Phenotypic characterization of normotolerant hypertensive patients.

Abstract

BACKGROUND: Normotolerant subjects (NGT) are considered at low risk, even if a plasma glucose value ≥155mg/dl for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify NGT at high-risk for type-2 diabetes and subclinical organ damage. Insulin resistance (IR) contributes to the pathogenesis of impaired glucose tolerance and participates to the development of subclinical organ damage. However, it is unknown whether NGT<155 subjects are at low risk for the development of subclinical organ damage independently from other metabolic variables, such as IR/hyperinsulinemia. METHODS: From a large cohort of about 1200 uncomplicated hypertensive outpatients underwent to OGTT, we selected 645 NGT subjects, 319 men and 326 women aged 47.6±10.6. All subjects underwent standard echocardiography for measurement of left ventricular mass (LVM), and carotid ultrasonography for evaluation of intima media thickness (IMT). Finally, we estimated glomerular filtration rate (e-GFR) by using the new equation proposed by investigators in the chronic kidney disease epidemiology (CKD-EPI) collaboration. RESULTS: NGT<155 subjects into upper tertile of 1-h post-load insulin had a worse lipemic profile, a higher hs-CRP, creatinine, LVM, e-GFR and IMT. Comparing the NGT groups, we observed that metabolic and hemodynamic parameters of NGT<155 subjects into upper tertile of 1-h post-load insulin were similar to that observed in NGT≥155 subjects. Similarly, fasting and both 1-h and 2-h post-load insulin values were similar to that observed in NGT≥155. CONCLUSIONS: We documented that hypertensive NGT subjects have different phenotypic patterns, particularly in their metabolic profile and in presence of subclinical organ damage.

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Phenotypic characterization of normotolerant hypertensive patients
Francesco Perticone⁎, Angela Sciacqua, Maria Perticone, Sofia Miceli, Raffaele Maio, Joseph E. Tassone,
Franco Arturi, Giorgio Sesti
Department of Experimental and Clinical Medicine “G. Salvatore”, University Magna Græcia of Catanzaro, Italy
a b s t r a c ta r t i c l e i n f o
Article history:
Received 12 July 2011
Received in revised form 18 August 2011
Accepted 21 August 2011
Available online xxxx
Keywords:
Insulin resistance
Subclinical organ damage
Essential hypertension
Background: Normotolerantsubjects(NGT)areconsideredatlowrisk,evenifaplasmaglucosevalue≥155 mg/dl
for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify NGT at
high-riskfortype-2diabetesandsubclinicalorgandamage.Insulinresistance(IR)contributestothepathogenesis
of impaired glucose tolerance and participates to the development of subclinical organ damage. However,
it is unknown whether NGTb155 subjects are at low risk for the development of subclinical organ damage
independently from other metabolic variables, such as IR/hyperinsulinemia.
Methods: From a large cohort of about 1200 uncomplicated hypertensive outpatients underwent to OGTT,
we selected 645 NGT subjects, 319 men and 326 women aged 47.6±10.6. All subjects underwent standard
echocardiography for measurement of left ventricular mass (LVM), and carotid ultrasonography for eval-
uation of intima media thickness (IMT). Finally, we estimated glomerular filtration rate (e-GFR) by using
the new equation proposed by investigators in the chronic kidney disease epidemiology (CKD-EPI) collab-
oration.
Results: NGTb155 subjects into upper tertile of 1-h post-load insulin had a worse lipemic profile, a higher
hs-CRP, creatinine, LVM, e-GFR and IMT. Comparing the NGT groups, we observed that metabolic and he-
modynamic parameters of NGTb155 subjects into upper tertile of 1-h post-load insulin were similar to
that observed in NGT≥155 subjects. Similarly, fasting and both 1-h and 2-h post-load insulin values
were similar to that observed in NGT≥155.
Conclusions: We documented that hypertensive NGT subjects have different phenotypic patterns, particu-
larly in their metabolic profile and in presence of subclinical organ damage.
© 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Diabetes mellitus is a powerful risk factor for cardiovascular dis-
ease associated with high morbidity and mortality rates. Diabetic
patients also have an increased incidence of heart failure, which
has been traditionally attributed to the development of ischemic
complications and myocardial abnormalities, such as left ventricular
hypertrophy (LVH) and impairment of cardiac function, that concur
to define the diabetic cardiomyopathy. All these abnormalities con-
tribute to the early appearance of diastolic dysfunction that leads to
chronic heart failure, independently of other cardiovascular dis-
eases. In addition, subjects with impaired glucose tolerance (IGT)
and/or impaired fasting glucose (IFG) are characterized by an unfa-
vorable cardiovascular risk profile [1], demonstrating that glucose
metabolism worsening, tested by an oral glucose tolerance test
(OGTT), is more strongly associated with both subclinical target
organ damage and atherosclerotic disease.
