Prehypertension is associated with central obesity but not specifically with insulin resistance/ metabolic syndrome John R. Petrie,1 Beverley Balkau,2 Andrea Natali3 and the RISC investigators 1University of Dundee, UK; 2INSERM Unit 780, Villejuif,

1
Prehypertension is associated with central
obesity but not specifically with insulin
resistance/ metabolic syndromeJohn R. Petrie,1
Beverley Balkau,2 Andrea Natali3 and the RISC
investigators1University of Dundee, UK 2INSERM
Unit 780, Villejuif, Paris, France and
3University of Pisa, Italy.
EUROPEAN GROUP FOR THE STUDY OF INSULIN RESISTANCE
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PI Prof Ele Ferrannini
Abstract
Methods
Summary
Materials Methods
Results (2)
Whether insulin resistance (IR) is present in
prehypertension is controversial. JNC7 defines
prehypertension as a blood pressure (BP)
120-139/80-89 mmHg, whereas the European Society
of Hypertension (ESH 2007) divides this category
into Normal (120-129 and/or 80-84 mmHg) and
High-Normal (130-139 and/or 85-89 mmHg). We
analysed baseline data from the Relationship
between Insulin Sensitivity and Cardiovascular
disease (RISC) study, a large prospective cohort
of non-hypertensive non-diabetic men and women
(age 30-60 years, BMI 17-44 kg/m2) from 18
European centres characterised for insulin
sensitivity (IS) by a standardised
hyperinsulinaemic euglycaemic clamp (IS defined
as M/I) to determine (i) whether Optimal, ESH
Normal and ESH High-Normal categories of
normotension are characterized by different IS
and metabolic phenotype and (ii) at what levels
of systolic and diastolic BP any thresholds in
the relationship between BP and IS occur. BP was
measured in triplicate using a standard OMRON
705CP device with data available from 1,384
participants (n1,261 with clamp-measured IS).
ESH High-Normal BP was associated with higher
overall and central adiposity e.g. waist
mean(SD) in Optimal, Normal, and High Normal men
91(10), 93(10), 97(9) cm women 79(11), 85(11),
90(12), both plt0.0001 ANOVA and higher heart
rate, but few other major clinical
characteristics. In the entire study population,
IS and diastolic BP were correlated (r -0.22,
plt0.0005) independently of confounders.
Decision-tree analysis, used to create splits in
the data which maximize differences between
branches of the splits, identified two potential
threshold values for both systolic BP (108 and
115 mmHg, r0.19) and diastolic BP (68 and 75
mmHg, r0.23) i.e. best splits were below both
ESH and JNCVII-defined Optimal BP (120/80 mmHg).
We conclude that prehypertension is associated
with obesity but not specifically with IR or the
metabolic syndrome.


MALE
FEMALE

• Blood pressure frequency distribution was
  shifted to the right in males with half the
  prevalence of Optimal BP (twice the prevalence of
  High Normal BP) in comparison with females.
• Lower BP in females was not explained by age,
  body fat, physical exercise or alcohol
  consumption (as expected these were different
  according to gender).
• After adjusting for age and centre, High Normal
  BP was associated with higher overall and central
  adiposity and a higher heart rate in comparison
  with Optimal BP both in males and females.
• In males only, High Normal BP was associated
  with a mildly elevated serum cholesterol.
• In females only, High Normal BP was associated
  with older age, higher triglycerides and a higher
  prevalence of impaired glucose tolerance.
• There was a non-linear relationship between
  insulin sensitivity (M/I) and diastolic BP
  partition analysis indicated potential thresholds
  at 76 mmHg for males and 78 mmHg for females.

• The Relationship between Insulin Sensitivity and
  Cardiovascular disease (RISC) Study recruited 615
  men and 789 women in 18 European centres in
  20022004.
• The Methods of RISC have been published.4 In
  brief, inclusion criteria were age 3060 years,
  no symptomatic cardiovascular disease, blood
  pressure lt140/90 mmHg, total cholesterol lt7.8
  mmol/L, triglycerides lt4.6 mmol/L, and glucose
  (fasting/2 hours after oral glucose tolerance
  test) lt7.0/11.1 mmol/L.
• A hyperinsulinaemic euglycaemic (40
  mU.min-1.m-2) clamp was used to measure insulin
  sensitivity (M/ I value in µmol/min/kgffm per
  µU/l).
• Blood samples were assayed in central
  laboratories.
• Blood pressure was measured using the same
  automated device in all centres (OMRON 705CP,
  Omron Healthcare GmbH, Hamburg, Germany).
• Decision-tree analysis was used to explore the
  data for potential thresholds by creating splits
  which maximize differences between the resulting
  branches
• 
  DEFINITIONS

