The Metabolic Syndrome Its Prevalence and Association with Coronary Artery Disease in Type 2 Diabetes

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1 REVIEW ARTICLE JIACM 2006; 7(1): 32-8 Abstract The Metabolic Syndrome Its Prevalence and Association with Coronary Artery Disease in Type 2 Diabetes Vijay Achari*, AK Thakur**, Arun K Sinha*** Objective: While the metabolic syndrome is a well recognised entity in type 2 diabetes, only a few international studies exist on the prevalence of this syndrome and its association with CAD. We examined these factors as well as other risk factors in data from a cardiac centre in Patna, India. Research design and methods: 928 diabetics (602 males, 326 females) attending the diabetic clinic of Heart Hospital between were assessed for the presence of metabolic syndrome (insulin resistance syndrome) using the criteria of Alberti and Zimmet as well as for the presence of coronary artery disease (CAD) by appropriate invasive and non-invasive methods of testing. Other major risk factors like smoking, hypertension, and dyslipidaemia were also assessed in this study. All patients had either ischaemic heart disease on the basis of ECG changes indicating definite ischaemia/infarction, or a positive treadmill test or other stress test, or had CABG/PTCA/angiographically documented disease. Results: 596 (64.2%) were positive for the metabolic syndrome while 516 (55.6%) tested positive for coronary artery disease; there was a strong correlation between these entities (p = < 0.001). When the individual components of the metabolic syndrome were tested for their relationship with coronary artery disease, it was found that obesity and microalbuminuria had the strongest association with the presence of ischaemic heart disease. Obesity (either central/visceral or generalised) was found in 452 (48.7%) diabetics, of which 282 (62.4 %) had ischaemic heart disease as compared to only 234 (49.1%) of 476 non obese diabetics with coronary artery disease (p = < ). Microalbuminuria was also strongly associated with CAD of the 312 with this condition 180 had ischaemic heart disease (p = < 0.001). Hypertension showed a weaker correlation (p = 0.03) while elevated triglyceride levels showed no association. Elevated total cholesterol and LDL cholesterol levels initially showed a weak association with CAD (p = 0.042); however, this was eliminated on multivariate logistic regression analysis. Smoking was strongly associated with the presence of CAD (p < 0.001).On multivariate logistic regression analysis the only factors associated with CAD were metabolic syndrome (p = 0.002), obesity (p = 0.000), hypertension (p = 0.033), nephropathy (p = 0.008) age (p = 0.000) and smoking (p = 0.006). Conclusion: It is therefore concluded that the presence of the metabolic syndrome is a strong marker indicating the likelihood of CAD, while the strongest associations of CAD were found with obesity and microalbuminuria. This seems more strongly significant than traditional risk factors like elevated LDL cholesterol, hypertension, and triglycerides. Key words: Coronary artery disease, Diabetes, Metabolic syndrome, Risk factors. Introduction Coronary artery disease (CAD) is the major cause of mortality and morbidity worldwide in type 2 diabetes, 65-80% of the deaths from type 2 diabetes are due to cardiovascular or cerebrovascular complications 1-3. It is estimated that the presence of diabetes exaggerates the risk of CAD 2-4 fold. A recent Finnish population based study suggested that type 2 diabetes proven MI have the same risk of MI as in non diabetics with proven MI 4. There is a considerable body of evidence that the metabolic syndrome (syndrome X) originally described by Reaven 5 and subsequently modified, plays a pivotal role in the development of this condition by providing a multitude of risk factors which tend to multiply the effect of each other on the vascular system. This effect is particularly pronounced in persons of south Asian origin 6. The importance of the metabolic syndrome as a single major risk factor in its own right has been recognised by Deedwania et al 7 and ATP III of the National Cholesterol Education Program 8. While there have been several studies on the prevalence of CAD in diabetics particularly in south India 9 and others 10, the exact prevalence of the metabolic syndrome and the importance of its individual components in the development of CAD is less well investigated in India. A recent study on young north Indian patients with CAD confirmed the association with metabolic syndrome, but * Department of Medicine, Patna Medical College Hospital, and Consultant Endocrinologist, Heart Hospital, Patna ** Medical Director, Heart Hospital, Patna, *** Department of Statistics, Patna University, Bihar.

