Dyslipidemia refers to the derangements of one or many

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1 Dyslipidemia in Asian Indians : Determinants and Significance A Misra*, Kalpana Luthra**, NK Vikram* Update Article Abstract Data suggest that lipid fractions other than total cholesterol, i.e. serum triglycerides (TG) and highdensity lipoprotein (HDL) cholesterol are important for the pathogenesis of atherosclerosis. A combination of hypertriglyceridemia, low levels of HDL-cholesterol and high levels of small dense lowdensity lipoprotein, termed as atherogenic dyslipidemia, is particularly seen in Asian Indians. Although precise reason for such dyslipidemia is unknown, genetic predisposition and characteristic body composition (excess truncal subcutaneous fat and intraabdominal fat) may be important contributors. A common interface between such body composition and dyslipidemia in Asian Indians is high tendency to develop insulin resistance, more than the other ethnic groups. The general guidelines for the management of dyslipidemia in Asian Indians should be according to National Cholesterol Education Program, Adult Treatment Panel III. However, optimal management requires consideration of ethnicspecific dietary, lifestyle and management factors to formulate individual treatment guidelines. INTRODUCTION Dyslipidemia refers to the derangements of one or many of the lipoproteins; elevations of total cholesterol, lowdensity lipoprotein (LDL) cholesterol and/or triglycerides, or low levels of high-density lipoprotein (HDL) cholesterol while elevation of lipoproteins alone is labeled as hyperlipidemia. The term atherogenic dyslipidemia denotes a combination of elevated triglycerides and small-dense LDL particles, and low levels of HDL- cholesterol. Dyslipidemia may result from over-production or lack of clearance of the lipoprotein particles, or may be related to other defects in the apolipoproteins or metabolic enzyme deficiencies. The pathways and means of lipid metabolism in the human body reflect interactions of genetics, complex biochemical processes influenced by medical disorders, medications, and/or environmental factors. A primary dyslipidemia (e.g. familial hypercholesterolemia) typically refers to a genetic defect in the lipid metabolism that causes abnormal lipid levels. A secondary dyslipidemia may be due to a variety of reasons; environmental factors (diet rich in saturated fat or a sedentary lifestyle), diseases (type 2 diabetes, hypothyroidism, obstructive jaundice etc.), and medications (thiazide diuretics, progestins, anabolic steroids etc.). Secondary dyslipidemias could be corrected or ameliorated by treating the underlying disorder. *Dept. of Medicine; **Biochemistry, All India Institute of Medical Sciences, New Delhi , India. Received : ; Accepted : Dyslipidemia, particularly hypercholesterolemia and atherogenic dyslipidemia, have been closely implicated in the pathogenesis of coronary heart disease (CHD). A great deal of attention has been recently given to Asian Indians because of high prevalence of CHD in this ethnic group. The following discussion will focus on the salient features and recent knowledge in dyslipidemia, particularly in reference to Asian Indians. We shall not be including discussion on lipoprotein(a) in this review. We researched the topic using the following keywords Asian Indians, Asians South Asians and Indians and dyslipidemia, hyperlipidemia triglycerides HDL-cholesterol from Pubmed database (National Library of Medicine, Bethesda, MD, USA) and from the non-indexed publications of relevant governmental institutions in India. We also tabulated the average levels of serum triglycerides and HDL- cholesterol in Asian Indians residing in India and compared them with those of Caucasians from pooled data of various studies in Figs. 2 and 3. These data may not be strictly comparable; nonetheless interesting differences were noticed as discussed later. Atherogenic Dyslipidemia and Small-dense LDL Hypertriglyceridemia is a marker for the abnormal lipoprotein pattern known as the atherogenic lipoprotein phenotype that consists of raised triglyceride levels and small-dense LDL particles, and low HDL-cholesterol levels. The latter two abnormalities occur due to an increase in the triglyceride component of triglyceride-rich lipoproteins 1,2 and increased activity of hepatic lipase. 3 The composition of particles within a particular class may differ significantly. In JAPI VOL. 52 FEBRUARY

