Hypertriglyceridemia: Management of Atherogenic Dyslipidemia

RECOMMENDATIONS FROM A CONSENSUS PANEL

Associate Investigator, Gladstone Institute of Cardiovascular Disease, Clinical Professor of Medicine, University of California, San Francisco, School of Medicine, San Francisco, California

Professor of Internal Medicine, University of Texas Health Science Center, San Antonio, Texas

Professor of Medicine, University of South Dakota, South Dakota Health Research Foundation, Sioux Falls, South Dakota

Clinical Instructor, Pharmacy and Medicine, State University of New York at Buffalo, Clinical Pharmacy Coordinator, VA Western New York Healthcare System, Buffalo, New York

Past President, Association of Family Practice Physician Assistants, Staff Physician Assistant, Halyburton Naval Hospital, Cherry Point, North Carolina

The definitive role of triglycerides (TG) as a risk factor for coronary heart disease (CHD) is still unclear, but increasing data indicate that they are an important factor in assessing a patient’s cardiovascular risk. For 20 years, low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were the focus of CHD risk assessment and treatment. Although statin trials have demonstrated that low LDL-C significantly decreases the incidence of cardiovascular disease (CVD), more cardiovascular events still occurred than were prevented.^1-6 This, and the growing awareness of the causes and consequences of the metabolic syndrome (MetS) and type 2 diabetes mellitus (DM), led the National Cholesterol Education Program Adult Treatment Panel’s third report (ATP III) to emphasize elevated TG as a risk marker, especially when associated with low levels of high-density lipoprotein cholesterol (HDL-C).⁷ The potential implications of hypertriglyceridemia (HTG) as a risk marker for premature CHD are discussed below and appropriate clinical management of HTG is described.

  CLINICAL CONSEQUENCES OF ELEVATED TG

Elevated TG (TABLE 1)^7,8 are of clinical concern because they often signal the presence of insulin resistance, a syndrome associated with increased risk of developing type 2 DM, CHD, or acute pancreatitis.^9,10 When serum TG increase above 150 mg/dL, atherogenic TG and cholesterol-enriched particles accumulate and the risk of CHD increases.^11,12 As TG levels increase from 150 to 500 mg/dL, the likelihood that a patient may be affected by MetS or type 2 DM increases; for very high levels (TG >1000 mg/dL), acute pancreatitis becomes an additional concern.^7,8,10

Revised standards for hypertriglyceridemia

  PATTERNS OF HTG

Familial HTG, characterized by a family history of isolated HTG, is commonly seen in clinical practice and can have various lipid patterns.¹⁰ It is uncertain whether familial HTG is associated with increased CHD risk.¹³ Most commonly, patients demonstrate type IV hyperlipoproteinemia, which includes elevated levels of TG (between 250 and 500 mg/dL) and the very-low density lipoproteins (VLDL) that transport them, and normal LDL-C and apolipoprotein B (apo-B) levels. Patients with poorly controlled diabetes and excessive alcohol intake may demonstrate the type V phenotype, which includes more pronounced TG elevation, and increased VLDL and chylomicron levels.

Chylomicronemia syndrome is usually due to a combination of genetic and acquired causes of HTG. It may occur secondary to genetic deficiencies of lipoprotein lipase or apo-C-II, which are extremely rare. Triglyceride levels of 1000 to 10,000 mg/dL are seen from the time of birth. Onset of such severe HTG in adults is most often a consequence of a combination of genetic and acquired disorders.¹⁴ Although recurrent pancreatitis is associated with type I and V phenotypes, patients with the latter also may be at increased risk for CHD, but those with the former do not appear to be.^10,13

  HTG AND CARDIOVASCULAR RISK

Determining the effect of HTG on CHD risk was complicated by the close relation of elevated TG with other metabolic abnormalities and the variability in types of HTG, some of which are not linked with accelerating atherosclerosis or increasing risk of premature CHD.¹⁰ Early data did not provide strong, consistent evidence for HTG as a cardiovascular risk factor, but in 1988 when the Framingham Heart Study showed a statistically significant relation of elevated TG to CHD in women and elevated TG in 30% of patients with a myocardial infarction (MI), it became important to understand the impact of one on the other.