2 the sample size was small and all the subjects were non diabetics with normal or impaired glucose tolerance. This study is an attempt to enhance the available knowledge in this field, as well as compare its relative importance with known and established risk factors. Research design and methods 928 patients having type 2 diabetes (602 males, 326 females) attending the out-patient or diabetic clinics of Heart Hospital, Kankarbagh, between were selected for this cross-sectional study. All patients had complete data including detailed history and physical examination which included examination of the waist-hip ratio (WHR), full biochemical data including a lipid profile, renal, hepatic, and thyroid function tests. Lipid profiles were taken from fasting blood samples; patient on lipid lowering drugs or other conditions that might alter the lipid profile were excluded from the study. Traditional risk factors for CAD like hypertension, smoking (cigarettes or bidis) were also considered in our analysis. The quality of diabetic control was assessed from the mean glycosylated haemoglobin (HbA1c) levels for one year during or prior to the study. The diagnosis of the metabolic syndrome was based on the following criteria as recommended by WHO 12 : 1. Impaired glucose regulation or diabetes. 2. Insulin resistance. 3. Raised arterial pressure 160/ Raised plasma triglyceride 150 mg/dl and/or low HDL cholesterol < 35 mg/dl in men, or < 39 mg/dl in women. 5. Central obesity (males: waist hip ratio, 0.9; females: waist to hip ratio 0.85) and/or generalised obesity (BMI30 kg/m 2 ). 6. Microalbuminuria: (UAER 20 g/min or albumin creatinine ratio 20 mg/g). To satisfy the criterion of metabolic syndrome, a patient needed to have either criterion (1) or (2) positive along with at least 2 of the 4 remaining criteria 2-6. Since all patients in the study were diabetic, insulin estimation was not considered necessary and the presence of 2 of 4 indirect criteria (criteria 2-6) was regarded as sufficient for the diagnosis. The diagnosis of coronary artery disease was based on the following criteria: 1. History of angina/mi with previously documented disease. 2. ECG following Minnesota codes 1-1, 4-1, 5-9, 5-2, or History of PTCA/CABG or angiographically documented disease. 4. A treadmill or stress echocardiogram study suggesting myocardial ischaemia. All patients who did not fulfill any of the criteria 1-3 had a stress test done in order to detect silent ischaemia. Patients with new or recent diagnosis of CAD were included in the study. Statistical analysis The data were analysed by standard statistical techniques: Student s test for interval data and Chi square for nominal data. A p-value less than 0.05 was regarded as significant. Presence of CAD was regarded as the dependent variable while other known and putative risk factors for CAD were independent variables. All these were subjected to multivariate logistic regression analysis using Minitab Statistical Software. Results The basic physical and biochemical characteristics of the diabetics are summarised in Table I. Males were significantly older, heavier, and had a higher waist/hip ratio (WHR). 596 (64.2%) patients fulfilled the criteria of the metabolic syndrome. Among the various constituents hypertriglyceridaemia was the most common, followed by obesity (of which visceral and generalised forms were present in nearly equal proportions), hypertension and microalbuminuria; low HDL cholesterol was the least common finding (Table II). The most common pattern of CAD was a history of stable angina/previous MI (301 patients, 52.6%). A positive stress test in asymptomatic diabetics was also fairly common (158 patients,27.6%) (Table IV). Journal, Indian Academy of Clinical Medicine Vol. 7, No. 1 January-March,

3 Table I: Basic physical and biochemical parameters and presence of metabolic syndrome. Males (n = 602) Females (n = 326) Mean P Age (years) ± ± ± 17.2 < 0.01 Duration of diabetes (yrs.) 8.62 ± ± ± 6.01 NS Mean wt. (kg) 60.4 ± ± ± 11.2 < 0.05 Mean waist-hip ratio (WHR) 0.89 ± ± < 0.01 Mean B. P. Systolic ± ± ± 19.7 NS Diastolic 87.4 ± ± ± 11.2 NS HbA1c (mean) 8.01 ± ± ± 1.32 NS Serum creatinine (mean) (mg/dl) 1.22 ± ± ± 1.02 NS Table II: Metabolic syndrome and type 2 diabetes analysis of individual components. Diabetics with Metabolic Syndrome = 596 (64.2%) Hypertension = 360 (38.9%) Obesity = 452 (48.7%) Generalised (combined with visceral) = 224* Visceral = 228 Hypertriglyceridaemia (triglycerides 150 mg/dl) = 516 (55.4%) Low HDL Cholesterol = 250 (26.9%) Microalbumiuria = 312 (33.6%) *All patients with generalised obesity also had visceral obesity; the reverse was not true. Of the 928 patients, 516 (55.6%) fulfilled at least one criterion of coronary artery disease. Diabetic patients with