two thirds of patients with type 2 diabetes (75%)'. The risk of both cardiovascular and cerebrovascular morbidity and mortality is considerably increased in patients with both conditions, as hypertension and diabetes are multiplicative risk factors for the development of coronary heart disease, sudden cardiac death, heart failure, and peripheral arterial occlusive disease2,3. In hypertensive diabetics the mortality risk is four times higher than in patients without these two diseases. Effective antihypertensive therapy is therefore vital, and of great significance for the patients' prognosis. According to the WHO/ISH guidelines, patients in whom these conditions are present concomitantly, irrespective of the stage of the disease, are at 'high risk'4. A large cross- sectional study carried out in primary care diagnosed comorbidity of the two diseases in 10% of men and 9% of women5'6. More than 80% of the patients also had additional diseases or complications.

An effective lowering of blood pressure reduces the cardiovascular risk in hypertensive subjects with diabetes to a greater degree than in hypertensive patients without diabetes7-9. In addition, antihypertensive therapy is one of the most important therapeutic measures in diabetics10. It reduces the incidence of microvascular complications to a greater degree than normalization of hyperglycaemia, and thus leads to a substantial reduction in macrovascular complications, and accordingly also of premature mortality11,12.

Unfortunately, despite this knowledge, the clear benefit of effective blood pressure lowering therapy in hypertensive diabetics is frequently insufficiently realized, and this can lead to secondary diseases that could possibly be avoided. In the above- mentioned cross-sectional study (HYDRA), for example, only a quarter of the patients involved had a normalized blood pressure.

The angiotensin-II receptor antagonist irbesartan achieves an effective 24-h lowering of blood pressure both when given as monotherapy and in combination with hydrochlorothiazide13,14. However, with a comparable antihypertensive effect, it has proved to be better tolerated than ACE inhibitors13 or beta blockers16. In addition, irbesartan has been shown to have a marked nephroprotective effect17'18 and is therefore currently approved not only for the treatment of hypertension, but also for the therapy of renal disease in patients with hypertension and diabetes. Angiotensin receptor antagonists such as irbesartan are the therapy of first choice in all major guidelines, and are recommended especially for patients with diabetic nephropathy4,19,20.

This open, observational study investigated the antihypertensive and nephroprotective effect of a switch (or de novo therapy) from various previous antihypertensive drugs to irbesartan or an irbesartanbased regimen in patients with hypertension and type 2 diabetes over a period of 3 months.

Method

Design and patients

This study was carried out as an open, prospective observational study by 8714 family practitioners (general practitioners, doctors of internal medicine). In accordance with 67(6) of the German Medicines Act, it was notified to the Federal Institute for Medicinal Products and Medical devices (BfArM) and to the Federal Association of Health Insurance Fund Physicians. The physicians were free in their selection of diabetics with arterial hypertension; these had either not received any previous therapy or in the physicians' opinion were not adequately controlled. No inclusion or exclusion criteria beyond the indications and restrictions given in the product information were defined. Nor were there any instructions for the diagnosis or therapy of the patients, so as to reflect the conditions of everyday practice as closely as possible. Patients who received irbesartan 300 mg (Aprovel, SanofiAventis Deutschland GmbH, Berlin) as monotherapy or in combination with 12.5mg hydrochlorothiazide (HCTZ; CoAprovel, Sanofi-Aventis Deutschland GmbH, Berlin) were documented. If necessary, other antihypertensives could also be prescribed, and these also had to be documented on the case report forms.

Course of the study

At inclusion in to the study, demographic data, duration of hypertension and diabetes, antihypertensive drug therapy before the switch to irbesartan, and additional antihypertensive drugs and concomitant diseases (with particular attention being paid to cardiovascular complications of hypertension) were documented. Blood pressure was measured at the beginning of the study and after 3 months by sphygmomanometry or automated, validated devices after a period of rest in supine position. It should be noted, however, that this was a naturalistic study with no monitor carrying out quality assurance. The following cardiovascular parameters were taken from the file if they were present: albumin, creatinine, blood glucose and HbA^sub 1c^, smoking, HDL cholesterol, LDL cholesterol, and serum triglycrides. Test strips were used for the examination of microalbuminuria or proteinuria, with the categories being negative, 10mg/L, 30mg/L, 80mg/L and 150mg/ L. The creatinine values in the urine were documented in the categories being negative, 10mg/dL, 50mg/dL, 100mg/dL, 100mg/dL, 200mg/dL and 300mg/dL. After 3 months, in addition to the blood pressure measurement, the laboratory parameters were again documented. The test for microalbuminuria was also repeated. In addition, the antihypertensive medication and concomitant medication were documented. The following parameters were calculated from the available data: pulse pressure (systolic minus diastolic blood pressure), responder (reduction in DBP ≥ lOmmHg or DBP < 90 mmHg), overall normalization (defined as SBP < 140 mmHg and DBP < 90 mmHg) and diastolic normalization rates (DBP < 90mmHg).

