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Insulin resistance is associated with the metabolic syndrome and is not directly linked to coronary artery disease
Clinica Chimica Acta 412 (2011) 1003–1007
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Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
Insulin resistance is associated with the metabolic syndrome and is not directly linked to coronary artery disease Alexander Vonbank a,b,c, Christoph H. Saely a,b,c, Philipp Rein a,b,c, Stefan Beer a,b,c, Johannes Breuss a,c, Christian Boehnel a,c, Heinz Drexel a,b,c,d,⁎ a
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria Private University of the Principality of Liechtenstein, Triesen, Liechtenstein d Drexel University College of Medicine, Philadelphia, PA, USA b c
a r t i c l e
i n f o
Article history: Received 4 September 2010 Received in revised form 5 February 2011 Accepted 5 February 2011 Available online 12 February 2011 Keywords: Insulin resistance HOMA index Metabolic syndrome Coronary artery disease Coronary atherosclerosis Coronary angiography Atherothrombosis
a b s t r a c t Background: Insulin resistance (IR) is the key feature of the metabolic syndrome (MetS). Its association with directly visualized coronary atherosclerosis is unclear. We hypothesised that insulin resistance is associated with both angiographically determined coronary artery disease (CAD) and with the MetS. Methods: In 986 consecutive patients undergoing coronary angiography for the evaluation CAD, IR was determined by the HOMA index; the MetS was defined according to NCEP-ATPIII criteria; and significant CAD was diagnosed when coronary stenoses ≥50% were present. Results: HOMA IR scores were higher in MetS patients than in subjects without the MetS (4.9 ± 6.4 vs. 2.2 ± 2.0; p b 0.001). HOMA IR did not differ significantly between patients with significant CAD and those who did not have significant CAD. When both, the presence of MetS and of significant CAD were considered, HOMA IR was significantly higher in patients with the MetS both among those who had significant CAD (4.9 ± 6.8 vs. 2.2 ± 1.8; p b 0.001) and among those who did not have significant CAD (5.0 ± 5.8 vs. 2.1 ± 2.3; p b 0.001), it did not differ significantly between patients with significant CAD and subjects without significant CAD among patients with the MetS nor among those without MetS. Similar results were obtained with the IDF definition of the MetS. Conclusion: IR is significantly associated with the MetS but not with angiographically determined CAD. IR may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Overweight and obesity have risen dramatically in the past several decades. This resulted in a marked increase in the prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular risk factors including central adiposity, hypertension, dyslipidemia and impaired glucose metabolism [1–3]. According to Adult Treatment Panel III criteria (ATP III) [4] the MetS is diagnosed in the presence of at least 3 out of the 5 criteria: abdominal obesity, high triglycerides, low HDL cholesterol, elevated fasting glucose and high blood pressure. The such diagnosed MetS, as a clinical entity, substantially increases the risk of cardiovascular events both in the primary [5–8] and in the secondary [9] prevention settings [7,10–14]. In particular, the MetS confers an increased risk of premature coronary artery disease.
⁎ Corresponding author at: VIVIT Institute, Feldkirch, Carinagasse 47, A-6807 Feldkirch, Austria. Tel.: + 43 5522 303 2670; fax: + 43 5522 303 7533. E-mail address: [email protected] (H. Drexel). 0009-8981/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2011.02.008
Pathophysiologically, insulin resistance is considered the key feature of the MetS [15]. Indeed, insulin resistance is associated with all component features of the MetS [16–18]. In epidemiological studies insulin resistance typically is quantified by the HOMA index. Importantly, insulin resistance significantly predicts cardiovascular events in prospective studies [19,20]. In particular, we could previously show that HOMA insulin resistance and the MetS are mutually independent predictors of future cardiovascular events [15]. Thus, HOMA insulin resistance contains prognostic information over and above the clinical entity of the MetS [15]. Of note, however, the association of insulin resistance with directly visualized atherosclerosis is unclear. This is a clinically important issue, because visualization of atherosclerosis represents other features of atherothrombotic disease than the clinical cardiovascular event does. The clinical cardiovascular event is precipitated by the rupture of an atherosclerotic plaque and subsequent thrombotic vessel obliteration. Thus, both atherosclerotic and thrombotic processes are involved. Importantly, however, risk factors driving the progress of atherosclerosis are not identical to the risk factors
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enhancing thrombosis. For example, myocardial infarction, a frequently applied endpoint in clinical studies, does not optimally reflect the atherogenicity of metabolic parameters. It is the last step in the development of atherothrombotic coronary artery disease (CAD), and thrombogenic factors ultimately determine whether or not infarction occurs [21,22]. By coronary angiography, to the opposite, preferentially atherosclerosis is assessed. Therefore, in order to assess the atherogenicity of risk factors it appears important to also investigate their association with angiographically determined coronary atherosclerosis. We therefore determined HOMA insulin resistance in a large cohort of angiographically characterized coronary patients. We hypothesised that insulin resistance is associated with both angiographically determined CAD and with the MetS. 2. Materials and methods 2.1. Study subjects From August 2005 through December 2007 we enrolled 986 consecutive Caucasian patients who were referred to elective coronary angiography for the evaluation of established or suspected stable CAD. Patients undergoing coronary angiography for other reasons were not enrolled. In particular, no patients with acute coronary syndromes were enrolled, which appears important because acute coronary syndromes have the potential to transiently alter metabolic characteristics including lipid parameters and fasting glucose [23]. Six patients with type 1 diabetes and 49 patients with insulin therapy were excluded from the analyses. From our patients, 134 had previously undergone angioplasty and 51 had previously received coronary artery bypass grafts. Information on conventional cardiovascular risk factors was obtained by a standardized interview; and systolic/diastolic blood pressure was measured by the Riva–Rocci method under resting conditions in a sitting position at the day of hospital entry at least 5 h after hospitalization. Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [24], and type 2 diabetes mellitus (T2DM) was diagnosed according to World Health Organization criteria [25]. Height and weight were recorded, and body mass index (BMI) was calculated as body weight (kg)/height (m)2. Overall, 69.5% of our patients were on aspirin, 49.7% on statins, 1.4% on fibrates, 11.9% on calcium antagonists, 55.2% on beta adrenoreceptor blocking agents, 24.9% on diuretics, 35.4% on angiotensin converting enzyme inhibitors, and 18.7% on angiotensin II receptor blocking agents. Among patients with T2DM, 33.7%, 53.7%, 0.6%, and 3.4% were receiving – alone or in combination – sulfonylurea, metformin, acarbose, and glitazones, respectively. According to National Cholesterol Education Programme ATP-III criteria (NCEP-ATPIII) [26], the MetS was diagnosed in the presence of any three of: waist circumference N102 cm in men and N88 cm in women, triglycerides ≥150 mg/dl (1.7 mmol/l), high density lipoprotein (HDL) cholesterol b40 mg/dl (1.0 mmol/l) in men and b50 mg/dl (1.3 mmol/l) in women, blood pressure ≥130/≥85 mm Hg, or fasting glucose ≥ 100 mg/dl (5.6 mmol/l). Using International Diabetes Federation (IDF) criteria [27] , the MetS was diagnosed in patients who had a large waist circumference (≥94 cm in men and ≥80 cm in women) plus any two of: triglycerides ≥150 mg/dl (1.7 mmol/l) or specific treatment for this lipid abnormality, high density lipoprotein (HDL) cholesterol b40 mg/d (1.0 mmol/l) in males and b50 mg/dl (1.3 mmol/l) in females or specific treatment for this lipid abnormality, systolic blood pressure ≥ 130 or diastolic blood pressure ≥85 mm Hg or treatment of previously diagnosed hypertension, and fasting plasma glucose ≥100 mg/dl (5.6 mmol/l) or previously diagnosed T2DM.
