This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oberman, A. Search for Related Content PubMed Articles by Oberman, A.

Hypertriglyceridemia and Coronary Heart Disease

Department of Medicine Division of Preventive Medicine The University of Alabama at Birmingham Birmingham, Alabama 35205-4785

Address correspondence to: Robert A. Kreisberg, M.D., Dean and Vice President for Health Affairs, University of South Alabama, CSAB 170, Mobile, Alabama 36688-0002.

	Introduction

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

 
THE INTRICATE association between hypertriglyceridemia (HTG) and coronary atherosclerosis has been difficult to unravel. The key issue is whether HTG directly causes atherosclerotic cardiovascular disease (CVD) or whether it is merely a marker for a cluster of CVD risk factors. HTG is intimately related to a constellation of metabolic abnormalities linked to atherosclerosis, often termed the metabolic syndrome (1). This syndrome consists of a lipid triad of high triglyceride (TG): 1) small dense low-density lipoprotein (LDL) particles and low high-density lipoprotein cholesterol (HDL-C) plus insulin resistance; 2) hypertension; and 3) a prothrombotic state. Furthermore, statistical analyses to determine whether TG is an independent risk factor for coronary heart disease (CHD) are complex and difficult to interpret. This is due, in part, to the greater biologic variability in TG levels (coefficient of variation, 20%) than in cholesterol (2, 3). Most importantly, if the effect of TG is mediated through decreased HDL-C, small dense LDL, or enhanced thrombogenicity, then adjustments for these variables highly related to TG should be made with caution in multivariate models studying TG effects. It is quite possible that the true risk of HTG is underestimated when adjustments are made for closely correlated metabolic abnormalities, such as reduced HDL-C that is in the pathway leading to atherosclerosis.

There is a growing awareness of the potential atherogenicity of TG-rich lipoproteins (TGRLPs), including very low-density lipoproteins (VLDL), chylomicrons, and their remnants, which is reflected, in part, by HTG (4, 5, 6, 7). A fasting TG level alone may be a relatively insensitive test for detection of abnormalities in TGRLPs. This risk association for CVD varies with the size and composition of the different TGRLPs (5, 6, 8). TGRLPs, on a particle basis, contain far more cholesterol than does LDL. Although the percentage of the particle represented by cholesterol is less in TGRLPs than in LDL, the absolute amount of cholesterol per particle is greater because of the larger size of the particle (8, 9). The cholesterol in TGRLPs contained in small VLDL, remnant VLDL, and intermediate density lipoprotein (IDL) are included in the calculated LDL cholesterol (LDL-C) derived from the Friedewald equation (2). This equation, although useful, is inaccurate when the TG level is 400 mg or higher due to the variable cholesterol enrichment of VLDL or to an increased IDL with higher cholesterol to TG ratios (2, 3).

Despite these issues, epidemiologic, interventional, and pathophysiologic studies support a relationship between HTG and atherosclerosis. Because intervention by cholesterol lowering in major trials reduces the risk of first-time or recurrent CHD events only by about 35% (10, 11, 12, 13) compared with placebo, identification of other potential targets for therapy to further reduce the risk becomes important (14, 15). Although uncertainties about the role of TG exist, much is known about the relation of HTG to CVD. Consequently, treatment of HTG and, more specifically, increased levels of TGRLPs is more rational than intervention for the growing list of emerging, but more speculative, CHD risk factors such as procoagulants, Lp(a), small dense LDL-C, homocysteine, insulin resistance, and inflammatory markers (14, 15). We will briefly review the epidemiologic and interventional data, discuss the potential mechanisms by which HTG is related to CHD, and present recommendations for therapy.

	Epidemiologic studies

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

 
Elevated TG and reduced HDL-C is a common pattern seen among patients who have had a myocardial infarction (MI) and among coronary-prone families (16). The idea that IDL and VLDL are associated with the development and progression of CHD is not new. Gofman et al. (17) recognized the importance of TGRLPs more than 40 yr ago and derived an atherogenic index based on lipids weighted toward the lipoprotein Sf fraction 12–400. In 1959, Albrink and Man (18) reported an association between TG levels and CHD. Subsequently, Albrink (19) postulated that two lipid disorders were atherogenic, one was related to cholesterol and involved LDL, and the other was related to TG and involved VLDL.

An early prospective study from the Cardiovascular Health Center (Albany, NY) corroborated this association of TG with CHD (20). Later, prospective studies concluded that TG was a risk factor for MI and CHD deaths, even after adjustment for other risk factors. After a 14-yr follow-up in the Stockholm Prospective Study, plasma TG was more important as a risk factor for new MI than cholesterol in a logistic multivariate analysis (21). When the men were divided into four groups according to cholesterol and TG levels, the rate of new MI was highest in those men who had high levels of both plasma lipids. In the Paris Prospective Study, TG contributed to CHD risk after adjustment for other risk factors when the cholesterol was less than 220 mg/dL (22). With extended mean follow-up of 11 yr, only TG exhibited a significant effect on CHD deaths among those with impaired glucose tolerance or diabetes (23).

