Non-statin therapies for LDL-C lowering in management of ASCVD risk: 2022 ACC expert consensus
Key Takeaway
The ACC convened a writing committee to provide guidance for implementation of newer non-statin therapies for LDL-C lowering in the management of ASCVD risk, which recommended that, while proceeding with the addition of non-statin therapy to maximally tolerated statin therapy, the following should be considered*:
- In adults with ASCVD not at VHR (threshold LDL-C <55 mg/dL and ≥50% LDL-C reduction)
- Addition of ezetimibe and/or PCSK9 mAb
- For additional LDL-C lowering, bempedoic acid or inclisiran may be considered
- In adults with ASCVD not at VHR (threshold LDL-C <70 mg/dL and ≥50% LDL-C reduction)
- Addition of ezetimibe
- For additional LDL-C lowering, may consider adding/replacing with PCSK9 mAb
- Thereafter lowering with bempedoic acid or inclisiran may be considered
- In adults with clinical ASCVD and baseline LDL-C ≥190 mg/dL (threshold LDL-C <70 mg/dL and ≥50% LDL-C reduction)
- Addition of ezetimibe and/or PCSK9 mAb
- For additional LDL-C lowering, may consider bempedoic acid/inclisiran
- Thereafter may consider LDL apheresis under care of lipid specialist
- In adults with clinical ASCVD, at VHR and baseline LDL-C ≥190 mg/dL (threshold LDL-C <55 mg/dL and ≥50% LDL-C reduction)
- Addition of ezetimibe and/or PCSK9 mAb
- For additional LDL-C lowering, may consider bempedoic acid/inclisiran
- Thereafter lowering with evinacumab, lomitapide and/or LDL apheresis
- In adults with possible statin associated side effects (SASE)
- Consider PCSK9 mAb and/or ezetimibe
- For additional LDL-C lowering, bempedoic acid/inclisiran
- Thereafter lowering with evinacumab for HoFH
- Simultaneous addition of 2 agents may be considered for more rapid risk reduction of recurrent events, in some adults from above categories requiring greater LDL-C reduction than any therapy alone can expect to achieve.
- Maximally tolerated statin therapy with/without ezetimibe and PCSK9 mAb, or maximally tolerated statin therapy and ezetimibe can be considered.
Why This Matters
Since publication of the 2018 AHA/ACC/ multisociety cholesterol guideline, several newer non-statin agents have demonstrated LDL-C lowering efficacy, received approval, and been made available for management of at-risk patients.
- However, this led to gaps in expert guidance with reference to the role of available non-statin therapies.
The ACC convened a writing committee, in 2021 to address current gaps in care for LDL-C lowering to reduce ASCVD risk and to provide further recommendations regarding use of newer non-statin therapies.
- This was extensively based on the evidence provided by the 2013 ACC/AHA and 2018 AHA/ACC/multisociety cholesterol guidelines.
Guidance was provided to answer the questions regarding the use of non-statin therapies with reference to patient populations, situations, and type of newer non-statin therapies to be considered.
Study Design
The solution set oversight committee provided algorithms endorsing 4 evidence-based patient management groups identified in the guidelines and assumed the patients to be taking or having attempted to take maximally tolerated dose of statin and trying to determine the need for additional therapy to further reduce ASCVD risk:
- Adults (≥20 years) with clinical ASCVD on statin therapy for secondary prevention
- Adults (≥20 years) with LDL-C ≥190 mg/dL on statin therapy for primary prevention
- Adults (45–70 years) without ASCVD but with diabetes LDL-C <190 mg/dL on statin therapy for primary prevention
- Adults (45–70 years) without ASCVD or diabetes LDL-C 70–189 mg/dL and an estimated 10-year risk for ASCVD ≥7.5%, on statin therapy for primary prevention
The recommendation process did not involve formal systematic reviews, grading of evidence, or synthesis of evidence.
Key Highlights
The ACC provided practical guidance for clinicians and patients in situations not covered by the 2018 AHA/ACC/multisociety cholesterol guideline until a formal review of scientific evidence and cardiovascular outcomes trials of newer agents for ASCVD risk reduction was completed.
