| HIGH TRIGLYCERIDES AND HEART DISEASE | ||||||||||||||||||||||||||||||||||||||||||||||||
| Arvind Gupta | ||||||||||||||||||||||||||||||||||||||||||||||||
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 INTRODUCTION |
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| Hyperlipidaemia occurs due to increased concentrations of cholesterol or triglycerides and frequently both are raised. It is important to know the distribution of cholesterol in the different lipoprotein fractions. The main fractions are the very low density lipoproteins (VLDL) which are triglyceride rich, the low density lipoproteins (LDL) and the high density lipoproteins (HDL) which also carry a good deal of cholesterol in conjunction with lecithin. The HDL fraction is a scavenger lipoprotein responsible for removal of excess cholesterol from tissues.1 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Triglycerides concentrations in apparently healthy people is subject to variations decreasing with fast and increasing with meals from 35-130mg/dl. A high fasting triglycerides level in plasma >150mg/dl is associated, quite often with high plasma cholesterol. A low plasma HDL cholesterol <40mg/dl in presence of hypertriglyceridaemia may be described as atherogenic dyslipidaemia. In general, changes in the amount and nature of dietary fat effect plasma triglycerides in the same manner as they do plasma cholesterol. Increased intake of refined carbohydrates, sugar, saturated fat, alcohol, diabetes and low physical activity are common causes of high plasma triglycerides.2 | ||||||||||||||||||||||||||||||||||||||||||||||||
| The hyperlipidaemias were classified by Fredrickson on the basis of abnormalities in plasma lipoproteins into five types with two subtypes (Table 1). However, except for two types based on genetics, the other types have no unique distinguishing feature and differences in lipoprotein patterns are not clear. Three clinical groups of hyperlipidaemias are described. These are (1) primary genetic disorders, (2) hyperlipidaemia secondary to established diseases and (3) acquired diet-related hyperlipidaemia. The first two are not very common. High serum triglyceride levels with or without low HDL is a risk factor for coronary artery disease (CAD).3 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Table 1: Common Hyperlipidemias | ||||||||||||||||||||||||||||||||||||||||||||||||
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| METABOLISM
AND CLASSIFICATION |
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| The independent association between plasma triglyceride levels and cardiovascular. disease has been controversial, but it is now recognized that triglycerides are an independent risk factor for atherosclerotic vascular disease.3 Triglycerides are transported in a number of different lipoprotein fractions, which have different atherogenic potential. Elevated triglyceride levels are also associated with a number of pro-atherogenic metabolic and physiologic changes, such as increased small dense LDL particles, low HDL cholesterol levels, and increased levels of procoagulant molecules. Finally, elevated fasting triglycerides are strongly predictive of abnormalities in postprandial lipoprotein metabolism, which are associated with increased cardiovascular risk.2 | ||||||||||||||||||||||||||||||||||||||||||||||||
| A practical approach to diagnosis and management of elevated triglycerides requires understanding of normal triglyceride metabolism.4 Chylomicrons are synthesized and secreted by intestinal epithelial cells in response to the ingestion of dietary fat. As chylomicrons enter capillaries, they bind to the enzyme lipoprotein lipase, which is anchored to capillary endothelial cells via proteoglycans. Lipoprotein lipase is activated by apolipoprotein C-II (apoC-II) on the chylomicron surface to hydrolyze the core triglyceride to free fatty acids, which are taken into tissues for oxidation (e.g., adipose tissue). After much of the chylomicron triglyceride core is hydrolyzed, the particle dissociates from lipoprotein lipase as a chyclomicron remnant. The remnant particles are rapidly removed from the circulation by the liver through the binding of apo-E on the remnant particle surface to heparan sulfate proteoglycans and subsequently the LDL receptor or the LDL receptor-related protein (LRP). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Very-low-density lipoproteins (VLDL) are triglyceride-rich lipoproteins that are produced by the liver. Similar to chylomicrons, VLDL triglycerides are hydrolyzed by lipoprotein lipase. When VLDL remnants dissociate from lipoprotein lipase, they are called intermediate-density lipoproteins (iDL). IDL particles may be taken up by receptors on the liver, or they may be converted further to LDL. ApoE mediates the hepatic uptake of IDL via either the LDL receptor or the LRP. IDL particles not catabolized by this route are converted to LDL by a process that involves hepatic lipase. Hypertriglyceridemia can be of : | ||||||||||||||||||||||||||||||||||||||||||||||||
