Professional Documents
Culture Documents
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
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
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
Transparency
ip
Declaration of Funding:
This review received funding support from Servier, France.
cr
Declaration of financial/other relationships:
BL has received honoraria for consultancy and conferences from Bayer, Roche and Servier. CMRO
us
peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgements:
an
Medical writing and editorial support, under the guidance of the authors, was provided by Hélène
Dassule, PhD. This support was funded by Servier.
M
ed
pt
ce
Ac
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
included.
ip
cr
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
us
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
an
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
M
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
ed
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
pt
beyond those of blood pressure control, will help us differentiate between anti-hypertensive choices.
ce
Ac
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
cr
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.
us
an
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
M
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-
pt
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
Ac
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.
t
In this narrative review, we will focus on the effect of antihypertensive treatment with
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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.
cr
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-
us
independent pathways.
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-
ed
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
pt
[24].
ce
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
Ac
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
hemoglobin levels that were present at the end of the randomized trial had no longer been
ip
significant since they were measured at the first post-trial visit (~3 years) (Table 1) [30].
cr
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
us
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
an
in ADVANCE, but decreases in blood pressure were not accompanied by lower mortality rates (Table
2) [31].
M
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
ed
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
pt
Methods
Ac
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].
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
cr
function, and ventriculoarterial coupling independently of blood pressure in hypertensive patients
with diabetes (N = 56), to improve arterial compliance while reducing arterial pressure, total
us
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
an
treatment increased glycosaminoglycan levels, which are markers of arterial stiffness, and reversed
coronary arteriole remodeling independently of blood pressure effects [40,48].
M
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
ed
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
pt
(-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
ce
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
Ac
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].
t
Indapamide has also been shown to downregulate the sympathetic nervous system, correct
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
cr
modulation of these pathways by indapamide intersects with the complex pathophysiology of
diabetic complications.
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
ed
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-
pt
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),
ce
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
Ac
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
t
Diabetes) substudy, N = 1,502], in which a 19% relative risk reduction (95% confidence interval: -7 to
Downloaded by [University of New England] at 06:54 09 January 2018
ip
38%; p = 0.13) in the primary composite cardiovascular endpoint was observed [82].
cr
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
us
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
an
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
M
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
ed
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,
pt
thereby, once again, suggesting the existence of blood pressure-independent pathways [54].
ce
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
Ac
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.
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
cr
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
us
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
an
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
M
the deleterious accumulation of AGEs in diabetic tissue by promoting the sequestering of AGEs and
by reducing the uptake of AGEs into cells.
ed
Angiotensin-converting enzyme inhibitors are often considered to be equivalent. They have all been
pt
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
ce
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
Ac
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
inhibitors and the balance between blood pressure-dependent and –independent pathways.
cr
Differentiating angiotensin-converting enzyme inhibitors from angiotensin receptor blockers
Although ARBs are also recommended as first-line treatments for hypertension in patients with
us
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
an
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].
M
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
ed
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
pt
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.
ce
Perindopril/indapamide combination
Ac
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.
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
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
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
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
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
patients with and without diabetes mellitus? Overview and meta-analyses of randomized trials. J
Hypertens 2017;35:922-44.
cr
7. van Sloten TT, Henry RM, Dekker JM, et al. Endothelial dysfunction plays a key role in
increasing cardiovascular risk in type 2 diabetes: the Hoorn study. Hypertension 2014;64:1299-305.
8.
us
Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase
activity by posttranslational modification at the Akt site. The Journal of clinical investigation
2001;108:1341-8.
an
9. Pahwa R, Nallasamy P, Jialal I. Toll-like receptors 2 and 4 mediate hyperglycemia induced
macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx. J
Diabetes Complications 2016;30:563-72.
M
10. Lee CH, Shieh YS, Hsiao FC, et al. High glucose induces human endothelial dysfunction
through an Axl-dependent mechanism. Cardiovasc Diabetol 2014;13:53.
ed
11. Singh R, Alavi N, Singh AK, et al. Role of angiotensin II in glucose-induced inhibition of
mesangial matrix degradation. Diabetes 1999;48:2066-73.
12. Giacchetti G, Sechi LA, Rilli S, et al. The renin-angiotensin-aldosterone system, glucose
pt
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
24. Persson F, Lindhardt M, Rossing P, et al. Prevention of microalbuminuria using early
intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: A systematic
cr
review. J Renin Angiotensin Aldosterone Syst 2016;17
25. Dickerson JE, Hingorani AD, Ashby MJ, et al. Optimisation of antihypertensive treatment by
26.
us
crossover rotation of four major classes. Lancet 1999;353:2008-13.
