CARDIOLOGY TODAY March 2008
Emerging Data in the Treatment of Mixed Dyslipidemia

Download and mail the CME quiz

| |

---

Introduction A new look in mixed dyslipidemia. Christie M. Ballantyne, MD, Course Chair Mechanisms of action of triglyceride-lowering drugs William S. Harris, PhD Epidemiologic evidence support triglycerides as an independent risk biomarker for coronary disease Michael Miller, MD, FACC, FAHA COMBOS: Results of the combination of prescription omega-3 plus simvastatin trial Harold E. Bays, MD, FACP Case Studies Michael H. Davidson, MD, FACC, FACP, Course Director

Introduction

The paradigm for risk management of patients with dyslipidemia is changing. Formerly, risk factors included high LDL cholesterol levels and smoking. However, the current epidemics of obesity and metabolic syndrome are causing more patients to develop mixed dyslipidemia as a result of high triglycerides and low HDL cholesterol levels, as well as elevated LDL cholesterol values. To prevent these risks in patients, physicians must explore new treatments.

Vindico Medical Education, in co-sponsorship with Albert Einstein College of Medicine and Montefiore Medical Center,provided coverage at a symposium conducted at the 2007 Annual Meeting of the American Heart Association, where faculty members presented information about future treatment options for patients with dyslipidemia.

We would like to thank the faculty for sharing their insights during the symposium.

Christie M. Ballantyne, MD, Course Chair

Michael H. Davidson, MD, FACC, FACP, Course Director

Christie M. Ballantyne, MD, Course Chair Director, Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Co-Director, Lipid Metabolism and Atherosclerosis Clinic, The Methodist Hospital, Chief, Section of Atherosclerosis, Department of Medicine, Baylor College of Medicine, Director, Maria and Alando J. Ballantyne, MD, Atherosclerosis Laboratory, Professor of Medicine with a Joint Appointment in Pediatrics, Baylor College of Medicine, President, Southwest Lipid Association; Houston, Texas. William S. Harris, PhD Director, Nutrition and Metabolic Disease Research Center, Sanford University of South Dakota Medical Center, Professor of Medicine, Sanford School of Medicine, University of South Dakota; Sioux Falls, South Dakota. Michael Miller, MD, FACC, FAHA Associate Professor of Medicine, Epidemiology and Preventive Medicine, University of Maryland School of Medicine; Director, Center for Preventive Cardiology, University of Maryland Medical Center; Baltimore, Maryland. Harold E. Bays, MD, FACP Medical Director/President, Louisville Metabolic and Atherosclerosis Research Center, Inc, Partner, Louisville Endocrinology P.S.C.; Louisville, Kentucky. Michael H. Davidson, MD, FACC, FACP Course Director Clinical Professor, Director, Preventive Cardiology, University of Chicago, Pritzker School of Medicine; Chicago, Illinois.

A new look in mixed dyslipidemia
Christie M. Ballantyne, MD

Patients with mixed dyslipidemia are at high risk for coronary heart disease (CHD) events. In particular, diabetic dyslipidemia, characterized by the triad of a high level of triglycerides, a low level of high-density lipoprotein (HDL) cholesterol, and an abundance of atherogenic small, dense low-density lipoprotein (LDL) particles, confers a high risk of CHD events. The National Cholesterol Education Program Adult Treatment Panel III identified diabetes as a CHD risk equivalent requiring aggressive risk-reduction strategies.¹ Although statins are the first step in the treatment of diabetic dyslipidemia, these patients remain at high risk despite statin therapy, presumably due to the elevated level of triglyceride and low HDL level that are not adequately treated by statins.

Please review the following case study of a 62-year-old man with type 2 diabetes for 5 years and the corresponding questions:

A 62-year-old man with type 2 diabetes for 5 years presents for a new patient examination. He has a history of angina. He is an ex-smoker, his body mass index is 28.6 kg/m², and his waist circumference is 40 inches. His current medications are glipizide (10 mg/day) and metformin (1,000 mg twice daily) to treat his diabetes, the combination of lisinopril/hydrochlorothiazide (20 mg/12.5 mg) to treat his hypertension, simvastatin (40 mg/day), and aspirin (325 mg/day). On this regimen, his LDL cholesterol is 69 mg/dL, his HDL cholesterol is 38 mg/dL, and his triglyceride level is 330 mg/dL. He has 1+ protein on urinalysis. His blood glucose level is 160 mg/dL and his HbA1c is 7.3%. He has a normal thyroid stimulating hormone.

What is this man's risk for a cardiovascular event over the next 5 years: 0% to 5% 5% to 10% 10% to 20% 20% to 30% >30%

According to the Heart Protection Study, patients with diabetes and arterial disease who were randomized to sim vastatin had a 5-year event rate of 31%. ² Therefore, although the patient in the case study is being treated with evidence-based therapies, his residual risk of disease merits intensifying his therapy.

In which of the following outcomes studies were patients with triglyceride levels >200 mg/dL enrolled: Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Helsinki Heart Study Treating to New Targets (TNT) Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) Veterans Affairs-HDL Intervention Trial (VA-HIT) None of the above

None of these trials based enrollment on an elevation in triglyceride values. In the FIELD study, patients needed a triglyceride level >1 mmol/L (>89 mg/dL) to be enrolled, a level not considered to be elevated.³ The lack of clinical trials designed specifically to test hypotheses in patients with hypertriglyceridemia is disappointing for clinicians who practice evidence-based medicine.

Which of the following would you consider as the first choice to add to this patient’s regimen: Colesevelam Ezetimibe Fenofibrate Pioglitazone Niacin Omega-3 fatty acids None of the above

Although colesevelam improves glucose control and would be beneficial in this patient with diabetes, it also increases triglyceride levels, which would be detrimental to this patient with a triglyceride level of 330 mg/dL.

Two CHD prevention trials with fibrates have assessed their efficacy in subgroup analyses of patients with diabetes. Trials of fibrate therapy that included subgroups of patients with diabetes were the primary-prevention Helsinki Heart Study and the secondary-prevention VA-HIT.^4,5

Only 135 patients with diabetes were enrolled in the Helsinki Heart Study, and assignment to active treatment with gemfibrozil was associated with a 68% reduction in the incidence of CHD compared with placebo in this subgroup, a reduction that failed to achieve statistical significance because of low power.

