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Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Vascular legacy beyond blood pressure control:


benefits of perindopril/indapamide combination in
hypertensive patients with diabetes

Bernard I. Lévy & Stefano Taddei

To cite this article: Bernard I. Lévy & Stefano Taddei (2018): Vascular legacy beyond blood
pressure control: benefits of perindopril/indapamide combination in hypertensive patients with
diabetes, Current Medical Research and Opinion, DOI: 10.1080/03007995.2018.1425674

To link to this article: https://doi.org/10.1080/03007995.2018.1425674

Accepted author version posted online: 08


Jan 2018.

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Download by: [University of New England] Date: 09 January 2018, At: 06:54
Vascular legacy beyond blood pressure control: benefits of perindopril/indapamide combination in
hypertensive patients with diabetes

Bernard I. Lévy [1], Stefano Taddei [2],

1. Inserm U970 & IVS, 8 rue Guy Patin, 75010, Paris France
2. Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126
Pisa, Italy

Corresponding author: Bernard I. Lévy, Bernard.levy@inserm.fr

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Transparency

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Declaration of Funding:
This review received funding support from Servier, France.

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Declaration of financial/other relationships:
BL has received honoraria for consultancy and conferences from Bayer, Roche and Servier. CMRO

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peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements:
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Medical writing and editorial support, under the guidance of the authors, was provided by Hélène
Dassule, PhD. This support was funded by Servier.
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Abstract

Objectives: Much of the chronic care of patients with type 2 diabetes mellitus and hypertension
involves the prevention of diabetic complications. Renin-angiotensin system inhibitors are
recommended as first-line therapies because of their nephroprotective properties. Their
combination with metabolically neutral diuretics is recommended to reduce blood pressure,
morbidity, and mortality. Our objective was to review the mechanisms by which the combination of
the angiotensin-converting enzyme inhibitor, perindopril, and metabolically neutral thiazide-like
diuretic, indapamide, targets the pathways involved in microvascular and macrovascular diabetic
complications.

Methods. For this narrative review, extensive literature searches were performed using
Pubmed/Medline. Articles published in English describing clinical trials and mechanism of action
studies that were relevant to the treatment patients with perindopril and/or indapamide were

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included.

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Results. Perindopril/indapamide treatment has been shown to reduce blood pressure and to have
significant beneficial effects on arterial distensibility, kidney structure and function, and endothelial
function. Recent data also suggest that perindopril may reduce the deleterious accumulation of

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advanced glycation end products in diabetic tissue. In the Action in Diabetes and Vascular Disease:
Preterax and Diamicron MR Controlled Evaluation diabetes trial, perindopril/indapamide treatment
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significantly reduced the relative risk of microvascular and macrovascular events by 9%,
cardiovascular mortality by 18%, and all-cause mortality by 14%. Interestingly, 6 years after the end
of the double-blind period, follow-up data showed that the beneficial effects on mortality continued
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to be significant even though differences in blood pressure and glycated hemoglobin levels had not
been significant for several years. Together these data suggest that treatment with
perindopril/indapamide has microvascular and macrovascular effects that extend beyond blood
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pressure lowering and that this treatment might confer a long-lasting beneficial vascular legacy.

Conclusion. Moving forward, understanding the pathophysiological bases of the effects that extend
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beyond those of blood pressure control, will help us differentiate between anti-hypertensive choices.
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Introduction

Hypertension and diabetes mellitus are frequently associated comorbid conditions. Studies have
shown that over a billion persons worldwide are hypertensive [1] and that approximately 20% of
hypertensive patients have type 2 diabetes mellitus [2]. Data have also shown that 81% of patients
with type 2 diabetes mellitus are hypertensive [3].

The chronic association of hypertension and diabetes is of particular note because it produces
profound pathophysiological changes in the vasculature that lead to microvascular and
macrovascular complications, such as nephropathy and cardiovascular disease. As these
complications ultimately lead to significant morbidity and mortality, the worldwide burden of this
comorbid association is significant.

Anti-hypertensive medications are routinely prescribed to decrease blood pressure and to reduce

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morbidity and mortality in these patients. However, only 30% of hypertensive patients with diabetes
who are treated with anti-hypertensives reach blood pressure control [4] and the reduction of blood

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pressure is believed to address the pathophysiological pathways only partially as residual risk in
patients with controlled hypertension is significant [5,6]. These data highlight an unmet need for
both better blood pressure reducing strategies and for strategies that can address pathways that
extend beyond blood pressure control.
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The pathophysiologic pathways and processes that underlie this deleterious comorbid association
are numerous and complex in the way they interact with each other (Figure 1). Hyperglycemia-
induced endothelial dysfunction, for instance, has been shown to be a key component in the
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development of vascular complications as it is independently associated with cardiovascular events


[7]. As endothelial dysfunction increases, vascular structure is altered, endothelium-dependent
vasomotor function is decreased, endothelium-dependent vasodilation is impaired, and the stage is
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set for diabetic complications. The molecular pathways that lead to hyperglycemia-induced
endothelial dysfunction are still being defined, but have been shown to be linked to reduced nitric
oxide production, reduced vascular endothelial growth factor levels, and increased nuclear factor-
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kappa B activation, inflammation, and oxidative stress [8-10].


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Long-term hyperglycemia also increases angiotensin II (Ang II) formation in renal tissue, where it
stimulates mesangial matrix synthesis and accumulation, increases the renal production of reactive
oxygen species, and causes renal fibrosis [11,12]. Hyperglycemia-induced upregulation of tissue Ang
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II is also associated with increases in inflammation, oxidative stress, thrombosis, and vascular
remodeling [12].

In addition, a lot of data now describe the fact that hyperglycemia leads to the formation of
advanced glycation end products (AGEs), which are associated with the progression of macrovascular
and microvascular diabetic complications, such as peripheral artery disease, arterial stiffness, and
diabetic nephropathy [13-19]. Recently, epidemiological data have shown that in patients with type 2
diabetes mellitus, high levels of plasma AGEs are associated with cardiovascular events [20]. At a
molecular level, AGEs are formed when glucose and its metabolites modify free amino groups non-
enzymatically. Carboxymethyllysine, pentosidine, pyrraline, and imidazolone, which are common
AGEs, can induce functional changes in vasculature by crosslinking collagen [21]. In addition, when
AGEs bind to their receptor (RAGE), they upregulate adhesion, local inflammation, and oxidative
stress through mitogen-activated protein kinase pathways, NF-kappa B coupled signaling, and
increased expression of transforming growth factor-beta and vascular endothelial growth factor [22].

