By Clinical Content Hub

Hypercholesterolemia is linked to the development of atherosclerotic cardiovascular disease (ASCVD) and high levels of low-density lipoprotein cholesterol (LDL-C) are a primary contributor.1 The leading cause of global morbidity and mortality is ASCVD, which includes acute coronary syndrome, myocardial infarction, and atherogenic ischemic stroke.2



Causes of Hypercholesterolemia

Familial hypercholesterolemia is caused by an autosomal-dominant mutation affecting one of several genes involved in the breakdown of cholesterol.4 Heterozygous familial hypercholesterolemia (HeFH) results when a patient inherits one mutation from a parent, whereas homozygous familial hypercholesterolemia (HoFH) occurs when a patient inherits a genetic mutation from each parent. One 1 of every 400,000 individuals will be diagnosed with HoFH and if untreated, it can lead to ASCVD in teenagers.3,6
 
For patients with familial and nonfamilial hypercholesterolemia, the risk of developing ASCVD or the severity of existing ASCVD drives patient treatment goals. The risk of existing ASCVD is calculated based on a person’s levels of LDL-C and total cholesterol in addition to contributing factors like age, sex, and the presence of hypertension and diabetes mellitus. However, risk calculators may over or underestimate the risk for ASCVD because of chronic inflammatory conditions and racial and socioeconomic factors.2

Treatment of Hypercholesterolemia

Treatment guidelines for hypercholesterolemia vary. For example, the 2020 American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines recommend an LDL-C goal as low as 55 mg/dL for patients with progressive ASCVD,7 whereas the American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend an LDL-C goal of less than 70 mg/dL for those same patients.1 Clinicians should weigh the risk vs benefit of aggressive treatment in each patient.
 
Statin therapy is the cornerstone of drug treatment for hypercholesterolemia. Unfortunately, despite statin treatment, many patients remain above their guideline-recommended LDL-C goal. The adverse effects of statins can often be dose-limiting, which can minimize the benefit of therapy. Patients who can tolerate high-intensity statin dosing may still struggle to reach their treatment goals if their baseline levels of LDL-C were high before initiation of therapy. In this case, treatment with one or more additional medications is recommended to further reduce LDL-C.

Oral Treatment Options

Several oral therapy options are available for patients with hypercholesterolemia resistant to maximally-tolerated statin dosing. Commonly used in conjunction with statins, these agents may also be used concurrently with each other. All treatment options should be provided as an adjunct to a healthy diet.
 
Ezetimibe. Ezetimibe is a first-line therapy addition to statin treatment. It has minimal adverse effects and lowers LDL-C approximately 13% to 20% by inhibiting the intestinal absorption of cholesterol.1 In the IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878), patients with acute coronary syndrome who received ezetimibe plus a statin had lower LDL-C and improved cardiovascular outcomes compared with patients who received statin monotherapy.8
 
Bempedoic acid. Bempedoic acid inhibits cholesterol biosynthesis in the liver and was approved by the US Food and Drug Administration in 2020.9 Indicated as adjunct therapy for patients diagnosed with HeFH or established ASCVD, bempedoic acid lowers LDL-C by 27% to 30%,10 and a fixed-dose combination with ezetimibe can lower LDL-C by approximately 40%.11
 
Bempedoic acid is recommended in the 2020 AACE/ACE algorithm for the management of dyslipidemia,7 but cardiovascular morbidity and mortality in patients treated with the drug are still under investigation (ClinicalTrials.gov Identifier: NCT02993406). Additionally, patients with a history of tendon disorders should avoid the drug, and uric acid levels should be monitored, especially in patients with gout.9
 
Lomitapide. Lomitapide reduces LDL-C by around 40% in patients with HoFH when used in conjunction with statin therapy.12 There is a risk for hepatotoxicity associated with the drug, so prescribing providers and patients must be registered with a Risk Evaluation and Mitigation Strategy (REMS) program.
 
