Dyslipidemia and ASCVD Risk Assessment

Dyslipidemia Pathophysiology & Pharmacotherapy Part 2

• Learning objectives for pathophysiology include describing lipoproteins and their functions, explaining lipid metabolism through exogenous and endogenous pathways, identifying risk factors for dyslipidemia and ASCVD, and describing different types of dyslipidemias.
• Learning objectives for pharmacotherapy include utilizing clinical information and calculators to assess ASCVD risk, describing the mechanism of action, side effects, and counseling points for statins and non-statin agents, applying patient characteristics to select appropriate lipid-lowering therapies to manage dyslipidemia and reduce ASCVD risk, and developing monitoring and follow-up plans, including steps to further optimize therapies or manage adverse effects related to the management of dyslipidemia.
• Recommended readings include Chapter 32 of DiPiro's Pharmacotherapy, the 2018 AHA/ACC/Multisociety Guideline on the Management of Blood Cholesterol.
• A review question details the scenario of a 58-year-old patient, including lipid panel, blood pressure, and medications, and asks for calculated LDL-C, classification of lipid panel components, 10-year ASCVD risk according to Pooled Cohort Equation, and patient classification.
• Review question 5 presents scenarios to assess how ASCVD risk might change for this patient, based on factors like age, sex, smoking status, and blood pressure values.
• Limitations of the PCE (Pooled Cohort Equation) include not accounting for the severity of other conditions such as diabetes, limited racial representation in the calculation, use of a social vulnerability index based on zip code instead of race, and age limitations, primarily for primary prevention.
• The roadmap for dyslipidemia shows a progression from ASCVD assessment to lipoprotein assessment, cholesterol synthesis and metabolism to dyslipidemias, medications for dyslipidemia, treatment pathways, and monitoring and follow-up.

Medications to Treat Dyslipidemias

• Several major medications to treat dyslipidemia are discussed, including statins (in particular, high, moderate, and low-intensity statin doses, and the efficacy of each), ezetimibe, inclisiran, omega-3 fatty acids, PCSK9 inhibitors, and fibrates.
• Each medication class is associated with unique properties, advantages, and disadvantages, particularly regarding mechanism of action, side effects, drug-drug interactions, active metabolites, half-lives, and lipophilicity.
• Statins, a particular class, are a primary first-step treatment for dyslipidemia after lifestyle interventions.
• Additional counseling points relating to statins, which are a crucial consideration, include their potential risk of muscle symptoms, and new onset diabetes, and the importance to avoid the nocebo effect.
• Review question 6 asks students to identify the high-intensity statins from the various presented options.

Statins: Properties, Dosing, and Counseling

• Statins, as HMG-CoA reductase inhibitors, are a primary treatment pathway for dyslipidemia.
• The MOA of statins involves inhibiting the rate-limiting enzyme in cholesterol synthesis.
• Key properties include drug-drug interactions, lipophilicity, active metabolites, half-lives.
• Dosage and intensity levels are presented differentiating high, moderate, and low intensity levels of statin dosages based on LDL-C reduction criteria.
• Important considerations for counseling patients on statin use include potential adverse effects, such as statin-associated muscle symptoms (SAMS), new-onset diabetes, severe hepatotoxicity, and rare but serious complications like rhabdomyolysis.

Ezetimibe

• The mechanism of action of ezetimibe involves inhibiting cholesterol absorption in the small intestine
• Indications for its use include patients with primary or mixed hyperlipidemia, including familial hypercholesterolemia (HoFH) in combination with statins.
• Its efficacy is presented as LDL-C lowering, and clinical outcomes are positive.
• Ezetimibe is generally well-tolerated and affordable.
• A clinical trial ("RACING") showed positive results for combination therapies using ezetimibe and statins.

PCK9-inhibitors

• PCK9-inhibitors exhibit an efficacy of 45% to 64% in LDL-C reduction when added to a statin.
• A Minimal DDI (consider mAB) occurs for this category, and its administration is most commonly via subcutaneous injection.
• Important clinical outcomes include benefits to reduce CVD Events.
• Key individuals for considering PCK9 inhibitors include patients with primary hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and other populations with elevated LDL-C that experience treatment difficulty or intolerance.

