- Email: [email protected]
Treating Mixed Hyperlipidemia and the Atherogenic Lipid Phenotype for Prevention of Cardiovascular Events
REVIEW
Treating Mixed Hyperlipidemia and the Atherogenic Lipid Phenotype for Prevention of Cardiovascular Events Melvyn Rubenfire, MD,a Robert D. Brook, MD,a Robert S. Rosenson, MDb a Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich; bMount Sinai Heart, Mount Sinai School of Medicine, New York, NY.
ABSTRACT Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non-HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterollowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin ⫹ fibrate should be considered second-line therapy until the efficacy and safety are established. © 2010 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2010) 123, 892-898 KEYWORDS: Atherogenic lipid phenotype; Coronary disease prevention; Mixed hyperlipidemia
Coronary heart disease prevention guidelines advocate targeting non-high density lipoprotein (HDL) cholesterol in patients with elevated triglycerides.1 The rationale is based on the incremental risk associated with mixed hyperlipidemia and the atherogenic lipoprotein (or lipid) phenotype, a common high-risk lipid profile defined as the triad of low HDL cholesterol, high triglycerides, and increase in small lipoprotein particles.2 Although triglycerides are broadly associated with cardiovascular risk, the atherogenicity of
Funding: Cardiovascular Division, Preventive Cardiology Fund. Conflict of interest: M. Rubenfire, none; R.D. Brook, none; R.S. Rosenson is a consultant to LipoScience, Inc., and Roche. He receives honoraria from Abbot Labs, and Roche. He reports stock ownership in LipoScience, Inc. Authorship: All authors had access to the data and played a role in writing this manuscript. Reprint requests should be addressed to Melvyn Rubenfire, MD, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106. E-mail address: [email protected]
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2010.03.024
triglyceride-rich particles varies considerably.2 Because non-HDL cholesterol represents the total amount of cholesterol in the potentially atherogenic lipoproteins, it is not surprising that it is a superior risk predictor to low-density lipoprotein (LDL) cholesterol and remains a predictor of cardiovascular outcomes on drug treatment.3,4 The ability to reduce cardiovascular risk in patients with mixed hyperlipidemia and the atherogenic lipid phenotype is thus best assessed by the reduction in non-HDL cholesterol or apolipoprotein B, the protein on the surface of non-HDL particles.4
BENEFITS ASSOCIATED WITH INTENSE LOWERING OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL AND RESIDUAL RISK Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) reduce cardiovascular events and cardiovascular and total mortality independently of baseline LDL cholesterol.5,6 The approximate 25% reduction in cardio-
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vascular events attributable to statins in most studies is dose TREATING MIXED HYPERLIPIDEMIA AND THE dependent and highly correlated with the reduction of LDL ATHEROGENIC LIPID PHENOTYPE cholesterol.5-7 Despite the relative risk reduction, there reLifestyle Changes mains a 14% 5-year risk of a cardiovascular event in those receiving statins compared with 18% in those receiving The most important and cost-effective interventions for placebo,8 which prompts considmixed hyperlipidemia and the eration for targeting other lipids atherogenic lipid phenotype are an and lipoproteins with combination appropriate diet (Mediterranean CLINICAL SIGNIFICANCE therapies. diet), targeted weight loss, exerBoth direct and indirect evicise, and smoking cessation.16-19 ● Non-HDL cholesterol and apolipoprotein dence show that targeting lipid Each of these lifestyle changes is B are markers of risk. analytes other than LDL cholesassociated with a reduction in car● The high residual risk of coronary events terol may be of additional value. diovascular events. Consideration on statins suggests a role for treating Statin benefits are of a similar orshould be given to individual and non-HDL cholesterol. der of magnitude in diabetic and group interaction with nutritionnondiabetic persons; however, diists, behaviorists, and lifestyle ● Elevated triglycerides and non-HDL choabetic subjects receiving statins coaches to facilitate behavioral lesterol can be lowered with omega-3 have a 30% increase in the cardiochange. fatty acids, niacin, and fibrates. vascular event rate compared with nondiabetic subjects.8,9 To some Intensifying Statin ● Present evidence supports the use of degree, the incremental risk in distatins and niacin as the preferred comTherapy abetes is attributable to the atherobination in patients with mixed There is considerable evidence genic lipid phenotype. The latter that intensification of statin therhyperlipidemia. can be further characterized by elapy should precede combination evated triglycerides, low levels of therapy for patients with increased HDL cholesterol and apolipoprorisk associated with the non-HDL tein A-1, increased apolipoprotein B and very-low-density cholesterol level and mixed hyperlipidemia (type IIb phelipoprotein remnant particles, and predominantly small notype or LDL cholesterol and triglycerides ⬎ 75th percenLDL particles.10 Elevated triglycerides and a low HDL chotile for age and gender). The magnitude of decrease in LDL lesterol remain a predictor of cardiovascular events in patients cholesterol and statin dose each correlate with the benetreated with intense statin dosing and very low levels of LDL fit.7,8,20 High statin dosing is effective in persons with met11,12 Epidemiologic, coronary angiographic, and cholesterol. abolic syndrome and normal levels of LDL cholesterol, some clinical trial evidence support a conclusion that tarmost of whom have the atherogenic lipid phenotype.6,21 The geting low HDL cholesterol and apolipoprotein A-1, nonbenefit seen in persons with coronary heart disease and HDL cholesterol, increased triglycerides (very-low-density “healthy men and women” may be partially due to the dose-response anti-inflammatory effect.6,21 Also, there is a lipoprotein remnants), and estimated levels of small LDL 1:1 relationship between percent non-HDL cholesterol lowparticles would further reduce cardiovascular events and 2,10-14 ering and percent reduction in cardiovascular events using Further, that a significant cardiovascular mortality. monotherapy with lipid-modifying drugs,3 and the greatest number of persons with a triglyceride level greater than 200 degree of non-HDL cholesterol lowering occurs with highmg/dL fail to reach National Cholesterol Education Prodose statins even among patients with high triglyceride gram goals also supports a strategy of combination lipid15 levels (ⱖ300 to ⬍ 800 mg/dL).22 lowering medication therapies. The choices for therapies to supplement statins for tarStatin ⴙ Niacin for Low High-Density geting the atherogenic lipid phenotype and non-HDL cholesterol currently include niacin, fibrates, and omega-3 fatty Lipoprotein Cholesterol and the Atherogenic acids. We present the argument that after therapeutic lifeLipid Phenotype style changes, the first priority should be the maximally Monotherapy with nicotinic acid (niacin) was proven effectolerated effective dose of a statin. Evidence supports the tive for reducing cardiovascular events (29% less re-infarcaddition of niacin as the second agent. In some situations, tion) in the Coronary Drug Project approximately 35 years high-dose omega-3 fatty acid therapy could be the first ago,23 a magnitude comparable to statins. Ten years after agent added to statins (and possibly part of triple therapy). study completion, there was a lower total mortality in the Although fibrate monotherapy alone or in combination with niacin group than in those assigned to placebo.24 Further, non-statin LDL cholesterol-lowering agents can be effective the reduction in long-term mortality attributable to niacin in mixed hyperlipidemia when statins are not tolerated, the was comparable in those without and with metabolic syncombination of statin ⫹ fibrate should be considered secdrome, which is characterized by mixed hyperlipidemia.25 The early and long-term benefits are likely related to the ond-line therapy.
