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 investigators1University of Dundee, UK; 2INSERM Unit 780, Villejuif, Paris, France; and 3University of Pisa, Italy.

Abstract

Background

Methods

EGIR-RISC Study Group

References1. 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.

• 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, p<0.0001, n=333).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.

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 (n=1,261 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 p<0.0001 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, p<0.0005) 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, r=0.19) and diastolic BP (68 and 75 mmHg, r=0.23): 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.

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. NovellaMalmö, 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 Albumin:creatinine – 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.

RISC is supported by the European Union (QLG1-CT-2001-01252) and by AstraZeneca; EGIR receives support from Merck-Serono

Summary

• 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.

EUROPEAN GROUP FOR THE STUDY OF INSULIN RESISTANCE

PI: Prof Ele Ferrannini

• The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) Study recruited 615 men and 789 women in 18 European centres in 2002–2004. • The Methods of RISC have been published.4 In brief, inclusion criteria were: age 30–60 years, no symptomatic cardiovascular disease, blood pressure <140/90 mmHg, total cholesterol <7.8 mmol/L, triglycerides <4.6 mmol/L, and glucose (fasting/2 hours after oral glucose tolerance test) <7.0/11.1 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

Results (1)

Aims

Materials & MethodsResults (2)

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?

Conclusion

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.

J JJ

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60 65 70 75 80 85 90

DBP (mmHg)

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.

MALE FEMALE

mmHg European Society for Hypertension

NHLBI Joint National Committee 7 (JNC7)

<120 Optimal Normal 120-129/ 80-84 Normal 130-139/ 85-89 High Normal

}Prehypertension

Male (601) BP* 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 <0.0001

Age (yrs) 43±8 42±8 44±8 ns 43±8 47±8 50±7° <0.0001 <0.0001

SBP (mmHg)113±5 124±3° 133±4° <0.0001 109±7 123±5° 133±4° <0.0001 <0.0001

DBP(mmHg) 71±5 76±4° 82±4° <0.0001 70±5 78±5° 81±5° <0.0001 ns

HR (b/min) 65±10 67±10 68±10° <0.03 70±10 72±10 73±10° <0.01 <0.0001

Waist (cm) 91±10 93±10 97±9° <0.0001 79±11 85±11 90±12° <0.0001 <0.0001

WHR 0.92±0.10 0.92±0.06 0.95±0.12° <0.05 0.81±0.10 0.83±0.08 0.86±0.11° <0.01 <0.0001

BMI (kg/m2) 25.6±3.2 26.4±3.5 27.3±3.4° <0.0001 23.9±3.8 26.3±4.6 28.1±5.2° <0.0001 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 <0.0001

Smoke (Y/EX)

24/30 30/26 22/26 ns 24/29 30/20 32/19 ns ns

PA (counts)#359±185 350±172 337±181 ns 341±162 298±108 319±278 ns <0.05

Alc. (gr/week)

93±77 106±107 117±112 ns 50±58 56±75 51±68 ns <0.0001

T.Chol (mM) 4.72±0.86 4.92±0.87 5.07±0.88° <0.003 4.67±0.86 4.95±0.91 5.17±1.00 ns ns

HDL-C (mM) 1.22±0.30 1.25±0.31 1.28±0.27 ns 1.59±0.38 1.57±0.39 1.56±0.34 ns <0.0001

Tg (mM) # 1.18±0.68 1.30±0.82 1.27±0.642 ns 0.88±0.46 1.04±0.52 1.12±0.49° <0.002 <0.0001

Alb/crea # 0.38±0.80 0.34±0.70 0.49±1.67 ns 0.60±2.25 0.51±1.16 0.35±0.43 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° <0.02 ns

M/I 126±64.1 130±66.2 106±58.6 ns 158.7±66.3 143.4±58.8 128.6±69.8° ns ns