- Email: [email protected]
Association of the Metabolic Syndrome and Insulin Resistance With Silent Myocardial Ischemia in Patients With Type 2 Diabetes Mellitus
Association of the Metabolic Syndrome and Insulin Resistance With Silent Myocardial Ischemia in Patients With Type 2 Diabetes Mellitus Carmine Gazzaruso, MD, PhDa,*, Sebastiano B. Solerte, MDb, Emanuela De Amici, MDa, Marco Mancini, MDa, Arturo Pujia, MDc, Pietro Fratino, MDd, Andrea Giustina, MDe, and Adriana Garzaniti, MDf Metabolic syndrome is associated with elevated morbidity and mortality for overt coronary artery disease (CAD). In diabetic patients, CAD is often silent. The relation between metabolic syndrome and silent CAD has never been studied. We investigated whether metabolic syndrome is associated with silent CAD in patients with type 2 diabetes mellitus. We evaluated the prevalence of metabolic syndrome in 169 patients with uncomplicated diabetes and angiographically verified silent CAD and in 158 diabetic patients without myocardial ischemia on exercise electrocardiography, 48hours ambulatory electrocardiography, and stress echocardiography. The groups were comparable for gender, age, glycemic control, and diabetes duration. Metabolic syndrome was defined according to the National Cholesterol Education Program criteria. To estimate insulin resistance in patients treated with diet alone or oral agents (122 patients with CAD and 115 patients without CAD), the Homeostasis Model Insulin-Resistance Assessment (HOMA) was used. The prevalence of metabolic syndrome (59.8% vs 44.3%, p ⴝ 0.005) and HOMA (5.4 ⴞ 2.1 vs 4.9 ⴞ 2.8, p ⴝ 0.044) were significantly higher in those with CAD than in those without CAD. Multiple logistic regression analysis showed that the metabolic syndrome was associated with silent CAD (odds ratio 2.44, 95% confidence interval 1.19 to 5.02, p ⴝ 0.015). Among patients on diet alone or oral agents, the HOMA was the strongest predictor of silent CAD (odds ratio 10.16, 95% confidence interval 2.60 to 39.63, p <0.001). In conclusion, our data have shown an independent association of metabolic syndrome and insulin resistance with silent CAD in patients with type 2 diabetes mellitus. Other studies are needed to establish whether metabolic syndrome and HOMA are reliable markers to identify diabetic patients for additional screening for silent CAD. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97: 236 –239)
We investigated the possible association between metabolic syndrome and angiographically documented silent coronary artery disease (CAD) in patients with type 2 diabetes mellitus.
Methods We analyzed the study population from 2 of our previous investigations.1,2 The population, design, and methods of
a
IRCCS Maugeri Foundation Hospital, Pavia; bDepartment of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia; cDepartment of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro; dAzienda Sanitaria Locale, Pavia; eDepartment of Internal Medicine, University of Brescia, Brescia; and fDiabetes Center, Pavia, Italy. Manuscript received May 17, 2005; revised manuscript received and accepted July 28, 2005. *Corresponding author: Tel: 39-0382-593-734; fax: 39-0382-593-081. E-mail address: [email protected] (C. Gazzaruso). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.07.133
the 2 studies have been previously described.1,2 In brief, in the first study,1 1,323 patients with uncomplicated type 2 diabetes mellitus without any clinical or electrocardiographic evidence of CAD were consecutively evaluated. Of these, 103 had angiographically documented CAD. As a control group, 103 patients were recruited and matched by age, gender, and duration of diabetes to the patients with CAD. In the patients without CAD, the results of exercise electrocardiography, 48-hour ambulatory electrocardiograpjy, and stress echocardiography were negative for silent myocardial ischemia. In the second study,2 1,971 patients with uncomplicated type 2 diabetes mellitus without clinical signs of cardiovascular disease and with a negative history of CAD were consecutively evaluated. Patients with electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction underwent a noninvasive test for CAD (electrocardiographic stress testing and/or scintigraphy). Of those patients, 75 had angiographically documented CAD. As a control group, 75 subwww.AJConline.org