In other prospective studies, the strong association between TG level and CHD in univariate analyses disappeared when other risk factors, particularly HDL-C, were added in multivariate analyses. In the Honolulu Heart Study, the TG value at ages below 60 was an independent predictor of CHD, but not at older ages (24). The Framingham Heart Study reported that elevated TG levels increased the risk of CHD among women but not men after adjustment for HDL-C (25). There was no independent association of TG levels with the 12-yr incidence of death from CHD in the Lipid Research Clinic follow-up study, except for subgroups of younger subjects with lower HDL-C and LDL-C levels (26). The association was small and not statistically significant after adjustment for plasma glucose level. Yet the Caerphilly and Speedwell studies reported TG independently related to CHD risk (27). The 1992 NIH Consensus Development Panel on Triglyceride, High Density Lipoprotein and Coronary Artery Disease concluded that there was insufficient evidence for causality between high levels of plasma TG and CHD, but that TGRLPs can be atherogenic (4).

Evidence from new, larger prospective studies and meta-analyses inextricably link TG to CHD. Austin et al. (28) have performed meta-analyses on population-based prospective studies, ensuring that elevations in fasting TG preceded the onset of fatal and nonfatal CHD events. Sixteen studies representing 2,445 events among 46,413 men followed for an average of 8.4 yr and five studies representing 439 events among 10,864 women followed for an average of 11.4 yr were included. A 1-mmol/L (90 mg/dL) increase in TG was associated with a 32% increase in CHD in men and a 76% increase in CHD in women. After adjusting for HDL-C and other pertinent variables in studies with data available, there still was a significant increase of 14% for men and 37% for women (Fig. 1). In this study (28) and others (25, 29, 30), TG tends to be a more potent risk factor among women.

View larger version (23K): [in this window] [in a new window]   Figure 1. Meta-analysis of TG and CVD. Multivariate-adjusted relative risk (RR) estimates and 95% confidence intervals for the association between incident CVD and a 1-mmol/L increase in TG, by gender, for those studies that adjusted for HDL-C. RR values are given on the x-axis on a natural logarithm scale. The y-axis lists each study included in the meta-analysis, ordered by sample size, and the summary RR. FHS, Framingham Heart Study; WCGS, Western Collaborative Health Study; ROG, Rome Occupational Groups; LRC, Lipid Research Clinics Follow-up Study; PROCAM, Prospective Cardiovascular Munster Study; CSCHDS, Caerphilly and Speedwell Collaborative Heart Disease Studies. Note: In a recent report from the PROCAM study, in which the follow-up period was extended to 8 yr, the multivariate RR reached statistical significance. (Modified from Ref. 28.)

	Randomized controlled trials

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

LDL particle size is highly correlated with the TG level, and this confuses the issue (44). Some prospective studies find that LDL particle size is an independent CHD risk factor, whereas others do not. In the Quebec Cardiovascular Study (45) and the Stanford Five City Study (46), the presence of small dense LDL was associated with increased CHD risk, independent of TG. In the Physicians Health Study, LDL size was associated with CHD, but not after adjustment for TG (47).

In the St. Thomas Atherosclerosis Regression Study, an angiographic study, on trial small dense LDL as well as IDL particles were associated with CHD progression (48). In the Stanford Coronary Risk Intervention Project, a predominance of small dense LDL at baseline predicted the therapeutic response of lipid-lowering therapy on CHD progression (49). Because TG levels are the most important determinant of LDL size, these observations suggest that TGRLPs may, in part, moderate an atherogenic effect through change in content and structure of LDL. Because the primary purpose of these studies was to evaluate the effects of LDL-C lowering, it is theoretically possible that TG and TGRLPs finally emerge as a risk factor when the role of LDL-C in atherosclerosis is corrected or minimized. If so, pharmacotherapy to address persisting or concomitant abnormalities in TGRLPs in patients with CHD may result in yet further risk reduction.

Interpreting trials of TG-lowering and CHD can be difficult because TG-lowering drugs (fibrates, nicotinic acid) also change the concentrations of LDL-C and HDL-C, the size of the LDL particle, and the concentration of fibrinogen and PAI-1 (50). From a pragmatic standpoint, it may not be important to know whether TG is an independent CHD risk factor or is a marker associated with atherogenic factors because atherosclerosis is multifactorial and its treatment should address HTG and all associated atherogenic factors. It is unusual for a patient to have an isolated high TG level without other coronary risk factors. This makes it difficult to attribute benefit of therapy to a change in one parameter when all changes may be anti-atherogenic. The precise mechanism may not be important if therapeutic intervention decreases morbidity and mortality.

In the Bezafibrate Coronary Atherosclerosis Intervention Trial, 81 young men with CHD were randomized to treatment with bezafibrate or placebo after baseline coronary angiography (51). Coronary angiography was repeated after an interval of 30 months. Bezafibrate reduced angiographic progression of coronary atherosclerosis by 65% (assessed by changes in minimum luminal diameter). In addition, clinical events occurred in 11 placebo patients but in only 3 bezafibrate-treated patients. In this study, there was no change in the concentration of LDL-C, whereas HDL-C increased by 9% and TG decreased by 35%. Overall, changes in angiographic parameters and clinical events were similar to those observed with statin regression trials.

In the Lopid Coronary Atherosclerosis Trial, 375 men with CHD and low HDL-C were randomized to treatment with placebo or gemfibrozil (52). Angiograms obtained at entry into the study were compared with those completed at 32 months. LDL-C decreased by 12% (from 148 mg/dL to 130 mg/dL), TG decreased by 40% (from 152 mg/dL to 92 mg/dL), and HDL-C increased by 12% (from 34 mg/dL to 38 mg/dL). These changes were associated with slowed progression of atherosclerotic lesions.

