Journal of the American Society of Hypertension 9(1) (2015) 21–28
Research Article
Natriuresis and blood pressure reduction in hypertensive patients with diabetes mellitus: the NESTOR study Yi Zhang, MD, PhDa,b, Davide Agnoletti, MD, PhDb, Ji-Guang Wang, MD, PhDc, Yawei Xu, MD, PhDa, and Michel E. Safar, MDb,* a
Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China; Diagnosis and Therapeutic Center, Hotel-Dieu, Assistance Publique – Hopitaux de Paris, Paris Descartes University, Paris, France; and c Centre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Manuscript received July 25, 2014 and accepted October 8, 2014 b
Abstract The antihypertensive effect of indapamide has never been clearly understood, particularly in hypertensive patients with diabetes mellitus. A total of 565 patients were randomly selected to receive either indapamide 1.5 mg or enalapril 10 mg daily for 12 months. Brachial blood pressure (BP) and plasma and urinary electrolytes were measured at baseline and at the end of follow–up. Sodium and potassium levels and excretion rates were measured in overnight urine collections. After 12 months’ treatment, similar significant reductions were observed in systolic and diastolic BP and pulse pressure levels in both treatment arms (P < .001). However, age, body mass index, diabetes duration, and plasma sodium reductions were shown to be major, independent factors influencing BP reduction with indapamide, but not with enalapril. Regression coefficients were positive for age and plasma sodium reductions (P .009) but negative for body mass index and diabetes duration (P .008). Similar findings were observed for pulse pressure. These results were more notable in elderly patients, did not differ regardless of whether BP reduction was measured in absolute or percent values, and were associated with increased sodium and potassium excretion rates.Indapamide is more effective than enalapril at reducing BP in elderly diabetic hypertensives with marked sodium retention. J Am Soc Hypertens 2015;9(1):21–28. Ó 2015 American Society of Hypertension. All rights reserved. Keywords: Blood pressure reduction; electrolyte excretion; enalapril; hypertension; indapamide.
Introduction Epidemiological studies have extensively emphasized the close relationship between increased blood pressure (BP) and the incidence and prevalence of cardiovascular (CV) diseases.1 Additionally, a number of prospective trials have focused on the importance of BP reduction and have concluded that systolic BP is a more reliable indicator for assessing CV risk than diastolic BP.2,3 In the Preterax in
Conflict of interest: The authors declare no conflicts of interest. This study was supported by an unrestricted grant from the Institut de Recherches Internationales Servier. *Corresponding author: Michel E. Safar, MD, Centre de Diagnostic et de Therapeutique, H^otel-Dieu 1, place du Parvis NotreDame, 75181 Paris Cedex 04, France. Tel: 00 33 1 42 34 80 25; Fax: 00 33 1 42 34 86 32. E-mail: [email protected]
Regression of Arterial Stiffness in a Controlled DoubleBlind (REASON) study, the combination of the angiotensin–converting enzyme inhibitor (ACEI) perindopril with the diuretic compound indapamide was shown to normalize systolic BP and pulse pressure (PP) to a significantly greater extent than the beta–blocker atenolol alone; the latter having previously been shown to significantly improve survival in hypertensive subjects with high CV risk.4 The mechanism of this BP reduction is very simple, combining angiotensin blockade with the potentiating effect of the diuretic. This interpretation is, however, not systematically observed in all patients and must be discussed on the basis of at least two possibilities. First, the renal mechanisms of diuretic substances can vary greatly from one compound to another. Second, hypertension is frequently associated with numerous other CV risk factors, which greatly complicate data interpretation. The most important and frequently observed CV risk factor is
1933-1711/$ - see front matter Ó 2015 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2014.10.003
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Y. Zhang et al. / Journal of the American Society of Hypertension 9(1) (2015) 21–28
diabetes mellitus, which involves a maladaptive interaction of factors such as calorie intake, level of activity, and insulin resistance.5 An independent analysis of the antihypertensive effect of angiotensin blockade and diuretics is therefore warranted in patients with hypertension and diabetes mellitus. The diuretic indapamide has several specific features.6,7 First, compared with the diuretic hydrochlorothiazide, indapamide has less effect on urinary potassium loss and preserves renal function more effectively during long term treatment.8 Second, indapamide has significant anti– oxidant properties, due principally to the effect of the main metabolites.9 Third, although a high–sodium diet is significantly associated with increased stiffness of carotid arteries in spontaneously hypertensive rats, the reverse effect is observed during treatment with indapamide, which acts through a specific proteoglycan–related mechanism.10 These effects observed with indapamide, and which are associated with reduced systolic BP in the elderly, are not observed with hydrochlorothiazide.11 In a previous study of patients with hypertension and diabetes mellitus,12 indapamide sustained release (SR) 1.5 mg was compared with enalapril 10 mg per day. Results showed that for a similar, significant reduction in mean arterial pressure, an equipotent decrease in microalbuminuria was also observed after 12 months of treatment. Consequently, using the same procedure and for a given mean BP reduction, the antihypertensive effects of each agent can be independently studied. In the present study of 565 hypertensive individuals with type 2 diabetes mellitus, we therefore set out to investigate the antihypertensive effect and potential role of each agent after 12 months of treatment.
