Original Article
Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
N Engl J Med 2010; 362:906-916March 11, 2010
- Abstract
Background
Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided.
Methods
We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 μg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary.
Results
The addition of placebo or eprotirome at a dose of 25, 50, or 100 μg daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome.
Conclusions
In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins. (ClinicalTrials.gov number, NCT00593047.)
Media in This Article
Figure 1
Effects of Eprotirome on Serum Levels of Cholesterol, Lipoproteins, and Triglycerides.Figure 2
Serum Levels of Thyroid Hormones during Eprotirome Therapy.Article Activity
- Article
The association between elevated levels of circulating low-density lipoprotein (LDL) cholesterol and an increased risk of atherosclerotic cardiovascular disease is well established,1 as are the reductions in both levels of serum cholesterol and the risk of cardiovascular disease that occur with the use of inhibitors of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase.1 However, the efficacy of statins is limited if stringent goals for serum LDL cholesterol levels are not achieved2 in patients receiving statins alone3 or if side effects develop that require a dose reduction or discontinuation of the agent.4 Furthermore, statins are less effective in lowering levels of other lipoproteins, such as triglycerides5 and Lp(a) lipoprotein,6 that are associated with the risk of atherosclerotic vascular disease.
Recent reports have indicated that new drugs such as ezetimibe and torcetrapib, which have novel mechanisms of action, either have not shown an incremental reduction of secondary end points in atherosclerotic disease, such as carotid intima–media thickness,7,8 or have had unanticipated adverse effects.9 Consequently, additional agents that target the metabolism of lipoproteins to improve outcomes in patients with cardiovascular disease would be beneficial. The cholesterol-lowering effect of thyroid hormone in patients with hypothyroidism was described in 1930.10 LDL is the principal lipoprotein that is reduced; the reduction is induced by increased hepatic clearance11 due to increased expression of the hepatic LDL-receptor gene.12-14 In rodents, thyromimetic compounds also accelerate clearance of cholesterol by the liver by increasing the high-density lipoprotein (HDL) receptor called scavenger receptor B1 (SR-B1),15 increasing the activity of cholesterol 7α-hydroxylase,14,16 and increasing fecal excretion of cholesterol and bile acids.16 Previous attempts to mimic these actions with thyroid hormone metabolites17,18 and analogues16,19-22 have confirmed their cholesterol-lowering properties. However, the development of some of these drugs was discontinued because of adverse effects related to thyroid hormonelike actions, including possible deaths due to cardiac causes associated with D-thyroxine23 and adverse effects on bone associated with tiratricol.18
Eprotirome (KB2115) (Karo Bio) is a thyroid hormone analogue containing two bromides that, as compared with triiodothyronine, has minimal uptake in nonhepatic tissues. It has a modestly higher affinity for the triiodothyronine receptor (TR) β isoform, which mediates the lipid-lowering actions of thyroid hormone,15 as compared with its affinity for the TRα isoform in the heart.24 In a previous 2-week clinical trial, eprotirome was reported to reduce levels of serum total and LDL cholesterol and apolipoprotein B without evident side effects.25 Because statin treatment has well-established efficacy in patients with hypercholesterolemia, the present 12-week study was designed to determine whether adding eprotirome to statin therapy would provide an incremental benefit in lowering levels of atherogenic lipoproteins without adverse extrahepatic thyromimetic effects.
Methods
Study Design
This randomized, placebo-controlled, double-blind, double-dummy trial was conducted at 15 sites and was approved by regional ethics committees and regulatory authorities and by the institutional review board at each participating center. Karo Bio sponsored the study. All participants provided written informed consent. An independent data and safety monitoring board monitored the laboratory results and adverse events. The site investigators, patients, and sponsor were unaware of the laboratory data on lipid and thyroid hormone levels. All the authors participated in the study design. The data collection and statistical analysis were performed by Pharma Consulting Group. Two academic authors and one industry author reviewed and verified the data and analysis, and additional analyses were performed by the Pharma Consulting Group at the request of these authors. The first author wrote the first draft of the manuscript, and all authors participated in its review and revision and vouch for the accuracy and integrity of the reported data.
