Risk variables for coronary artery disease in Asian Indians

Risk Variables for Coronary Artery Disease in Asian Indians Ambady Ramachandran, MD, PhD, Immaneni Sathyamurthy, MD, DM, Chamukuttan Snehalatha, MSc, DSc, Kumpatla Satyavani, MSc, MTech, Selvaraj Sivasankari, MSc, Jaya Misra, MBBS, Maligail R. Girinath, MS, MCh, and Vijay Viswanathan, MD, PhD No large study from India has addressed the association of risk variables with coronary artery disease (CAD) in angiographically proved cases. In this study, we analyzed the association of anthropometric variables, lipoproteins, and coagulation parameters with CAD in those cases proved by coronary angiography. A crosssectional study of 447 men >25 years old, classified as with CAD or without CAD, was performed. Men treated with aspirin or lipid-lowering agents, and those with renal, hepatic, or thyroid diseases were excluded. Associations of these variables with CAD were evaluated by univariate and multiple logistic regression analyses. The effect of diabetes on the CAD profile was also analyzed. Prevalences of diabetes and hypertension were significantly higher among those with CAD (p <0.001

for both). Lipid profile abnormalities, except lipoprotein (Lp(a)), were associated with CAD. Antibodies to oxidized low-density lipoprotein was higher in patients with CAD. Fibrinogen levels were higher in CAD, but plasminogen activator inhibitor-1 did not show an association with CAD. In the multiple logistic regression analysis, age, body mass index, very-low-density lipoprotein cholesterol, total to high-density lipoprotein cholesterol ratio, and fibrinogen showed significant independent association with CAD. Several lipid abnormalities were associated with CAD in Asian Indians, but no significant association was seen with Lp(a) levels. 䊚2001 by Excerpta Medica, Inc. (Am J Cardiol 2001;87:267–271)

ecent studies from India show that the prevalence of coronary artery disease (CAD) in the native R matches the high prevalence in urban population

METHODS

1–3

migrant Indians.4 –7 High prevalence as well as a clustering of several cardiovascular risk factors have been observed in the urban south Indian population.1 Conventional risk variables do not explain the excess prevalence of CAD among Asian Indians in the United Kingdom4 and in the United States6; insulin resistance has been considered to be the probable cause for the differences between Asian Indians and the white populations. The prevalence of diabetes is also high in Asian Indians,4,8 which further increases the risk of CAD.9,10 So far, no large study from India has reported on the association of lipid parameters and the previously mentioned variables with angiographically proved CAD. In this study, we analyzed the association of anthropometric variables, lipid parameters, including apolipoproteins-A1 and -B and lipoprotein(a) (Lp(a)), oxidized low-density lipoprotein (LDL) antibodies, fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) with angiographically proved CAD, in nondiabetic and diabetic subjects in India. From the Diabetes Research Centre and M.V. Hospital for Diabetes; and Cardiology Department, Apollo Hospital, Madras, India. Manuscript received May 22, 2000; revised manuscript received and accepted August 7, 2000. Address for reprints: Ambady Ramachandran, MD, PhD, Diabetes Research Centre and M.V. Hospital for Diabetes, 4, Main Road, Royapuram, Madras-600 013, India. E-mail: ramachandran@ vsnl.com. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 February 1, 2001

Subjects: The study group consisted of 447 men ⱖ25 years old (220 subjects from southern India and 227 from other parts of the country) who underwent coronary angiography for typical or atypical chest pain from February to July 1999. Men receiving aspirin or lipid-lowering agents, and those with renal, hepatic, or thyroid diseases were excluded from the study. Classification was assessed as follows: group 1 (no coronary artery disease), subjects without any electrocardiographic or echocardiographic evidence of myocardial infarction and with angiographically normal coronary arteries; and group 2 (subjects with CAD), all patients with electrocardiographic or echocardiographic evidence of myocardial infarction and those with obstructive lesions (ⱖ50%) on coronary angiography in any of the coronary arteries or their branches. Informed consent of the patients and the approval of the ethics committees of the Diabetes Research Center and Apollo Hospitals were obtained for the study. Height, weight, waist, and hip measurements were made using standard procedures; body mass index (kilograms per square meter) and waist-to-hip ratio were also calculated. Details of demographic and clinical history, family history of diabetes, ischemic heart disease and hypertension, smoking, and alcohol consumption were recorded by personal interview. Biochemical investigations: Blood samples for laboratory investigations were collected after a 12-hour overnight fast and were aliquoted into tubes contain0002-9149/01/$–see front matter PII S0002-9149(00)01356-4