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known effects on lipoprotein and other atherothrombotic factors, including on-treatment increase in HDL cholesterol and apolipoprotein A-1; decrease in thrombosis; reduction in lipoprotein (a); and possibly reverse cholesterol transport with plaque stabilization, plaque regression, and reduction in new plaque formation.26 The use of niacin has been limited by an annoying flush and concern for toxicities. Clinical use and compliance improved with the development of safe nocturnal extendedrelease niacin27 and a polygel formulation that have less flushing. Niacin has minimal effect on glycemic control and minimal hepatotoxicity when dosed at 2000 mg or less.28,29 Clinical trials have demonstrated the safety and efficacy of statin ⫹ niacin in mixed lipid disorders with a low HDL cholesterol. Compared with simvastatin alone, at 24 weeks 2000 mg extended-release niacin ⫹ 40 mg simvastatin reduced triglycerides by 31.8% and increased HDL cholesterol by 21.9% (P ⬍ .001 for each).30 The combination of niacin with other lipid-lowering drugs has been shown to reduce progression and promote regression of coronary and carotid atherosclerosis and improve clinical outcomes.14,31,32 The most telling is the recent report of Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 HDL and LDL Treatment Strategies, which was designed to compare the effects of 2 combination therapies: niacin ⫹ statin or ezetimibe ⫹ statin on carotid intima–media thickness over a 14-month period.32 Eligible patients had coronary disease or were high risk, and had a baseline LDL cholesterol less than 100 mg/dL and an HDL cholesterol less than 50 mg/dL for men and less than 55 mg/dL for women. Niacin ⫹ statin was associated with a greater reduction in carotid intima–media thickness and a reduction in cardiovascular events when compared with ezetimibe ⫹ statin (1% vs 5%, P ⫽ .04).32 Two large clinical outcome trials designed to assess the benefit of niacin in combination with statin therapy on cardiovascular events are scheduled to be completed by 201133 and 2013.34 Until the results are known, the available safety and efficacy data suggest niacin ⫹ statin is an appropriate choice for patients with a low HDL cholesterol and coronary heart disease or at high risk with or without the atherogenic lipid phenotype. In those with mixed hyperlipidemia or persistent elevation of non-HDL cholesterol on statin ⫹ niacin, consideration can be given to dose titration of omega-3 fatty acids from 1 to 4 g.
Statin ⴙ Omega-3 Fatty Acids The safest treatment option after optimizing statin therapy in patients with mixed hyperlipidemia is the combination statin ⫹ omega-3 fatty acids. In addition to decreasing triglycerides, fish consumption and dietary marine oil have been shown to reduce cardiovascular events and coronary disease mortality.35-38 Putative mechanisms for omega-3 fatty acids reducing the risk for cardiovascular events include a decrease in triglycerides and very-low-density lipoprotein remnants, antiarrhythmic, antiplatelet, and antiinflammatory effects.39,40 The combination of statins with
moderate to high-dose (4000 mg) omega-3 fatty acids is safe and effective for lowering LDL cholesterol and triglycerides but has minimal effect on HDL cholesterol.41 Triglycerides decrease by approximately 8% for every gram of omega-3 fatty acids, but the dose response is highly variable and dependent on triglyceride level and other lipidlowering drugs. If triglycerides and non-HDL cholesterol remain above goal, high doses (4000 mg of eicosapentaenoic acid ⫹ docosahexaenoic acid) can be effective. However, in persons with a low HDL cholesterol and decrease in apolipoprotein A-1 or the atherogenic lipid phenotype, other strategies such as niacin would be preferable.
Fibrate Monotherapy and Combination Therapy Fibrates are a class of lipid-lowering drugs used primarily for hypertriglyceridemia, but other lipid-modulating actions and anti-inflammatory and anti-thrombotic effects suggest a role for reducing cardiovascular events.42 In a pooled metaanalysis of placebo-controlled fibrate trials, the lipid effects included a reduction in total cholesterol (⬃8%) and triglycerides (⬃30%), and an increase in HDL cholesterol (⬃9%).43 A modest effect on LDL cholesterol (mean decrease ⬃9%) ranges from an increase of 10% in mixed hyperlipidemia and hypertriglyceridemia to a decrease of up to 20% in pure hypercholesterolemia. The adverse effect of fibrates include a less than 1% increased risk for myopathy ranging from myalgias to rhabdomyolysis. Higher risk for fibrate myopathy includes the combination with statins; diabetic patients; elderly patients; patients with hypothyroidism, renal, and hepatic dysfunction; and patients who have had recent surgery or trauma.44 The combination of lipid and non-lipid effects makes fibrates attractive for the atherogenic lipid phenotype, but use should be based on trial evidence. The evidence of a clinical benefit from fibrate monotherapy is inconsistent. Of the fibrates that are approved by the US Food and Drug Administration (gemfibrozil, fenofibrate, fenofibric acid), only gemfibrozil has been shown to reduce cardiovascular events in a placebo-controlled trial. In the Helsinki Heart Study, compared with placebo, gemfibrozil 600 mg twice daily reduced cardiovascular events by 34% in middle-aged dyslipidemic men (non-HDL cholesterol ⬎ 200 mg/dL) without known coronary heart disease, but the benefit at 5 years was limited to those with mixed hyperlipidemia and increased triglycerides and low HDL cholesterol.45 The Department of Veterans Affairs High-density Lipoprotein Intervention Trial study was conducted in men with a low HDL cholesterol and peripheral vascular disease.46 At a median follow-up 5.1 years, gemfibrozil resulted in a 22% reduction in nonfatal myocardial infarction and coronary heart disease death. The benefit was strongly correlated with on-treatment HDL cholesterol but not triglycerides or LDL cholesterol. Coronary heart disease events were reduced by 11% with gemfibrozil for every 5