| · Elevated chylomicrons
(type I or V hyperlipoproteinemia), · VLDL (type IV or type IIb hyperlipoproteinemia), or · Lipoprotein remnants (type III hyperlipoproteinemia). |
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| The type of lipoprotein that is elevated is an important determinant of the degree of cardiovascular risk and the specific therapeutic approach, and it is important to consider which lipoproteins are elevated in patients with hypertriglyceridemia. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Type
I hyperlipoprotenemia: |
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| Many patients with fasting hypertriglyceridemia have an inherited factor that causes or contributes to the elevated triglycerides. Familial chylomicronemia syndromes (type I hyperlipoproteinemia) are characterized by markedly elevated levels of chylomicrons in fasting plasma. The major clinical features are eruptive xanthomas and recurrent episodes of pancreatitis. These are autosomal recessive disorders caused by mutations in either lipoprotein lipase (LPL) or its essential cofactor apoC-II. Patients with LPL deficiency and apoC-II deficiency usually present in infancy or childhood with recurrent abdominal pain, acute pancreatitis, or eruptive xanthomas. Triglyceride levels are virtually always greater than 1000 mg/dL and may increase to 10,000 mg/dL or greater. Because chylomicrons contain cholesterol, total cholesterol levels are also extremely elevated. The diagnosis can be confirmed by the quantitation of LPL activity in plasma obtained 10 minutes after intravenous heparin injection (60 U/kg). The mainstay of therapy for LPL deficiency and apoC-II deficiency is restriction of total dietary fat. If dietary fat restriction alone is unsuccessful, some patients may respond to a trial of fish oils. During an attack of severe pancreatitis in a patient with apoC-II deficiency, infusion of fresh-frozen plasma may provide adequate apoC-II to activate endogenous LPL and improve hypertriglyceridemia. Premature atherosclerosis is not generally a feature of this disease, consistent with the concept that large chylomicrons are not ahterogenic. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Type
V hyperlipoprotenemia: |
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| Type V hyperlipoproteinemia is characterized by elevations in chylomicrons and VLDL and, similar to the familial hyperchylomicronemia syndrome, is associated with fasting triglyceride levels greater than 1000 mg/dL and risk for acute pancreatitis. In contrast to LPL and apoC-II deficiency, however, this syndrome generally presents in adulthood and is frequently associated with obesity, type II diabetes, or other secondary causes of hypertriglyceridemia. Restriction of dietary fat and weight loss are the initial therapeutic approach, but if fasting triglycerides remain greater than 1000 mg/dL, drug therapy is indicated. Fibrates are generally the drug class of choice, and fish oils and niacin can be useful as well. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Isolated
hypertriglyceridemia: |
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| Hypertriglyceridemia characterized by elevated VLDL is commonly seen in clinical practice. Familial hypertriglyceridemia (FHTG) is an autosomal dominant trait characterized by elevated VLDL cholesterol with normal LDL cholesterol (type IV pattern) and family history of elevated triglycerides. It occurs in about 1 in 500 persons. The metabolic basis of this disorder is heterogeneous and related to impaired lipolysis of triglycerides or increased triglyceride production. Genetic overproduction of apoC-III could cause this syndrome, but this remains unproven. Triglyceride levels usually range from 250 to 1000 mg/dL, with normal to modesty increased cholesterol levels. This syndrome can be but is not necessarily associated with increased risk for premature cardiovascular disease. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Familial
combined hyperlipidemia: |