At the end of the study the patients were explicitly questioned about adverse events (AEs), and these were documented in detail (nature, time, duration, outcome, and causal relationship to the irbesartan therapy). In cases of serious adverse events, these were immediately reported by the physicians to the pharmaceutical manufacturer, who reported them to the BfArM within the stipulated period.

Statistical analysis

In accordance with the analysis plan, descriptive statistics were employed and the evaluation was based on exploratory data analysis. Comparisons were made of systolic and diastolic blood pressure and of the proportion of patients with positive microalbuminuria at the beginning of the study and at the follow-up examination. Standard deviations of mean values were calculated. The 95% confidence interval was specified for the blood pressure reduction. Subgroup analyses were performed \separately for patients with irbesartan 300 mg or irbesartan/HCTZ according to sex, age, body mass index (BMI), baseline blood pressure, and differing previous and concomitant medication. As some patients were treated with several antihypertensive drugs and were thus represented in several subgroups, no statistical between-group comparisons were carried out. The data were analysed with SAS 8.2 software21. To be able to document previously unknown, very rare AEs, the number of cases was set at about 30000 patients: with this, AEs can be documented with an incidence of 0.32%.

Results

Basic characteristics

In the study period from September 2003 to May 2004 a total of 31 793 patients were included (49.0% men, 49.7% women, 1.3% no information). The mean age of the patients was 62.6 10.6 years, the mean BMI was 28.3 4.3 kg/m^sup 2^. Accordingly, the majority of the patients (81%) was either overweight (BMI 25-29.9; 53.7%) or obese (BMI ≥ 30; 27.6%). The patients had high blood pressure for a mean of 8.0 6.0 years. Diabetes had been present for 6.5 5.8 years. More than two thirds of the patients (72%) had diseases in addition to hypertension and diabetes. Table 1 displays the prevalence of concomitant diseases at the beginning of the study.

The most frequent previous antihypertensive medications were ACE inhibitors (45.3%), beta blockers and diuretics (each 35.7%) and calcium antagonists (27.7%). Nineteen per cent of the patients had not been treated previously with any antihypertensive medication. At the beginning of the study, 37.7% were prescribed irbesartan 300mg as monotherapy and 60.6% irbesartan 300 mg in combination with HCTZ 12.5mg (no information for 1.7%). The choice of the antihypertensive agent (irbesartan mono vs. combination with HCTZ) was at the discretion of the physician and was related to the need for further blood pressure reduction. No other dosages of irbesartan were used. Additional antihypertensive medication was used in 56.9% of the patients, and was maintained largely unchanged until the end of the study (Table 2). The most frequent combination was with a beta blocker (23.7%), calcium antagonists (15.4%) or a diuretic other than HCTZ (9.3%).

Lowering of blood pressure

Overall, there was a mean reduction in systolic blood pressure of 22.5 mmHg and of diastolic blood pressure of 10.7mmHg. Table 3 summarizes the results according to the therapeutic regimen with irbesartan or irbesartan plus HCTZ. Both when irbesartan was used alone and when it was combined with hydrochlorothiazide, the greatest lowering of blood pressure was achieved in patients who had a high baseline blood pressure (grade 3). The analysis of further subgroups (separated according to age, sex, BMI, previous and concomitant medication) revealed a comparable reduction (not presented).

After 3 months of irbesartan treatment, mean pulse pressure (difference between systolic and diastolic blood pressure) was significantly reduced, on average by 11.6 mmHg from 66.9 mmHg to 55.3 mmHg. Here too the greatest reduction was observed in patients with a particularly high baseline systolic blood pressure.

There were 83.4% of the patients who were responders to the irbesartan treatment, with a lowering of diastolic blood pressure by at least 10 mmHg or an absolute value < 90 mmHg (Figure 1). These results are summarized in Figure 1.

Microalbuminuria

Thirty-six point five percent of the patients were known to have microalbuminuria or proteinuria prior to the study. For patients with a positive albumin test at the beginning of the study the irbesartan treatment resulted in a relative risk reduction of 41.5% (p < 0.05; Figure 2). The mean albumin excretion of initially 40.338.0mg/L had fallen to 32.3 60.5mg/L, with no differences between men and women (mean reduction: 22.7 32.9mg/L). Only 198 patients (1.3%) with previously negative albumin excretion had a positive test value after 3 months.