Patients were enrolled from November 12, 2007, through January 15, 2008. Patients who were eligible for the study began a 4-week dietary lead-in phase during which they consumed a National Cholesterol Education Program step 1 diet while continuing to receive simvastatin or atorvastatin. Patients were then randomly assigned to eprotirome or placebo for 12 weeks. Patients were reassessed 4 weeks after discontinuing eprotirome treatment, while they were still receiving statin therapy.
The study drug was administered as enteric-coated tablets containing placebo or 25, 50, or 100 μg of eprotirome. The dose of eprotirome was increased at 2-week intervals (Figure 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Patients continued to receive their previous statin dose.
The primary efficacy variable was the change in the level of serum LDL cholesterol from baseline to week 12. Secondary efficacy variables were changes in levels of total cholesterol, HDL cholesterol, triglycerides, free fatty acids, apolipoprotein A-I, apolipoprotein B, and Lp(a) lipoprotein and changes in the ratio of apolipoprotein B to apolipoprotein A-I.
Safety assessments included documentation of adverse events; heart rate and rhythm, blood pressure, and body weight; and electrocardiography and laboratory tests, including thyroid and liver-function tests (details are provided in the Supplementary Appendix).
Study Patients
Eligible patients were 18 to 65 years of age and had received stable treatment with simvastatin (≤40 mg daily) or atorvastatin (≤20 mg daily) for at least 3 months before entry into this study but continued to have an LDL cholesterol level of 116 mg per deciliter or more (≥3.0 mmol per liter). Patients were excluded if they had a history of thyroid disease, cardiac arrhythmia, heart failure (New York Heart Association class II or higher), myocardial infarction within the previous 6 months, coronary-artery bypass or percutaneous intervention, or stroke or transient ischemic attack; diabetes requiring medication other than metformin; liver disease; abuse of alcohol or drugs within the previous 2 years; or coagulopathy. Additional exclusion criteria were childbearing potential, a clinically significant drug allergy, and a condition that might compromise compliance. Patients with blood pressure of more than 160/95 mm Hg, a glycated hemoglobin level of more than 7.0%, or a level of aspartate aminotransferase or alanine aminotransferase that was more than 1.5 times the upper limit of the normal range were excluded. Treatment with beta-adrenergic blockers, anticoagulants, estrogen, progesterone, or another investigational drug was not permitted.
Statistical Analysis
The estimated sample size was based on detection of a mean decrease in the LDL cholesterol level of 19.5 mg per deciliter (0.5 mmol per liter) between patients who received eprotirome and patients who received placebo, with a two-sided type I error of less than 5%. We calculated that 172 patients would be required for a statistical power of 80% or more. Efficacy analyses included data from all patients who received study medication and for whom serial LDL cholesterol measurements were available. The safety analysis included all patients who received eprotirome or placebo.
Statistical analyses were based on the absolute change in LDL cholesterol levels between baseline (the covariate) and week 12 (the explanatory variable) in analysis of covariance. If the overall F statistic revealed a difference between the groups, a pairwise comparison of placebo with each treatment group was performed. If the model's assumptions were not fulfilled, nonparametric testing was performed. For assessment of the dose–response relationship, the Jonckheere–Terpstra test was used.26 Missing efficacy values after week 2 were imputed by the last-observation-carried-forward method.