Preventive Cardiology/Metabolic Syndrome and Silent CAD
jects were recruited and matched by age, gender, and duration of diabetes to the patients with CAD. In patients without CAD, the results of exercise electrocardiography, 48-hour ambulatory electrocardiography, and stress echocardiography were negative for silent myocardial ischemia. From the above studies, we evaluated the prevalence of metabolic syndrome in 169 patients with uncomplicated type 2 diabetes and angiographically documented asymptomatic CAD and in 158 patients with type 2 diabetes without myocardial ischemia. Metabolic syndrome was defined according to the National Cholesterol Education Program (NCEP) criteria.3 Previously recruited1,2 diabetic patients had metabolic syndrome if 2 of the following criteria were fulfilled: hypertension (blood pressure ⱖ130/85 mm Hg or specific treatment); triglycerides ⱖ150 mg/dl; high-density lipoprotein ⬍40 mg/dl in men or ⬍50 mg/dl in women; and central obesity (waist circumference ⬎102 cm in men or ⬎88 cm in women). In non-insulin–treated patients, insulin resistance was estimated using the Homeostasis Model Insulin-Resistance Assessment (HOMA).4 Insulin resistance was defined as the highest quartile of the HOMA index5 found in our group of blood donors.6 As a cutpoint to define insulin resistance, a HOMA value of 2.6 was used, as reported by several studies.6 – 8 Waist circumference and insulin levels are routinely measured in our outpatient department, and the data for those parameters were obtained from our database. Insulin was measured by radioimmunoassay (INSI K5, DiaSorin, Saluggia, Italy). All other parameters used to ascertain the presence of metabolic syndrome have been previously reported.1,2 In the present study, we enrolled only patients with data on waist circumference and insulin levels evaluated in the year before the diagnosis of silent CAD or the exclusion of silent myocardial ischemia. Of the 169 patients with silent CAD, 98 were derived from the population with normal electrocardiographic findings at rest1 and 71 from those with electrocardiographic abnormalities.2 Of the 158 patients without CAD, 83 were derived from the first study,1 59 from the second study,2 and 16 were from both studies.1,2 Nine patients with CAD and 4 without CAD in the previous studies1,2 were not enrolled in the present investigation because data on waist circumference and/or insulin levels were collected ⬎12 months before the diagnosis of silent CAD or the exclusion of silent myocardial ischemia (7 with CAD and 3 without CAD) or the data on waist circumference or insulin levels were not available (2 with CAD and 1 without). Statistical analysis: Lipid parameters were adjusted for body mass index, smoking, drug intake, presence of hypertension, and microalbuminuria using analysis of covariance. We assessed differences in Gaussian variables by Student’s t test and differences in non-Gaussian variables using the Mann-Whitney U statistical test. The Pearson chi-square test was used for frequency comparison. A multiple logistic regression analysis with the presence of silent CAD as the
237
dependent variable was performed. Odds ratios (ORs) were estimated, and the results are given as ORs and 95% confidence intervals (CIs). Data are presented as means ⫾ SDs, unless otherwise stated; p ⬍0.05 was considered significant.