In the Helsinki Heart Study, a 5-yr randomized trial conducted exclusively in men without prior CHD, gemfibrozil reduced the risk of fatal CHD and nonfatal MI by 35% (from 4.1% to 2.7%; an absolute risk reduction of 1.4%) (53). By way of comparison, the absolute risk reduction in other primary prevention studies was 2.4% in the West of Scotland Coronary Prevention Study and 2.3% in the Air Force/Texas Coronary Atherosclerosis Prevention Study. The changes in LDL-C did not completely explain the response. Over 80% of the risk reduction from gemfibrozil occurred in men whose LDL to HDL-C ratio was more than 5 and whose TG was more than 200 mg/dL (35). Interestingly, this was the same group of men in PROCAM who were at highest risk of CHD. In the Veterans Administration HDL-cholesterol Intervention Trial, 2531 veterans with CHD and HDL-C less than 40 mg/dL and LDL-C less than 140 mg/dL were randomized to receive placebo or gemfibrozil for 5 yr (54). The combined clinical end point of fatal CHD and nonfatal MI was reduced by 22% (absolute reduction, 4.4%), even though LDL-C levels were unchanged by gemfibrozil. TG was reduced by 31% (from 166 mg/dL to 115 mg/dL), and HDL-C was increased by 6.8% (from 32 mg/dL to 34.2 mg/dL). The reduction in events was greater than predicted by the epidemiologic relationship between HDL-C and CHD (55). This strongly suggests that changes in other lipoproteins, coagulation factors, or other etiologic factors may have been important.

Overall, these studies further support the concept that measures that reduce levels of TGRLPs retard progression of CHD and decrease clinical events.

	Pathophysiology

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

 
HTG indicates that there are increased numbers and/or increased size and TG content of TGRLPs. HTG is genetically, biochemically, and clinically heterogeneous. Some patients with HTG are at increased risk of developing CHD, and some are not; currently, it is impossible to separate those who are from those who are not based solely on their TG level. This suggests that certain TGRLPs may be atherogenic or are associated with metabolic abnormalities that are atherogenic. When HTG is due to large TG-enriched VLDL, there may be relatively less VLDL-C than when it is due to increased numbers of small/remnant VLDL, which carry proportionately more cholesterol (56). The contribution of these different-sized VLDL particles to non-HDL-C would be very different.

It is also likely that TGRLPs change the composition or amounts of other lipoproteins to create a more atherogenic milieu. Furthermore, there is an inverse relationship between TG level and the presence of small dense LDL particles (5). Except when the pattern of small dense LDL particles is inherited, changes in TG over the relatively narrow range of 80–250 mg/dL is associated with a change in LDL size and a shift from large buoyant particles to small dense particles. Approximately 90% of persons with TG of 250 mg/dL will have converted to an atherogenic LDL profile characterized by a predominance of small dense particles (57). This raises several questions: 1) are small dense LDL particles responsible for the atherogenicity of TGRLPs? 2) are small LDL particles a marker for atherogenic TGRLPs? and 3) should we pay more attention to changes in TG levels below 200 mg/dL, a range considered by the National Cholesterol Education Program (NCEP) to be normal but shown in several studies to confer excess risk (33, 34)?

A prevailing concept is that HTG due to the accumulation of IDL, small VLDL, and remnants of VLDL and chylomicrons will be atherogenic because their relatively small particle size enables them to infiltrate the artery wall in a manner similar to LDL (58) and initiate the cascade of events that lead to atherosclerosis (59). These events include lipoprotein oxidation, adherence, and migration of monocytes into the artery wall; differentiation of monocytes into macrophages; formation of foam cells; recruitment of T-lymphocytes; and the development of inflammation; all are related to the release of adhesion molecules and other cytokines (59). Another explanation for the atherogenicity of IDL and small VLDL is their ability to be converted to LDL. In addition, the association of a hypercoagulable state with HTG may promote thrombosis in patients with underlying atherosclerosis (1). Larger TGRLPs (large VLDL, chylomicrons), such as occur with estrogen replacement, the use of alcohol, and in patients with familial HTG and familial hyperchylomicronemia, are less likely to enter the wall of the artery and, therefore, may be less atherogenic. It is nevertheless possible that lipolysis of such particles at the arterial surface may have pathologic consequences. For some individuals a more atherogenic form of HTG may be suspected by the finding of a strong family history of premature CHD or by the presence of disorders associated with an increased risk of CHD, such as diabetes mellitus, chronic renal disease, and familial combined hyperlipidemia. TGRLPs may be more important for the progression of mildly stenotic coronary artery lesions (<50% diameter stenosis) than for severe stenosis (6). This may have important clinical relevance because it has been well documented that the lesions predictive of coronary events tend to be through plaque rupture in atheromata, constricting less than 50% of the coronary artery lumen (60).