Thus, the complexity of processes that lead to diabetic vascular complications needs to be
considered when therapeutic choices are made. Anti-hypertensive medications, which, as mentioned
earlier, are essential treatments, lower blood pressure and reduce morbidity associated with
hypertension, but their long-term effects on endothelial dysfunction are not well understood. Thus,
ideally, treatments need to control blood pressure and to target pathways that are upstream and/or
independent of blood pressure regulation.

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In this narrative review, we will focus on the effect of antihypertensive treatment with
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perindopril/indapamide combination. We will start with the larger context of renin-angiotensin-
aldosterone system (RAAS) and then focus on indapamide, perindopril, and their combination.

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Although blood pressure reduction most certainly underlies many of the benefits observed with this
treatment, throughout this review we will highlight effects that appear to involve blood pressure-

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independent pathways.

Renin-angiotensin-aldosterone system inhibitors, alone and in combination


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Renin-angiotensin-aldosterone system inhibitors have become one of the main therapeutic options
for patients with hypertension and diabetes: they reduce blood pressure and are nephroprotective.
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Consensus statements and guidelines agree that hypertensive patients with diabetes and
microalbuminuria or macroalbuminuria should be treated with an angiotensin-converting enzyme
(ACE) inhibitor or an angiotensin receptor blocker (ARB) [23]. In fact, a recent review and meta-
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analysis (N = 16,921) suggests that even patients with diabetes, but normal albuminuria, should be
treated with an ACE inhibitor or an ARB in order to reduce the risk of developing microalbuminuria
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[24].
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As RAAS inhibitors alone are rarely sufficient to control blood pressure in this patient population, the
question of a second anti-hypertensive medication often arises. Strategies for combining anti-
hypertensive medications are based on the idea that complementary mechanisms of actions can
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better target the complexity of the pathophysiology of hypertension and offset feedback loops and
escape mechanisms [25] [26]. For instance, ACE inhibitors reduce vascular resistance and modulate
volume control thereby lowering preload and afterload. Addition of a diuretic causes additional
volume loss, which can further reduce preload and enhance the patient’s sensitivity to the ACE
inhibitor. In patients with diabetes, the combination of an ACE inhibitor and a diuretic that does not
increase glycemia may be particularly beneficial because salt retention is often associated with
diabetes. Such an approach has been endorsed by European, American, and Canadian guidelines
[23,26,27].
In line with this reasoning, extensive data suggest that treatment of patients with diabetes with a
combination of perindopril, an ACE inhibitor, and indapamide, a metabolically neutral thiazide-like
diuretic [28], improves microvascular and macrovascular outcomes without negatively affecting
glycemia [29]. In the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and
DiamicroN MR Controlled Evaluation), which enrolled a broad range of patients with type 2 diabetes
mellitus (N = 11,140), a mean of 4.3 years of perindopril/indapamide treatment on top of existing
standard treatment for diabetes reduced the relative risk of microvascular and macrovascular events
by 9% (vs placebo; p = 0.04), cardiovascular mortality by 18% (vs placebo; p = 0.03), and all-cause
mortality by 14% (vs placebo; p = 0.03) [29]. Six years after the end of the double-blind period
(ADVANCE-ON, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled
Evaluation posttrial ObservatioNal study), follow-up data showed that the beneficial effects on
mortality continued to be significant (for cardiovascular mortality: hazard ratio of 0.88 [95%
confidence interval: 0.77 to 0.99; p = 0.04] and for all-cause mortality: hazard ratio of 0.91 [95%
confidence interval: 0.84 to 0.99; p = 0.03]), even though differences in blood pressure and glycated

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hemoglobin levels that were present at the end of the randomized trial had no longer been

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significant since they were measured at the first post-trial visit (~3 years) (Table 1) [30].

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Interestingly, similar mortality benefits have not been observed in other large-scale diabetes trials
that evaluated anti-hypertensive medications, a majority of which evaluated blood pressure-lowering

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strategies that were based on a RAAS inhibitor [31]. In trials, such as the ACCORD (Action to Control
Cardiovascular Risk in Diabetes) trial, for instance, blood pressure control may have been tighter than
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in ADVANCE, but decreases in blood pressure were not accompanied by lower mortality rates (Table
2) [31].
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Together the ADVANCE and ADVANCE-ON clinical data suggest that treatment with
perindopril/indapamide has microvascular and macrovascular effects that extend beyond blood
pressure control, that endure over time, and therefore that can be thought of as the vascular legacy
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of treatment [29,30,32].In the following sections, we will look at what is known about the
mechanism of action of perindopril and indapamide (Table 3) as it relates to blood pressure
reduction, vascular function, endothelial function, and AGE-related pathways in patients with
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diabetes and hypertension [33-59]. Then, we will focus on perindopril/indapamide in order to


explore the bases of the ADVANCE and ADVANCE-ON observations.
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Methods
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For this narrative review, extensive literature searches were performed in the Pubmed/Medline
database to identify articles published in English describing clinical trials, particularly outcome trials
and mechanism of action studies that were relevant to therapy with perindopril and indapamide in
patients with hypertension and type 2 diabetes mellitus. The main search terms were indapamide,
perindopril, combination treatment, mechanism of action, hypertension, and diabetes. Separate sub-
searches were performed to narrow results and included terms for perindoprilat,
hydrochlorothiazide, endothelial function, endothelial dysfunction, microvascular, macrovascular,
vasodilation, natriuresis, adhesion, inflammation, oxidative stress, bradykinin, mitogen-activated
protein kinase pathways, NF-kappa B, transforming growth factor-beta, vascular endothelial growth
factor, advanced glycation end products, advanced glycation end products receptor, angiotensin
receptor blocker. Initial searches were limited to abstracts; searches were then broadened using
terms in key words fields. Results of the searches were divided into primary data publications and
review articles. For primary data publications, publications of all dates were considered for
relevance, but articles published since 2010 were favored. Reference lists of review articles published
starting in 2014 were searched for relevant publications. Additional references were identified by the
pharmaceutical manufacturer of perindopril and indapamide, Servier.

Indapamide

Indapamide, which has been shown to be metabolically neutral in a wide range of patients [28,60-
62], is a well characterized compound that has significant blood pressure-lowering effects as well as
microvascular and macrovascular effects [49,59,60,63,64].