Triglycerides appear to affect cardiovascular risk in several ways. They are the primary driver of the metabolic disarray of elevated TG, low HDL-C, and small, dense LDL (sdLDL) that characterizes atherogenic dyslipidemia, which plays a major role in overall cardiovascular risk.¹⁵ The TG-rich lipoproteins chylomicrons, VLDL, and their remnants appear to be present in atherosclerotic plaque,^16,17 indicating that the cholesterol in TG-enriched lipoproteins may directly contribute to atherosclerosis. In hypertriglyceridemic patients, TG-enriched LDL-C and HDL-C particles become substrates for hepatic lipase, ultimately resulting in increased catabolism of HDL-C and production of the more atherogenic sdLDL. Finally, HTG may contribute to additional pathologic processes associated with MetS and cardiovascular risk, including increased coagulability, impaired fibrinolysis, impaired endothelial function, and increased inflammation, although this remains uncertain.^16,18

  EVIDENCE OF TG AS AN INDEPENDENT RISK FACTOR

Three key articles concerning the role of TG were published in 1998, and this evidence led ATP III to adopt elevated TG as an independent, albeit not a major, risk factor for CHD.⁷ The first was a meta-analysis of population-based prospective studies involving Caucasian men and women followed for 8.4 and 11.4 years, respectively.¹⁹ Results demonstrated a 32% increase in CVD risk for men and a 76% increase for women for each 89 mg/dL increase in TG. After adjusting for HDL-C and other risk factors, the CVD risk was found to be increased 14% in men (relative risk [RR]=1.14) and 37% in women (RR=1.37), and remained statistically significant (FIGURE 1).

The Baltimore Coronary Observational Study was a retrospective cohort trial that evaluated TG levels in adults with angiographically defined CHD.²⁰ During the 18-year follow-up, patients were stratified by death from ischemic heart disease, nonfatal MI, or need for coronary revascularization. When adjusted for age, sex, and beta-blocker use, TG >100 mg/dL were associated with a RR of 1.5 for CHD.

Finally, the Copenhagen Male Study demonstrated a positive relation between TG and ischemic heart disease.²¹ White men, aged 53 to 74 years and free of evident CVD, were followed for 8 years. Compared with the RR for the lowest third of TG levels (adjusted for traditional risk factors, including HDL-C), the RR of ischemic heart disease for the middle and highest third of TG levels were 1.5 (P=.05) and 2.2 (P<.001), respectively. Similar findings also were noted with increasing TG within each level of HDL-C, including those with high HDL-C levels.

  RISK ASSESSMENT MEASURES

Determining if HTG predicts CHD among individual patients can be complex, although using specific measures can help identify higher-risk individuals.

Non-HDL measures (TC minus HDL-C) account for all atherogenic particles and are stronger indicators of CHD risk than is LDL-C. Because of its clinical utility, ATP III suggests using non-HDL as a secondary target for therapy.

Another simple calculation that strongly correlates with the presence of insulin resistance, a preponderance of sdLDL (phenotype B), and significantly higher CHD risk is an elevated TG:HDL ratio. Values above 3.5 are highly predictive of the presence of insulin resistance and, in one study, a ratio of TG:HDL greater than 3.8 identified 79% of patients with phenotype B.¹⁷

  NONPHARMACOLOGIC THERAPY

A multifaceted approach is necessary and most effective in the management of HTG.²² Prior to treatment, patients should be evaluated for possible secondary causes of HTG.¹⁰ The use of nonpharmacologic approaches is always first-line therapy for HTG. Of all lipid parameters, TG are the most responsive to and could be managed completely with therapeutic lifestyle changes, namely, diet and exercise.²³ A nutrition and exercise consult should be considered to maximize the effectiveness of lifestyle changes.

  PHARMACOLOGIC THERAPY

Drug therapy for HTG is often required, particularly for patients with very high TG levels (>500 mg/dL). It is imperative to choose appropriate drug therapy (TABLE 2),^24,25 as certain agents, particularly the bile acid sequestrants cholestyramine, colestipol, and colesevelam, have the potential to worsen HTG when used as a monotherapy. Adverse drug reactions are also a concern, especially when certain lipid-lowering agents are used in combination (TABLE 3).^7,26-28 A management approach for HTG is suggested on PAGE S6.

Pharmacotherapy: Effect on serum lipids

Adverse drug reactions and implications of hypertriglyceridemic agents

Niacin

Niacin has been used to treat various forms of dyslipidemia for over 50 years and beneficially affects all major lipoproteins.²⁹ Niacin possesses a wide dosing range, but usual doses are 2000 mg/d or less due to adverse effects. Flushing is the most common adverse effect and causes discontinuation rates of 10% to 50%.³⁰ This adverse effect can be minimized by aspirin (or other nonsteroidal anti-inflammatory drugs) administration 30 minutes prior to the niacin dose or by using an extended-release niacin product. Other adverse effects of and contraindications to niacin are listed in TABLE 3.