2 the case of LDL particles, some are larger and more buoyant (LDL A), whereas others are smaller and denser (LDL B). 4 The LDL A particles contain more cholesterol ester per particle than do the LDL B particles. When a triglyceride from verylow density lipoprotein (VLDL) is exchanged for a cholesterol ester in LDL by the action of the enzyme cholesterol ester transfer protein (CETP), the VLDL becomes enriched in cholesterol ester, and LDL becomes enriched in triglyceride. Further, the triglyceride in LDL is hydrolyzed by lipoprotein lipase or hepatic lipase resulting in a smaller, denser LDL particle. Thus, increased VLDL secretion results in increased generation of small-dense LDL particles, which more likely when serum triglyceride concentrations are > 1.5 mmol/l. 5-7 High levels of small dense LDL promote atherogenesis by the following mechanisms: a) rapid infiltration of small dense LDL into the arterial wall than do normal-sized LDL; b) increased susceptibility to retention in the extracellular matrix 8 and c) increased oxidation. 9 Evidence for increased atherogenicity of small-dense LDL particle emanates from the epidemiological association studies. Low levels of HDLcholesterol are often caused by the core lipid exchanges, as well as accelerated clearance of HDL particles, explaining frequent occurrence of hypertriglyceridemia and low HDLcholesterol levels. Abnormal Regional Fat Distribution and Dyslipidemia (Fig. 1) Individuals with abnormal fat distribution, characterized by a high waist-to-hip circumference ratio or high truncal subcutaneous fat appear to be predisposed to developing insulin resistance and dyslipidemia. 10,11 Such a body composition is commonly seen in Asian Indians Patients with upper body obesity have higher levels of non-esterified fatty acids (NEFAs) than do those with lower body obesity, and the effect is further enhanced in the presence of resistance to the action of insulin on abdominal adipocytes. In the presence of excess NEFAs hepatic glucose output is increased. In addition, hepatic steatosis occurs and VLDL output from liver increases markedly that reduces HDLcholesterol due to the mechanisms outlined earlier, thus Fig. 1: Metabolic events leading to atherogenic dyslipidemia in Asian Indians NEFAs: Non-esterified fatty acids, VLDL: Very low-density lipoprotein, : Combination of lipoprotein abnormalities constituting atherogenic dyslipidemia, CETP: Cholesterol-ester transfer protein, HDL: High-density lipoprotein, LDL: Low-density lipoprotein. Thick arrows indicate major direction of metabolic events. increasing concentration of small-dense LDL. Hepatic clearance of insulin is decreased causing further hyperinsulinemia. Finally, lipids tend to accumulate in the skeletal muscles (intra-myocellular lipids, IMCL) and interfere with the action of insulin. 17 Insulin resistance, hyperglycemia and dyslipidemia are end-points of complex metabolic interactions. Dyslipidemia in Asian Indians Investigations from several groups, including ours, have shown that Asian Indians are predisposed to develop type 2 diabetes, proatherogenic metabolic abnormalities (metabolic syndrome, insulin resistance syndrome) and CHD. 12,18-23 The metabolic syndrome is a constellation of risk factors such as abdominal obesity, insulin resistance, glucose intolerance, hypertriglyceridemia, low levels of HDL-cholesterol and elevated blood pressure occurring in the same individual. 18,24 Atherogenic dyslipidemia is associated with metabolic syndrome and may be responsible for accelerated atherosclerosis. 8 It is opined that although the total cholesterol levels in Asian Indians is similar or lower as compared to Caucasians, 25 and atherogenic dyslipidemia is more common, which may contribute to CHD. Table 1 shows representative investigations of dyslipidemia in the Asian Indians residing in India. We have selected only those studies that were population-based and consisted of a substantial subject sample. Overall the prevalence of dyslipidemia ranged from 10-73%. Specifically, prevalence of hypercholesterolemia was 28% in urban subjects as compared to 22% in the rural subjects. 