VA-HIT enrolled 627 patients with diabetes, and this subgroup had a statistically significant 24% reduction in CHD events with randomization to gemfibrozil vs. placebo. In VA-HIT, the mean baseline LDL cholesterol was only 112 mg/dL; the mean baseline HDL cholesterol was 32 mg/dL, and mean triglyceride levels at baseline were 160 mg/dL.

Interpretation of FIELD is complex.³ It did not achieve its primary endpoint—a significant reduction in CHD death and nonfatal myocardial infarction (MI) with randomization to fenofibrate vs. placebo. The relative risk reduction on the primary outcome with active therapy was 11% (P =.16), with no benefit of fenofibrate on CHD death but a significant (P =.01) 24% reduction in nonfatal MI. The difficulty in interpreting this study lies in the large number of patients who initiated statin therapy during the trial. Interpretation of the results may have been easier if all patients had been taking a statin at baseline. Nevertheless, subgroup analysis showed no effect of fenofibrate on secondary prevention of CHD (patients with a history of cardiovascular disease in FIELD did not have better results if randomized to fenofibrate), and the patient in the case study has arterial disease. Therefore, the data do not support the use of a fibrate in the case patient.

A trial of combination lipid-modifying therapy, the Action to Control Cardiovascular Risk in Diabetes (ACCORD),⁶ is ongoing. ACCORD is attempting to simultaneously assess degrees of therapy intensity, including glucose control, blood pressure control, and lipid modification, on the incidence of major cardiovascular events in approximately 10,000 patients with type 2 diabetes. In ACCORD, the addition of fenofibrate to baseline simvastatin is being assessed.

A post-hoc analysis of the Coronary Drug Project reveals a favorable effect of monotherapy with high-dose niacin (3 g/day) on the incidence of nonfatal MI compared with placebo in patients with elevated levels of fasting plasma glucose.⁷

The Atherothrombosis Drug Intervention for Metabolic Syndrome with Low HDL/High Triglycerides and its Impact on Global Health Outcomes (AIM HIGH) is an ongoing study in which approximately 3,000 statin-naïve men and women aged 45 years or older with CHD or a CHD risk equivalent are randomized to 40 mg/day simvastatin alone or plus 2,000 mg/day niacin extended release. In both groups, simvastatin can be titrated to 80 mg/day if LDL cholesterol remains >80 mg/dL after 4 weeks. To qualify for inclusion, men must have a baseline HDL cholesterol <40 mg/dL and women must have a baseline HDL cholesterol of <50 mg/dL, and the triglyceride level at baseline must be between 150 mg/dL and 400 mg/dL. The primary outcome is time to a first major adverse cardiovascular event.

In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, caused a significant reduction in triglyceride levels (P<.0001), a significant increase in HDL cholesterol levels (P<.0001), and a significant reduction in the LDL cholesterol/HDL cholesterol ratio (P<.0001) compared with placebo in patients with type 2 diabetes.⁸ Pioglitazone failed to significantly reduce the incidence of a composite of vascular events that comprised the primary endpoint but was associated with a significant 16% reduction in the combined risk of death, MI, and stroke (P =.027). Patients treated with pioglitazone experienced a 28% reduction (P =.045) in the incidence of a second MI and a 37% reduction (P =.035) in the occurrence of an acute coronary syndrome.

The GISSI-Prevenzione trial was conducted in 11,324 post-MI patients who were randomly assigned supplements of omega-3 fatty acids, 1 g/day (800 mg to 882 mg of EPA/DHA ethyl esters), vitamin E, 300 mg/day, both, or neither for 3.5 years.⁹ The dosage was not sufficiently high to favorably alter triglyceride levels. Instead, the goal of the study was to observe the biologic effects of omega-3 fatty acids. The primary combined efficacy endpoint was the incidence of death, nonfatal MI, and stroke.

Omega-3 fatty acids were associated with a significant (P<.01) reduction in all cause mortality, which was apparent as early as 90 days. This reduction in mortality is believed to result from a significant (P<.001) reduction in sudden cardiac death.¹⁰ Vitamin E had no effect on any endpoint.

The Japan Eicosapentaenoic Acid (EPA) Lipid Intervention Study (JELIS) is the first large-scale, prospective, randomized trial to combine statins and omega-3 fatty acid therapy to determine whether the combined treatment would afford additional clinical benefits in preventing major coronary events.¹¹

In this open-label trial of 18,645 patients with hypercholesterolemia, 9,326 were assigned to EPA (1,800 mg/day) in addition to statin therapy, and 9,319 were assigned to statin therapy alone. Statin therapy consisted of 10 mg/day prava statin, or 5 mg/day simvastatin. The primary endpoint was the incidence of major coronary events (defined as sudden cardiac death, fatal or nonfatal MI, unstable angina pectoris, and coronary artery bypass graft/percutaneous coronary intervention) at a mean of 4.6 years.

The primary endpoint was achieved in 2.8% patients treated with EPA plus statin compared with 3.5% patients treated with a statin alone, resulting in a 19% reduction (P =.011). This reduction in the primary endpoint was independent of the reduction in total cholesterol and LDL cholesterol.

Conclusion

Patients with mixed dyslipidemia have high residual risk of CHD events even after statin therapy. Although several therapies may be added to statins to further manage dyslipidemia, outcomes data lack information about the use of most of these agents with a statin.

However, evidence shows that fibrates, niacin, and omega-3 fatty acids reduce cardiovascular risk. No completed trials have examined the addition of these agents to statins in patients with mixed hyperlipidemia.

References

1. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the National Cholesterol Education Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
2. Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet.2003;361:2005-2016.
3. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849-1861.
4. Koskinen P, Mänttäri M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care. 1992;15:820-825.
5. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.
6. www.clinicaltrials.gov/ct/gui/show/NCT00000620?order=29. Last accessed January 17, 2008.
7. Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2005;95:254-257.
8. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.
9. GISSI Prevenzione investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354:447-455. [published correction: Lancet. 2001;357:642.]
10. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.
11. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.