Similarly, insulin resistance (IR) is another risk factor that is linked
to the appearance and progression of cardiovascular disease, both as
an independent risk factor as well as through its association with
other risk factors such as obesity and hypertension [2,3]. Moreover,
it is associated with left ventricular mass (LVM) increase, intima-
media thickness (IMT), arterial stiffness and renal function, all inde-
pendent predictors of subsequent cardiovascular events [1,4–6].
According to the molecular theory of diabetic cardiomyopathy,
hyperglycemia seems to be the main pathogenetic factor, which
causes abnormalities at the cardiac myocyte level, eventually leading
to structural and functional abnormalities [7]. In keeping with this,
we recently reported, in a large sample of newly diagnosed hyperten-
sive patients, that normotolerant (NGT) subjects with 1-h post-load
glucose ≥155 mg/dL (NGT≥155), compared with NGT with 1-h
post-load glucose b155 mg/dL (NGTb155), have a higher LVM and a
greater prevalence of LVH similar to that of IGT and diabetic patients
[8]; in addition, they have higher IMT [9] and lower estimated glo-
merular filtration rate (e-GFR) [10] when compared with NGTb155.
On the basis of these evidences, we suggested the usefulness to re-
consider the concept that NGT subjects are a homogeneous group
with a low cardiovascular risk. This recommendation has clinical
relevance because emphasizes the importance of the phenotypic
International Journal of Cardiology xxx (2011) xxx–xxx
⁎ Corresponding author at: Department of Medicina Sperimentale e Clinica, Univer-
sity Magna Græcia of Catanzaro, Italy, Campus Universitario di Germaneto, V.le Europa,
88100, Catanzaro (Italy). Tel.: +39 0961 3647149.
E-mail address: perticone@unicz.it (F. Perticone).
IJCA-13888; No of Pages 5
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2011.08.076
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard
Please cite this article as: Perticone F, et al, Phenotypic characterization of normotolerant hypertensive patients, Int J Cardiol (2011),
doi:10.1016/j.ijcard.2011.08.076

Page 2

characterization in stratifying the profile of cardiovascular or cardio-
metabolic risk in each subject. However, it is unknown whether
NGTb155 subjects are at low risk for the development of subclini-
cal organ damage independently from other metabolic variables,
such as IR/hyperinsulinemia.
To evaluate whether cardio-metabolic factors may help to identify
subjects with NGTb155 at enhanced risk for cardiovascular disease,
we compared clinical characteristics, including IR/hyperinsulinemia
and subclinical organ damage, in a group of newly diagnosed hyper-
tensive subjects.
2. Materials and methods
2.1. Study population
From a large cohort of about 1200 uncomplicated hypertensive outpatients
underwent to OGTT, we selected 645 NGT subjects, 319 men and 326 women aged
47.6±10.6, participating to the CAtanzaro MEtabolic RIsk factors Study (CATAMERIS).
All subjects were Caucasian and underwent physical examination and review of their
medical history. Causes of secondary hypertension were excluded by appropriate clinical
and biochemical tests. Other exclusion criteria were history or clinical evidence of coro-
nary, valvular heart disease, congestive heart failure, hyperlipidemia, peripheral vascular
disease, chronic gastrointestinal diseases associated with malabsorption, chronic pancre-
atitis, history of any malignant disease, history of alcohol or drug abuse, liver or kidney
failureandtreatmentsabletomodifyglucosemetabolism.Nosubjectshadeverbeentrea-
ted with antihypertensive drugs. All subjects underwent anthropometrical evaluation:
weight, height and body mass index (BMI).
After 12-h fasting, a 75 g OGTT was performed with 0, 30, 60, 90 and 120 min sam-
pling for plasma glucose and insulin. Glucose tolerance status was defined on the basis
of OGTT using the World Health Organization (WHO) criteria. Insulin sensitivity was
evaluated using the Matsuda index [insulin sensitivity index (ISI)], calculated as fol-
lows: 10,000/square root of [fasting glucose (mmol per liter)×fasting insulin (mU
per liter)]×[mean glucose×mean insulin during OGTT]. The Matsuda index is strongly
related to euglycemic hyperinsulinemic clamp that represents the gold standard test
for measuring insulin sensitivity [11]. Baseline IR was estimated by HOMA-index. The
Ethical Committee approved the protocol and informed written consent was obtained
from all participants. All the investigations were performed in accordance with the
principles of the Declaration of Helsinki.