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ing appropriate anticoagulants for different assays listed below. Plasma glucose was estimated by glucose oxidase peroxidase method. Glycosylated hemoglobin (HbA1C) was estimated by the turbidimetric inhibition immunoassay using hemolyzed whole blood. The Tina-quant hemoglobin-A1C kit (Boehringer-Mannheim, Mannheim, Germany) was used on the Hitachi auto analyzer 902 (Hitachi, Boehringer). The intraassay coefficient of variation was ⬍6.2%. Lipids: Fresh fasting serum samples were used for estimation of total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, Lp(a), apolipoprotein-A1 and apolipoprotein-B. Very-low-density lipoprotein (VLDL) cholesterol was calculated by Friedwald’s formula and low-density lipoprotein (LDL) cholesterol was obtained by subtracting the sum of VLDL cholesterol and HDL cholesterol fractions from the total cholesterol values. Ratios of total cholesterol to HDL cholesterol and LDL cholesterol to HDL cholesterol were calculated. Lp(a), apolipoprotein-A1 and apolipoprotein-B were estimated by the immunoturbidimetric methods using the kits supplied by Boehringer Mannheim (Tina-quant reagents). The lowest detection limit for Lp(a) was 0.06 g/L and the intra-assay variations were ⬍4.5%. The intra-assay coefficient of variation for apolipoprotein-A1 was ⬍5.6%; it was ⬍3.6% for apolipoprotein-B. The ratio of apolipoprotein-A1 to apolipoprotein-B was calculated. All the lipid parameters were estimated using the Hitachi 902 system. Coagulation factors: Fibrinogen content was estimated in citrate plasma, stored at ⫺70°C using reagents (Pacific Hemostasis, Huntersville, North Carolina). PAI-1 was estimated in citrate plasma by the enzyme-linked immunosorbent assay procedure using a commercial kit supplied by Innogenetics N.V. (Brussels, Belgium). Oxidized LDL antibodies were estimated in serum samples (stored at ⫺70°C) using enzyme-linked immunosorbent assay reagents (BIOMEDICA, Geselleschaft, Germany). Hypertension was defined as systolic blood pressure ⱖ140 mm Hg and/or diastolic blood pressure ⱖ90 mm Hg on ⱖ2 occasions, and/or history of antihypertensive therapy. Glucose tolerance was classified as normal if the fasting plasma glucose was ⬍110 mg/dl (⬍6.1 mmol/ L), and as impaired if fasting glucose ranged from 110 to 125 mg/dl (6.1 to 6.9 mmol/L). Diabetes was diagnosed if the fasting plasma glucose was ⱖ126 mg/dl (7.0 mmol/L) or if there was a definite history of diabetes with records of treatment.11 Statistical analysis: Group means were compared by analysis of variance or t test. Skewed variables were log transformed before the analysis. The mean and SD reported for such variables are the antilogged values. For parameters significantly correlated to age, mean of age-adjusted values were used for comparisons. Interquartile ranges of the biochemical variables were calculated using the nondiabetic, non-CAD cases as the control group. The prevalence of CAD in quartiles of each biochemical parameter was computed for the 268 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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total group, for both nondiabetic and diabetic subjects. A test of trend across the quartiles was done by trend chi-square test and a test for general association between the quartiles of the variables and CAD was also performed using the chi-square test, with Yate’s correction. Multiple logistic regression analyses were done to identify the association of the anthropometric, hemodynamic, and biochemical variables with CAD. The variables were dichotomized, either as positive and negative, or as above and below the reference median value (control group).