We need better clinical laboratory techniques to differentiate patients with atherogenic HTG from those with nonatherogenic HTG, much as we now do by fractionating cholesterol in patients with hypercholesterolemia and separating those with increased LDL-C from those with increased levels of HDL-C. Some studies have pointed out the importance of apo B in distinguishing patients who are at greater vs. lesser risk for CHD (45, 61, 62). Apo B is the major apo in chylomicrons, VLDL, IDL, and LDL. In contrast to cholesterol, there is a constant 1:1 molar ratio of apo B per LDL and VLDL particle, providing an estimate of atherogenic lipoprotein particle number (62). Currently, because of a lack of standardization of the procedure, the use of apo B as a risk factor cannot be generally recommended for clinical purposes. However, the correlation between non-HDL-C (total cholesterol minus HDL-C) and apo B 100 concentrations seems to be especially strong in patients with TG less than 300 mg/dL (correlation coefficient, 0.95), as well as in those with higher TG (correlation coefficient, 0.80) (63). The non-HDL-C index provides another means for assessing the atherogenicity of plasma lipids and potential for lipid-lowering therapy. Once the lipoprotein abnormality has been established, non-HDL-C in hypertriglyceridemic patients may be a better guide than LDL-C to CVD risk and efficacy of lipid-lowering agents (63). The LDL-C may underestimate the risk contributed by elevated TGRLPs because the cholesterol in remnant lipoproteins is not taken into account (64). Non-HDL-C contains all of the cholesterol present in lipoprotein particles now considered to be potentially atherogenic [VLDL, IDL, LDL, and Lp(a)]. Unlike the Friedewald formula, this index does not require any assumptions about the relation of VLDL-C to plasma TG concentrations. Perhaps the non-HDL-C value is the best currently available way of making a distinction among atherogenic lipoprotein profiles (65).

Another consideration is postprandial increases in TG, which may be a more important indicator of atherogenicity than the fasting TG level (66). Postprandial levels of TG and small chylomicron remnants have been related to CHD and progression of coronary atherosclerosis (5, 67, 68). Plasma TG at 2 h, LDL-C, and basal proinsulin also independently related to the common carotid intima-media thickness in healthy middle-aged men when other risk factors were taken into account (69). The postprandial increase in TG (the area under the curve following a fat challenge) is directly related to the fasting TG level even when it is within the normal range. Consequently, exposure of the endothelium and vessel wall to atherogenic TGRLPs will be better reflected by the mean daytime TG level than by the fasting TG level.

In addition to the atherogenicity of TGRLPs, it is likely that the numerous nonlipid metabolic abnormalities associated with insulin resistance play an important role in the development of CHD (1). Consequently, simply reducing the concentration of TGRLPs and TG levels with drugs may only partially reduce risk if insulin resistance and its attendant abnormalities are not also corrected with aggressive lifestyle changes: weight loss, exercise, and so forth. Even though the mechanisms are poorly understood, TGRLP levels are important in the development of CVD (7). Current evidence indicates that TG should be evaluated and reduced to the most desirable levels as dictated by the lipoprotein profile and accompanying nonlipid risk factors. The NCEP Adult Treatment Panel II modified the criteria proposed by the 1992 Consensus Development Conference and defined HTG as borderline high (200–400 mg/dL), high (400–1000 mg/dL), and very high (>1000 mg/dL) (70). Whether these cutoffs are optimal for treating HTG and whether lowering TG can reduce CHD events awaits appropriate large-scale trials.

	Provisional therapeutic recommendations

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

 
The evidence from research on basic mechanisms, epidemiologic relationships, and the few randomized controlled trials relating TG to CVD is compelling, as is the plausibility that TGRLPs are atherogenic (71). This inevitably leads to the conclusion that patients with increased TGRLPs (as reflected by the TG concentration) merit therapy. However, the TG threshold for initiation of therapy and the goals of therapy cannot be clearly articulated. Consequently, recommendations concerning therapy must be provisional and amenable to prompt revision, as our understanding of this controversial area evolves. We propose that a desirable TG level is less than 150–200 mg/dL and that the non-HDL-C level should be less than 160 mg/dL [sum of LDL-C 130 mg/dL + VLDL-C 30 mg/dL (TG 150 mg/dL)] in high-risk patients and less than 130 mg/dL in those who have CVD. Therapy should be considered when the TG or non-HDL-C exceeds these limits. As a general rule, the desirable non-HDL-C level can be estimated by adding 30 mg/dL to the current NCEP guidelines for LDL-C.

The non-LDL-C level should be optimized in patients with combined hyperlipidemia (160 mg/dL for primary prevention and 130 mg/dL for secondary prevention). The target TG for achieving this goal would be 150 mg/dL if NCEP LDL-C goals are also achieved. The non-HDL-C will be important for assessing the efficacy of therapy in patients at high risk of CHD, such as those with combined hyperlipidemia, type 2 diabetes mellitus, and end-stage renal disease, in whom dyslipidemia is common. In type 2 diabetic patients, as well as those with CVD, the LDL-C and non-HDL-C goals should be less than 100 mg/dL and less than 130 mg/dL, respectively, because the risk of fatal CHD and nonfatal MI in asymptomatic diabetic patients is similar to that of nondiabetics with established CHD (72).

The following guidelines for lipid management for hypertriglyceridemic patients are suggested:

Repeat fasting lipid (total cholesterol, LDL-C, HDL-C, TG) measurements must be obtained to confirm the presence of HTG and associated lipid abnormalities before initiating therapy. Secondary causes of HTG also should be excluded at this time.

Lifestyle changes are fundamental and should be implemented as the first line of therapy. Such changes should include weight reduction (73, 74), use of diets that limit saturated fat (75–77) regular physical activity (74, 78, 79), cessation of cigarette smoking (80), reduction or elimination of alcohol consumption (81), and, if diabetic, fastidious control of hyperglycemia (82, 83). HTG in diabetic patients is multifactorial, and intensive glycemic control will often improve HTG but not normalize the TG. Associated metabolic abnormalities should also be addressed to reduce the global risk of CVD.