2.2. Blood pressure measurements
Readings of clinic blood pressure (BP) were obtained in the left arm of the supine
patients, after 5 min of quiet rest, with a mercury sphygmomanometer. Minimum
three BP readings were taken on three separate occasions at least 2 weeks apart. Sys-
tolic and diastolic BP (SBP, DBP) were recorded at the first appearance (phase I) and
the disappearance (phase V) of Korotkoff sounds. Baseline BP values were the average
of the last two of the three consecutive measurements obtained at intervals of 3 min.
Patients with a clinic SBP SBP N140 mmHg and/or DBP N90 mmHg were defined as
hypertensive.
2.3. Laboratory determinations
All laboratory measurements were performed after at least 12 fasting hours. Plasma
glucose was determined immediately by the glucose oxidase method [Glucose analyzer,
Beckman Coulter, Milan; intra-assay coefficient of variation (CV) 2.2%, inter-assay CV
3.8%].Triglyceride, total, low and high-density lipoprotein (LDL, HDL) cholesterol concen-
trations were measured by enzymatic methods (Roche Diagnostics GmbH, Mannheim,
Germany). Serum insulin was determined in duplicate by a highly specific radioimmuno-
assayusing twomonoclonalantibodies;intra-assay CV2.1%, inter-assay CV2.9%. Circulat-
ing IGF-1 was obtained in duplicate using a site-specific (cross-reactivity: human insulin
undetectable, intact proinsulin undetectable) and sensitive immunoradiometric assay
(Nichols Advantage Kit from Nichols Institute Diagnostics, San Clemente, California,
USA;intra-assayCV5.2%,inter-assayCV5.7%;internalreferencevaluesinhealthysubjects
71–360 ng/ml).
2.4. Echocardiograms
Tracings were taken with the patient in partial left decubitus position, using a
VIVID 7 Pro ultrasound machine (GE Technologies, Milwaukee, Wisconsin, USA) with
an annular phased array 2.5 MHz transducer. Echocardiographic readings were made
in random order by the investigator, who had no knowledge of patients' BP and
other clinical data. Only frames with optimal visualization of cardiac structures were
considered for reading. The mean values from at least five measurements of each pa-
rameter for each patient were computed. Having the same experienced sonographer
(MS) perform all studies in a dimly lit and quiet room optimized the reproducibility
of measurements. In our laboratory, the intra-observer CVs are 3.85% for posterior
wall (PW) thickness, 3.70% for interventricular septal (IVS) thickness, 1.50% for left
ventricular internal diameter (LVID) and 5.10% for left ventricular mass (LVM).
Tracings were recorded under two-dimensional guidance and M-mode measure-
ments were taken at the tip of the mitral valve or just below. Measurements of IVS
thickness, PW thickness and LVID were made at end-diastole and end-systole, as
recommended by the American Society of Echocardiography [12]. LVM was calculated
using the Devereux formula [13] and normalized by body surface area (LVMI).
2.5. Intima-media thickness measurements
Carotid ultrasonography was performed during the same echocardiographic
examination, using linear probes of 7.5 to 10 MHz. Intima media thickness (IMT)
was defined as the distance between the leading edge of the lumen-intima echo
and the leading edge of the media adventitia echo [14]. Mean IMT was defined
as the average of the IMT values of the near and far wall in the left and right carotid arter-
ies, measured at a site freeof plaque 10to 15 mm proximal to the carotid bulb. Valuesare
expressed in millimeters. Whenever a plaque was present, defined as a focal lesion
N1.2 mm thick, measurements were performed before or after the plaque. All measure-
ments were performed offline by a single experienced examiner who was unaware of
the subjects' clinical and laboratory findings.
2.6. Renal function
Creatinine measurements were carried out by using Jaffe methodology and by
the URICASE/POD (Boehringer Mannheim, Mannheim, Germany) method imple-
mented in an auto-analyzer. Values of estimated glomerular filtration rate (e-GFR)
(mL/min/1.73 m2) were calculated by using the new equation proposed by investi-
gators in the chronic kidney disease epidemiology (CKD-EPI) collaboration. This
equation was developed from a much large cohort of patients, including both normal
and CKD individuals, than the MDRD study. We preferred this equation because it is
more accurate in subjects with GFRN60 mL/min/1.73 m2, as our patients were sup-
posed to have considering the creatinine valueb1.5 mg/dL [15].