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In the cardiovascular system, both microvascular and macrovascular benefits have been observed.
Indapamide has been shown to improve measures of arterial function (Figure 2A), ventricular

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function, and ventriculoarterial coupling independently of blood pressure in hypertensive patients
with diabetes (N = 56), to improve arterial compliance while reducing arterial pressure, total

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peripheral vascular resistance, blood vessel stress, and heart load in hypertensive patients (N = 10),
and to reduce left ventricular mass in hypertensive patients with left ventricular hypertrophy (N =
411) [36,58,65]. In addition, studies in spontaneously hypertensive rats have shown that indapamide
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treatment increased glycosaminoglycan levels, which are markers of arterial stiffness, and reversed
coronary arteriole remodeling independently of blood pressure effects [40,48].
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Microvascular benefits have also been observed in the kidney. In hypertensive patients with diabetes
in the pivotal NESTOR (Natrilix SR versus Enalapril Study in Type 2 diabetic hypertensives with
micrOalbuminuRia) study (N = 570), microalbuminuria was reduced after 1 year of treatment with
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indapamide [49]. In the comparison with enalapril, which is recognized as being nephroprotective,
the significant decrease from baseline in urinary albumin-creatinine ratio was similar between groups
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(-35% and -39% in the indapamide and the enalapril groups, respectively) as was the restoration of
normoalbuminuria (40% and 42% of the patients, respectively) [49]. In addition, in patients with
diabetes and microalbuminuria (N = 31), indapamide reduced urinary albumin excretion rates
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compared to baseline [39]. Indapamide treatment has also been shown to preserve renal function, as
measured by creatinine clearance, in patients with impaired renal function and moderate
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hypertension (N = 28) [47].

These microvascular and macrovascular benefits are likely to be attributable to both blood pressure-
dependent and blood pressure-independent effects. Blood pressure-dependent effects, for instance,
are largely ascribed to indapamide’s direct vasodilatory properties and to its mild, but significant,
natriuretic effects [59,66]. Blood pressure-independent effects are less well understood, but may
include some of the pleiotropic effects that have been described, such as anti-oxidation and anti-
inflammation. Indapamide and its 5-OH metabolite have been shown to be superoxide radical anion
scavengers [57] and to reduce platelet aggregation [53]. In the renal cortices of spontaneously
hypertensive rats, oxidative stress and inflammation were reduced by indapamide treatment as
measured by decreases in expression of p47phox, nuclear factor-kappa B, transforming growth
factor-beta 1, and phosphorylated mitogen-activated protein kinase [45].

In addition, indapamide has been associated with blood pressure-independent improvements in


endothelial function. In hypertensive patients with diabetes, flow-mediated dilation, a marker of
endothelium-dependent vasodilation, was increased by indapamide compared to baseline [58]. In
this study, differences with hydrochlorothiazide treatment were significant despite similar
improvements in blood pressure [58]. Additional evidence of indapamide’s effect on the
endothelium has been observed in spontaneously hypertensive rats, where indapamide has been
shown to inhibit endothelium-dependent contractions of isolated aorta rings [34] and to increase
levels of endothelium-derived hyperpolarizing factors (also known as epoxyeicosatrienoic acids) in
renal microvessels independently of blood pressure [45].

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Indapamide has also been shown to downregulate the sympathetic nervous system, correct
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noradrenaline reactivity, increase renal prostaglandin levels, reduce transmembrane calcium influx,
and modulate phosphate balance [67-72]. Much work will be needed to understand how the

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modulation of these pathways by indapamide intersects with the complex pathophysiology of
diabetic complications.

Differentiating indapamide from hydrochlorothiazide


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Although thiazide-like diuretics are often grouped with thiazide diuretics, important distinctions exist
and have led the British Hypertension Society and the Canadian Hypertension Society to recommend
that thiazide-like diuretics, such as indapamide, be prescribed instead of thiazide diuretics, such as
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hydrochlorothiazide [23,73]. This recommendation was largely based on data that have shown that
indapamide, unlike hydrochlorothiazide, is metabolically neutral, has a greater duration of action and
volume distribution, and is associated with better organ protection and better outcomes [74]. In
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particular, effects on mortality, though not evaluated in comparative trials, appear to be markedly
different. In MRFIT (Multiple Risk Factor Intervention Trial) (N = 12,866), in patients who were
randomized to a special intervention program that included hydrochlorothiazide for 10 years, all-
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cause mortality and coronary artery disease-related mortality were higher than in patients who were
randomized to usual care; whereas in HYVET (Hypertension in the Very Elderly Trial) (N = 3,845),
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mortality was lower in the indapamide (+/- perindopril) group than in the placebo group [60,75]. A
similar observation was made in a 2010 meta-analysis which showed that reduction in mortality was
only found in the HYVET trial; in other trials investigating thiazides or thiazide-like diuretics, no
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significant effects on mortality were observed [76]. These data, however, need to be considered in
light of the fact that the HYVET patient population was highly selected as it only included very elderly
patients. Part of the mortality effect may be attributable to the specifics of this patient population.

Significant differences in pathways beyond blood pressure control have also been noted. For
example, though both treatments led to similar blood pressure reductions, indapamide improved
endothelial function, whereas hydrochlorothiazide did not [58]; indapamide reduced left ventricular
mass, whereas hydrochlorothiazide did not [77]; and indapamide increased creatinine clearance in
hypertensive patients with impaired renal function, whereas hydrochlorothiazide decreased it [47].
Moreover, in patients with diabetes, indapamide lowered albuminuria, whereas hydrochlorothiazide
did not (two separate trials) [39,78]. Lastly, in vitro, indapamide, unlike hydrochlorothiazide, has also
been shown to reduce oxidative stress and platelet aggregation [53,57].

Perindopril

As with indapamide, studies have shown that treatment with perindopril, a highly lipophilic ACE
inhibitor [79,80], is associated with significant macrovascular and microvascular benefits and low
cardiovascular outcome rates. In the EUROPA (EUropean trial on Reduction Of cardiac events with
Perindopril in stable coronary Artery disease) study conducted in a population of low risk patients
with stable coronary heart disease (N = 12,218), 4 years of treatment with perindopril resulted in a
20% reduction in the relative risk of reaching the composite outcome (cardiovascular death,
myocardial infarction, cardiac arrest) compared to placebo (p = 0.0003) [81]. These results were
confirmed in the diabetic subgroup [PERSUADE (Perindopril Substudy in Coronary Artery Disease and

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Diabetes) substudy, N = 1,502], in which a 19% relative risk reduction (95% confidence interval: -7 to
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38%; p = 0.13) in the primary composite cardiovascular endpoint was observed [82].