Results Table 1 lists the features of the 2 study groups. No difference in diabetes treatment was found between the 2 groups. Among the patients with CAD, no differences in the prevalence of metabolic syndrome between those with normal resting electrocardiographic findings and those with electrocardiographic abnormalities were found (62.2% vs 56.3%). Waist circumference (103.4 ⫾ 13.0 vs 92.4 ⫾ 8.9 cm), body mass index (27.7 ⫾ 3.6 vs 24.7 ⫾ 2.6 kg/m2), triglycerides (2.0 ⫾ 0.6 vs 1.4 ⫾ 0.5 mmol/L), and the presence of hypertension (72.4% vs 33.1%) were significantly higher and high-density lipoprotein significantly lower (1.1 ⫾ 0.2 vs 1.3 ⫾ 0.2 mmol/L) in patients with metabolic syndrome than in those without (p ⬍0.001). Multiple logistic regression analysis was performed with the presence/absence of asymptomatic CAD as the dependent variable and the following as predictive variables9: gender, age, diabetes duration, hypertension, family history of CAD, smoking, microalbuminuria, hemoglobin A1c, body mass index, cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, metabolic syndrome, and autonomic dysfunction. Variables were categorized as previously shown.9 In our diabetic patients, the categorization of metabolic syndrome was made according to the NCEP definition: ⱖ2 NCEP criteria versus ⬍2 NCEP criteria. Table 2 lists the results of the multivariate analysis. Microalbuminuria, hypercholesterolemia, smoking, metabolic syndrome, and a family history of CAD were predictors of silent CAD. Waist circumference did not enter the model, if tested as a potential predictor instead of body mass index. The aggregation of 3 NCEP criteria (OR 2.71, 95% CI 1.24 to 4.34, p ⫽ 0.009) and 4 NCEP criteria (OR 2.74, 95% CI 1.37 to 4.15, p ⫽ 0.003) were more strongly associated with silent CAD than metabolic syndrome, if tested as potential predictors, instead of metabolic syndrome. A separate analysis showed that of the NCEP criteria, only high-density lipoprotein levels were associated with silent CAD (OR 2.04, 95% CI 1.23 to 3.38, p ⫽ 0.005). Table 3 lists the characteristics of patients treated with diet alone or oral agents, stratified according to the presence or absence of silent CAD. The multiple logistic regression analysis in this subgroup showed that microalbuminuria (OR 5.75, 95% CI 2.28 to 9.86, p ⬍0.001), hypercholesterolemia (OR 4.26, 95% CI 1.85 to 9.82, p ⬍0.001), smoking (OR 3.22, 95% CI 1.67 to 6.20, p ⬍0.001), and metabolic syndrome (OR 2.49, 95% CI 1.06 to 5.86, p ⫽ 0.015) were predictors of silent CAD. When HOMA was added to the list of potential predictors, the analysis showed that HOMA (OR 10.16, 95% CI 2.60 to 39.63, p ⬍0.001), microalbu-
238
The American Journal of Cardiology (www.AJConline.org)
Table 1 Features of type 2 diabetic patients with and without silent coronary artery disease (CAD) Variable
CAD
Men/women Age (yrs) Duration of diabetes (yrs) Body mass index (kg/m2) Waist circumference (cm) Hemoglobin Alc (%) Total cholesterol (mmol/L) Low-density lipoprotein (mmol/L) High-density lipoprotein (mmol/L) Triglycerides (mmol/L) Microalbuminuria Smokers Family history of CAD Hypertension Autonomic neuropathy Fasting plasma glucose (mmol/L) Fasting Insulin (mU/L)* HOMA* Metabolic syndrome
p Value
Yes (n ⫽ 169)
No (n ⫽ 158)
138/31 58.2 ⫾ 6.3 7.3 ⫾ 5.5 26.5 ⫾ 3.3 98.6 ⫾ 12.5 7.7 ⫾ 1.4 5.6 ⫾ 0.9 3.2 ⫾ 1.0 1.1 ⫾ 0.2 1.8 ⫾ 0.6 44.9% 50.9% 37.9% 49.7% 18.3% 8.3 ⫾ 2.9 15.5 ⫾ 4.0 5.4 ⫾ 2.1 59.8%
130/28 57.9 ⫾ 6.4 7.5 ⫾ 5.3 26.1 ⫾ 3.6 97.7 ⫾ 12.5 7.4 ⫾ 1.3 5.4 ⫾ 1.0 3.1 ⫾ 1.1 1.2 ⫾ 0.2 1.6 ⫾ 0.6 12.7% 26.6% 27.8% 57.6% 13.9% 8.1 ⫾ 3.5 13.9 ⫾ 4.3 4.9 ⫾ 2.8 44.3%
0.883 0.639 0.656 0.341 0.894 0.165 0.092 0.239 ⬍0.001 0.052 ⬍0.001 ⬍0.001 0.054 0.152 0.278 0.669 0.005 0.044 0.005
* Insulin-treated patients excluded. Table 2 Results of multiple logistic regression analysis with presence of silent coronary artery disease CAD as dependent variable in diabetic patients Predictor Microalbuminuria Hypercholesterolemia Smoking Metabolic syndrome Family history of CAD
Odds Ratio
95% Confidence Intervals
p Value
5.53 3.58 2.55 2.44 1.88
3.00–10.18 1.83–6.99 1.49–4.36 1.19–5.02 1.05–3.37
⬍0.001 ⬍0.001 ⬍0.001 0.015 0.034
minuria (OR 5.61, 95% CI 2.54 to 12.40, p ⬍0.001), hypercholesterolemia (OR 4.66, 95% CI 1.92 to 11.31, p ⬍0.001), and smoking (OR 3.42, 95% CI 1.73 to 6.73, p ⬍0.001) were predictors of silent CAD. The metabolic syndrome did not enter the model (p ⫽ 0.080).
