Treatment options for the management of hypertriglyceridemia: Strategies based on the best-available evidence

Journal of Clinical Lipidology (2012) 6, 413–426

Review Article

Treatment options for the management of hypertriglyceridemia: Strategies based on the best-available evidence Kevin C. Maki, PhD, FNLA*, Harold E. Bays, MD, FNLA, Mary R. Dicklin, PhD Biofortis Clinical Research, 211 E. Lake Street, Addison, IL 60101, USA (Drs. Maki and Dicklin); and Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY, USA (Dr. Bays) KEYWORDS: Coronary heart disease; Fibrates; Hypertriglyceridemia; Low-density lipoprotein cholesterol; Niacin; Omega-3 fatty acids; Statins; Triglycerides

Abstract: A severe elevation in triglycerides (TG; $500 mg/dL) increases the risk for pancreatitis. TG levels $200 mg/dL are associated with a greater risk of atherosclerotic coronary heart disease (CHD). However, no outcomes trials exist to assess the efficacy of TG lowering for preventing pancreatitis in patients with severe hypertriglyceridemia. Similarly, no completed prospective outcomes trial exists to support or refute a reduction in CHD risk resulting from lipid-altering therapy in patients specifically selected for the presence of hypertriglyceridemia. This review examines the available evidence for the use of statins, omega-3 fatty acids, fibrates, and niacin in the management of hypertriglyceridemic patients. Results from CHD outcomes trials support statins as the first-line lipid-altering drug therapy to reduce CHD in hypercholesterolemic patients, and subgroup analyses suggest statins are efficacious in hypertriglyceridemic patients with fasting TG levels ,500 mg/dL. Omega-3 fatty acids and fibrates are reasonable first drug options for patients with TG $500 mg/dL and often are used to lower TG levels with the objective of reducing pancreatitis risk, although a statin or niacin may also be reasonable options. Combination lipid drug therapy may be needed to achieve both low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol treatment goals for CHD prevention in patients with elevated TG levels, particularly those with TG $500 mg/dL. Additional clinical outcomes data are needed to provide a more evidence-based rationale for clinical lipid management of hypertriglyceridemic patients. Ó 2012 National Lipid Association. All rights reserved.

Introduction The scientific evidence supporting the health benefits of reducing triglyceride (TG) levels is curiously sparse. When TG levels are very high (ie, $500 mg/dL), lowering TG is recommended to reduce the risk of pancreatitis, although no randomized, placebo-controlled trial has been completed to verify this presumed benefit.1 When TG are 200 to 499 mg/ * Corresponding author. E-mail address: [email protected] Submitted September 27, 2011. Accepted for publication April 4, 2012.

dL, clinicians often implement therapy to lower TG for the purpose of reducing the risk of atherosclerotic coronary heart disease (CHD). However, no adequately powered clinical outcomes trial has yet been completed to directly demonstrate that treatment of hypertriglyceridemic patients improves CHD outcomes. Thus, clinicians are left in the position of treating patients with elevated TG levels on the basis of, at best, post-hoc subgroup analyses from clinical trials not specifically designed to evaluate treatment in a hypertriglyceridemic population. Given the high prevalence of hypertriglyceridemia in the U.S. population and its association with CHD risk, a large-scale clinical outcomes study focusing on hypertriglyceridemia

1933-2874/$ - see front matter Ó 2012 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2012.04.003

414 management is clearly needed. Therefore, the aims of this article are: (1) to review the published literature regarding the efficacy of lipid-altering therapies for the treatment of hypertriglyceridemic patients; and (2) to suggest treatment options on the basis of the best-available evidence, albeit with the caveat that considerable clinical judgment is necessary in light of the limited availability of adequate data from clinical outcomes trials to guide treatment decisions.

Prevalence of hypertriglyceridemia Hypertriglyceridemia is increasingly common in the United States, with this increasing prevalence paralleling the sharp increase in the incidence of obesity during the past few decades.2–4 According to the cutpoints established by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III of TG levels of $150 mg/dL, $200 mg/dL, and $500 mg/dL, the data from the National Health and Nutrition Examination Survey (1999–2004) revealed prevalence values of 33.1%, 17.8%, and 1.7%, respectively.3 On the basis of the 2010 U.S. population of 226,082,000 persons $20 years of age,5 74.6 million U.S. adults have elevated TG levels: 34.4 million with TG in the range of 150 to 199 mg/dL (‘‘borderline high’’), 36.4 million with TG 200 to 499 mg/dL (‘‘high’’), and 3.8 million with TG $500 mg/dL (‘‘very high’’).

Disease risks associated with hypertriglyceridemia Very high TG levels ($500 mg/dL) increase the risk of acute pancreatitis, which is a condition with high morbidity and potential mortality.4 Other complications of very high TG levels include skin manifestations (eg, eruptive xanthoma) and fatty liver.4 Elevated TG $200 mg/dL is associated with an increased risk for CHD.6–8 A pooled analysis of 29 prospective studies found that patients in the highest versus the lowest tertile of TG values had an odds ratio of 1.72 for CHD (95% confidence interval [95% CI] 1.56–1.90).8 Although this relationship was attenuated by adjustment for traditional CHD risk factors, particularly high-density lipoprotein cholesterol (HDL-C) concentration, it remained statistically significant in multivariate analyses.8 An elevated TG level is also associated with increased risk for stroke and other forms of atherosclerotic cardiovascular disease.9 Although still somewhat speculative, one potential explanation for the relationship between high TG levels and CHD is that once very low-density lipoprotein (VLDL) and chylomicron particles become partially delipidated, the resulting remnants of these TG-rich lipoproteins may be atherogenic, and levels of these potentially atherogenic remnants are elevated in patients with hypertriglyceridemia.10,11 Another possible explanation is that hypertriglyceridemia is associated with an increase in a predominance of circulating small, dense low-density lipoprotein (LDL) particles.12,13 The risk of CHD appears to align more