2.7. Statistical analysis
Data are expressed as mean±SD, and comparisons among groups were made by
Student's t test or the chi-squared test, as appropriate. Differences were assumed to
be significant at Pb0.05. All comparisons were performed using the statistical package
SPSS 16.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
3. Results
3.1. Study population
Subjects were divided into three tertiles on the basis of their 1-h
post-load insulin, and then we compared subjects included in the
first and upper tertile to better highlight the effects of hyperinsuline-
mia on metabolic parameters and subclinical organ damage. Demo-
graphic, clinical, and biochemical data of the study population,
stratified according to 1-h post-load plasma glucose and by tertile of
1-h post-load insulin, are reported in Table 1. There were no signifi-
cant differences between tertiles for gender distribution, age, BMI,
fasting glucose, smokers and DBP both in NGTb155 and NGT≥155.
On the contrary, subjects allocated into upper tertile of 1-h post-
load insulin of both groups had higher values of fasting insulin, 2-h
post-load insulin and HOMA-index in comparison with those in the
first tertile; obviously, Matsuda index/ISI and IGF-1 values were sig-
nificantly lower in the upper tertile when compared with that in
the first tertile.
In NGT≥155 group, no significant differences between tertiles
were observed for 1-h and 2-h post-load glucose, creatinine, total
and LDL cholesterol, hs-CRP, LVMI, e-GFR and IMT. On the contrary,
in NGTb155 group, subjects into upper tertile of insulin had a
worse lipemic profile, a higher hs-CRP, creatinine, LVMI, IMT, and a
lower e-GFR and IGF-1 values. Comparing the NGT groups, we ob-
served that metabolic and hemodynamic parameters of NGTb155
subjects into upper tertile of 1-h post-load insulin were similar to
that observed in NGT≥155 subjects. Similarly, fasting and both 1-h
and 2-h post-load insulin values were similar to that observed in
NGT≥155.
In Fig. 1 we report LVMI, IMT and e-GFR mean values stratified by
tertiles of 1-h post-load insulin.
2
F. Perticone et al. / International Journal of Cardiology xxx (2011) xxx–xxx
Please cite this article as: Perticone F, et al, Phenotypic characterization of normotolerant hypertensive patients, Int J Cardiol (2011),
doi:10.1016/j.ijcard.2011.08.076

Page 3

4. Discussion
The main and novel finding obtained in this study is that hyper-
tensive NGT subjects are characterized by different phenotypic
patterns, particularly in terms of their metabolic profile and the
presence of subclinical organ damage. Particularly, our data show
that NGTb155 subjects in the upper tertile of insulin have signifi-
cantly total and LDL cholesterol concentrations in comparison with
subjectsinthefirsttertileofinsulin,demonstratinga differentmetabol-
ic profile between groups. In addition, they show significantly higher
SBP and hs-CRP values, as well as LVMI and IMT, and lower e-GFR, all
parameters that concur to define a different cardiovascular risk profile.
On the contrary, no significant differences were observed between the
two tertiles in NGT≥155 group.
In addition to that previously reported about the clinical and
echocardiographic characteristics observed in normotolerant sub-
jects with 1-h post-load glucose b155 or ≥155 mg/dl [8], we also
observed an important phenotypic heterogeneity in NGTb155. In
particular, the finding clinically relevant consists in the fact that
most of these subjects, to maintain 1-h post-load glucose at value
less than 155 mg/dl, have high post-load insulin levels, probably as
a consequence of reduced peripheral insulin sensitivity. This hy-
pothesis may be supported by the HOMA – an index of hepatic
insulin resistance – values that do not show an important differ-
ence in hepatic insulin sensitivity in all groups. On the contrary,
the Matsuda index, which better correlates with peripheral insu-
lin sensitivity measured with the hyperinsulinemic–euglycemic clamp,
issignificantlydifferentbetweengroups,confirmingthenegativeimpact
of compensatory post-load hyperinsulinemia on development and pro-
gressionofsubclinicalorgandamage.Obviously,thisraisesanimportant
question about the actual biological significance of metabolic abnormal-
ities at baseline and after loading. Our data seem to provide greater bio-
logicalsignificancetothepost-loadhyperinsulinemiaratherthanfasting
hyperinsulinemia, at least in hypertensive patients. In fact, NGTb155
subjectsenclosed in the upper tertile of post-load insulin have higher
values of LVMI and IMT, and lower values of e-GFR in comparison
with those enclosed in the first tertile. All these characteristics
concur to define a different cardiovascular risk profile between
these two phenotypes that, according to current guidelines and
consolidated clinical practice are considered at low risk. Yet, it
has long been known that the presence of IR/hyperinsulinemia
Table 1
Anthropometric, biochemical and hemodynamic characteristics of NGTb155 and NGT≥155 subjects according to increasing tertiles of 1-h post-load insulin.