Coronary angiography was performed with the Judkin's technique. Stenosis severity was assessed by visual inspection by a team of two investigators who were blinded to serologic assays. Coronary artery stenoses with lumen narrowing ≥50% were considered significant, the extent of CAD was defined as the number of significant coronary stenoses in a given patient, and coronary arteries were defined as normal in the absence of any visible lumen narrowing at angiography, as described previously [28]. The Ethics Committee of the University of Innsbruck approved the present study, and all participants gave written informed consent. 2.2. Laboratory analyses Venous blood samples were collected after an overnight fast of 12 h before angiography was performed, and laboratory measurements were performed from fresh serum samples, as described previously [29]. Serum triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol, HDL cholesterol, apolipoprotein B, apolipoprotein A1, CRP, and plasma glucose were determined on a Cobas Integra 800® (Roche, Basel, Switzerland). Hemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography on an ADAMS A1c HA-8160® (Menarini, Florenz, Italy). Plasma insulin was measured with a Roche Cobas E601® (Roche, Basel, Switzerland). HOMA index was calculated by the formula fasting insulin [μU/ml] × fasting glucose [mg/dl]/405 [30]. 2.3. Statistical analysis Differences in patient characteristics were tested for statistical significance with the Chi square test for categorical variables; the Mann–Whitney-U and Kruskal–Wallis tests were used for continuous variables, as appropriate. Spearmen rank correlation coefficients were calculated. To test for independent determinants of continuous variables, analysis of covariance (ANCOVA) was performed, using a general linear model approach. Results are given as mean ± standard deviation if not denoted otherwise. P-values b0.05 were considered significant. Sample size calculations showed that assuming a standard deviation of 1.5 times the population mean, 393 patients would be needed per study group to detect a between-group difference of HOMA insulin resistance scores of 20% with a power of 80% at an alpha-fault of 0.05. Statistical analyses were performed with the software package SPSS 11.0 for Windows (SPSS, Inc., Chicago, IL). 3. Results 3.1. Patient characteristics Overall, the characteristics of our study population were typical for a cohort undergoing coronary angiography for the evaluation of CAD, with a preponderance of male gender (64.6%), and a high prevalence of T2DM (19.4%), hypertension (80.8%), and smoking (59.2%). Overall, 330 (35.5%) of our patients had the MetS as defined by NCEP-ATP-III criteria, and in 510 patients (54.9%) coronary angiography revealed significant CAD with coronary stenoses ≥50%. From our patients, 280 had neither the MetS (ATP-III definition) nor significant CAD, 144 had the MetS, but not significant CAD, 304 did not have the MetS but had significant CAD, and 203 had both, the MetS and significant CAD. Table 1 summarizes characteristics of our patients in these four groups. 3.2. Insulin resistance in study groups HOMA insulin resistance scores were significantly higher in MetS patients than in subjects without the MetS (4.9 ± 6.4 vs. 2.2 ± 2.0; p b 0.001). In contrast, HOMA insulin resistance did not differ significantly between patients with significant CAD and those who
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Table 1 Patient characteristics in subgroups with respect to both the presence of coronary artery disease and of the metabolic syndrome.
Age (years) Male gender (%) BMI (kg/m²) Waist-to-hip ratio Waist circumference (m) Hypertension (%) Smoking (%) Type 2 Diabetes (%) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting glucose (mg/dl) Fasting insulin (μU/ml) Postchallenge glucose (mg/dl) HbA1c (%) Apolipoprotein A1 (mg/dl) Apolipoprotein B (mg/dl) CRP (mg/dl) Leukocytes (109/l) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Alcohol consumption (g/day)
CAD+/MetS + (203)
CAD+/MetS− (304)
CAD−/MetS + (144)
CAD−/MetS− (280)
p-value
64.7 ± 10 69.4 29.6 ± 4.0 1.0 ± 0.6 1.06 ± 0.10 87.0 70.8 44.0 193.0 ± 48 125.9 ± 40 47.5 ± 14 183.9 ± 103 124.4 ± 43 20.8 ± 61 173.1 ± 87 6.6 ± 1.0 141.4 ± 26 88.7 ± 25 0.48 ± 0.7 7.1 ± 1.8 138.6 ± 17 82.7 ± 11 30.9 ± 18
67.6 ± 10 78.0 26.1 ± 3.5 0.9 ± 0.6 0.94 ± 0.09 67.5 61.4 10.2 191.3 ± 45 123.6 ± 42 59.8 ± 15 113.6 ±72.6 97.5 ± 25 9.2 ± 6 124.3 ± 62 5.9 ± 0.7 155.9 ± 25 79.1 ± 22 0.42 ± 0.9 6.5 ± 1.8 134.7 ± 18 80.2 ± 9 28.1 ± 20
64.8 ± 10 43.7 31.3 ± 4.6 1.0 ± 0.6 1.07 ± 0.10 81.7 50.7 39.4 199 ± 49 131.2 ± 43 51.0 ± 14 188.2 ± 100 124.2 ± 49 16.3 ± 12 175.9 ± 90 6.5 ± 1.4 148.6 ± 26 90.0 ± 26 0.45 ± 0.5 7.1 ± 1.8 140.1 ± 16 84.1 ± 10 33.3 ± 23
63.5 ± 11 53.5 26.6 ± 4.1 0.9 ± 0.7 0.95 ± 0.12 56.8 52.4 4.1 200.5 ± 45 129.8 ± 39 64.7 ± 18 108 ± 62 92.8 ± 16 8.8 ± 6 107.3 ± 38 5.7 ± 0.5 163.9 ± 30 80.8 ± 21 0.37 ± 0.5 6.3 ± 1.8 133.0 ± 16 80.9 ± 9 30.7 ± 18
p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p = 0.032 p = 0.100 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p = 0.246
BMI denotes body mass index, LDL low density lipoprotein, HDL high density lipoprotein, and CAD coronary artery disease; postchallenge glucose is plasma glucose at 2 h after an oral 75 g glucose load. To convert values for fasting plasma glucose to mmol/l multiply by 0.0555, to convert values for triglycerides to mmol/l multiply by 0.0113 and to convert total cholesterol, LDL cholesterol, or HDL cholesterol to mmol/l multiply by 0.0259; p-values are given for the all overall difference between study groups.