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mg/dL increase in HDL cholesterol (P ⫽ .02). The reduction in cardiovascular events could not be explained solely on the basis of change in HDL cholesterol.47 Diabetic persons treated with gemfibrozil had a 41% reduction in coronary heart disease deaths and a 41% reduction in strokes, and nondiabetic persons with higher insulin levels had greater benefit. The magnitude of benefit of gemfibrozil in these 2 trials in patients with low HDL cholesterol and increased triglycerides is similar to that expected from standard-dose statins in patients with moderate elevation of LDL cholesterol.8 The efficacy and safety data from Department of Veterans Affairs High-density Lipoprotein Intervention Trial and the Helsinki Heart Study would suggest gemfibrozil is an appropriate monotherapy for statin-intolerant patients with vascular disease or high risk based on the atherogenic lipid phenotype. Although there are no long-term safety data available, a combination of gemfibrozil ⫹ ezetimibe or ⫹ omega-3 fatty acids could be considered in statin-intolerant diabetic and nondiabetic persons with mixed hyperlipidemia and the atherogenic lipid phenotype.48 Monotherapy with fenofibrate failed to reach its primary end point of reducing coronary disease mortality in diabetic patients in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, but did decrease microvascular complications.49 However, in a post hoc analysis there was a 27% reduction in cardiovascular events in participants in the FIELD trial with hypertriglyceridemia and low HDL cholesterol.50 In view of the results of pharmacokinetic studies and effects on lipids and peak LDL particle size, the combination of fenofibrate ⫹ ezetimibe with or without omega-3 fatty acids could be considered in statin-intolerant patients with diabetes or the metabolic syndrome, mixed hyperlipidemia, and atherogenic dyslipidemia.51
Statin ⴙ Fibrate Combination Therapy Should Be a Secondary Option Despite the robust effect of potent statin and fibrate combinations on atherogenic lipids and lipoproteins and the reasonable degree of safety in small trials,52 both guideline and drug information sources discourage combination therapy because of a concern for serious muscle toxicity and the lack of efficacy in a large outcome trial. Statins are well tolerated, but it is estimated that in clinical practice up to 10% to 15% of patients receiving statins have muscular symptoms.53 In a managed care setting, compared with a control cohort, the relative risk of clinical myositis (symptoms and elevated creatine kinase) from statin and statin ⫹ fibrate was 2.98 and 9.1, respectively.54 Fenofibric acid, which was designed as a safe alternative to fenofibrate, shows great promise for the atherogenic lipid phenotype. The recent Food and Drug Administration approval was based on demonstration of safety and efficacy on lipid parameters in 2700 patients with mixed dyslipidemia.55 Feno-
895 fibric acid (135 mg) and moderate-dose statins resulted in sustained improvements in triglycerides, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, very-low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein.55 The safety of combination therapy was excellent in this large cohort of patients, but clinical experience may differ in drug-naïve patients, the elderly, and those with impaired renal function and hypothyroidism who were excluded from the studies. The role of statin ⫹ fibrate combination therapy for reducing cardiovascular events in diabetes was recently reported from the Action to Control Cardiovascular Risk in Diabetes trial.56 The cardioprotective efficacy of Table 1
Considerations before Using Combination Therapies
1. Increased myalgia, myositis, and rhabdomyolysis and the additional risk associated with other drug interactions (eg, amiodarone), hypothyroid, and stress using statin ⫹ fibrate. Although the risk is reduced with newer formulations, fibrates still pose a myopathy risk similar to that of statin monotherapy, which exceeds that of niacin or omega-3 fatty acids (alone or combined with a statin). 2. Difficulty in discerning which drug is responsible for side effects and hepatic toxicity. 3. Increased costs associated with assessing adverse events, particularly determining which drug is causing myalgias and toxicity, and subsequent treatment and dosing. 4. Patient incorrectly attributes problem to statins and may be unwilling to try statin monotherapy after an adverse event on combination statin ⫹ fibrate. 5. Risk of nocebo effect when patient is aware of potential drug interactions. 6. Need for increased vigilance, cost, and inconvenience of monitoring for toxicity with which patients may be noncompliant. 7. Physicians may be unaware of risks of combination therapy. 8. Increased warfarin bioavailability and international normalized ratio, and need for more careful monitoring with fibrates.* 9. No proven outcome data in combination studies. 10. Potential for (typically unrecognized) “disappearing” HDL syndrome with fibrates, particularly in combination with thiazolidinediones, resulting in severe paradoxical decreases in HDL cholesterol and apolipoprotein A-1. 11. Risks of liver enzyme elevations with fibrates (⬎3-fold alanine aminotransferase/aspartate aminotransferase) typically greater than statin combinations including prescription extended-release niacin (0%-⬍1%) or omega-3 fatty acids.* 12. Potential for reflex increases in LDL cholesterol (14.5%45%) on fibrates in patients with initially moderate-tosevere elevations in triglycerides (⬎350 mg/dL) that may mitigate the benefit of the statin.* HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein. http://www.trilipix.com/trilipix/patient/prescribing-information.jsp http://rxabbott.com/pdf/simcor_pi.pdf http://us.gsk.com/products/assets/us_lovaza.pdf http://www.rxabbott.com/pdf/niaspan.pdf *See full prescribing details.
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simvastatin ⫹ fenofibrate was compared with simvastatin alone. Simvastatin was given open labeled at baseline, and fenofibrate 160 mg or placebo was begun 4 weeks later. The average daily dose of simvastatin on trial was approximately 22 mg. Over a mean follow-up of 4.7 years, the combination of fenofibrate and simvastatin did not reduce the rate of any of the major cardiovascular events. Of serious concern was a significant difference in prespecified subgroups by gender; men improved and women were possibly harmed. Although the study was not powered to assess efficacy on the basis of baseline lipids, there was a borderline significant (P ⫽ 0.06) reduction in major cardiovascular events in persons with a triglyceride level of 204 mg/dL or greater and an HDL cholesterol level of 34 mg/dL or less, the latter typical of the atherogenic lipid phenotype. The interpretation and implications for clinical practice of trials evaluating drugs with considerable commercial value, such as Action to Control Cardiovascular Risk in
Diabetes,56 AIM-HIGH (Niacin Plus Statin to Prevent Vascular Events),50 and HPS2-THRIVE aims to find out whether by combining niacin (a drug that has been available for 50 years) with a new drug laropiprant (which reduces the side-effects of niacin) is beneficial,51 should be performed by non-involved expert observers.57
Potential Problems with Combination Therapies Table 1 summarizes the potential problems associated with combination therapy for treating mixed hyperlipidemia and the atherogenic lipid phenotype. The complexity and cost of assessing muscle and neuropathic symptoms should be part of the selection of best lipid treatment strategies. Noncompliance with statins is a significant problem that affects outcome,58 which would be magnified by combining lipid therapies that share potential side effects and toxicities.
