May/June 2023"Practice Guidelines: Updated guidelines for the management of dyslipidemia and the prevention

Updated guidelines for the management of dyslipidemia and the prevention of cardiovascular disease in adults by pharmacistsHazal E. Babadagli, BScPharm, PharmD; Arden R. Barry, BSc, BSc(Pharm), PharmD, ACPR; George Thanassoulis, MD, MSc, FRCPC; Glen J. Pearson, BSc, BScPhm, PharmD, FCSHP, FCCS© The Author(s) 2023img2

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DOI: 10.1177/17151635231164989IntroductionCardiovascular disease (CVD) is the second leading cause of death in Canada.¹ The prevalence of ischemic heart disease continues to rise, highlighting the importance of effective long-term risk factor management.² Pharmacist-led dyslipidemia management has been demonstrated to lead to significant improvements in patient outcomes.^3-5 In this article, we provide guidelines on the management of dyslipidemia that are tailored to pharmacists, based on the 2021 Canadian Cardiovascular Society (CCS) Dyslipidemia Guidelines.⁶ Notable updates in the new CCS guidelines since the 2016 version are highlighted in Table 1.Who should be screened?The CCS dyslipidemia guidelines continue to recommend screening all individuals 40 years of age or older as well as all individuals with 1 or more risk factors, as listed in Table 2. Further emphasis is given to screening of women who have had pregnancy complications. In addition to women with hypertensive disorders of pregnancy, the new CCS dyslipidemia guidelines have expanded their recommendation to include screening all women with a history of gestational diabetes, preterm birth, stillbirth, low-birth-weight infant or placental abruption. These pregnancy complications have been associated with a higher risk of developing cardiovascular risk factors, in addition to atherosclerotic CVD (ASCVD).^7,8How should patients be screened?General screeningThe CCS dyslipidemia guidelines continue to recommend the screening tests highlighted in Table 2. As per the previous guidelines, a lipid panel is recommended to be done in the nonfasting state unless the patient has a triglyceride (TG) level >4.5 mmol/L. Notable updates in the new guidelines are the roles of lipoprotein(a) (Lp[a]), non–high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B (ApoB), as described below.Role of Lp(a)A notable update in the new CCS guidelines is the recommendation to measure Lp(a) once in a person’s lifetime as part of initial lipid screening. Lp(a) is an LDL-like particle in which ApoB is covalently bound to a plasminogen-like molecule called apolipoprotein(a). It is genetically determined, so it is generally stable throughout an individual’s life and is not influenced by age, sex, fasting state, inflammation, or lifestyle factors. Studies have demonstrated that high levels of Lp(a) have been associated with an increase in cardiovascular risk.^9-12 For patients with an elevated Lp(a) of ≥50 mg/dL, earlier and more intensive management of cardiovascular risk factors is recommended. Lp(a) does not yet have a treatment target or threshold, as there is currently established lack of quality evidence demonstrating a cardiovascular benefit with a reduction in Lp(a), which is another justification of why repeated measurements of Lp(a) are not currently indicated.Role of non–HDL-C and ApoBFurther emphasis is given in the new guidelines to the roles of non–HDL-C and ApoB in the screening and monitoring of patients. These 2 lipid parameters are now generally preferred over LDL-C when interpreting lipid results because they provide a more accurate assessment of the total concentration of atherogenic particles compared with LDL-C. This has translated to a superior cardiovascular risk prediction when compared with LDL-C.^13,14 The new guidelines also recommend using non–HDL-C and ApoB over LDL-C in patients with a TG level >1.5 mmol/L. Above this TG value, some cholesterol in LDL particles is replaced by TG, which promotes production of more atherogenic small dense LDL particles and makes the amount of cholesterol in LDL an unreliable reflection of LDL particle number.⁶ Notably, the new guidelines include slightly modified non–HDL-C and ApoB parameters compared with the 2016 CCS guidelines to more accurately represent the same population percentile equivalents as LDL-C.Summary

New evidence in the management of dyslipidemia has recently led to the publication of the 2021 Canadian Cardiovascular Society (CCS) dyslipidemia guidelines.

This focused practice guideline update is tailored to pharmacists, based on the specific recommendations from the 2021 CCS dyslipidemia guidelines.

This practice guideline update outlines the new recommendations and provides tips on implementation, including which patients to screen, how to perform cardiovascular risk assessment, and how to intensify therapy beyond statin treatment.

