Hyperlipidemia, particularly hypercholesterolemia, is a common metabolic disorder. Increased low density lipoprotein cholesterol (LDL-C) is causally linked to atherosclerotic cardiovascular disease (ASCVD). Cholesterol (i.e., LDL-C) particles accumulate in atherosclerotic lesions (plaques) in arteries, reducing the flow of blood and causing ischemia in downstream tissues, causing debilitating chronic illnesses such as coronary artery disease (CAD) and peripheral artery disease (PAD). In the most serious cases, the plaques may erode or rupture, causing thrombosis and completely blocking blood flow to the downstream tissues, resulting in myocardial infarction (MI), stroke, or acute limb-threatening ischemia. Thus, control of LDL-C levels is paramount to both prevent the development of ASCVD (“primary prevention”) and to prevent adverse events in patients with established ASCVD (“secondary prevention”).
Two sets of guidelines are currently available to guide physicians in the…
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Hyperlipidemia, particularly hypercholesterolemia, is a common metabolic disorder. Increased low density lipoprotein cholesterol (LDL-C) is causally linked to atherosclerotic cardiovascular disease (ASCVD). Cholesterol (i.e., LDL-C) particles accumulate in atherosclerotic lesions (plaques) in arteries, reducing the flow of blood and causing ischemia in downstream tissues, causing debilitating chronic illnesses such as coronary artery disease (CAD) and peripheral artery disease (PAD). In the most serious cases, the plaques may erode or rupture, causing thrombosis and completely blocking blood flow to the downstream tissues, resulting in myocardial infarction (MI), stroke, or acute limb-threatening ischemia. Thus, control of LDL-C levels is paramount to both prevent the development of ASCVD (“primary prevention”) and to prevent adverse events in patients with established ASCVD (“secondary prevention”).
Two sets of guidelines are currently available to guide physicians in the lipid management of their patients:
These two documents and the key recommendations from each are discussed in the sections below.
2018 AHA/ACC/Multisociety Guideline on the Management of Blood Cholesterol
The 2018 AHA/ACC/Multisociety guideline represents an update on the earlier guideline, released in 2013. The most important change in the 2013 guideline – the removal of absolute LDL-C targets for therapy in favor of percent reduction from baseline – is maintained in the 2018 guidelines. However, LDL-C levels are reintroduced as a way to guide appropriate use of nonstatin therapies, which are given more attention than in the 2013 guidelines, reflecting the better evidence for the safety and efficacy of ezetimibe and anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) available at the time. Like in the 2013 guideline, the 2018 guideline focuses on four “statin benefit groups,” defined as follows:
Patients with established clinical ASCVD
Patients with severe primary hypercholesterolemia (a baseline LDL-C level ≥190 mg/dL)
Patients 40-75 years of age with diabetes and a baseline LDL-C level of 70-189 mg/dL
Patients 40-75 years of age with an estimated 10-year ASCVD risk of ≥7.5% to <20% (“intermediate risk”) and ≥20% (“high risk”) and select patients with an estimated 10-year ASCVD risk of 5% to <7.5% (“borderline risk”)
Individual recommendations are provided for each of the four statin benefit groups. As in other ACC/AHA guidelines, each recommendation is assigned a class of recommendation (COR; i.e., the strength of the recommendation based on the risk-to-benefit ratio) and a level of evidence (LOE; it, the quality and quantity of relevant scientific evidence from clinical trials) (Figure 21-1).
In addition to the specific recommendations, the 2018 guidelines also provide 10 “take-home” messages to reduce the risk of ASCVD; these are presented in Table 21-1.
The first statin benefit group are patients with clinically established ASCVD (the secondary prevention group). Unlike the 2013 cholesterol management guideline, which did not further subdivide this group of patients other than by age, the 2018 ACC/AHA/Multisociety guideline distinguishes between patients with ASCVD at very high risk (Table 21-2) and those with not very high risk ASCVD.