RESULTS Among the 447 men selected, 271 subjects had symptoms or history suggestive of cardiac disease. Among these subjects, 184 had angina, 81 had a history of myocardial infarction, 4 had recurrent angina after coronary bypass surgery, and 2 patients had left ventricular dysfunction. All these 271 subjects had CAD findings on angiography. The remaining 176 subjects had atypical chest pain, 9 of whom had CAD findings on angiography. No evidence of CAD was seen in 167 patients (group 1 without CAD) and in 280 patients (group 2 with CAD). Prevalence of diabetes was higher in group 2 (n ⫽ 146, 52.1%) compared with group 1 (n ⫽ 55, 32.9%) (chi-square 14.8, p ⬍0.0001). Prevalence of CAD was 53.7% in normoglycemic subjects (95 of 177), 53.6% in subjects with impaired fasting glucose (37 of 69) (chi-square 8.6, p ⫽ 0.003 vs normal), and 73.6% in diabetic subjects (148 of 201) (chi-square 15.5, p ⬍0.001 vs normal). Hypertension was also more prevalent in group 2 (58.5%) compared with group 1 (42.7%) (chi-square 10.2, p ⫽ 0.0014). The median values of systolic and diastolic blood pressure in nonhypertensive subjects were 130 and 84 mm Hg, respectively. In group 1, 125 patients (74.8%) had values above the median of either or both the blood pressure readings, and in group 2, 247 patients (88.2%) had similar high values (chi-square 12.4, p ⬍0.004). Rates of smoking (37.8% in group 1 and 40.4% in group 2) and alcohol consumption (19.8% in group 1 and 22.2% in group 2) were similar in both groups. Prevalence of 3-vessel disease was seen more in the diabetic subjects with CAD (n ⫽ 90, 70.9%) compared with the nondiabetic subjects with CAD (n ⫽ 56, 50.9%) (chi-square 9.1, p ⬍0.003). Table 1 shows the comparison of the anthropometric and biochemical profiles of the 2 groups. The values of fasting plasma glucose, glycosylated hemoglobin, LDL cholesterol, apolipoprotein-A1, fibrinogen, and oxidized LDL antibodies were corrected for age before statistical comparison. Age, body mass index, and waist-to-hip ratio were significantly higher in patients with CAD. All the lipid parameters except Lp(a) were significantly higher, and HDL cholesterol was significantly lower in group 2. Antibodies to oxidized LDL showed a significant negative correlation with PAI-1 only in control subjects (nondiabetic patients without CAD) and its levels were also higher in group 2. Lp(a) concentrations were highly skewed and the FEBRUARY 1, 2001

TABLE 1 Anthropometric and Biochemical Characteristics of Subjects With and Without CAD