With the known value of pharmacist-led dyslipidemia management, these proposed practice guidelines will assist pharmacists in practising to their full scope of practice and taking an active role in the management of patients with dyslipidemia.

Who should receive therapy?Statins remain the recommended first-line therapy for all patients with dyslipidemia.⁶ To determine who to treat, pharmacists first need to assess a patient’s cardiovascular risk. Patient risk may be divided into 2 categories: primary cardiovascular prevention (Figure 1) and those with statinindicated conditions, which automatically confer a higher risk of CVD (Figure 2). For primary prevention patients, pharmacists should estimate a patient’s long-term cardiovascular risk using a validated risk calculator (e.g., Framingham Risk Score: https://ccs.ca/app/uploads/2020/12/FRS_eng_2017_fnl1.pdf). Statin therapy is then recommended based on the patient’s cardiovascular risk score (low, intermediate, or high) and baseline lipid levels. For all patients who already have a statin-indicated condition, statin therapy should be recommended, as they have demonstrated the largest absolute benefit in reducing cardiovascular events in these group of patients.Résumé

De nouvelles données sur la prise en charge de la dyslipidémie ont récemment mené à la publication des lignes directrices 2021 de la Société canadienne de cardiologie (SCC) sur la dyslipidémie.

Cette mise à jour des lignes directrices axées sur la pratique est adaptée aux pharmaciens, et fondée sur les recommandations spécifiques des lignes directrices 2021 de la SCC sur la dyslipidémie.

Cette mise à jour des lignes directrices axées sur la pratique décrit les nouvelles recommandations et fournit des conseils sur leur mise en œuvre, y compris sur les patients qui doivent se soumettre à un dépistage, sur la manière d’évaluer le risque cardiovasculaire et sur la façon d’intensifier le traitement autre que le traitement par statine.

Compte tenu de la valeur reconnue de la prise en charge de la dyslipidémie par les pharmaciens, cette proposition de lignes directrices axées sur la pratique aidera les pharmaciens à exercer pleinement leur profession et à jouer un rôle actif dans la prise en charge des patients atteints de dyslipidémie.

Assess cardiovascular risk

Statin-indicated conditions (patients are automatically considered to be at high cardiovascular risk):

a. LDL-C ≥5 mmol/L, ApoB ≥1.45 g/L, or non– HDL-C ≥5.8 mmol/L or documented familial hypercholesterolemia

b. Most patients with diabetes mellitus:

i. ≥40 years of age, or

ii. ≥30 years of age with ≥15 years’ duration, or

iii. presence of microvascular complications

c. Chronic kidney disease (CKD) not treated with chronic dialysis, defined as age ≥50 years and estimated glomerular filtration rate <60 mL/min/1.73 m² or albumin-to-creatinine ratio >3 mg/mmol

d. Patients with ASCVD (this refers to all clinical conditions of atherosclerotic origin):

i. Coronary artery disease:

Acute coronary syndrome (ACS)
History of coronary artery bypass graft surgery or coronary stenting
Stable or unstable angina
Documented coronary artery disease by angiography

ii. Cerebrovascular disease:

Stroke
Transient ischemic attack
Documented carotid disease

iii. Peripheral artery disease:

Claudication and/or ankle-brachial index <0.9
Femoral popliteal bypass graft surgery

iv. Abdominal aortic aneurysm (atherosclerosis is a known culprit):

Abdominal aorta >3.0 cm
Previous aortic aneurysm surgery

Primary prevention patients (need to determine the patient’s baseline cardiovascular risk):

Cardiovascular risk can be assessed using the following validated scores:

i. The modified Framingham 10-year Risk Score (FRS), available in the CCS guideline app ii. “Cardiovascular age” using the Cardiovascular Life Expectancy Model (online calculator available in the CCS guideline app or at http://myhealthcheckup.com/cvd/?lang=e) iii. For women with hypertensive disorders of pregnancy, the guidelines recommend favouring cardiovascular age over 10-year risk calculators b. Coronary artery calcium (CAC) score: i. CAC score testing involves a computed tomography scan of the chest to quantify calcification of the coronary arteries, which is a marker of atherosclerotic plaque. ii. Some intermediate-risk patients and subset of low-risk patients may undergo CAC screening. iii. CAC measurement >0 Agatston units (AU) confirms the presence of atherosclerotic plaque. A score >100 AU indicates significant coronary plaque burden and is considered to be a statinindicated condition. Pharmacists can play an active role in identifying these patients to help initiate statin therapy.Tab1Tab2Initiate statin therapy according to cardiovascular risk