Results
Characteristics of the Patients
Of the 329 patients who underwent screening, 189 were randomly assigned to a study drug and included in the safety analysis. Since no serial measurements of LDL cholesterol levels were available for 5 patients, 184 patients were included in the efficacy analysis, and 168 patients completed the trial. Table 1Table 1
Baseline Characteristics of the Patients. shows the demographic and clinical characteristics of the patients in the study. The mean LDL cholesterol level was 141 mg per deciliter (3.6 mmol per liter). Most patients (98%) were receiving statin therapy for the primary prevention of atherosclerotic vascular disease. All patients received a consistent statin dose throughout the study.Serum Lipoprotein Levels
Levels of serum LDL cholesterol at week 12 were reduced from mean baseline levels, which were between 138 and 144 mg per deciliter (3.6 and 3.7 mmol per liter), to 127, 113, 99, and 94 mg per deciliter (3.3., 2.9, 2.6, and 2.4 mmol per liter), corresponding to mean reductions from baseline of 7%, 22%, 28%, and 32% in the groups of patients who received placebo or 25, 50, or 100 μg of eprotirome, respectively (Figure 1Figure 1
Effects of Eprotirome on Serum Levels of Cholesterol, Lipoproteins, and Triglycerides. and Table 2Table 2
Serum Lipid and Lipoprotein Levels at Baseline and at 12 Weeks.) The proportions of patients who had an LDL cholesterol level of less than 100 mg per deciliter (<2.6 mmol per liter) at week 12 were 6% in the group of patients who received a statin plus placebo and 36%, 50%, and 57% in the three groups of patients who received a statin plus 25, 50, or 100 μg of eprotirome, respectively. Similarly, at week 12, reductions in levels of apolipoprotein B from mean baseline levels (between 110 and 115 mg per deciliter) were 8, 24, 28, and 36 mg per deciliter (mean reductions from baseline, 6%, 20%, 24%, and 30%) in the placebo group and the low-dose, medium-dose, and high-dose eprotirome groups, respectively.Levels of serum triglycerides, which were between 132 and 155 mg per deciliter (1.5 and 1.7 mmol per liter) at baseline, had changed at 12 weeks by 3, −29, −34, and −61 mg per deciliter in the placebo group and the 25-μg, 50-μg, and 100-μg eprotirome groups (mean changes from baseline, 5%, −16%, −16%, and −33%), respectively. Also, levels of serum Lp(a) lipoprotein decreased with the addition of eprotirome to statins; the median baseline values were between 27 and 36 mg per deciliter, and the values at 12 weeks were 42, 20, 23, and 15 mg per deciliter (mean reductions from baseline, 10%, 27%, 32%, and 43%) in the placebo group and the low-dose, medium-dose, and high-dose eprotirome groups, respectively. In a post hoc analysis, there were similar reductions among the one third of patients with the highest baseline Lp(a) lipoprotein levels (>70 mg per deciliter) (Table 2, and Figure 2 in the Supplementary Appendix).
Modest changes in levels of serum HDL cholesterol were observed at 12 weeks: 0.8, −2.8, −3.3, and −2.5 mg per deciliter (0.02, −0.07, −0.08, and −0.06 mmol per liter) in the placebo group and the groups that received 25 μg, 50 μg, and 100 μg of eprotirome, respectively. Similar changes were observed in levels of apolipoprotein A-I. Neither the type of statin nor the statin dose influenced any of the efficacy variables when they were tested as covariates.