did not have significant CAD (3.3 ± 4.6 vs. 3.0 ± 4.0; p = 0.221). When both, the presence of the MetS and of significant CAD were considered (Fig. 1), HOMA insulin resistance was significantly higher in patients with the MetS both among those who had significant CAD (4.9 ± 6.8 vs. 2.2 ± 1.8; p b 0.001) and among those who did not have significant CAD (5.0 ± 5.8 vs. 2.1 ± 2.3; p b 0.001) whereas it did not differ significantly between patients with significant CAD and subjects without significant CAD in patients with the MetS (4.9 ± 6.8 vs. 5.0 ± 5.8; p = 0.487) nor in those without the MetS (2.2 ± 1.8 vs. 2.1 ± 2.3; p = 0.198). Further, HOMA insulin resistance scores did not significantly differ between patients with coronary stenoses ≥70% and those without such lesions (3.4 ± 4.9 vs. 3.0 ± 3.8; p = 0.152) nor between patients with any CAD at angiography and those who did not have CAD at angiography (3.4 ± 4.6 vs. 3.2 ± 4.2; p = 0.605). In addition, HOMA insulin resistance scores did nor differ significantly between patients with one, two, or three vessel disease (3.4 ± 3.6; 3.9 ± 6.8; and 3.5 ±
3.4; p trend = 0.287), and there was no correlation between HOMA insulin resistance and the extent of CAD (r = 0.030; p = 0.361). 3.3. Associations of individual MetS components with HOMA Univariately, HOMA insulin resistance scores were significantly higher in patients who fulfilled the large waist (4.2 ± 5.6 vs. 2.5 ± 2.6; p b 0.001), the low HDL cholesterol (4.9 ± 4.7 vs. 3.1 ± 4.4; p b 0.001), the high blood pressure (3.5 ± 4.5 vs. 2.5 ± 4.3; p b 0.001), the high glucose (5.8 ± 6.7 vs. 2.1 ± 1.7; p b 0.001) or the high triglycerides criteria (4.6 ± 6.6 vs. 3.5 ± 3.1; p b 0.001) when compared to patients who did not fulfill the respective MetS criteria. 3.4. Results of multivariate analyses In line with our univariate results, analysis of covariance (ANCOVA) adjusting for age, gender, smoking, LDL cholesterol, and alcohol consumption showed that HOMA insulin resistance was significantly associated with the MetS as diagnosed by ATP-III criteria (F= 6.7; p = 0.010) but not with significant CAD (F= 0.84; p = 0.358). Further, in line with the results from univariate analyses, a logistic regression model controlling for age, gender, smoking, LDL cholesterol, alcohol consumption, and, additionally, for the MetS did not show an association of insulin resistance with significant CAD independent of the presence of the metabolic syndrome (standardized adjusted odds ratio (OR)= 1.01 [0.97–1.04]; p = 0.843). When all 5 MetS traits were forced into one ANCOVA model, HOMA insulin resistance remained significantly associated with the clinical entity of the MetS even after adjustment for its single stigmata (F= 85.1; p b 0.001). 3.5. Gender subgroups
Fig. 1. HOMA insulin resistance scores in subgroups with respect to both the presence of coronary artery disease and of the metabolic syndrome. Graphs show mean values together with standard deviations. CAD denotes coronary artery disease; MetS metabolic syndrome. HOMA homeostasis model assessment.