Authors/Task Force Members, Ryden L, Grant PJ, et al. ESC Guidelines on diabetes, pre-
an
diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on
diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and
developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart
M
J 2013;34:3035-87.
27. Standards of Medical Care in Diabetes-2016: Summary of Revisions. Diabetes Care 2016;39
Suppl 1:S4-5.
ed
28. Kuo SW, Pei D, Hung YJ, et al. Effect of indapamide SR in the treatment of hypertensive
patients with type 2 diabetes. Am J Hypertens 2003;16:623-8.
29. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and
pt
indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus
(the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829-40.
ce
30. Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose
control in type 2 diabetes. N Engl J Med 2014;371:1392-406.
31. Garcia-Donaire JA, Segura J, Cerezo C, et al. A review of renal, cardiovascular and mortality
Ac
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
41. Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor for advanced
glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy.
cr
Journal of the American Society of Nephrology : JASN 2005;16:2363-72.
42. Ghiadoni L, Magagna A, Versari D, et al. Different effect of antihypertensive drugs on conduit
artery endothelial function. Hypertension 2003;41:1281-6.
43.
us
Guerin AP, Blacher J, Pannier B, et al. Impact of aortic stiffness attenuation on survival of
an
patients in end-stage renal failure. Circulation 2001;103:987-92.
44. Koz C, Baysan O, Yokusoglu M, et al. The effects of perindopril on aortic elasticity and
inflammatory markers in hypertensive patients. Medical science monitor : international medical
M
46. Mackenzie IS, McEniery CM, Dhakam Z, et al. Comparison of the effects of antihypertensive
agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension
2009;54:409-13.
pt
Cardiol 1996;77:23B-5B.
48. Mancini M, Scavone A, Sartorio CL, et al. Effect of different drug classes on reverse
remodeling of intramural coronary arterioles in the spontaneously hypertensive rat. Microcirculation
Ac
2016;24:In press.
49. Marre M, Puig JG, Kokot F, et al. Equivalence of indapamide SR and enalapril on
microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study. J
Hypertens 2004;22:1613-22.
50. Nankervis A, Nicholls K, Kilmartin G, et al. Effects of perindopril on renal histomorphometry
in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study. Metabolism
1998;47:12-5.
51. Nedogoda SV, Ledyaeva AA, Chumachok EV, et al. Randomized trial of perindopril, enalapril,
losartan and telmisartan in overweight or obese patients with hypertension. Clin Drug Investig
2013;33:553-61.
52. Ogilvie RI, Anand S, Roy P, et al. Perindopril for control of blood pressure in patients with
hypertension and other cardiovascular risk factors: an open-label, observational, multicentre, general
practice-based study. Clin Drug Investig 2008;28:673-86.
53. Rendu F, Bachelot C, Molle D, et al. Indapamide inhibits human platelet aggregation in vitro:
comparison with hydrochlorothiazide. J Cardiovasc Pharmacol 1993;22 Suppl 6:S57-63.
54. Thybo NK, Stephens N, Cooper A, et al. Effect of antihypertensive treatment on small arteries
of patients with previously untreated essential hypertension. Hypertension 1995;25:474-81.
55. Tropeano AI, Boutouyrie P, Pannier B, et al. Brachial pressure-independent reduction in
carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives.
Hypertension 2006;48:80-6.
56. Tsoukas G, Anand S, Yang K, et al. Dose-dependent antihypertensive efficacy and tolerability
of perindopril in a large, observational, 12-week, general practice-based study. Am J Cardiovasc
Drugs 2011;11:45-55.
57. Vergely C, Walker MK, Zeller M, et al. Antioxidant properties of indapamide, 5-OH
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
paramagnetic resonance. Mol Cell Biochem 1998;178:151-5.
58. Vinereanu D, Dulgheru R, Magda S, et al. The effect of indapamide versus
cr
hydrochlorothiazide on ventricular and arterial function in patients with hypertension and diabetes:
results of a randomized trial. Am Heart J 2014;168:446-56.