Journal of Clinical Lipidology, Vol 6, No 5, October 2012 closely with the LDL particle concentration than with the LDL cholesterol (LDL-C) level; individuals with hypertriglyceridemia often have a greater LDL particle concentration than would be suggested by the LDL-C concentration.12,13 Although both small and large LDL particles are atherogenic, some evidence suggests that smaller, denser LDL particles may be more atherogenic than larger, more buoyant LDL particles because they (1) reside longer in plasma as the result of a low affinity for hepatic LDL receptors, (2) are smaller in diameter and can more easily enter the subendothelial space, (3) have increased interactivity with arterial proteoglycans, and (4) are more susceptibile to oxidative modification.14,15 At present it remains uncertain whether the gradient of atherogenicity across the spectrum of small to large LDL, if present, is sufficiently steep to have clinical importance.16 This question is difficult to address in epidemiological investigations because LDL particle size is highly correlated with other metabolic abnormalities and is also associated with the fasting TG concentration in a nonlinear manner. A threshold appears to exist for a fasting TG concentration above which there will be a predominance of small, dense LDL particles (pattern B) and below which large, more buoyant particles will predominate (pattern A). The TG concentration that produces a shift from one subclass pattern to another varies with each patient. At a fasting TG concentration ,100 mg/dL, w85% of the population has pattern A, whereas at a fasting TG concentration .250 mg/dL, w85% will have pattern B.17,18 Thus, lowering the TG concentration from 600 mg/dL to 260 mg/dL is unlikely to change a patient’s LDL particle size because most patients have a threshold for shifting LDL subclass pattern within the range of 100 to 250 mg/dL.18,19 In addition to its association with increased concentrations of LDL particles and a predominance of small, dense LDL particles, hypertriglyceridemia is often accompanied by other metabolic and hemodynamic disturbances that may increase the risk of CHD,11 including reduced levels of HDL-C and the presence of obesity, insulin resistance, metabolic syndrome, type 2 diabetes mellitus, elevated circulating levels of free fatty acids, increased levels of thrombotic and inflammatory markers, and/or greater plasma viscosity.7,11,20–22 Approaches for management of hypertriglyceridemia will differ with regard to their influences on these variables, which might have implications for CHD risk reduction.

Lipid treatment targets The NCEP ATP III recommends a non-HDL-C treatment goal as a secondary treatment target for patients with TG levels $200 mg/dL with the primary treatment target being LDL-C (Table 1).23,24 Non-HDL-C (calculated as total cholesterol – HDL-C) includes cholesterol carried by all potentially atherogenic lipoprotein particles: LDL, lipoprotein (a), intermediate density lipoproteins, VLDL, chylomicron particles and their remnants. Compared with LDL-C, non-HDL-C correlates more strongly with the apolipoprotein (Apo) B concentration.25

Maki et al Table 1

Management of hypertriglyceridemia

415

U.S. NCEP ATP III LDL-C and Non-HDL-C treatment goals*,23,24

Risk category

LDL-C treatment goal

Non-HDL-C treatment goal if TG $200 mg/dL

High risk: CHD† or CHD risk equivalents‡ (10-yr risk .20%) Moderately high risk: 21 risk factorsx (10-yr risk 10% to 20%) Moderate risk: 21 risk factorsx (10-yr risk ,10%) Lower risk: 0–1 risk factorjj

,100 mg/dL (,70 mg/dL as a therapeutic option){ ,130 mg/dL (,100 mg/dL as a therapeutic option) ,130 mg/dL

,130 mg/dL (,100 mg/dL as a therapeutic option){ ,160 mg/dL (,130 mg/dL as a therapeutic option) ,160 mg/dL

,160 mg/dL

,190 mg/dL

ATP, adult treatment panel; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; non-HDL-C, non-high-density lipoprotein cholesterol; TG, triglycerides. *To convert cholesterol from mg/dL to mmol/L, divide by 38.6; to convert TG from mg/dL to mmol/L, divide by 88.5. †CHD includes history of myocardial infarction, unstable angina, stable angina, coronary artery procedures (angioplasty or bypass surgery), or evidence of clinically significant myocardial ischemia. ‡CHD risk equivalents include clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease [transient ischemic attacks or stroke of carotid origin or .50% obstruction of a carotid artery]), diabetes, and 21 risk factors with 10-yr risk for hard CHD .20%. xRisk factors include cigarette smoking, hypertension (blood pressure $140/90 mm Hg or on antihypertensive medication), low HDL-C (,40 mg/dL), family history of premature CHD (in male first-degree relative ,55 yrs of age; in female first-degree relative ,65 yrs of age), and age (men $45 yrs; women $55 yrs). {Very high risk favors the optional LDL-C goal of ,70 mg/dL, and in patients with high TG, non-HDL-C ,100 mg/dL. jjAlmost all people with 0 or 1 risk factor have a 10-yr risk ,10% and 10-yr risk assessment in people with 0 or 1 risk factor is thus not necessary.

Because one molecule of Apo B is found on each potentially atherogenic lipoprotein particle, the Apo B concentration is often considered a direct indicator of the number of circulating atherogenic lipoprotein particles.26 Apo B-100 represents particles of hepatic origin, whereas the truncated form, Apo B-48, is contained in chylomicron particles and their remnants of intestinal origin. Non-HDL-C is generally a stronger predictor of CHD risk than LDL-C, regardless of whether TG levels are elevated.27 Results from many, but not all, studies in which investigators compared non-HDL-C and Apo B suggest Apo B is a somewhat better predictor of CHD risk than non-HDL-C.4 Whether Apo B or LDL particle concentration treatment targets in lieu of, or as an adjunct to, the currently recommended LDL-C and nonHDL-C treatment goals would yield superior results with regard to efficacy or cost-effectiveness for CHD prevention in hypertriglyceridemic patients remains unresolved.28,29

Secondary causes of hypertriglyceridemia Secondary causes of hypertriglyceridemia include medications such as estrogens, some beta-blockers (eg, propranolol), glucocorticoids, cyclosporine, tacrolimus, protease inhibitors, some antipsychotics, thiazide diuretics, and isotretinoin.4 When possible, alternative medications having no dyslipidemic effects, or at least less dyslipidemic effects, should be prescribed for hypertriglyceridemic patients. Medical conditions that can exacerbate elevated TG levels include uncontrolled diabetes mellitus, untreated hypothyroidism, and nephrotic syndrome; their treatment will often reduce the TG concentration. Ethanol-induced fatty liver can contribute to hypertriglyceridemia, and acute ethanol intake increases the TG concentration in patients without previous

hypertriglyceridemia.4 Interestingly, ethanol intake in patients with baseline hypertriglyceridemia may not always worsen elevated TG levels, and routine, chronic ethanol intake at modest levels (#2 units of ethanol per day) may actually reduce TG levels in some patients, possibly due to improved insulin sensitivity.30