As in all other patients, a healthy lifestyle should be emphasized in patients with ASCVD. For lipid-lowering therapy, the guidelines recommend initiation of high intensity statin therapy in all patients with very high risk ASCVD and patients with not very high risk ASCVD who are ≤75 years of age (COR I; LOE A); for patients older than 75 with ASCVD not at high risk, the guidelines consider it reasonable to initiate moderate-to-high intensity statin therapy (COR IIa; LOE B-R), or continue the current statin regimen (COR IIa; LOE C-LD). For patients with not very high risk ASCVD who are 75 or younger and cannot tolerate high-intensity statin therapy, moderate-intensity statin therapy is indicated (COR I; LOE A). For patients in this group whose LDL-C level is 70 mg/dL or higher on maximally-tolerated statin therapy, the addition of ezetimibe may be reasonable (COR IIb; LOE B-R). For patients with very high risk ASCVD whose LDL-C level remains at or above 70 mg/dL despite maximally tolerated statin therapy, the addition of ezetimibe is reasonable (COR IIa; LOE B-R), and ezetimibe should be added before a PCSK9 mAb (COR I; LOE B-NR). However, addition of a PCSK9 mAb is reasonable in patients with LDL-C ≥70 mg/dL or non-high density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL on maximally tolerated lipid-lowering therapy (COR IIa; LOE A). These recommendations are shown in the algorithm in Figure 21-2.
The other three statin benefit groups are in the primary prevention category. For patients with baseline LDL-C ≥190 mg/dL and patients with diabetes 40-75 years of age, the guideline is clear: high-intensity (COR I; LOE B-R) and moderate-intensity (COR I; LOE A) statin therapy, respectively, is indicated, without the need for risk assessment. In the diabetes group, a high-intensity statin can be considered after a risk assessment (COR IIa; LOE B-R). In the final statin benefit group – patients 40-75 years of age without diabetes and with an LDL-C level ≥70 mg/dL to <190 mg/dL – the 10-year ASCVD risk assessment using the Pooled Cohort Equations form the basis for further patient classification and choice of therapy. Based on the probability of ASCVD developing in the next 10 years, these patients are classified as:
Low risk (<5%), for whom only lifestyle interventions are recommended (COR I; LOE B-NR)
Borderline risk (≥5% to <7.5%), for whom the presence of risk enhancers (see list in Figure 3) may trigger a discussion about initiating a moderate-intensity statin therapy (COR IIb; LOE B-R)
Intermediate risk (≥7.5% to <20%), for whom moderate-intensity statin therapy is indicated if the risk estimate and risk enhancers favor it (COR I; LOE A)
High risk (≥20%), for whom a high-intensity statin is indicated (COR I; LOE A)
If the decision about whether to initiate statin therapy is uncertain in intermediate risk (and selected borderline risk) patients, coronary artery calcium (CAC) scoring may be useful; with an Agatston unit score of 0 favors no statin, 1-99 favors statin and 100 or higher (or 75th percentile or higher) more strongly favors statin therapy (COR IIa; LOE B-NR). These recommendations are summarized in Figure 21-3.
For patients younger than 40, lifestyle changes to prevent the development of ASCVD are generally favored. However, statin therapy may be situationally useful even in younger parents. For example, in patients with familial hypercholesterolemia older than 20, statins are indicated (COR I; LOE B-R). In patients 20-39 years of age, statins can be considered in those with a family history of premature ASCVD and an LDL-C level ≥160 mg/dL. For adults 75 years of age and older with LDL-C 70-189 mg/dL, a moderate-intensity statin therapy may be reasonable (COR IIb; LOE B-R).
In addition to recommendations on the initiation of statin and other lipid-lowering therapy in patients in the four statin benefit groups, the 2018 ACC/AHA/Multisociety guideline also contains recommendations about:
Monitoring the response to LDL-C-lowering therapy (assess by measurement of fasting lipids and appropriate safety indicators 4-12 weeks after statin initiation or dose adjustment and every 3-12 months thereafter, as needed; COR I; LOE A)
Appropriate approaches for pediatric patients (refer to the guideline publication for specific recommendations)
Patient ethnicity, which may influence ASCVD risk, the utility of techniques such as CAC, and statin tolerability (it is reasonable to review the racial/ethnic characteristics; COR IIa; LOE B-NR)
Conditions specific to women (e.g., premature menopause, pregnancy-related disorders), which should be considered (COR I; LOE B-NR) for both lifestyle and pharmacologic therapy; women on statin therapy should (COR I; C-LD) be on reliable contraception and stop statin therapy 1-2 months before attempting pregnancy (COR I; C-LD)
Hypertriglyceridemia (refer to the guideline publication for specific recommendations)
Comorbidities, including chronic kidney disease (CKD), chronic inflammatory disorders and HIV infection (refer to the guideline publication for specific recommendations)
Statin safety and statin-associated side effects (SASEs) (refer to the guideline publication for specific recommendations)
Enlarge Figure 21-1: Levels of Evidence and Classes of Recommendation in the 2018 AHA/ACC/Multisociety Guidelines. Source: Adapted from Grundy SM, et al. J Am Coll Cardiol. 2019;73(24):3168-3209.