Injectable Treatment Options
 
The development of injectable treatment options for drug-resistant hypercholesterolemia is rapidly expanding, and clinical practice guidelines do not include the most recently available medications.1,7 For all injectable therapies, the lack of long-term safety information and the high cost are currently the largest barriers to implementation.
 
Alirocumab and Evolovumab. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism.13 Alirocumab and evolocumab are monoclonal antibodies delivered by subcutaneous injection that increase the clearance of LDL-C by inhibiting PCSK9. In addition to lowering LDL-C by 50% to 60%, both alirocumab and evolocumab significantly reduce cardiovascular events in patients with ASCVD.13,14
 
The 2018 AHA/ACC clinical guidelines recommend the addition of a PCSK9 inhibitor when a patient fails to meet an LDL-C target despite a maximally tolerated statin dose plus ezetimibe. The preference for adding ezetimibe before a PCSK9 inhibitor is primarily driven by cost.1
 
Evinacumab. Given as a monthly intravenous infusion for patients with HoHF,6 evinacumab is a monoclonal antibody that enables a faster breakdown of fats in the body. Evinacumab reduces LDL-C by approximately 49% and should be added to a maximally tolerated statin dose with or without ezetimibe.15
 
Inclisiran. Unlike other injectable products, inclisiran is not a monoclonal antibody. Inclisiran is a small interfering RNA molecule that disrupts the production of PCSK9 in the liver.16 It is indicated as adjunct therapy for patients with HeFH or established ASCVD.17
 
A reduction in LDL-C of at least 50% places inclisiran on par with the efficacy of alirocumab and evolocumab.15 One notable difference is the frequency of administration. Alirocumab and evolocumab require a subcutaneous injection every 2 to 4 weeks,13,14 whereas inclisiran is administered as a subcutaneous injection as an initial dose, at 3 months, and every 6 months thereafter.17 The minimal burden of treatment could have a large impact on therapy adherence. Inclisiran is the newest therapeutic option on the market for the treatment of hypercholesterolemia.
 
Lipoprotein Apheresis
 
Lipoprotein apheresis, which removes lipoproteins by precipitation, filtration, or adsorption, is the last-resort option for the management of hypercholesterolemia despite treatment with a statin and ezetimibe. Lipoprotein apheresis is reserved for patients with HoFH or HeFH.18 Each weekly or biweekly session reduces LDL-C by approximately 50% to 70%.19 Limited apheresis centers and the large time commitment create barriers to use.
 
The development of alirocumab, evolocumab, and lomitapide have enabled patients to reduce the frequency of lipoprotein apheresis or cease the therapy entirely.19-21 Although patients receiving lipoprotein apheresis were included in trials for evinacumab, additional research is needed to understand the impact evinacumab could have on the frequency and necessity of lipoprotein apheresis.15


Which adjunct medications can reduce LDL-C by ≥45%?
Flip
Alirocumab, evolocumab, evinacumab, and inclisiran reduce LDL-C by ≥45%.

Putting It All Together

The 2018 AHA/ACC and the 2020 AACE/ACE guidelines agree that ezetimibe should be the first addition when statin monotherapy is insufficient.1,7 Beyond that, there is less guidance as drug development has provided several new therapy options.

Decisions on the escalation of therapy require a multifactorial approach. Factors such as the extent of additional LDL-C lowering required, patient preference of route of administration, risk of long-term adverse events, and cost must all be considered when selecting the next line of therapy appropriate for each individual patient.
 
Patients with HoFH have additional options such as evinacumab or lomitapide but may have a reduced or negligible response to PCSK9 inhibitors depending on the genetic mutations present.20



To help patients reach their LDL-C goals, clinicians should consider reviewing all the new medication options available and working with patients to determine the most appropriate option.