Methods Study Design and Population The NESTOR (Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetic subjects with micrOalbuminuRia) study, was a multicenter, double–blind, placebo– controlled, randomized clinical trial with two parallel treatment arms: indapamide SR 1.5 mg daily and enalapril 10 mg daily. Of the initial 1223 patients, 570 were randomized to either the indapamide regimen or the enalapril regimen. Treatment was given once daily over the 12–month study period, after an initial 4–week placebo run–in period, during which any previous antihypertensive therapy was withdrawn. Inclusion criteria were: age 35 to 80 years, type 2 diabetes, essential hypertension (systolic BP 140–180 mm Hg and diastolic BP 40 kg/m2), hematuria or leucocyturia, and urinary tract infection. Five further patients were excluded from the present analysis because of incomplete data concerning sodium and potassium concentrations. Details of the study design can be found in our previous publications.12–14 As from week 6, additional open–label antihypertensive treatment could be added in a stepwise manner to achieve target BP levels (systolic BP
Research Article
Natriuresis and blood pressure reduction in hypertensive patients with diabetes mellitus: the NESTOR study Yi Zhang, MD, PhDa,b, Davide Agnoletti, MD, PhDb, Ji-Guang Wang, MD, PhDc, Yawei Xu, MD, PhDa, and Michel E. Safar, MDb,* a
Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China; Diagnosis and Therapeutic Center, Hotel-Dieu, Assistance Publique – Hopitaux de Paris, Paris Descartes University, Paris, France; and c Centre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Manuscript received July 25, 2014 and accepted October 8, 2014 b
Abstract The antihypertensive effect of indapamide has never been clearly understood, particularly in hypertensive patients with diabetes mellitus. A total of 565 patients were randomly selected to receive either indapamide 1.5 mg or enalapril 10 mg daily for 12 months. Brachial blood pressure (BP) and plasma and urinary electrolytes were measured at baseline and at the end of follow–up. Sodium and potassium levels and excretion rates were measured in overnight urine collections. After 12 months’ treatment, similar significant reductions were observed in systolic and diastolic BP and pulse pressure levels in both treatment arms (P < .001). However, age, body mass index, diabetes duration, and plasma sodium reductions were shown to be major, independent factors influencing BP reduction with indapamide, but not with enalapril. Regression coefficients were positive for age and plasma sodium reductions (P .009) but negative for body mass index and diabetes duration (P .008). Similar findings were observed for pulse pressure. These results were more notable in elderly patients, did not differ regardless of whether BP reduction was measured in absolute or percent values, and were associated with increased sodium and potassium excretion rates.Indapamide is more effective than enalapril at reducing BP in elderly diabetic hypertensives with marked sodium retention. J Am Soc Hypertens 2015;9(1):21–28. Ó 2015 American Society of Hypertension. All rights reserved. Keywords: Blood pressure reduction; electrolyte excretion; enalapril; hypertension; indapamide.