26 In urban New Delhi, the prevalence rate of hypertriglyceridemia was 61% in non-obese subjects as compared to ~73% in obese subjects. 27 Subjects belonging to low socio-economic stratum and residing in the urban slums also showed substantial prevalence of hypercholesterolemia (~27%) and hypertriglyceridemia (~12-17%). 16,28 However, it is difficult to compare observations of the various studies due to different sampling procedures, heterogeneity in the population samples, different methodologies used for estimations of lipoproteins and different cut-offs taken to define dyslipidemia. Figs. 2 and 3 show average levels of serum triglycerides and HDL-cholesterol from collated data from several studies in various subpopulations of Asian Indians as compared with Caucasians, respectively. The serum triglyceride levels are highest in urban Asian Indians residing in India and migrant Asian Indians. Further, even the average serum triglyceride level of rural-based Asian Indians is higher that Caucasians (Fig. 2). The highest average levels of HDL-cholesterol among Asian Indians have been reported from the physically active Asian Indians residing in rural India (Fig. 3). Gupta et al (1997) showed that ~24% of the urban population of north India had low levels of HDL-cholesterol. 26 Our group recorded low levels of HDL-C levels in 15-16% of the people belonging to low socio-economic stratum living in New Delhi. 28 No investigator, however, has studied isolated low HDL-C levels in healthy Asian Indians residing in India. It JAPI VOL. 52 FEBRUARY 2004

3 Table 1: Representative studies showing average lipid levels in Asian Indians residing in India Authors Age group Total cholesterol Triglycerides Low-density High-density (y) lipoprotein lipoprotein cholesterol cholesterol Urban Vikram et al, M: 3.45±0.64(331) M: 0.94±0.34(331) M: 1.8±0.61(331) M: 1.22±0.17(331) F: 3.87±0.65 (46) F: 0.95±0.34(46) F: 2.24±0.62(46) F: 1.19±0.17(46) Lubree et al, ±0.88 (150) 1.18 (150) ND 0.93±0.26(150) Bhattacharya et al, M: 5.5±1.11 (184) M: 0.92±0.34 (184) ND ND F: 6.4±1.16 (77) F: 0.88±0.40 (77) Snehlatha et al, M: 5.1±1.0 (396) M: 1.65±1.59(396) ND ND F: 5.3±1.0 (258) F: 1.48±1.6(258) Mohan et al, ±1.03(479)* 1.5±0.9(479)* ND ND Chadha et al, M: 5.31±1.08(681) M: 1.62±0.54(681) M: 3.05±1.02(539) M: 1.42±0.33(539) F:4.11±1.07(1084) F: 1.57±0.57(1084) F: 3.0±1.01(806) F: 1.48±0.34(806) Gupta et al, ±1.11 (199) 1.87±0.62 (199) 2.78±0.98 (199) 1.11±0.31(199) Urban Slums Vikram et al M: 4.67±1.02 (170) M: 1.48±1.73 (170) M: 3.04±1.02 (170) M: 1.03±0.14 (170) F: 4.66±1.22 (469) F: 1.41±0.73 (469) F: 2.98±1.18 (469) F: 1.06±0.18 (469) Rural Gupta et al, ±0.95(202) 1.37±0.51(202) 2.5±0.85(202) 1.13±0.33(202) Chadha et al, M: 4.64±0.7(100) M: 1.63±0.33(100) M: 2.60±0.74(100) M: 1.30±0.29(100) F: 4.64±0.70(259) F: 1.58±0.28(259) F: 2.57±0.62(259) F: 1.34±0.24(259) All values in mmol/l, Numbers with parentheses indicate the number of males or females, respectively. M, males; F, females, *Total number of subjects including males and females, Only male subjects ND: not done Caucasians 2390 Caucasians 2390 Asian Indians-migrant 3881 Asian Indians-migrant slums 197 slums 339 Asian Indians-rural 561 Asian Indians-rural Serum triglycerides (mg/dl) Fig. 2 : Average levels of serum triglyceride of Asian Indians compared to Caucasians Total number of subjects is indicated against the bars. The data were pooled from the following studies: Asian Indians-rural: Gupta et al. 26, Chadha et al. 50. Asian Indiansurban slums: Misra et al. 16. : Reddy et al. 51, Chadha et al. 50, Gupta et al. 26. Migrant Asian Indians: McKeigue et al. 52, Hughes et al. 53, Tan et al. 54, Patel et al. 55, Deurenberg-Yap et al. 56. Caucasians: McKeigue et al. 52, Patel et al. 55. High-density lipoprotein cholesterol (mg/dl) Fig. 3: Average levels of high-density lipoprotein cholesterol of Asian Indians compared to Caucasians Total number of subjects is indicated against the bars. The data were pooled from the following studies: Asian Indians-rural: Gupta et al. 26, Lubree et al. 57, Chadha et al. 50, slums: Misra et al. 16, Lubree et al. 57. Asian Indians-urban: Reddy et al. 51, Lubree et al. 57, Chadha et al. 50, Gupta et al. 26 Migrant Asian Indians: McKeigue et al. 52, Hughes et al. 53, Tan et al. 54, Patel et al. 55, Deurenberg-Yap et al. 56. Caucasians: McKeigue et al. 52, Patel et al. 55. appears that average HDL-cholesterol concentrations in all Asian subgroups whether residing in India or elsewhere are lower than Caucasians. For example, according to Tai et al ~34% of the subjects with isolated low HDL-cholesterol levels in the multi-ethnic population in Singapore were Asian Indians. 29 They further added that a higher number of Asian Indians with low levels of HDL-cholesterol and hypertriglyceridemia had glucose intolerance, were obese, and had higher degree of insulin resistance as compared to Chinese and Malays. 29 Recent data show that low levels of HDL-cholesterol may be particularly pronounced in migrant Asian Indian women as compared to Caucasians. 25 Adverse anthropometric profile has been noted in hyperlipidemic Asian Indian males by our group in a casecontrol study. Of note, these patients were non-obese based on body mass index, but still had higher waist circumference (p < 0.001), waist-to-hip circumference ratio (p < 0.01), individual skinfold thicknesses (p < 0.001), sum of JAPI VOL. 52 FEBRUARY

4 four skinfold thicknesses (p < 0.001), and percentage of body fat (p < 0.001) as compared to normolipidemic males. Based on the above important observations, the authors stressed that, while dealing with hyperlipidemic Asian Indians, physicians should consider waist circumference, percentage of body fat, and its ratio with BMI, in addition to BMI in the clinical assessment. 15 Determinants of Dyslipidemia in Asian Indians A multitude of factors may contribute to dyslipidemia in Asian Indians. 1. Physical Activity: Asian Indians are more physically inactive as compared to many ethnic groups. In particular, low level of physical activity has been reported in children and young adults.30 However, precise contribution of physical inactivity to dyslipidemia in the Asian Indians populations is unknown. 1. Diet: Asian Indian diets rich in carbohydrate and low in ω-3 polyunsaturated fatty acids may exacerbate hypertriglyceridemia. 20 Dyslipidemic profile is commonly seen in the vegetarians. 20 The precise role of dietary factors in genesis of dyslipidemia in Asian Indians remains to be defined. 2. Body Composition: Migrant Asian Indians and Asian Indians residing in urban India have body composition conducive to development of dyslipidemia. 20 Excess truncal fat and increased intra-abdominal fat accumulation have been linked to insulin resistance and consequent atherogenic dyslipidemia (Fig. 1). 3. Genetic predisposition: It may be an important factor even for non-familial dyslipidemia in Asian Indians, however very few studies are available. Association of apolipoprotein B gene polymorphisms (Xba I and EcoRI) with hyperlipidemia has been shown in migrant Asian Indians, 31,32 as opposed to absence of association shown in hyperlipidemic and normolipidemic subjects by our group. 33 We have reported positive correlation between apolipoprotein E3/E3 phenotype and low levels of HDLcholesterol in a case-control study. 34 Overall, consistent effect of apolipoprotein E gene polymorphisms on the plasma triglyceride and HDL- cholesterol levels has not been observed. Variations in the magnitude of the differential effects of E2 and E4 allele on plasma cholesterol levels could be due to gene-environment interactions. In another study conducted in north India, APOC3 SstI gene polymorphism (S1S1, S1S2 and S2S2 genotypes) and plasma triglyceride levels have been shown. 