Once cardiovascular risk assessment is complete, pharmacists should use the results to engage with their patient in a shared decision-making process. This includes:

Ensuring that the patient understands their baseline cardiovascular risk
Discussing the benefits that statins may offer in terms of cardiovascular risk reduction and their possible adverse effects
Addressing any misconceptions that the patient may have about their cardiovascular risk and therapeutic options

Recommend initiating statin therapy according to the guidelines:

Primary prevention patients (Figure 1):
1. High-cardiovascular-risk patients (10-year FRS ≥20%): statin therapy recommended in all patients
2. Intermediate-cardiovascular-risk patients (10-year FRS of 10%-19.9%): recommend statin therapy if
  - LDL-C ≥3.5 mmol/L, or non–HDL-C ≥4.2 mmol/L, or ApoB ≥1.05 g/L or
  - Other groups include patients fulfilling the HOPE-3 trial¹⁵ criteria or patients who present with specific risk modifiers (new recommendation in the guidelines), as detailed in Figure 1
3. Low-cardiovascular-risk patients (10-year FRS of <10%): statin therapy generally not recommended for most low-risk individuals; however, exceptions for low-risk patient groups who may benefit from statin therapy are detailed in Figure 1
Patients with statin-indicated conditions (Figure 2): statin therapy recommended in all patients.

Treatment in older adults:

Emerging evidence continues to demonstrate that there are benefits to maintaining low levels of atherogenic lipoproteins at any age. This includes the benefits of lipid-lowering therapy for primary prevention patients who are ≥75 years of age.^16,17

How should therapy be intensified?Use thresholds (as opposed to targets) for therapy intensificationOnce statin therapy is initiated, therapy is then intensified if a patient’s follow-up lipid parameter remains above the defined threshold. This is a change from the previous approach that used a specific lipid target. There are several reasons why targets were changed to thresholds in the new guidelines. There is no robust randomized controlled trial evidence to support clear targets to which LDL-C, non–HDL-C, or ApoB levels should be lowered. Instead, trials have generally used thresholds of LDL-C (or non–HDL-C or ApoB) levels for initiation and intensification of therapy. Recent trials in secondary ASCVD prevention patients have used an LDL-C threshold of 1.8 mmol/L for intensification of therapy beyond statins, which is reflected in the algorithm of the new guidelines (Figure 2).^18,19 Lower concentrations of plasma LDL-C levels are associated with a lower risk of ASCVD events, which supports a causal relationship between LDL-C (as well as non–HDL- C and ApoB) and ASCVD.^18-25 Furthermore, recent evidence does not suggest that there are any risks associated with achieving very low LDL-C levels in trials with moderate duration of follow-up.^26,27

Once patients are on a maximally tolerated statin dose, through shared decision-making with the patient, the new guidelines recommend titration of therapy based on the following thresholds:

a. Statin-indicated conditions: i. In patients with a baseline LDL ≥5 mmol/L (or ApoB ≥1.45 g/L or non–HDL-C ≥5.8 mmol/) or documented familial hypercholesterolemia, consider therapy intensification with ezetimibe or a PCSK9 inhibitor if LDL-C ≥2.5 mmol/L (or <50% reduction), or ApoB ≥0.85 g/L, or non– HDL-C ≥3.2 mmol/L. ii. In patients with diabetes mellitus or CKD, intensify therapy with ezetimibe (or bile acid sequestrants as an alternative) if LDL-C ≥2.0 mmol/L (or <50% reduction), or ApoB ≥0.80 g/L, or non–HDL-C ≥2.6 mmol/L. iii. In patients with ASCVD, consider therapy intensification with ezetimibe and/or a PCSK9 inhibitor if LDL-C ≥1.8 mmol/L, or ApoB ≥0.7 g/L, or non–HDL-C ≥2.4 mmol/L (Figure 3), or iv. In patients with ASCVD, consider therapy intensification with icosapent ethyl (IPE) if TG ≥1.5-5.6 mmol/L.B. Primary prevention patients: i. Intensify therapy with ezetimibe (or a bile acid sequestrant as an alternative) if LDL-C >2 mmol/L, or ApoB >0.8 g/L, or non–HDL-C >2.6 mmol/L.Use thresholds (as opposed to targets) for therapy intensificationOnce statin therapy is initiated, therapy is then intensified if a patient’s follow-up lipid parameter remains above the defined threshold. This is a change from the previous approach that used a specific lipid target. There are several reasons why targets were changed to thresholds in the new guidelines. There is no robust randomized controlled trial evidence to support clear targets to which LDL-C, non–HDL-C, or ApoB levels should be lowered. Instead, trials have generally used thresholds of LDL-C (or non–HDL-C or ApoB) levels for initiation and intensification of therapy. Recent trials in secondary ASCVD prevention patients have used an LDL-C threshold of 1.8 mmol/L for intensification of therapy beyond statins, which is reflected in the algorithm of the new guidelines (Figure 2).^18,19 Lower concentrations of plasma LDL-C levels are associated with a lower risk of ASCVD events, which supports a causal relationship between LDL-C (as well as non–HDL- C and ApoB) and ASCVD.^18-25 Furthermore, recent evidence does not suggest that there are any risks associated with achieving very low LDL-C levels in trials with moderate duration of follow-up.^26,27Fig1Fig2Nonstatin therapy optionsSince the 2016 CCS guidelines, new evidence has provided further clarity on the role of nonstatin therapy, as summarized in Table 3. Further details on the role of nonstatin therapy options are described below.Ezetimibe. The 2021 CCS dyslipidemia guidelines continue to recommend ezetimibe as second-line therapy based on the results of the IMPROVE-IT trial, which was presented in the 2016 CCS guidelines.^33,34 Briefly, the IMPROVE-IT trial showed a modest reduction in a composite cardiovascular outcome when ezetimibe was added to statin therapy in patients with a recent ACS. Ezetimibe is recommended as potential add-on therapy to statins in both primary and secondary prevention patients. However, because ezetimibe reduces LDL-C by approximately 20% on top of statin therapy, it may be preferrable to start with a PCSK9 inhibitor as an add-on therapy if a patient has ASCVD and an LDL-C >2.2 mmol/L (or >20% above threshold).PCSK9 inhibitors. Since the 2016 CCS dyslipidemia guidelines, 2 new trials (FOURIER and ODYSSEY OUTCOMES) with PCSK9 inhibitors have been published (refer to Table 3 for details).^18,19 Both evolocumab and alirocumab lower LDL-C by about 60% when used in addition to statin therapy and are approved for add-on therapy to statins in secondary ASCVD prevention patients and familial hypercholesterolemia patients. Cost may be a barrier to access to PCSK9 inhibitor therapy.IPE. IPE is a prescription-only, highly purified formulation of ethyl eicosapentaenoic acid (EPA) that was recently approved for use in Canada on the basis of the REDUCE-IT trial (refer to Table 3 for details).²⁸ However, cost may be a barrier to access. Pharmacists should inform patients of the potential benefits, as well as the cost of IPE, to engage in a shared decision-making process when this therapy is indicated.Omega-3 polyunsaturated fatty acids. While IPE has been shown to decrease cardiovascular events, it should not be inferred that the same benefit could be extrapolated to other omega-3 formulations, which include a combination of nonpurified EPA, docosahexaenoic acid, alpha linolenic acid, or other omega fatty acids (e.g., omega-6 or omega-9 fatty acids) from over-the-counter supplements or dietary sources. The guidelines do not recommend the use of these agents for CVD risk reduction.^29-32There are no new recommendations regarding the specific use of fibrates, bile acid sequestrants, or niacin since the 2016 CCS guidelines.What lifestyle modifications are recommended?The 2021 CCS dyslipidemia guidelines continue to recommend health behaviour modifications as the cornerstone of CVD prevention in all patients.^6,35,36 Pharmacists can reinforce the following lifestyle modifications:

Tobacco: Counsel and assist with the cessation of tobacco use.

Alcohol: Educate patients on what is considered a safe amount of alcohol consumption, and encourage patients to adhere to these limits. In Canada’s new guidance on alcohol and consumption report,³⁷ it is recognized that no amount of alcohol is good for your health, and drinking even a small amount has potential negative consequences. Importantly, it is identified that the risk for heart disease and stroke increases with consumption of 7 or more drinks per week.

Diet: Encourage all patients to maintain a healthy dietary pattern, such as the Mediterranean diet, avoiding trans fats and substituting polyunsaturated fats for saturated fats.

Activity: Encourage all patients to achieve 150 minutes of moderate to vigorous aerobic activity per week, in addition to adding muscle- and bone-strengthening activities at least 2 days per week. In secondary prevention patients, reducing sedentary behaviour can be additive to regular physical activity for reducing cardiovascular events.