The only role for fish oil (-3 fatty acids) supplements is in treating resistant HTG inadequately controlled by diet and drugs. The TG response to fish oil is dose dependent; TG concentrations decrease up to 30% at a daily dose of 3 g and up to 50% at a daily dose of 9 g (44). Intake of fish oil has a minimal, although variable, effect on cholesterol and tends to slightly increase LDL-C. It also enhances fibrinolysis and reduces platelet aggregation (84). Contrary to earlier views, fish oil supplementation does not seem to alter glucose tolerance (85).

Elevated LDL-C and TG 200–400 mg/dL (Fig. 2). The first priority of therapy in patients with HTG is treatment of an elevated LDL-C (70). The more potent statins frequently will control HTG as well as increased LDL-C, particularly when the increase in LDL-C is proportionally greater than the increase in TG when the TG is less than 400 mg/dL. The magnitude of the TG reduction with statins is directly related to the baseline TG value (44). Resins are not recommended for LDL-C reduction if TGs are borderline or higher because they tend to increase VLDL synthesis and TG levels (44). Generally, statins do not reduce TG by more than 35–40%, and some patients require a greater reduction (86). If statins do not reduce the TG to less than 150–200 mg/dL, then additional therapy may be required. Nicotinic acid can be substituted for a statin, contingent on patient acceptance, with the hope of reaching a dose that optimally reduces LDL-C and TG and increases HDL-C. The use of nicotinic acid is relatively contraindicated in patients who have the metabolic syndrome, in whom it may precipitate frank diabetes, or patients who have diabetes, in whom it worsens hyperglycemia (87, 88). However, there is relatively little data to support these recommendations (87, 88). Larger, better designed trials of nicotinic acid for treating dyslipidemias in patients with diabetes are needed.

Alternatively, fibrates or nicotinic acid can be added to a statin to take advantage of their complementary actions on lipoproteins. Despite the warnings against use of statins and fibrates or nicotinic acid in combination, they are usually safe and effective (50, 89–91). The major concern, severe myopathy and rhabdomyolysis, occurs in approximately 1% of patients on combination therapy (89). Such adverse events should be preventable by judicious use of this combination and careful monitoring. Factors that predispose to adverse interactions (e.g. hypothyroidism, renal failure, use of interacting medications, and so forth) should be identified before combining these drugs. To warrant the additional risk of using these drugs in combination, the risk of future CVD events should be high, at least 10% over the ensuing 5-yr period. The same is true for the combined use of statins with nicotinic acid. Statins are less effective in reducing the LDL-C in patients with combined hyperlipidemia than in patients with isolated increases in LDL-C. The LDL-C response to fibrates cannot be predicted accurately. This is due to increased efficiency of "downstream" conversion of VLDL to LDL. If these added LDL particles cannot be cleared from the blood, levels of LDL-C will increase during administration of fibrates.

TG more than 400 mg/dL and LDL-C less than 130 mg/dL. Fibrates are the drugs of first choice for patients with TG more than 400 mg/dL and LDL-C less than 130 mg/dL. Nicotinic acid also may be a reasonable option if the TG is not excessively high. Because the mechanisms of action of fibrates and nicotinic acid are different, they can be successfully used in combination in some patients and should be considered in patients with massive HTG or those at risk for pancreatitis. Because of the limitations of the Friedewald equation, the LDL-C concentration cannot be calculated in such patients. Using a reliable method to directly measure LDL-C may be helpful. Therapy should be initiated with the goal of reducing TG to less than 400 mg/dL, allowing additional therapeutic decisions to be made when the LDL-C can be accurately assessed.

Patients with HTG of this magnitude frequently have a low or normal LDL-C, which tends to increase as the TG decreases. This may be a problem in patients with low or normal LDL-C at baseline treated with fibrates. Fibrates, however, increase the buoyancy of LDL particles and perhaps makes them less atherogenic (57).

TG more than 400 mg/dL and LDL-C more than 130 mg/dL. The drugs of choice for TG more than 400 mg/dL are fibrates and nicotinic acid. If tolerated, nicotinic acid in this situation may be preferable because of its LDL-C lowering effect. However, the addition of a statin may be necessary if the LDL-C is elevated. As noted above, the combination of fibrates and nicotinic acid can be used and should be considered in patients with marked HTG or those at risk for pancreatitis.

View larger version (33K): [in this window] [in a new window]   Figure 2. Management of HTG. After careful assessment of the dyslipidemia, the initial effort should be directed toward lifestyle changes. Drug therapy depends on the level of TG elevation and whether or not it is accompanied by an elevated LDL-C.

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

	Footnotes

 
"Clinical Perspectives" are an occasional feature of The Journal of Clinical Endocrinology & Metabolism. They present the opposing views of invited contributors on a topic. All reprints must include the complete Clinical Perspective, so that each section can be read in context.

Accepted March 6, 2000.