Introduction Epidemiological studies have extensively emphasized the close relationship between increased blood pressure (BP) and the incidence and prevalence of cardiovascular (CV) diseases.1 Additionally, a number of prospective trials have focused on the importance of BP reduction and have concluded that systolic BP is a more reliable indicator for assessing CV risk than diastolic BP.2,3 In the Preterax in
Conflict of interest: The authors declare no conflicts of interest. This study was supported by an unrestricted grant from the Institut de Recherches Internationales Servier. *Corresponding author: Michel E. Safar, MD, Centre de Diagnostic et de Therapeutique, H^otel-Dieu 1, place du Parvis NotreDame, 75181 Paris Cedex 04, France. Tel: 00 33 1 42 34 80 25; Fax: 00 33 1 42 34 86 32. E-mail: [email protected]
Regression of Arterial Stiffness in a Controlled DoubleBlind (REASON) study, the combination of the angiotensin–converting enzyme inhibitor (ACEI) perindopril with the diuretic compound indapamide was shown to normalize systolic BP and pulse pressure (PP) to a significantly greater extent than the beta–blocker atenolol alone; the latter having previously been shown to significantly improve survival in hypertensive subjects with high CV risk.4 The mechanism of this BP reduction is very simple, combining angiotensin blockade with the potentiating effect of the diuretic. This interpretation is, however, not systematically observed in all patients and must be discussed on the basis of at least two possibilities. First, the renal mechanisms of diuretic substances can vary greatly from one compound to another. Second, hypertension is frequently associated with numerous other CV risk factors, which greatly complicate data interpretation. The most important and frequently observed CV risk factor is
1933-1711/$ - see front matter Ó 2015 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2014.10.003
22
Y. Zhang et al. / Journal of the American Society of Hypertension 9(1) (2015) 21–28
diabetes mellitus, which involves a maladaptive interaction of factors such as calorie intake, level of activity, and insulin resistance.5 An independent analysis of the antihypertensive effect of angiotensin blockade and diuretics is therefore warranted in patients with hypertension and diabetes mellitus. The diuretic indapamide has several specific features.6,7 First, compared with the diuretic hydrochlorothiazide, indapamide has less effect on urinary potassium loss and preserves renal function more effectively during long term treatment.8 Second, indapamide has significant anti– oxidant properties, due principally to the effect of the main metabolites.9 Third, although a high–sodium diet is significantly associated with increased stiffness of carotid arteries in spontaneously hypertensive rats, the reverse effect is observed during treatment with indapamide, which acts through a specific proteoglycan–related mechanism.10 These effects observed with indapamide, and which are associated with reduced systolic BP in the elderly, are not observed with hydrochlorothiazide.11 In a previous study of patients with hypertension and diabetes mellitus,12 indapamide sustained release (SR) 1.5 mg was compared with enalapril 10 mg per day. Results showed that for a similar, significant reduction in mean arterial pressure, an equipotent decrease in microalbuminuria was also observed after 12 months of treatment. Consequently, using the same procedure and for a given mean BP reduction, the antihypertensive effects of each agent can be independently studied. In the present study of 565 hypertensive individuals with type 2 diabetes mellitus, we therefore set out to investigate the antihypertensive effect and potential role of each agent after 12 months of treatment.
Methods Study Design and Population The NESTOR (Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetic subjects with micrOalbuminuRia) study, was a multicenter, double–blind, placebo– controlled, randomized clinical trial with two parallel treatment arms: indapamide SR 1.5 mg daily and enalapril 10 mg daily. Of the initial 1223 patients, 570 were randomized to either the indapamide regimen or the enalapril regimen. Treatment was given once daily over the 12–month study period, after an initial 4–week placebo run–in period, during which any previous antihypertensive therapy was withdrawn. Inclusion criteria were: age 35 to 80 years, type 2 diabetes, essential hypertension (systolic BP 140–180 mm Hg and diastolic BP 40 kg/m2), hematuria or leucocyturia, and urinary tract infection. Five further patients were excluded from the present analysis because of incomplete data concerning sodium and potassium concentrations. Details of the study design can be found in our previous publications.12–14 As from week 6, additional open–label antihypertensive treatment could be added in a stepwise manner to achieve target BP levels (systolic BP