Implementation tips for pharmacistsClinical trial evidence has demonstrated the value of pharmacist screening for dyslipidemia and prescribing in improving control of dyslipidemia when added to usual medical care.^3,4 Consequently, pharmacists should practise to the full scope possible in their province to take an active role in the management of patients with dyslipidemia and at risk for cardiovascular disease.Fig3

Identify and screen patients:

Some pharmacies provide point-of-care testing for lipid values depending on availability and provincial legislation.
Conduct cardiovascular risk assessment for patients identified in Table 2 (whom to screen for dyslipidemia) using the modified FRS or the Cardiovascular Life Expectancy Model.
Be aware of patients with a statin-indicated condition, as there is no need to conduct a cardiovascular risk assessment to guide treatment decisions since this group is treated based on clinical conditions (Figure 2).
Where authorized, order appropriate laboratory assessments as outlined in Table 2 (what to screen for dyslipidemia).

Ensure that all patients are treated appropriately:

Emphasize the importance of health behaviour modifications for all patients at risk of cardiovascular disease.
Recognize patients who would benefit from initiation of a statin:
- Those with a statin-indicated condition
- High-risk primary prevention patients (modified FRS ≥20%)
- Intermediate-risk primary prevention patients (modified FRS 10%-19.9%) and an LDL-C ≥3.5 mmol/L (or non–HDL-C ≥4.2 mmol/L or ApoB ≥1.05 g/L)
Ensure that patients who are eligible for statin therapy are receiving a high-intensity or maximally tolerated dose.
Monitor response to statin therapy and determine patients who may be appropriate for intensification of lipid-lowering therapy (addition of ezetimibe and/or a PCSK9 inhibitor) based on the recommended lipid thresholds (Figure 2) and facilitate medication access, where appropriate.
Identify patients who may benefit from the addition of IPE, such as those with ASCVD who are receiving a maximally tolerated statin dose, with TG ≥1.5 to 5.6 mmol/L (refer to Figure 3, for all eligible patients) and facilitate medication access, where appropriate.
Do not recommend over-the-counter omega-3 fatty acids for cardiovascular risk reduction, and educate patients who are self-selecting these products about the recent evidence demonstrating a lack of benefit.
Ensure that patients are educated about the risks and benefits of any lipid-lowering therapy they are prescribed.

Tab3ConclusionThe 2021 CCS dyslipidemia guidelines are relevant to pharmacists who provide care to patients with dyslipidemia and who are at risk for cardiovascular disease. This article summarizes the updated dyslipidemia guidelines for pharmacists, but readers are encouraged to refer to the full guidelines for additional details.⁶ In addition, pharmacists can access several useful practice tools and education resources for the management of dyslipidemia on the CCS website (https://www.ccs.ca/en/guidelines/guideline-resources).From the Mazankowski Alberta Heart Institute (Babadagli, Pearson), Edmonton; the Department of Medicine (Pearson), Division of Cardiology, Faculty of Medicine and Dentistry, University of Alberta; Pharmacy Services, Alberta Health Services (Babadagli), Edmonton, Alberta; Lower Mainland Pharmacy Services (Barry), Jim Pattison Outpatient Care and Surgery Centre, Surrey, BC; the Faculty of Pharmaceutical Sciences (Barry), University of British Columbia, Vancouver, BC; and the Department of Medicine and the Research Institute (Thanassoulis), McGill University Health Centre Montreal, Quebec. Contact Glen.Pearson@ualberta.ca.Author Contributions: G. J. Pearson initiated the project. G. Thanassoulis and G. J. Pearson were co-chairs on the guideline panel, A. R. Barry was a member of the primary panel of the 2021 CCS Dyslipidemia Guidelines Committee, and all were authors of the original publication. H. E. Babadagli and G. J. Pearson were responsible for translating the content from the 2021 CCS Dyslipidemia Guideline and preparing the initial draft of this article. All authors revised the draft manuscript for important intellectual content and gave final approval of the version to be published.Declaration of Conflicting Interests: The authors declare no potential or actual conflict of interest with respect to research, authorship and/or publication of this article.Funding: The authors received no financial support for the research, authorship and/or publication of this article.ORCID iDs: Arden R. Barry https://orcid.org/0000-0002-0287-898XGlen J. Pearson https://orcid.org/0000-0003-3281-7915References

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