Figure 1 A suggested algorithm for the atherogenic lipid profile and mixed hyperlipidemia. ALP ⫽ atherogenic lipid profile; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; apoB ⫽ apoliprotein B; EPA ⫽ eicosapentaenoic acid; DHA ⫽ docosahexaenoic acid; TG ⫽ triglyceride; CV ⫽ cardiovascular; LFT ⫽ liver function test; TLC ⫽ Therapeutic Lifestyle Changes; BAS ⫽ Bile Acid Sequestrant.
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Serious muscle toxicity is rare with both statins and fibrates, and the combination of statin ⫹ fenofibric acid seems safe. Because a significant percentage of patients with mixed hyperlipidemia and the atherogenic lipid phenotype (eg, those with diabetes, metabolic syndrome, obesity, and chronic kidney disease) have musculoskeletal symptoms, it is difficult for both patients and caregivers to discern the source. For example, 15% of the diabetic subjects in the FIELD trial receiving fenofibrate or placebo had musculoskeletal symptoms.49
SUGGESTED THERAPEUTIC APPROACH In consideration of the existing evidence, the approach to the atherogenic lipid phenotype and mixed hyperlipidemia in patients with and without atherosclerotic disease should begin with targeting the non-HDL cholesterol and apolipoprotein B with therapeutic lifestyle changes. Figure 1 describes a 5-step treatment algorithm that begins with the highest tolerated dose of a potent triglyceride-lowering statin with the target of non-HDL cholesterol or apolipoprotein B dependent on the presence of atherosclerotic disease per the guidelines.1-3 In patients with triglycerides greater than 150 mg/dL, non-HDL cholesterol greater than 130 mg/dL, and HDL cholesterol lower than 40 mg/dL, and all patients with known cardiovascular disease (secondary prevention), omega-3 fatty acid therapy should be considered. Higher doses can be used as required if appropriate (Step 2). If non-HDL cholesterol or apolipoprotein B remains above goal, and particularly if the HDL cholesterol or apolipoprotein A-1 is low, niacin should be titrated to the maximally tolerated dosage up to 2000 mg/d (Step 3). If not tolerated, a statin ⫹ fibrate (fenofibrate or fenofibric acid) can be an alternative (Step 4). In some circumstances with severe mixed hyperlipidemia (triglycerides remain elevated), and with appropriate considerations given to the risk/benefit ratio, triple or quadruple therapy may be warranted. Bile acid sequestrant therapy is not recommended if triglycerides are greater than 300 mg/dL (particularly in dysbetalipoproteinemia); however, it may be used (with or without ezetimibe) if non-HDL cholesterol or apolipoprotein B remains above goal once triglycerides are controlled (Step 5). If after statin ⫹ omega-3 fatty acids ⫹ niacin, non-HDL cholesterol is elevated and triglycerides are at or close to goal, consideration can be given to ezetimibe as the fourth agent. In statin-intolerant patients, consider niacin ⫹ omega-3 fatty acids (Step 3) followed by ezetimibe, a bile acid sequestrant, and a fibrate. In rare situations when triglycerides are greater than 1000 mg/dL, a fibrate should be used first (Step 4) with omega-3 fatty acids if necessary. A statin typically will also be required to control non-HDL cholesterol, either added later or as part of initial statin ⫹ fibrate combination therapy.
CONCLUSIONS We recognize that ongoing clinical outcome trials and further studies related to the safety and efficacy of lipid-
897 lowering combinations may lead to an evolution in this suggested approach. Given the substantial number of patients who require combination treatment to reach American Heart Association/American College of Cardiology and National Cholesterol Education Program goals and the prevalence of mixed lipid disorders and the atherogenic lipid phenotype, we welcome this much needed outcome data.
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18. Roussell MA, Kris-Etherton. Effects of lifestyle intervention on high density lipoprotein cholesterol levels. J Clin Lipidol. 2007;1:65-73. 19. Johnson JL, Slentz CA, Houmard JA, et al. Exercise training amount and intensity on metabolic syndrome (from Studies of a Targeted Risk Reduction Intervention through Defined Exercise. Am J Cardiol. 2007; 100:1759-1766. 20. LaRosa JC, Grundy SM, Waters DD, et al. for the Treating to Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1-11. 21. Deedwania P, Barter P, Carmena R, et al. for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets Study. Lancet. 2006;368:919-928. 22. Hunninghake DB, Stein EA, Bays HE, et al. Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in patients with hypertriglyceridemia. Coron Artery Dis. 2004;15:115-123. 23. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381. 24. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255. 25. Canner PL, Furberg CD, McGovern ME. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2006;97: 477-479. 26. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis. 2003;171:87-96. 27. Rubenfire M, for the IMPACT Study Group. Safety and compliance with once-daily niacin extended-release/lovastatin as Initial Therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) Study. Am J Cardiol. 2004;94:306-311. 28. Goldberg A, Alagona P Jr, Capuzzi DM, et al. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol. 2000;85:1100-1105. 29. Grundy SM, Vega GL, McGovern ME, et al. for the Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once daily niacin for the treatment of dyslipidemia associated with type 2 diabetes. Arch Intern Med. 2002;162:1568-1576. 30. Ballantyne CM, Davidson MH, McKenney J, et al. Comparison of the efficacy and safety of combination tablet of niacin extended-release and simvastatin with simvastatin monotherapy: the SEACOAST II (high-dose) study. J Clin Lipidol. 2008;2:79-90. 31. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298. 32. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009; 361:1-10. 33. Niacin Plus Statin to Prevent Vascular Events AIM-HIGH. Available at: http://clinicaltrials.gov/ct/show/NCT00120289. Accessed August 4, 2010. 34. Treatment of HDL to reduce the incidence of vascular events HPS2THRIVE. Available at: http://clinicaltrials.gov/ct/show/NCT00461630. Accessed July 19, 2010. 35. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction; diet and reinfarction trial (DART). Lancet. 1989;334:757-761. 36. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447-455. 37. GISSI-HF investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:9645:12231230. 38. Saito Y, Mitsuhiro Y, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200:135-140.