Fibrates

Fenofibrate and gemfibrozil are fibric acid derivatives that are commonly used to treat HTG in the United States. The usual dose of gemfibrozil is 600 mg twice daily; for fenofibrate, multiple formulations are available with varying doses given once daily. Use of these agents in combination with a statin has recently become more commonplace. While most individuals are able to tolerate this combination, a substantial number of rhabdomyolysis cases with the combined use of gemfibrozil and a statin have been reported to the US Food and Drug Administration (FDA).³¹ Pharmacokinetic studies indicate that gemfibrozil inhibits the metabolism of most statins (via glucuronidation), resulting in higher statin concentrations.³² Conversely, fenofibrate does not appear to alter serum levels of statins.³³ When using a statin and fibrate together, close monitoring and educating patients to report any unexplainable weakness or myalgia is crucial.

Statins

Primarily, statins lower LDL-C, although moderate reductions in TG directly proportional to LDL-C reduction also are noted. Generally, when TG values are very high (>500 mg/dL), statins appear to be less effective,⁷ although atorvastatin, 80 mg daily, has been shown to reduce TG by 45% in patients with a baseline TG level of approximately 600 mg/dL.³⁴ Overall, statins are well tolerated; discontinuation rates are reported to be less than 4% secondary to adverse effects (TABLE 3).³⁵

Omega-3 Fatty Acids

Early observational evidence, supported by subsequent data, suggested that diets rich in fish oils are associated with a lower risk of acute MI.³⁶ After an 11-year follow-up, the Physicians Health Study found that those who consumed at least 1 fish meal per week experienced a significant (52%) reduction in sudden cardiac death, compared with those who consumed fish only monthly.³⁷ The Diet and Reinfarction Trial, which involved post-MI men (N=2033), found that those randomized to receive advice on fish consumption experienced a significant (29%) reduction in overall mortality after 2 years compared with those who received usual care. A subgroup that was given fish oil capsules (900 mg eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]/day) experienced even greater reductions in CHD events.³⁸

The long-term benefits of omega-3 fatty acids (FAs) also have been demonstrated in secondary prevention. The GISSI-Prevenzione trial is the largest clinical trial showing cardiovascular benefits with omega-3 acid ethyl esters.³⁹ Post-MI patients (N=11,324) were randomized to 1 of 4 arms and followed for 3.5 years. The arms consisted of omega-3 acid ethyl esters (850 mg EPA + DHA/d), vitamin E (300 mg/d), both omega-3 acid ethyl esters and vitamin E, or neither. Supplementation with vitamin E demonstrated no benefit, while EPA + DHA significantly reduced total mortality and sudden cardiac death by 20% and 45%, respectively. Further analyses indicated that these benefits became evident early in treatment. Total mortality was significantly reduced at 3 months (RR=0.59) and the risk of sudden cardiac death was significantly reduced at 4 months (RR=0.47) (FIGURE 2).⁴⁰ These results are particularly impressive considering this population was well treated with other cardiovascular agents and followed a Mediterranean diet.

Sources of omega-3 FAs

The cardioprotective component of fish oils is the omega-3 FAs, specifically the essential FAs EPA and DHA.⁴¹ Modern diets are generally low in omega-3 FAs.⁴²

Capsules required to provide cardiovascular and triglyceride benefits with selected omega-3 fatty acid products

The omega-3 group of essential FAs includes C18:3 (alpha-linolenic acid), C20:5 (EPA), and C22:6 (DHA). The evidence of a cardioprotective effect of the alpha-linolenic acid, which is derived from plants such as flaxseed, canola, and soybean oils, and walnuts, is much less robust than for EPA and DHA, which are derived from marine sources, especially salmon, mackerel, sardines, and tuna.^36,41 A number of omega-3 FA dietary supplements of varying EPA/DHA content are available without a prescription (TABLE 4).^26,43 The therapeutic doses for HTG of these dietary supplements differ from the labeled doses. The only prescription product, omega-3 acid ethyl esters (Omacor^®), hereafter referred to as P-OM3, was approved by the FDA in 2004. Unlike nonprescription omega-3 FA dietary supplements, P-OM3 met the FDA requirements for efficacy and safety and is indicated in the management of HTG.

Clinical trials involving P-OM3

Several clinical trials have demonstrated the efficacy and safety of P-OM3. Harris et al randomized 42 patients with a TG level between 500 and 2000 mg/dL to P-OM3, 4 g/d, or placebo (corn oil) for 16 weeks.⁴⁴ After 16 weeks, the TG and TC levels of those who received P-OM3 were reduced by 45% and 15%, respectively, while increasing HDL-C 13% and LDL-C 31%. No change in the lipoprotein profile was seen with placebo. Pownall et al had similar results in a 6-week trial of 40 patients with mean baseline TG, 801 mg/dL; TC, 326 mg/dL; HDL-C, 17 mg/dL; and LDL-C, 43 mg/dL.⁴⁵ Patients received either P-OM3, 4 g/d, or placebo. At the end of the trial, TG were reduced 39% and TC 10%, while HDL-C and LDL-C increased 6% and 17%, respectively. No serious side effects were reported and the drop-out rate was very low.