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Although no large outcome perindopril monotherapy trials have been specifically performed in
patients with diabetes, perindopril has been shown to improve measures of arterial and

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microvascular health in this patient population. In the 7-month DAPHNET (Diabetes Artery
Perindopril Hypertension Normalization Excess sTiffness) study (N = 57), treatment of hypertensive
patients with diabetes with full-dose perindopril (equivalent to perindopril arginine 10 mg) reduced
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carotid artery stiffness by improving distensibility significantly more than standard-dose perindopril
(equivalent to perindopril arginine 5 mg). As the study was designed such that blood pressure
reductions would be similar in both dose groups, these data suggest that the improvement in arterial
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stiffness was a blood pressure-independent effect (Figure 2B) [55]. Other studies in hypertensive
patients, who were not necessarily diabetic, have also shown that perindopril treatment can prevent
the progression of non-calcified coronary plaques, improve aortic elasticity, and reduce central aortic
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blood pressure, pulse-wave velocity, augmentation index, intima-media thickness, left ventricular
hypertrophy, and small artery remodeling [35,46,51,54,83]. In particular, in the 1995 Thybo et al.
study, improvements in small artery morphology were not linked to changes in blood pressure,
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thereby, once again, suggesting the existence of blood pressure-independent pathways [54].
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Microvascular benefits have also been observed in the kidney. In subjects with diabetes and
microalbuminuria (N = 40), for instance, three years of treatment with perindopril resulted in
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significantly smaller increases in glomerular basement membrane thickness and in a trend towards
less interstitial fibrosis than treatment with placebo [50]. Consistent with these data, in a rat model
of hypertensive diabetes, glomerulosclerosis and tubular-interstitial damage were reduced with
perindopril treatment [38]. In a rat model of diabetes, accumulation of extracellular matrix
associated with diabetic nephropathy (renal type IV collagen) was attenuated by perindopril
treatment [84]. These data, thus, suggest that perindopril treatment can reduce and/or delay the
progression of diabetes-related structural glomerular damage.

As an ACE inhibitor, perindopril promotes vascular health by inhibiting the synthesis of Ang II, which
mediates vasoconstriction, inflammation, lipid accumulation, and thrombogenesis. In addition,
perindopril inhibits the degradation of bradykinin, which independently reduces blood pressure,
oxidative stress, apoptosis, thrombin-induced platelet activation, inflammation, and fibrosis [85-89].
These effects were illustrated in the PERTINENT (PERindopril-Thrombosis, InflammatioN, Endothelial
Dysfunction and Neurohormonal Activation Trial) substudy of EUROPA (N = 1,200), in which
treatment of patients with stable coronary artery disease with perindopril decreased Ang II levels,
increased bradykinin and endothelial nitric oxide synthase levels, and reduced levels of tumor
necrosis factor-alpha, apoptosis, and Von Willebrand factor, a marker of endothelial damage [37].
Attenuation of inflammation was also noted in a study of 109 hypertensive patients who were
treated with perindopril for 20 weeks [44] and improvements in endothelial function of peripheral
conduit arteries were observed after perindopril treatment in hypertensive patients (N = 170) [42].
The improvement in flow-mediated dilation of the brachial artery appeared to occur independently
of blood pressure control [42]. Thus, although both the modulation of the RAAS and the bradykinin
pathways affect blood pressure, some effects appear to be blood pressure-independent.

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Modulation of the AGE-related pathways may be another example of a blood pressure-independent
effect of perindopril. In plasma samples from patients with type I diabetes (N = 22), treatment with

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perindopril increased soluble RAGE levels and complexes between soluble RAGE and
carboxymethyllysine-modified proteins [41]. In rat models for diabetic nephropathy, treatment with
perindopril reduced tubular-interstitial damage, macrophage infiltration, and expression of

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scavenger receptor A, which binds and takes up AGEs into cells [90]. Similarly, in models of diabetic
central nervous system complications, treatment with perindopril reduced AGE accumulation in
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serum and brain, reduced oxidative stress in the brain, and inhibited memory decline and neuronal
degeneration [91]. In another model for cerebral diabetic complications, perindopril reduced
oxidative stress and RAGE activation [92]. Together, these data suggest that perindopril may reduce
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the deleterious accumulation of AGEs in diabetic tissue by promoting the sequestering of AGEs and
by reducing the uptake of AGEs into cells.
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Differentiating perindopril from other angiotensin-converting enzyme inhibitors

Angiotensin-converting enzyme inhibitors are often considered to be equivalent. They have all been
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shown to reduce blood pressure and to improve nephropathy by promoting arteriolar vasodilation,
attenuating intra-glomerular pressure, and reducing Ang II-mediated damage to the glomerulus and
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tubular interstitium. Though few head-to-head comparisons have been performed, significant
differences among ACE inhibitors are emerging. A large retrospective study of hypertensive patients
in China (N = 15,622), for example, showed that 5 years of perindopril treatment resulted in
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significantly lower rates of all-cause mortality and cardiovascular mortality than treatment with
lisinopril [93]. In addition, in a meta-analysis of 26 studies, treatment with perindopril was associated
with a 28% reduction in the rate of myocardial infarction, whereas with ramipril treatment, the
reduction rate was only 19% [94]. Lastly, in a meta-analysis of 20 cardiovascular RAAS inhibitor
morbidity-mortality trials, the only trials that showed survival benefits included perindopril as one of
the antihypertensive treatments [95].

As blood pressure reductions are typically equivalent, the pathophysiological bases of these
observations are likely to lie in differences in blood pressure-independent pathways and in
differences in pharmacokinetic and pharmacodynamic properties. For instance, in animal models, at
equal levels of blood pressure reduction, only perindopril significantly reduced apoptosis compared
to baseline; ramipril, quinapril, trandolapril, and enalapril did not [96]. In addition, perindopril has
greater affinity for heart tissue/homogenate than quinapril, ramipril, enalapril, fosinopril, or captopril
[97]; and perindopril has a linear dose response curve, whereas other ACE inhibitors have flat blood
pressure dose response curves [56,98].

Moreover, differences in association and dissociation constants for bradykinin and Ang I have been
observed. In double displacement in vitro binding assays, the bradykinin/Ang I selectivity ratios
varied significantly from 1.44 for perindoprilat, to 1.16 for ramiprilat, 1.09 for quinaprilat, 1.08 for
trandolaprilat, and 1.00 enalaprilat (p vs perindopril <0.001) [85]. The biological implications of these
bradykinin/Ang I selectivity ratios have not been fully investigated, but they suggest that with
perindopril, more extensive inhibition of bradykinin metabolism is taking place [99]. Although there
are many gaps in our current knowledge, the balance between preservation of bradykinin and
inhibition of Ang II formation may be the key to understanding differences in outcomes between ACE

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inhibitors and the balance between blood pressure-dependent and –independent pathways.