39. Balk EM, Lichtenstein AH, Chung M, et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease: a systematic review. Atherosclerosis. 2006;189:19-30. 40. Davidson MH. Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids. Am J Cardiol. 2006;98(suppl):27i-33i. 41. Davidson MH, Maki KC, Bays H, et al. Effects of prescription omega3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A2 mass in statin-treated subjects with hypertriglyceridemia. J Clin Lipidol. 2009;3:332-340. 42. Rosenson RS. Fenofibrate: treatment of hyperlipidemia and beyond. Exp Rev Cardiovasc Ther. 2008;6:1319-1330. 43. Saha SA, Kizhakepunner LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease-a pooled metaanalysis of long-term randomized placebo-controlled clinical trials. Am Heart J. 2007;154:943-953. 44. Usman M, Peter R. Fibrate therapy: safety considerations. Curr Opin Lipidol. 2007;18:702-704. 45. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: a primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia; safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-1245. 46. Robins SJ, Collins D, Witte JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. 2001;285:1585-1591. 47. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention (VA-HIT). Arch Intern Med. 2002;162:2597-2604. 48. Reyderman L, Kosoglou T, Statkevich P, et al. Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil. Int J Clin Pharm Ther. 2004;42:512-518. 49. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised control trial. Lancet. 2005: 366;1849-1861. 50. NHMRC Clinical Trials Centre. Fenofibrate reduces the risk of amputations in patients with type 2 diabetes. Available at: http://www.fieldstudy.info/ investigators/CTC_PR_2008.asp. Accessed August 15, 2010. 51. Tribble DL, Farnier M, Macdonell G, et al. Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia. Metab Clin Exp. 2008;57:796-801. 52. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol. 2005;45:1649-1653. 53. Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr Opin Lipidol. 2007;18:401-408. 54. McClure DL, Valuck RJ, Glanz M, et al. Statin and statin—fibrate use was significantly associated with increased myositis risk in a managed care population. J Clin Epidemiol. 2007;60:812-818. 55. Bays HE, Jones PH, Mohiuddin SM, et al. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidol. 2008; 2:426-435. 56. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574. 57. Psaty BM, Furberg CD, Ray WA, Weiss NS. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. JAMA. 2004;292:2622-2631. 58. Ho PM, Magid DJ, Shetterly SM, et al. Medication nonadherence is associated with a broad range of adverse outcomes in patients with coronary artery disease. Am Heart J. 2008;155:772-779.
Treating Mixed Hyperlipidemia and the Atherogenic Lipid Phenotype for Prevention of Cardiovascular Events Melvyn Rubenfire, MD,a Robert D. Brook, MD,a Robert S. Rosenson, MDb a Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich; bMount Sinai Heart, Mount Sinai School of Medicine, New York, NY.
ABSTRACT Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non-HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterollowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin ⫹ fibrate should be considered second-line therapy until the efficacy and safety are established. © 2010 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2010) 123, 892-898 KEYWORDS: Atherogenic lipid phenotype; Coronary disease prevention; Mixed hyperlipidemia
Coronary heart disease prevention guidelines advocate targeting non-high density lipoprotein (HDL) cholesterol in patients with elevated triglycerides.1 The rationale is based on the incremental risk associated with mixed hyperlipidemia and the atherogenic lipoprotein (or lipid) phenotype, a common high-risk lipid profile defined as the triad of low HDL cholesterol, high triglycerides, and increase in small lipoprotein particles.2 Although triglycerides are broadly associated with cardiovascular risk, the atherogenicity of
Funding: Cardiovascular Division, Preventive Cardiology Fund. Conflict of interest: M. Rubenfire, none; R.D. Brook, none; R.S. Rosenson is a consultant to LipoScience, Inc., and Roche. He receives honoraria from Abbot Labs, and Roche. He reports stock ownership in LipoScience, Inc. Authorship: All authors had access to the data and played a role in writing this manuscript. Reprint requests should be addressed to Melvyn Rubenfire, MD, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106. E-mail address: [email protected]
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2010.03.024
triglyceride-rich particles varies considerably.2 Because non-HDL cholesterol represents the total amount of cholesterol in the potentially atherogenic lipoproteins, it is not surprising that it is a superior risk predictor to low-density lipoprotein (LDL) cholesterol and remains a predictor of cardiovascular outcomes on drug treatment.3,4 The ability to reduce cardiovascular risk in patients with mixed hyperlipidemia and the atherogenic lipid phenotype is thus best assessed by the reduction in non-HDL cholesterol or apolipoprotein B, the protein on the surface of non-HDL particles.4
BENEFITS ASSOCIATED WITH INTENSE LOWERING OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL AND RESIDUAL RISK Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) reduce cardiovascular events and cardiovascular and total mortality independently of baseline LDL cholesterol.5,6 The approximate 25% reduction in cardio-
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vascular events attributable to statins in most studies is dose TREATING MIXED HYPERLIPIDEMIA AND THE dependent and highly correlated with the reduction of LDL ATHEROGENIC LIPID PHENOTYPE cholesterol.5-7 Despite the relative risk reduction, there reLifestyle Changes mains a 14% 5-year risk of a cardiovascular event in those receiving statins compared with 18% in those receiving The most important and cost-effective interventions for placebo,8 which prompts considmixed hyperlipidemia and the eration for targeting other lipids atherogenic lipid phenotype are an and lipoproteins with combination appropriate diet (Mediterranean CLINICAL SIGNIFICANCE therapies. diet), targeted weight loss, exerBoth direct and indirect evicise, and smoking cessation.16-19 ● Non-HDL cholesterol and apolipoprotein dence show that targeting lipid Each of these lifestyle changes is B are markers of risk. analytes other than LDL cholesassociated with a reduction in car● The high residual risk of coronary events terol may be of additional value. diovascular events. Consideration on statins suggests a role for treating Statin benefits are of a similar orshould be given to individual and non-HDL cholesterol. der of magnitude in diabetic and group interaction with nutritionnondiabetic persons; however, diists, behaviorists, and lifestyle ● Elevated triglycerides and non-HDL choabetic subjects receiving statins coaches to facilitate behavioral lesterol can be lowered with omega-3 have a 30% increase in the cardiochange. fatty acids, niacin, and fibrates. vascular event rate compared with nondiabetic subjects.8,9 To some Intensifying Statin ● Present evidence supports the use of degree, the incremental risk in distatins and niacin as the preferred comTherapy abetes is attributable to the atherobination in patients