Mechanisms of action of triglyceride-lowering drugs
William S. Harris, PhD

The two main triglyceride-containing lipoproteins are very-low density lipoprotein (VLDL) and chylomicrons.

VLDL is secreted from the liver and is metabolized by lipoprotein lipase, a capillary-bound enzyme that removes the triglyceride from the particle. The VLDL particle shrinks as the core components are removed. As it shrinks, VLDL becomes an intermediate-density lipoprotein and a low-density lipoprotein (LDL).

Chylomicrons are produced in the gut from dietary fat. As with VLDL, lipoprotein lipase clears the triglyceride from the chylomicron particle, producing a remnant particle that is picked up by the liver.

Drug mechanisms to lower triglycerides

Niacin, fibrates and prescription omega-3 fatty acids are approved for the treatment of patients with hypertriglyceridemia.

Adipose tissue releases free fatty acids that drive the production of triglycerides in the liver. Niacin has two mechanisms by which it reduces triglyceride levels. It blocks the release of free fatty acids from adipose tissue, which also results in a reduced rate of secretion of VLDL particles.

Fibrates have no effect on free fatty acid kinetics. Instead, fibrates inhibit the secretion of triglycerides from the liver, which reduces levels of blood triglycerides and stimulates the clearance of triglycerides by activating lipoprotein lipase.

Omega-3 fatty acids act similarly to fibrates to reduce triglyceride levels. Although they operate differently in the liver, prescription omega-3 fatty acids inhibit the release of triglycerides from the liver, reducing the number of VLDL particles. They also stimulate lipoprotein lipase, which increases the rate of clearance of triglycerides from the plasma.

Enhanced triacylglycerol (triglyceride) clearance may contribute to the hypotriacylglycerolemic effect of omega-3 fatty acids in humans. Healthy patients and hypertriacylglycerolemic patients were given a placebo (olive oil) or a fish-oil concentrate (41% eicosapentaenoic acid and 23% docosahexaenoic acid) in two independent, randomized, blind trials.¹

In the healthy patients, the fish oil concentrate decreased plasma triacylglycerol concentrations by 18%, whereas in the hypertriacylglycerolemic patients, concentrations were reduced by 35%. LDL cholesterol concentrations increased by 25% in the latter group. Fish oil concentrate increased the endogenous activities of lipoprotein lipase by 62% and hepatic lipase by 68% in the healthy patients, but only lipoprotein lipase by 65% in the patients with hypertriacylglycerolemia.

These data suggest that endogenous lipase activities may be altered by nutritional interventions and that accelerated lipolysis may contribute, at least in part, to the observed effects of omega-3 fatty acids on human lipoprotein metabolism.

Evidence also indicates that omega-3 increases plasma lipoprotein lipase and lipoprotein lipase gene expression in adipose tissue. In a randomized, double-blind, placebo-controlled, crossover study, 51 men who expressed an atherogenic lipoprotein phenotype had their diets supplemented with fish oil for 6 weeks, producing a 35% decrease in fasting plasma triglyceride, attenuation of the postprandial triglyceride response, and a decrease in small, dense LDL.² These changes were accompanied by a marked increase in the concentration of lipoprotein lipase mRNA in adipose tissue and post-hepatic lipoprotein lipase. Also, evidence showed an association between lipoprotein lipase gene expression and polymorphism in the apolipoprotein E gene.

The atherogenic lipoprotein phenotype originates from defects in triglyceride metabolism that include the impaired clearance of triglyceride-rich lipoproteins in the postprandial period, coupled with an oversupply of lipid substrates for the production of triglyceride and secretion of apolipoprotien B as triglyceride-rich VLDL in the liver (Figure).

A physiologic increase in LDL cholesterol occurs in patients receiving fibrates or omega-3 fatty acids by stimulating lipoprotein lipase activity. A blockade of lipoprotein lipase, the enzyme that removes the triglyceride from the VLDL particle, is responsible for elevated triglyceride levels in patients with hypertriglyceridemia. Removing this blockade by stimulating lipoprotein lipase activity with a fibrate or omega-3 fatty acids decreases the number of VLDL particles and results in a small increase in LDL.

Triglyceride Metabolism Figure. The atherogenic lipoprotein phenotype originates from defects in triglyceride metabolism. Dunbar RL, Rader DJ. Demystifying triglycerides: A practical approach for the clinician. Cleve Clin J Med. 2005;72(8):661-680. Reprinted with permission. Copyright © 2005 Cleveland Clinic. All rights reserved.

Effects of fibrates and omega-3 fatty acids on lipid profiles

The effects of fenofibrate and prescription omega-3 fatty acids on lipid profiles have been assessed in patients with hypertriglyceridemia. The pattern of response was similar with each agent.

In a double-blind prospective trial, 42 patients with triglyceride levels of 500 mg/dL to 2,000 mg/dL were randomized to placebo or omega-3 acid ethyl esters, 4 g/day, for 4 months.³ Compared with baseline values, omega-3 acid ethyl esters significantly reduced mean triglyceride concentrations by 45% (P<.00001), total cholesterol by 15% (P<.001), VLDL cholesterol by 32% (P<.0001) and the total cholesterol:high-density lipoprotein (HDL) cholesterol ratio by 20% (P =.0013), and increased HDL cholesterol by 13% (P = .014) and LDL cholesterol by 31% (P =.0014). Placebo had no effect on these parameters.

In a randomized double-blind, placebo-controlled, multicenter trial of fenofibrate, 147 adults with a history of type IV or V hyperlipoproteinemia were recruited.⁴ Type IV is isolated hyperlipoproteinemia, with triglycerides between 200 and 1,000 mg/dL, whereas type V is severe hyperlipoproteinemia, with triglycerides >1,000 mg/dL. After a 6-week to 12-week dietary stabilization period and a 4-week placebo period, patients whose 12-hour fasting total plasma triglyceride levels ranged from 350 mg/dL to 1,500 mg/dL were continued in the study. Patients were stratified into two groups based on their triglyceride levels at entry—group A (350 mg/dL to 499 mg/dL) and group B (500 mg/dL to 1,500 mg/dL). Patients in each group were randomly assigned to receive 100 mg of fenofibrate or placebo three times daily for 8 weeks.

