Keywords

Introduction and Definitions

  • Dyslipidemia (DLD) is a metabolic derangement causing a persistent elevation in plasma cholesterol and/or triglycerides. The three manifestations of dyslipidemia are:

    • Hypercholesterolemia

    • Hypertriglyceridemia

    • Mixed hyperlipidemia [1, 2]

  • Common manifestations of DLD include:

    • High total cholesterol (TC)

    • High triglycerides (TG)

    • High low-density lipoprotein-cholesterol (LDL-C)

    • Low high-density lipoprotein-cholesterol (HDL-C)

    • Elevated non-high-density lipoprotein-cholesterol (non-HDL-C)

    • Altered lipoprotein compositions such as increased apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)] [2, 3]

  • Primary disorders of lipid metabolism include familial hypercholesterolemia (FH), familial combined hyperlipidemia, and familial dysbetalipoproteinemia [4].

  • The most common primary disorder is FH, which affects ~1 in 200 individuals; most cases are due to a heterozygous mutation. Combined hyperlipidemia affects ~1 in 100 individuals [5, 6].

  • Patients with phenotype for FH (LDL-C > 190 mg/dL) have a 20-fold increased risk for cardiovascular disease and accelerated atherosclerosis [7].

  • Secondary dyslipidemia can be a consequence of obesity, diabetes mellitus type I or II, hypothyroidism, obstructive liver diseases, chronic kidney disease, and certain drugs (i.e., progestins, androgens, beta-blockers, anabolic steroids, retinoids, cyclosporine, and phenothiazines) [8].

  • Table 11.1 shows reference values for TG, LDL-C, and HDL-C levels [8, 9] for patients without known atherosclerotic cardiovascular disease (ASCVD).

Table 11.1 Low-density lipoprotein-cholesterol (LDL-C), low high-density lipoprotein-cholesterol (HDL-C)
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Dyslipidemia and Cardiovascular Disease

  • ASCVD remains the leading cause of morbidity and mortality globally. In the United States, this results in an annual estimated cost of >$200 billion [9, 10].

  • It is crucial to screen, diagnose,and treat dyslipidemia in the general population due to the high attributable risk for atherosclerotic and non-atherosclerotic cardiovascular disease.

  • Dyslipidemia increases atherosclerosis and ASCVD risk by accelerating the atherogenic process.

Therapeutic Agents

  • Statin therapies have a proven substantial benefit in the primary and secondary prevention of ASCVD, and recent evidence reveals that this benefit far outweighs potential risks [9].

  • Other lipid-lowering therapies include:

    • LDL-C-lowering agents:

      • Ezetimibe

      • Bile acid sequestrants

      • Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

    • Triglyceride-lowering agents:

      • Fibrates

      • Niacin

      • Icosapent ethyl (a pure omega-3 fatty acid derivative of EPA) [9]

  • Statins remain the cornerstone of treatment. Table 11.2 outlines the currently available statins with intensity levels [9].

  • High-intensity statins have a ≥50% reduction of LDL-C, moderate-intensity statins result in 30–49% reduction of LDL-C, and low intensity confers a <30% reduction of LDL-C [9].

  • Statins interact with several medications. Risk mitigation strategies should be used when co-prescribing with one of these medications (either limiting the dose, avoiding co-administration, or using an alternative statin which does not have a direct effect). Table 11.3 lists common medications [9].

Table 11.2 Intensity of statin therapy with current available statins
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Table 11.3 Adapted from 2019 cholesterol guidelines[6] Statins requiring a risk mitigation approach
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Guidelines

  • The American College of Cardiology/American Heart Association (ACC/AHA) 2019 combined cholesterol guidelines emphasize the importance of a heart-healthy lifestyle throughout the lifetime.

  • In patients with clinical ASCVD, high-risk ASCVD, severe primary hypercholesterolemia, and populations with diabetes mellitus, statin therapy is recommended as first line. Table 11.4 highlights primary and Table 11.5 highlights secondary prevention strategies.

Clinical Pearl

In patients (age 40–75 years) without known ASCVD, the first step is to use the pooled cohort equation (PCE) calculator to calculate an individual’s ASCVD risk score which is divided into low risk (<5%), borderline risk (5 to <7.5%), intermediate risk (≥7.5 to <20%), and high risk (≥20%). In patients with low and intermediate categories, the risk-enhancing factors (outlined in Table 11.6) should be considered.

Table 11.4 Primary prevention guidelines from ACC/AHA 2019 for initiating statin therapy in patients without prior ASCVD
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Table 11.5 Secondary prevention guidelines for known clinical ASCVD as per ACC/AHA guidelines, statin as first line after healthy lifestyle emphasis
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Table 11.6 Risk enhancers as outlined by ACC/AHA Guidelines which confer additional ASCVD risk
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Monitoring

  • Monitoring response to LDL-C lowering agents is recommended and should be undertaken after initiation of agents or addition of agents.