DISCUSSION

We have investigated the risk variables associated with patients Group 1 Group 2 with CAD compared with patients Without CAD With CAD without CAD, classified on the basis (n ⫽ 167) (n ⫽ 280) p Value of coronary angiography. The study Age (yrs) 47.8 ⫾ 10.5 56.2 ⫾ 8.8 ⬍0.001 population was from different parts 2 Body mass index (kg/m ) 24.1 ⫾ 3.7 25.2 ⫾ 3.9 0.003 of urban India and the patients beWaist:hip ratio 0.93 ⫾ 0.06 0.94 ⫾ 0.05 0.03 † longed to the upper-middle and high Fasting plasma glucose (mmol/L) 6.4 ⫾ 2.1 7.3 ⫾ 2.7 ⬍0.001 Glycosylated hemoglobin (%)† 6.6 ⫾ 1.6 7.2 ⫾ 1.6 ⬍0.001 socioeconomic class. It is well Lipids (mmol/L) known that the risk of CAD is higher Cholesterol 5.0 ⫾ 1.0 5.3 ⫾ 1.2 0.001 in patients with diabetes mellitus.9,10 Triglycerides* 1.6 ⫻/⫼ 0.02 1.8 ⫻/⫼ 0.02 0.007 † Although this study was not deLDL cholesterol 3.1 ⫾ 0.9 3.5 ⫾ 1.1 0.002 signed to estimate the risk of CAD HDL cholesterol* 1.0 ⫻/⫼ 0.03 0.9 ⫻/⫼ 0.03 0.05 VLDL cholesterol* 0.7 ⫻/⫼ 0.04 0.8 ⫻/⫼ 0.04 0.005 conferred by diabetes, the observaLDL cholesterol/HDL cholesterol 3.2 ⫻/⫼ 1.4 3.6 ⫻/⫼ 1.4 0.001 tion of a high proportion of diabetes Cholesterol/HDL cholesterol 5.3 ⫾ 1.3 5.8 ⫾ 1.5 ⬍0.001 in subjects with CAD (52.1% vs † Oxidized LDL antibodies (mU/ml)* 325 ⫻/⫼ 2.6 416 ⫻/⫼ 2.1 0.015 32.9%, p ⬍0.001) has suggested that Apo-A1 (gm/L)† 1.07 ⫾ 0.17 1.03 ⫾ 0.14 0.01 Apo-B (gm/L) 1.01 ⫾ 0.22 1.09 ⫾ 0.26 0.001 there is a high risk conferred by diApo-A1 /ApoB 1.07 ⫻/⫼ 1.3 1.05 ⫻/⫼ 1.3 ⬍0.001 abetes. There was also a higher prevLp(a) (mg/dl)* 20.0 ⫻/⫼ 3.4 23.0 ⫻/⫼ 3.3 NS alence of hypertension in the CAD PAI-1 (ng/ml)* 94.9 ⫻/⫼ 1.4 97.2 ⫻/⫼ 1.5 NS † group. Rates of smoking and alcohol 2.98 ⫾ 0.87 3.55 ⫾ 0.99 ⬍0.001 Fibrinogen (gm/L) consumption did not differ between *Geometric mean ⫻/⫼ SD; †age-adjusted values. groups 1 and 2. Other values expressed as mean ⫾ SD. Univariate analysis showed that Conversion factors: glucose: mg/dl ⫽ mmol/l ⫻ 18; cholesterol: mg/dl ⫽ mmol/L ⫻ 38.7; triglycgeneral adiposity (body mass index) erides; mg/dl ⫽ mmol/L ⫻ 88.6. and upper body adiposity (waist-tohip ratio) were significantly related to CAD. Body mass index was indegeometric mean values were not significantly dif- pendently and significantly associated with CAD, ferent between the 2 groups. Concentrations of even after adjusting for age. Mean body mass index of PAI-1 also did not differ between the groups. the controls and the subjects with CAD was lower Plasma fibrinogen concentrations were higher (p compared with their Western counterparts, reflecting ⬍0.001) in the subjects with CAD. There was no the trend in the general population in India and significant intragroup differences in any of the vari- abroad.6,8 The mechanism of insulin resistance itself seems to be different in ethnic groups with differences ables in 1- or 3-vessel disease (data not shown). Table 2 shows the association and the trend in in the risk of CAD, as suggested by a recent study prevalence of CAD in the quartiles of the biochemical from the United Kingdom that examined intramyocelvariables studied. In the total group and in the nondi- lular lipid content and failed to find a direct correlation abetic group significant associations were noted be- with insulin resistance in Indians, unlike that in Cau12 tween CAD and variables other than HDL cholesterol, casians. The only difference between the diabetic and nonLp(a), and PAI-1. Strongest associations of CAD were diabetic patients with CAD was the presence of a seen with low values of apolipoprotein-A1 and apolihigher fibrinogen level in the former group. The inpoprotein-B ratios and fibrinogen values (p ⬍0.0001). creasing trend and association of CAD with the quarIn the diabetic subjects no such significant association tiles of the risk variables was seen only in the nondiwas seen with any of the variables. There was an abetic and total group. In the diabetic group, the increasing trend for CAD with increasing quartiles of prevalence of CAD across the quartiles was not sigfibrinogen (p ⫽ 0.012), but there was a lack of asso- nificantly different, indicating a general increase in the ciation. Fibrinogen was the only variable found to be risk variables with the development of diabetes. The higher in the diabetic subjects with CAD when com- Multiple Risk Factor Intervention Trial demonstrated pared with the nondiabetic subjects with CAD (3.64 ⫾ that risk factors such as hypertension, hypertriglycer1.04 vs 3.38 ⫾ 0.87 g/L, p ⬍0.05). idemia, hyperinsulinemia, low HDL cholesterol, and Age, body mass index, VLDL cholesterol, LDL/ obesity were operative in a qualitatively similar fashHDL cholesterol ratio, and fibrinogen showed signif- ion both in the diabetic and nondiabetic subjects.9 icant independent association with CAD (Table 3). However, at any given cholesterol level, the risk of Age, body mass index, and triglycerides showed sig- CAD mortality was higher in the diabetic cohort than nificant association with CAD when oxidized LDL in the nondiabetic cohort. was included in the analysis. Age, triglycerides, and Univariate analysis showed that cholesterol, triLDL cholesterol were significantly associated with glycerides, and abnormalities in the fractions of choCAD in the third model, which also included PAI-1 lesterol and oxidized LDL antibodies were signifi(n ⫽ 177). cantly associated with CAD. In the multivariate analCORONARY ARTERY DISEASE/CAD RISK VARIABLES

