Clinical Lipid Management

Introduction

Cholesterol remains a fundamental causal factor in the development of atherosclerotic cardiovascular disease (ASCVD). This module provides a concise overview of the clinical management of cholesterol in adults, giving clinicians the key information needed to prevent ASCVD events and manage common lipid disorders.

The greatest emphasis is placed on treatment recommendations supported by strong to moderate evidence from randomized trials of drug therapy. Therefore, the main recommendations for evidence-based patient care come from the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol (referred to as the 2018 multi-society cholesterol guideline).

Because not all clinical questions can be answered from this body of evidence, expert guidance is provided based on the evidence available from clinical trials, meta-analyses of randomized trials that were not included in the dataset considered for the 2018 multi-society cholesterol guideline, post hoc analyses of randomized trials, analyses of observational clinical datasets and, in rare instances, epidemiologic studies.

Historical Overview

Over 150 years ago, Virchow and colleagues described the accumulation of lipid as the hallmark of atherosclerotic plaque. Since then, an extensive body of epidemiologic evidence has shown a direct relationship between blood cholesterol levels and ASCVD, a relationship magnified in the presence of other cardiovascular risk factors. The causal role of cholesterol in atherosclerosis has been proven in numerous clinical trials showing that lowering total and low-density lipoprotein cholesterol (LDL-C) slows the development of atherosclerosis and prevents clinical events.

In the 1970s and 1980s, the first clinical trials of lipid-modifying drug therapy (using niacin, gemfibrozil, or bile acid sequestrants) were performed in high-risk populations with ASCVD—men with severe hypercholesterolemia, with and without clinical coronary artery disease (CAD).

Statins were developed in the 1980s and have gone on to revolutionize the treatment of cholesterol to prevent ASCVD. Based on an extensive body of evidence from at least 28 randomized trials in a broad range of populations, statins are considered first-line therapy for ASCVD prevention.

The first National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP I) was published in 1988 and made recommendations regarding screening, desirable normal and high blood cholesterol levels and dietary treatment. As results from the early randomized trials became available, updated recommendations were provided in ATP II in 1993. ATP II recommended using risk status to guide the intensity of lipid-lowering therapy, with an emphasis on setting an LDL-C goal of <100 mg/dL for those with clinical ASCVD (secondary prevention). Step I and II cholesterol-lowering diets were recommended.

Numerous primary and secondary prevention statin trials were completed in the late 1990s and early 2000s, guiding the development of ATP III, published in 2001 and updated in 2004. ATP III again used risk status to guide the intensity of therapy and added numerous LDL-C and non–high-density lipoprotein cholesterol (non–HDL-C) treatment goals, depending on the level of risk. The concept of metabolic syndrome was introduced and therapeutic lifestyle changes (diet, physical activity, and weight control) were strongly emphasized. Statins were recommended as first-line therapy, but the use of other lipid-modifying drugs was encouraged to reach LDL-C and non–HDL-C goals.

2013 ACC/AHA Cholesterol Guideline

In 2008, the National Heart, Lung and Blood Institute (NHLBI) convened ATP IV, and charged the Panel with developing an evidence-based cholesterol guideline for reducing the risk of cardiovascular events using evidence from randomized, controlled trials (RCTs). The Panel undertook a rigorous systematic review and guideline development process that adhered to principles set forth by the Institute of Medicine in Clinical Practice Guidelines We Can Trust. These recommendations were transitioned to the American College of Cardiology/American Heart Association (ACC/AHA) for implementation, as the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease (ASCVD) Risk. This guideline was supported by accompanying ACC/AHA guidelines for the assessment of ASCVD risk, lifestyle and obesity.

The 2013 ACC/AHA cholesterol guideline introduced a new paradigm for cholesterol treatment focused on the potential to receive a net ASCVD risk reduction benefit from drug therapy. It provides recommendations for the use of statin, as well as nonstatin, therapy in groups of patients most likely to benefit. This paradigm moves away from LDL-C and non–HDL-C treatment goals used in previous guidelines. As is typical for a new paradigm, the 2013 ACC/AHA cholesterol guideline was initially met with some criticism, primarily from lipidologists concerned by the move away from LDL-C and non–HDL-C treatment targets. However, analyses subsequent to the release of the 2013 ACC/AHA cholesterol guideline have overwhelmingly supported the 2013 ACC/AHA guideline’s new paradigm focused on net benefit from drug therapy rather than cholesterol goal achievement.