59.
us
Zhang Y, Agnoletti D, Wang JG, et al. Natriuresis and blood pressure reduction in
hypertensive patients with diabetes mellitus: the NESTOR study. J Am Soc Hypertens 2015;9:21-8.
an
60. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age
or older. N Engl J Med 2008;358:1887-98.
61. Prisant LM, Beall SP, Nichoalds GE, et al. Biochemical, endocrine, and mineral effects of
M
people with hypertension: results from active treatment extension to Hypertension in the Very
Elderly randomised controlled trial. BMJ 2012;344:d7541.
ce
65. Gosse P, Sheridan DJ, Zannad F, et al. Regression of left ventricular hypertrophy in
hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study. J
Hypertens 2000;18:1465-75.
Ac
66. Leenen FH, Smith DL, Boer WH, et al. Diuretic and cardiovascular effects of indapamide in
hypertensive subjects: a dose-response curve. Curr Med Res Opin 1983;8 Suppl 3:47-52.
67. Roush GC, Sica DA. Diuretics for Hypertension: A Review and Update. Am J Hypertens
2016;29:1130-7.
68. LeBel M, Grose JH, Belleau LJ, et al. Antihypertensive effect of indapamide with special
emphasis on renal prostaglandin production. Curr Med Res Opin 1983;8 Suppl 3:81-6.
69. Waeber B, Rotaru C, Feihl F. Position of indapamide, a diuretic with vasorelaxant activities, in
antihypertensive therapy. Expert Opin Pharmacother 2012;13:1515-26.
70. Plante GE, Lafreniere MC, Tam PT, et al. Effect of indapamide on phosphate metabolism and
vascular reactivity. Am J Med 1988;84:26-30.
71. Schini VB, Dewey J, Vanhoutte PM. Effects of indapamide on endothelium-dependent
relaxations in isolated canine femoral arteries. Am J Cardiol 1990;65:6H-10H.
72. Mironneau J, Savineau JP, Mironneau C. Compared effects of indapamide,
hydrochlorothiazide and chlorthalidone on electrical and mechanical activities in vascular smooth
muscle. Eur J Pharmacol 1981;75:109-13.
73. National Clinical Guideline Centre. Hypertension. Clinical management of primary
hypertension in adults (NICE clinical guideline 127). London, United Kingdom 2011.
74. DiNicolantonio JJ. Hydrochlorothiazide: is it a wise choice? Expert Opin Pharmacother
2012;13:807-14.
75. Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor
Intervention Trial. Circulation 1990;82:1616-28.
76. Bejan-Angoulvant T, Saadatian-Elahi M, Wright JM, et al. Treatment of hypertension in
patients 80 years and older: the lower the better? A meta-analysis of randomized controlled trials. J
Hypertens 2010;28:1366-72.
t
Downloaded by [University of New England] at 06:54 09 January 2018
77. Senior R, Imbs JL, Bory M, et al. Indapamide reduces hypertensive left ventricular
ip
hypertrophy: an international multicenter study. J Cardiovasc Pharmacol 1993;22 Suppl 6:S106-10.
78. Hallab M, Gallois Y, Chatellier G, et al. Comparison of reduction in microalbuminuria by
cr
enalapril and hydrochlorothiazide in normotensive patients with insulin dependent diabetes. BMJ
1993;306:175-82.
79.
us
Dinicolantonio JJ, Lavie CJ, O'Keefe JH. Not all angiotensin-converting enzyme inhibitors are
equal: focus on ramipril and perindopril. Postgrad Med 2013;125:154-68.
an
80. Todd PA, Fitton A. Perindopril. A review of its pharmacological properties and therapeutic
use in cardiovascular disorders. Drugs 1991;42:90-114.
81. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with
M
stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the
EUROPA study). Lancet 2003;362:782-8.
82. Daly CA, Fox KM, Remme WJ, et al. The effect of perindopril on cardiovascular morbidity and
ed
mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur
Heart J 2005;26:1369-78.
83. Revel F, Gallois H, Le Coz Y, et al. [Course of the left ventricular mass in a population of 893
pt
hypertensive patients. Effects of treatment with perindopril]. Ann Cardiol Angeiol (Paris)
1994;43:594-9.
ce
84. McLennan SV, Kelly DJ, Cox AJ, et al. Decreased matrix degradation in diabetic nephropathy:
effects of ACE inhibition on the expression and activities of matrix metalloproteinases. Diabetologia
2002;45:268-75.