Discussion The main findings of the present study were that in patients with type 2 diabetes the presence of metabolic syndrome was associated with silent angiographically verified CAD and that this association was independent of common cardiovascular risk factors. These findings underline that in patients with type 2 diabetes the metabolic syndrome seems to further increase the global risk of silent CAD due to the presence of other cardiovascular risk factors. The additional risk of silent CAD due to the metabolic syndrome may be caused by the aggregation of multiple risk factors into the
metabolic syndrome with a more than additive increase in the global risk. Nevertheless, insulin resistance, the pathophysiologic defect of metabolic syndrome, may independently contribute to increase the global risk of silent CAD. Recent studies have shown that the HOMA index, a reliable marker of insulin resistance,4 is an independent cardiovascular risk factor.10 –12 We also tested the hypothesis that insulin resistance is independently associated with silent CAD in a large subgroup of diabetic patients treated with diet alone or oral agents. Our data showed that HOMA was significantly associated with silent CAD and that its predictive power for silent CAD was even greater than that of the metabolic syndrome. Future studies should also clarify whether metabolic syndrome and insulin resistance can predict a worse prognosis in patients with silent CAD. A possible mechanism linking metabolic syndrome to silent CAD is that these 2 conditions may share a common pattern of cardiovascular risk factors, such as dyslipidemia, hypertension, smoking, and microalbuminuria. Nevertheless, this hypothetical mechanism may generically explain an association between metabolic syndrome and CAD, but not a specific association between metabolic syndrome and silent CAD. It is intriguing to hypothesize that 1 possible link between insulin resistance and the lack of symptoms of CAD may be represented by autonomic neuropathy. A dysregulation of autonomic nervous balance, with a prevalence of sympathetic or parasympathetic nervous activity, is a feature of insulin resistance,13 and it may even play a role in its pathogenesis.14 Moreover, autonomic neuropathy, with the initial prevalence of sympathetic tone, has been associated with asymptomatic CAD, especially in diabetic patients.15–17 We did not find any significant correlation
Preventive Cardiology/Metabolic Syndrome and Silent CAD
239
Table 3 Features of type 2 diabetic patients treated with diet alone or oral agents, stratified according to presence/absence of silent coronary artery disease (CAD) Variable
Men/women Age (yrs) Duration of diabetes (yrs) Body mass index (kg/m2) Waist circumference (cm) Hemoglobin Alc (%) Total cholesterol (mmol/L) Low-density lipoprotein (mmol/L) High-density lipoprotein (mmol/L) Triglycerides (mmol/L) Microalbuminuria Smokers Family history of CAD Hypertension Autonomic neuropathy Fasting plasma glucose (mmol/L) Fasting insulin (mU/L) Homeostasis Model Insulin-Resistance Assessment Metabolic syndrome
between autonomic dysfunction and silent CAD, but we could not exclude that an impairment in autonomic nervous function may play, at least partially, a role in the association between metabolic syndrome and the absence of symptoms of CAD. 1. Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, De Amici E, Geroldi D, Fratino P. Assessment of asymptomatic coronary artery disease in apparently uncomplicated type 2 diabetic patients: a role for lipoprotein(a) and apolipoprotein(a) polymorphism. Diabetes Care 2002;25:1418 –1424. 2. Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, Fratino P. Silent coronary artery disease in type 2 diabetes mellitus: the role of lipoprotein(a), homocysteine and apo(a) polymorphism. Cardiovasc Diabetol 2002;1:5. 3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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 –2497. 4. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412– 419. 5. Alberti KGMM, Zimmet PZ, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998;15:539 –543. 6. Gazzaruso C, Bruno R, Garzaniti A, Giordanetti S, Fratino P, Sacchi P, Filice G. Hypertension among HIV-patients: prevalence and relationships to insulin resistance and metabolic syndrome. J Hypertens 2003;21:1377–1382. 7. Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, Carmena R. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care 2003;26:3320 –3325. 8. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Brunneck study. Diabetes 1998; 47:1643–1649.