Lifestyle management The primary goal of therapy for individuals with severe hypertriglyceridemia of TG $500 mg/dL (with fasting chylomicronemia) is to lower TG to prevent pancreatitis.1 Typically, these patients are placed on a very low-fat diet (#15% of calories) and administered fibrates, niacin, and/ or fish oil.1 The first line of therapy for more moderately elevated TG is therapeutic lifestyle changes, including increased physical activity, appropriate nutrition, and weight reduction in overweight or obese individuals.1,31,32 In fact, few lipid abnormalities respond as well to lifestyle changes as do elevated TG levels. Increasing the carbohydrate content of the diet, particularly dietary fructose, can increase TG, and a high glycemic load is associated with visceral adiposity, lipid dysregulation, and decreased insulin sensitivity, all of which are associated with greater CHD risk.33–35 Thus, moderating intakes of carbohydrates, particularly foods or beverages with a high glycemic index and/or high fructose content (including those with high sucrose, which is 50% fructose by weight), may help to lower the TG concentration. Smoking cessation and reducing or eliminating alcohol consumption can also often lower elevated TG levels.1 For individuals with borderline high TG levels (150–199 mg/dL), pharmacotherapy is generally not recommended in

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Journal of Clinical Lipidology, Vol 6, No 5, October 2012 CHD risk.24 The subsections to follow contain a brief discussion of pharmacologic options for treating high TG levels of 200 to 499 mg/dL.

the absence of additional lipid abnormalities that would otherwise warrant treatment (eg, elevated LDL-C). Instead, emphasis is generally placed on lifestyle approaches (eg, body fat loss in overweight patients, increased physical activity, moderation of carbohydrate intake), as well as dietary adjuncts such as viscous fibers (10–25 g/d) and plant sterols or stanols (w2 g/d). Although some evidence exists that plant sterols/stanols may lower TG in hypertriglyceridemic individuals,36 these dietary adjuncts mainly lower LDL-C (usually by 5%–15% each), which will help patients to reach their LDL-C and non-HDL-C treatment goals.37 In patients with very high TG levels ($500 mg/dL), the priority is to lower TG with the objective of reducing the risk of pancreatitis. When TG levels are 200 to 499 mg/dL, despite lifestyle recommendations, pharmacologic therapy should be considered if nonpharmacologic approaches have been insufficient to attain LDL-C and non-HDL-C treatment targets that are appropriate for a patient’s risk category.

Statins In the authors’ view, statins should be first-line drug therapy for most patients with a fasting TG concentration of 200 to 499 mg/dL. Statins have the most favorable effects upon the lipoprotein parameters with the most established clinical relevance, including LDL-C, non-HDL-C and Apo B (Table 2).21,40–70 In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, rosuvastatin 10 to 40 mg reduced LDL-C 46% to 55%, atorvastatin 10 to 80 mg reduced LDL-C 37% to 51%, simvastatin 10 to 80 mg reduced LDL-C 28% to 46%, and pravastatin 10 to 40 mg reduced LDL-C 20% to 30% from mean baseline levels of w155 to 165 mg/dL.44 Across the same doses, rosuvastatin increased HDL-C 8% to 10%, atorvastatin 2% to 6%, simvastatin 5% to 7%, and pravastatin 3% to 6% from mean baseline levels ranging from 49 to 51 mg/dL. Importantly, in this same head-to-head, comparative trial of dyslipidemic patients with baseline TG levels ranging from 172 to 187 mg/dL, TG were reduced by 20% to 26% with rosuvastatin, 20% to 28% with atorvastatin, 12% to 18% with simvastatin, and 8% to 13% with pravastatin.44 In the subset of patients with baseline TG $200 mg/dL, the rosuvastatin 20-mg and atorvastatin 40-mg groups had the greatest achievement of both LDL-C and non-HDL-C ATP III treatment goals (84%), with the lowest percentages of goal achievement among those in the simvastatin and pravastatin groups (15% to 60%).45 In patients with mixed dyslipidemia and TG $200 mg/dL, the prescribing information suggests that fluvastatin may reduce LDL-C by 22% to 33%, increase HDL-C by 6% to 11%, and reduce TG by 17% to 25%.43 In a phase III study of pitavastatin 2 mg/d versus pravastatin 10 mg/d, patients with baseline TG levels $150 mg/dL experienced TG lowering of 23.3%, which was similar to the TG reduction with pravastatin (20.2%).47 LDL-C reductions were 37.6% and 18.4% for pitavastatin and pravastatin, respectively, and HDL-C was increased by 8.9% and 9.8%, respectively.

Pharmacologic therapy Statins, fibrates, fish oil/omega-3-fatty acids, and niacin all substantially lower TG.1 Agents used for the management of diabetes mellitus and obesity, including pioglitazone, metformin, and orlistat, may also produce TG reductions but are not specifically approved for lipid modification in hypertriglyceridemic patients.38 Bile acid sequestrants may increase TG levels and are not used as drug therapy to treat hypertriglyceridemia.39 In patients with very high TG levels ($500 mg/dL), first-line drug therapy is often a fibrate or prescription fish oil, which typically produce TG reduction in the range of 40% to 60%.1,4,21 Combination lipid-altering drug therapy may be required to achieve and maintain LDL-C and non-HDL-C levels below the treatment goals appropriate for the patient’s risk category. On the basis of the NCEP ATP III guidelines, the initial objective of pharmacotherapy for patients with high TG levels (200–499 mg/dL) is to achieve the patient’s LDL-C treatment goal, and secondarily the non-HDL-C treatment goal (30 mg/dL greater than the LDL-C goal) to lower

Table 2 Lipid effects (ranges; %) in subjects with primary hyperlipidemia/mixed dyslipidemia and isolated hypertriglyceridemia treated with statins, omega–3 fatty acids, fenofibrate/fenofibric acid/gemfibrozil, and niacin Type of dyslipidemia/medication Mixed dyslipidemia Statins40–47 Omega–3 fatty acids48–50 Fenofibrate, fenofibric acid and gemfibrozil21,51–56 Niacin57–61 Isolated hypertriglyceridemia Statins40–42,62,63 Omega–3 fatty acids48,64–68 Fenofibrate, fenofibric acid and gemfibrozil51–53,56,69,70

TG 210 219 224 25

LDL-C to to to to

237 244 236 238

221 to 252 226 to 252 246 to 262

226 26 25 23

to to to to

HDL-C 263 125 231 217

227 to 245 117 to 149 13 to 147

15 25 110 110

Non-HDL-C 116 17 116 126

244 to 260 21 to 27 217 NR

13 to 122 19 to 114 118 to 123

229 to 252 210 to 214 NR

to to to to

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; NR, not reported; TG, triglycerides.