VariablesNGTb155 (n=450)NGT≥155 (n=195)
I tertileIII tertile
P
I tertile III tertile
P
(N=150)(N=150)(N=65)(N=65)
Gender, male/female
Age, years
BMI, kg/m2
Fasting glucose, mg/dl
1-h glucose, mg/dl
2-h glucose, mg/dl
Fasting insulin, μU/ml
1-h insulin, μU/ml
2-h insulin, μU/ml
HOMA
MATSUDA index/ISI
IGF-1, ng/ml
Creatinine, mg/dl
e-GFR, ml/min/1.73 m2)
Total cholesterol, mg/dl
HDL-cholesterol, mg/dl
LDL-cholesterol, mg/dl
Triglyceride, mg/dl
Hs-CRP, mg/L
Current smokers, n (%)
SBP, mmHg
DBP, mmHg
LVMI, g/m2
IMT, mm
56/94
45.8±10.4
28.4±4.1
89.6±11.1
111.2±24.7
100.1±19
9.1±5.5
39.7±11.7
34.9±17.2
2.0±1.4
108.8±40.9
194.5±98.1
0.75±0.16
112.2±24.5
198.3±38.7
55.0±14.3
121.7±34.7
108.4±58
1.9±1.4
43(28.6%)
140.4±9.1
85.1±11.6
105.8±28.0
0.65±0.19
68/82
47.8±10.6
28.9±4.8
91.3±9.7
127.2±19.5
102.0±20.6
14.5±8.6
160.0±64.3
104.7±73.7
3.1±2.0
48.0 ±19.4
155.3±63.2
0.83±0.20
95.4±23.3
209.9±39.7
49.3±12.9
133.7±36.9
133.0±67.1
2.7±1.9
45(30.0%)
145.7±8.0
86.3±9.9
120.5±40.1
0.81±0.18
0.197*
0.100
0.333
0.159
b0.0001
0.407
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.011
b0.0001
0.004
b0.0001
b0.0001
0.899*
b0.0001
0.336
b0.0001
b0.0001
36/29
49.9±7.5
29.3±4.7
95.4±11.3
180.9±23.5
112.2±18.0
10.7±6.1
53.0±15.6
43.8±24.3
2.3±1.5
72.7±34.8
193.9±94.2
0.84±0.23
97.2±25.4
199.5±32.4
55.1±12.5
123.4±35.7
106.5±51.8
2.4±1.4
19(29.2%)
145.4±8.8
86.2±6.6
116.3±27
0.83±0.28
41/24
49.2±10.7
29.6±3.6
95.6±10.8
182.6±22.4
110.1±20.2
13.9±5.9
188.6±40.1
126.1±66.9
3.3±1.4
33.4±11.8
146.8±63.0
0.87±0.23
95.4±27.4
200.7±30.4
47.0±11.8
128.6±28.1
122.6±50.9
2.7±1.6
20(30.8%)
146.4±8.4
85.2±10.8
120.1±32.1
0.86±0.36
0.475*
0.667
0.684
0.918
0.674
0.533
0.003
b0.0001
b0.0001
b0.0001
b0.0001
0.001
0.458
0.698
0.828
b0.0001
0.358
0.076
0.257
0.999*
0.509
0.525
0.466
0.597
* χ² test; NGT=normal glucose tolerance; BMI=body mass index; HOMA=homeostasis model assessment; ISI=insulin sensitivity index; hs-CRP=high sensitivity C-reactive
protein; LVMI=left ventricular mass index; e-GFR=estimated glomerular filtration rate; IMT=intima-media thickness.
Fig. 1. In this picture we graphically report the indexed left ventricular mass (LVMI),
intima-media thickness (IMT) and estimated glomerular filtration rate (e-GFR) mean
values stratified by tertiles of 1-h post-load insulin in NGTb155 and NGT≥155
subjects.