In subgroup analyses with respect to gender the results were concordant with those from the total study group: HOMA insulin resistance scores were significantly higher in female MetS patients than in female subjects without the MetS (4.4 ± 4.6 vs. 1.8 ± 1.1; p b 0.001). In contrast, HOMA insulin resistance did not differ significantly between female patients with significant CAD and those who did not have significant CAD (2.9± 3.3 vs. 2.7 ± 3.0; p = 0.906). Similarly, HOMA
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insulin resistance scores were significantly higher in male MetS patients than in men without the MetS (6.4± 5.8 vs. 2.3 ± 2.2; p b 0.001) but were not significantly different between men with significant CAD and men without significant CAD (4.3± 4.1 vs. 3.2 ± 3.1; p = 0.139). 3.6. Exclusion of patients without T2DM In a further subgroup analysis, we excluded subjects with T2DM. HOMA insulin resistance scores were significantly higher in patients with MetS than in subjects without MetS among non-diabetic subjects (3.7 ± 3.2 vs. 1.9 ± 1.3; p b 0.001) but were again not significantly different between the patients with significant CAD and those without significant CAD (2.5 ± 2.3 vs. 2.4 ± 2.0; p = 0.757). 3.7. IDF definition of the MetS The prevalence of the MetS according to the IDF definition was 40.4%. Considering both the IDF MetS and the presence of significant CAD, 265 patients had neither the IDF MetS nor significant CAD, 155 had the MetS, but not significant CAD, 289 did not have the MetS but had significant CAD, and 222 had both, the MetS according to IDF criteria and significant CAD. As with the ATP-III definition of the MetS, HOMA insulin resistance was significantly higher in patients with the IDF MetS than in subjects who did not have the IDF MetS in the total study population (4.6 ± 4.3 vs. 2.4 ± 3.1; p b 0.001) and both in the subgroup of subjects without significant CAD (4.9 ± 4.4 vs. 2.3 ± 2.0, p b 0.001) and among patients with significant CAD (4.2 ± 4.1 vs. 2.6 ± 3.9; p b 0.001), whereas HOMA insulin resistance did not differ significantly between patients with significant CAD and those without significant CAD both among subjects without the IDF MetS (p = 0.270) and among patients who had the MetS according to IDF criteria (p = 0.784). 4. Discussion From our results we conclude that insulin resistance as assed by the HOMA index is significantly associated with the MetS but is not directly linked with angiographically determined coronary atherosclerosis. Insulin resistance may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis. Insulin resistance pathophysiologically is the key feature of the MetS, and correlations between HOMA insulin resistance and the MetS as a clinical entity have been described in numerous previous investigations [16,17,31]. Further to the results of these studies and the various studies which showed an association between MetS and CAD [32–34] we demonstrate the association of insulin resistance with the clinical entity of the metabolic syndrome and with the individual metabolic syndrome stigmata among coronary patients, a population of a particular clinical interest. An important and somewhat surprising finding of our investigation is that insulin resistance is not associated with coronary atherosclerosis. Hardly any data are available from the literature on the association between insulin resistance and the coronary angiographic state. Existing studies were not sufficiently powered and yielded conflicting results [35–40]. Our study, however, was adequately powered to firmly support also a negative finding. Thus, our investigation for the first time firmly establishes that there is no association between insulin resistance and angiographically visualized coronary atherosclerosis. This is a pathophysiologically important finding because prospective studies in an apparent contradiction to our angiographic study showed that insulin resistance is a significant predictor of clinical cardiovascular events. In this context it is important to consider that the direct visualization of atherosclerosis may reflect other features of the development of atherothrombotic disease than clinical cardio-
vascular events. Whereas the clinical cardiovascular event is precipitated by thrombosis (and therefore strongly represents the effect of thrombogenic stimuli), directly visualized atherosclerosis rather resembles atherogenesis [28]. This may suggest that insulin resistance is rather associated with atherothrombosis than with the process of atherosclerosis itself. The essential strength of our study is direct visualization of coronary atherosclerosis by means of coronary angiography. Further strengths are the large sample size (indeed, this is the first investigation which was adequately powered to address the association between HOMA insulin resistance and the coronary angiographic state) and the meticulous acquisition of patient data. By design, we investigated patients undergoing coronary angiography for the evaluation of stable CAD. This of course is a specific patient population, the results from which are not necessarily generalizable to other populations, e.g. in the primary prevention setting. However, the population we chose to investigate is clinically important, because coronary angiography in current clinical practice, is the gold standard for the evaluation of CAD in high risk patients [41]. We acknowledge the limitations that our investigation is a single center study and that angiograms were evaluated at only one time-point. From our cross-sectional data the causality of relationships between parameters cannot be proven, and a future study longitudinally addressing the association of insulin resistance with the progression of angiographically characterized CAD of course would be of interest. Further, there are limitations of the HOMA technique to measure insulin resistance. The HOMA index on the one hand is a firmly established measure of insulin resistance which is typically applied in large scale epidemiological studies and therefore guarantees the comparability of our study results to the data from the literature. However, on the other hand it is seldom used for clinical decision making and, more importantly, it should be considered that HOMA insulin resistance scores like all established markers of insulin resistance are based on the estimation of insulin effects on glucose metabolism which of course do not optimally reflect the much broader metabolic consequences of insulin resistance, e.g. in lipid metabolism. Future research aiming at the investigation of insulin resistance over and above the insulin-glucose axis would be very interesting in epidemiological studies. Markers reflecting these aspects of insulin resistance might be of great interest as indicators of cardiovascular risk. Whatever, with respect to HOMA insulin resistance, our study clearly shows a lack of association between insulin resistance and angiographically determined coronary atherosclerosis. References [1] Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000;152:897–907. [2] Meigs JB. Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 2000;152:908–11. [3] Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607. [4] Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [5] Hu G, Qiao Q, Tuomilehto J. The metabolic syndrome and cardiovascular risk. Curr Diab Rev 2005;1:137–43. [6] Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16. [7] Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diab Care 2001;24:683–9. [8] Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391–7. [9] Arca M. Atorvastatin efficacy in the prevention of cardiovascular events in patients with diabetes mellitus and/or metabolic syndrome. Drugs 2007;67(Suppl 1): 43–54. [10] Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16.