Thyroid Function
No change in the level of serum thyrotropin was detected in the patients who received eprotirome (Figure 2Figure 2
Serum Levels of Thyroid Hormones during Eprotirome Therapy.). Dose-dependent reductions of 22 to 34% in levels of serum total thyroxine and of 12 to 21% in levels of free thyroxine were observed in patients who received eprotirome. However, the mean levels of total thyroxine and free thyroxine remained within or at the lower limit of their respective reference ranges (Figure 2), and this effect was reversed on discontinuation of eprotirome. There were no changes in levels of serum total triiodothyronine or free triiodothyronine at any dose of eprotirome. In patients who received eprotirome therapy, the level of serum thyroxine-binding globulin was reversibly decreased (although to a lesser extent than thyroxine) by 14 to 21% (data not shown).Adverse Effects
In patients who received eprotirome, no significant changes were observed in body weight, heart rate, or systolic or diastolic blood pressure. No abnormal cardiac rhythm or electrocardiographic changes, including the QT interval corrected for heart rate, were detected. No pattern of symptoms suggesting clinical thyrotoxicosis or hypothyroidism was observed. Serum markers of bone turnover, including bone-specific alkaline phosphatase, and type I collagen breakdown product, were unchanged. An isolated, nonsignificant 3 to 19% increase in the level of serum procollagen type I N-terminal propeptide (PINP) was observed in the highest-dose group, but a similar idiopathic increase in the level of PINP has been observed during statin treatment.27
In patients who received eprotirome, there was a dose-dependent increase in sex hormone–binding globulin, as previously observed with clinical and experimental thyrotoxicosis and exposure to thyromimetic agents with hepatic activity.28 No adverse effects related to sexual dysfunction were observed, and levels of serum free testosterone in men and estradiol in women were unchanged (Table 4 and Table 5 in the Supplementary Appendix). Mild and reversible increases in levels of serum alanine aminotransferase were observed. One patient each in the groups that received 25 μg and 50 μg of eprotirome had confirmed alanine aminotransferase levels that were more than 3 times the upper limit of the normal range; the highest level was 5.3 times the upper limit. In the first of these patients, the alanine aminotransferase level normalized spontaneously during continued treatment. The second patient was found to abuse alcohol and was excluded from the subsequent portion of the study. A concomitant increase in the bilirubin level was not seen in any of the patients. Single instances of eight adverse events categorized as serious because of hospitalization were reported, but none was considered to have been related to the study medication by the study investigators, the sponsor, or the central drug-safety evaluator.
The total numbers of adverse events during the study were similar among the study groups (82, 97, 115, and 68 adverse events in the placebo group and the low-dose, medium-dose, and high-dose eprotirome groups, respectively), and the majority of these events were mild (77%) or moderate (21%). Table 3Table 3
Adverse Events, According to Study Group. lists adverse events that occurred in at least 5% of the patients in any study group. Additional details regarding adverse events and discontinuation of treatment are included in the Supplementary Appendix.Discussion
In this 12-week trial, the addition of eprotirome to statin therapy resulted in substantial further reductions in levels of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B. In patients who had a mean baseline serum LDL cholesterol level of 141 mg per deciliter, the use of eprotirome in addition to statin therapy was associated with a reduction in the level of LDL cholesterol to less than 100 mg per deciliter in 36% of patients receiving 25 μg, 50% of patients receiving 50 μg, and 57% of patients receiving 100 μg of eprotirome per day. Eprotirome was associated with larger decreases in levels of serum LDL cholesterol than would be expected with a doubling of the statin dose.29 Furthermore, the mean levels of two other atherogenic lipids that are known to have a lower response to statin treatment alone — triglycerides and Lp(a) lipoprotein — were reduced in patients receiving eprotirome with statin therapy. Unlike the findings in previous studies of similar agents,17,30 eprotirome therapy for 12 weeks did not appear to be associated with adverse thyromimetic effects on the heart, bone, or secretion of thyrotropin.
The further reductions in levels of LDL cholesterol that we found with the addition of eprotirome to statin therapy suggest that these two classes of drugs may work through complementary mechanisms. In addition to the direct and indirect stimulation of hepatic LDL-receptor expression by thyroid hormone,13 both triiodothyronine and a selective thyromimetic agent have been shown in animal models to amplify several steps in reverse cholesterol transport. These steps include increasing levels of the hepatic HDL receptor SR-B1,16 stimulating the expression and activity of cholesterol 7α-hydroxylase (the rate-limiting enzyme in bile acid biosynthesis from cholesterol),14,16 accelerating secretion of hepatic cholesterol by increasing the expression of the ABCG5 and ABCG8 transporters,31 and inhibiting absorption of intestinal cholesterol.32
The triglyceride-lowering effect of eprotirome in patients treated with statins appears to be important. The observed mean reductions of up to 37% in triglyceride levels were larger than those generally observed with other drugs used to treat hypertriglyceridemia.33 The mechanism of triglyceride lowering is probably decreased hepatic production of very-low-density lipoprotein, reflecting inhibited expression of sterol regulatory element-binding protein-1c.16,31 Unlike endogenous hyperthyroidism, in which higher levels of triglycerides can result from increased free fatty acid flux from adipose tissue to the liver,34 eprotirome therapy was not associated with elevated free fatty acid levels. Particularly in view of its potent effect in lowering levels of apolipoprotein B, eprotirome may represent a useful treatment for combined hyperlipidemia, which is associated with a major cardiovascular risk with even relatively low triglyceride levels.33 Eprotirome might prove useful in combination with fibrates or nicotinic acid as well as in combination with statins.