CAD
p Value
Yes (n ⫽ 122)
No (n ⫽ 115)
97/27 58.4 ⫾ 6.5 6.9 ⫾ 5.3 26.5 ⫾ 3.3 98.7 ⫾ 13.3 7.3 ⫾ 1.5 5.6 ⫾ 0.9 3.0 ⫾ 0.9 1.2 ⫾ 0.2 1.8 ⫾ 0.6 41.8% 49.2% 37.7% 50.8% 13.9% 7.9 ⫾ 2.4 15.5 ⫾ 4.0 5.4 ⫾ 2.1 59.0%
93/22 58.1 ⫾ 6.4 7.2 ⫾ 5.4 26.1 ⫾ 3.7 97.3 ⫾ 12.5 7.3 ⫾ 1.3 5.4 ⫾ 0.9 2.9 ⫾ 0.9 1.2 ⫾ 0.2 1.7 ⫾ 0.6 12.2% 24.4% 27.8% 57.4% 12.2% 7.8 ⫾ 3.3 13.9 ⫾ 4.3 4.9 ⫾ 2.8 45.2%
0.792 0.710 0.994 0.958 0.217 0.914 0.814 0.740 0.690 0.779 ⬍0.001 ⬍0.001 0.105 0.310 0.687 0.475 0.005 0.044 0.033
9. Gazzaruso C, Giordanetti S, De Amici E, Bertone G, Falcone C, Geroldi D, Solerte SB, Garzaniti A. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation 2004;110:22–26. 10. Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K. Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in health middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol 2000;20: 538 –544. 11. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic patients: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25:1135–1141. 12. Hanley AJG, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002; 25:1177–1184. 13. Laitinen T, Vauhkonen IK, Niskanen LK, Hartikainen JE, Lansimies EA, Uusitupa MI, Laakso M. Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects. Diabetes 1999;48:1295–1299. 14. Lindmark S, Wiklund U, Bjerle P, Eriksson JW. Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first-degree relatives of type 2 diabetes patients and control subjects. Diabet Med 2003;20:399 – 405. 15. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26:1553–1579. 16. Valensi P, Sachs RN, Harfouche B, Lormeau B, Paries J, Cosson E, Paycha F, Leutenegger M, Attali JR. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001;24:339 –343. 17. Wackers FJT, Young L, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taellefer R, Wittlin SD, Heller GV, Engel S, et al, for the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004;27:1954 –1961.
We investigated the possible association between metabolic syndrome and angiographically documented silent coronary artery disease (CAD) in patients with type 2 diabetes mellitus.
Methods We analyzed the study population from 2 of our previous investigations.1,2 The population, design, and methods of
a
IRCCS Maugeri Foundation Hospital, Pavia; bDepartment of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia; cDepartment of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro; dAzienda Sanitaria Locale, Pavia; eDepartment of Internal Medicine, University of Brescia, Brescia; and fDiabetes Center, Pavia, Italy. Manuscript received May 17, 2005; revised manuscript received and accepted July 28, 2005. *Corresponding author: Tel: 39-0382-593-734; fax: 39-0382-593-081. E-mail address: [email protected] (C. Gazzaruso). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.07.133
the 2 studies have been previously described.1,2 In brief, in the first study,1 1,323 patients with uncomplicated type 2 diabetes mellitus without any clinical or electrocardiographic evidence of CAD were consecutively evaluated. Of these, 103 had angiographically documented CAD. As a control group, 103 patients were recruited and matched by age, gender, and duration of diabetes to the patients with CAD. In the patients without CAD, the results of exercise electrocardiography, 48-hour ambulatory electrocardiograpjy, and stress echocardiography were negative for silent myocardial ischemia. In the second study,2 1,971 patients with uncomplicated type 2 diabetes mellitus without clinical signs of cardiovascular disease and with a negative history of CAD were consecutively evaluated. Patients with electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction underwent a noninvasive test for CAD (electrocardiographic stress testing and/or scintigraphy). Of those patients, 75 had angiographically documented CAD. As a control group, 75 subwww.AJConline.org
Preventive Cardiology/Metabolic Syndrome and Silent CAD