Maki et al

Management of hypertriglyceridemia

Few groups have examined the effects of statins in patients with very high TG levels, which is important because the greater the baseline TG level, the greater the potential percent reduction in TG with lipid-altering drug therapy. In clinical studies in which investigators examined subjects with hypertriglyceridemia, greater efficacy statins (eg, atorvastatin 10–80 mg/d or rosuvastatin 5–40 mg/d) reportedly reduced TG levels 21% to 52%.40,41 In one illustrative clinical trial in patients with a baseline mean TG of 603 mg/dL, atorvastatin reduced TG by 46% at the 80-mg dose compared with a 9% reduction in the placebo group.62 In another trial of patients with baseline median TG levels 398 to 463 mg/dL, rosuvastatin 40 mg/d reduced the median TG level by 43%.63 Very limited data are available wherein the effects of statin therapy were directly compared with agents more commonly viewed as ‘‘TG-lowering,’’ such as fibrates or prescription fish oil. The absence of head-to-head clinical trials makes it difficult to know whether statins are more or less effective than other lipid-altering agents for lowering TG levels in patients with high or very high TG levels. However, what can be reasonably inferred from comparing the results of existing clinical trials is that statins are more effective than fibrates and/or fish oils for lowering LDL-C, non-HDL-C, and Apo B concentrations.71 Perhaps most important is the substantial body of evidence from large-scale clinical trials supporting statins in reducing coronary mortality and adverse coronary events in primary and secondary prevention.72–88 Although the large-scale statin trials conducted to date have not enrolled patients selected specifically for hypertriglyceridemia, subgroup analyses have investigated the effects on CHD risk of statin use in high-risk hypertriglyceridemic individuals (Table 3).72–79,89–99 In the Scandinavian Simvastatin Survival Study (4S), the relative risk (RR) and 95% CI of the overall population (n 5 4444) for simvastatin versus placebo was 0.66 (0.59–0.75; P , .001).75,82 Major coronary event risk was reduced more among participants with high TG and low HDL-C (0.48, 95% CI 0.33–0.69; P , .001) than in the subgroup of subjects with isolated LDL-C elevation (0.86; 0.59–1.26).76 In the West of Scotland Coronary Prevention Study (WOSCOPS) of 6000 middle-aged men with hypercholesterolemia and no previous history of myocardial infarction, treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes (RR reduction 31%; 95% CI 17–43; P , .001) in the overall population.72 Among TG subgroups ,148 mg/dL and $148 mg/dL, risk reductions (95% CI) were not significantly different: 29% (95% CI 4–48; P 5 .024) and 32% (95% CI 12–47; P 5 .003), respectively. Investigators from the Cholesterol and Recurrent Events (CARE) trial examined the effects of pravastatin in 4159 men and women with previous myocardial infarction and demonstrated a reduction in coronary events with treatment that was not significantly different whether TG was above or below the median.73 However, a trend was present for greater risk reduction in those with TG below the median value: for

417 those with TG ,144 mg/dL, risk reduction was 32% (95% CI 18–43; P , .001), compared with 15% (95% CI –1 to 29) for those with TG $144 mg/dL (P 5 .07).73 In the Prospective Pravastatin Pooling Project, which included data from WOSCOPS, CARE, and the Long-term Intervention with Pravastatin in Ischemic Disease trials, event rates were lower in the pravastatin group than in the placebo group across the range of TG concentrations.74 For the categories of baseline TG of ,133, 133 to 219, and $220 mg/dL, RR reductions for CHD death or nonfatal myocardial infarction were 29% (95% CI 19–38; P , .001), 26% (95% CI 16–35; P , .001), and 17% (95% CI –1 to 32; P 5 .057), respectively, and the P-value for interaction was .42. For CHD death, nonfatal myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty, the RR reductions according to TG categories of ,133, 133 to 219, and $220 mg/dL, were 27% (95% CI 19–34; P , .001), 24% (95% CI 16–32; P , .001), and 15% (95% CI 2–26; P 5 .029), respectively, and the P-value for interaction was .055. A prospective meta-analysis of data from 90,056 patients in 14 randomized statin trials indicated a highly significant reduction in incidence of first major vascular event (myocardial infarction or coronary death, coronary revascularization, fatal and nonfatal stroke) per mmol/L LDL-C reduction (RR 0.79; 95% CI 0.77–0.81; P ,.001).79 Subgroup analysis of these data according to baseline TG indicated similar proportional reductions in major vascular event rates per mmol/ L LDL-C reduction. Relative risks for subjects with TG #124, .124 to 177, and .177 mg/dL were 0.78 (95% CI 0.71–0.85), 0.77 (95% CI 0.71–0.84), and 0.76 (95% CI 0.69–0.83), respectively (trend test P-value 5 .6).79 In the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), rosuvastatin was associated with a 44% reduction in the hazard for the primary end point, occurrence of first major cardiovascular event (HR 0.56; 95% CI 0.46–0.69; P , .001).77 In a subgroup analysis of 5695 older individuals ($70 years of age) in JUPITER, the rates of the primary end point for placebo and rosuvastatin were 1.99 and 1.22 per 100 person-years of follow-up, respectively (HR 0.61; 95% CI 0.46–0.82; P , .001).78 The effect of rosuvastatin among these older subjects was similar between those with TG ,150 mg/dL (n 5 4074, primary end point incidence rates of 2.14 and 1.19 for placebo and rosuvastatin, respectively; HR 0.56) and those with TG $150 mg/dL (n 5 1620, primary end-point incidence rates of 1.62 and 1.28 for placebo and rosuvastatin, respectively; HR 0.79).78 Ninety-five percent CIs were shown in a figure, but the actual values were not reported in the publication.78 Because of the favorable CHD outcomes with statin therapy overall and in hypertriglyceridemic patient subgroups, the authors view statins as a reasonable first-line drug therapy for many, perhaps most, hypertriglyceridemic patients. Reports suggest statin therapy may be associated with increased risk for the development of type 2 diabetes mellitus, with some authors also suggesting greater doses