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| Familial combined hyperlipidemia (FCHL) is an autosomal dominant trait generally characterized by elevated VLDL cholesterol and LDL cholesterol (type IIb pattern) and a family history of combined hyperlipidemia. It occurs in about 1 in 200 persons. The genetic cause of FCHL is unknown, but overproduction of VLDL is a common metabolic basis of this condition. Triglyceride levels usually are 150 to 500 mg/dL, total cholesterol levels are 200 to 400 mg/dL, and HDL cholesterol levels are almost always decreased. The hallmark biochemical finding is increased small dense LDL particles, which are considered highly atherogenic. FCHL is frequently associated with premature coronary artery disease that often appears to be out of proportion to the modest degree of hyperlipidemia. An estimated 20% of patients with premature coronary artery disease have FCHL. Most patients with FCHL are candidates for drug therapy, with statins generally the drug class of choice. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Remnant
hypertriglyceridemia: |
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| Hypertriglyceridemia can be caused by elevated remnant lipoproteins. Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is characterized by the accumulation of chylomicron and VLDL remants in fasting plasma as a result of mutations in apolipoprotein E, the major ligand for clearance of lipoprotein remnant particles. The most common form is autosomal recessive resulting from homozygosity for the apoE2 allele. Persons with the E2/E2 genotype develop familial dysbetalipoproteinemia if an additional predisposing factor is also present; some of these factors are obesity, diabetes mellitus, hypothyroidism, renal disease, and alcohol use. Rarely, mutations in apoE other than apoE2 can cause a dominantly inherited form of familial dysbetalipoproteinemia. Patients with familial dysbetalipoproteinemia may have tubero-eruptive xanthomas (small papules on the elbows and knees) or palmar xanthomas (orange-yellow discoloration of the creases of the palms and wrists). Premature atherosclerosis is often seen in this disorder. In contrast to other conditions associated with elevated triglycerides, HDL cholesterol levels are usually normal in patients with familial dysbetalipoproteinemia. The diagnosis can be supported by lipoprotein ultracentrifugation demonstrating a ratio of VLDL cholesterol to plasma triglyceride greater than 0.3 (suggesting cholesterol-enriched VLDL particles) and confirmed by documenting the apoE2/E2 genotype. Most patients with familial dysbetalipoprotenemia require drug therapy, with fibrates, niacin, and statins all reasonable first-line drugs. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary
hypertriglyceridemia: |
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| Hypertriglyceridemia is often secondary to, or exacerbated by, other medical problems or environmental factors. Excess alcohol intake is commonly associated with hypertriglyceridemia, probably by stimulating hepatic secretion of VLDL. The usual lipoprotein pattern with alcohol consumption is type IV (increased VLDL), but persons with an underlying predisposition to defective clearance of triglyceride-rich lipoproteins may develop severe hypertriglyceridemia (type V pattern). Type II diabetes mellitus is frequently associated with elevated triglycerides, and triglyceride levels are even more predictive of cardiovascular risk in diabetics than in nondiabetics. Insulin resistance results in impaired capacity to catabolize chylomicrons and VLDL as well as excess hepatic triglyceride and VLDL production. Obesity can be associated with elevated triglycerides in the absence of diabetes. Nephrotic syndrome and end-stage renal disease are virtually always associated with elevated triglyceride levels. In postmenopausal women, estrogen replacement often increases triglyceride levels and may markedly exacerbate pre-existing hypertriglyceridemia. Other drugs that increase triglycerides include isotretinoin, ß-blockers, thiazide diuretics, and human immunodeficiency virus (HIV) protease inhibitors (Table 2). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Table 2: Common Causes of Secondary Hypertriglyceridemia | ||||||||||||||||||||||||||||||||||||||||||||||||
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| TRIGLYCERIDES
AND CORONARY ARTERY DISEASE |