GUIDANCE FOR ADULTS WITH CLINICAL ASCVD ON STATIN THERAPY FOR SECONDARY PREVENTION
| Patient group | Threshold not achieved on maximally tolerated statin | Following to be considered as initial nonstatin agent and addition of other agents as needed for desired LDL-C reduction | ||
| 1 | 2 | 3 | ||
| Adults with clinical ASCVD, at VHR | ≥50% LDL-C reduction and LDL-C <55 mg/dL (or non-HDL-C <85 mg/dL) | Ezetimibe and/or PCSK9 mAb | May consider bempedoic acid or inclisiran | NA |
| Adults with clinical ASCVD, not at VHR | ≥50% LDL-C reduction and LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) | Ezetimibe | May consider adding or replacing with PCSK9 mAb | May consider bempedoic acid or inclisiran |
| Adults with clinical ASCVD and baseline LDL-C ≥190 mg/dL not due to secondary causes without clinical or genetic diagnosis of FH | ≥50% LDL-C reduction and LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) | Ezetimibe and/or PCSK9 mAb | May consider bempedoic acid or inclisiran | May consider LDL apheresis under care of lipid specialist |
| Adults with clinical ASCVD at VHR and baseline LDL-C ≥190 mg/dL not due to secondary causes without clinical or genetic diagnosis of FH | ≥50% LDL-C reduction and LDL-C <55 mg/dL (or non-HDL-C <85 mg/dL) | Ezetimibe and/or PCSK9 mAb | May consider bempedoic acid or inclisiran | May consider evinacumab, lomitapide, and/or LDL apheresis for HoFH under care of lipid specialist |
Considerations that may favor the initial choice of non-statin agent
| Ezetimibe | PCSK9 mAb | Bempedoic acid | Inclisiran |
| Patients who require <25% additional lowering of LDL-C, patients with recent ACS <3 months, cost considerations, ease of use, and patient preferences | Patients who require >25% additional lowering of LDL-C or based on clinicianpatient decisionmaking | Need for further LDL-C reduction (with a mean expected reduction of approximately 17%), documented statin intolerance, and ease of use for patients who prefer to avoid injectable medications | Patients with adverse effects from both PCSK9 mAbs or those who may be unable to self-inject; if inclisiran is to be used, it should be used in place of a PCSK9 mAb |
| ABBREVIATIONS: ACS, acute coronary syndrome; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin type 9 monoclonal antibody. |
|||
GUIDANCE FOR ADULTS WITH POSSIBLE SASE
| Patient group | Theraphy | ||
| First-line | Second-line | Third-line | |
| Adults with clinical ASCVD at VHR/baseline LDL-C ≥190 mg/dL | Ezetimibe and/or PCSK9 mAb | Bempedoic acid / inclisiran | Evinacumab for HoFH |
| Adults without clinical ASCVD and LDL-C ≥190 mg/dL | |||
| Adults with clinical ASCVD not VHR | NA | ||
| Adults without clinical ASCVD and/or with/without diabetes | Ezetimibe | Bile acid sequestrant | Bempedoic acid |
| Adults without clinical ASCVD and with baseline LDL-C ≥190 mg/dL not due to secondary causes, on statin therapy for primary prevention | ||
| If ≥50% LDL-C reduction and LDL-C <100 mg/dL (or non-HDL-C <130 mg/dL) is not achieved on maximally-tolerated statin therapy, following to be considered as initial non-statin agent and addition of other agents as needed for desired LDL-C reduction: | ||
| Ezetimibe and/or PCSK9 mAb | May consider bempedoic acid or inclisiran | May consider evinacumab, lomitapide, and/or LDL apheresis for HoFH under care of lipid specialist |
| Adults without clinical ASCVD and with diabetes and baseline LDL-C <190 mg/dL, on statin therapy for primary prevention | ||
| In adults aged 40-75 years and ≥20% 10-year risk, if ≥50% LDL-C reduction and LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) is not achieved on maximally tolerated statin therapy, ezetimibe may be considered. |
| Adults without clinical ASCVD or diabetes (LDL-C 70–189 mg/dL) | ||
| In adults aged 40–75 years and ≥20% high 10-year risk, if ≥50% LDL-C reduction and LDL-C <70 mg/dL is not achieved, ezetimibe may be considered. |
| Adults without clinical ASCVD or diabetes or LDL-C ≥190 mg/dL | ||
| For those with coronary artery calcium scores ≥1,000 AU, based on the high ASCVD risk in such individuals, if maximally tolerated statin and ezetimibe therapy results in inadequate lowering of LDL-C, with <50% LDL-C reduction or LDL-C ≥70 mg/dL, the addition of a PCSK9 mAb may be considered. |
ABBREVIATIONS:
ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesteremia; LDL-C, low-density lipoprotein cholesterol; PCSK9 mAb, proprotein convertase subtilisin/kexin type 9 monoclonal antibody.
For additional details, please refer to the source publication Lloyd-Jones DM, et al.
To get SI units from mg/dL to mmol/L multiply by 0.02586.
* From figures 2A–D and figure 7 of source publication Lloyd-Jones DM, et al.
† Key limitations for all 4 study groups
ABBREVIATIONS:
ACC, American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; ASCVD, atherosclerotic cardiavascular disease; 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 type 9 monoclonal antibody; SASE, statin-associated side effects; VHR, very high risk.
Limitations
- Suggested non-statin therapies had not been well studied in the patient population.
- Generalizability of the recommendations provided for the use of all statin add-on therapies for ethnic minorities was uncertain.
- Detailed recommendations for other special populations of patients with specific comorbidities/conditions were not provided.
Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, 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. doi: 10.1016/ j.jacc.2022.07.006. PMID: 36031461.
MAT-KW-2300054/V1/FEB2023