Clinical Pearl

  • Effects should be assessed by measuring fasting or non-fasting lipid levels 4–12 weeks after starting statin therapy or after a dose adjustment. After that, consider measuring every 3–12 months based on need to assess adherence or safety [9].

Special Populations

  • Special consideration should be given to the following:

    • Elderly (age >75 years) patients

    • Racial/ethnic backgrounds

    • Women

    • Adults with HIV

    • Adults with CKD

  • See Table 11.7 for a summary of these populations.

Table 11.7 Special populations to consider for lipid-lowering agents, based on ACC/AHA 2019 guidelines
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Triglyceride-Lowering Therapy

  • Hypertriglyceridemia (HTG) is a distinct lipid abnormality, and certain triglyceride-lowering agents have been found to reduce either ASCVD risk or the risk of pancreatitis. These include prescription strength omega-3 fatty acids and fibrates such as fenofibrate and gemfibrozil, which are peroxisome proliferator-activated receptor-α (PPAR-α) agonists.

  • Recent trials have shown benefit with icosapent ethyl (a pure omega-3 fatty acid derivative of EPA). REDUCE-IT showed a 25% reduction in the risk of ischemic events and CVD death with 4 grams of icosapent ethyl superimposed on use of moderate- to high-intensity statins in high-risk patients with either ASCVD or diabetes mellitus with elevated fasting triglyceride levels of 135–499 mg/dL [11]. However, guidelines have yet to endorse its use, and it should be considered on a case-by-case basis.

  • Statins remain the first-line therapy for TG lowering. See Table 11.8 for the most recent recommendations from the American Heart Association.

  • Fibric acid derivatives (fenofibrate and gemfibrozil) are renally excreted, and the safety of these needs to be considered with possible dose adjustments, particularly in those on statin therapy.

Clinical Pearl

  • The National Kidney Foundation and National Lipid Association recommend dose adjustment of fibrates based on estimated glomerular filtration rate (eGFR).

  • Fenofibrate is the preferred fibrate to use with statin therapy; gemfibrozil inhibits the glucuronidation of statins which increases the blood level of the statin and therefore increases the risk of myopathy and rhabdomyolysis. Gemfibrozil should not be combined with statin therapy [12, 13].

Table 11.8 Highlights the treatment for moderate and severe hypertriglyceridemia as outlined by the most recent ACC/AHA guidelines [6]
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Addressing Side Effects

  • Statin therapy is safe and generally well tolerated. Statin-associated side effects may be present in a few patients [9].

  • Statin-associated muscle symptoms (SAMS) are the most common side effect and include myalgias (observationally reported in 5–20% of patients).

  • The rarer SAMS:

    • Myositis/myopathy with elevated creatine kinase (CK)

    • Rhabdomyolysis (CK >10x upper limit of normal [ULN])

    • Statin-associated autoimmune myopathy (only in case reports)

  • Statins have also been associated with new-onset diabetes mellitus in predisposed individuals with BMI > 30, fasting glucose >100, metabolic syndrome, and prediabetes [9].

  • Observational studies report transaminase elevation >3× ULN and rarely hepatic failure, but these are rare to infrequent occurrences [9].

  • To address SAMS, a statin rechallenge should be considered with an alternative statin, or a dose reduction with or without decrease in frequency of administration.

  • It is crucial to have a clinician-patient risk discussion (CPRD) regarding potential adverse effects, drug-drug interactions, ASCVD risk reduction benefit, and patient preferences to promote a shared decision-making (SDM) process before prescribing therapy.

Emerging Lipid-Lowering Agents

  • Several newer lipid-lowering agents are on the horizon. Several new therapies target atherogenic lipids (LDL-C, Lp(a), non-HDL-C, remnants) using a variety of different mechanisms [14].

  • These newer agents are promising and may prove beneficial for patients, highlighted in Table 11.9.

Table 11.9 Current and new lipid-lowering therapeutics
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Key Learning Points

  1. 1.

    Dyslipidemia (DLD) is a metabolic derangement causing a persistent elevation in plasma cholesterol and/or triglycerides. The three manifestations of dyslipidemia are hypercholesterolemia, hypertriglyceridemia, and mixed hyperlipidemia.

  2. 2.

    It is crucial to screen, diagnose, and treat dyslipidemia in the general population due to the high attributable risk for cardiovascular disease. Dyslipidemia increases atherosclerosis and ASCVD risk by accelerating the atherogenic process.

  3. 3.

    Statin therapies have a substantial benefit in the primary and secondary prevention of ASCVD, and recent evidence reveals that this benefit far outweighs potential risks.