Insulin resistance and triglyceride/HDLc index are associated with coronary artery disease
- Marcello C Bertoluci†1,
- Alexandre S Quadros†2,
- Rogério Sarmento-Leite†2 and
- Beatriz D Schaan†2, 3Email author
© Bertoluci et al; licensee BioMed Central Ltd. 2010
Received: 11 November 2009
Accepted: 3 February 2010
Published: 3 February 2010
Insulin-resistance is associated with cardiovascular disease but it is not used as a marker for disease in clinical practice.
To study the association between the homeostatic model assessment (HOMA-IR) and triglyceride/HDLc ratio (TG/HDLc) with the presence of coronary artery disease in patients submitted to cardiac catheterization.
In a cross-sectional study, 131 patients (57.0 ± 10 years-old, 51.5% men) underwent clinical, laboratory and angiographic evaluation and were classified as No CAD (absence of coronary artery disease) or CAD (stenosis of more than 30% in at least one major coronary artery).
Prevalence of coronary artery disease was 56.7%. HOMA-IR and TG/HDLc index were higher in the CAD vs No CAD group, respectively: HOMA-IR: 3.19 (1.70-5.62) vs. 2.33 (1.44-4.06), p = 0.015 and TG/HDLc: 3.20 (2.38-5.59) vs. 2.80 (1.98-4.59) p = 0.045) - median (p25-75). After a ROC curve analysis, cut-off values were selected based on the best positive predictive value for each variable: HOMA-IR = 6.0, TG/HDLc = 8.5 and [HOMA-IR×TG/HDLc] = 28. Positive predictive value for coronary artery disease for HOMA-IR>6.0 was 82.6%, for TG/HDLc>8.5 was 85.7% and for [HOMA-IR×TG/HDLc]>28 was 88.0%. Adjusted relative risk (age, gender, diabetes, body mass index, systolic blood pressure) for the presence of coronary artery disease was: for HOMA-IR>6.0, 1.47 (95.CI: 1.06-2.04, p = 0.027), for TG/HDLc>8.5, 1.46 (95% CI:1.07-1.98), p = 0.015) and for [HOMA-IR × TG/HDLc] >28, 1.64 (95%CI: 1.28-2.09), p < 0.001).
Increased HOMA-IR, TG/HDLc and their product are positively associated with angiographic coronary artery disease, and may be useful for risk stratification as a high-specificity test for coronary artery disease.
Insulin resistance is associated with cardiovascular disease . Possible mechanisms include induction of pro-inflammatory and pro-coagulant states which are detrimental to endothelial function and may play an important role in mediating atherogenesis .
Homeostatic model assessment of insulin resistance (HOMA-IR) has emerged as a practical and simple method for estimating insulin resistance. This index was extensively validated in comparison with the gold-standard method for the evaluation of insulin resistance, the hyperinsulinemic euglycemic glucose clamp technique . While this method is currently not routinely used as a cardiovascular risk marker, we hypothesized that it could be potentially useful since hyperglycemia and hyperinsulinemia are both related to cardiovascular disease. Also, since triglycerides and HDL are independent predictors of cardiovascular risk , their ratio could be used as a simple cardiovascular risk marker.
The aim of the present study was to study the association between HOMA-IR and the triglyceride/HDLc ratio with the presence of coronary artery disease in patients who were submitted to coronary angiography and to define the best cut-off values for clinical practical use.
This was a cross-sectional study with patients referred for coronary angiography at a reference center for interventional cardiology. Between December 2002 and December 2003, 150 patients were screened and 131, who presented inclusion criteria and accepted to participate, were included. Inclusion criteria were age between 30 and 80 years old, chest pain, documented ischemia or clinical referral for coronary angiography by the attending physician. Exclusion criteria were: previous myocardial infarction in the last 60 days, heart transplantation or revascularization procedure, known malignant neoplasia, haemodialysis or current insulin therapy.
A clinical questionnaire, physical examination and a 12 h-fasting blood sample collection were performed on all patients immediately before coronary angiography. Each subject gave written consent and the study protocol was approved by the Hospital Ethics Committee.
On the day of the procedure, a fasting blood sample was obtained for glucose, total cholesterol, high-density cholesterol (HDL-c), triglycerides (TG), creatinine, fibrinogen and ultrasensitive C-reactive protein (CRP). Laboratory measurements were performed using automated enzymatic commercial kits (Roche, Mannheim, GE). Fibrinogen was evaluated on a Fibrintimer II (Dade Behring Inc, Newark, Marburg, Germany) and processed in the auto-analyser (CA-540, Sysmex). The concentration of low-density cholesterol (LDL-c) was calculated with Friedwald's formula. Serum insulin was determined by enzyme immunoassay commercial kits (Abbott-Murex, Park, IL, USA) and CRP by nephelometry (nephelometer BN100, Dade Behring Inc., Marburg, Germany). Insulin resistance was assessed by the HOMA-IR (homeostasis model assessment of insulin resistance) method, as previously described .
Coronary angiographies were performed using Siemens Axiom Artis equipment (Munich, Germany), and all procedures followed standard routines. The coronary angiograms were evaluated by two experienced interventional cardiologists, unaware of the patients' clinical presentation. Lesions quantification were performed using a quantitative coronary angiography (QCA) software and were stratified in mild (up 30% in lumen narrowing), moderate (30 to 70% in lumen narrowing) or severe (greater than 70% in lumen narrowing) disease. Angiographic evidence of coronary artery disease was classified as: No CAD (complete absence of detectable coronary artery disease) or CAD (30% or more stenosis in at least one major coronary artery) to assure coronary artery disease presence and avoid inclusion or misinterpretation of patients with incipient or very mild disease.