Conclusion
Results (1)
Prehypertension as defined by the European
Society of Hypertension (but not as defined by
JNC7), is associated with excess overall and
central adiposity but not with the typical full
blown phenotype of the metabolic syndrome.
Male (601) Male (601) Male (601) BP Female (783) Female (783) Female (783) BP Gender
Optimal Normal High N Optimal Normal High N
N/ 219/36.4 249/41.4 133/22.2 527/67.3 178/22.7 78/10.0 lt0.0001
Age (yrs) 438 428 448 ns 438 478 507 lt0.0001 lt0.0001
SBP (mmHg) 1135 1243 1334 lt0.0001 1097 1235 1334 lt0.0001 lt0.0001
DBP(mmHg) 715 764 824 lt0.0001 705 785 815 lt0.0001 ns
HR (b/min) 6510 6710 6810 lt0.03 7010 7210 7310 lt0.01 lt0.0001
Waist (cm) 9110 9310 979 lt0.0001 7911 8511 9012 lt0.0001 lt0.0001
WHR 0.920.10 0.920.06 0.950.12 lt0.05 0.810.10 0.830.08 0.860.11 lt0.01 lt0.0001
BMI (kg/m2) 25.63.2 26.43.5 27.33.4 lt0.0001 23.93.8 26.34.6 28.15.2 lt0.0001 ns
FH-D () 23.5 26.3 31.0 ns 26.9 29.3 42.9 ns ns
FH-HT () 31.1 42.4 43.4 ns 43.4 56.3 45.5 ns lt0.0001
Smoke (Y/EX) 24/30 30/26 22/26 ns 24/29 30/20 32/19 ns ns
PA (counts) 359185 350172 337181 ns 341162 298108 319278 ns lt0.05
Alc. (gr/week) 9377 106107 117112 ns 5058 5675 5168 ns lt0.0001
T.Chol (mM) 4.720.86 4.920.87 5.070.88 lt0.003 4.670.86 4.950.91 5.171.00 ns ns
HDL-C (mM) 1.220.30 1.250.31 1.280.27 ns 1.590.38 1.570.39 1.560.34 ns lt0.0001
Tg (mM) 1.180.68 1.300.82 1.270.642 ns 0.880.46 1.040.52 1.120.49 lt0.002 lt0.0001
Alb/crea 0.380.80 0.340.70 0.491.67 ns 0.602.25 0.511.16 0.350.43 ns ns
IFG 6.11 () 1.4 2.8 4.6 ns 1.8 2.3 5.1 ns ns
IGT () 9.0 7.2 12.0 ns 9.7 7.3 21.8 lt0.02 ns
M/I 12664.1 13066.2 10658.6 ns 158.766.3 143.458.8 128.669.8 ns ns
EGIR-RISC Study Group
Background
Project Management Board B Balkau (Villejuif,
France) SW Coppack (London, England) JM
Dekker(Amsterdam, The Netherlands) E Ferrannini
(Pisa, Italy) A Mari (Padova, Italy) A Natali
(Pisa, Italy) JR Petrie (Dundee, UK) M Walker
(Newcastle, England). RISC recruitment
centres Amsterdam, The Netherlands R.J. Heine,
J Dekker, G Nijpels, W Boorsma Athens Greece A
Mitrakou, S Tournis, K Kyriakopoulou Belgrade,
Serbia and Montenegro N Lalic, K Lalic, A Jotic,
L Lukic, M Civcic Dublin, Ireland J Nolan, TP
Yeow, M Murphy, C DeLong, G Neary, MP Colgan
Frankfurt, Germany T Konrad, H Böhles, S
Fuellert, F Baer, H Zuchhold Geneva,
Switzerland A Golay, V. Barthassat, V.
Makoundou, TNO Lehmann, E. Harsch Bobbioni, T
Merminod Glasgow, Scotland J Petrie, C Perry, F
Neary, C MacDougall, K Shields, L Malcolm
Kuopio, Finland M Laakso, U Salmenniemi, A Aura,
R Raisanen, U Ruotsalainen, T Sistonen, M
Laitinen London, England SW Coppack, N
McIntosh, P Khadobaksh Lyon, France M Laville,
F. Bonnet, A Brac de la Perriere, C
Louche-Pelissier, C Maitrepierre, J Peyrat, A
Serusclat Madrid, Spain R. Gabriel, EM Sánchez,
R. Carraro, A Friera, B. Novella Malmö, Sweden
(1) P Nilsson, M Persson, G Östling, (2) O
Melander, P Burri Milan, Italy PM Piatti, LD
Monti, E Setola, F Minicucci, A Colleluori
Newcastle-upon-Tyne, England M Walker, IM
Ibrahim, M Jayapaul, D Carman, Y McGrady, D
Richardson Odense, Denmark H Beck-Nielsen, P
Staehr, K Hojlund, V Jensen, C Olsen Perugia,
Italy GB Bolli, F Porcellati, C Fanelli, M
Romolini, F Calcinaro, A Saturni Pisa, Italy E
Ferrannini, A Natali, E Muscelli, S Pinnola, M
Kozakova, L Landucci Rome, Italy G Mingrone, P
Di Rocco, C Guidone, A Favuzzi Vienna, Austria
W Waldhäusl, M Roden, C Anderwald, A Hofer Core
laboratories and reading centres Lipids
Dublin, Ireland P Gaffney, J Nolan, G Boran
Hormones Odense, Denmark C Olsen, L Hansen, H
Beck-Nielsen Urine Albumincreatinine
Amsterdam, The Netherlands A Kok, J Dekker
Genetics Newcastle-upon-Tyne, England S Patel,
M Walker. Stable isotope analysis Pisa, Italy
A Gastaldelli,D Ciociaro Ultrasound reading
centre Pisa, Italy M Kozakova, E Ferrannini.
Data Management Villejuif, France B Balkau, L
Mhamdi. Mathematical modelling and website
management Padova, Italy A Mari, G Pacini,C
Cavaggion. Coordinating office Pisa, Italy SA
Hills, L Mota, L Landucci. Further information
on the RISC project and participating centres can
be found at www.egir.org.