3
F. Perticone et al. / International Journal of Cardiology xxx (2011) xxx–xxx
Please cite this article as: Perticone F, et al, Phenotypic characterization of normotolerant hypertensive patients, Int J Cardiol (2011),
doi:10.1016/j.ijcard.2011.08.076

Page 4

may be considered as one of the fundamental pathophysiologic
disturbances responsible for the cardiovascular disorders present
in individuals at high risk for developing cardiovascular disease
[2–4].
Subclinical organ damage represents an intermediate stage in
the continuum of vascular disease and a determinant of overall
cardiovascular risk. It is well established that IR/hyperinsulinemia
participates to development and progression of the organ damage
in its multiple manifestations. In keeping with this, endothelial
dysfunction that may occur on the basis of impaired insulin signal-
ing in the vasculature, coupled with increased responses of vascu-
lar smooth muscle cells to the mitogenic actions of insulin and
enhanced sensitivity to vasoactive peptides such as angiotensin II
have also been proposed to contribute to accelerated atherosclero-
sis in insulin resistant states [16,17]. In addition, several lines of
evidence suggest that IR/hyperinsulinemia may directly promote
the growth of cardiac mass and left ventricular dysfunction even
in absence of hypertension and atherosclerotic coronary artery dis-
ease [1,18]. In addition, IR/hyperinsulinemia increases LVM by the
insulin binding to its receptors and to insulin-like growth factor-1
(IGF-1) receptors, expressed in the myocardium [19,20]. Moreover,
hyperinsulinemia may cause renal sodium retention, affecting car-
diac preload, which is another factor involved in LVM increase [21].
The activation of both the renin–angiotensin–aldosterone system
and sympathetic nervous system are other important mechanisms
potentially involved in cardiac mass increase promoting oxidative
stress, stimulating cardiac fibroblast, and increasing heart rate
and cardiac overload [5]. Finally, there is evidence that impaired
insulin sensitivity may be involved in the development of renal
dysfunction at an early stage, before the onset of diabetes [22,23].
IR/hyperinsulinemia has been suggested to contribute to renal
damage through several pathophysiologic mechanisms, including
up-regulation of TGF-ß, endothelin-1, and components of the renin–
angiotensin–aldosterone system, which have been shown to promote
mitogenic and fibrotic processes in the kidney [21]. Furthermore, it
has been demonstrated the existence of an inverse relationship
between fasting insulin and IGF-1, as a consequence of a dynamic
balance between them [24], and that reduced IGF-1 levels may ac-
count for the reduction of e-GFR [25] because there is evidence
that IGF-1 enhances both renal blood flow and GFR by stimulating
IGF-1 receptors [26]; according with this, in subjects in the upper
tertile of insulin we observed lower IGF-1 values than in those in
the first tertile.
Based on the abovementioned, it is plausible to assume that
the IR/hyperinsulinemia promotes the subclinical organ damage,
increasing cardiovascular risk, long before the clinical onset of di-
abetes. Moreover, since these findings were obtained in a hyper-
tensive population, it is also plausible that hypertension should
not be considered a simple hemodynamic disorder, but a cluster
of metabolic and hemodynamic alterations that interact in a mul-
tiplicative manner in the appearance and progression of cardiovas-
cular disease. However, the most clinically relevant result, reported in
this paper, is the fact that measurements of glycemia alone during an
OGTT allow for a partial stratification of the risk of cardiovascular
disease. In fact, many subjects with NGT, characterized by high
post-load insulin levels, would be considered at low cardiovascular
risk despite the concomitant presence of subclinical organ damage.
Therefore, it would be useful to measure insulin levels during an
OGTT, giving the fact that many subjects with NGT with 1-h post-
load glucose b155 mg/dL already have a worse cardiometabolic
risk profile and early signs of subclinical damage.
4.1. Conclusions
In conclusion, results of this study indicate that hypertensive NGT
individuals are heterogeneous in regard to plasma glucose/insulin
homeostasis, subclinical organ damage and cardiovascular risk pro-
file. Particularly, there are significant differences in 1-h and 2-h
post-load insulin. In addition, NGT subjects with high post-load insu-
lin differ from those with low post-load insulin with regard to sub-
clinicalorgan damageandcardiovascular
triglyceride, HDL- and LDL-cholesterol). Therefore, it may be of im-
portant clinical relevance to well characterize NGT, paying attention
not only to 2-h but also to 1-h post-load metabolic modifications,
and to investigate subclinical organ damage that appears precocious-
ly, before the clinical manifestation of diabetes.
risk factors(SBP,
Conflict of interest
None.
Acknowledgement
“The authors of this manuscript have certified that they comply
with the Principles of Ethical Publishing in the International Journal
of Cardiology [27]”.
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