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[27] The IDF consensus worldwide definition of the metabolic syndrome [article online]. Available from http://www.idf.org/webdata/docs/metac_syndrome_def. pdf 2005. [28] Drexel H, Amann FW, Beran J, et al. Plasma triglycerides and three lipoprotein cholesterol fractions are independent predictors of the extent of coronary atherosclerosis. Circulation 1994;90:2230–5. [29] Saely CH, Koch L, Schmid F, et al. Lipoprotein(a), type 2 diabetes and vascular risk in coronary patients. Eur J Clin Investig 2006;36:91–7. [30] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28: 412–9. [31] Hanley AJ, Karter AJ, Festa A, et al. Factor analysis of metabolic syndrome using directly measured insulin sensitivity: the Insulin Resistance Atherosclerosis study. Diabetes 2002;51:2642–7. [32] Solymoss BC, Bourassa MG, Campeau L, et al. Effect of increasing metabolic syndrome score on atherosclerotic risk profile and coronary artery disease angiographic severity. Am J Cardiol 2004;93:159–64. [33] Yavuz MT, Yavuz O, Yazici M, et al. Interaction between Chlamydia pneumoniae seropositivity, inflammation and risk factors for atherosclerosis in patients with severe coronary stenosis. Scand J Clin Lab Investig 2006;66:523–34. [34] Kasai T, Miyauchi K, Kubota N, et al. The relationship between the metabolic syndrome defined by various criteria and the extent of coronary artery disease. Atherosclerosis 2008;197:944–50. [35] Takezako T, Saku K, Zhang B, Shirai K, Arakawa K. Insulin resistance and angiographical characteristics of coronary atherosclerosis. Jpn Circ J 1999;63: 666–73. [36] Sekiguchi M, Kurabayashi M, Adachi H, Hoshizaki H, Oshima S, Taniguchi K. Usefulness of insulin resistance measured by homeostasis model assessment in predicting restenosis after coronary stent placement in nondiabetic patients. Am J Cardiol 2004;93:920–2. [37] Shinozaki K, Suzuki M, Ikebuchi M, Hara Y, Harano Y. Demonstration of insulin resistance in coronary artery disease documented with angiography. Diab Care 1996;19:1–7. [38] Graner M, Syvanne M, Kahri J, Nieminen MS, Taskinen MR. Insulin resistance as predictor of the angiographic severity and extent of coronary artery disease. Ann Med 2007;39:137–44. [39] Radke PW, Voswinkel M, Reith M, et al. Relation of fasting insulin plasma levels to restenosis after elective coronary stent implantation in patients without diabetes mellitus. Am J Cardiol 2004;93:639–41. [40] Ley CJ, Swan J, Godsland IF, Walton C, Crook D, Stevenson JC. Insulin resistance, lipoproteins, body fat and hemostasis in nonobese men with angina and a normal or abnormal coronary angiogram. J Am Coll Cardiol 1994;23:377–83. [41] Galassi AR, Tamburino C. Follow-up of patients undergoing percutaneous coronary intervention. Ital Heart J 2005;6:530–9.
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Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
Insulin resistance is associated with the metabolic syndrome and is not directly linked to coronary artery disease Alexander Vonbank a,b,c, Christoph H. Saely a,b,c, Philipp Rein a,b,c, Stefan Beer a,b,c, Johannes Breuss a,c, Christian Boehnel a,c, Heinz Drexel a,b,c,d,⁎ a
Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria Private University of the Principality of Liechtenstein, Triesen, Liechtenstein d Drexel University College of Medicine, Philadelphia, PA, USA b c
a r t i c l e
i n f o
Article history: Received 4 September 2010 Received in revised form 5 February 2011 Accepted 5 February 2011 Available online 12 February 2011 Keywords: Insulin resistance HOMA index Metabolic syndrome Coronary artery disease Coronary atherosclerosis Coronary angiography Atherothrombosis
a b s t r a c t Background: Insulin resistance (IR) is the key feature of the metabolic syndrome (MetS). Its association with directly visualized coronary atherosclerosis is unclear. We hypothesised that insulin resistance is associated with both angiographically determined coronary artery disease (CAD) and with the MetS. Methods: In 986 consecutive patients undergoing coronary angiography for the evaluation CAD, IR was determined by the HOMA index; the MetS was defined according to NCEP-ATPIII criteria; and significant CAD was diagnosed when coronary stenoses ≥50% were present. Results: HOMA IR scores were higher in MetS patients than in subjects without the MetS (4.9 ± 6.4 vs. 2.2 ± 2.0; p b 0.001). HOMA IR did not differ significantly between patients with significant CAD and those who did not have significant CAD. When both, the presence of MetS and of significant CAD were considered, HOMA IR was significantly higher in patients with the MetS both among those who had significant CAD (4.9 ± 6.8 vs. 2.2 ± 1.8; p b 0.001) and among those who did not have significant CAD (5.0 ± 5.8 vs. 2.1 ± 2.3; p b 0.001), it did not differ significantly between patients with significant CAD and subjects without significant CAD among patients with the MetS nor among those without MetS. Similar results were obtained with the IDF definition of the MetS. Conclusion: IR is significantly associated with the MetS but not with angiographically determined CAD. IR may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Overweight and obesity have risen dramatically in the past several decades. This resulted in a marked increase in the prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular risk factors including central adiposity, hypertension, dyslipidemia and impaired glucose metabolism [1–3]. According to Adult Treatment Panel III criteria (ATP III) [4] the MetS is diagnosed in the presence of at least 3 out of the 5 criteria: abdominal obesity, high triglycerides, low HDL cholesterol, elevated fasting glucose and high blood pressure. The such diagnosed MetS, as a clinical entity, substantially increases the risk of cardiovascular events both in the primary [5–8] and in the secondary [9] prevention settings [7,10–14]. In particular, the MetS confers an increased risk of premature coronary artery disease.