The benefits of P-OM3 also have been investigated in patients with established CHD. One randomized, double-blind study involved 59 patients currently receiving simvastatin (10-40 mg/d).⁴⁶ After 24 weeks, patients who received P-OM3, 2 g twice daily, in combination with simvastatin were found to have an additional 20% to 30% reduction in TG levels and 30% to 40% reduction in VLDL levels. Changes in LDL-C and HDL-C were negligible. These results were sustained in those who continued 24 weeks of open-label treatment.

Meta-analyses of omega-3 FAs

While observational data and clinical trials have demonstrated favorable cardiovascular effects with omega-3 FAs, meta-analyses provide conflicting data. Studer et al evaluated the effects of different antilipidemic therapies on mortality.⁴⁷ Compared with control groups, risk ratios of cardiac and total mortality for omega-3 FAs were 0.68 and 0.77, respectively. The authors concluded that statins and omega-3 FAs were the most effective of all lipid-lowering interventions at reducing all-cause mortality. In contrast, a recent meta-analysis based on a Cochrane review concluded that there was no clear evidence that dietary or supplemental omega-3 FAs alter total mortality or combined cardiovascular events in people with, or at high risk of, CVD or in the general population.⁴⁸ However, the authors also concluded that there is no evidence that people should be advised to stop taking rich sources of omega-3 FAs. The difference was due to the inclusion of one large, relatively poorly controlled study⁴⁹ with a negative outcome in the Cochrane review.

  MECHANISMS OF OMEGA-3 FAS

Plaque stabilization and antiarrhythmic effects may account for much of the benefit of omega-3 FAs. In a study of the effect of omega-3 FAs on atherosclerotic plaque composition, the treatment group had more thick fibrous caps with fewer inflammatory cells.⁵⁰ The authors concluded that atherosclerotic plaques readily incorporate omega-3 FAs, which improve plaque stability.

Omega-3 FAs have demonstrated antiarrhythmic properties in experimental models and reduced sudden cardiac death in previous clinical trials. Two recent trials randomized patients with implantable cardioverter-defibrillators (ICDs) to omega-3 FAs or placebo and measured the time to first ICD treatment for ventricular tachycardia or fibrillation. Leaf et al reported a strong, but statistically insignificant trend toward a prolongation in the time to the first ICD treatment or death from any cause with omega-3 FAs (2600 mg EPA/DHA daily).⁵¹ Conversely, Raitt et al concluded omega-3 FAs (1800 mg EPA/DHA daily) did not reduce the risk of ventricular tachycardia or fibrillation and may be proar-rhythmic in some individuals.⁵² This inconsistency may be explained by substantial differences in the ICD patients in the Leaf et al and the Raitt et al studies, and between the ICD patients and the previous populations (post-MI and atrial fibrillation) that experienced clear benefit with omega-3 FAs.

Another study evaluated the effects of omega-3 FAs on atrial fibrillation following coronary artery bypass grafting (CABG). Patients were randomized to usual care or omega-3 FAs (1700 mg EPA/DHA daily) at least 5 days prior to CABG and monitored for the occurrence of atrial fibrillation during hospitalization.⁵³ Omega-3 FA supplementation resulted in a 54% reduction in the frequency of post-CABG atrial fibrillation and a shorter length of hospitalization.

  SUMMARY

The role TG play in CVD may not be fully understood, but present data suggest HTG independently increases the risk of premature CHD and very high levels of TG are a major risk factor for acute pancreatitis. When managing elevated TG, the primary care clinician must assess the presence of related comorbidities and levels of other lipoproteins to best gauge the patient’s overall cardiovascular risk. Further, choosing the appropriate drug therapy is important for effectively lowering TG and ultimately reducing the risk for a cardiovascular event or episode of pancreatitis. Niacin, fibrates, and P-OM3 are effective in lowering the TG level, while statins at the doses usually prescribed are only modestly effective. The benefits of niacin and fibrates may be limited by side effects. P-OM3 has been shown to effectively reduce TG and is well tolerated.

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This supplement to The Journal of Family Practice is supported by a grant from Reliant Pharmaceuticals, Inc. It was submitted by the Primary Care Education Consortium and the Texas Academy of Family Physicians and was edited and peer-reviewed by The Journal of Family Practice.

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