	References

Top Introduction Epidemiologic studies Randomized controlled trials Pathophysiology Provisional therapeutic... References

 

1. Grundy SM. 1998 Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol. 81(Suppl 4A):18B–25B.
2. National Cholesterol Education Program Working Group on Lipoprotein Measurement. 1995 Recommendations on lipoprotein measurement. Part 1, section 3: accuracy of LDL-cholesterol measurements. NIH Publication No. 95-3044.
3. Betteridge DJ. 1996 Lipids: current perspectives, vol. 1, lipids and lipoproteins. London: Martin Dunitz; 21–42.
4. NIH Consensus Development Panel on Triglyceride, High Density Lipoprotein, and Coronary Heart Disease. 1993 J Am Med Assoc. 269:505–510.
5. Krauss RM. 1998 Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol. 81:13B–17B.
6. Hodis HN. 1999 Triglyceride-rich lipoprotein remnant particles, and risk of atherosclerosis. Circulation. 99:2852–2854.[Free Full Text]
7. Havel RJ. 1990 Role of triglyceride-rich lipoproteins in progression of atherosclerosis. Circulation. 81:694–696.[Free Full Text]
8. Gianturco SH, Bradley WA. 1999 Pathophysiology of triglyceride-rich lipoproteins in atherosclerosis: cellular aspects. Clin Cardiol. 22(Suppl II):II7–II14.
9. Havel RJ, Kane JP. 1989 Introduction: structure, and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, Inc.; 1129–1138.
10. Scandinavian Simvastatin Survival Group. 1994 Randomized trial of cholesterol lowering in 4444 participants with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet. 344:1383–1389.[CrossRef][Medline]
11. Shepherd J, Cobbe SM, Ford I, et al. for the West of Scotland Coronary Prevention Study Group. 1995 Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 333:1301–1307.[Abstract/Free Full Text]
12. Downs JR, Clearfield M, Weis S, et al. 1998 Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. J Am Med Assoc. 279:1615–1622.[Abstract/Free Full Text]
13. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. 1998 Prevention of cardiovascular events and death with pravastatin inpatients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 339:1349–1357.[Abstract/Free Full Text]
14. Harjai KJ. 1999 Potential new cardiovascular risk factors: left ventricular hypertrophy, homocysteine, lipoprotein(a), triglycerides, oxidative stress, and fibrinogen. Ann Intern Med. 131:376–386.[Abstract/Free Full Text]
15. Fuster V, Gotto AM, Libby P, et al. 1996 Task Force 1. Pathogenesis of coronary disease: the biologic role of risk factors. J Am Coll Cardiol. 27:964–1047.[CrossRef][Medline]
16. Williams RR, Hopkins PN, Hunt SC, et al. 1990 Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah. Arch Intern Med. 150:582–588.[Abstract/Free Full Text]
17. Gofman JW, Strisower B, deLalla O, et al. 1953 Index of coronary artery atherogenesis. Mod Med. 119–140.
18. Albrink MJ, Man EB. 1959 Serum triglycerides in coronary artery disease. Arch Intern Med. 103:4–8.[Abstract/Free Full Text]
19. Albrink MJ. 1962 Triglycerides, lipoproteins, and coronary artery disease. Arch Intern Med. 109:345–359.
20. Brown DF, Kinch SH, Doyle JT. 1965 Serum triglycerides in health and in ischemic heart disease. N Engl J Med. 273:947–952.
21. Carlson LA, Bottiger LE, Ahfeldt PE. 1979 Risk factors for myocardial infarction in the Stockholm prospective study. A 14-year follow-up focussing on the role of plasma triglycerides and cholesterol. Acta Medica Scandinavia. 206:351–360.[Medline]
22. Cambien F, Jacqueson A, Richard JL, et al. 1986 Is the serum triglyceride a significant predictor of coronary death in "normocholesterolemic" subjects? The Paris Prospective Study. Am J Epidemiol. 124:624–632.[Abstract/Free Full Text]
23. Fontbonne A, Eschwege E, Cambien F, et al. 1989 Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia. 32:300–304.[CrossRef][Medline]
24. Benfante RJ, Reed DM, MacLean CJ, Yano K. 1989 Risk factors in middle age that predict early and late onset of coronary heart disease. J Clin Epidemiol. 42:95–104.[CrossRef][Medline]
25. Wilson PWF, Anderson KM, Castelli WP. 1991 The impact of triglycerides on coronary heart disease: The Framingham Study. In: Gotto Jr AM, Paoletti R, eds. Atherosclerosis reviews, vol. 22. New York: Raven Press; 59–63.
26. Criqui MH, Heiss G, Cohn R, et al. 1993 Plasma triglyceride level and mortality from coronary heart disease. N Engl J Med. 328:1220–1225.[Abstract/Free Full Text]
27. Bainton D, Miller NE, Bolton CH, et al. 1992 Plasma triglyceride and high density lipoprotein cholesterol as predictors of ischaemic heart disease in British men. Br Heart J. 68:60–66.[Abstract/Free Full Text]
28. Austin MA, Hokanson JE, Edwards KL. 1998 Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 81(Suppl 4A):7B–12B.
29. Haim M, Benderly M, Brunner D, et al. 1999 Elevated serum triglyceride levels and long-term mortality in patients with coronary heart disease: The Bezafibrate Infarction Prevention (BIP) Registry. Circulation. 100:475–482.[Abstract/Free Full Text]
30. Miller M. 1999 The epidemiology of triglyceride as a coronary artery disease risk factor. Clin Cardiol. 22:II-1–II-6.
31. Assman G, Schulte H. 1992 Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (The PROCAM Experience). Am J Cardiol. 70:733–737.[CrossRef][Medline]