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| In many epidemiological studies, a positive relation has been reported between triglyceride level and risk of CAD.2 However, the usefulness of measuring triglycerides in general screening strategies has been questioned because multivariate analysis control for HDL cholesterol usually eliminates or substantially diminishes the role of triglycerides as a marker of CAD. The interpretation of multivariate models which include triglyceride and HDL-cholesterol is complex and associated with several problems. Both risk factors have distinct role in CAD and in comparison with HDL, the distribution of triglyceride level is markedly skewed, requiring logarithmic transformation for distribution dependent analysis.5 Finally, adding to the complexity some individuals with very high triglyceride levels such as those with lipoprotein phenotype I and V, appear to have no increase risk of CAD. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Austin et al6 described an atherogenic lipoprotein phenotype B characterised by moderate hypertriglyceridaemia, a high proportion of small dense LDL, a high level of apolipoprotein B and a low level of apolipoprotein A1 and HDL. Atherogenic phenotype B can be differentiated from benign phenotype A by simple measurements of triglycerides and HDL. A triglyceride value of 95 mg/dl discriminates the 2 phenotypes in 83% of cases where an HDL value of 39 mg/dl separates the two groups in 72% cases. The prevalence of this atherogenic phenotype is 25% in whites. | ||||||||||||||||||||||||||||||||||||||||||||||||
| The Baltimore Coronary Observational Study7 emphasised that serum triglycerides below 200 mg/dl are generally considered desirable, but the median level of triglyceride in US population is about 100 mg/dl. This is in contrast to serum total cholesterol levels for which both the mean and median levels are about 200 mg/dl. In this study, triglycerides more than 100 mg/dl as the cut point for assessing the CAD risk associated with triglyceride level. During a follow up of 18 years, this study showed an odds ratio for CAD of 1.5 for serum fasting triglycerides levels >100gm/dl compared to those with triglyceride level <100mg/dl. The odds ratio for CAD for triglycerides >200mg/dl vs similar to that of diabetes in this study. Hokanson and Austin8 in one meta-analysis involving 46,413 men and 10,884 women reported that 90 mg/dl increase in triglycerides levels was associated with a 30% increase in cardiovascular risk in men and a 75% increase in risk in women. In the Copenhagen Male Study,9 the 8-year incidence of CAD in subjects with serum triglycerides levels between 142 and 221 mg/dl was 14% versus 9.5% in those with total cholesterol >310 mg/dl. The Physicians Health Study10 has reported an odds ratio for CAD of 1.4 per 100 mg/dl increase in non-fasting triglycerides levels. In the Quebec Cardiovascular Study,11 the odds ratio for CAD was higher for triglycerides than other lipoproteins (triglyceride level >135mg/dl, OR 3.5; LDL>143mg/dl, OR 2.4; small dense LDL, OR 2.5; apolipoprotein B>110mg/dl, OR 2.7). In addition elevated triglycerides had a higher prevalence (77%) than elevated LDL (68%), elevated apolipoprotein B (69%) and small dense LDL (69%). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Triglycerides levels have an influence on LDL particle size, density, distribution and composition leading to smaller, denser and more atherogenic particles.1 However, triglycerides are inadequate surrogates for atherogenic lipoproteins because chylomicrons and large very low density lipoproteins (VLDL) particles are not atherogenic. This explains why the risk of CAD is not greater in Frederickson Type 1 and Type V dyslipidemia. Serum triglycerides levels provide an indirect measurement of LDL particle size whereas the apoliporotein B provide a reasonable estimate of the number of atherogenic particles.6 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Table 3: Prevalence of CAD, and coronary risk factors in rural and urban subjects | ||||||||||||||||||||||||||||||||||||||||||||||||
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| TRIGLYCERIDE
LEVELS IN INDIANS |
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| Several case control studies and populations surveys from India have reported serum level of triglycerides, HDL cholesterol and few have also reported VLDL cholesterol levels.12 While Gupta et al13 found no rural-urban differences in serum HDL and triglycerides, Singh et al14 reported significantly higher mean levels and higher prevalence of hypertriglyceridaemia in urban compared to rural subjects. The prevalence of low HDL was significantly greater in urban compared to rural population. However, diabetes mellitus and central obesity were significantly greater in urban population and high triglycerides in Indians may be a reflection of increased prevalence of