In groups A and B, patients who received fenofibrates had statistically significant reductions in levels of total cholesterol, VLDL cholesterol, total triglycerides, and VLDL triglycerides, and significant increases in HDL cholesterol. Patients in group B also experienced a significant increase in LDL cholesterol levels. Sixteen of the 75 patients who received fenofibrates and 11 of the 72 patients who received placebo reported adverse events that were potentially drug related. Most of these were gastrointestinal; a few reported musculoskeletal and skin reactions.

Safety profiles

Contraindications, precautions, and the potential for drug interactions differentiate fenofibrate from prescription omega-3 fatty acids. According to the package insert for fenofibrate, it is contraindicated in patients with hepatic, renal, or gall bladder disease, and cautious use is warranted in patients with elevated liver function tests or cholelithiasis. Fenofibrate interacts with coumadin, resins, statins, and cyclosporine, and its use with statins is not recommended unless the physician believes that the benefits outweigh the risks of myopathy and rhabdomyolysis.

In contrast, prescription omega-3 fatty acids have no contraindications, and no precautions for its use appear in the package insert. Recipients of prescription omega-3 fatty acids who are also taking anticoagulants should be monitored periodically for a prolongation in bleeding time. They can be used safely with statins; in patients taking simvastatin, an additional 23% lowering in triglycerides is observed with the use of prescription omega-3 fatty acids.

Conclusion

Niacin, fibrates, and prescription omega-3 fatty acids reduce triglyceride secretion from the liver by different mechanisms. Only fibrates and prescription omega-3 fatty acids also enhance triglyceride clearance. Fibrates and prescription omega-3 fatty acids have similar effects on lipid profiles in patients with high triglycerides.

References

1. Harris WS, Lu G, Rambor GS, et al. Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases. Am J Clin Nutr. 1997;66:254-260.
2. Khan S, Minihane AM, Talmud PJ, et al. Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype. J Lipid Res. 2002;43:979-985.
3. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4:385-391.
4. Goldberg AC, Schonfeld G, Feldman EB, et al. Fenofibrate for the treatment of type IV and V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study. Cin Ther. 1989;11:69-83.

Epidemiologic evidence supports triglycerides as an independent risk biomarker for coronary disease
Michael Miller, MD, FACC, FAHA

According to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), elevated triglycerides are a biomarker for increased risk of coronary heart disease (CHD). Elevations in serum triglycerides are associated with increased levels of atherogenic remnant lipoproteins. Because very low density lipoprotein (VLDL) cholesterol is the most available measure of atherogenic remnant lipoproteins, it can be combined with low density lipoprotein (LDL) to estimate the non-high density lipoprotein (non-HDL = total cholesterol-HDL, target for non-HDL <130 mg/dL) level thereby representing the concentrations of atherogenic lipoproteins more effectively than LDL alone.

When serum triglycerides are elevated, the non-HDL level enhances CVD risk prediction, and the NCEP ATP III recommends that non-HDL be a secondary target of therapy when triglyceride levels are >200 mg/dL. The NCEP ATP III does not have a target triglyceride level at this time.¹

In 2007 the American Diabetes Association (ADA) and the American Heart Association (AHA) issued a joint scientific statement for the primary prevention of CVD in patients with diabetes.² They recommend that LDL be the primary target of lipid-lowering therapy in patients with diabetes with a goal of <100 mg/dL. They also report that triglyceride-rich lipoproteins, especially VLDL, are often elevated in patients with diabetes, and serve as a precursor for atherogenic VLDL remnant particles. The AHA and NCEP recommends a non-HDL cholesterol goal of <130 mg/dL in patients with triglyceride levels of 200 mg/dL to 499 mg/dL. If levels of triglyceride >500 mg/dL, then triglyceride lowering becomes a priority in the management of dyslipidemia.

Evidence of risk

Several studies indicate that an elevated level of triglycerides is associated with increased CHD risk. The 8-year Prospective Cardiovascular Munster Study (PROCAM) found that high triglyceride levels increased CHD risk among middle-aged men in addition to their LDL or HDL levels. PROCAM included 4,639 men with no history of myocardial infarction or stroke and showed a six-fold increased CHD risk in those with triglyceride levels >200 mg/dL and LDL/HDL ratios >5 (P =.01).³

PROCAM researchers found that 44 CHD events occurred per 1,000 patients with triglyceride levels <200 mg/dL, 93 events per 1,000 patients with triglyceride levels of 200 mg/dL to 399 mg/dL, 132 events per 1,000 patients having triglyceride levels of 400 mg/dL to 799 mg/dL, and 81 events per 1,000 patients with triglyceride levels of >800 mg/dL.⁴

The largest and most comprehensive epidemiological assessment of the association between triglyceride values and CHD risk in Western populations was a meta-analysis of 29 studies including 262,525 participants and 10,158 patients with CHD. Researchers reported an adjusted odds ratio of 1.72 (95% CI, 1.56-1.90) for those with log-triglyceride values in the top third of the population compared to those in the bottom third.⁵ This odds ratio was adjusted in all but one of the 29 studies for age, sex, smoking status, and lipid concentrations, and most studies also adjusted for blood pressure.

The data indicate that the impact of triglycerides on risk is similar in women and men, regardless of follow-up duration. The data also suggest no important differences in the strength of associations between triglycerides and CHD in studies of fasting participants compared with those of nonfasting participants. A highly significant association exists between triglyceride value and CHD risk.