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TABLE 2 Trend in Prevalence of CAD in the Quartiles of the Biochemical Variables in the Total Cohort and in Nondiabetic Subjects CAD (%) Prevalence in Quartiles

Cholesterol LDL cholesterol Oxidized LDL antibodies HDL cholesterol* Triglycerides VLDL cholesterol Apo-A1* Apo-B Apo-A1/B* Lp(a) Fibrinogen PAI-1

Total Cohort

Nondiabetic subjects

1

2

3

4

Trend Chi-Square

Chi-Square for Association df 3

Trend Chi-Square

Chi-Square for Association df 3

56 58 39 70 52 52 74 57 79 62 51 55

54 53 59 61 62 61 59 51 67 62 56 47

69 68 65 65 67 68 68 68 56 61 63 57

72 72 45 55 69 69 52 74 51 66 81 60

9.4† 8.2† 0.9† 4.2† 7.5† 7.5† 7.8† 10.1‡ 23‡ 0.2 22.6‡ 0.7

11.3† 11.6† 13.7† 5.8 8.19 8.19 13.6† 14.0† 23.6† 0.6 24.9‡ 2.2

12.1‡ 12.8‡ 1.3 2.3 7.4† 8.7† 6.5‡ 15.5‡ 25.2‡ 0.1 11.9‡ 0.1

16.8‡ 15.1† 3.9 4.3 10.6† 11.0† 10.4† 21.6‡ 25.5‡ 0.2 14.9‡ 1.7

*Highest values in quartile 1. † p ⱕ 0.05; ‡p ⱕ 0.001; other parameters showed no significance. Diabetic subjects are not shown (see below and text). In diabetic subjects there was a significant trend with fibrinogen (chi-square 6.3, p ⫽ 0.012) but no significant association (chi-square 6.6, p ⫽ 0.09) with CAD; oxidized LDL antibodies showed an association with CAD in diabetes only (chi-square 13.0, p ⫽ 0.005). Apo ⫽ apolipoprotein; df ⫽ degrees of freedom.