References

1. Grundy S, Stone N, Bailey A, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guideline. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
 
2. Arnett D, Blumenthal R, Albert M, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596-e646. doi:10.1161/CIR.0000000000000678
 
3. Tsao C, Aday A, Almarzooq Z, et al; on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2022 update: a report from the American Heart Association. Circulation. 2022;145(8):e153-e639. doi:10.1161/CIR.0000000000001052
 
4. Beheshti S, Madsen C, Varbo A, Nordestgaard B. Worldwide prevalence of familial hypercholesterolemia: meta-analysis of 11 million subjects. J Am Coll Cardiol. 2020;75(20):2553–2566. doi:10.1016/j.jacc.2020.03.057
 
5. Stanaway J, Afshin A, Gakidou E, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159): 1923-1994. doi:10.1016/S0140-6736(18)32225-6
 
6. FDA approves add-on therapy for patients with genetic form of severely high cholesterol. US Food and Drug Administration. Updated April 1, 2021. Accessed February 19, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol
 
7. Handelsman Y, Jelllinger P, Guerin C, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm – 2020 executive summary. Endocr Pract. 2020;26(10):1196-1224. doi:10.4158/CS-2020-0490
 
8. Cannon C, Blazing M, Giugliano R, et al; for the IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397. doi:10.1056/NEJMoa1410489
 
9. Nexletol. Prescribing information. Esperion Therapeutics, Inc; 2020. Accessed March 3, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf
 
10. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intoleranceJ Clin Lipidol. 2016;10(3):556-567. doi:10.1016/j.jacl.2015.12.025
 
11. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapyEur J Prev Cardiol. 2020;27(6):593-603. doi:10.1177/2047487319864671
 
12. Alonso R, Cuevas A, Mata P. Lomitapide: a review of its clinical use, efficacy, and tolerabilityCore Evid. 2019;14:19-30. doi:10.2147/CE.S174169
 
13. Sabatine MS, Giugliano RP, Keech AC, et al; for the FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular diseaseN Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
 
14. Schwartz GG, Steg PG, Szarek M, et al; for the ODYSSEY OUTCOMES Committee and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndromeN Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174
 
15. Raal F, Rosenson R, Reeskamp L, et al; for the ELIPSE HoFH Investigators. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383:711-720. doi:10.1056/NEJMoa2004215
 
16. Ray K, Landmesser U, Leiter L, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2016;376:1430-1440. doi:10.1056/NEJMoa1615758
 
17. Leqvio. Prescribing information. Novartis Pharmaceuticals; 2021. Accessed March 3, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214012lbl.pdf
 
18. Baum S, Sampietro T, Datta D, et al. Effect of evolocumab on lipoprotein apheresis requirement and lipid levels: results of the randomized, controlled, open-label DE LAVAL study. J Clin Lipidol. 2019;13(6):901-909. doi:10.1016/j.jacl.2019.10.003
 
19. Kayikcioglu M. LDL apheresis and Lp (a) apheresis: a clinician’s perspective. Curr Atheroscler Rep. 2021;23(15). doi:10.1007/s11883-021-00911-w
 
20. Stefanutti C, Julius U, Watts G, et al; and the MIGHTY MEDIC Multinational Society. Toward an international consensus- integrating lipoprotein apheresis and new lipid-lowering drugs. J Clin Lipidol. 2017;11(4):858-871.e3. doi:10.1016/j.jacl.2017.04.114
 
21. Moriarty P, Parhofer K, Babirak S, et al. Alirocumab in patients with heterozygous familial hypercholesterolemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J. 2016;37(48):3588-3595. doi:10.1093/eurheartj/ehw388
 
22. Zetia. Prescribing information. Merck/Schering-Plough Pharmaceuticals; 2007. Accessed March 3, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21445lbl.pdf
 
23. Juxtapid. Prescribing information. Aegerion Pharmaceuticals, Inc; 2012. Accessed March 3, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf
 
24. Praluent. Prescribing information. Regeneron, Inc.; 2015. Accessed March 3, 2022. https://www.regeneron.com/downloads/praluent_pi.pdf
 
25. Repatha. Prescribing information. Amgen Inc.; 2021. Accessed March 3, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125522s029s031lbl.pdf
 
26. Evkeeza. Prescribing information. Regeneron Pharmaceuticals, Inc.; 2021. Accessed March 3, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
 
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cardiology Advisor had no role in this content’s preparation.

Reviewed March 2022