The basis for elevated levels of triglycerides serving as a CHD risk biomarker stems from associated increases in cholesterol-enriched atherogenic remnant particles, the byproduct of the hydrolysis of triglyceride-rich lipoproteins.⁶ In addition, hypertriglyceridemia may also be associated with increased blood viscosity that in part may be related to upregulation of coagulation factor VIII and plasminogen activator inhibitor.⁷

Hypertriglyceridemia and mechanisms of atherosclerosis

Chylomicron remnants may promote inflammation following endothelial transcytosis by upregulating adhesion molecule expression and macrophage chemotaxis. Remnant particles may be directly incorporated by macrophages analogous to modified LDL, which in turn serves to contribute to foam cell formation and plaque growth. Growth factors that are also elaborated in this proinflammatory milieu promote smooth muscle cell proliferation. Migration of smooth muscle cells from the media to the intimal surface leads to deposition of fibrous tissue, producing raised plaques protruding into the lumen⁸ (Figure).

In patients with hyperinsulinemia or excessive visceral fat, free fatty acids are released from adipocytes leading to hepatic VLDL overpopulation. The increase in triglyceride-rich particles enhances CETP mediated exchange of triglyceride for cholesteryl ester contained in HDL and LDL. The results are hypertriglyceridemic LDL and HDL particles that are further catabolized by hepatic lipase to small and dense cholesterol-depleted particles. Whether and to what extent particle compositional changes in LDL and/or HDL impact vascular disease rates if at all, however, remains controversial. Therefore, the best evidence supporting elevated trigylceride as it relates to CHD is due to its association with atherogenic remnant particles.

Chylomicron Remnant-Induced Development of Atherosclerosis Figure. Chylomicron remanants may induce changes in endothelial cells and monocytes that cause monocyte rolling. Image courtesy of Kenneth C, Yu W. Postprandial lipoproteins and atherosclerosis. Front Biosci. 2001;6:D332-54.

Mixed hyperlipidemia

Clinicians should recognize that elevated triglyceride levels are often accompanied by mixed hyperlipidemia, defined as elevations in LDL and triglyceride, often with reciprocal low HDL. In some cases however, elevated triglycerides remain an independent risk factor for CHD after adjustment for HDL. For example, in the Baltimore Coronary Observational Long-Term study (COLTS), 740 patients presenting for coronary arteriography between 1977 and 1978 were followed for 18 years. Of these, 350 had arteriographically defined CAD, and 199 events occurred during the follow-up period. The mean LDL and HDL levels were 153 mg/dL and 35 mg/dL in CAD patients compared to 149 mg/dL and 39 mg/dL in controls. Moreover, triglyceride levels were 160 mg/dL among CAD patients (consistent with a pattern of mixed hyperlipidemia) vs. 137 mg/dL among controls (P =.03). Patients with triglyceride levels of 100 mg/dL had significantly reduced CAD event survival compared with those with triglyceride levels of <100 mg/dL (P =.008).¹⁰

Moreover, a subanalysis of the Helsinki Heart Study demonstrated that the group at highest risk of initial CHD events were placebo-treated patients with triglyceride levels >204 mg/dL and an LDL/HDL ratio >5. This group evidenced approximately three times as many events than those more favorable LDL/HDL ratios.

In the Scandinavian Simvastatin Survival Study, in which all patients had high LDL (mean = 190 mg/dL), the highest event rates were observed in association with elevated triglycerides and low HDL. Specifically, the 5-year event rate in untreated patients was 35.9% as compared to the 20.9% event rate with isolated elevation in LDL.¹¹ Once again, these results support the concept that patients at highest risk of CHD events (primary and recurrent events) barring monogenic abnormalities are those with mixed hyperlipidemia.

In a recent subanalysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy, the combination of low on-treatment LDL <70 mg/dL and triglyceride (<150 mg/dL) was associated with reduced death, myocardial infarction, and recurrent acute coronary syndrome (ACS) as compared to higher levels of each during the 2-year follow-up (HR 0.72, 95% CI 0.54 to 0.94, P = 0.017).¹²

In summary, the epidemiologic evidence supports triglycerides as associated with increased coronary risk owing to increases in atherogenic remnant particles. The higher risk is magnified when combined with elevated LDL. Conversely, lowering both LDL and triglycerides appears to be clinically superior to reduction of LDL alone following an acute coronary syndrome.

References

1. Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143-3421.
2. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30:162-172.
3. Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol. 1996;77:1179-1184.
4. Assman G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol. 1992;70:733-737.
5. Sarwar N, Danesh J, Elrlksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450-458.
6. Ooi TC, Cousins M, Ooi DS, et al. Postprandial remnant-like lipoproteins in hypertriglyceridemia. J Clin Endocrinol Metab. 2001;86:3134-3142.
7. Rosenson RS, Shott S, Tangney CC. Hypertriglyceridemia is associated with an elevated blood viscosity Rosenson: triglycerides and blood viscosity. Atherosclerosis. 2002;161:433-439.
8. Kenneth C, Yu W. Postprandial lipoproteins and atherosclerosis. Front Biosci. 2001;6:D332-D354.
9. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506.
10. Miller M, Seidler A, Moalemi A, Pearson TA. Normal triglyceride levels and coronary artery disease events: the Baltimore Coronary Observational Long-Term Study. J Am Coll Cardiol. 1998;31:1252-1257.
11. Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051.
12. Miller M, Cannon C, Murphy SA, Qin J, Ray KK, Braunwald E, for the PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low density lipoprotein cholesterol after an acute coronary syndrome in the PROVE IT-TIMI 22 Trial. J Am Coll Cardiol. 2008;51:724-730.

COMBOS: Results of the combination of prescription omega-3 plus simvastatin trial
Harold E. Bays, MD, FACP

Patients with persistent fasting triglyceride levels >200 mg/dL after achieving their low density lipoprotein (LDL) cholesterol goal with statin therapy often present a challenge to clinicians. According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) the next treatment goal is to lower non-high density lipoprotein (non-HDL) cholesterol, which sums the cholesterol carried by atherogenic lipoproteins. From a practical standpoint, this often means lowering triglycerides, because fasting triglycerides are carried by very low density lipoprotein (VLDL) particles, which carry cholesterol measured by non-HDL cholesterol measurements.¹

Omega-3 fatty acids significantly lower triglycerides, raise high density lipoprotein (HDL), and although not always consistent, may also lower non-HDL cholesterol and apoB.