2018 Multi-Society Cholesterol Guideline

The current guideline on cholesterol management was released in 2018, as a collaboration between the ACC, the AHA and ten other professional societies. Importantly, the paradigm of not treating to specific LDL-C targets, first introduced in the 2013 ACC/AHA guideline, was maintained. The primary aim of the 2018 multi-society guideline was to provide guidance updated with data that became available since the release of the 2013 ACC/AHA guideline. This included primarily more information on the appropriate uses of nonstatin therapies (ezetimibe and PCSK9 inhibitors), a new ASCVD risk categorization, additional risk factor considerations, categorization of ASCVD into very high risk and not very high risk, and more information on specific groups, including children and racial/ethnic groups. The 2018 multi-society guideline also included specific thresholds of when to consider nonstatins in addition to statin therapy.

The evidence supporting the 2018 multi-society cholesterol guideline recommendations is reviewed in subsequent sections. The most important randomized trials, meta-analyses and other analyses published after the 2018 multi-society cholesterol guideline are also reviewed, along with their implications for clinical practice.

Management of Patients Beyond the 2018 Multi-Society Guideline

The 2018 multi-society cholesterol guideline focused on the strongest available evidence to guide pharmacologic treatment of cholesterol to reduce ASCVD risk. Clinicians at a minimum should be maximizing statin therapy in the patients most likely to benefit based on the evidence from clinical trials. This module will also provide clinical management recommendations for the many groups of patients who were not included in randomized cardiovascular outcomes trials, who cannot tolerate maximal statin therapy, or statin-treated patients who might benefit from additional LDL-C lowering. Expert guidance for managing hypertriglyceridemia and patients with familial hyperlipidemias is also provided.

Evolving Role of Nonstatins in ASCVD Prevention

Statins are first-line therapy for ASCVD risk reduction, yet some patients could benefit from further LDL-C lowering with a nonstatin to reduce their ASCVD risk. Information on individual nonstatins is presented in dedicated section. Recommendations from the 2018 multi-society guideline and the 2022 ACC Expert Consensus Decision Pathway on nonstatins are presented. Additionally, a framework based on the potential for a net ASCVD risk reduction benefit is provided to aid decisions on whether to initiate nonstatin therapy.

Other Highlights

Other highlights include:

• Bottom Line feature: Summarizes the essential clinical take-home recommendations for the section.
• Lipid and lipoprotein basics: A basic introduction to lipid and lipoprotein metabolism highlighting the most important concepts for understanding familial lipid disorders.
• Familial lipid disorders: Clinicians should be familiar with familial hypercholesterolemia diagnosis and screening. For those who are interested and for reference, a general overview of lipoproteins and their role in atherogenesis is provided, as is a brief description of less common genetic lipid disorders.
• Lifestyle recommendations: Lifestyle is the foundation of ASCVD risk reduction efforts. Current recommendations for diet, physical activity and weight control are reviewed.
• Risk assessment for primary prevention: Evidence-based approaches to estimating and refining a patient’s ASCVD risk estimate are provided that may enhance the Clinician-Patient Discussion.
• Special issues in women, older adults and race/ethnicity: Less randomized trial evidence is available for women, individuals >75 years of age and non-Caucasian populations. Issues regarding safety and efficacy are discussed and treatment approaches based on the best available evidence are discussed.
• Lipid management in special clinical populations: Lipid management can be challenging in some groups of patients due to increased ASCVD risk, adverse effects of drug therapy and increased safety concerns due to drug-drug interaction. Expert guidance is based on the available evidence.
• Comparative effectiveness of lipid drug therapy: The comparative efficacy and safety of currently available statin and nonstatin drugs are provided to inform drug choice decision. For easy reference, appropriate uses, mechanisms of action, lipid-modifying efficacy, cardiovascular benefits and safety for each class of lipid-modifying drugs are reviewed.
• Role for PCSK9 inhibitors: Data from phase 2 and 3 trials and FDA-approved indications are reviewed and the clinical application of these drugs is discussed.
• Management of hypertriglyceridemia: A straightforward and evidence-based approach to triglycerides is provided.