jects were recruited and matched by age, gender, and duration of diabetes to the patients with CAD. In patients without CAD, the results of exercise electrocardiography, 48-hour ambulatory electrocardiography, and stress echocardiography were negative for silent myocardial ischemia. From the above studies, we evaluated the prevalence of metabolic syndrome in 169 patients with uncomplicated type 2 diabetes and angiographically documented asymptomatic CAD and in 158 patients with type 2 diabetes without myocardial ischemia. Metabolic syndrome was defined according to the National Cholesterol Education Program (NCEP) criteria.3 Previously recruited1,2 diabetic patients had metabolic syndrome if 2 of the following criteria were fulfilled: hypertension (blood pressure ⱖ130/85 mm Hg or specific treatment); triglycerides ⱖ150 mg/dl; high-density lipoprotein ⬍40 mg/dl in men or ⬍50 mg/dl in women; and central obesity (waist circumference ⬎102 cm in men or ⬎88 cm in women). In non-insulin–treated patients, insulin resistance was estimated using the Homeostasis Model Insulin-Resistance Assessment (HOMA).4 Insulin resistance was defined as the highest quartile of the HOMA index5 found in our group of blood donors.6 As a cutpoint to define insulin resistance, a HOMA value of 2.6 was used, as reported by several studies.6 – 8 Waist circumference and insulin levels are routinely measured in our outpatient department, and the data for those parameters were obtained from our database. Insulin was measured by radioimmunoassay (INSI K5, DiaSorin, Saluggia, Italy). All other parameters used to ascertain the presence of metabolic syndrome have been previously reported.1,2 In the present study, we enrolled only patients with data on waist circumference and insulin levels evaluated in the year before the diagnosis of silent CAD or the exclusion of silent myocardial ischemia. Of the 169 patients with silent CAD, 98 were derived from the population with normal electrocardiographic findings at rest1 and 71 from those with electrocardiographic abnormalities.2 Of the 158 patients without CAD, 83 were derived from the first study,1 59 from the second study,2 and 16 were from both studies.1,2 Nine patients with CAD and 4 without CAD in the previous studies1,2 were not enrolled in the present investigation because data on waist circumference and/or insulin levels were collected ⬎12 months before the diagnosis of silent CAD or the exclusion of silent myocardial ischemia (7 with CAD and 3 without CAD) or the data on waist circumference or insulin levels were not available (2 with CAD and 1 without). Statistical analysis: Lipid parameters were adjusted for body mass index, smoking, drug intake, presence of hypertension, and microalbuminuria using analysis of covariance. We assessed differences in Gaussian variables by Student’s t test and differences in non-Gaussian variables using the Mann-Whitney U statistical test. The Pearson chi-square test was used for frequency comparison. A multiple logistic regression analysis with the presence of silent CAD as the
237
dependent variable was performed. Odds ratios (ORs) were estimated, and the results are given as ORs and 95% confidence intervals (CIs). Data are presented as means ⫾ SDs, unless otherwise stated; p ⬍0.05 was considered significant.
Results Table 1 lists the features of the 2 study groups. No difference in diabetes treatment was found between the 2 groups. Among the patients with CAD, no differences in the prevalence of metabolic syndrome between those with normal resting electrocardiographic findings and those with electrocardiographic abnormalities were found (62.2% vs 56.3%). Waist circumference (103.4 ⫾ 13.0 vs 92.4 ⫾ 8.9 cm), body mass index (27.7 ⫾ 3.6 vs 24.7 ⫾ 2.6 kg/m2), triglycerides (2.0 ⫾ 0.6 vs 1.4 ⫾ 0.5 mmol/L), and the presence of hypertension (72.4% vs 33.1%) were significantly higher and high-density lipoprotein significantly lower (1.1 ⫾ 0.2 vs 1.3 ⫾ 0.2 mmol/L) in patients with metabolic syndrome than in those without (p ⬍0.001). Multiple logistic regression analysis was performed with the presence/absence of asymptomatic CAD as the dependent variable and the following as predictive variables9: gender, age, diabetes duration, hypertension, family history of CAD, smoking, microalbuminuria, hemoglobin A1c, body mass index, cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, metabolic syndrome, and autonomic dysfunction. Variables were categorized as previously shown.9 In our diabetic patients, the categorization of metabolic syndrome was made according to the NCEP definition: ⱖ2 NCEP criteria versus ⬍2 NCEP criteria. Table 2 lists the results of the multivariate analysis. Microalbuminuria, hypercholesterolemia, smoking, metabolic syndrome, and a family history of CAD were predictors of silent CAD. Waist circumference did not enter the model, if tested as a potential predictor instead of body mass index. The aggregation of 3 NCEP criteria (OR 2.71, 95% CI 1.24 to 4.34, p ⫽ 0.009) and 4 NCEP criteria (OR 2.74, 95% CI 1.37 to 4.15, p ⫽ 0.003) were more strongly associated with silent CAD than metabolic syndrome, if tested as potential