IHD were more often males and had a longer duration of diabetes. They were also significantly older than diabeties without CAD. They also had higher waist-hip ratio and mean body weight, systolic and diastolic BP. The quality of glycaemic control as manifested by glycosylated haemoglobin levels and renal function (serum creatinine levels) did not show any difference. Among traditional risk factors only an older age and smoking seemed very significant (Table III). The strongest correlation was found with obesity (both generalised and abdominal) and microalbuminuria. Hypertension was also associated with CAD but was weaker in significance. The other components of the metabolic syndrome (low HDL, elevated triglyerides) did not have any relationship with IHD. While elevated triglycerides were very common, levels were equally distributed in both groups (Table V). Mean total cholesterol level, LDL, and TC/HDL ratio showed an association, although comparatively weaker, with the presence of CAD (Table VI). An analysis of these data by multivariate logistic regression analysis (Table VII) showed that obesity (either central or generalised), older age, smoking history, nephropathy (manifested in most cases by microalbuminuria) and hypertension, in that order were important associations of CAD. The Metabolic syndrome (as a whole) was strongly associated with presence of CAD. On the contrary, an elevated triglyceride level or reduced HDL cholesterol failed to achieve statistical significance. The association of total cholesterol, LDL cholesterol, or HDL cholesterol was not found significant on multivariate analysis although it seemed to be weakly significant on univariate analysis (Table VI and VII). 34 Journal, Indian Academy of Clinical Medicine Vol. 7, No. 1 January-March, 2006

4 Table III: Comparison of some physical and biochemical features of the 2 groups of diabetics. Diabetes with Diabetes without P CAD (n = 516) CAD (n = 412) Mean age 59.4 ± ± 19.2 < 0.01 Sex Male Female Duration of diabetes (in yrs.) ± ± Mean wt. (kg) 61.3 ± ± 11.7 < 0.05 WHR (mean) 0.93 ± ± 0.12 < B.P. Systolic ± ± 19.1 < Diastolic 88.7 ± ± 10.7 Mean HbA1c 8.01 ± ± 2.26 NS Serum creatinine mg/dl (mean) 1.21 ± ± 0.68 NS Metabolic syndrome present < Metabolic syndrome absent < Smokers (recent or past 1 yr) < Table IV: Patterns of CAD in diabetics. Angina/previous MI 301 Treadmill/stress echo positive 158 Coronary angiography +ve 43 History of PTCA/CABG 14 Total 516 Discussion Both insulin resistance syndrome and coronary artery disease are very common in Asian Indians and it has been postulated that insulin resistance could probably be a culprit in the high prevalence of coronary artery disease in Indians 13. Type 2 diabetes is a heterogenous group and may be characterised by disorders of insulin action or insulin secretion, either of which may be a predominant feature. Haffner and coworkers 14 reported that insulin resistance was present in more than 85% of individuals with diabetes. The present study revealed a slightly lower prevalence of 64.2% possibly because indirect evidence (surrogate markers) of insulin resistance were used which are less sensitive than insulin stimulated glucose uptake by euglycaemic clamp technique. The prevalence of coronary artery disease was very high; more than half the patients (55.6%) with diabetes had some evidence of CAD. This is much higher than the figures of 17.8%, 15.7% and 19% respectively as reported by Mohan et al 9, Walia 10 and WHO 15. It is likely that the high prevalence was due to either: a. Late diagnosis of diabetes due to low socio-economic condition and poor health awareness. b. Presentation to a cardiac referral centre and a medical college hospital because of advanced or uncontrolled disease. c. Use of stress testing in all asymptomatic patients (the earlier studies by Walia and Mohan used only clinical and ECG criteria). As expected, there was a strong correlation of the metabolic syndrome as a whole with the presence of coronary artery disease. In particular, obesity and microalbuminuria was found to be markers for the presence of CAD. Older age was also a strong marker for CAD. This was in agreement with the results of Walia et al 10. Several other studies indicate that microalbuminuria is an indicator of early mortality from cardiovascular disease and maybe more important than the conventional risk factors. Elevated total cholesterol and LDL cholesterol showed a weak association with CAD on univariate analysis; however, this was not significant after multivariate analysis. Triglyceride and HDL cholesterol levels did not show any association at all with CAD. Journal, Indian Academy of Clinical Medicine Vol. 7, No. 1 January-March,