Enlarge Figure 21-2: 2018 ACC/AHA/Multisociety Guideline: Secondary Prevention Algorithm for Patients with Clinical ASCVD. *See Table 2. Source: Modified from Grundy SM, et al. J Am Coll Cardiol. 2019;73(24):3168-3209 and https://www.acc.org/~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/Guidelines/2018/Guidelines-Made-Simple-Tool-2018-Cholesterol
Enlarge Figure 21-3: 2018 ACC/AHA/Multisociety Guideline: Primary Prevention Algorithm. apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; HIV, human immunodeficiency virus; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a). Source: Modified from Grundy SM, et al. J Am Coll Cardiol. 2019;73(24):3168-3209 and https://www.acc.org/~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/Guidelines/2018/Guidelines-Made-Simple-Tool-2018-Cholesterol.pdf.
2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk
In 2018, when the current ACC/AHA/Multisociety guideline was published, the only nonstatins with evidential support were ezetimibe and PCSK9 mAbs. Since then, new nonstatin therapies – bempedoic acid and inclisiran – have been developed. Bempedoic acid is a prodrug whose active metabolite is an inhibitor of the enzyme ATP citrate lyase, which acts upstream of HMG-CoA reductase; therefore, bempedoic acid acts on the same pathway as statins. Inclisiran is a novel PCSK9 inhibitor; however, unlike prior PCSK9 inhibitors which were mAbs, inclisiran is a small interfering RNA (siRNA) that targets the PCSK9 mRNA for degradation, thereby reducing the amount of available PCSK9 enzyme.
To help guide the clinical decision making process in a way that reflects these changes in the therapeutic landscape, the ACC assembled a group of clinical experts in 2022 to produce an Experts Consensus Decision Pathway (ECDP) on the use of nonstatins for LDL-C lowering. While the 2022 ECDP offers an update to many recommendations from the 2018 ACC/AHA/Multisociety guideline, it is important to stress that it does not represent a formal update to the guideline, since its creation did not involve formal systematic reviews or the synthesis or grading of evidence; the aim was to provide practical guidance until a new set of guidelines can be produced.
The 2022 ECDP contains four algorithms for secondary prevention. The first algorithm concerns patients with not very high ASCVD without primary hypercholesterolemia (Figure 21-4). If ≥50% LDL-C reduction and an LDL-C level of <70 mg/dL (or non-HDL-C level of <100 mg/dL) cannot be achieved on maximally tolerated statin therapy, nonstatin options for these patients include: 1) ezetimibe; 2) PCSK9 mAb; and 3) bempedoic acid or inclisiran.
The second algorithm is intended for patients with clinical ASCVD and primary hypercholesterolemia, but without clinical or genetic diagnosis of familial hypercholesterolemia (Figure 21-5). If these patients cannot achieve ≥50% LDL-C reduction and an LDL-C level of <70 mg/dL (or non-HDL-C level of <100 mg/dL) on maximally tolerated statin therapy, the following nonstatin options may be considered: 1) ezetimibe and/or PCSK9 mAb; 2) bempedoic acid or inclisiran; 3) LDL apheresis.
The third secondary prevention algorithm is intended for patients with very high risk clinical ASCVD without primary hypercholesterolemia (Figure 21-6). The threshold for considering nonstatin therapies in these patients is <50% LDL-C reduction and an LDL-C level of ≥55 mg/dL (or non-HDL-C level of ≥85mg/dL), with the following nonstatin options for consideration: 1) ezetimibe and/or PCSK9 mAb; 2) bempedoic acid or inclisiran.