⁎ Corresponding author at: VIVIT Institute, Feldkirch, Carinagasse 47, A-6807 Feldkirch, Austria. Tel.: + 43 5522 303 2670; fax: + 43 5522 303 7533. E-mail address: [email protected] (H. Drexel). 0009-8981/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2011.02.008
Pathophysiologically, insulin resistance is considered the key feature of the MetS [15]. Indeed, insulin resistance is associated with all component features of the MetS [16–18]. In epidemiological studies insulin resistance typically is quantified by the HOMA index. Importantly, insulin resistance significantly predicts cardiovascular events in prospective studies [19,20]. In particular, we could previously show that HOMA insulin resistance and the MetS are mutually independent predictors of future cardiovascular events [15]. Thus, HOMA insulin resistance contains prognostic information over and above the clinical entity of the MetS [15]. Of note, however, the association of insulin resistance with directly visualized atherosclerosis is unclear. This is a clinically important issue, because visualization of atherosclerosis represents other features of atherothrombotic disease than the clinical cardiovascular event does. The clinical cardiovascular event is precipitated by the rupture of an atherosclerotic plaque and subsequent thrombotic vessel obliteration. Thus, both atherosclerotic and thrombotic processes are involved. Importantly, however, risk factors driving the progress of atherosclerosis are not identical to the risk factors
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enhancing thrombosis. For example, myocardial infarction, a frequently applied endpoint in clinical studies, does not optimally reflect the atherogenicity of metabolic parameters. It is the last step in the development of atherothrombotic coronary artery disease (CAD), and thrombogenic factors ultimately determine whether or not infarction occurs [21,22]. By coronary angiography, to the opposite, preferentially atherosclerosis is assessed. Therefore, in order to assess the atherogenicity of risk factors it appears important to also investigate their association with angiographically determined coronary atherosclerosis. We therefore determined HOMA insulin resistance in a large cohort of angiographically characterized coronary patients. We hypothesised that insulin resistance is associated with both angiographically determined CAD and with the MetS. 2. Materials and methods 2.1. Study subjects From August 2005 through December 2007 we enrolled 986 consecutive Caucasian patients who were referred to elective coronary angiography for the evaluation of established or suspected stable CAD. Patients undergoing coronary angiography for other reasons were not enrolled. In particular, no patients with acute coronary syndromes were enrolled, which appears important because acute coronary syndromes have the potential to transiently alter metabolic characteristics including lipid parameters and fasting glucose [23]. Six patients with type 1 diabetes and 49 patients with insulin therapy were excluded from the analyses. From our patients, 134 had previously undergone angioplasty and 51 had previously received coronary artery bypass grafts. Information on conventional cardiovascular risk factors was obtained by a standardized interview; and systolic/diastolic blood pressure was measured by the Riva–Rocci method under resting conditions in a sitting position at the day of hospital entry at least 5 h after hospitalization. Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [24], and type 2 diabetes mellitus (T2DM) was diagnosed according to World Health Organization criteria [25]. Height and weight were recorded, and body mass index (BMI) was calculated as body weight (kg)/height (m)2. Overall, 69.5% of our patients were on aspirin, 49.7% on statins, 1.4% on fibrates, 11.9% on calcium antagonists, 55.2% on beta adrenoreceptor blocking agents, 24.9% on diuretics, 35.4% on angiotensin converting enzyme inhibitors, and 18.7% on angiotensin II receptor blocking agents. Among patients with T2DM, 33.7%, 53.7%, 0.6%, and 3.4% were receiving – alone or in combination – sulfonylurea, metformin, acarbose, and glitazones, respectively. According to National Cholesterol Education Programme ATP-III criteria (NCEP-ATPIII) [26], the MetS was diagnosed in the presence of any three of: waist circumference N102 cm in men and N88 cm in women, triglycerides ≥150 mg/dl (1.7 mmol/l), high density lipoprotein (HDL) cholesterol b40 mg/dl (1.0 mmol/l) in men and b50 mg/dl (1.3 mmol/l) in women, blood pressure ≥130/≥85 mm Hg, or fasting glucose ≥ 100 mg/dl (5.6 mmol/l). Using International Diabetes Federation (IDF) criteria [27] , the MetS was diagnosed in patients who had a large waist circumference (≥94 cm in men and ≥80 cm in women) plus any two of: triglycerides ≥150 mg/dl (1.7 mmol/l) or specific treatment for this lipid abnormality, high density lipoprotein (HDL) cholesterol b40 mg/d (1.0 mmol/l) in males and b50 mg/dl (1.3 mmol/l) in females or specific treatment for this lipid abnormality, systolic blood pressure ≥ 130 or diastolic blood pressure ≥85 mm Hg or treatment of previously diagnosed hypertension, and fasting plasma glucose ≥100 mg/dl (5.6 mmol/l) or previously diagnosed T2DM.
Coronary angiography was performed with the Judkin's technique. Stenosis severity was assessed by visual inspection by a team of two investigators who were blinded to serologic assays. Coronary artery stenoses with lumen narrowing ≥50% were considered significant, the extent of CAD was defined as the number of significant coronary stenoses in a given patient, and coronary arteries were defined as normal in the absence of any visible lumen narrowing at angiography, as described previously [28]. The Ethics Committee of the University of Innsbruck approved the present study, and all participants gave written informed consent. 2.2. Laboratory analyses Venous blood samples were collected after an overnight fast of 12 h before angiography was performed, and laboratory measurements were performed from fresh serum samples, as described previously [29]. Serum triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol, HDL cholesterol, apolipoprotein B, apolipoprotein A1, CRP, and plasma glucose were determined on a Cobas Integra 800® (Roche, Basel, Switzerland). Hemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography on an ADAMS A1c HA-8160® (Menarini, Florenz, Italy). Plasma insulin was measured with a Roche Cobas E601® (Roche, Basel, Switzerland). HOMA index was calculated by the formula fasting insulin [μU/ml] × fasting glucose [mg/dl]/405 [30]. 2.3. Statistical analysis Differences in patient characteristics were tested for statistical significance with the Chi square test for categorical variables; the Mann–Whitney-U and Kruskal–Wallis tests were used for continuous variables, as appropriate. Spearmen rank correlation coefficients were calculated. To test for independent determinants of continuous variables, analysis of covariance (ANCOVA) was performed, using a general linear model approach. Results are given as mean ± standard deviation if not denoted otherwise. P-values b0.05 were considered significant. Sample size calculations showed that assuming a standard deviation of 1.5 times the population mean, 393 patients would be needed per study group to detect a between-group difference of HOMA insulin resistance scores of 20% with a power of 80% at an alpha-fault of 0.05. Statistical analyses were performed with the software package SPSS 11.0 for Windows (SPSS, Inc., Chicago, IL). 3. Results 3.1. Patient characteristics Overall, the characteristics of our study population were typical for a cohort undergoing coronary angiography for the evaluation of CAD, with a preponderance of male gender (64.6%), and a high prevalence of T2DM (19.4%), hypertension (80.8%), and smoking (59.2%). Overall, 330 (35.5%) of our patients had the MetS as defined by NCEP-ATP-III criteria, and in 510 patients (54.9%) coronary angiography revealed significant CAD with coronary stenoses ≥50%. From our patients, 280 had neither the MetS (ATP-III definition) nor significant CAD, 144 had the MetS, but not significant CAD, 304 did not have the MetS but had significant CAD, and 203 had both, the MetS and significant CAD. Table 1 summarizes characteristics of our patients in these four groups. 3.2. Insulin resistance in study groups HOMA insulin resistance scores were significantly higher in MetS patients than in subjects without the MetS (4.9 ± 6.4 vs. 2.2 ± 2.0; p b 0.001). In contrast, HOMA insulin resistance did not differ significantly between patients with significant CAD and those who
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Table 1 Patient characteristics in subgroups with respect to both the presence of coronary artery disease and of the metabolic syndrome.