32. Assman G, Schulte H, Funke H, Von Eckardstein A. 1998 The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J. 19(Suppl M):M8–M14.
33. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. 1998 Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. Circulation. 97:1029–1036.[Abstract/Free Full Text]
34. Miller M, Seidler A, Moalemi A, Pearson TA. 1998 Normal triglyceride levels and coronary artery disease events: The Baltimore Coronary Observational Long-Term Study. J Am Coll Cardiol. 31:1252–1257.[Abstract/Free Full Text]
35. Manninen V, Tenkanen L, Koskinen P, et al. 1992 Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Circulation. 85:37–45.[Abstract/Free Full Text]
36. Sattar N, Packard CJ, Petrie JR. 1998 The end of triglycerides in cardiovascular risk assessment?: Rumours of death are greatly exaggerated. Br Med J. 317:553–554.[Free Full Text]
37. Phillips N, Waters D, Havel R. 1993 Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation. 88:2762–2770.[Abstract/Free Full Text]
38. Hodis H, Mack W, Azen S, et al. 1994 Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation. 90:42–49.[Abstract/Free Full Text]
39. Krauss RM, Lindgren FT, Williams PT, et al. 1987 Intermediate-density lipoproteins, and progression of coronary artery disease in hypercholesterolemic men. Lancet. 2:62–65.[CrossRef][Medline]
40. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP. 1990 Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Circulation. 81:470–476.[Abstract/Free Full Text]
41. Bissett JK, Wyeth RP, Matts JP, Johnson JW. 1993 Plasma lipid concentrations and subsequent coronary occlusion after a first myocardial infarction. The POSCH Group. Am J Med Sci. 305:139–144.[Medline]
42. Pedersen TR, Olsson AG, Faergeman O, et al. 1998 Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 97:1453–1460.[Abstract/Free Full Text]
43. Pfeffer M, Sacks F, Moye L, et al. 1999 Influence of baseline lipids on effectiveness of pravastatin in the CARE trial. J Am Coll Cardiol. 33:125–130.[Abstract/Free Full Text]
44. Knopp RH. 1999 Drug treatment of lipid disorders (Review). N Engl J Med. 341:498–511.[Free Full Text]
45. Lamarche B, Tchernof A, Moorjani S, et al. 1997 Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec cardiovascular study. Circulation. 95:69–75.[Abstract/Free Full Text]
46. Gardner C, Fortmann S, Krauss R. 1996 Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. J Am Med Assoc. 276:875–881.[Abstract/Free Full Text]
47. Stampfer M, Krauss R, Ma J, et al. 1996 A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. J Am Med Assoc. 276:882–888.[Abstract/Free Full Text]
48. Watts GF, Mandalia S, Brunt J, Slavin B, Coltart D, Lewis B. 1993 Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas atherosclerosis regression study (STARS). Metabolism. 42:1461–1467.[CrossRef][Medline]
49. Miller B, Alderman E, Haskell W, Fair J, Krauss R. 1996 Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford coronary risk intervention project. Circulation. 94:2146–2153.[Abstract/Free Full Text]
50. Fruchart JC, Brewer Jr B, Leitersdorf E. 1998 Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Am J Cardiol. 81:912–917.[CrossRef][Medline]
51. Ruotolo G, Ericsson CG, Tettamanti C, et al. 1998 Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the bezafibrate coronary atherosclerosis intervention trial (BECAIT). J Am Coll Cardiol. 32:1648–1656.[Abstract/Free Full Text]
52. Syvänne M, Nieminen M, Frick MH, et al. 1998 Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation. 98:1993–1999.[Abstract/Free Full Text]
53. Frick MH, Elo O, Haapa K, et al. 1987 Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 317:1237–1245.[Abstract]
54. Rubins HB, Robins SJ, Collins D, et al. for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. 1999 Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 341:410–418.[Abstract/Free Full Text]
55. Gordon DJ, Probstfield JL, Garrison RJ, et al. 1989 High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 79:8–15.[Abstract/Free Full Text]
56. Packard CJ, Shepherd J. 1997 Lipoprotein heterogeneity and apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol. 17:3542–3556.[Abstract/Free Full Text]
57. Austin M, King MC, Vranizan K, Krauss R. 1990 Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation. 82:495–506.[Abstract/Free Full Text]
58. Nordestgaard B, Tybjærg-Hansen A, Lewis B. 1992 Influx in vivo of low density, intermediate density, and very low density lipoproteins into aortic intimas of genetically hyperlipidemic rabbits. Arterioscler Thromb. 12:6–18.[Abstract/Free Full Text]
59. Ross, R. 1999 Atherosclerosis—an inflammatory disease. N Engl J Med. 340:115–126.[Free Full Text]
60. Fuster V, Fallon JT, Badimon JJ, Nemerson Y. 1997 The unstable atherosclerotic plaque: clinical significance and therapeutic intervention. Thromb Haemost. 78:247–255.[Medline]
61. Lamarche B, Tchernof A, Mauriege P, et al. 1998 Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. J Am Med Assoc. 279:1955–1961.[Abstract/Free Full Text]
62. Rader DJ, Hoeg JM, Brewer HB. 1994 Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med. 120:1012–1025.[Abstract/Free Full Text]