The Combination of Prescription Omega-3 Plus Simvastatin (COMBOS) trial evaluated the common clinical presentation of statin-treated patients who, after achieving their LDL cholesterol treatment goal, have persistent triglyceride levels 200 mg/dL to 499 mg/dL.

COMBOS design

COMBOS assessed if therapeutic doses of omega-3 fatty acids added to stable statin therapy improved non-HDL cholesterol levels, triglyceride levels, and other lipid parameters.² COMBOS also evaluated the safety of adding prescription omega-3 fatty acids to stable statin therapy in hypertriglyceridemic patients whose LDL cholesterol was >10% of their NCEP ATP III treatment goals, and assessed the effects upon LDL particle size, LDL subclass pattern, and lipoprotein associated phospholipase A2 (LpPLA2).^2-4

COMBOS included 254 men and women aged 18 to 79 years with fasting triglyceride levels between 200 mg/dL and 499 mg/dL who were receiving stable statin therapy to control LDL cholesterol. All patients had LDL cholesterol levels less than 10% above their NECP ATP III goals when assessed 2 weeks and 1 week prior to randomization. All patients received 40 mg simvastatin daily for 8 weeks before randomization. They were then randomized to receive 4 g prescription omega-3 fatty acids, taken as two capsules twice a day or four capsules once a day, in addition to 40 mg simvastatin (n=122) or placebo plus 40 mg simvastatin daily (n=132) for 8 weeks.

Many in the COMBOS study were representative of a metabolic syndrome population, with mean blood glucose levels of 109.8 mg/dL in the group assigned to prescription omega-3 fatty acids and 106.9 mg/dL in the placebo group, with waist circumferences of 103.5 cm and 104.4 cm, respectively. Average weight was 91 kg in the treatment group and 92.9 kg in the placebo group.

Median baseline LDL cholesterol levels were 90.7 mg/dL in the prescription omega-3 fatty acid recipients and 88.2 mg/dL in the placebo recipients. At baseline, median triglyceride levels were 267.8 mg/dL in the active treatment group and 270.7 mg/dL in the placebo group; median HDL cholesterol levels were 46 mg/dL and 43.3 mg/dL, respectively; and median non-HDL cholesterol levels were 137 mg/dL and 141.3 mg/dL, respectively.

COMBOS results

The main outcome of this trial was the change in non-HDL cholesterol, which significantly decreased by 7.9% in the prescription omega-3 fatty acid subjects compared to a decrease of 1.5% found in those randomized in placebo (P<.001). Triglyceride levels were significantly decreased by 29.5% in the active treatment group compared with a decrease of 6.3% in the placebo group. VLDL cholesterol levels significantly decreased by 27.5% and 7.2% respectively, and HDL cholesterol levels significantly increased by 3.4% in the treated patients but decreased by 1.2% in the placebo patients. Median apoB levels significantly decreased. (P =.0232).

Median LDL cholesterol levels increased by 0.7% in the prescription omega-3 fatty acids group and declined by 2.8% in the placebo group, which was not of significant difference (P =.0522). Non-HDL cholesterol and triglyceride levels were predicted to decrease; but it was unknown whether the addition of prescription omega-3 fatty acids would cause a loss in the benefit of the statin on LDL cholesterol levels. These data do not suggest a clinically significant increase in LDL cholesterol levels when prescription omega-3 fatty acids are added to simvastatin.

Adverse experiences occurred in 41.8% of the prescription omega-3 fatty acid recipients and 47.7% of the placebo group. Nasopharyngitis, upper respiratory tract infection, diarrhea, dyspepsia, bronchitis, cystitis, alanine aminotransferase (ALT) increase, and gastroenteritis occurred in more than 1% of patients and with a greater incidence among those receiving prescription omega-3 fatty acids. No significant differences occurred between groups. Some patients experienced eructation, and the incidence was slightly increased in the prescription omega-3 fatty acids group.

Four patients assigned prescription omega-3 fatty acids experienced serious adverse experiences (Table). None were considered by the investigators to be due to the study drug.

COMBOS Safety Assessment *Adverse experiences shown occurred in >1% of patients and at a greater rate in the P-OM3 plus simvastatin group. †None of these serious adverse experiences were considered by the investigators to be related to the study treatment. In three subjects, the event resolved without changing the study regimen. In one event, study medication was discontinued and the experience was ongoing at the end of the study. Adapted with permission from Davidson MH, Stein EA, Bays HE, et al. Clin Ther. 2007;29:1354-1367.

Tertiary assessment results

Further analysis demonstrated that patients achieving the lowest triglyceride levels also achieved the greatest increase in LDL particle size. Patients with end-of-treatment triglyceride levels of >250 mg/dL had a decrease in LDL particle size of 0.20 nm, those with triglyceride levels between 200 mg/dL and 249 mg/dL had a 0.15-nm increase in LDL particle size, patients achieving triglyceride levels of 150 mg/dL to 199 mg/dL showed a 0.40-nm increase in LDL particle size, and those achieving triglyceride levels <150 mg/dL had a 0.60-nm increase in LDL particle size.

When the LDL subclass pattern was analyzed, and baseline vs. end-of-treatment values compared, the proportion of patients expressing pattern A (representing a shift from small dense LDL to larger LDL) was increased with prescription omega-3 fatty acid therapy. Concomitantly, the proportion of patients who expressed pattern B, representing a shift from larger, and potentially less atherogenic LDL to small dense LDL, was decreased. These changes correlated with the reduction in triglyceride level.

Although no change in the levels of C-reactive protein was observed among COMBOS patients receiving prescription omega-3 fatty acids, a significant reduction occurred in the level of the inflammatory marker Lp-PLA₂. Patients treated with prescription omega-3 fatty acids had a significant 10.7% decrease in Lp-PLA₂ levels compared with a 1.4% decrease among placebo patients.⁴

Conclusion

Many patients with mixed dyslipidemia have persistent hypertriglyceridemia after statin monotherapy. Adding prescription omega-3 fatty acid therapy may improve not only triglycerides in these patients, but also improve secondary lipid treatment targets, such as non-HDL-C levels.