Finally, the fourth secondary prevention algorithm concerns patients with very high risk clinical ASCVD and clinical diagnosis or genetic confirmation of familial hypercholesterolemia (Figure 21-7). Like for other patients with very high risk ASCVD, the threshold for considering nonstatin therapies in this patient group is <50% LDL-C reduction and an LDL-C level of ≥55 mg/dL (or non-HDL-C level of ≥85mg/dL). The following nonstatin options may be considered: 1) ezetimibe and/or PCSK9 mAb; 2) bempedoic acid or inclisiran; 3) evinacumab, lomitapide and/or LDL apheresis for homozygous familial hypercholesterolemia.
The 2022 ECDP also provides four algorithms relevant for primary prevention of ASCVD. For patients with primary hypercholesterolemia and no ASCVD (Figure 21-8), nonstatins may be considered if maximally tolerated statin therapy fails to result in ≥50% LDL-C reduction and LDL-C <100 mg/dL (or non-HDL-C <130 mg/dL). Suggested options include: 1) ezetimibe and/or a PCSK9 mAb; 2) bempedoic acid or inclisiran; 3) evinacumab, lomitapide, and/or LDL apheresis for homozygous familial hypercholesterolemia.
The second 2022 ECDP primary prevention algorithm concerns patients with diabetes (Figure 21-9). In these patients, the ECDP states that ezetimibe may be considered in the subset of patients whose 10-year ASCVD risk is 20% or higher and in whom a high-intensity statin regimen did not succeed in achieving a ≥50% reduction in LDL-C levels and whose LDL-C level remains ≥70 mg/dL (or non-HDL-C level ≥100 mg/dL).
The third 2022 ECDP primary prevention algorithm concerns the last statin benefit group - patients with none of ASCVD, diabetes, or primary hypercholesterolemia, but with at least borderline 10-year ASCVD risk (Figure 21-10). The ECDP considers nonstatin therapy appropriate in patients at high 10-year ASCVD risk who fail to achieve ≥50% reduction in LDL-C levels and whose LDL-C level remains ≥70 mg/dL on maximally tolerated statin therapy. In these patients, ezetimibe may be considered.
The ECDP also states that ezetimibe may be considered in patients with intermediate and select patients with borderline 10-year ASCVD risk whose CAC score is ≥100 Agatston units (or ≥75th percentile), if the statin therapy did not result in ≥50% reduction in LDL-C levels (and an LDL-C level of <70 mg/dL) (Figure 21-11). In patients with a CAC score of 1000 Agatston units or higher, if the addition of ezetimibe fails to meet this target, the ECDP states that it may be reasonable to consider adding a PCSK9 mAb.
Finally, the 2022 ECDP also includes an algorithm for patients with suspected SASEs. If a patient proves intolerant of ≥2 statin regimens with one attempt at the lowest FDA-approved dose and a trial of alternative dosing regimens, nonstatin therapies shown in Figure 21-12 may be considered, depending on the patient’s clinical scenario.