risk level of these parameters is lower for Indians than for Western populations.17 ␤ SE OR CI p Value Fibrinogen was an independent Without PAI-1 and Oxidized LDL Antibodies (n ⫽ 447) risk factor for CAD in Asian Indians, with higher values in the diabetic Age 0.10 0.01 1.1 1.07–1.13 ⬍0.001 subjects with CAD. Fibrinogen has Body mass index 0.56 0.24 1.74 1.09–2.8 0.019 VLDL cholesterol 0.48 0.24 1.61 1.0–2.6 0.049 been reported to be a part of the Cholesterol/HDL cholesterol 0.50 0.24 1.65 1.03–2.6 0.037 metabolic syndrome and an indepenFibrinogen 0.48 0.23 1.61 1.0–2.5 0.033 dent proarteriosclerotic agent.18 PAI-1 did not have a significant Without PAI-1 (n ⫽ 291) association with CAD in this study, in contrast to reports on other ethnic Age 0.11 0.02 1.12 1.08–1.2 ⬍0.001 Body mass index 0.57 0.29 1.77 1.0–3.1 0.048 groups.19,20 PAI-1 concentration Triglycerides 0.83 0.28 2.29 1.3–4.0 0.003 might be dependent on insulin resistance as shown by Haffner et al.20 In Oxidized LDL Antibodies ⫹ PAI-1 ⫹ All Other Variables (n ⫽ 177) this study, we did not measure insulin concentrations. We did not obAge 0.10 0.02 1.05 1.06–1.1 ⬍0.001 serve any correlation between the Triglycerides 0.96 0.37 2.61 1.3–5.4 ⬍0.001 LDL cholesterol 0.94 0.35 2.56 1.3–5.1 ⬍0.008 Lp(a) levels and CAD. Lp(a) concentrations were highly skewed, varying *Age-adjusted values were used. from ⬍0.1 to 189 mg/dl even in the Independent variables: age, body mass index, waist:hip ratio, glycosylated hemoglobin,* hypertension, cholesterol, triglycerides, LDL cholesterol,* HDL cholesterol, LDL/HDL cholesterol, cholesterol/HDL nondiabetic patients without CAD. cholesterol, oxidized LDL antibodies,* VLDL cholesterol, apolipoprotein-A1, *apolipoprotein-A1/apoliTwo other angiographic studies from poprotein-B, Lp(a), PAI-1, fibrinogen.* India21,22 failed to observe an assoSignificant variables are shown. ciation, whereas a few other studies CI ⫽ confidence interval; OR ⫽ odds ratio. have found an association of Lp(a) with CAD in Indians.23,24 The reasons for the differences may be due ysis, VLDL cholesterol and the ratio of total to differences in criteria of classification of CAD as cholesterol to HDL cholesterol were found to be well as in the methods of estimation of Lp(a). Craig et strongly and independently associated with CAD. al,25 in a meta-analysis, also observed that the sepaSeveral other studies have also found the ratio to be ration in values between the cases and controls was superior in predicting the risk of CAD.13,14 In our not sufficient to allow the use of Lp(a) as a screening study group, increased triglycerides was also associ- test. Because sample storage might affect Lp(a) valated with CAD, in accordance with similar observa- ues, we estimated Lp(a) in freshly collected, fasting tions made in earlier studies.15–17 It appears that the serum samples. The mean concentration of Lp(a) in TABLE 3 Results of Multiple Logistic Regression Analyses: Dependent Variable CAD Versus Non-CAD

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Indians living in southern India was higher than the values in white population,26 and the values agreed with the other reports on Indian populations.23,24,26 The role of Lp(a) in CAD needs further analysis, probably by studying its phenotypes, which account for most of the variations in its concentrations. Several lipid parameters and fibrinogen were associated with CAD in Indians, but Lp(a) showed no association with CAD in this study. Only prospective studies will offer explanations for the major variations seen in the nature of risk variables associated with CAD in the Indian population. Acknowledgment: We thank Cholayle Kizhake Sathish Kumar, BS, for helping in the collection of blood samples.

1. Ramachandran A, Snehalatha C, Latha E, Satyavani K, Vijay V. Clustering of

cardiovascular risk factors in urban Asian Indians. Diabetes Care 1998;21:967– 971. 2. Mohan V, Premalatha G, Sastry NG. Ischaemic heart disease in south Indian NIDDM patients—a clinic based study on 6597 NIDDM patients. Int J Diab Dev Countries 1995;15:64 – 67. 3. Gopinath N, Chadha SL, Sehgal A, Shekhawat S, Tandon R. What is a ‘desirable’ lipid profile? Ind Heart J 1994;46:325–327. 4. McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 1991;337:382–386. 5. Shaukat N, de Bono DP. Are Indo-origin people especially susceptible to coronary artery disease? Postgrad Med J 1994;70:315–318. 6. Enas EA, Yusuf S, Mehta JL. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol 1992;70:945–949. 7. Balarajan R. Ethnicity and variations in mortality from coronary heart disease. Health Trends 1996;28:45–51. 8. Ramachandran A, Snehalatha C, Latha E, Vijay V, Viswanathan M. Rising prevalence of NIDDM in urban population in India. Diabetologia 1997;40:232– 237. 9. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434 – 444. 10. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229 –234.