References

1. Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143-3421.
2. Davidson MH, Stein EA, Bays HE, et al. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367.
3. Maki KC, et al. FASEB J. 2007;21:231-232. Abstract.
4. Shalwitz RA, et al. ATVB Abstract P328. Arterioscler Thromb Vasc Biol. 2007;27:e93.

Case Study 1 Mild hypertriglyceridemia in a South Asian patient with type 2 diabetes A 31-year-old South Asian man presents for a coronary heart disease (CHD) risk assessment. He is 5’10”, weighs 181 pounds, has a waist circumference of 36”, and a blood pressure of 135/85 mm Hg. He has had type 2 diabetes for 3 years. He takes 1,000 mg of metformin and 40 mg of atorvastatin once daily. His mother had coronary artery bypass graft surgery with complications at age 53. Lipid panel: total cholesterol: 207 mg/dL; high-density lipoprotein cholesterol: 30 mg/dL; low-density lipoprotein cholesterol: 107 mg/dL; and triglycerides: 350 mg/dL. Blood glucose level: 130 mg/dL. Other laboratory values: creatinine:1 mg/dL; creatinine clearance: 103.1 mL/min; blood urea nitrogen: 14 mg/dL; and uric acid: 9.1 mg/dL. DR. DAVIDSON: This patient has all the criteria for a metabolic syndrome: waist circumference of 36” (for Asian man); elevation in triglycerides; low HDL cholesterol level; systolic blood pressure >130 mm Hg, fasting glucose of 100 mg/dL. DR. MILLER: In addition to lifestyle changes, fenofibrates and omega-3 fatty acids should now be considered beyond statin therapy to lower his elevated triglyceride levels. Equally important is better control of his glucose, because without improvement in this metabolic parameter, it is highly unlikely that triglyceride levels will normalize. DR. BALLANTYNE: His lipid levels are not adequate despite being on 40 mg of atorvastatin, which indicates a severe, probably hereditary, dyslipidemia that may be familial combined hyperlipidemia. Knowing his baseline LDL cholesterol level, his mother’s lipid profile, and his lipoprotein (a) level would be helpful. I would target LDL cholesterol <100 mg/dL. A carotid ultrasound can measure his intima-media thickness. If he has atherosclerosis, then I may use three therapies, adding any of those mentioned in addition to a statin, and maybe even change his statin. DR. BAYS: I would look at fish oils as revealing the true atherogenicity of this person’s dyslipidemia. Omega-3 fatty acids, like fibrates, convert VLDL particles to LDL particles, and if I treat a patient with a triglyceride level of 350 mg/dL with omega-3 fatty acids, the LDL cholesterol level will often increase. I would treat this patient with omega-3 fatty acids, leave him on atorvastatin and perhaps add ezetimibe. DR. HARRIS: His LDL cholesterol may not increase if you put him on fish oil because he is on atorvastatin already. If he were on monotherapy with omega-3 fatty acids and his triglycerides were higher, the LDL cholesterol level may rise. DR. DAVIDSON: I would use fenofibrate because it lowers uric acid levels. Adding niacin instead may make controlling his glucose difficult. Ultimately, we realize that unless he reduces his caloric intake and loses weight, we will probably use multiple drugs.

Case Study 2 Severe hyper-triglyceridemia in a patient with type 2 diabetes A 36-year-old woman is referred to the lipid clinic by a dermatologist. She was diagnosed with type 2 diabetes 3 years ago, has a history of pancreatitis, a sedentary lifestyle, has smoked one pack per day for 10 years, and denies the use of alcohol or illicit drugs. Her mother and father are alive and well. Physical examination shows eruptive xanthomas. and the dermatologist’s biopsy revealed triglycerides in the skin lesions. Blood pressure: 133/89 mm Hg; heart rate: 91 bpm; height: 5’5”; weight: 235 pounds; waist circumference: 41”; body mass index: 30.9 UNITS. Laboratory results: total cholesterol: 300 mg/dL; HDL cholesterol: 20 mg/dL; LDL cholesterol: not calculated; triglycerides: 900 mg/dL, blood glucose: 115 mg/dL. Other laboratory values: creatinine, 1.6 mg/dL; blood urea nitrogen (BUN), 13 mg/dL; uric acid, 3.2 mg/dL, Hgb A1C level: 7.3%. DR. DAVIDSON: Cigarette smoking does not cause hypertriglyceridemia. Low HDL cholesterol and inactivity do. DR. MILLER: The patient has a primary hypertriglyceridemia. I would confirm that some of the exogenous causes, such as alcohol, are withdrawn. Estrogen-related therapies also trigger high triglycerides. We have had success using omega-3 fatty acids and fibrates. In concert with weight loss and exercise, we have had success with omega-3 fatty acids in lowering triglycerides in patients with baseline values as high as 8,000 mg/dL. However, I am unaware of any studies that have evaluated either omega-3 fatty acids or fibrates prospectively for the prevention of recurrent pancreatitis. Omega-3 fatty acids possess anti-inflammatory properties that may be clinically useful in patients with systemic inflammatory processes. DR. BAYS: The issue is the patient’s prior bout of pancreatitis. The first priority should be to lower the triglycerides to <500 mg/dL. I would start with diet and lifestyle changes. It is extraordinary how effective weight reduction and a diet low in simple carbohydrates are in lowering triglycerides in patients. She does not admit to alcohol use. The effects of alcohol are complicated. Although it can cause fatty liver and increase triglycerides, chronic low alcohol consumption can reduce triglycerides by improving glucose sensitivity. In studies in which Dr. Ballantyne was a co-author, intermittent alcohol intake increased triglyceride levels in individuals without hypertriglyceridemia but had little effect on those who already had hypertriglyceridemia. A diet with a low glycemic index is important. We provide patients with a handout that lists glycemically acceptable and glycemically unacceptable diets. We eliminate fruit juices and sugared soda from the diets of patients with hypertriglyceridemia. Once we remove these and add omega-3 fatty acids, we may try to lower triglycerides to <500 mg/dL, and then focus on the atherogenicity that remains with triglycerides at this level. DR. BALLANTYNE: One could use niacin in this case but cautiously up-titrate it due to the blood glucose of 115 mg/dL. The creatinine level of 1.6 is a concern if we use fenofibrate. It may increase but it may be a lab error because the BUN was normal. I would perform a urinalysis to rule out nephrotic syndrome. One of the issues with alcohol is an interaction with dietary fat. A high fat load plus alcohol can increase her triglycerides to as high as 2,000 mg/dL or 3,000 mg/dL in the postprandial state. In addition, a meal of fried foods can induce another episode of pancreatitis. Her fat intake must be reduced. She should eat lean cuts of meat and avoid sugars. Exercise, weight loss, and dietary changes can reduce triglyceride levels to between 200 mg/dL and 300 mg/dL. The HDL cholesterol of 20 mg/dL is also worrisome but could be a laboratory error due to the high triglyceride level. DR. DAVIDSON: Does assessing triglycerides in the nonfasting state have value as a predictor of vascular events? DR. MILLER: The fasting triglyceride level correlates with the postprandial level. Typically, the postprandial triglyceride peak levels occur 4 hours after a fatty meal. However, because fat content and composition is highly variable it is difficult to accurately predict the expected postprandial triglyceride response, although >50% is a reasonable estimate. Therefore, a fasting triglyceride level of 150 mg/dL is likely to increase well beyond 200 mg/dL during the day, depending on the dietary fat consumed. As a result, a “non-fasting” triglyceride level >200 mg/dL should be followed up with the more traditional and standardized fasting level to determine whether and to what extent lifestyle and other measures may need to be instituted.