Table 1. Basic characteristics and concomitant diseases (total: n = 31 793)

Laboratory parameters

The mean blood glucose value of 142.5 37.2mg/dL was reduced after 3 months by 18.3 29.2mg/dL to 124.929.5mg/dL and HbA^sub 1c^ fell from 6.61.1% to 6.3 0.9%. With regard to lipid values, there was a slight increase in mean HDL cholesterol from 50.5 21.1 mg/dL to 52.1 18.4mg/dL; and a reduction in LDL cholesterol from 146.5 37.4mg/dL to 135.8 32.2mg/dL. The mean LDL/HDL ratio of initially 3.2 1.2 fell correspondingly to 2.8 0.9, and was thus in the normal range at the end of the study. The slightly elevated triglycrides of 199.3 75.8mg/ dL were reduced to 180.0 + 61.9 mg/dL.

Tolerability

The tolerability of treatment with irbesartan was good, which was seen in a very low incidence of ADRs ('adverse drug reactions'). In total, 122 ADRs in 101 patients were documented (i.e. in 0.3% of all patients). In the case of 66 of these ADRs (in 56 patients, 0.2%) a connection with the trial medication was described by the physician as 'possible' in 42 events (34.4%) and 'probable' in 24 events (19.7%). During the study there were 15 serious AEs ('serious adverse events', 0.05%) in 9 patients, with a 'possible' connection in 2 events (13.3%) and a 'probable' relationship in 1 event (6.7%); 12 of these events had no causal relationship to the trial medication.

Discussion

Blood pressure lowering effect

In this study in hypertensive type 2 diabetics a switch from various types of antihypertensive medication to irbesartan or irbesartan/hydrochlorothiazide led to an ? effective lowering of blood pressure. A mean lowering of blood pressure of -23/-11 mmHg was achieved in a large non-homogenous patient group with a variety of comorbidities. Most patients had obviously not been adequately controlled with the previous antihypertensive medication and some of them had even been untreated, as the mean blood pressure was quite high. Both the marked systolic and diastolic blood pressure lowering effect was of a comparable magnitude as in other observational studies with irbesartan22,23. In view of the known association between level of blood pressure and cardiovascular diseases, this result should be accompanied by a considerable reduction in risk. Obviously, the duration of the study was too short to observe such a reduction. Results from the UKPDS study24 had shown that a lowering of mean systolic blood pressure by 10 mmHg is associated with an 11- 15% reduction in diabetes-related mortality, risk of myocardial infarction, microvascular complications or any diabetesrelated complications. Even more important than the lowering of diastolic blood pressure, the lowering of systolic blood pressure in particular is associated with a reduction in secondary renal diseases, and is, therefore, of great significance for diabetes patients23. Also patients who had previously been treated with ACE inhibitors profited in this study from a switch to the angiotensinII antagonist irbesartan, as had also been demonstrated previously in observational studies with irbesartan of similar design23. Both in the group of patients treated with irbesartan 300 mg as monotherapy and in the group treated with the irbesartan 300mg + 12.5mg HCTZ, more than 50% of the patients could be treated for their hypertension satisfactorily (see Table 2).

Table 2. Concomitant medication

Table 3. Reduction of blood pressure 3 months after change to irbesartan 300mg and irbesartan 300mg + 12.5mg HCTZ

Figure 1. Responder (83.4 0.2) and overall normalization rate (42.7 0.3) of blood pressure after three months' treatment with irbesartan

Figure 2. Proportion of patients with microalbuminuria reduced from 36.5% at baseline to 21.5% after switch to irbesartan for 3 months with a relative risk reduction of 41.5% (absolute 15%), p < 0.05

With 83%, a responder rate clearly higher than in studies with other angiotensin-II antagonists26,27 was seen, defined by a reduction in diastolic blood pressure of at least 10mmHg or a value < 90mmHg. In the work by Conlin26,27 for ATI blocker monotherapy (losartan, valsartan, candesartan, etc.) responder rates of only 48%- 55% are reported, and for the combinations 56%-70%. The number of patients with a normalized blood pressure after 3 months of treatment was 43% (SBP < 140 mmHg and DBP < 90mmHg), respectively 73.8% defined as diastolic value < 90mmHg, and the response for patients with mild to moderate hypertension was comparable with previous studies.

Lowering of pulse pressure

From a mean pulse pressure of 66.8 mmHg at the beginning of the study, the switch to irbesartan or irbesartan/HCTZ produced a significant reduction of 11.6 mmHg after 3 months. As a result, according to the current assessment of the value of pulse pressure, which is thought to be an independent cardiovascular risk factor, a clear reduction of risk could be expected28-30. Thus, in normo- and hypertensive patients there is assumed to be an increased risk of cardiovascular morbidity and mortality when PP values are > 60 mmHg, and an increased cerebrovascular risk when mean and diastolic pressures are clearly raised31.