Enlarge Figure 21-4: 2022 ECDP Algorithm for Secondary Prevention in Patients with Not Very High Risk ASCVD. Notes: *See Table 2 for criteria for defining patients at very high risk. †The writing committee emphasizes that these are not firm triggers for adding medication, but factors that may be considered within the broader context of an individual patient’s clinical situation. ‡Clinicians should preferentially prescribe drugs that have been shown in randomized controlled trials to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions and consider patient preferences. §Consider only if on maximally tolerated statin therapy and either ezetimibe or bile acid sequestrants, with persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). Strongly consider if patient is unable to tolerate even low-intensity statin therapy or alternative statin therapy dosing regimens (every other day, twice weekly, or weekly) and attempts to lower LDL-C with ezetimibe or a bile acid sequestrant result in persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). It is reasonable to engage in a clinician-patient discussion with consideration of net risk reduction benefits of a PCSK9 inhibitor, cost, administration by subcutaneous injection, every 14-day or monthly dosing schedule, and storage requirements (refrigeration). ∥Strongly consider a PCSK9 inhibitor if the patient is unable to tolerate even low-intensity statin therapy or alternative statin therapy dosing regimens (every other day, twice weekly, or weekly) and attempts to lower LDL-C with ezetimibe or a bile acid sequestrant result in persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). ¶No outcome studies exist for bempedoic acid or inclisiran. #A PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes. Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects from both PSCK9 mAbs, or those who may be unable to self-inject. There is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be in place of a PCSK9 mAb. **Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; ECDP, Expert Consensus Decision Pathway; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin type 9 monoclonal antibody; RD/RDN, registered dietitian/registered dietitian nutritionist; SASE, statin-associated side effect. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-5: 2022 ECDP Algorithm for Secondary Prevention in Patients with Clinical ASCVD and Primary Hypercholesterolemia (but no Diagnosed Familial Hypercholesterolemia). Notes: *For example, hypothyroidism, nephrosis, extreme dietary patterns (eg, anorexia nervosa). †The writing committee emphasizes that these are not firm triggers for adding medication, but factors that may be considered within the broader context of an individual patient’s clinical situation. ‡May consider lomitapide or LDL apheresis in appropriate patients. §If patients with clinical ASCVD and LDL-C ≥190 mg/dL require >25% additional lowering of LDL-C, a PCSK9 mAb may be preferred as the initial nonstatin agent. It is reasonable to engage in a clinician–patient discussion with consideration of net risk reduction benefits of a PCSK9 inhibitor, cost, administration by subcutaneous injection, every 14-day or monthly dosing schedule, and storage requirements (eg, refrigeration). Consider only if on maximally tolerated statin therapy with persistent <50% LDL-C reduction and LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). Strongly consider PCSK9 mAb if the patient is unable to tolerate even low-intensity statin therapy or alternative statin therapy dosing regimens (every other day, twice weekly, or weekly) and attempts to lower LDL-C with ezetimibe or a bile acid sequestrant result in persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). ∥Clinicians should preferentially prescribe drugs that have been shown in randomized controlled trials to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug-drug interactions and consider patient preferences. ¶No outcome studies exist for bempedoic acid or inclisiran. #A PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes. Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects from both PSCK9 mAbs, or those who may be unable to self-inject. There is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be in place of a PCSK9 mAb. **Limited data are available for apheresis. Patients with clinical ASCVD and persistent elevation of LDL-C >200 mg/dL without a clinical or genetic diagnosis of familial hypercholesterolemia, may be candidates for LDL apheresis under the care of a lipid specialist. ††Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; ECDP, Expert Consensus Decision Pathway; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin 9 monoclonal antibody; RD/RDN, registered dietitian/registered dietitian nutritionist; SASE, statin-associated side effect. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-6: 2022 ECDP Algorithm for Secondary Prevention in Patients with Very High Risk Clinical ASCVD. Notes: *See Table 2 for criteria for defining patients at very high risk. †In very high-risk patients who require greater lowering of LDL-C at the time of an ASCVD event, initiation of combination therapy with high-intensity or maximally tolerated statin therapy and ezetimibe or maximally tolerated statin therapy with/without ezetimibe and PCSK9 mAbs may be considered. ‡The writing committee emphasizes that these are not firm triggers for adding medication but factors that may be considered within the broader context of an individual patient’s clinical situation. §If adults with clinical ASCVD at very high risk on a statin therapy for secondary prevention require >25% additional lowering of LDL-C, a PCSK9 inhibitor may be preferred as the initial