35 Finally, polymorphisms of the APOC3 promoter (-455 T/C and -482 C/T) were frequently encountered in young migrant Asian Indians and closely correlated with reduced concentrations of apolipoprotein A-I 36. Genetic investigation of hyperlipidemia in Asian Indians need more research attention. Management of Dyslipidemia in Asian Indians The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) reinforced LDL as the primary target of cholesterol-lowering therapy with the optimal goal of its level below 100 mg/dl. 37 The panel recommends treatment beyond LDL lowering for patients with triglyceride levels of 200 mg/dl and above. Non-HDL cholesterol, which is derived from subtracting HDLcholesterol concentration from total cholesterol level, representing the sum of all atherogenic lipoproteins, has been identified as a secondary target of therapy in patients with elevated triglyceride levels. Managing and monitoring non- HDL cholesterol may be particularly important for Asian Indians. Further, the fact that the prevalence of CHD is nearly two-fold higher in the presence of combination of hypertriglyceridemia and low HDL-cholesterol levels 38 is relevant to the management of dyslipidemia in Asian Indians. For effective lipid lowering in Asian Indians, the following principles and interventions are suggested; 1. Maintenance in regular aerobic physical activity is a simple and important measure. 2. It is advisable to increase intake of ω-3 polyunsaturated fatty acids in diets, particularly for the vegetarians. 16 Effective lowering of serum triglyceride levels and increase HDL-cholesterol levels has been noticed with the use of moderate to high doses of ω-3 polyunsaturated fatty acids taken as fish oils. 39,40 3. HMG-CoA reductase inhibitors, (statins), are very effective in reducing LDL-cholesterol levels. The newer statins (Atorvastatin and Rosuvastatin) reduce serum triglyceride levels by nearly 15-20% 41 and also increase the LDL particle diameter, 42 but they do not have any significant effect on HDL-cholesterol levels. 4. Fibrates are more effective than statins in reducing serum triglyceride levels and increasing HDL-cholesterol levels. 43 Atherogenic dyslipidemia in Asian Indians may be well managed by the use of fibrates. 5. Niacin is more effective than either statins or fibrates in increasing HDL- cholesterol levels (~35%), 44 however it may not be tolerated by many patients. Sustained release preparations of niacin may be associated with lower adverse effects, but are not presently available in India. 6. For effective treatment of hypertriglyceridemia and low HDL-cholesterol levels, a combination of statins with fibrates or niacin may be tried although adverse drug reactions may increase. Recent evidence indicates that combination of statins and fibrates is well tolerated. 45,46 Adequate spacing of administration of both the drugs by several hours, gradual upward dose titration, and careful monitoring of liver function and creatine phosphokinase levels is essential to minimize adverse effects Fibrates and ω-3 polyunsaturated fatty acids also have anti-inflammatory properties, and may be additionally useful in Asian Indians who have high prevalence of subclinical inflammation, 48 more than that noticed in Caucasians JAPI VOL. 52 FEBRUARY 2004

5 Pitfalls and Future Directions The research in this area is in preliminary stages. Concerted research efforts, clinical and experimental, need to be devoted to investigate determinants, pathogenesis and correct management of dyslipidemia in Asian Indians. An area of particular concern is knowledge and awareness of the guidelines for the management of dyslipidemia, in physicians in India. Nearly 40% of the patients prescribed lipid-lowering drugs did not meet the NCEP (ATP II) criteria for the initiation of lipid lowering drug therapy in north India. 49 The correct knowledge of the guidelines for lipid lowering needs to be reinforced to the Indian physicians by lectures and continuing medical education. Finally, to initiate young physicians in these subjects, the undergraduate teaching curriculum should include lectures on hyperlipidemia. Acknowledgement The study was partially supported by a financial grant from the Department of Science and Technology, Ministry of Science and Technology, Government of India, New Delhi. REFERENCES 1. Richards EG, Grundy SM, Cooper K. Influence of plasma triglycerides on lipoprotein patterns in normal subjects and in patients with coronary artery disease. Am J Cardiol 1989;63: Schaefer EJ, Levy RI, Anderson DW, Danner RN, Brewer HB, Jr., Blackwelder WC. Plasma-triglycerides in regulation of HDL-cholesterol levels. Lancet 1978;2: Blades B, Vega GL, Grundy SM. Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler Thromb 1993;13: Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 1982;23: Griffin BA, Freeman DJ, Tait GW, Thomson J, Caslake MJ, Packard CJ, Shepherd J. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis 1994;106: Griffin BA, Minihane AM, Furlonger N, et al. Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects. Clin Sci (Lond) 1999;97: Sattar N, Greer IA, Louden J, et al. Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small, dense low density lipoprotein. J Clin Endocrinol Metab 1997;82: Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998;81:18B-25B. 9. de Graff J, Hak-Lemmers HLM, Hectors PNM, Demacker JCM, Stalenholf AFH. Enhanced susceptibility to invitro oxidation of the dense low density lipoprotein subfractions in healthy subjects. Arterioscler Thromb 1991;11: Misra A, Garg A, Abate N, Peshock RM, Stray-Gundersen J, Grundy SM. Relationship of anterior and posterior subcutaneous abdominal fat to insulin sensitivity in nondiabetic men. Obes Res 1997;5: Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and adipose tissue depots. Nutrition 2002;19: Misra A. Body composition and the metabolic syndrome in Asian Indians: a saga of multiple adversities. Natl Med J India 2003;16: Misra A. Impact of ethnicity on body fat patterning in Asian Indians and Blacks: Relationship with insulin resistance. Nutrition 2003;19: Misra A. Revision of limits of body mass index to define overweight and obesity are needed for the Asian ethnic groups. Int J Obes and Relat Metab Disord 2003;27: Misra A, Athiko D, Sharma R, Pandey RM, Khanna N. Nonobese hyperlipidemic Asian northern Indian males have adverse anthropometric profile. Nutr Metab Cardiovasc Dis 2002;12: Misra A, Sharma R, Pandey RM, Khanna N. Adverse profile of dietary nutrients, anthropometry and lipids in urban slum dwellers of northern India. Eur J Clin Nutr 2001;55: Perseghin G, Scifo P, De Cobelli F, et al. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 1999;48: Misra A. Insulin resistance syndrome: current perspective and its relevance in Indians. Indian Heart J 1998;50: Misra A, Vikram NK. Insulin resistance syndrome (metabolic syndrome) and Asian Indians. Curr Sci 2002;83: (available at Misra A, Vikram NK. Insulin resistance syndrome (metabolic syndrome) and obesity in Asian Indians: Evidence and implications. Nutrition 2003 (in press). 21. Vikram NK, Pandey RM, Misra A, Sharma R, Rama Devi J, Khanna N. Non-obese (BMI<25 kg/m 2 ) Asian Indians with normal waist circumference have high cardiovascular risk. Nutrition 2003;19: Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation 1998;97: Reddy KS. Cardiovascular diseases in the developing countries: dimensions, determinants, dynamics and directions for public health action. Public Health Nutr 2002;5: Reaven GM. Banting lecture Role of insulin resistance in human disease. Diabetes 1988;37: Gama R, Elfatih AB, Anderson NR. Ethnic differences in total and HDL cholesterol concentrations:caucasians compared with predominantly Punjabi Sikh Indo-Asians. Ann Clin Biochem 2002;39 (Pt 6): Gupta R, Prakash H, Kaul V. Cholesterol lipoproteins, triglycerides, rural-urban differences and prevalence of dyslipidaemia among males in Rajasthan. J Assoc Physicians India 1997;45: Gopinath N, Chadha SL, Jain P, Shekhawat S, Tandon R. An epidemiological study of obesity in adults in the urban population of Delhi. J Assoc Physicians India 1994;42: Misra A, Pandey RM, Devi JR, Sharma R, Vikram NK, Khanna N. High prevalence of diabetes, obesity and dyslipidaemia in urban slum population in northern India. Int J Obes Relat Metab JAPI VOL. 52 FEBRUARY