Age (years) Male gender (%) BMI (kg/m²) Waist-to-hip ratio Waist circumference (m) Hypertension (%) Smoking (%) Type 2 Diabetes (%) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting glucose (mg/dl) Fasting insulin (μU/ml) Postchallenge glucose (mg/dl) HbA1c (%) Apolipoprotein A1 (mg/dl) Apolipoprotein B (mg/dl) CRP (mg/dl) Leukocytes (109/l) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Alcohol consumption (g/day)
CAD+/MetS + (203)
CAD+/MetS− (304)
CAD−/MetS + (144)
CAD−/MetS− (280)
p-value
64.7 ± 10 69.4 29.6 ± 4.0 1.0 ± 0.6 1.06 ± 0.10 87.0 70.8 44.0 193.0 ± 48 125.9 ± 40 47.5 ± 14 183.9 ± 103 124.4 ± 43 20.8 ± 61 173.1 ± 87 6.6 ± 1.0 141.4 ± 26 88.7 ± 25 0.48 ± 0.7 7.1 ± 1.8 138.6 ± 17 82.7 ± 11 30.9 ± 18
67.6 ± 10 78.0 26.1 ± 3.5 0.9 ± 0.6 0.94 ± 0.09 67.5 61.4 10.2 191.3 ± 45 123.6 ± 42 59.8 ± 15 113.6 ±72.6 97.5 ± 25 9.2 ± 6 124.3 ± 62 5.9 ± 0.7 155.9 ± 25 79.1 ± 22 0.42 ± 0.9 6.5 ± 1.8 134.7 ± 18 80.2 ± 9 28.1 ± 20
64.8 ± 10 43.7 31.3 ± 4.6 1.0 ± 0.6 1.07 ± 0.10 81.7 50.7 39.4 199 ± 49 131.2 ± 43 51.0 ± 14 188.2 ± 100 124.2 ± 49 16.3 ± 12 175.9 ± 90 6.5 ± 1.4 148.6 ± 26 90.0 ± 26 0.45 ± 0.5 7.1 ± 1.8 140.1 ± 16 84.1 ± 10 33.3 ± 23
63.5 ± 11 53.5 26.6 ± 4.1 0.9 ± 0.7 0.95 ± 0.12 56.8 52.4 4.1 200.5 ± 45 129.8 ± 39 64.7 ± 18 108 ± 62 92.8 ± 16 8.8 ± 6 107.3 ± 38 5.7 ± 0.5 163.9 ± 30 80.8 ± 21 0.37 ± 0.5 6.3 ± 1.8 133.0 ± 16 80.9 ± 9 30.7 ± 18
p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p = 0.032 p = 0.100 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p b 0.001 p = 0.246
BMI denotes body mass index, LDL low density lipoprotein, HDL high density lipoprotein, and CAD coronary artery disease; postchallenge glucose is plasma glucose at 2 h after an oral 75 g glucose load. To convert values for fasting plasma glucose to mmol/l multiply by 0.0555, to convert values for triglycerides to mmol/l multiply by 0.0113 and to convert total cholesterol, LDL cholesterol, or HDL cholesterol to mmol/l multiply by 0.0259; p-values are given for the all overall difference between study groups.
did not have significant CAD (3.3 ± 4.6 vs. 3.0 ± 4.0; p = 0.221). When both, the presence of the MetS and of significant CAD were considered (Fig. 1), HOMA insulin resistance was significantly higher in patients with the MetS both among those who had significant CAD (4.9 ± 6.8 vs. 2.2 ± 1.8; p b 0.001) and among those who did not have significant CAD (5.0 ± 5.8 vs. 2.1 ± 2.3; p b 0.001) whereas it did not differ significantly between patients with significant CAD and subjects without significant CAD in patients with the MetS (4.9 ± 6.8 vs. 5.0 ± 5.8; p = 0.487) nor in those without the MetS (2.2 ± 1.8 vs. 2.1 ± 2.3; p = 0.198). Further, HOMA insulin resistance scores did not significantly differ between patients with coronary stenoses ≥70% and those without such lesions (3.4 ± 4.9 vs. 3.0 ± 3.8; p = 0.152) nor between patients with any CAD at angiography and those who did not have CAD at angiography (3.4 ± 4.6 vs. 3.2 ± 4.2; p = 0.605). In addition, HOMA insulin resistance scores did nor differ significantly between patients with one, two, or three vessel disease (3.4 ± 3.6; 3.9 ± 6.8; and 3.5 ±
3.4; p trend = 0.287), and there was no correlation between HOMA insulin resistance and the extent of CAD (r = 0.030; p = 0.361). 3.3. Associations of individual MetS components with HOMA Univariately, HOMA insulin resistance scores were significantly higher in patients who fulfilled the large waist (4.2 ± 5.6 vs. 2.5 ± 2.6; p b 0.001), the low HDL cholesterol (4.9 ± 4.7 vs. 3.1 ± 4.4; p b 0.001), the high blood pressure (3.5 ± 4.5 vs. 2.5 ± 4.3; p b 0.001), the high glucose (5.8 ± 6.7 vs. 2.1 ± 1.7; p b 0.001) or the high triglycerides criteria (4.6 ± 6.6 vs. 3.5 ± 3.1; p b 0.001) when compared to patients who did not fulfill the respective MetS criteria. 3.4. Results of multivariate analyses In line with our univariate results, analysis of covariance (ANCOVA) adjusting for age, gender, smoking, LDL cholesterol, and alcohol consumption showed that HOMA insulin resistance was significantly associated with the MetS as diagnosed by ATP-III criteria (F= 6.7; p = 0.010) but not with significant CAD (F= 0.84; p = 0.358). Further, in line with the results from univariate analyses, a logistic regression model controlling for age, gender, smoking, LDL cholesterol, alcohol consumption, and, additionally, for the MetS did not show an association of insulin resistance with significant CAD independent of the presence of the metabolic syndrome (standardized adjusted odds ratio (OR)= 1.01 [0.97–1.04]; p = 0.843). When all 5 MetS traits were forced into one ANCOVA model, HOMA insulin resistance remained significantly associated with the clinical entity of the MetS even after adjustment for its single stigmata (F= 85.1; p b 0.001). 3.5. Gender subgroups
Fig. 1. HOMA insulin resistance scores in subgroups with respect to both the presence of coronary artery disease and of the metabolic syndrome. Graphs show mean values together with standard deviations. CAD denotes coronary artery disease; MetS metabolic syndrome. HOMA homeostasis model assessment.