Inclisiran

• Inclisiran, an RNAi therapy, is indicated for lowering LDL-C in various conditions, including familial hypercholesterolemia (HeFH or HoFH) and ASCVD.
• Its administration is done by injection every 6 months.
• A clinical trial (“ORION”) showed positive results for decreasing several major events associated with CVD.

Bempedoic Acid

• Bempedoic Acid is an alternative therapy to lower LDL-C.
• It lowers LDL-C via a different mechanism and can be utilized for patients unable to tolerate statins.
• Concerns regarding bempedoic acid include increased risk for gout and Achilles tendon rupture, but risks can be mitigated via appropriate patient selection.

Additional Lipid-Lowering Therapies

• Fibrates are used for lowering triglycerides; however, they carry a risk of muscle symptoms, especially when combined with statins.
• Niacin, a Vitamin B derivative, is less frequently used due to common side effects, such as flushing.
• Bile acid sequestrants block bile acid absorption, decreasing the reabsorption of cholesterol.

Fish Oils

• Fish oils, containing omega-3 fatty acids, may decrease triglycerides, however, they do not consistently reduce ASCVD risk significantly.
• EPA may be most effective in reducing triglycerides.

Additional Lipid-Lowering Therapies

• Evanicumab is an Angiopoietin-like 3 (ANGPTL3) inhibitor, indicated for patients with homozygous familial hypercholesterolemia (HoFH) ≥ 5 years old and offers potential benefit off-label in other populations, primarily administered via IV infusion.
• Lomitapide, an oral drug, suppresses microsomal triglyceride transfer protein (MTP) and may lead to significant gastrointestinal upset.
• Review question 7 asks which treatments are administered via parenteral routes, highlighting the importance of understanding the administration methods of various drugs.

Lifestyle Therapy

• Lifestyle therapies for dyslipidemia include following a Mediterranean diet with high omega-3 fatty acids, decreased saturated fats, and increased fiber.
• Increased physical activity of 150 minutes per week is strongly recommended.
• Dietary supplements, such as garlic, red yeast rice, and fish oils, may be considered; however, more recent evidence suggests their significant benefit is unsubstantiated.
• Recommendations to modify select lipid parameters include increasing soluble fiber and phytosterol intake to lower LDL-C and increasing physical activity, smoking cessation, and weight loss to increase HDL-C and lower triglycerides.

Evolving Lipid Landscape

• An overview of the evolving understanding of lipid disorders is presented highlighting the different stages of guidelines (ATP I, II, III and AHA/ACC guidelines) and the progression of treatment recommendations (statins, bile acid resins, nicotinic acid, fibrates) from the 1980s to 2018.
• Each stage of evolution included treatment parameters and guidelines used to assess risk/identify treatment options for different population groups based on age requirements.
• Highlighting risk-enhancing factors associated with diabetes or specific to diabetes is recommended.

Simplified Approach to Treatment

• A simplified approach to treating dyslipidemia is present along with treatment threshold recommendations, for individuals with history of ASCVD and those with no history, and focusing on several risk factors including diabetes, age, and 10-year risk score.
• This approach simplifies the evaluation process by prioritizing ASCVD status, LDL-C levels, diabetes status, and age range when determining statin benefit groups.

Clinical ASCVD (Secondary Prevention)

• The clinical presentation of individuals with a history of ASCVD is presented, including risk factors like recent ACS, MI, ischemic stroke, symptomatic PAD, High-Risk conditions, including age, history of CABG/PCI (outside of ACS event), and diabetes mellitus, along with a detailed outline for treatment (High-intensity statin based on criteria).
• These considerations offer a structured approach to evaluate specific individuals' risk profiles.

Primary Prevention of ASCVD

• An approach to primary prevention of ASCVD, based on risk assessment and clinical parameters, is presented.
• Treatment options are stratified by LDL-C values and age, and risk factors, such as 10-year risk score, are considered, providing a tiered approach to intervention.

Additional Considerations for Statin Therapy

• Additional considerations regarding statin treatments for special populations like HIV-positive individuals are presented.
• The role of statins is emphasized in reducing adverse events and mortality linked to CVD.
• Statin benefits for patients with HIV are presented, including data from clinical trials to support the consideration, suggesting a probable benefit of statins, potentially linked to the inflammatory response.
• General considerations for older adults and women of childbearing age are also present to determine benefits and risks.