with mixed There is considerable evidence genic lipid phenotype. The latter that intensification of statin therhyperlipidemia. can be further characterized by elapy should precede combination evated triglycerides, low levels of therapy for patients with increased HDL cholesterol and apolipoprorisk associated with the non-HDL tein A-1, increased apolipoprotein B and very-low-density cholesterol level and mixed hyperlipidemia (type IIb phelipoprotein remnant particles, and predominantly small notype or LDL cholesterol and triglycerides ⬎ 75th percenLDL particles.10 Elevated triglycerides and a low HDL chotile for age and gender). The magnitude of decrease in LDL lesterol remain a predictor of cardiovascular events in patients cholesterol and statin dose each correlate with the benetreated with intense statin dosing and very low levels of LDL fit.7,8,20 High statin dosing is effective in persons with met11,12 Epidemiologic, coronary angiographic, and cholesterol. abolic syndrome and normal levels of LDL cholesterol, some clinical trial evidence support a conclusion that tarmost of whom have the atherogenic lipid phenotype.6,21 The geting low HDL cholesterol and apolipoprotein A-1, nonbenefit seen in persons with coronary heart disease and HDL cholesterol, increased triglycerides (very-low-density “healthy men and women” may be partially due to the dose-response anti-inflammatory effect.6,21 Also, there is a lipoprotein remnants), and estimated levels of small LDL 1:1 relationship between percent non-HDL cholesterol lowparticles would further reduce cardiovascular events and 2,10-14 ering and percent reduction in cardiovascular events using Further, that a significant cardiovascular mortality. monotherapy with lipid-modifying drugs,3 and the greatest number of persons with a triglyceride level greater than 200 degree of non-HDL cholesterol lowering occurs with highmg/dL fail to reach National Cholesterol Education Prodose statins even among patients with high triglyceride gram goals also supports a strategy of combination lipid15 levels (ⱖ300 to ⬍ 800 mg/dL).22 lowering medication therapies. The choices for therapies to supplement statins for tarStatin ⴙ Niacin for Low High-Density geting the atherogenic lipid phenotype and non-HDL cholesterol currently include niacin, fibrates, and omega-3 fatty Lipoprotein Cholesterol and the Atherogenic acids. We present the argument that after therapeutic lifeLipid Phenotype style changes, the first priority should be the maximally Monotherapy with nicotinic acid (niacin) was proven effectolerated effective dose of a statin. Evidence supports the tive for reducing cardiovascular events (29% less re-infarcaddition of niacin as the second agent. In some situations, tion) in the Coronary Drug Project approximately 35 years high-dose omega-3 fatty acid therapy could be the first ago,23 a magnitude comparable to statins. Ten years after agent added to statins (and possibly part of triple therapy). study completion, there was a lower total mortality in the Although fibrate monotherapy alone or in combination with niacin group than in those assigned to placebo.24 Further, non-statin LDL cholesterol-lowering agents can be effective the reduction in long-term mortality attributable to niacin in mixed hyperlipidemia when statins are not tolerated, the was comparable in those without and with metabolic syncombination of statin ⫹ fibrate should be considered secdrome, which is characterized by mixed hyperlipidemia.25 The early and long-term benefits are likely related to the ond-line therapy.
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known effects on lipoprotein and other atherothrombotic factors, including on-treatment increase in HDL cholesterol and apolipoprotein A-1; decrease in thrombosis; reduction in lipoprotein (a); and possibly reverse cholesterol transport with plaque stabilization, plaque regression, and reduction in new plaque formation.26 The use of niacin has been limited by an annoying flush and concern for toxicities. Clinical use and compliance improved with the development of safe nocturnal extendedrelease niacin27 and a polygel formulation that have less flushing. Niacin has minimal effect on glycemic control and minimal hepatotoxicity when dosed at 2000 mg or less.28,29 Clinical trials have demonstrated the safety and efficacy of statin ⫹ niacin in mixed lipid disorders with a low HDL cholesterol. Compared with simvastatin alone, at 24 weeks 2000 mg extended-release niacin ⫹ 40 mg simvastatin reduced triglycerides by 31.8% and increased HDL cholesterol by 21.9% (P ⬍ .001 for each).30 The combination of niacin with other lipid-lowering drugs has been shown to reduce progression and promote regression of coronary and carotid atherosclerosis and improve clinical outcomes.14,31,32 The most telling is the recent report of Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 HDL and LDL Treatment Strategies, which was designed to compare the effects of 2 combination therapies: niacin ⫹ statin or ezetimibe ⫹ statin on carotid intima–media thickness over a 14-month period.32 Eligible patients had coronary disease or were high risk, and had a baseline LDL cholesterol less than 100 mg/dL and an HDL cholesterol less than 50 mg/dL for men and less than 55 mg/dL for women. Niacin ⫹ statin was associated with a greater reduction in carotid intima–media thickness and a reduction in cardiovascular events when compared with ezetimibe ⫹ statin (1% vs 5%, P ⫽ .04).32 Two large clinical outcome trials designed to assess the benefit of niacin in combination with statin therapy on cardiovascular events are scheduled to be completed by 201133 and 2013.34 Until the results are known, the available safety and efficacy data suggest niacin ⫹ statin is an appropriate choice for patients with a low HDL cholesterol and coronary heart disease or at high risk with or without the atherogenic lipid phenotype. In those with mixed hyperlipidemia or persistent elevation of non-HDL cholesterol on statin ⫹ niacin, consideration can be given to dose titration of omega-3 fatty acids from 1 to 4 g.
Statin ⴙ Omega-3 Fatty Acids The safest treatment option after optimizing statin therapy in patients with mixed hyperlipidemia is the combination statin ⫹ omega-3 fatty acids. In addition to decreasing triglycerides, fish consumption and dietary marine oil have been shown to reduce cardiovascular events and coronary disease mortality.35-38 Putative mechanisms for omega-3 fatty acids reducing the risk for cardiovascular events include a decrease in triglycerides and very-low-density lipoprotein remnants, antiarrhythmic, antiplatelet, and antiinflammatory effects.39,40 The combination of statins with
moderate to high-dose (4000 mg) omega-3 fatty acids is safe and effective for lowering LDL cholesterol and triglycerides but has minimal effect on HDL cholesterol.41 Triglycerides decrease by approximately 8% for every gram of omega-3 fatty acids, but the dose response is highly variable and dependent on triglyceride level and other lipidlowering drugs. If triglycerides and non-HDL cholesterol remain above goal, high doses (4000 mg of eicosapentaenoic acid ⫹ docosahexaenoic acid) can be effective. However, in persons with a low HDL cholesterol and decrease in apolipoprotein A-1 or the atherogenic lipid phenotype, other strategies such as niacin would be preferable.