predictors, instead of metabolic syndrome. A separate analysis showed that of the NCEP criteria, only high-density lipoprotein levels were associated with silent CAD (OR 2.04, 95% CI 1.23 to 3.38, p ⫽ 0.005). Table 3 lists the characteristics of patients treated with diet alone or oral agents, stratified according to the presence or absence of silent CAD. The multiple logistic regression analysis in this subgroup showed that microalbuminuria (OR 5.75, 95% CI 2.28 to 9.86, p ⬍0.001), hypercholesterolemia (OR 4.26, 95% CI 1.85 to 9.82, p ⬍0.001), smoking (OR 3.22, 95% CI 1.67 to 6.20, p ⬍0.001), and metabolic syndrome (OR 2.49, 95% CI 1.06 to 5.86, p ⫽ 0.015) were predictors of silent CAD. When HOMA was added to the list of potential predictors, the analysis showed that HOMA (OR 10.16, 95% CI 2.60 to 39.63, p ⬍0.001), microalbu-
238
The American Journal of Cardiology (www.AJConline.org)
Table 1 Features of type 2 diabetic patients with and without silent coronary artery disease (CAD) Variable
CAD
Men/women Age (yrs) Duration of diabetes (yrs) Body mass index (kg/m2) Waist circumference (cm) Hemoglobin Alc (%) Total cholesterol (mmol/L) Low-density lipoprotein (mmol/L) High-density lipoprotein (mmol/L) Triglycerides (mmol/L) Microalbuminuria Smokers Family history of CAD Hypertension Autonomic neuropathy Fasting plasma glucose (mmol/L) Fasting Insulin (mU/L)* HOMA* Metabolic syndrome
p Value
Yes (n ⫽ 169)
No (n ⫽ 158)
138/31 58.2 ⫾ 6.3 7.3 ⫾ 5.5 26.5 ⫾ 3.3 98.6 ⫾ 12.5 7.7 ⫾ 1.4 5.6 ⫾ 0.9 3.2 ⫾ 1.0 1.1 ⫾ 0.2 1.8 ⫾ 0.6 44.9% 50.9% 37.9% 49.7% 18.3% 8.3 ⫾ 2.9 15.5 ⫾ 4.0 5.4 ⫾ 2.1 59.8%
130/28 57.9 ⫾ 6.4 7.5 ⫾ 5.3 26.1 ⫾ 3.6 97.7 ⫾ 12.5 7.4 ⫾ 1.3 5.4 ⫾ 1.0 3.1 ⫾ 1.1 1.2 ⫾ 0.2 1.6 ⫾ 0.6 12.7% 26.6% 27.8% 57.6% 13.9% 8.1 ⫾ 3.5 13.9 ⫾ 4.3 4.9 ⫾ 2.8 44.3%
0.883 0.639 0.656 0.341 0.894 0.165 0.092 0.239 ⬍0.001 0.052 ⬍0.001 ⬍0.001 0.054 0.152 0.278 0.669 0.005 0.044 0.005
* Insulin-treated patients excluded. Table 2 Results of multiple logistic regression analysis with presence of silent coronary artery disease CAD as dependent variable in diabetic patients Predictor Microalbuminuria Hypercholesterolemia Smoking Metabolic syndrome Family history of CAD
Odds Ratio
95% Confidence Intervals
p Value
5.53 3.58 2.55 2.44 1.88
3.00–10.18 1.83–6.99 1.49–4.36 1.19–5.02 1.05–3.37
⬍0.001 ⬍0.001 ⬍0.001 0.015 0.034
minuria (OR 5.61, 95% CI 2.54 to 12.40, p ⬍0.001), hypercholesterolemia (OR 4.66, 95% CI 1.92 to 11.31, p ⬍0.001), and smoking (OR 3.42, 95% CI 1.73 to 6.73, p ⬍0.001) were predictors of silent CAD. The metabolic syndrome did not enter the model (p ⫽ 0.080).
Discussion The main findings of the present study were that in patients with type 2 diabetes the presence of metabolic syndrome was associated with silent angiographically verified CAD and that this association was independent of common cardiovascular risk factors. These findings underline that in patients with type 2 diabetes the metabolic syndrome seems to further increase the global risk of silent CAD due to the presence of other cardiovascular risk factors. The additional risk of silent CAD due to the metabolic syndrome may be caused by the aggregation of multiple risk factors into the
metabolic syndrome with a more than additive increase in the global risk. Nevertheless, insulin resistance, the pathophysiologic defect of metabolic syndrome, may independently contribute to increase the global risk of silent CAD. Recent studies have shown that the HOMA index, a reliable marker of insulin resistance,4 is an independent cardiovascular risk factor.10 –12 We also tested the hypothesis that insulin resistance is independently associated with silent CAD in a large subgroup of diabetic patients treated with diet alone or oral agents. Our data showed that HOMA was significantly associated with silent CAD and that its predictive power for silent CAD was even greater than that of the metabolic syndrome. Future studies should also clarify whether metabolic syndrome and insulin resistance can predict a worse prognosis in patients with silent CAD. A possible mechanism linking metabolic syndrome to silent CAD is that these 2 conditions may share a common pattern of cardiovascular risk factors, such as dyslipidemia, hypertension, smoking, and microalbuminuria. Nevertheless, this hypothetical mechanism may generically explain an association between metabolic syndrome and CAD, but not a specific association between metabolic syndrome and silent CAD. It is intriguing to hypothesize that 1 possible link between insulin resistance and the lack of symptoms of CAD may be represented by autonomic neuropathy. A dysregulation of autonomic nervous balance, with a prevalence of sympathetic or parasympathetic nervous activity, is a feature of insulin resistance,13 and it may even play a role in its pathogenesis.14 Moreover, autonomic neuropathy, with the initial prevalence of sympathetic tone, has been associated with asymptomatic CAD, especially in diabetic patients.15–17 We did not find any significant correlation