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Differentiating angiotensin-converting enzyme inhibitors from angiotensin receptor blockers

Although ARBs are also recommended as first-line treatments for hypertension in patients with

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diabetes, there are important distinctions between the two classes of RAAS inhibitors. When
reductions in blood pressure are accounted for, ACE inhibitors are associated with significantly lower
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mortality rates than ARBs [6,94,95,100,101]. In the particular case of patients with diabetes, meta-
analyses suggest that ACE inhibitors reduce major cardiovascular events, all-cause mortality, and
cardiovascular mortality, but ARBs do not [102,103].
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The pathophysiological bases of the observations are still being investigated; however, at least two
differences that are linked to vascular protection have been identified. First and foremost, ARBs do
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not prevent the degradation of bradykinin. Second, ACE inhibitors and ARBs do not appear to be
equivalent when it comes to reversing endothelial dysfunction. In a study of 168 patients diagnosed
with essential hypertension, treatment with perindopril, but not with the ARB telmisartan, improved
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peripheral conduit artery endothelial dysfunction despite the fact that blood pressure reductions
were similar [42]. Additional studies would be needed to explore the impact of these observations.
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Perindopril/indapamide combination
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The combination of perindopril and indapamide would be expected to be metabolically neutral and
to confer significant reductions in blood pressure and blood pressure-related morbidity, but also
significant benefits attributable to the targeting of blood pressure-independent pathways [104-106].
Combination-specific effects can also be expected due to the modulation of complementary
pathways and the inhibition of escape mechanisms.

In patients with diabetes, improvements in microvascular and macrovascular outcomes and in


prognosis have mostly been reported in the ADVANCE and PREMIER (Preterax in Albuminuria
Regression) trials [29,107]. As noted in the introduction, 4 years of perindopril/indapamide
treatment significantly reduced morbidity and mortality compared to placebo even though two-
thirds of placebo patients were taking a RAAS inhibitor by the end of follow-up; and 6 years after the
end of ADVANCE, the mortality benefits that were observed at the end of the 4-year study were still
significant (Figure 3) [30]. These results from ADVANCE-ON are particularly noteworthy because
between-group differences in blood pressure and glycated hemoglobin levels were no longer
significant and fewer than 10% of patients were still taking study treatment [30]. Furthermore,
analysis of outcomes in patients who had permanently discontinued treatment during ADVANCE
showed that one year after discontinuation, between-group differences in blood pressure were not
significant, but that outcome rates for macrovascular and microvascular events and all-cause
mortality for patients in the perindopril/indapamide group were lower than those in patients in the
placebo group (Figure 4) [108]. Together these data indicate that perindopril/indapamide treatment
confers clinically significant long-term benefits, some of which extend beyond the duration of
treatment.

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This residual vascular effect, which can be thought of as the vascular legacy of well-managed
treatment with perindopril/indapamide, was also illustrated in a recent systemic review and meta-

cr
analysis [109]. In particular, in the HYVET indapamide (+/- perindopril) hypertension trial, decreases
in all-cause mortality and cardiovascular mortality were significant during the post-trial follow-up
period, thereby showing that this type of persistent, post-trial effect is visible in several trials that
included perindopril/indapamide as a treatment.
us
an
Intermediary endpoints and data from hypertension trials support and complement these results and
provide insight into mechanisms of action. Effects of combination treatment on macrovascular
health, for instance, have been described in trials in hypertensive patients. Data from the REASON
M

(Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind Study) hypertension study (N


= 471) showed that 12 months of treatment with perindopril/indapamide significantly improved
arterial stiffness and vessel wall structure. Treatment with perindopril/indapamide decreased large
ed

vessel pulse-wave velocity and aortic augmentation index, lowered brachial blood pressure, carotid
artery systolic blood pressure, and pulse pressure, and attenuated carotid wave reflections,
compared to treatment with atenolol [110,111].
pt

As wave reflections are also measures of left ventricular afterload, myocardial hypertrophy, and
ce

myocardial oxygen consumption, the results of the REASON study also suggest a significant effect of
perindopril/indapamide treatment on the myocardium [112]. In fact, analyses of patients with left
Ac

ventricular hypertrophy in the REASON (N = 214) and PICXEL (Perindopril/Indapamide in a double


blind Controlled study versus Enalapril in Left ventricular hypertrophy) (N = 556) trials have shown
that perindopril/indapamide treatment significantly decreased left ventricular mass compared to
comparator (atenolol and enalapril, respectively) [112,113]. In REASON, these results remained
significant even after adjustment for brachial systolic blood pressure and heart rate [112]. Similarly,
in ADVANCE, decreases in end organ damage were observed in the echocardiography substudy (N =
555). Four years of treatment with perindopril/indapamide led to a reduction in left ventricular mass
compared to placebo [114]. Importantly, a small study of 20 hypertensive patients with left
ventricular hypertrophy showed that decreases in left ventricular mass index after
perindopril/indapamide treatment was associated with significant increases in myocardial blood flow
[115]. Together these data, which are consistent with the ADVANCE data that show a 14% decrease
in total coronary events with treatment [29], support the idea that perindopril/indapamide has
significant effects on the coronary and peripheral arterial systems and on the myocardium.

Significant renal microvascular effects have also been observed. In a recently published study,
microalbuminuria decreased in 75% of hypertensive patients with diabetes and microalbuminuria (N
= 59) and mean microalbuminuria levels decreased from 45 mg/L to 30 mg/L (p <0.0001) after 6
months of treatment with open-label perindopril/indapamide [105]. In ADVANCE,
perindopril/indapamide was shown to reduce the risk of having a renal event (-21%; p <0.0001
compared to placebo) and of developing microalbuminuria and macroalbuminuria (-21%; p <0.0001
compared to placebo and -31%; p <0.003 compared to placebo, respectively) [116]. Moreover, the
likelihood of nephropathy regression was 16% higher in the perindopril/indapamide group than in
the placebo group (p = 0.002) [116]. These relative risk reductions were maintained regardless of
kidney function [117]. The value of combination treatment was also illustrated in the PREMIER trial

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ip
(N = 457), in which hypertensive patients with diabetes were randomized to perindopril/indapamide
or enalapril [107]. After 1 year, regardless of blood pressure reduction, perindopril/indapamide

cr
treatment was significantly more effective than enalapril treatment in reducing the rate of urinary
albumin excretion (Figure 5).

us
In support of these clinical data, treatment with perindopril/indapamide has been shown to protect
renal structure and function in animal studies [118,119]. In a rat model of renal failure, treatment
an
with perindopril/indapamide improved renal structure and function by normalizing glomerular
filtration and renal hemodynamic parameters, by preventing glomerular hyalinosis and tubular-
interstitial damage, and by reducing hypertrophy of superficial glomeruli, mesangial expansion of
M

deep glomeruli, markers of fibrosis, and proteinuria [118]. Importantly, the effect of combination
perindopril/indapamide on proteinuria and glomerular injury was larger than that of perindopril or
indapamide in monotherapy [119].
ed

Improvements in endothelial function, small vessel structure, and microvascular rarefaction may
underlie many of the observations in the cardiovascular and renal systems [120-123]. In treatment-
pt

naive patients with essential hypertension (N = 62), 24 weeks of treatment with


perindopril/indapamide improved endothelium-dependent and endothelium-independent
ce

vasodilation [122]. In particular, brachial artery flow-mediated dilation was significantly increased by
perindopril/indapamide, but not by atenolol. This effect was independent from blood pressure
Ac

reduction [122]. In another study of endothelium dysfunction (N = 193), patients whose blood
pressure was controlled with perindopril/indapamide treatment showed better endothelial response
than patients whose blood pressure was controlled with other treatments [123].