In subgroup analyses with respect to gender the results were concordant with those from the total study group: HOMA insulin resistance scores were significantly higher in female MetS patients than in female subjects without the MetS (4.4 ± 4.6 vs. 1.8 ± 1.1; p b 0.001). In contrast, HOMA insulin resistance did not differ significantly between female patients with significant CAD and those who did not have significant CAD (2.9± 3.3 vs. 2.7 ± 3.0; p = 0.906). Similarly, HOMA
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insulin resistance scores were significantly higher in male MetS patients than in men without the MetS (6.4± 5.8 vs. 2.3 ± 2.2; p b 0.001) but were not significantly different between men with significant CAD and men without significant CAD (4.3± 4.1 vs. 3.2 ± 3.1; p = 0.139). 3.6. Exclusion of patients without T2DM In a further subgroup analysis, we excluded subjects with T2DM. HOMA insulin resistance scores were significantly higher in patients with MetS than in subjects without MetS among non-diabetic subjects (3.7 ± 3.2 vs. 1.9 ± 1.3; p b 0.001) but were again not significantly different between the patients with significant CAD and those without significant CAD (2.5 ± 2.3 vs. 2.4 ± 2.0; p = 0.757). 3.7. IDF definition of the MetS The prevalence of the MetS according to the IDF definition was 40.4%. Considering both the IDF MetS and the presence of significant CAD, 265 patients had neither the IDF MetS nor significant CAD, 155 had the MetS, but not significant CAD, 289 did not have the MetS but had significant CAD, and 222 had both, the MetS according to IDF criteria and significant CAD. As with the ATP-III definition of the MetS, HOMA insulin resistance was significantly higher in patients with the IDF MetS than in subjects who did not have the IDF MetS in the total study population (4.6 ± 4.3 vs. 2.4 ± 3.1; p b 0.001) and both in the subgroup of subjects without significant CAD (4.9 ± 4.4 vs. 2.3 ± 2.0, p b 0.001) and among patients with significant CAD (4.2 ± 4.1 vs. 2.6 ± 3.9; p b 0.001), whereas HOMA insulin resistance did not differ significantly between patients with significant CAD and those without significant CAD both among subjects without the IDF MetS (p = 0.270) and among patients who had the MetS according to IDF criteria (p = 0.784). 4. Discussion From our results we conclude that insulin resistance as assed by the HOMA index is significantly associated with the MetS but is not directly linked with angiographically determined coronary atherosclerosis. Insulin resistance may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis. Insulin resistance pathophysiologically is the key feature of the MetS, and correlations between HOMA insulin resistance and the MetS as a clinical entity have been described in numerous previous investigations [16,17,31]. Further to the results of these studies and the various studies which showed an association between MetS and CAD [32–34] we demonstrate the association of insulin resistance with the clinical entity of the metabolic syndrome and with the individual metabolic syndrome stigmata among coronary patients, a population of a particular clinical interest. An important and somewhat surprising finding of our investigation is that insulin resistance is not associated with coronary atherosclerosis. Hardly any data are available from the literature on the association between insulin resistance and the coronary angiographic state. Existing studies were not sufficiently powered and yielded conflicting results [35–40]. Our study, however, was adequately powered to firmly support also a negative finding. Thus, our investigation for the first time firmly establishes that there is no association between insulin resistance and angiographically visualized coronary atherosclerosis. This is a pathophysiologically important finding because prospective studies in an apparent contradiction to our angiographic study showed that insulin resistance is a significant predictor of clinical cardiovascular events. In this context it is important to consider that the direct visualization of atherosclerosis may reflect other features of the development of atherothrombotic disease than clinical cardio-
vascular events. Whereas the clinical cardiovascular event is precipitated by thrombosis (and therefore strongly represents the effect of thrombogenic stimuli), directly visualized atherosclerosis rather resembles atherogenesis [28]. This may suggest that insulin resistance is rather associated with atherothrombosis than with the process of atherosclerosis itself. The essential strength of our study is direct visualization of coronary atherosclerosis by means of coronary angiography. Further strengths are the large sample size (indeed, this is the first investigation which was adequately powered to address the association between HOMA insulin resistance and the coronary angiographic state) and the meticulous acquisition of patient data. By design, we investigated patients undergoing coronary angiography for the evaluation of stable CAD. This of course is a specific patient population, the results from which are not necessarily generalizable to other populations, e.g. in the primary prevention setting. However, the population we chose to investigate is clinically important, because coronary angiography in current clinical practice, is the gold standard for the evaluation of CAD in high risk patients [41]. We acknowledge the limitations that our investigation is a single center study and that angiograms were evaluated at only one time-point. From our cross-sectional data the causality of relationships between parameters cannot be proven, and a future study longitudinally addressing the association of insulin resistance with the progression of angiographically characterized CAD of course would be of interest. Further, there are limitations of the HOMA technique to measure insulin resistance. The HOMA index on the one hand is a firmly established measure of insulin resistance which is typically applied in large scale epidemiological studies and therefore guarantees the comparability of our study results to the data from the literature. However, on the other hand it is seldom used for clinical decision making and, more importantly, it should be considered that HOMA insulin resistance scores like all established markers of insulin resistance are based on the estimation of insulin effects on glucose metabolism which of course do not optimally reflect the much broader metabolic consequences of insulin resistance, e.g. in lipid metabolism. Future research aiming at the investigation of insulin resistance over and above the insulin-glucose axis would be very interesting in epidemiological studies. Markers reflecting these aspects of insulin resistance might be of great interest as indicators of cardiovascular risk. Whatever, with respect to HOMA insulin resistance, our study clearly shows a lack of association between insulin resistance and angiographically determined coronary atherosclerosis. References [1] Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000;152:897–907. [2] Meigs JB. Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 2000;152:908–11. [3] Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607. [4] Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [5] Hu G, Qiao Q, Tuomilehto J. The metabolic syndrome and cardiovascular risk. Curr Diab Rev 2005;1:137–43. [6] Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16. [7] Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diab Care 2001;24:683–9. [8] Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391–7. [9] Arca M. Atorvastatin efficacy in the prevention of cardiovascular events in patients with diabetes mellitus and/or metabolic syndrome. Drugs 2007;67(Suppl 1): 43–54. [10] Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16.
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