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Journal of Clinical Lipidology, Vol 6, No 5, October 2012

Table 3 Overall and hypertriglyceridemic subgroup results from large-scale primary and secondary prevention cardiovascular disease event trials that used statins, fibrates, fish oil, and niacin Trial Statin trials WOSCOPS72 High TG Subgroup72 CARE73 High TG Subgroup73 Prospective Pravastatin Pooling Project74 Highest TG tertile subgroup74 4S75 Dyslipidemic subgroup76 JUPITER77 Older subjects with high TG subgroup78 CTT Collaborators79

Highest TG tertile subgroup79 Fibrate trials HHS89 High TG, high LDL-C/HDL-C subgroup90 High TG, high BMI subgroup91 BIP92 High TG subgroup92 VA-HIT93 High TG subgroup93 FIELD94 High TG subgroup95 High TG, low HDL-C subgroup95 ACCORD96 High TG, low HDL-C subgroup96 Fish oil trial JELIS97 High TG, low HDL-C subgroup98 Niacin trial AIM-HIGH99

Drug

Median follow-up, yr

Risk difference vs. placebo, %

95% CI (P-value)

Pravastatin

5

Pravastatin

5

Pravastatin

5–6

Simvastatin

5

Rosuvastatin

5

Simvastatin/pravastatin/ lovastatin/atorvastatin/ fluvastatin

5

231 232 224 215 223 215 234 252 244 221 221

217, 243 212, 247 29, 236 1, 229 218, 228 22, 226 225, 241 231, 267 231, 254 NR (NS)* 219, 223

224 234 272 271 29 240 222 227 211 223 227 28 231

(,.001) (.003) (.003) (.07) (,.001) (.029) (,.001) (,.001) (,.001) (,.001)

217, 231 (,.001) 28.2, 252.6 NR (,.05)* 243, 285 NR (NS) NR (.02) 27, 235 27, 242 225, 5 26, 237 29, 242 221, 8 NR (,.05)*

Gemfibrozil

5

(,.02)

Bezafibrate

6

Gemfibrozil

5

Fenofibrate

5

Fenofibrate

5

EPA

5

219 253

25, 231 (.011) 22, 277 (.043)

Niacin

3

12

213, 21 (NS)

(,.001)

(.006) (.01) (NS) (,.01) (.005) (NS)

ACCORD, Action to Control Cardiovascular Risk in Diabetes; AIM-HIGH, Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes; BIP, Bezafibrate Infarction Prevention; BMI, body mass index; CARE, Cholesterol and Recurrent Events; CI, confidence interval; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; HDL-C, high-density lipoprotein cholesterol; HHS, Helsinki Heart Study; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LDL-C, low-density lipoprotein cholesterol; NR, not reported; NS, not significant; TG, triglycerides; VA-HIT, Veterans Affairs HDL Intervention Trial; WOSCOPS, West of Scotland Coronary Prevention Study. *Actual P-value was not reported.

of statin might be associated with greater risk than lowerdose statin therapy, although such findings have not been universal.77,100–103 However, the benefit of statin treatment for reducing cardiovascular disease event risk appears to substantially outweigh any possible increased risk for diabetes mellitus.77,101 Fish oil and omega-3 fatty acids Most fish oil preparations contain high amounts of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). EPA and DHA (2–4 g/d) reduce TG by approximately 20% to 55% and lower TG-rich lipoproteins.1,64–66 Evidence from clinical trials suggests

that EPA and DHA doses of at least $2 g/d are required for significant lipid effects, with little evidence to support lipidaltering efficacy of doses of EPA and DHA ,1 g/d.104,105 In addition to lowering TG, EPA and DHA have several other biological actions that could potentially contribute to CHD risk reduction, even at lower doses, such as antidysrhythmic, antithrombotic, anti-inflammatory, endothelial protective, and blood pressure–lowering effects.30,66,106–108 In some European and Asian countries, prescription omega-3 fatty acids are approved for secondary cardiovascular disease prevention at a dosage of 1.0 g/d.109,110 Morbidity and mortality data for greater doses of omega-3 fatty acids are lacking.108

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Omega-3 fatty acids reduce hepatic secretion of TG-rich VLDL particles, reduce the TG content of secreted VLDL particles, and increase TG clearance from the blood by lowering the concentration of Apo CIII, an inhibitor of lipoprotein lipase activity.18,111–115 In addition, omega-3 fatty acids containing EPA and DHA increase the rate of conversion of VLDL to LDL particles and reduce the exchange of TG for cholesteryl esters in circulation, which may produce an increase in plasma LDL-C levels.64,111–113,116–120 However, the overall number of atherogenic particles is typically not increased.18,66,107,115 The Diet And Reinfarction Trial121 and Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto MiocardicoPrevenzione Trial122 have reported that increased consumption of fish or fish oil supplements reduces coronary death in postinfarction patients. More recently, investigators from the Japan EPA Lipid Intervention Study (JELIS) demonstrated the efficacy of pure EPA (1.8 g/d) in the prevention of CHD events in hypercholesterolemic patients receiving statin treatment (Table 3).97,123 The study sample included 18,645 subjects, including 3664 with a previous myocardial infarction, coronary intervention, or unstable angina pectoris. The HR for the primary outcome, incidence of major coronary events, was 0.81 (95% CI 0.69–0.95) overall97 and 0.77 (95% CI 0.63–0.96) in those with a previous myocardial infarction.123 In a subgroup analysis of JELIS, compared with patients with normal levels of serum TG and HDL-C, those with elevated TG ($150 mg/dL) and low HDL-C (,40 mg/dL) had significantly greater risk of CHD (HR 1.71; 95% CI 1.11–2.64; P 5.014), and EPA treatment reduced this risk by 53% (HR 0.47; 95% CI 0.23–0.98; P 5 .043).98 In this highTG, low-HDL-C subgroup, TG levels were significantly reduced from baseline by 23% with EPA versus 18% with control (P 5 .012 vs. control); changes from baseline in total-C (217% in both groups), LDL-C (EPA 220% vs. control 222%), and HDL-C (122% in both groups) were not statistically different between groups.98 Because differences in lipid effects compared to control were small, it appears likely that mechanisms beyond lipid alteration likely account for at least some of the observed benefit. In the Multicenter, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension (MARINE) study of patients with very high TG levels ($500 mg/dL), a highly purified form of EPA (ethyl icosapentate) comprising at least 96% ethyl ester and no DHA (similar to the product used in JELIS) reduced TG by 19.7% at 2 g/d and 33.1% at 4 g/d without significantly increasing LDL-C levels.67 Results from ANCHOR, another study of ethyl icosapentate in patients on a background of statin therapy with TG levels $200 mg/dL and ,500 mg/dL, indicated significant TG reductions, beyond those achieved by a statin, of 10.1% at 2 g/d and 21.5% at 4 g/d, and a significant reduction in LDL-C in the 4 g/d group (26.2% vs. placebo).50 The results from MARINE and ANCHOR seem to support the hypothesis that products containing EPA alone lack the LDL-C elevating effect of