Fibrate Monotherapy and Combination Therapy Fibrates are a class of lipid-lowering drugs used primarily for hypertriglyceridemia, but other lipid-modulating actions and anti-inflammatory and anti-thrombotic effects suggest a role for reducing cardiovascular events.42 In a pooled metaanalysis of placebo-controlled fibrate trials, the lipid effects included a reduction in total cholesterol (⬃8%) and triglycerides (⬃30%), and an increase in HDL cholesterol (⬃9%).43 A modest effect on LDL cholesterol (mean decrease ⬃9%) ranges from an increase of 10% in mixed hyperlipidemia and hypertriglyceridemia to a decrease of up to 20% in pure hypercholesterolemia. The adverse effect of fibrates include a less than 1% increased risk for myopathy ranging from myalgias to rhabdomyolysis. Higher risk for fibrate myopathy includes the combination with statins; diabetic patients; elderly patients; patients with hypothyroidism, renal, and hepatic dysfunction; and patients who have had recent surgery or trauma.44 The combination of lipid and non-lipid effects makes fibrates attractive for the atherogenic lipid phenotype, but use should be based on trial evidence. The evidence of a clinical benefit from fibrate monotherapy is inconsistent. Of the fibrates that are approved by the US Food and Drug Administration (gemfibrozil, fenofibrate, fenofibric acid), only gemfibrozil has been shown to reduce cardiovascular events in a placebo-controlled trial. In the Helsinki Heart Study, compared with placebo, gemfibrozil 600 mg twice daily reduced cardiovascular events by 34% in middle-aged dyslipidemic men (non-HDL cholesterol ⬎ 200 mg/dL) without known coronary heart disease, but the benefit at 5 years was limited to those with mixed hyperlipidemia and increased triglycerides and low HDL cholesterol.45 The Department of Veterans Affairs High-density Lipoprotein Intervention Trial study was conducted in men with a low HDL cholesterol and peripheral vascular disease.46 At a median follow-up 5.1 years, gemfibrozil resulted in a 22% reduction in nonfatal myocardial infarction and coronary heart disease death. The benefit was strongly correlated with on-treatment HDL cholesterol but not triglycerides or LDL cholesterol. Coronary heart disease events were reduced by 11% with gemfibrozil for every 5
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mg/dL increase in HDL cholesterol (P ⫽ .02). The reduction in cardiovascular events could not be explained solely on the basis of change in HDL cholesterol.47 Diabetic persons treated with gemfibrozil had a 41% reduction in coronary heart disease deaths and a 41% reduction in strokes, and nondiabetic persons with higher insulin levels had greater benefit. The magnitude of benefit of gemfibrozil in these 2 trials in patients with low HDL cholesterol and increased triglycerides is similar to that expected from standard-dose statins in patients with moderate elevation of LDL cholesterol.8 The efficacy and safety data from Department of Veterans Affairs High-density Lipoprotein Intervention Trial and the Helsinki Heart Study would suggest gemfibrozil is an appropriate monotherapy for statin-intolerant patients with vascular disease or high risk based on the atherogenic lipid phenotype. Although there are no long-term safety data available, a combination of gemfibrozil ⫹ ezetimibe or ⫹ omega-3 fatty acids could be considered in statin-intolerant diabetic and nondiabetic persons with mixed hyperlipidemia and the atherogenic lipid phenotype.48 Monotherapy with fenofibrate failed to reach its primary end point of reducing coronary disease mortality in diabetic patients in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, but did decrease microvascular complications.49 However, in a post hoc analysis there was a 27% reduction in cardiovascular events in participants in the FIELD trial with hypertriglyceridemia and low HDL cholesterol.50 In view of the results of pharmacokinetic studies and effects on lipids and peak LDL particle size, the combination of fenofibrate ⫹ ezetimibe with or without omega-3 fatty acids could be considered in statin-intolerant patients with diabetes or the metabolic syndrome, mixed hyperlipidemia, and atherogenic dyslipidemia.51
Statin ⴙ Fibrate Combination Therapy Should Be a Secondary Option Despite the robust effect of potent statin and fibrate combinations on atherogenic lipids and lipoproteins and the reasonable degree of safety in small trials,52 both guideline and drug information sources discourage combination therapy because of a concern for serious muscle toxicity and the lack of efficacy in a large outcome trial. Statins are well tolerated, but it is estimated that in clinical practice up to 10% to 15% of patients receiving statins have muscular symptoms.53 In a managed care setting, compared with a control cohort, the relative risk of clinical myositis (symptoms and elevated creatine kinase) from statin and statin ⫹ fibrate was 2.98 and 9.1, respectively.54 Fenofibric acid, which was designed as a safe alternative to fenofibrate, shows great promise for the atherogenic lipid phenotype. The recent Food and Drug Administration approval was based on demonstration of safety and efficacy on lipid parameters in 2700 patients with mixed dyslipidemia.55 Feno-
895 fibric acid (135 mg) and moderate-dose statins resulted in sustained improvements in triglycerides, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, very-low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein.55 The safety of combination therapy was excellent in this large cohort of patients, but clinical experience may differ in drug-naïve patients, the elderly, and those with impaired renal function and hypothyroidism who were excluded from the studies. The role of statin ⫹ fibrate combination therapy for reducing cardiovascular events in diabetes was recently reported from the Action to Control Cardiovascular Risk in Diabetes trial.56 The cardioprotective efficacy of Table 1
Considerations before Using Combination Therapies
1. Increased myalgia, myositis, and rhabdomyolysis and the additional risk associated with other drug interactions (eg, amiodarone), hypothyroid, and stress using statin ⫹ fibrate. Although the risk is reduced with newer formulations, fibrates still pose a myopathy risk similar to that of statin monotherapy, which exceeds that of niacin or omega-3 fatty acids (alone or combined with a statin). 2. Difficulty in discerning which drug is responsible for side effects and hepatic toxicity. 3. Increased costs associated with assessing adverse events, particularly determining which drug is causing myalgias and toxicity, and subsequent treatment and dosing. 4. Patient incorrectly attributes problem to statins and may be unwilling to try statin monotherapy after an adverse event on combination statin ⫹ fibrate. 5. Risk of nocebo effect when patient is aware of potential drug interactions. 6. Need for increased vigilance, cost, and inconvenience of monitoring for toxicity with which patients may be noncompliant. 7. Physicians may be unaware of risks of combination therapy. 8. Increased warfarin bioavailability and international normalized ratio, and need for more careful monitoring with fibrates.* 9. No proven outcome data in combination studies. 10. Potential for (typically unrecognized) “disappearing” HDL syndrome with fibrates, particularly in combination with thiazolidinediones, resulting in severe paradoxical decreases in HDL cholesterol and apolipoprotein A-1. 11. Risks of liver enzyme elevations with fibrates (⬎3-fold alanine aminotransferase/aspartate aminotransferase) typically greater than statin combinations including prescription extended-release niacin (0%-⬍1%) or omega-3 fatty acids.* 12. Potential for reflex increases in LDL cholesterol (14.5%45%) on fibrates in patients with initially moderate-tosevere elevations in triglycerides (⬎350 mg/dL) that may mitigate the benefit of the statin.* HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein. http://www.trilipix.com/trilipix/patient/prescribing-information.jsp http://rxabbott.com/pdf/simcor_pi.pdf http://us.gsk.com/products/assets/us_lovaza.pdf http://www.rxabbott.com/pdf/niaspan.pdf *See full prescribing details.