In this same study, capillary density and perfusion in the dorsum of the fingers of patients whose
hypertension was controlled with perindopril/indapamide was significantly higher than that in
patients whose blood pressure was controlled with other treatments (Figure 6) [123]. Consistent
with these data, which suggest a blood pressure-independent effect of perindopril/indapamide on
microvascular rarefication, treatment of rats with renovascular hypertension with
perindopril/indapamide for 4 weeks, normalized coronary microvessel (arteriolar and capillary)
densities [124]. The importance of combination treatment was also underscored in this study as
treatment with perindopril monotherapy only affected arteriole density and treatment with
indapamide monotherapy only affected capillary myocardial density [124]. More recently,
improvements in coronary microcirculation were observed in spontaneously hypertensive rats, in
which treatment with perindopril/indapamide resulted in significantly decreased coronary
microvascular remodeling [115]. The reversal of coronary microvascular rarefaction and remodeling,
which suggests a decrease in hemodynamic resistance and an increase in tissue perfusion, may
underlie some of the improvements in outcomes.

Although very few studies have looked at the molecular pathways affected by
perindopril/indapamide treatment, we can surmise that many of the molecular pathways that
mediate the effects of perindopril and indapamide are still involved. To this effect, in animal models,
treatment with perindopril/indapamide increased levels of vascular endothelial growth factor and
nitric oxide synthase [125-127]. Additional studies will be needed to determine complementary and

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potentially synergistic effects of these molecular pathways.

cr
Conclusions

us
Much of the chronic care of patients with type 2 diabetes and hypertension involves the prevention
of diabetic complications. Many molecular and pathophysiological processes, such as RAAS
pathways, AGE-related pathways, and endothelial dysfunction, are involved in the onset and
an
development of these microvascular and macrovascular complications and, as such, need to be
targeted by well thought-out therapeutic strategies. Perindopril/indapamide combination has been
shown to reduce blood pressure significantly, to decrease the relative risk of microvascular and
M

macrovascular events by 9%, of cardiovascular mortality by 18%, and of all-cause mortality by 14%,
and to be metabolically neutral. In particular, many of the beneficial microvascular and
macrovascular effects appear to be attributable to properties that extend beyond blood pressure
ed

reduction. Moving forward, a deeper understanding of blood pressure-independent effects will


continue to help us to differentiate between anti-hypertensive treatment choices.
pt
ce
Ac
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Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death. Prog Cardiovasc
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102. Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and
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angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular


events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med 2014;174:773-85.
103. Lv J, Perkovic V, Foote CV, et al. Antihypertensive agents for preventing diabetic kidney
disease. Cochrane Database Syst Rev 2012;12:CD004136.
104. Farsang C. Efficacy and tolerability of fixed-dose combination of perindopril/indapamide in
type 2 diabetes mellitus: PICASSO trial. Adv Ther 2014;31:333-44.
105. Netchessova TA, Shepelkevich AP, Gorbat TV, et al. Efficacy of single-pill
perindopril/indapamide in patients with hypertension and type 2 diabetes. High Blood Press
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106. Nadhazi Z, Dezsi CA. The Results of ACES (Antihypertensive Combinations' Long Term Efficacy
Comparing Study): Analysis of Metabolic Effects of Antihypertensive Combination Therapies. Clin
Drug Investig 2016;36:819-27.
107. Mogensen CE, Viberti G, Halimi S, et al. Effect of low-dose perindopril/indapamide on
albuminuria in diabetes: preterax in albuminuria regression: PREMIER. Hypertension 2003;41:1063-
71.
108. Hirakawa Y, Arima H, Webster R, et al. Risks associated with permanent discontinuation of
blood pressure-lowering medications in patients with type 2 diabetes. J Hypertens 2016;34:781-7.
109. Hirakawa Y, Arima H, Rodgers A, et al. Cumulative in-trial and post-trial effects of blood
pressure and lipid lowering: systematic review and meta-analysis. J Hypertens 2017
110. Asmar RG, London GM, O'Rourke ME, et al. Improvement in blood pressure, arterial stiffness
and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive
patient: a comparison with atenolol. Hypertension 2001;38:922-6.
111. London GM, Asmar RG, O'Rourke MF, et al. Mechanism(s) of selective systolic blood pressure

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reduction after a low-dose combination of perindopril/indapamide in hypertensive subjects:

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comparison with atenolol. J Am Coll Cardiol 2004;43:92-9.
112. de Luca N, Mallion JM, O'Rourke MF, et al. Regression of left ventricular mass in hypertensive