Levels of serum HDL cholesterol and apolipoprotein A-I were minimally but significantly reduced with the addition of eprotirome to statin therapy. Although a low level of HDL cholesterol has been linked to an increased cardiovascular risk, it remains uncertain whether treatment-induced changes in HDL levels translate into an altered incidence of cardiovascular disease. The decrease we observed may reflect increased cholesterol flux through the HDL reverse cholesterol pathway rather than reduced production of HDL and apolipoprotein A-I.16 Studies in rodents showing that hepatic expression of apolipoprotein A-I messenger RNA,35 as well as levels of cholesterol 7α-hydroxylase14,16 and SR-B1,16 are increased by thyroid hormone support this hypothesis.
A third potentially favorable effect of the addition of eprotirome to statin treatment was a reduction in the serum level of Lp(a) lipoprotein, which is a putative risk factor for cardiovascular disease.7 Because there have not been effective agents to lower levels of Lp(a) lipoprotein, there is actually little evidence that pharmacologic treatment prevents cardiovascular disease in persons with high levels of circulating Lp(a) lipoprotein. There are inverse correlations between measured levels of Lp(a) lipoprotein and both kringle IV repeats in the LPA gene and particle size, neither of which were assessed in this study. Nonetheless, if confirmed, this effect of eprotirome suggests that the compound might be used to test the hypothesis that lowering of Lp(a) lipoprotein levels would be beneficial.
In assessing the safety of eprotirome, it is vital to consider adverse thyromimetic effects, particularly an increase in the resting heart rate, atrial dysrhythmias, and accelerated bone turnover leading to mineral loss. Paradoxically, suppression of pituitary secretion of thyrotropin by a thyromimetic agent could also result in a hypothyroid state in tissues not targeted by the drug. Such adverse effects have been encountered with several previously investigated thyroid hormone analogues.17,36 In our trial of eprotirome, we observed no symptoms suggesting either clinical thyrotoxicosis or hypothyroidism, no increased heart rate or dysrhythmias, no reductions in body weight, no pattern of serologic markers indicating accelerated bone turnover, and no thyrotropin suppression. However, this was only a 12-week study, and despite the apparently stable thyrotropin level, serum total and free thyroxine concentrations were modestly decreased in patients who received eprotirome therapy, with no reduction in the level of serum triiodothyronine. Although the level of thyroxine-binding globulin in serum was also decreased, the extent of its reduction did not fully explain the decreased levels of total thyroxine. One additional explanation for the thyroxine-lowering effect of eprotirome is increased activity of type I iodothyronine monodeiodinase in the liver, an expected consequence of the increased hepatic action of thyroid hormone.37 Indeed, this could represent an appropriate response to the introduction of a thyromimetic agent, causing a reciprocal reduction in endogenous thyroid hormone activity in extrahepatic tissues. Nonetheless, given the short duration of the present trial, careful monitoring for effects on the thyroid must be a component of longer and larger clinical trials of eprotirome in the future.
The transient elevations in hepatocellular enzyme levels seen with combined eprotirome and statin therapy are similar to those known to occur with other lipid-lowering drugs targeting the liver, such as statins alone, fibrates, and niacin. The mechanism for these increases in the alanine aminotransferase level remains incompletely understood. In this study, most elevations in the alanine aminotransferase level were mild and fully reversed despite continued treatment. It is also reassuring that the few patients with a serum alanine aminotransferase level that was more than three times the upper limit of the normal range had no other clinical or biochemical indications of hepatotoxicity.