Preventive Cardiology/Metabolic Syndrome and Silent CAD
239
Table 3 Features of type 2 diabetic patients treated with diet alone or oral agents, stratified according to presence/absence of silent coronary artery disease (CAD) Variable
Men/women Age (yrs) Duration of diabetes (yrs) Body mass index (kg/m2) Waist circumference (cm) Hemoglobin Alc (%) Total cholesterol (mmol/L) Low-density lipoprotein (mmol/L) High-density lipoprotein (mmol/L) Triglycerides (mmol/L) Microalbuminuria Smokers Family history of CAD Hypertension Autonomic neuropathy Fasting plasma glucose (mmol/L) Fasting insulin (mU/L) Homeostasis Model Insulin-Resistance Assessment Metabolic syndrome
between autonomic dysfunction and silent CAD, but we could not exclude that an impairment in autonomic nervous function may play, at least partially, a role in the association between metabolic syndrome and the absence of symptoms of CAD. 1. Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, De Amici E, Geroldi D, Fratino P. Assessment of asymptomatic coronary artery disease in apparently uncomplicated type 2 diabetic patients: a role for lipoprotein(a) and apolipoprotein(a) polymorphism. Diabetes Care 2002;25:1418 –1424. 2. Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, Fratino P. Silent coronary artery disease in type 2 diabetes mellitus: the role of lipoprotein(a), homocysteine and apo(a) polymorphism. Cardiovasc Diabetol 2002;1:5. 3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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 –2497. 4. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412– 419. 5. Alberti KGMM, Zimmet PZ, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998;15:539 –543. 6. Gazzaruso C, Bruno R, Garzaniti A, Giordanetti S, Fratino P, Sacchi P, Filice G. Hypertension among HIV-patients: prevalence and relationships to insulin resistance and metabolic syndrome. J Hypertens 2003;21:1377–1382. 7. Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, Carmena R. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care 2003;26:3320 –3325. 8. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Brunneck study. Diabetes 1998; 47:1643–1649.
CAD
p Value
Yes (n ⫽ 122)
No (n ⫽ 115)
97/27 58.4 ⫾ 6.5 6.9 ⫾ 5.3 26.5 ⫾ 3.3 98.7 ⫾ 13.3 7.3 ⫾ 1.5 5.6 ⫾ 0.9 3.0 ⫾ 0.9 1.2 ⫾ 0.2 1.8 ⫾ 0.6 41.8% 49.2% 37.7% 50.8% 13.9% 7.9 ⫾ 2.4 15.5 ⫾ 4.0 5.4 ⫾ 2.1 59.0%
93/22 58.1 ⫾ 6.4 7.2 ⫾ 5.4 26.1 ⫾ 3.7 97.3 ⫾ 12.5 7.3 ⫾ 1.3 5.4 ⫾ 0.9 2.9 ⫾ 0.9 1.2 ⫾ 0.2 1.7 ⫾ 0.6 12.2% 24.4% 27.8% 57.4% 12.2% 7.8 ⫾ 3.3 13.9 ⫾ 4.3 4.9 ⫾ 2.8 45.2%
0.792 0.710 0.994 0.958 0.217 0.914 0.814 0.740 0.690 0.779 ⬍0.001 ⬍0.001 0.105 0.310 0.687 0.475 0.005 0.044 0.033
9. Gazzaruso C, Giordanetti S, De Amici E, Bertone G, Falcone C, Geroldi D, Solerte SB, Garzaniti A. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation 2004;110:22–26. 10. Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K. Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in health middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol 2000;20: 538 –544. 11. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic patients: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25:1135–1141. 12. Hanley AJG, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002; 25:1177–1184. 13. Laitinen T, Vauhkonen IK, Niskanen LK, Hartikainen JE, Lansimies EA, Uusitupa MI, Laakso M. Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects. Diabetes 1999;48:1295–1299. 14. Lindmark S, Wiklund U, Bjerle P, Eriksson JW. Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first-degree relatives of type 2 diabetes patients and control subjects. Diabet Med 2003;20:399 – 405. 15. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26:1553–1579. 16. Valensi P, Sachs RN, Harfouche B, Lormeau B, Paries J, Cosson E, Paycha F, Leutenegger M, Attali JR. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001;24:339 –343. 17. Wackers FJT, Young L, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taellefer R, Wittlin SD, Heller GV, Engel S, et al, for the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004;27:1954 –1961.