The following are key points to remember from this review article about lipid management for the prevention of atherosclerotic cardiovascular disease (ASCVD):

1. This excellent review summarizes the available information regarding the pathogenesis of atherosclerosis; lipid metabolism and the targets for pharmacotherapy; primary prevention use of the American College of Cardiology/American Heart Association (ACC/AHA) Risk Calculator for 10-year and lifetime risk, the recommended risk enhancers, and use of the coronary calcium score; lipid management in secondary prevention and agents in development; statin intolerance; and a new tool for estimating low-density lipoprotein cholesterol (LDL-C).
2. There is a correlation between LDL-C and ASCVD and recent evidence supports the concept of “lower is better,” with the magnitude of event reduction proportional to the degree of LDL-C lowering. For every 39 mg/dl reduction in LDL-C, there is a >20% reduction in ASCVD events and 10% reduction in all-cause mortality. Considering the benefit of lowering LDL-C increases with the increasing risk, the focus for treatment is to identify persons at greatest risk of CVD and to treat with high-intensity statins.
3. Decisions for CV risk management should be shared between the clinician and patient including 10-year risk of ASCVD using the ACC/AHA risk calculator (http://www.cvriskcalculator.com/), which is intended for adults 40-75 years of age but can be used to estimated lifetime risk of younger persons. Patients are categorized as low (<5%), borderline (5-<7.5%), intermediate (7.5%-<20%), or high risk (≥20%). Estimation of lifetime risk in adults <40 years of age, or 40-59 years of age who have a 10-year risk <7.5%, facilitates discussion of value of a healthy lifestyle.
4. The foundation for managing risk factors for ASCVD is adoption of a healthy lifestyle including achieving a normal weight and blood sugar, and increasing physical activity that benefits lipids and provides other benefits.
5. Statin and other lipid-lowering drug options are based on individual risk. High-intensity statins to reduce LDL-C by ≥50% are used for high-risk, and for those at intermediate-risk, moderate-intensity statin to reduce LDL-C by ≥30%. For the very high-risk patient based on LDL-C >189 mg/dl, nonstatins including ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may be considered. Recommendations for statin therapy include those 40-75 years of age with LDL-C ≥70 mg/dl who have diabetes or a 10-year risk of ASCVD ≥7.5%. After considering the 10-year risk of ASCVD, risk enhancers and a coronary artery calcium (CAC) score can be used for individual treatment choices for those who are borderline-risk or low-risk with family history of premature coronary heart disease (CHD).
6. Risk enhancers include a history of pre-eclampsia, early menopause, rheumatologic diseases, HIV infection, strong family history of premature CHD, South Asian ancestry, chronic kidney disease, triglycerides >175 mg/dl, elevated apolipoprotein B, elevated high-sensitivity C-reactive protein, or lipoprotein(a) [Lp(a)]. Each can used to decide using or increasing intensity of statins in the borderline-risk or low- to intermediate-risk groups. Statins are recommended for a CAC score >100 or 75th percentile for age/sex/race, but also considered in persons with a score of 1-99, particularly if they are ≥55 years of age. For those with a CAC = 0, statin treatment can be withheld or deferred, with the exception of those who are smokers or have familial hypercholesterolemia.
7. In persons with severe hypercholesterolemia defined as an LDL-C ≥190 mg/dl, high-intensity statin therapy is recommended. If the LDL-C remains ≥100 mg/dl, consideration should be given to ezetimibe, a PCSK9 inhibitor, or both. Similarly, in patients with diabetes, there is no need to use the risk calculator. A moderate-intensity statin is recommended. And for those with multiple risk factors, consideration should be given to high-intensity statin to reduce LDL-C by ≥50%.
8. In persons with ASCVD, the LDL-C should be reduced by ≥50% with the highest tolerated dose of high-intensity statin. If LDL remains >70 mg/dl, it is reasonable to add ezetimibe. For those at very high risk such as a recent acute coronary syndrome, multiple ASCVD events, or a prior CV event with multiple risk factors, it is reasonable to add a PCSK9 inhibitor. For persons ≥75 years, initiation or continuation of moderate- or high-intensity statin is reasonable. Dose may need to be reduced in those at risk for adverse effects from drug interactions.
9. Long-chain n-3 polyunsaturated fatty acids, EPA + DHA, or EPA alone reduce triglycerides by reducing VLDL particle formation and VLDL triglyceride clearance in the circulation. Severe hypertriglyceridemia (>500 mg/dl) should be treated with 4 g of n-3 fatty acids to reduce triglycerides by 20-30%. Lower doses have not been shown to be effective for primary or secondary prevention. The recent REDUCE-IT study demonstrated that persons with high- risk ASCVD or diabetes with one additional vascular risk factor, and triglyceride level of 135-500 mg/dl with well-controlled LDL-C on a statin, who received 4g of icosapent ethyl had a 25% reduction of major CV events that was not related to effect on triglycerides. Icosapent ethyl is a proprietary and highly purified form of EPA. The REDUCE-IT study findings should not be generalized to recommend a dietary supplement with fish oil. It is thought that the value of icosapent ethyl is related to other mechanisms including anti-inflammatory and anti-thrombotic.
10. Patients on lipid-altering agents should be monitored 4-12 weeks after initiation or dose adjustment and then at least annually to assure adherence to the drug and lifestyle. Statin intolerance is defined as the inability to tolerate at least two different statins, including at least one at the lowest starting dose. The accuracy of low levels of LDL-C, particularly when the triglycerides are elevated, is better estimated by the Martin/Hopkins than with the Friedewald equation.
11. Several new agents are in clinical trials including an oral nonstatin inhibitor of ATP citrate that up-regulates LDL receptor activity as do other LDL-C lowering drugs; longer-acting PCSK9 inhibitors; and anti-sense drugs targeting Lp(a), angiopoietin-like 3, lipoprotein lipase, and apo C-3, each of which has the potential for decreasing ASCVD events beyond that attributable to lowering the LDL-C.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Exercise, Smoking

Keywords: Apolipoproteins B, Atherosclerosis, Blood Glucose, Cholesterol, LDL, Coronary Disease, C-Reactive Protein, Diabetes Mellitus, Type 2, Dyslipidemias, Eicosapentaenoic Acid, Exercise, Fatty Acids, Omega-3, Fish Oils, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Hypolipidemic Agents, Hypertriglyceridemia, Lipids, Plaque, Atherosclerotic, Primary Prevention, Proprotein Convertases, Risk Factors, Risk Management, Secondary Prevention, Smoking, Triglycerides

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