• Insulin resistance is a feature of essential
  hypertension as assessed in case-control studies
  using the gold standard hyperinsulinaemic
  euglycaemic clamp technique.1
• Impaired insulin-mediated glucose uptake may be
  of relevance in the pathophysiology of
  hypertension.
• One early case-control study reported that
  insulin sensitivity was reduced by 30 in
  normotensive offspring of hypertensive patients.2
  However, whether insulin sensitivity is impaired
  in prehypertension remains controversial.
• The EGIR clamp-pooling project, reported in
  1997 that diastolic blood pressure across the
  normal range was inversely correlated with
  insulin sensitivity (r-0.34, plt0.0001, n333).3
  
• The relationship between blood pressure and
  insulin sensitivity as measured by a standard
  clamp technique has not, however, previously been
  studied in a large healthy population.

References
Aims

1. Ferrannini E, Buzzicoli G, Bonadonna R, Giorico
   MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi
   L, Bevilqacqua S. Insulin resistance in
   essential hypertension. N Engl J Med 1987 317,
   350-357.
2. Ferrari P, Weidmann P, Shaw S, Giachino D, Riesen
   W, Allemann Y, Heynan G. Altered insulin
   sensitivity, hyperinsulinaemia and dyslipidaemia
   in individuals with a hypertensive parent. Am J
   Med 1991 91 589-596.
3. Ferrannini E, Natali A, Capaldo B, Lehtovirta M,
   Jacob S, Yki-Jarvinen H. Insulin resistance,
   hyperinsulinaemia, and blood pressure role of
   age and obesity. European Group for the Study of
   Insulin Resistance (EGIR). Hypertension 1997 30
   1144-9.
4. Hills SA, Balkau B, Coppack S, Dekker JM, Mari A,
   Natali A, Walker M, Ferrannini E EGIR-RISC study
   group. The EGIR-RISC study (The European Group
   for the study of Insulin Resistance relationship
   between insulin sensitivity and cardiovascular
   disease) I. Methodology and objectives.
   Diabetologia 2004 47 566-70.

To determine 1) Are the features of the
metabolic syndrome and/or insulin resistance
present in pre hypertensive individuals? What is
the role of gender and obesity? 2) Are the three
classes of normal blood pressure (Optimal, Normal
and High normal, according to ESH 2007
guidelines) characterized by different metabolic
phenotypes and different degrees of insulin
sensitivity? 3) Is the association between blood
pressure and insulin resistance linear or is
there a threshold and, if this is the case, where
does any threshold occur?
BP indicates statistical significance for the
effect for blood pressure classification with age
and centre as covariate Gender indicates
statistical significance for the effect of
gender with age, blood pressure category and
centre as covariate. indicates that High normal
or Normal blood pressure classes were
statistically significant (vs Optimal) with age
and centre as covariate.
RISC is supported by the
European Union (QLG1-CT-2001-01252) and by
AstraZeneca EGIR receives support from
Merck-Serono