Ac
85. Ceconi C, Francolini G, Olivares A, et al. Angiotensin-converting enzyme (ACE) inhibitors have
different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol 2007;577:1-
6.
86. Gainer JV, Morrow JD, Loveland A, et al. Effect of bradykinin-receptor blockade on the
response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N
Engl J Med 1998;339:1285-92.
87. Oeseburg H, Iusuf D, van der Harst P, et al. Bradykinin protects against oxidative stress-
induced endothelial cell senescence. Hypertension 2009;53:417-22.
88. Murphey LJ, Malave HA, Petro J, et al. Bradykinin and its metabolite bradykinin 1-5 inhibit
thrombin-induced platelet aggregation in humans. J Pharmacol Exp Ther 2006;318:1287-92.
89. Chao J, Li HJ, Yao YY, et al. Kinin infusion prevents renal inflammation, apoptosis, and fibrosis
via inhibition of oxidative stress and mitogen-activated protein kinase activity. Hypertension
2007;49:490-7.
90. Sun L, Wen JH, Sun HL, et al. Perindopril attenuates renal tubulointerstitium injury by
inhibiting scavenger receptor A over-expression in diabetic rats. J Endocrinol Invest 2012;35:511-5.
91. Zakaria MN, El-Bassossy HM, Barakat W. Targeting AGEs Signaling Ameliorates Central
Nervous System Diabetic Complications in Rats. Adv Pharmacol Sci 2015;2015:346259.
92. Goel R, Bhat SA, Hanif K, et al. Perindopril Attenuates Lipopolysaccharide-Induced
Amyloidogenesis and Memory Impairment by Suppression of Oxidative Stress and RAGE Activation.
ACS Chem Neurosci 2016;7:206-17.
93. Tsoi KK, Wong MC, Tam WW, et al. Cardiovascular mortality in hypertensive patients newly
prescribed perindopril vs. lisinopril: a 5-year cohort study of 15,622 Chinese subjects. Int J Cardiol
2014;176:703-9.
94. Savarese G, Costanzo P, Cleland JG, et al. A meta-analysis reporting effects of angiotensin-
t
Downloaded by [University of New England] at 06:54 09 January 2018
converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J
ip
Am Coll Cardiol 2013;61:131-42.
95. van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors
cr
reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-
aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012;33:2088-97.
96.
us
Ceconi C, Francolini G, Bastianon D, et al. Differences in the effect of angiotensin-converting
enzyme inhibitors on the rate of endothelial cell apoptosis: in vitro and in vivo studies. Cardiovasc
an
Drugs Ther 2007;21:423-9.
97. Ferrari R. Preserving bradykinin or blocking angiotensin II: the cardiovascular dilemma.
Dialogues in cardiovascular medicine 2004;9:71-89.
M
98. Taddei S. RAS inhibitors' dose-dependent efficacy: myth or reality? Curr Med Res Opin
2015;31:1245-56.
99. Taddei S, Bortolotto L. Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity. Am
ed
Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death. Prog Cardiovasc
Dis 2016;58:473-82.
102. Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and
Ac
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
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
cr
patients treated with perindopril/indapamide as a first-line combination: the REASON
echocardiography study. Am J Hypertens 2004;17:660-7.
us
113. Dahlöf B, Gosse P, Gueret P, et al. Perindopril/indapamide combination more effective than
enalapril in reducing blood pressure and left ventricular mass: the PICXEL study. J Hypertens
an
2005;23:2063-70.
114. Investigators AES, Group AC. Effects of perindopril-indapamide on left ventricular diastolic
function and mass in patients with type 2 diabetes: the ADVANCE Echocardiography Substudy. J
M
Hypertens 2011;29:1439-47.
115. Neglia D, Fommei E, Varela-Carver A, et al. Perindopril and indapamide reverse coronary
microvascular remodelling and improve flow in arterial hypertension. J Hypertens 2011;29:364-72.
ed
116. de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in
type 2 diabetes. Journal of the American Society of Nephrology : JASN 2009;20:883-92.
117. Heerspink HJ, Ninomiya T, Perkovic V, et al. Effects of a fixed combination of perindopril and
pt
indapamide in patients with type 2 diabetes and chronic kidney disease. Eur Heart J 2010;31:2888-
96.
ce
118. Renaud IM, Chainey A, Belair MF, et al. Long-term protection of obese Zucker rat kidneys
from fibrosis and renal failure with an angiotensin-converting enzyme inhibitor/diuretic combination.