5 Table V: Correlation of the metabolic syndrome constituents with coronary artery disease. CAD present CAD absent P Metabolic syndrome present (n = 596) < Metabolic syndrome absent (n = 332) < Hypertension < 0.01 Obesity Generalised < Visceral Triglyeride level NS HDL Cholesterol NS Microalbuminuria or proteinuria < Table VI: Mean lipid levels in diabetes. Diabetes with Diabetes without P CAD (n = 516) CAD (n = 412) Mean total cholesterol (mg/dl) ± ± 32.8 < 0.05 Mean LDL cholesterol (mg/dl) ± ± Mean HDL cholesterol (mg/dl) ± ± 9.01 NS Mean triglyceride (mg/dl) ± ± NS TC / HDL ratio ± ± 0.36 < 0.05 Table VII: Logistic regression table (for all risk factors). Predictor Coeff. S.D. P value Odds ratio 95% C.I. Constant * Lower Metabolic syndrome (any combination) ** Age * Sex (male) Duration HbA1c TC HDL LDL VLDL TG Retinopathy Nephropathy (microalbuminuria) * Neuropathy Obesity (Generalised / visceral) ** Upper Hypertension * Smoking ** * Significant, ** Strongly significant 36 Journal, Indian Academy of Clinical Medicine Vol. 7, No. 1 January-March, 2006

6 A study by Ramachandran et al 19 indicated that central obesity was the most important cardiovascular risk factor in urban south Indians. Our study revealed that central as well as generalised obesity were nearly equally prevalent. In contrast to the study of Walia et al 10 and Mohan 9, abnormalities in lipid profile (e.g., elevated total cholesterol, LDL cholesterol, low HDL, abnormal TC/HDL ratio or high triglycerides did not appear to be significant factors on multivariate logistic regression analysis. The United Kingdom Prospective Diabetes Study (UKPDS) also indicated that elevated LDL cholesterol, decreased HDL cholesterol are major risk factors for CAD in diabetic subjects 20. The WHO multinational study and Paris prospective study 21 indicated that only hypertriglyceridaemia was significantly associated with CAD in diabetic patients. This observation requires further confirmation from detailed multicentric prospective studies on Indian diabetics. Another study by Mohan and others 22 in south India on the prevalence of diabetes, IGT and CAD indicated that only age and higher LDL cholesterol were associated with CAD; other factors did not achieve statistical significance. A study by Thulaseedharan and Augusti 23 showed similar results. There has been controversy about the importance of hypertriglyceridaemia as a risk factor for CAD 24, 25. However, a recent study by Rajmohan et al 26 on diabetic individuals surviving an MI showed no evidence of an association of isolated hypertriglyeridaemia with coronary artery disease. Our study did not show any association of triglycerides with CAD on multivariate analysis, and hence it is in agreement with the studies of Mohan and Rajmohan. The only recent major studies on the metabolic syndrome include a recent population based study by Isomaa and coworkers 27 in Finland and Sweden which concluded that the metabolic syndrome was present in 10% of subjects with normal glucose tolerance 50% of subjects with impaired fasting glucose or impaired glucose tolerance, and 80% of subjects with type 2 diabetes. The risk of coronary artery disease and stroke was markedly increased (nearly three-fold) in those with the syndrome and of the individual components microalbuminuria seemed the strongest predictor. Our results are slightly different in that obesity was more strongly associated with CAD than microalbuminuria. A more recent study by Lakka and coworkers in Finnish males 28 indicated that the metabolic syndrome as per WHO criteria was associated with times increased CVD mortality and times all cause mortality. These were also the findings of the San Antonio Heart Study 29. A recent study in India by Jhamb and others 30 has shown the importance of insulin resistance as a risk factor for carotid artery intima-media thickness (CCA-IMT), an indirect marker for atherosclerosis. It may therefore be summarised that both the metabolic syndrome and coronary artery disease are very common in type 2 diabetes. Obesity, microalbuminuria, and to a lesser extent hypertension, are strong markers indicating the presence of the latter supplanting the importance of many traditional risk factors. Among the traditional risk factors, only age and smoking seemed to be strongly significant. In a diabetic, with any of the components of the metabolic syndrome, a careful search should be made for the presence of CAD and all the associated conditions should be treated aggressively so that some of the profound and life threatening consequences of the disease may be prevented or alleviated. References 1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors and 12 years cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 1993; 16: Schwortz CJ, Valente AJ, Spraque EA et al. Pathogenesis of the atherosclerotic lesion: Implications