63. Frost PH, Havel RJ. 1998 Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy. Am J Cardiol. 81(4A):26B–31B.
64. Grundy SM. 1998 Consensus statement: role of therapy with "statins" in patients with hypertriglyceridemia. Am J Cardiol. 81:1B–6B.[CrossRef][Medline]
65. Havel RJ. 1998 Plasma triglycerides and the clinician: time for reassessment. Editorial comment. J Am Coll Cardiol. 31:1258–1259.[Free Full Text]
66. Chung BH, Tallis GA. 1992 Postprandial lipoproteins and atherosclerosis. In: Kreisberg RA, Segrest JE, eds. Plasma lipoproteins and coronary artery disease. Boston: Blackwell Scientific Publications; 183–199.
67. Patsch JR, Miesenböck G, Hopferwieser T, et al. 1992 Relation of triglyceride metabolism and coronary artery disease. Arterioscler Thromb. 12:1336–1345.[Abstract/Free Full Text]
68. Karpe F, Steiner G, Uffelman K, Olivecrona T, Hamsten A. 1994 Postprandial lipoproteins and progression of coronary atherosclerosis. Atherosclerosis. 106:83–97.[CrossRef][Medline]
69. Boquist S, Ruotolo G, Tang R, et al. 1999 Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation. 100:723–728.[Abstract/Free Full Text]
70. National Cholesterol Education Program. 1993 Second report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel II). Bethesda, MD: National Institutes of Health National Heart, Lung and Blood Institute, NIH Publication No. 93-3095.
71. Hodis HN, Mack WJ, Krauss RM, Alaupovic P. 1999 Pathophysiology of triglyceride-rich lipoproteins in atherosclerosis: clinical aspects. Clin Cardiol. 22(Suppl II):II15–II20.
72. Haffner S, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. 1998 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. 339:229–234.[Abstract/Free Full Text]
73. Eckel RH. 1999 The importance of timing and accurate interpretation of the benefits of weight reduction on plasma lipids. Obes Res. 7:227–228.[Medline]
74. Hardman AE. 1999 Physical activity, obesity and blood lipids. Int J Obes Relat Metab Disord. 23(Suppl 3):S64–S71.
75. Grundy SM, Denke MA. 1990 Dietary influences on serum lipids and lipoproteins. J Lipid Res. 31:1149–1172.[Abstract]
76. Yu-Poth S, Zhao G, Etherton T, Naglak M, Jonnalagadda S, Kris-Etherton PM. 1999 Effects of the National Cholesterol Education Program’s Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis. Am J Clin Nutr. 69:632–646.[Abstract/Free Full Text]
77. Kris-Etherton PM, for the Nutrition Committee. 1999 Monosaturated fatty acids and risk of cardiovascular disease. Circulation. 100:1253–1258.[Free Full Text]
78. Durstine JL, Haskell WL. 1994 Effects of exercise training on plasma lipids and lipoproteins. Exerc Sport Sci Rev. 22:477–521.[Medline]
79. U.S. Department of Health and Human Services. 1996 Physical activity and health: a report of the surgeon general. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 111.
80. Craig WY, Palomaki GE, Haddow JE. 1989 Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. Br Med J. 298:784–788.
81. Pownall HJ, Ballantyne CM, Kimball KT, Simpson SL, Yeshurun D, Gotto Jr AM. 1999 Effect of moderate alcohol consumption on hypertriglyceridemia: a study in the fasting state. Arch Intern Med. 159:981–987.
82. Haffner S. 1998 Management of dyslipidemia in adults with diabetes. Diabetes Care. 21:160–178.[Abstract]
83. American Diabetes Association. 2000 Management of dyslipidemia in adults with diabetes. Diabetes Care. 23(Suppl 1):S57–S60.
84. Stone NJ. 1996 Fish consumption, fish oil, lipids, and coronary heart disease. Circulation. 94:2337–2340.[Free Full Text]
85. Toft I, Bønaa KH, Ingebretsen OC, Nordøy A, Jenssen T. 1995 Effects of n-3 polyunsaturated fatty acids on glucose homeostasis and blood pressure in essential hypertension: a randomized, controlled trial. Ann Intern Med. 123:911–918.[Abstract/Free Full Text]
86. Stein E, Lane M, Laskarzewski P. 1998 Comparison of statins in hypertriglyceridemia. Am J Cardiol. 81(4A):66B–69B.
87. Kahn SE, Beard JC, Schwartz MW, et al. 1989 Increased ß-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance. Diabetes. 38:562–568.[Abstract]
88. Garg A, Grundy SM. 1990 Management of dyslipidemia in NIDDM. Diabetes Care. 13:153–169.[Abstract]
89. Shepherd J. 1995 Fibrates and statins in the treatment of hyperlipidemia: an appraisal of their efficacy and safety. Eur Heart J. 16:5–13.
90. Ellen RLB, McPherson R. 1998 Long-term efficacy, and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol. 81:60B–65B.[CrossRef]
91. Athyros V, Papageorgiou A, Hatzikonstandinou H, et al. 1997 Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol. 80:608–613.[CrossRef][Medline]

This article has been cited by other articles:

				R. A. Kreisberg and A. Oberman Lipids and Atherosclerosis: Lessons Learned from Randomized Controlled Trials of Lipid Lowering and Other Relevant Studies J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 423 - 437. [Full Text] [PDF]

				C. A. Aguilar-Salinas, G. Olaiz, V. Valles, J. M. R. Torres, F. J. G. Perez, J. A. Rull, R. Rojas, A. Franco, and J. Sepulveda High prevalence of low HDL cholesterol concentrations and mixed hyperlipidemia in a Mexican nationwide survey J. Lipid Res., August 1, 2001; 42(8): 1298 - 1307. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oberman, A. Search for Related Content PubMed Articles by Oberman, A.