Additional statin therapy: considerations

• Optimization of current regimen, including considering potential for incremental ASCVD risk reduction via lifestyle modifications and comorbidities are also emphasized for treatment.

Hypertriglyceridemia

• Conditions, medications, and secondary factors for elevated triglycerides levels are presented, and treatment goals are outlined.

Lipid Monitoring

• Recommendations on when to perform lipid panel checks (baseline and follow-up) and factors to consider, such as adherence assessment and efficacy assessment/guidance, are detailed.
• Monitoring and appropriate frequency for creatinine kinase, and liver function tests (LFT) are included in the discussion.

Optimization of Doses

• Strategies for optimizing statin doses when patients do not meet LDL-C reduction or threshold goals are presented, emphasizing important steps including assessments of adherence, risks, and increasing doses, and when additional non-statin therapies may be appropriate.

Statin-Associated Muscle Symptoms (SAMS)

• The relationship between statin use and the risk of muscle symptoms is examined, including demographic factors, statin properties (e.g. lipophilicity), and co-morbidities which may increase the risk.
• Specific considerations for classifying and managing statin-associated muscle symptoms, including appropriate follow-up (LFT's, CPK levels) are presented.

Review Question 10

• Case-based scenarios focusing on choosing appropriate treatment steps for patients with diabetes and LDL-C levels are presented. The proper clinical monitoring practices and consideration for lifestyle modification are included.
• Specific examples of treatment choices, such as titrating to a different statin or further evaluating lipid values, are elaborated upon.

Conclusion

• The concluding sections summarize the essential information regarding the body's lipid management, the treatment choices (statins), and considerations for additional treatments given the specific clinical situation.

Review Cases

• Detailed review cases highlight specific patient scenarios, presenting their age, medical history, current medications, and laboratory values.
• Discussion of approaches to assess ASCVD risk and determine if a patient falls within specific risk groups and/or treatment guidelines, such as those receiving statin therapy.
• The questions for each review case encourage critical thinking, promoting the application of previously learned material to clinical situations, and enabling the student to consider risks and benefits for each decision process.

Exam Review Material

• The format and potential content to expect for a dyslipidemia exam, is identified as 16 questions, with a variety of question formats.
• Case studies, and clinical vignettes are presented, providing a foundation for practical application of information.
• Additional review sections providing a reference for all content learned, which is useful for exam preparation, are emphasized.

Content (Lipids)

• Progress of atherosclerotic disease to ASCVD events and a general overview of lipids and lipoproteins, including similarities and differences, and function of major components, are presented.
• Cholesterol synthesis and the role of each lipoprotein for both exogenous and endogenous transport pathways, are detailed.
• Diagnostic characteristics, such as classification and causes of primary/familial vs secondary/acquired dyslipidemia, and other parameters such as SDOH, are discussed.
• Assessing the risk of ASCVD is highlighted, from lipid panel information from patients, including Friedwald equation restrictions, and lab tests such as hsCRP and CK; providing a comprehensive overview for exam preparation.

Content (Treatment & Monitoring)

• Important components for approaching treatment in patients with dyslipidemia are presented (statin benefit determination, treatment pathways, special populations such as those with triglycerides issues, and when non-statin therapies may be beneficial). This approach enables effective decision making for patient care.
• Important steps for monitoring patients and their treatment plans are detailed, alongside how to appropriately monitor patients, and specific parameters to pay attention to, when managing SAMS including frequency of blood draws, etc.

Advice

• Review questions in their entirety are recommended.
• The importance of reciting cases to aid in assimilation is strongly suggested.
• Students are strongly encouraged to not stress, and direct feedback and/or clarifying information from the instructor is encouraged.

Additional Considerations

• Optimization of current treatment regimens, potentially enhancing ASCVD risk reduction, are elaborated upon, including consideration of comorbidities that may increase or reduce risk, cost, and patient preferences.
• The importance of appropriate patient selection for each decision point is heavily emphasized, supporting a holistic approach to patient care.

Test your knowledge on the ASCVD risk estimator and its application in managing dyslipidemia. This quiz covers key concepts including medication classes, statin intensity, and the mechanisms of action for cholesterol-lowering drugs. Understand the limitations and components of cardiovascular health assessments.