In a ROC curve analysis, the best positive predictive values for HOMA-IR, TG/HDLc and their product (HOMA-IR×TG/HDLc) were defined as cut-off values for the study. Relative risks were determined between the presence or absence of coronary artery disease (outcomes) vs A. HOMA-IR higher/equal vs. lower than the cut-off level of 6.0, B. TG/HDLc index higher/equal vs. lower than the cut-off level of 8.5 and C. The product of HOMA-IR × TG/HDLc higher/equal vs. lower than the cut-off level of 28 interval, using multivariate Poisson regression adjusted for age, sex diabetes, body mass index and systolic blood pressure. For all tests a P value ≤ 0.05 was considered to be statistically significant.
Characteristics of the patients
Characteristics N = 131
N = 57
N = 74
55.3 ± 10.0
60.3 ± 10.5
29.8 ± 5.5
27.0 ± 4.4
Systolic BP (mmHg)
140.4 ± 26.6
140.1 ± 22.4
Diastolic BP (mmHg)
86.3 ± 17.2
84.3 ± 12.1
Diabetes Mellitus (%)
Arterial Hypertension (%)
Statin users (%)
9 ( 15.2)
15 ( 19.7)
Oral anti-diabetic agents (%)
Physically active (% of total)
12 (20.6 )
25 ( 32.9 )
5.9 ± 0.9
6.2 ± 1.1
Fasting plasma glucose (mg/dl)
101.1 ± 33.3
117.7 ± 48.7
117.2 ± 33.1
121.1 ± 37.3
49.8 ± 11.7
45.7 ± 10.5
C-Reactive Protein (mg/dl)
3.04 ± 2.05
3.24 ± 2.25
Serum creatinine (mg/dl)
0.96 ± 0.22
1.08 ± 0.35
336.9 ± 81.2
357.6 ± 97.3
HOMA-IR × TG/HDLc
Multivariate regression analysis and relative risks for coronary artery disease for HOMA-IR > 6, TG/HDLc index > 8.5 and [HOMA-IR × TG/HDLc] > 28 with adjustments.
HOMA IR >6.0
age, BMI, gender, diabetes, SBP
age, BMI, diabetes, SBP, gender
age, BMI, diabetes, SBP, gender
HOMA IR >6.0
age, BMI, diabetes, SBP
age, BMI, diabetes, SBP, gender
age, BMI, diabetes, SBP, gender
In the present study, we showed an association between insulin resistance, with the presence of coronary artery disease in patients referred for coronary angiography. A HOMA-IR higher than 6.0 and the TG/HDLc index above 8.5 were associated with the presence of coronary lesions, and it was independent of age, gender, body mass index, diabetes mellitus and systolic blood pressure. This effect was unlikely to be due to the use of anti-diabetic oral agents on HOMA-IR because patients on these medications were removed from the analysis and the results did not change. The product of HOMA-IR and TG/HDLc index had an even stronger association with the presence of coronary artery disease than each variable alone. Considering that these patients were in intermediate-high risk for coronary artery disease, these tests presented a very high positive predictive value.
Insulin resistance evaluated by the HOMA-IR and triglyceride measurements is usually not included in the recommendations for cardiovascular risk stratification . These conditions are generally considered emerging risk factors , although two meta-analyses have shown predictive value for cardiovascular outcomes [8, 9]. However, we did not find studies using both HOMA-IR and TG/HDLc, as a risk factor.
Although cause-effect conclusions cannot be drawn from cross-sectional studies, the associations observed in the present study raises the hypothesis that these measurements, used together, may optimize stratification of coronary artery disease risk. This is in accordance with prospective studies showing that insulin resistance, as evaluated by HOMA-IR  or by the euglycemic hyperinsulinemic clamp , indicates that it is associated with the occurrence of major cardiovascular events and coronary heart disease. In one study, increased HOMA-IR was associated with an increased incidence of myocardial infarction and death, even when the cardiovascular risk was adjusted for smoking and low physical activity. Interestingly, in that study, insulin resistance was defined in those subjects who present HOMA-IR in the 75th percentile (1.80 for women and 2.12 for men), a much lower threshold than used in the present study .
Hyperinsulinemia was shown to be an independent predictor of complex atherosclerotic lesions detected by echocardiography in the thoracic aorta in non-diabetic patients . Previous studies have investigated the association between angiographically proven coronary atherosclerosis and insulin resistance evaluated by a HOMA-IR higher than 1.8 (the median value). Patients with higher levels of insulin resistance had a more severe, extensive, and distal type of coronary artery disease .
Increased TG/HDLc index was also previously shown to be associated with ischemic heart disease. In a previous cohort study, asymptomatic men initially free from ischemic heart disease who presented eletrocardiographic changes after 8 years, had more fatal acute myocardial infarction when increased TG/HDLc was also present, indicating a synergistic effect of both low HDLc and high triglyceride levels .
A potential limitation of the present study is that sub-clinical or mild disease could be better assessed using intravascular ultrasound or optical coherence tomography. Also, LDL cholesterol levels, used in most studies and ascertained as classic risk factor for coronary artery disease, are actually estimations calculated with the same variables as in the TG/HDLc relationship with the exception of total cholesterol. Thus, considerable correlation between both values is expected. However, a comparison of TG/HDLc with LDL cholesterol levels is beyond the scope of the present study.
We believe that this simple and non-invasive set of tests may be a useful tool in optimizing the selection of patients to proceed to a more invasive investigation. Further longitudinal studies on insulin resistance and coronary artery disease should be undertaken in order to confirm these data in high-risk patients.
We conclude that because increased HOMA-IR, TG/HDLc and their product are positively associated with the angiographic coronary artery disease, they may be useful for cardiovascular risk stratification.
Financial support by Research Foundation of Rio Grande do Sul (FAPERGS).
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