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patients treated with perindopril/indapamide as a first-line combination: the REASON
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113. Dahlöf B, Gosse P, Gueret P, et al. Perindopril/indapamide combination more effective than
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114. Investigators AES, Group AC. Effects of perindopril-indapamide on left ventricular diastolic
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116. de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in
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118. Renaud IM, Chainey A, Belair MF, et al. Long-term protection of obese Zucker rat kidneys
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119. Hayakawa H, Coffee K, Raij L. Endothelial dysfunction and cardiorenal injury in experimental
salt-sensitive hypertension: effects of antihypertensive therapy. Circulation 1997;96:2407-13.
120. Sekuri C, Bayturan O, Gocer H, et al. Effects of low-dose combination therapy with an
angiotensin-converting enzyme inhibitor and a diuretic on flow-mediated vasodilation in
hypertensive patients: a 6-month, single-center study. Curr Ther Res Clin Exp 2003;64:715-24.
121. Joannides R, Bellien J, Thurlure C, et al. Fixed combination of perindopril and indapamide at
low dose improves endothelial function in essential hypertensive patients after acute administration.
Am J Hypertens 2008;21:679-84.
122. Ghiadoni L, Magagna A, Kardasz I, et al. Fixed dose combination of perindopril and
indapamide improves peripheral vascular function in essential hypertensive patients. Am J Hypertens
2009;22:506-12.
123. Debbabi H, Bonnin P, Levy BI. Effects of Blood Pressure Control With Perindopril/Indapamide
on the Microcirculation in Hypertensive Patients. Am J Hypertens 2010
124. Levy BI, Duriez M, Samuel JL. Coronary microvasculature alteration in hypertensive rats.
Effect of treatment with a diuretic and an ACE inhibitor. Am J Hypertens 2001;14:7-13.
125. You D, Cochain C, Loinard C, et al. Combination of the angiotensin-converting enzyme
inhibitor perindopril and the diuretic indapamide activate postnatal vasculogenesis in spontaneously
hypertensive rats. J Pharmacol Exp Ther 2008;325:766-73.
126. Silvestre JS, Kamsu-Kom N, Clergue M, et al. Very-low-dose combination of the angiotensin-
converting enzyme inhibitor perindopril and the diuretic indapamide induces an early and sustained
increase in neovascularization in rat ischemic legs. J Pharmacol Exp Ther 2002;303:1038-43.
127. Hayakawa H, Raij L. The link among nitric oxide synthase activity, endothelial function, and

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aortic and ventricular hypertrophy in hypertension. Hypertension 1997;29:235-41.

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Figures

Figure 1. Simplified model of the pathophysiological mechanisms involved in

diabetes and hypertension.

The pathophysiologic pathways and processes that underlie the deleterious comorbid

association between hypertension and diabetes mellitus are numerous and complex in the

way they interact with one another. AGE, advanced glycation end product; RAAS, renin-

angiotensin-aldosterone system.

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Figure 2. Blood pressure-independent effects of indapamide and perindopril

A) Effects of indapamide vs hydrochlorothiazide on pulse wave velocity, a parameter of

arterial stiffness, in patients with mild-to-moderate hypertension and type 2 diabetes (N =

56). Pulse wave velocity decreased significantly with indapamide treatment (*p <0.05, 6-

month follow-up versus baseline), but not with hydrochlorothiazide treatment. Changes from

baseline in pulse wave velocity were significantly different between groups (p = 0.005). This

significant difference was independent of blood pressure, as changes from baseline in blood

pressure were similar between groups (p >0.05) [58]. B) Effects of perindopril on carotid

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artery function in patients with essential hypertension and type 2 diabetes (N = 57;

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DAPHNET trial). Carotid distensibility increased more with 10 mg perindopril than with 5 mg

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perindopril after 7 months of treatment (p = 0.014, dose-period interaction, ANOVA). This

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significant difference was found to be independent of baseline distensibility, baseline blood

pressure, and 24-hour blood pressure reduction. The study was designed such that blood
an
pressure reductions would be similar in both dose groups. *Converted from tert-butylamine

salt to arginine salt (± indapamide 1.5 mg SR as needed in order for systolic blood pressure
M

reduction to be >10 mm Hg) [55]. Adapted with permission [55].


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Figure 3. Cumulative incidence of all-cause mortality in the blood-pressure–

lowering arm of the ADVANCE trial and post-trial follow-up ADVANCE-ON [29,30].

A) Cumulative incidence of all-cause mortality in the active treatment and placebo groups

during the ADVANCE in-trial period (median follow-up 4.4 years), the ADVANCE-ON post-

trial period (median follow-up 5.9 years), and overall (median follow-up 9.9 years). B) Mean

systolic and diastolic blood pressure during run-in (all patients on active treatment), after

randomization to active treatment or placebo during in-trial phase (mean follow-up 4.4 years);

and during the post-trial follow-up (first visit 2.9 years after the end of the in-trial phase and

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final visit another 3 years later). Δ = average difference between randomized groups during

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follow-up. Active group: perindopril/indapamide. BP, blood pressure; HR, hazard ratio; NS,

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not significant; R, randomization.

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Figure 4. Event rates of outcomes after permanent discontinuation in the

ADVANCE trial [108]

In the ADVANCE trial, 1557 patients permanently discontinued treatment of randomized

blood pressure-lowering medication (14% of overall study population). The mean difference

in blood pressure between the active and placebo groups observed before discontinuation

disappeared gradually after discontinuation. A) Combined macrovascular and microvascular

events. B) All-cause mortality. For perindopril/indapamide vs. placebo during the first year: *p

= 0.01; **p <0.01. All p-values were >0.10 for the comparison between the active and

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placebo groups after 1 year. Active treatment denotes the fixed-dose combination of

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perindopril and indapamide. The life-table method was used to estimate event rates at the

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mid-point of each 12-month interval [108].

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Figure 5. Change in albumin excretion rate after treatment with

perindopril/indapamide or enalapril in patients with diabetes and microalbuminuria in

the PREMIER trial [107]

In the PREMIER trial, after 52 weeks of treatment, changes in AER and changes in blood

pressure were significantly greater in the perindopril/indapamide group than in the enalapril

group. For AER, the estimated treatment effect after adjustment for systolic blood pressure*

was 0.78 (95% confidence interval: 0.64-0.94; p = 0.002). For blood pressure, the between

group differences were -3.0 mm Hg (95% confidence interval: -5.6 to -0.4; p = 0.012) for

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systolic blood pressure and -1.5 mm Hg (95% confidence interval: -3.0 to -0.1; p = 0.019) for

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diastolic blood pressure. AER, albumin excretion rate.

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Figure 6. Blood pressure-independent effects of perindopril/indapamide

treatment on the microcirculation (capillary density and perfusion parameter) [123]

Capillary density and perfusion in the dorsum of the fingers of patients whose hypertension

was controlled with perindopril/indapamide (mean SBP/DBP of 129 ± 8/ 78 ± 6 mm Hg) was

significantly higher than in the 2 other treatment groups: patients whose blood pressure was

controlled with other treatments (mean SBP/DBP of 131 ± 6/78 ± 5 mm Hg) and patients with

uncontrolled hypertension (mean SBP/DBP of 167 ± 8/100 ± 8 mm Hg). A) Capillary density

after treatment. Capillary density (during venous congestion) was assessed by intravital

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video capillaroscopy in the skin of the dorsum of middle phalanx of the non-dominant hand.

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B) Change in perfusion (laser Doppler signal after pilocarpine iontophoresis) was evaluated

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on the forearm skin by laser Doppler flowmetry. It is a measure of endothelium-dependent

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vasodilation. Mean values ± standard deviations are presented. Controlled with others was

defined as patients whose blood pressure was controlled with an antihypertensive treatment
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(angiotensin receptor blockers: 48%; dihydropyridine derivatives: 31%) other than an

angiotensin-converting enzyme inhibitor or a diuretic. ARB, angiotensin receptor blocker;


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DBP, diastolic blood pressure; NS, not significant; SBP, systolic blood pressure. Adapted
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with permission from figures 2 and 3 [123].