6 Disord 2001;25: Tai ES, Emmanuel SC, Chew SK, Tan BY, Tan CE. Isolated low HDL cholesterol: an insulin-resistant state only in the presence of fasting hypertriglyceridemia. Diabetes 1999;48: Dhingra V, Chatterjee A, Guleria R, Sharma R, Pandey RM, Talwar KK, Misra A. Adverse physical activity pattern in urban adolescents. J Assoc Physicians India 2002;50: Renges HH, Wile DB, McKeigue PM, Marmot MG, Humphries SE. Apolipoprotein B gene polymorphisms are associated with lipid levels in men of South Asian descent. Atherosclerosis 1991;91: Saha N, Tay JS, Heng CK, Humphries SE. DNA polymorphisms of the apolipoprotein B gene are associated with obesity and serum lipids in healthy Indians in Singapore. Clin Genet 1993;44: Misra A, Nishanth S, Pasha ST, Pandey RM, Sethi P, Rawat DS. Relationship of Xba1 and EcoR1 polymorphisms of apolipoprotein-b gene to dyslipidemia and obesity in Asian Indians in North India. Indian Heart J 2001;53: Luthra K, Bharghav B, Chabbra S, et al. Apolipoprotein E polymorphism in Northern Indian patients with coronary heart disease: phenotype distribution and relation to serum lipids and lipoproteins. Mol Cell Biochem 2002;232: Chhabra S, Narang R, Krishnan LR, et al. Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians. BMC Genet 2002;3: Miller M, Rhyne J, Khatta M, Parekh H, Zeller K. Prevalence of the APOC3 promoter polymorphisms T-455C and C-482T in Asian-Indians. Am J Cardiol 2001;87:220-1, A A4. 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: Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Relation of high TG-low HDL cholesterol and LDL cholesterol to the incidence of ischemic heart disease. An 8-year follow-up in the Copenhagen Male Study. Arterioscler Thromb Vasc Biol 1997;17: Abbey M, Clifton P, Kestin M, Belling B, Nestel P. Effect of fish oil on lipoproteins, lecithin:cholesterol acyltransferase, and lipid transfer protein activity in humans. Arteriosclerosis 1990;10: Lungershausen YK, Abbey M, Nestel PJ, Howe PR. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertens 1994;12: Olsson A, Istad H, Luurila O, et al. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J 2002;144: Pontrelli L, Parris W, Adeli K, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes. Metabolism 2002;51: Jonkers IJ, Mohrschladt MF, Westendorp RG, van der Laarse A, Smelt AH. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002;112: Garg A, Grundy S. Nicotinic acid as therapy for dyslipidemia in non-insulin dependent diabetes mellitus. JAMA 1990;264: Liamis G, Kakafika A, Bairaktari E, et al. Combined treatment with fibrates and small doses of atorvastatin in patients with mixed hyperlipidemia. Curr Med Res Opin 2002;18: Taher TH, Dzavik V, Reteff EM, Pearson GJ, Woloschuk BL, Francis GA. Tolerability of statin-fibrate and statin-niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events. Am J Cardiol 2002;89: Wierzbicki AS, Mikhailidis DP, Wray R, et al. Statin-fibrate combination: therapy for hyperlipidemia: a review. Curr Med Res Opin 2003;19: Vikram NK, Misra A, Dwivedi M, et al. Correlations of C- reactive protein levels with anthropometric profile, percentage of body fat and lipids in healthy adolescents and young adults in urban North India. Atherosclerosis 2003;168: Goyal P, Sharma G, Bal BS, et al. Prospective, noninterventional, uncontrolled, open-chart, pharmacoepidemiologic study of prescribing patterns for lipid-lowering drugs at a tertiary care teaching hospital in North India. Clin Ther 2002;24: Chadha SL, Gopinath N, Shekhawat S. Urban-rural differences in the prevalence of coronary heart disease and its risk factors in Delhi. Bull World Health Organ 1997;75: Reddy KS. Primordial prevention of coronary heart disease in India: challenges and opportunities. Prev Med 1999;29:S 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: Hughes K, Aw TC, Kuperan P, Choo M. Central obesity, insulin resistance, syndrome X, lipoprotein(a), and cardiovascular risk in Indians, Malays, and Chinese in Singapore. J Epidemiol Community Health 1997;51: Tan CE, Emmanuel SC, Tan BY, Jacob E. Prevalence of diabetes and ethnic differences in cardiovascular risk factors. The 1992 Singapore National Health Survey. Diabetes Care 1999;22: Patel S, Unwin N, Bhopal R, et al. A comparision of proxy measures of abdominal obesity in Chinese, European and South Asian adults. Diab Med 1999;16: Deurenberg-Yap M, Chew SK, Lin VF, Tan BY, van Staveren WA, Deurenberg P. Relationships between indices of obesity and its co-morbidities in multi-ethnic Singapore. Int J Obes Relat Metab Disord 2001;25: Lubree HG, Rege SS, Bhat DS, et al. Body fat and cardiovascular risk factors in Indian men in three geographical locations. Food Nutr Bull 2002;23: JAPI VOL. 52 FEBRUARY 2004