11. Alberti KGMM, Zimmet PZ, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: Diagnosis and classification of diabetes mellitus—provisional report of a WHO consultation. Diabetic Med 1998;15:539 –553. 12. Forouhi NG, Jenkinson G, Thomas EL, Mullick S, Mierisova S, Bhonsle U, McKeigue PM, Bell JD. Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and south Asian men. Diabetologia 1999;42:932–935. 13. Stampfer MJ, Sacks FM, Simonetta S, Willet WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins and the risk of myocardial infarction. N Engl J Med 1991;325:373–380. 14. Simons LA. Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol 1986;57:5G–10G. 15. Taskinen MR. Broader metabolic control in diabetes management. Diabetes Metabol Rev 1998;14:S39 –S43. 16. Turner RC, Millns H, Neil HAW, Stratton IM, Manley SE, Matthews DR, Holman RR, United Kingdom Prospective Diabetes Study Group. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study. BMJ 1998;316:823– 828. 17. Krishnaswami S, Prasad NK, Jose VJ. A study of lipid levels in Indian patients with coronary artery disease. Int J Cardiol 1989;24:337–345. 18. Bruno G, Cavallo-Perin P, Bargero G, D’Errico N, Borra M, Macchia G, Pagano G. Hyperfibrinogenemia, metabolic syndrome and coronary heart disease in type 2 diabetes: a population based study. Diabetologia 1999;42(suppl 13):A6. 19. Wagner AM, Bonet R, Perez A, Castellvi A, Calvo F, Ordonez J. Apolipoprotein (B) identifies dyslipidemic phenotypes associated with cardiovascular risk in normocholesterolemic type 2 diabetic patients. Diabetes Care 1999;22: 812– 817. 20. Haffner SM, Rewers M, D’Agostino R, Selby J, Mykkanen L, Savage PJ, Tracy R, Saad MF, Howard B. Insulin sensitivity in subjects with type 2 diabetes: relationship to cardiovascular risk factors: the insulin resistance atherosclerosis study. Diabetes Care 1999;22:562–568. 21. Jose VJ, Baruah, Selvakumar D, Selvakumar, Kanagasababathy, Jayaseelan. Serum lipoprotein (a) levels in ischemic heart disease. J Assn Phys India 1997; 45:766 –768. 22. Bahl VK, Vashist S, Chandra S, Sharma M, Wasir HS. Association of plasma proteins with angiographically defined coronary artery disease. Ind Heart J 1995;47:244 –247. 23. Mohan V, Rema M, Deepa R, Sastry NG, Haranath SP, Enas EA, Premalatha G. Lipoprotein (a) is an independent risk factor for coronary artery disease in NIDDM patients in South India. Diabetes Care 1998;21:1819 –1823. 24. Anand SS, Enas EA, Pogue J, Haffner S, Pearson T, Yusuf S. Elevated lipoprotein (a) levels in South Asians in North America. Metabolism 1998;47: 182–184. 25. Craig WY, Neveux LM, Palomaki GE, Cleveland MM, Haddow JE. Lipoprotein (a) as a risk factor for ischemic heart disease: meta analysis of prospective studies. Clin Chem 1998;44:2301–2306. 26. Bhatnagar D, Anand IS, Durrington PN, Wander GS, Mackness MI, Creed F, Tomenson B, Chandrashekhar Y, Winterbotham M, Britt RP, Keil HE, Sutton GC. Coronary risk factors in people from the Indian subcontinent living in West London and their siblings in India. Lancet 1995;345:405– 409.

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