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Tables

Table 1. Main results of the ADVANCE and ADVANCE-ON trials [29,30]

Relative
Hazard ratio
Variables Number of events risk p
(95% CI)
reduction

Per/Ind Placebo
N = 5569 N = 5571

ADVANCE

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Major macrovascular

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or microvascular 861 938 9% 0.91 (0.83–1.00) 0.041
event

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Death from any cause 408 471 14% 0.86 (0.75–0.98) 0.025

Death from
cardiovascular
disease
211 257 18%
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Total coronary events 468 535 14% 0.86 (0.76–0.98) 0.020
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Total renal events* 1243 1500 21% 0.79 (0.73–0.85) <0.0001


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ADVANCE-ON
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Death from any cause 1092 1173 9% 0.91 (0.84–0.99) 0.03


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Death from
cardiovascular 466 522 12% 0.88 (0.77–0.99) 0.04
disease
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Major macrovascular
1050 1116 8% 0.92 (0.85–0.99) 0.06
event†

*Mainly new microalbuminuria. †Myocardial infarction, stroke or death from cardiovascular


disease. ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR
Controlled Evaluation; ADVANCE-ON, Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation posttrial ObservatioNal study; CI, confidence
interval; Per/Ind, perindopril/indapamide.
Table 2. Reduction of blood pressure and mortality or renal endpoints in

studies of patients with type 2 diabetes mellitus

Mortality
rate in
SBP Primary the
Follow- % Baseline differenc endpoin control
Cardiovascular Total
Trial Treatment up diabetic SBP/DBP e vs t group
mortality mortality
(years) patients (mm Hg) control or renal (deaths
(mm Hg) event per 1000
patient-
years)
Intensive
(SBP <120
ACCORD mm Hg) vs +6% +7%

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5.0 100% 139/76 -14.2 - 10


N = 4733 standard (p = NS) (p = NS)

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(SBP <140
mm Hg)

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Perindopril/in -21%†
ADVANCE -18% -14%
dapamide vs 4.3 100% 145/81 -5.6 (p 18
N = 11140 (p = 0.027) (p = 0.025)
placebo <0.0001)
TRANSCEND Telmisartan
N = 5927 vs placebo
4.7 36% 141/82 -4.0
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+10%ǁ
(p = NS)
-5.5%‡
+3%
(p = NS)
+5%
(p = NS)
Candesartan:
25
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DIRECT Candesartan
4.7 100% 118/73 -3.3 (p = - 51; placebo: 4
N = 5231 vs placebo
0.024) 48
-20%†
IDNT Irbesartan vs +8% -8%
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2.6 100% 159/87 -3.3 (p = 55


N = 1148 placebo (p = NS) (p = NS)
0.02)
ROADMAP Olmesartan +394% +70%
3.2 100% 136/81 -3.0 - 2
N = 4447 vs placebo (p = 0.01) (p = NS)
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RENAAL Losartan vs -16%ǁ +2%


3.4 100% 153/82 -2.0 - 60
N = 1513 placebo (p =0.02) (p = NS)
Benazepril/a
-48%* 14
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ACCOMPLISH mlodipine vs -20% -10%


3.0 60% 145/80 -1.1 (p (both
N = 11506 benazepril/H (p = NS) (p = NS)
<0.0001) groups)
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ONTARGET Telmisartan 0%ǁ 0% -2%


4.7 38% 142/82 -0.9 NA§
N = 17118 vs ramipril (p = NS) (p = NS) (p = NS)
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Rates were derived from hazard ratios for ACCORD, ADVANCE, TRANSCEND, DIRECT ROADMAP, RENAAL,
ACCOMPLISH and from relative risk analyses for ONTARGET and unadjusted relative risks for IDNT. * Doubling of
serum creatinine, estimated glomerular filtration rate <15 mL/min/1·73 m2, or need for dialysis. † New or worsening
nephropathy [development of macroalbuminuria, doubling of serum creatinine to a level of at least 200 μmol/L, need
for renal replacement therapy, or death due to renal disease] or new microalbuminuria. ‡ Annual rate of change
urinary albumin excretion rate. ǁ Doubling serum creatinine, end-stage renal disease or death. § NA for telmisartan vs
ramipril comparison; 25 for all groups. ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy
in Patients Living with Systolic Hypertension; ACCORD, Action to Control Cardiovascular Risk in Diabetes;
ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; DBP,
diastolic blood pressure; DIRECT, DIabetic Retinopathy Candesartan Trials; HCTZ, hydrochlorothiazide; HR, hazard
ratio; IDNT, Irbesartan Diabetic Nephropathy Trial; NA, not available; NS, not significant; ONTARGET, Ongoing
Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; RENAAL, Reduction of Endpoints in
NIDDM with the Angiotensin II Antagonist Losartan; ROADMAP, Randomized Olmesartan And Diabetes
MicroAlbuminuria Prevention; SBP, systolic blood pressure; TRANSCEND, Telmisartan Randomized Assessment
Study in ACE-intolerant Subjects With Cardiovascular Disease Adapted with permission [31]

Table 3. Effects of indapamide and perindopril that result in vascular protection

and/or vascular function improvement

Indapamide Perindopril
Blood pressure reduction [59] Blood pressure reduction [52,56]

Improvement of arterial stiffness and Improvement of arterial stiffness and function

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arterial function [58] [43,46,51,55]

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Increase in glycosaminoglycan levels Reduction of carotid internal diameter [55]
(marker of arterial flexibility) [40]*

Improvement in total peripheral vascular


resistance [36] us
Prevention of the progression of non-calcified
coronary plaques [35]
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Reduction of small artery remodeling [48]* Reduction of small artery remodeling [48,54]*
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Improvement of endothelial function / Improvement of endothelial function / reduction


reduction of endothelial damage of endothelial damage [37,42]
[34,58]*[45]*
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Reduction of nephropathy Reduction of nephropathy (microalbuminuria


(microalbuminuria reduction) [39,49] reduction) [33]
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Preservation of renal function (creatinine Improvement/delayed structural glomerular


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clearance)[47] damage [38,50]*

Reduction in oxidative stress [57]*[45]* Reduction in oxidative stress and apoptosis


[37]
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Reduction in inflammation [45]* Reduction in inflammation [37,44]

Reduction in platelet aggregation [53]* Modulation of AGE pathway [41]

*Data from in vitro or animal studies

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