419 products containing DHA.124 Further research is needed to investigate the role of EPA vs. DHA on clinical outcomes in hypertriglyceridemic patients. Fibrates Fibrates (gemfibrozil, fenofibrate, and fenofibric acid are available in the United States) modulate the activity of peroxisome proliferator-activated receptor-alpha, resulting in increased lipoprotein lipase activity (causing catabolism of TG in VLDL and chylomicrons), reduced secretion of VLDL, inhibition of Apo CIII expression, and increased production of apolipoproteins Apo AI and Apo AII. Fibrates reduce TG by w30% to 60% and increase HDLC by w5% to 15%.1,21,51–53 The effect of fibrates on LDL-C levels are varied. In patients with marked hypertriglyceridemia, LDL-C may be unchanged or substantially increased,69 whereas fibrates usually reduce LDL-C (5%–20%) in individuals with elevated LDL-C and less severe hypertriglyceridemia.54 In addition, fibrates may reduce the number of small, more dense LDL particles.21,54,89,125 A large body of data supports fibrates as having favorable fasting lipid effects. However, several fibrate CHD prevention trials did not achieve statistical significance for the main CHD outcome in the overall population (Table 3). Unfortunately, these clinical trials were conducted in populations that were not specifically selected for the presence of hypertriglyceridemia. Therefore, a gap exists regarding the potential benefits of fibrates for CHD risk reduction among the group of patients most likely to be prescribed TG-lowering medications such as fibrates. Having said this, results from subgroup analyses support the view that patients with elevated TG and low HDL-C may show reduced CHD risk when treated with fibrates.90,92,94–96,126 In the Helsinki Heart Study (HHS), gemfibrozil significantly (P ,.02) reduced the incidence of CHD versus placebo by 34% (95% CI 28.2, 252.6) in the overall population of asymptomatic middle-aged men (n 5 2030 placebo and n 5 2051 gemfibrozil) with primary dyslipidemia (non-HDL-C $200 mg/dL) followed for 5 years89; and this finding was confirmed in an 18-year extension wherein the RR was reduced by 23% (P 5 .05).91 A further investigation of these data revealed a high-risk subgroup of individuals with TG .204 mg/dL and an LDL-C/HDL-C ratio .5 (n 5 138 placebo and n 5 154 gemfibrozil) that benefitted the most from gemfibrozil treatment, experiencing more than a 70% reduction in the incidence of cardiac events versus placebo (P 5 .005).90 Patients receiving a placebo in this subgroup had significantly increased risk of CHD (RR 1.81; 95% CI 1.16–2.81) that was nearly completely eliminated by gemfibrozil. A more recent analysis of these data revealed another high-risk subgroup.91 Those in the highest tertiles of both body mass index (.28 kg/m2) and TG levels ($184 mg/dL)127 had a 71% lower RR of CHD mortality with gemfibrozil therapy compared to those who received placebo (P , .001).91 In the Bezafibrate Infarction Prevention (BIP) Study, men with previous CHD and total-C 180 to 250 mg/dL,

420 HDL-C #45 mg/dL, TG #300 mg/dL, and LDL-C #180 mg/dL were treated with bezafibrate (n 5 1548) or placebo (n 5 1542) and followed for a mean of 6.2 years.92 The risk reduction in the primary end point of fatal or nonfatal myocardial infarction or sudden death was not significant (9.4%, P 5 .26). However, in post-hoc analyses, bezafibrate was shown to reduce the crude primary end-point rate in direct relationship with the level of baseline TG. In the subgroup of patients with baseline TG $200 mg/dL (n 5 225 placebo and n 5 234 bezafibrate), the cumulative probability of the primary end point was reduced by 39.5% (P 5 .02) but was not significantly reduced in the subgroup with TG ,200 mg/dL (n 5 1317 placebo and n 5 1314 bezafibrate). In the Veterans Affairs HDL Intervention Trial (VAHIT), men with a history of CHD who had low HDL-C (mean of 32 mg/dL) and low LDL-C (mean of 111 mg/dL) were treated with gemfibrozil (n 5 1264) or matching placebo (n 5 1267) and followed for 5 years.93 In the overall population, gemfibrozil significantly reduced the risk of a CHD event versus placebo by 22% (95% CI 27, 235; P 5 .006), and in the subgroup with TG $150 mg/dL the risk reduction was 27% (29, 242; P 5 .01).93 The risk reduction with gemfibrozil was greater with increasing tertiles of baseline TG concentrations: TG ,124 mg/dL (RR reduction 15%; 95% CI 37, 215), TG 124 to 180 mg/dL (22%; 95% CI 44, 29), and TG .180 mg/dL (28%; 95% CI 46, 24).126 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was designed to assess the effect of fenofibrate (n 5 4895) compared with placebo (n 5 4900) on cardiovascular events in a 5-year follow-up among men and women (50–75 years of age) with type 2 diabetes mellitus.94 Subjects had total-C of w116 to 251 mg/dL and TG w88 to 440 mg/dL. Plasma TG, LDL-C, and HDL-C levels responded favorably with treatment, but the prespecified primary outcome of coronary events (CHD, death, or nonfatal myocardial infarction) did not show a statistically significant difference between the treatment groups. There was a nonsignificant reduction of 11% (HR 0.89; 95% CI 0.75–1.05; P 5.16), which corresponded to a 24% reduction in nonfatal myocardial infarction (P 5.010) and a nonsignificant increase in CHD mortality.94 Subgroup analyses indicated a continuous positive relationship between TG levels and CHD.95 Hypertriglyceridemia ($204 mg/dL) alone was associated with a 23% RR reduction with fenofibrate therapy, P 5 .010 (P-value for treatment by group interaction 5 .468); and TG $204 mg/dL plus HDL-C ,40 mg/dL in men and ,50 mg/dL in women was associated with a 27% RR reduction, P 5 .005 with fenofibrate (P-value for treatment by group interaction 5 .093).95 In the lipid arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the use of fenofibrate plus simvastatin versus simvastatin alone was examined in 5518 patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease.96 Fenofibrate reduced TG levels versus placebo but did not significantly reduce