Nephroprotective efficacy

The clinical significance of microalbuminuria (MAU) has been studied in depth in recent years: in diabetics MAU provides not only prognostically important indications of microangiopathy (e.g. nephropathy), but also macroangiopathy at the cardiovascular end organs. On the basis of the data available, microalbuminuria is a significant independent cardiovascular risk factor and should be listed under 'new risk factors' in relevant national/international guidelines.

The effective reduction of (micro) albuminuria by irbesartan in this study is consistent with the result of the Irbesartan Micro- Albuminuria in Type 2 Diabetes Study (IRMA-2), which showed that the progression of nephropathy can be substantially slowed by irbesartan17. In the IRMA study, the restoration of normo- albuminuria after 2 years was 34% comp\ared with the initial value in the irbesartan 300mg group. In an open 6-month study in primary care, in patients with microalbuminuria the relative reduction was 53% after the switch (from 49% initially to 23%)24. Even patients with manifest nephropathy benefit from irbesartan treatment, as was shown in the IDNT study18.

An improvement was seen with regard to many other metabolic parameters, with a clear reduction in mean blood glucose value. These changes can be attributed in part to the study conditions, as improved patient compliance is to be expected as a result of these. The positive study results were achieved in more than half the patients on the irbesartan/HCTZ combination therapy. Diuretics - at least in high dosages - have been associated with undesirable metabolic effects, which is why their use in diabetics was not recommended. Nevertheless, there is clear evidence from several endpoint studies that thiazides are effective in reducing cardiovascular risk and mortality in hypertensive diabetics32. Accordingly, this group was included in the current recommendations on first choice treatment for diabetics issued by the American Diabetes Association, among others', a recommendation that advises low-dosed diuretics in combination with RAS blocking substances.

Tolerability

Irbesartan was very well tolerated both when administered alone and also in combination therapy. Only 0.3% of the patients reported AEs. This result is consistent with the already known tolerability of irbesartan in mono- or combination therapy that has been described as placebo-like33. Conversely, higher AE rates have been described in observational studies with other angiotensin-II antagonists (e.g. 6.1% with candesartan monotherapy34 and 2.5% with valsartan monotherapy35), albeit the observational nature of the study needs to be considered.

Method

The possible limitations of these results are due to the design of open prospective observational studies. For example, the influence of placebo effects is not taken into account, as the study was conducted without a control group. There was no randomization by the physician, therefore a selection bias and other unknown systematic errors cannot be excluded. The rather short duration of the study constitutes a further limitation, especially against the background of frequently life-long drug therapy that many patients have to accept. Possible advantages over controlled studies lie in the fact that this study reflects everyday practice. The direct switch from previous antihypertensive medication of various types reflects the typical everyday procedure. Observational studies also include patient groups with extensive comedication and comorbidity, with which the physician in primary care is very frequently confronted. They are thus a helpful complement to the results of randomized, controlled studies36.

Conclusion

In patients with hypertension and type 2 diabetes, a switch from various types of previous medication to the angiotensin-II antagonist irbesartan or combination therapy with HCTZ or de novo therapy with these two regimens lead to an effective and well tolerated lowering of blood and pulse pressure. Most of the patients were previously not adequately controlled with other antihypertensive medication, some of them had even been untreated. This, together with the simultaneously achieved nephroprotective effect as a result of reduced albumin excretion, suggests that a clear reduction in cardiovascular risk for the patient is to be expected.

Acknowledgement

Declaration of interest: The study was supported by Sanofi- Aventis Deutschland GmbH (Berlin).

We would like to thank the Institute Dr. Schauerte company, Munich, for the data processing and statistical evaluation and Simone Seibold, MD, for valuable assistance in the preparation of the manuscript.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3025_4, Accepted for publication: 19 July 2005

Published Online: 22 August 2005

doi:10.1185/030079905X61811

F. Strutz(a), P. Bramlage(b,c) and W. D. Paar(c)

a Department of Nephrology and Rheumatology, Georg-August University of Gttingen, Gottingen, Germany

b Institute of Clinical Pharmacology, Faculty of Medicine, Technical University Dresden, Dresden, Germany

c Aventis Pharma Deutschland GmbH, Medical Affairs Cardiovascular, Berlin, Germany

Address for correspondence: Professor Dr. Frank Strutz, Zentrum Innere Medizin, Abteilung Nephrologie & Rheumatologie, Robert-Koch- Strasse 40, 37099 Gottingen, Germany. Tel.: +49 (0) 551 398541; Fax: +49 (0) 551 398252; email: fstrutz@gwdg.de

Copyright Librapharm Sep 2005

Source: Current Medical Research and Opinion

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