Case Study 3 Mixed dyslipidemia and subclinical atherosclerosis A 54-year-old white man reports to the lipid clinic for a comprehensive evaluation and primary prevention. He is a nonsmoker, exercises regularly, has a low-fat and low-carbohydrate diet, and denies alcohol and illicit drug use. He is currently taking 20 mg simvastatin and 81 mg aspirin daily. The patient’s father died from a myocardial infarction at age 49. His sister, age 50, recently underwent percutaneous transluminal coronary angioplasty with stent placement in the left anterior descending and right coronary arteries. His mother has type 2 diabetes and is 75 years old. The patient is 5’11”, weights 190 pounds and has a waist circumference of 38 inches and a body mass index of 26.5. His blood pressure is 134/82 mm Hg, and his heart rate is 72 bpm. Lipid panel results are: total cholesterol: 170 mg/dL; HDL cholesterol: 30 mg/dL; LDL cholesterol: 90 mg/dL; triglycerides: 250 mg/dL; and non-HDL cholesterol: 140 mg/dL. His LDL particle number is elevated at 1407 nmol/L with the desirable number being less than 1000 nmol/L, and his apoB is also elevated at 130 mg/dL. Additional laboratory tests revealed a 2-hour postprandial glucose of 210 mg/dL and a hemoglobin A1c of 6.3. His liver enzymes were elevated with an alanine transaminsae of 65 u/L, Aspartate transaminase of 80 u/L and a GGT of 145 u/L, Kidney function tests revealed an impaired creatinine clearance of 1.5 mg/dL, an elevated blood urea nitrogen of 28 mg/dL and elevated uric acid of 9.1mg/dL. Computed tomography angiography showed significant coronary calcium as well as soft plaque in his left anterior descending artery and calcium in his other arteries. How would you treat this patient? Increase the dose of simvastatin to 40 mg /day A. Add 4 g prescription omega-3 fatty acids to 20 mg/day simvastatin B. Add 145 mg fenofibrate to 20 mg/day simvastatin, C. Add 1,000 mg niacin ER to 20 mg/day simvastatin D. Maintain current treatment of 20 mg/day simvastatin DR. MILLER: I would use omega-3 fatty acids but would probably also consider niacin therapy given his tendency to a low HDL cholesterol and elevation of triglycerides. Combination would be effective on top of his statin. DR. DAVIDSON: Would you have considered metformin for this patient? DR. MILLER: I would be more cautious in view of the reduced creatinine clearance. DR. DAVIDSON: Would you use pioglitazone? Would anybody use anything for his diabetes? DR. HARRIS: He fit the combination pattern well, so it is not unreasonable to use the omega-3s. DR. BAYS: I would consider using niacin in this patient. I would be a little concerned about the glucose level because it is borderline high, but given that he has evidence of atherosclerosis, niacin will be effective in improving triglycerides and raising HDL cholesterol. Because patients like this end up being on so many medications, I look at it from a strategic standpoint: what is the easiest way to get them from their baseline to target lipid levels? With niacin, you may reduce the triglycerides to <200 mg/dL, and you can increase the HDL cholesterol to as high as 35 mg/dL. Then I would focus on further lowering the LDL cholesterol level. One could make the case that he should be switched to the combination of ezetimibe plus simvastatin to drive the LDL cholesterol level down. DR. DAVIDSON: Would you catheterize him? DR. BALLANTYNE: No, I would perform a stress test. I do not catheterize based on coronary calcium score. If you see lesions on the angiogram, jump in and start to do something you can get in trouble. I agree that omega-3 fatty acids are fine but he needs more LDL cholesterol lowering. I am not happy about his LDL cholesterol being 90 mg/dL, and his apoB and lDL particle concentration is high. I would put him on a more effective statin instead of doubling the dose of simvastatin to 40 mg. I would go to atorvastatin, 40 mg/day, or rosuvastatin, or use ezetimibe plus simvastatin. COMMENT FROM AUDIENCE: Do you routinely treat chylomicron and check the level? COMMENT FROM AUDIENCE: There are no commercial assays currently available in the United States for chylomicron remnants. So we do not measure them, but there are some assays being tested. COMMENT FROM AUDIENCE: In the Honolulu Heart Study there was a good correlation between chylomicron remnants and triglyceride levels. COMMENT FROM AUDIENCE: This man has systolic hypertension that needs to be treated. DR. DAVIDSON: Yes, I think we all agree that this patient must be aggressively treated and that triglyceride lowering is a component of the overall global risk modification.