for diabetes mellitus. Diabetes Care 1992; 15: Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and Cardiovascular Disease a statement for health care professionals from the American Heart Association. Circulation 1999; 100: Haffner Steven M, Lehto Seppo, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in non diabetic subjects with and without prior myocardial infarction. N Eng J Med 1998; 339: Reaven GM. Banting Lecture Role of insulin resistance in human disease. Diabetes 1988; 37: Mc Keigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 1991; 387: Fagan T, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med 1998; 105 (suppl 1A): Journal, Indian Academy of Clinical Medicine Vol. 7, No. 1 January-March,

7 8. Executive Summary of the 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: Mohan V, Premlatha G, Sastry NG. Ischaemic heart disease in South Indian NIDDM subjects. Int J Diabetes Dev Countries 1995; 15: Walia Meenu, Agrawal AK, Shah P et al. Prevalence of coronary risk factors in Non-insulin Dependent (Type 2) Diabetes. JAPI 1999; 47: Misra A, Reddy RB, Reddy KS et al. Clustering of impaired glucose tolerance, hyperinsulinaemia and dyslipidaemia in young north Indian patients with coronary heart disease a preliminary case control study. Indian Heart J 1999; 51 (3): Alberti KGMM, Zimmet PZ, for the WHO consultation: Definition and diagnosis of complications. Part I Diagnosis and Classification of diabetes mellitus provisional report of a WHO consultation. Diab Med 1998; 15: Mc Keigue PM, Muller GJ, Marmot MG. Coronary heart disease in south Asians overseas a review. J Clin Epidemiol 1989; 42: Haffner SM, Mietinin H. Insulin resistance implications for type 2 diabetes mellitus and coronary heart disease. Am J Med 1997; 103: Kelly MW, Ahuja MMS, Bennett PH et al. The role of circulating glucose and triglyceride concentrations and their interaction with other risk factors as determinant of arterial disease in nine diabetic population samples from the WHO multinational study. Diabetes Care 1983; 6 (4): Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S et al. Urinary albumin excretion: an independent predictor of ischaemic heart disease. Arteriosel Thromb Vasc Biol 1999; 19: Kuusisto J, Mykkanen L, Pyoralla K, Laakso M. Hyperinsulinaemic microalbuminuria: a new risk factor for coronary heart disease. Circulation 1995; 91: Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin dependent diabetes mellitus: a systemic overview of the literature. Arch Int Med 1997; 157: Ramachandran A, Snehalatha C, Latha E, Vijay V, Satyavani K. Culstering of Cardiovascular risk factors in urban Asian Indians. Diabetes Care 1998; 21: Turner RC, Millnus H, Neel HAW et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus. United Kingdom prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316: Fontbonne A, Eschwege E, Cambrene F et al. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality its subjects with impaired glucose tolerance or Diabetes: Results from the year follow-up of the Paris prospective study. Diabetelogia 1989; 32: Mohan V, Deep R, Rani SS, Premlatha C. Prevalence of Coronary artery disease and its relationship to lipids in a selected population in South India: the Chennai Urban Population Study (CUPS No. 5). J Am Coll Cardiol 2001; 38: Thulaseedharan N, Augusti KT. Risk factors for coronary heart disease in Non-insulin Dependent. Diabetes Mellitus Indian Heart J 1995; 47: Hokauson JE, Austin MA. Plasma triglyceride level as a risk factor for cardiovascular disease independent of HDL cholesterol level: A meta-analysis of population based prospective studies. J Cardiovasc Risk 1996; 3: Grundy SM. Hypertriglyceridaemia, atherogenic dyslipidaemia and the metabolic syndrome. Am J Cardiol 1998; 81: 18B. 26. Rajmohan L, Deepa R, Mohan Anjana, Mohan V. Association between Isolated Hypercholesterolaemia, Isolated Hypertriglyceridaemia and Coronary Artery Disease in South Indian Type 2 Diabetic Patients. Indian Heart J 2000; 52: Isomaa B, Almgren P, Tuomi T et al. Cardiovascular mortality and morbidity associated with the metabolic syndrome. Diabetes Care 2001; 24: Lakka HM, Laaksonen DE, Lakka TA et al. The metabolic syndrome and total and cardiovascular mortality in middle-aged men. JAMA 2002; 288: Hanley AJ, Williams K, Stern MP, Haffner SM. Homoeostasis model of insulin resistance in relation to the incidence of cardiovascular disease: The San Antonio Study. Diabetes Care 2002; 25: Jhamb Rajat,Gaiha M,Chakravarti AL, Daga MK.Insulin resistance/hyperinsulinaemia as a risk factor for Common Carotid artery Intima/Media thickness in Essential Hypertension.Journal of Indian Academy of Clinical Medicine (JIACM) 2005; 6 (2): Journal, Indian Academy of Clinical Medicine Vol. 7, No. 1 January-March, 2006