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Current Opinion in Lipidology:
doi: 10.1097/MOL.0000000000000082
LIPID METABOLISM: Edited by Ernst J. Schaefer

Editorial introduction

Schaefer, Ernst J.

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Tufts University, Boston, Massachusetts, USA

Correspondence to Ernst J. Schaefer, MD, Cardiovascular Nutrition Laboratory, Human Nutrition Reseach Center on Aging at Tufts University, Boston, MA 02111, USA. Tel: +1 781 258 1454; fax: +1 617 556 3103

In last year's issue on lipid metabolism, the focus was on recent advances in the state of knowledge with regard to lipoprotein metabolism and therapeutic strategies for modulating lipoprotein levels and reducing cardiovascular disease risk. These treatments included alterations in dietary carbohydrates, cholesterol, fatty acids and proteins, as well as therapy with oestrogens, statins, ezetimibe, bile acid sequestrants, peroxisomal proliferator-activated receptors, niacin, microsomal transfer protein inhibitors, proprotein convertase subtilisin kexin type 9 inhibitors and cholesteryl ester transfer protein inhibitors. Since that time, another large trial seeking to show benefit of niacin along with the flushing inhibitor laropiprant versus placebo in statin-treated patients was negative, and this drug combination appeared to show some harm [1]. Moreover, a subanalysis of a prior trial in heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels indicated that niacin therapy may be of benefit on top of statin therapy in those with HDL-C values less than 32 mg/dl and triglycerides levels greater than 200 mg/dl [2].

New and controversial guidelines were released jointly by the American College of Cardiology and the American Heart Association in the USA in November of 2013 for the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults [3–5]. The committee concluded that there was no evidence to support specific low density lipoprotein cholesterol (LDL-C) and non-HDL-C targets; and the appropriate intensity of statin should be used to reduce atherosclerotic cardiovascular disease (ASCVD) risk; nonstatin therapies do not provide acceptable risk reduction compared with potential risk; use of the Global Risk Assessment Tool is recommended to assess 10-year CVD risk (; higher risk individuals are more likely to benefit from therapy; treatment decisions in selected individuals who are not included in the four statin benefit groups may be informed by other factors as recommended by the Risk Assessment Working Group; and lifestyle modification is the foundation of ASCVD risk reduction [3].

The committee defined four major groups recommended for statin therapy: individuals with evidence of clinical ASCVD (acute coronary syndrome, history of myocardial infarction, stable or unstable angina, coronary or other revascularization, stroke, transient ischemic attacks, and/or peripheral vascular disease should receive high-intensity statin and ideally get more than 50% LDL-C reduction; individuals with LDL-C at least 190 mg/dl should receive high-intensity statin; diabetic individuals aged 40–75 years with LDL-C of 70–189 mg/dl and without ASCVD should receive moderate-intensity statin, and get 30–50% LDL-C reduction; and individuals without ASCVD or diabetes and a 10-year ASCVD risk of at least 7.5% should receive low-intensity statin. Use the risk calculator at calculator. They defined statin intensity as high: atorvastatin 40–80 mg/day, rosuvastatin 20–40 mg/day; moderate: atorvastatin 10–20 mg/day, rosuvastatin 5–10 mg/day, simvastatin 20–40 mg/day, pravastatin 40 mg/day, lovastatin 40 mg/day, fluvastatin XL 80 mg/day or pitavastatin 2–4 mg/day; and low: simvastatin 10 mg/day, pravastatin 10–20 mg/day, lovastatin 20 mg/day, fluvastatin XL 20–40 mg/day or pitavastatin 1 mg/day. The guidelines also state that ‘clinicians treating high-risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a nonstatin cholesterol lowering drug’. High-risk individuals include those with ASCVD, those with LDL-C greater than 190 mg/dl and those with diabetes. In this situation, the guidelines recommend that clinicians preferentially prescribe drugs that have been shown in randomized clinical trials to provide ASCVD risk reduction benefits that outweigh the potential for adverse effects and drug–drug interactions [3]. Fibrates, niacin, resins and the statin/ezetimibe combination have all shown ASCVD risk reduction in randomized trials as compared with placebo.

The guidelines also emphasized the importance of ruling out secondary causes of elevated LDL-C (>160 mg/dl): increased dietary intake of saturated fat, trans fats, weight gain, anorexia, diuretics, cyclosporin, glucocorticoids, amiodorone, biliary obstruction, nephrotic syndrome, hypothyroidism, obesity, and pregnancy, as well as secondary causes of elevated triglycerides (>150 mg/dl): weight gain, very low fat diets, high intake of refined carbohydrate, excessive alcohol intake, oral oestrogens, glucocorticoids, bile acid sequestrants, protease inhibitors, retinoic acid, anabolic steroids, sirolimus, raloxifene, tamoxifen, beta blockers (except carvedilol), thiazides, hypothyroidism, diabetes, obesity and pregnancy.

The major problem with the new cholesterol guidelines is that in contrast to prior guidelines and current guidelines for blood pressure and diabetes treatment, there is no guidance for the healthcare provider as to what the target level of LDL-C should be [3,6,7]. In contrast to the blood pressure committee, these cholesterol committees did not invoke expert opinion to establish targets of treatment [3,7]. Their recommendations therefore undo 25 years of excellent and widely accepted guidelines based on committees that in part were chaired by the editor Scott Grundy. Moreover, there is no coverage of the various disorders of lipoprotein metabolism, especially those clearly associated with premature coronary heart disease, such as familial combined hyperlipidemia, familial hypercholesterolemia and familial lipoprotein (a) excess. For these reasons, these guidelines have been largely ignored by healthcare providers in the USA who continue to use the older guidelines that have established target of therapy for LDL-C.

The focus of the current issue is on recent advances in the state of knowledge with regard to lipoprotein and lipid metabolism and the various disorders of lipoprotein metabolism. The current issue includes chapters by Dr Francine Welty (pp. 161–168) on abetalipoproteinemia and hypobetalipoproteinemia, by Dr Shailendra Patel (pp. 169–175) on phytosterolemia, by Drs Marleen M.J. van Greevenbroek, Anton F.H. Stalenhoef, Jacqueline de Graaf, and Martijn CGJ Brouwers (pp. 176–182) on familial combined hyperlipidemia, by Drs Raul D. Santos and Raul C. Maranhao (pp. 183–188) on familial hypercholesterolemia, by Dr Stefania Lamon-Fava, Margaret R. Diffenderfer and Santica M. Marcovina (pp. 189–193) on familial lipoprotein (a) metabolism and excess, and by myself, Drs Anthanont and Asztaloson (pp. 194–199) on HDL composition, function, and deficiency states. In addition, we have chapters on the clinical utility of markers of cholesterol absorption and synthesis by Dr Helena Gylling (pp. 207–212), on human fatty acid and triglyceride metabolism by Dr Elizabeth J. Parks (pp. 213–220), and on the metabolism of large and small LDLs by Dr Margaret Diffenderfer (pp. 221–226). It is my hope that this issue will be of great interest to readers of Current Opinion in Lipidology.

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Conflicts of interest

There are no conflicts of interest.

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1. HPS2-THRIVE Collaborative GroupHPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, prespecified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34:1279–1291.

2. Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGHTrial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol 2013; 62:1580–1584.

3. Stone NS, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013; [Epub ahead of print].

4. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology American/Heart Association Task Force on Practice Guidelines. Circulation 2013; [Epub ahead of print].

5. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013; [Epub ahead of print].

6. American Diabetes AssociationStandards of medical care in diabetes: 2014. Diabetes Care 2014; 37 (Suppl 1):S14–S80.

7. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507–520.

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