insulin resistance syndrome and diabetes (Table 3).15 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Epidemiological studies show that the mean triglyceride levels in Indians are significantly greater than other developed countries such as China.12 These levels are equal to those of developed countries of North America and Europe whereas the total cholesterol levels are much lower. The triglyceride levels are also high among all social classes in India. A study from Orissa reported that while there was a clear social class gradient in total and LDL cholesterol levels, levels being highest in high social classes, the triglyceride levels were similar in all the socioeconomic classes.16 Dietary factors, especially the high carbohydrate diet, may be important. | ||||||||||||||||||||||||||||||||||||||||||||||||
| There is a significant increase in serum triglyceride levels over the years in Indian urban populations (Table 4).17 The importance of triglycerides in Indians need more prospective epidemiological studies. | ||||||||||||||||||||||||||||||||||||||||||||||||
| FACTORS
INFLUENCING TRIGLYCERIDES |
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| The main constitutional influences on plasma lipids and lipoproteins are age and sex.1 In cord blood total cholesterol levels range from 64-77 mg/d, distributed equally between LDL and HDL, with triglycerides in the region of 45 mg/dl. A rapid rise in cholesterol occurs during the first 6 months of life but there is little further change until after puberty, cholesterol and triglyceride values averaging approximately 155 and 58 mg/dl respectively. After the age of 15 years, LDL cholesterol and triglyceride levels rise more in boys than girls and, unlike the latter, their HDL cholesterol falls, reflecting the opposite effects of androgens and oestrogens.2,3 | ||||||||||||||||||||||||||||||||||||||||||||||||
| The main life style influences on plasma lipids are diet, exercise, seasonal variation and intercurrent illness.4 Saturated fats raise and polyunsaturated fats lower LDL cholesterol whereas excessive intake of carbohydrate and obesity increase triglyceride levels and lower HDL cholesterol. In contrast, exercise lowers triglyceride and raises HDL cholesterol, whereas alcohol increases both. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Table 4: Triglycerides in Indian Urban Subjects | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Day to day fluctuations in serum cholesterol range from 5-10%, roughly half of which reflects analytical variation. Recent food intake has little effect on serum cholesterol, whereas triglycerides rise markedly after a meal. Both lipids tend to be lower in summer than winter. Intercurrent disease can influence serum lipids acutely, as occurs after a myocardial infarct. There is a 24-h window of opportunity for measuring serum lipids following such an event, after which cholesterol levels fall and triglycerides rise, these changes persisting for several weeks. Underlying malignant disease sometimes manifests itself as an unexpected and sustained decrease in serum triglycerides. | ||||||||||||||||||||||||||||||||||||||||||||||||
| MANAGEMENT |
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| The management of patients with hypertriglyceridemia should first be focused on: | ||||||||||||||||||||||||||||||||||||||||||||||||
| · Elimination or treatment
of secondary causes and nonpharmacologic approaches · Alcohol intake should be reduced or eliminated · Drugs that exacerbate hypertriglyceridemia should be changed to an alternative or discontinued if possible · Women taking estrogens should consider discontinuing them if the triglyceride level is greater than 1000 mg/dL. · Diabetes mellitus should be optimally controlled. · Obese persons should lose weight. · Regular aerobic exercise can often have a significant impact on reducing triglyceride levels. · Restriction of total dietary fat can be effective · Persons are also highly respective to reducing intake of simple carbohydrates. |
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| The initial pharmacological management of hypertriglyceridemia is determined by the level of fasting triglycerides and the clinical assessment of cardiovascular risk. The most important clinical consequence of severe hypertriglyceridemia (>1000 mg/dL) is acute pancreatitis. Patients with fasting triglycerides greater than 1200 mg/dL despite maximal nonpharmacologic therapy should be treated to reduce the risk for acute pancreatitis. Three major drug classes are used to lower high triglyceride levels: | ||||||||||||||||||||||||||||||||||||||||||||||||