In conclusion, this randomized, placebo-controlled, double-blind trial showed that eprotirome is associated with further reductions in serum LDL cholesterol levels in patients who are already receiving statins. Eprotirome also has potent properties for lowering levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. These actions of eprotirome appear to take place without evidence of adverse effects on the heart, bone, or pituitary.
Presented in part at the annual meeting of the American College of Cardiology, Orlando, Florida, March 29, 2009.
Supported by Karo Bio and by grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, Karolinska Institutet, and the Stockholm City Council (all to Dr. Angelin).
Dr. Ladenson reports receiving consulting fees from Karo Bio and consulting and lecture fees from Genzyme; Dr. Kristensen, being an employee of and a shareholder in Karo Bio; Dr. Ridgway, receiving consulting fees from Karo Bio and lecture fees from Genzyme; Dr. Olsson, receiving consulting fees from AstraZeneca, Karo Bio, Merck, Pfizer, and Roche and lecture fees from AstraZeneca, Pfizer, and Roche; Mr. Carlsson, being an employee of Karo Bio and a shareholder in Karo Bio, Sectra, and Clinical Laserthermia Systems; Dr. Klein, receiving consulting fees from Karo Bio and Sanofi-Aventis; Dr. Baxter, receiving consulting fees from and being a shareholder in Karo Bio, and being listed as an inventor on a patent owned by the University of California for a compound with actions similar to those of eprotirome; Dr. Angelin, receiving consulting fees from Karo Bio, Resverlogix, and AstraZeneca, being a shareholder in Karo Bio, being a board member of and shareholder in AstraZeneca, and receiving research support from AstraZeneca.
No other potential conflict of interest relevant to this article was reported.
We thank the site investigators: Carl-Peter Anderberg, Katarina Berndtsson-Blom, Jan Eskilsson, Lars Haglund, Hans-Erik Johansson, Pekka Koskinen, Carl Johan Lindholm, Per Eric Lins, Ulrik Mathiesen, Aslak Rautio, Professor Folke Sjöberg, Jorma Strand, Matti Kuusela, and Toivo Piippo, and the independent data and safety monitoring board members: Anders Grahnén, Einar Björnsson, Gerhard Wikström, and Östen Ljunggren for their contributions; and Simeon Margolis for his review of an early version of the manuscript and valuable suggestions.
Source Information
From the Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (P.W.L.); Karo Bio, Huddinge (J.D.K., B.C.), the Faculty of Health Sciences, Linköping University and Stockholm Heart Center, Stockholm (A.G.O.), and the Department of Endocrinology, Metabolism, and Diabetes, and Center for Biosciences, Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm (B.A.) — all in Sweden; the Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora (E.C.R.); the Department of Medicine, North Shore University Hospital and the Feinstein Institute for Medical Research, Manhasset, NY (I.K.); and the Center for Diabetes Research, Methodist Hospital Research Institute, Houston (J.D.B.).
Address reprint requests to Dr. Angelin at the Department of Endocrinology, Metabolism, and Diabetes, M63, Karolinska University Hospital, Huddinge, S-14186 Stockholm, Sweden, or at bo.angelin@ki.se.
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Alberico L. Catapano, Željko Reiner, Guy De Backer, Ian Graham, Marja-Riitta Taskinen, Olov Wiklund, Stefan Agewall, Eduardo Alegria, M. John Chapman, Paul Durrington, Serap Erdine, Julian Halcox, Richard Hobbs, John Kjekshus, Pasquale Perrone Filardi, Gabriele Riccardi, Robert F. Storey, David Wood. (2011) ESC/EAS Guidelines for the management of dyslipidaemias. Atherosclerosis 217, 1-44
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(2010) Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. The Lancet 375:9726, 1634-1639
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