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simvastatin ⫹ fenofibrate was compared with simvastatin alone. Simvastatin was given open labeled at baseline, and fenofibrate 160 mg or placebo was begun 4 weeks later. The average daily dose of simvastatin on trial was approximately 22 mg. Over a mean follow-up of 4.7 years, the combination of fenofibrate and simvastatin did not reduce the rate of any of the major cardiovascular events. Of serious concern was a significant difference in prespecified subgroups by gender; men improved and women were possibly harmed. Although the study was not powered to assess efficacy on the basis of baseline lipids, there was a borderline significant (P ⫽ 0.06) reduction in major cardiovascular events in persons with a triglyceride level of 204 mg/dL or greater and an HDL cholesterol level of 34 mg/dL or less, the latter typical of the atherogenic lipid phenotype. The interpretation and implications for clinical practice of trials evaluating drugs with considerable commercial value, such as Action to Control Cardiovascular Risk in
Diabetes,56 AIM-HIGH (Niacin Plus Statin to Prevent Vascular Events),50 and HPS2-THRIVE aims to find out whether by combining niacin (a drug that has been available for 50 years) with a new drug laropiprant (which reduces the side-effects of niacin) is beneficial,51 should be performed by non-involved expert observers.57
Potential Problems with Combination Therapies Table 1 summarizes the potential problems associated with combination therapy for treating mixed hyperlipidemia and the atherogenic lipid phenotype. The complexity and cost of assessing muscle and neuropathic symptoms should be part of the selection of best lipid treatment strategies. Noncompliance with statins is a significant problem that affects outcome,58 which would be magnified by combining lipid therapies that share potential side effects and toxicities.
Figure 1 A suggested algorithm for the atherogenic lipid profile and mixed hyperlipidemia. ALP ⫽ atherogenic lipid profile; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; apoB ⫽ apoliprotein B; EPA ⫽ eicosapentaenoic acid; DHA ⫽ docosahexaenoic acid; TG ⫽ triglyceride; CV ⫽ cardiovascular; LFT ⫽ liver function test; TLC ⫽ Therapeutic Lifestyle Changes; BAS ⫽ Bile Acid Sequestrant.
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Serious muscle toxicity is rare with both statins and fibrates, and the combination of statin ⫹ fenofibric acid seems safe. Because a significant percentage of patients with mixed hyperlipidemia and the atherogenic lipid phenotype (eg, those with diabetes, metabolic syndrome, obesity, and chronic kidney disease) have musculoskeletal symptoms, it is difficult for both patients and caregivers to discern the source. For example, 15% of the diabetic subjects in the FIELD trial receiving fenofibrate or placebo had musculoskeletal symptoms.49
SUGGESTED THERAPEUTIC APPROACH In consideration of the existing evidence, the approach to the atherogenic lipid phenotype and mixed hyperlipidemia in patients with and without atherosclerotic disease should begin with targeting the non-HDL cholesterol and apolipoprotein B with therapeutic lifestyle changes. Figure 1 describes a 5-step treatment algorithm that begins with the highest tolerated dose of a potent triglyceride-lowering statin with the target of non-HDL cholesterol or apolipoprotein B dependent on the presence of atherosclerotic disease per the guidelines.1-3 In patients with triglycerides greater than 150 mg/dL, non-HDL cholesterol greater than 130 mg/dL, and HDL cholesterol lower than 40 mg/dL, and all patients with known cardiovascular disease (secondary prevention), omega-3 fatty acid therapy should be considered. Higher doses can be used as required if appropriate (Step 2). If non-HDL cholesterol or apolipoprotein B remains above goal, and particularly if the HDL cholesterol or apolipoprotein A-1 is low, niacin should be titrated to the maximally tolerated dosage up to 2000 mg/d (Step 3). If not tolerated, a statin ⫹ fibrate (fenofibrate or fenofibric acid) can be an alternative (Step 4). In some circumstances with severe mixed hyperlipidemia (triglycerides remain elevated), and with appropriate considerations given to the risk/benefit ratio, triple or quadruple therapy may be warranted. Bile acid sequestrant therapy is not recommended if triglycerides are greater than 300 mg/dL (particularly in dysbetalipoproteinemia); however, it may be used (with or without ezetimibe) if non-HDL cholesterol or apolipoprotein B remains above goal once triglycerides are controlled (Step 5). If after statin ⫹ omega-3 fatty acids ⫹ niacin, non-HDL cholesterol is elevated and triglycerides are at or close to goal, consideration can be given to ezetimibe as the fourth agent. In statin-intolerant patients, consider niacin ⫹ omega-3 fatty acids (Step 3) followed by ezetimibe, a bile acid sequestrant, and a fibrate. In rare situations when triglycerides are greater than 1000 mg/dL, a fibrate should be used first (Step 4) with omega-3 fatty acids if necessary. A statin typically will also be required to control non-HDL cholesterol, either added later or as part of initial statin ⫹ fibrate combination therapy.
CONCLUSIONS We recognize that ongoing clinical outcome trials and further studies related to the safety and efficacy of lipid-
897 lowering combinations may lead to an evolution in this suggested approach. Given the substantial number of patients who require combination treatment to reach American Heart Association/American College of Cardiology and National Cholesterol Education Program goals and the prevalence of mixed lipid disorders and the atherogenic lipid phenotype, we welcome this much needed outcome data.
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