| · Fibric acid derivatives, · Nicotinic acid, and · Fish oils. |
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| Fibrates are generally the drug class of choice for patients with triglycerides greater than 1000 mg/dL, and the two major options currently are gemfibrozil and micronized fenofibrate. Nicotinic acid (niacin) or fish oils may be considered in patients who do not tolerate or fail to respond adequately to fibrates. Fish oils can be particularly effective for severe hypertriglyceridemia but must be given at a dose of 6 to 9 g/d in three divided doses. Sometimes the combination of a fibrate and fish oils or fibrate and niacin is necessary for adequate control. Once trilyceride levels have been controlled, LDL cholesterol levels may remain elevated, and combination therapy in high-risk persons is a consideration. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Another situation in which drug therapy should be instituted to decrease triglyceride levels is in the patient with established coronary heart disease or with diabetes who has a fasting triglyceride level 400 to 1000 mg/dL. In this setting, lowering the triglyceride level may reduce cardiovascular risk and is also essential for optimal management of the LDL cholesterol level (which is often difficult to assess when the triglyceride level is >400 mg/dL). Fibrates, niacin, and statins are all potential first-line choices in this setting. For triglycerides closer to 1000 mg/dL, fibrates are generally the drug class of choice, whereas for triglycerides closer to 400 mg/dL, statins are probably preferred and may reduce triglycerides in addition to LDL cholesterol. Even if a fibrate successfully reduces the triglycerides, the LDL cholesterol frequently remains higher than the desirable level for this high-risk population. In this setting, combination therapy by addition of a statin to the fibrate should be considered. Although this combination has been rarely associated with severe myopathy, with appropriate patient education it can be safety used, and in patients with coronary heart disease or diabetes, the risk for persistently elevated LDL cholesterol is probably greater than the small risk for myopathy. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Moderate hypertriglyceridemia (triglyceride levels 200 to 400 mg/dL) is the most common form of elevated triglycerides and the most difficult with regard to decisions about need for drug therapy. Triglyceride levels in this range are frequently, but not invariably, associated with increased risk for premature atherosclerotic cardiovascular disease. In patients with established coronary heart disease (or diabetes without coronary heart disease), statins should be used to reduce the LDL cholesterol to a desirable range. Once the LDL cholesterol is in a desirable range, moderately elevated triglycerides could potentially be considered a secondary target for intervention. Two studies suggested that intervention with fibrates in this setting may further reduce cardiovascular risk. For patients with moderate hypertriglyceridemia without coronary heart disease or diabetes, the management should be dictated by the assessment of cardiovascular risk and the LDL cholesterol level. In general, if LDL cholesterol levels can be reliably determined, patients should be evaluated and managed based on the LDL cholesterol level. A moderately elevated triglyceride level may serve as an additional risk factor and tip the scales toward drug therapy in patients whose LDL cholesterol levels are in a grey zone. In this situation, direct quantitation of the number or size of LDL particles may be useful because greater quantity and smaller size LDL particles are associated with increased risk and may be an indication for more aggressive therapy. In general, statins are the drug class of choice in this setting, although niacin could be considered in patients whose LDL cholesterol is not exceptionally elevated and who have primarily elevated triglycerides, low HDL cholesterol, and increased small dense LDL. | ||||||||||||||||||||||||||||||||||||||||||||||||
| In Indians, there is no accepted cut off values for treatment of high triglycerides based on population based epidemiological studies.17,18 More research is needed in this direction. | ||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES |
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Available Volumes
| EDITOR IN CHIEF |
| Dr.
Rajeev Gupta (MD PhD FACC) |
 |
| HON. EDITOR |
| Dr.
Soneil Guptha (MD FACC FESC) |
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