nonstatin therapy. It is reasonable to engage in a clinician–patient discussion with consideration of net risk reduction benefits of a PCSK9 inhibitor, cost, administration by subcutaneous injection, an every 14-day or monthly dosing schedule and storage requirements (refrigeration). Consider only if on maximally tolerated statin therapy with persistent <50% LDL-C reduction or LDL-C ≥55 mg/dL (or non–HDL-C ≥85 mg/dL). Strongly consider if the patient is unable to tolerate even low-intensity statin therapy or alternative statin therapy dosing regimens (every other day, twice weekly, or weekly) and persistent <50% LDL-C reduction (or LDL-C ≥55 mg/dL or non–HDL-C ≥85 mg/dL). ∥Clinicians should preferentially prescribe drugs that have been shown in randomized controlled trials to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions and to consider patient preferences. ¶No outcome studies exist for bempedoic acid or inclisiran. #PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of demonstrated safety, efficacy and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes. Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects from both PSCK9 mAbs, or those who may be unable to self-inject. There is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be used in place of a PCSK9 mAb. **Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; ECDP, Expert Consensus Decision Pathway; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin type 9 monoclonal antibody; RD/RDN, registered dietitian/registered dietitian nutritionist; SASEs, statin-associated side effects. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-7: 2022 ECDP Algorithm for Secondary Prevention in Patients with Very High Risk Clinical ASCVD and Familial Hypercholesterolemia. Notes: *See Table 2 for criteria for defining patients at very high risk. †For example, hypothyroidism, nephrosis, extreme dietary patterns (eg, anorexia nervosa). ‡The writing committee emphasizes that these are not firm triggers for adding medication, but factors that may be considered within the broader context of an individual patient’s clinical situation. §May consider lomitapide or LDL apheresis in appropriate patients. ∥If patients with clinical ASCVD and LDL-C ≥190 mg/dL require >25% additional lowering of LDL-C, a PCSK9 mAb may be preferred as the initial nonstatin agent. It is reasonable to engage in a clinician-patient discussion with consideration of net risk reduction benefits of a PCSK9 inhibitor, cost, administration by subcutaneous injection, every 14-day or monthly dosing schedule and storage requirements (eg, refrigeration). Consider only if on maximally tolerated statin therapy with persistent <50% LDL-C reduction and LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). Strongly consider PCSK9 mAb if patient is unable to tolerate even low-intensity statin therapy or alternative statin therapy dosing regimens (every other day, twice weekly, or weekly) and attempts to lower LDL-C with ezetimibe or bile acid sequestrant result in persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). ¶Clinicians should preferentially prescribe drugs that have been shown in randomized controlled trials to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug-drug interactions and consider patient preferences. #No outcome studies exist for bempedoic acid or inclisiran. **A PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes. Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects from both PSCK9 mAbs, or those who may be unable to self-inject. There is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be in place of a PCSK9 mAb. ††No outcomes studies exist for evinacumab and lomitapide and limited data are available for apheresis. ‡‡Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; ECDP, Expert Consensus Decision Pathway; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin 9 monoclonal antibody; RD/RDN, registered dietitian/registered dietitian nutritionist; SASE, statin-associated side effect. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-8: 2022 ECDP Algorithm for Primary Prevention in Patients with Primary Hypercholesterolemia. Notes: *For example, hypothyroidism, nephrosis, extreme dietary patterns (eg, anorexia nervosa). †The writing committee emphasizes that these are not firm triggers for adding medication, but factors that may be considered within the broader context of an individual patient’s clinical situation. ‡May consider evinacumab, lomitapide, or LDL apheresis in appropriate patients. §If patients without clinical ASCVD and with LDL-C ≥190 mg/dL require >25% additional lowering of LDL-C, a PCSK9 mAb may be preferred as the initial nonstatin agent. It is reasonable to engage in a clinician-patient discussion with consideration of net risk reduction benefits of a PCSK9 inhibitor, cost, administration by subcutaneous injection, every 14-day or monthly dosing schedule and storage requirements (refrigeration). Consider only if on maximally tolerated statin therapy with persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). Strongly consider if fully statin intolerant and attempts to lower LDL-C with ezetimibe or BAS result in persistent <50% LDL-C reduction or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL). ∥Clinicians should preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions and consider patient preferences. ¶No outcome studies exist for bempedoic acid or inclisiran. #PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes. Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects from both PSCK9 mAbs, or those who may be unable to self-inject. There is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be in place of a PCSK9 mAb. **No outcome studies exist for evinacumab and lomitapide and limited data are available for LDL apheresis ††Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; BAS, bile acid sequestrant; ECDP, Expert Consensus Decision Pathway; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAB, proprotein convertase subtilisin/kexin 9 monoclonal antibody; RCT, randomized controlled trial; RD/RDN, registered dietitian/registered dietitian nutritionist; SASE, statin-associated side effect. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-9: 2022 ECDP Algorithm for Primary Prevention in Patients with Diabetes. Notes: *Diabetes-specific high-risk features include long duration (≥10 years for type 2 diabetes or ≥20 years for type 1 diabetes, albuminuria ≥30 mcg of albumin/mg creatinine, eGFR <60 mL/min/1.73 m2, retinopathy, neuropathy, ankle-brachial index <0.9. †The writing committee emphasizes that these are not firm triggers for adding medication, but factors that may be considered within the broader context of an individual patient’s clinical situation. ‡May consider a bile acid sequestrant as optional alternative agent if ezetimibe-intolerant and triglycerides <300 mg/dL. §Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; ECDP, Expert Consensus Decision Pathway; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RD/RDN, registered dietician/registered dietician nutritionist; SASE, statin-associated side effect. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-10: 2022 ECDP Algorithm for Primary Prevention in Patients without Diabetes or Primary Hypercholesterolemia. Notes: *Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; ECDP, Expert Consensus Decision Pathway; LDL-C, low-density lipoprotein cholesterol. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-11: 2022 ECDP Algorithm for Incorporation of the CAC Score in Clinical Decision-Making. Notes: *Fasting triglycerides ≥150 mg/dL following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, as well as evaluation and management of secondary causes of hypertriglyceridemia. ASCVD, atherosclerotic cardiovascular disease; AU, Agatston unit; CAC, coronary artery calcium; CHD, coronary heart disease; ECDP, Expert Consensus Decision Pathway; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin 9 monoclonal antibody. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
Enlarge Figure 21-12: 2022 ECDP Algorithm for Possible SASEs. Notes: *May consider BAS as optional alternative agent if ezetimibe-intolerant and triglycerides <300 mg/dL. †Depending on the amount of LDL-C lowering that is desired, clinicians may consider CAC scoring in these patients before alternative therapies and if the CAC score is 0, may consider deferring lipid-lowering therapy. ‡No outcome studies exist for bempedoic acid or inclisiran. §A PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes. Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects from both PSCK9 mAbs, or those who may be unable to self-inject. There is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be in place of a PCSK9 mAb. ∥Due to its demonstrated efficacy and relative safety as monotherapy and in combination with ezetimibe, in the opinion of the writing committee, bempedoic acid may be considered as third-line therapy in high-risk primary prevention patients intolerant of statin therapy. ASCVD, atherosclerotic cardiovascular disease; FDA, Food and Drug Administration; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin type 9 monoclonal antibody; SASE, statin-associated side effect. Source: Modified from Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418.
References
Robinson JG. Clinical Lipid Management, 2nd ed. Professional Communications Inc. 2023
Bardolia C, Amin NS, Turgeon J. Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol. Front Cardiovasc Med. 2021;8:789931.
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3168-3209.
Libby P, Buring JE, Badimon L, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5(1):56.
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.
Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-1418.
Dr. Robinson is Professor Emeritus at the University of Iowa in Iowa City. She has a medical degree and a Master's degree in Public Health from the University of Minnesota.
Dr. Robinson has published over 200 peer-reviewed articles in the area of lipid-modifying drugs, cardiovascular risk stratification, and cardiovascular prevention, with multiple recent publications in The New England Journal of Medicine and Journal of the American Medical Association. Dr. Robinson has researched a wide range of anti-atherosclerotic and metabolic agents, including lipid-modifying, anti-inflammatory, antihypertensive, weight loss, and diabetic treatments, as well as postmenopausal hormone therapy. She has also lectured widely on preventive cardiology and the diagnosis and treatment of disorders of lipid metabolism.
Dr. Robinson has served in leadership roles in multiple American Heart Association committees and was Vice-Chair for the American Heart Association/American College of Cardiology Cholesterol Guidelines. She was also a member of the American Heart Association/American College of Cardiology Risk Reduction Guidelines.
Financial Disclosures
The author has not disclosed any financial relationships.
Source: Content for this module was reproduced with permission from: Robinson JG. Clinical Lipid Management, 2nd ed. Professional Communications Inc. 2023. All rights reserved.
Citation
Reviewed on July 22, 2024
Robinson JG. Lipid Guidelines. July 22, 2024. Accessed January 18, 2025. https://www.healio.com/clinical-guidance/lipid-management/lipid-guidelines-treatment-guidelines
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