Fundam Clin Pharmacol 2004;18:437-47.
Ac
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
cr
us
an
M
ed
pt
ce
Ac
Figures
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.
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
cr
us
an
M
ed
pt
ce
Ac
Figure 2. Blood pressure-independent effects of indapamide and perindopril
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
artery function in patients with essential hypertension and type 2 diabetes (N = 57;
ip
DAPHNET trial). Carotid distensibility increased more with 10 mg perindopril than with 5 mg
cr
perindopril after 7 months of treatment (p = 0.014, dose-period interaction, ANOVA). This
us
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
Ac
ce
pt
ed
M
an
us
cr
ip
t
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
final visit another 3 years later). Δ = average difference between randomized groups during
ip
follow-up. Active group: perindopril/indapamide. BP, blood pressure; HR, hazard ratio; NS,
cr
not significant; R, randomization.
us
an
M
ed
pt
ce
Ac
Downloaded by [University of New England] at 06:54 09 January 2018
Ac
ce
pt
ed
M
an
us
cr
ip
t
Figure 4. Event rates of outcomes after permanent discontinuation in the
blood pressure-lowering medication (14% of overall study population). The mean difference
in blood pressure between the active and placebo groups observed before discontinuation
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
placebo groups after 1 year. Active treatment denotes the fixed-dose combination of
ip
perindopril and indapamide. The life-table method was used to estimate event rates at the
cr
mid-point of each 12-month interval [108].
us
an
M
ed
pt
ce
Ac
Downloaded by [University of New England] at 06:54 09 January 2018
Ac
ce
pt
ed
M
an
us
cr
ip
t
Figure 5. Change in albumin excretion rate after treatment with
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
t
Downloaded by [University of New England] at 06:54 09 January 2018
systolic blood pressure and -1.5 mm Hg (95% confidence interval: -3.0 to -0.1; p = 0.019) for
ip
diastolic blood pressure. AER, albumin excretion rate.
cr
us
an
M
ed
pt
ce
Ac
Figure 6. Blood pressure-independent effects of perindopril/indapamide
Capillary density and perfusion in the dorsum of the fingers of patients whose hypertension
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
after treatment. Capillary density (during venous congestion) was assessed by intravital
t
Downloaded by [University of New England] at 06:54 09 January 2018
video capillaroscopy in the skin of the dorsum of middle phalanx of the non-dominant hand.
ip
B) Change in perfusion (laser Doppler signal after pilocarpine iontophoresis) was evaluated
cr
on the forearm skin by laser Doppler flowmetry. It is a measure of endothelium-dependent
us
vasodilation. Mean values ± standard deviations are presented. Controlled with others was
defined as patients whose blood pressure was controlled with an antihypertensive treatment
an
(angiotensin receptor blockers: 48%; dihydropyridine derivatives: 31%) other than an
DBP, diastolic blood pressure; NS, not significant; SBP, systolic blood pressure. Adapted
ed
Ac
ce
pt
ed
M
an
us
cr
ip
t
Tables
Relative
Hazard ratio
Variables Number of events risk p
(95% CI)
reduction
Per/Ind Placebo
N = 5569 N = 5571
ADVANCE
t
Downloaded by [University of New England] at 06:54 09 January 2018
Major macrovascular
ip
or microvascular 861 938 9% 0.91 (0.83–1.00) 0.041
event
cr
Death from any cause 408 471 14% 0.86 (0.75–0.98) 0.025
Death from
cardiovascular
disease
211 257 18%
us 0.82 (0.68–0.98) 0.027
an
Total coronary events 468 535 14% 0.86 (0.76–0.98) 0.020
M
ADVANCE-ON
pt
Death from
cardiovascular 466 522 12% 0.88 (0.77–0.99) 0.04
disease
Ac
Major macrovascular
1050 1116 8% 0.92 (0.85–0.99) 0.06
event†
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%
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
(SBP <140
mm Hg)
cr
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
us
+10%ǁ
(p = NS)
-5.5%‡
+3%
(p = NS)
+5%
(p = NS)
Candesartan:
25
an
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%
M
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]
Indapamide Perindopril
Blood pressure reduction [59] Blood pressure reduction [52,56]
t
Downloaded by [University of New England] at 06:54 09 January 2018
ip
cr
Increase in glycosaminoglycan levels Reduction of carotid internal diameter [55]
(marker of arterial flexibility) [40]*