Journal of Clinical Lipidology, Vol 6, No 5, October 2012 the primary CHD outcome, the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (HR 0.92; P 5 .32) over the mean follow-up of 4.7 years. In subgroup analysis of patients with baseline TG in the highest tertile ($204 mg/dL) and baseline HDL-C below the lowest third (#34 mg/dL), the percent reduction in the primary cardiovascular disease end point was 31% (actual P-value and 95% CI were not reported). The primary outcome rate was 12.4% in the fenofibrate group (n 5 485) versus 17.3% in the placebo group (n 5 456), whereas the rates were 10.1% in both study groups for all other patients (n 5 2264 fenofibrate and n 5 2284 placebo; P 5 .057 for interaction). Taken together, evidence from clinical trials such as these suggests that if fibrates are to produce favorable CHD outcomes, they are most likely to do so in subjects with TG $200 mg/dL, particularly if accompanied by low HDL-C or an elevated LDL-C/HDL-C ratio. Results from a metaanalysis of the dyslipidemia subgroups from ACCORD, FIELD, BIP, HHS, and VA-HIT support the beneficial CHD event risk reducing effect of fibrates in this subgroup (Fig. 1).128 In this analysis, the odds ratio for a CHD event was reduced significantly by 35% (95% CI 22–46) in the subgroups with ‘‘dyslipidemia’’ compared with a nonsignificant reduction of 6% (95% CI –5, 16) in those without ‘‘dyslipidemia.’’128 Niacin Niacin at doses up to 3 g/d can lower plasma TG levels by 30% to 50%, increase levels of HDL-C by 20% to 30% and reduce LDL-C by 5% to 25%.1,60,61 The mechanisms of action of niacin are complex and include inhibition of hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis; accelerated intracellular hepatic Apo B degradation; decreased secretion of VLDL and LDL particles; impairment of the hepatic catabolism of Apo AI (vs. Apo AII), which increases HDL half-life and concentrations of Apo AI-containing HDL subfractions; and inhibition of the removal of HDL-Apo AI. Niacin may also increase the vascular endothelial cell reduction–oxidation state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. Although niacin may decrease free fatty acid mobilization from adipose tissue via the G protein– coupled receptor, this pathway may be only a minor factor in explaining the lipid effects of niacin.129 Although niacin is sometimes considered (although not proven in head-to-head clinical trials) to be less effective than fibrates for lowering TG levels, it may be more effective in increasing HDL-C levels and more consistent in lowering LDL-C levels. Niacin also reduces lipoprotein (a) concentration, an independent risk factor for cardiovascular disease. The use of niacin is limited by cutaneous flushing and pruritis, and less commonly, elevated liver enzymes, increased levels of uric acid, gastrointestinal distress and worsened glucose tolerance.60,130,131 The prostaglandin receptor blocker laropiprant, which is currently in development,

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Figure 1 (A) Data from subgroups of patients with dyslipidemia (n 5 2428 and 302 events among fibrate therapy and n 5 2298 participants and 408 events for placebo). (B) Data from the complementary subgroups without this type of dyslipidemia (ie, patients with a TG level ,204 mg/dL or HDL-C .34 mg/dL). Dyslipidemia subgroups were defined as follows: ACCORD (TG $204 mg/dL, HDL-C #34 mg/dL), FIELD (TG $204 mg/dL, HDL-C ,40 mg/dL in men and ,50 mg/dL in women), BIP (TG $200 mg/dL, HDL-C ,35 mg/dL), HHS (TG $204 mg/dL, HDL-C ,42 mg/dL), and VA-HIT (TG .180 mg/dL, HDL-C ,40 mg/dL). Permission to reprint figure has been requested from the Massachusetts Medical Society.128 ACCORD, Action to Control Cardiovascular Risk in Diabetes; CI, confidence interval; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; HHS, Helsinki Heart Study; TG, triglycerides; VA-HIT, Veterans Affairs HDL Intervention Trial.

significantly reduces the flushing associated with niacin administration.132,133 Concomitant administration of laropiprant with niacin in an extended release tablet is being examined in a large-scale intervention study of more than 25,000 subjects (men and women 50–80 years of age with a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral arterial disease, diabetes mellitus, or any evidence of symptomatic CHD) expected to be completed in 2013: the Heart Protection Study 2 Treatment of High-Density Lipoprotein to Reduce the Incidence of Vascular Events (HPS-2 THRIVE; http://clinicaltrials.gov/ct2/ show/NCT00461630). The first study that evaluated the effects of niacin on CHD outcomes, the Coronary Drug Project was conducted between 1966 and 1975, and showed that patients treated with niacin had a modest decrease in nonfatal myocardial infarction (8.9% vs. 12.2%) but no difference in all-cause mortality after 5 years.134 A 9-year, nonrandomized, nonblinded follow-up study to the Coronary Drug Project revealed a decrease in all-cause mortality in the original cohort treated with niacin (52% vs. 58%, P 5 .004).134 More recently, in the Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH) trial, investigators examined the effects of high-dose extended release niacin added to statin therapy in 3414 patients with heart and vascular disease and with low HDL-C (#40 mg/ dL for men and #50 mg/dL for women) and elevated TG ($125 mg/dL and #400 mg/dL).99 It was expected that 800 primary events would occur during a follow-up period of w5 years. However, results from a preplanned interim analysis suggested a lack of efficacy for niacin, and, in those treated with niacin versus placebo, a slightly greater rate of ischemic stroke. Therefore, the study was stopped after a mean follow-up of 3 years.99 The primary end point (first event of the composite of death from CHD, nonfatal

myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization) occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%; hazard ratio of 1.02; 95% CI 0.87–1.21; P 5 .79 by the log-rank test). Caution is warranted in the generalization/interpretation of these apparently negative findings in the AIM-HIGH trial. The treatment regimens used failed to maintain sufficient separation between the groups for the target lipid levels. For example, the mean difference between groups for LDL-C was 5 mg/dL and that for HDL-C was 4 mg/dL. Given these small differences and the background of a very low LDL-C level induced by statin therapy, it is unclear whether the failure to observe a reduction in cardiovascular disease risk resulted from insufficient separation in lipid levels or true lack of benefit. Many patients cannot reach the mean LDL-C and non-HDL-C levels observed in the statin-alone group in AIM-HIGH. Thus, it is premature to rule out potential benefit of niacin in all situations such as in patients with hypertriglyceridemia or mixed dyslipidemia. In contrast to AIM-HIGH, investigators in previous niacin outcome studies suggested clinical benefit in reducing CHD risk and/or reducing the progression of atherosclerosis (Coronary Drug Project,134 Familial Atherosclerosis Treatment Study,135 HDL Atherosclerosis Treatment Study,136 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6 HDL and LDL Treatment Strategies in Atherosclerosis137). However, additional data are needed to support use of niacin according to current standards of practice, in the context of use as add-on therapy to a statin, particularly in patients with mixed dyslipidemia. The HPS-2 THRIVE trial mentioned previously is expected to produce results that allow for a meaningful assessment of niacin add-on therapy, particularly with regard to pre-planned analyses of the subset of patients with hypertriglyceridemia.

422 Combination therapy Patients with combined or mixed dyslipidemia, which may include elevated TG and elevated LDL-C levels, often require combination drug therapy to achieve LDL-C and non-HDL-C treatment goals.1,24 Because statins are the firstline drug therapy for most lipid abnormalities, combination therapy most often involves a statin plus another drug.138–142 In the case of the patient with persistent hypertriglyceridemia despite statin therapy, an additional agent can be added to assist with attainment of the non-HDL-C treatment goal. At present, limited outcomes data are available to guide the clinician’s choice of add-on therapy. Available options to improve non-HDL-C levels include use of a fibrate, omega-3 fatty acids, or niacin. In some cases in which the TG levels are only modestly elevated, a cholesterol absorption inhibitor (ezetimibe) may be adminstered to modestly reduce TG levels, but perhaps more importantly, reduce non-HDL-C, LDL-C and Apo B levels. Although bile acid sequestrants can lower both LDL-C and non-HDL-C levels, they should be used with caution for patients with TG levels .300 mg/dL because, as noted previously, bile acid sequestrants tend to increase the TG concentration, and this class is therefore contraindicated in patients with very high TG levels. Another potential combination that may apply to the statin intolerant patient with hypertriglyceridemia and hypercholesterolemia is ezetimibe plus fenofibrate.143 Given the limited clinical trial evidence available to guide therapy, the selection of lipid-altering drugs to combine remains largely a matter of clinical judgment. Many patients with severe hypertriglyceridemia treated with a fibrate or fish oil require additional pharmacotherapy for TG lowering. Statins may be reasonable second-line drug treatment. Fibrates and fish oil may work through similar and partially overlapping mechanisms, thus, the incremental TG lowering with this combination therapy does not appear to be fully additive.144 It is therefore unclear whether adding a fibrate to omega-3 fatty acids, or adding omega-3 fatty acids to a fibrate would have greater TG-lowering efficacy than adding a statin to either as monotherapy. Most importantly, statins substantially reduce LDL-C and/or non-HDL-C, which are lipid treatment targets to reduce CHD risk. The caveat here would be the need to avoid the use of gemfibrozil in combination with many statins because of the increased risk of myopathy and rhabdomyolysis.145

Conclusions The available data from CHD outcomes trials suggest that statins are the most effective lipid-altering agents for reducing CHD risk. Subgroup analyses support the efficacy of statin therapy in patients with hypertriglyceridemia, although these results should be interpreted with some caution pending the availability of a large-scale clinical trial designed specifically to test the effects of statin therapy in hypertriglyceridemic patients. In the authors’ view, statins should

Journal of Clinical Lipidology, Vol 6, No 5, October 2012 be the first-line drug therapy for most hypertriglyceridemic patients with fasting TG ,500 mg/dL. Omega-3 fatty acid therapy or fibrates may often be reasonable as a first drug option for patients with very high TG ($500 mg/dL) for whom lowering the TG level to prevent pancreatitis is the first objective of lipid management. Most patients with severe hypertriglyceridemia will require combination lipid-altering drug therapy to attain treatment goals. Given the high prevalence of hypertriglyceridemia in the U.S. population and the association of elevated TG with CHD risk, additional CHD outcomes data are urgently needed to provide a solid scientific rationale for clinical lipid management of these patients.

Financial disclosure As employees of Biofortis Clinical Research, Dr. Maki and Dr. Dicklin have received research grants from Abbott Laboratories, Amarin Pharmaceuticals, GlaxoSmithKline, Merck & Co., Inc., Monsanto, Omthera, Solae, and Trygg Pharmaceuticals. Dr. Maki has received consulting fees from Abbott Laboratories, GlaxoSmithKline, Omthera, and Trygg Pharmaceuticals. Dr. Bays has received research grants from Abbott Laboratories, Amarin Pharmaceuticals, GlaxoSmithKline, Merck, Omthera, Trygg Pharmaceuticals, as well as other pharmaceutical companies. Dr. Bays has also served as a consultant/advisor to Abbott Laboratories, Amarin Pharmaceuticals, GlaxoSmithKline, Merck, and other pharmaceutical companies.

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