Guideline Recommendations, Clinical Trial Data, and New and Emerging Therapies

Supplements and Featured Publications, Hyperlipidemia: Effective Disease Management to Decrease Economic and Quality of Life Burden, Volume 27, Issue 4

Abstract

Nearly 93 million American adults have hyperlipidemia, a major risk factor for the development of atherosclerotic cardiovascular disease. Use of HMG-CoA reductase inhibitors (ie, statins) and ezetimibe have decreased hypercholesterolemia’s prevalence in the past decade, but poor adherence is common and leads to scenarios where patients do not derive the greatest possible benefit. In addition, statin resistance may play a role when patients’ LDL-C levels are not lowered to the expected extent despite good medication adherence. When statins fail to control hyperlipidemia, guidelines recommend furthering treatment by adding ezetimibe or a PCSK9 inhibitor. In November 2018, the American College of Cardiology and the American Heart Association updated their hyperlipidemia guideline. This revision recommends a more aggressive approach to hyperlipidemia. In patients who fail to respond to or cannot tolerate statins or ezetimibe, PCSK9 inhibitors are a reasonable treatment option. Large outcomes trials have compared the currently approved PCSK9 inhibitors with placebo and established that PCSK9 inhibitors lowered LDL-C by more than 50% below the statin-treated baseline and reduce cardiovascular outcomes. In addition, bempedoic acid, lomitapide, and evinacumab are available options that may be instituted in select patients. In development is inclisiran, a small interfering RNA molecule, which antagonizes PCSK9 production. With good adherence and the use of a greater assortment of medications, patients may experience atherogenic lipoprotein lowering, leading to a decrease in cardiovascular disease.

Am J Manag Care. 2021;27(3):S70-S75. https://doi.org/10.37765/ajmc.2021.88607

Introduction

Among both men and women, cardiovascular disease (CVD) was responsible for more than 31% of all deaths globally in 2016, making it the leading cause of death.1 In the United States, CVD’s prevalence in adults aged older than 20 years is 48% (121.5 million in 2016); prevalence increases with advancing age.2 By 2035, statistics indicate that approximately 45.1% of the US population or more than 130 million adults will have some form of CVD, which is an increase of 30%.3

One major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD)—hyperlipidemia—affects nearly 93 million American adults.2 Thus, hyperlipidemia is a major public health concern.4 Significant evidence supports reducing low-density lipoprotein cholesterol (LDL-C) to decrease ASCVD risk.2,4 For this reason, prescribers employ HMG-CoA reductase inhibitors, commonly referred to as statins, as therapy plus or minus ezetimibe fairly routinely.4 Use of these drugs has decreased hypercholesterolemia’s prevalence in the past decade. Unfortunately, cost, poor access to care, and adverse effects (AEs) have contributed to poor adherence; roughly 50% of patients discontinue lipid-lowering therapy within 1 year and 70% within 2 years.4 Medication adherence plays a large role in the efficacy of lipid-lowering agents. A generally accepted threshold for good adherence is greater than 80%, while poor adherence is typically set at the less than 50% mark.

In November 2018, the American College of Cardiology and the American Heart Association (ACC/AHA) updated their hyperlipidemia guideline.5 This update provides a summary with the “Top 10 Take-Home Messages” to employ in the lipid management of patients (see Table 1).5

Risk Stratification

The updated strategy advises a lifelong approach to lowering cholesterol, starting with a moderate recommendation in children as young as 2 years who have a family history of early CVD or significant high cholesterol.5 In other children, the guideline provides a weak recommendation for initial cholesterol blood tests between age 9 and 11 years to gauge lifetime risk early and detect lipid abnormalities. If dyslipidemia is identified in children or adolescents, healthy lifestyle changes are the preferred approach. Beginning at age 20 years, an assessment of lipids should be performed for all patients to estimate risk of CVD and determine a baseline lipid profile.5

The revised guideline continues to recommend statin therapy strongly for patients with an increased risk of ASCVD and emphasizes evaluating the magnitude of each patient’s response while on statin therapy.5 Based on significant evidence supporting the benefits of reducing LDL-C to reduce ASCVD, the guideline recommends using the maximally tolerated statin dose (see Table 25,6). For this reason, the guideline accentuates personalized assessment of risk for patients to determine risk of heart disease. Discussion of risk-enhancing factors (eg, family history of premature ASCVD, ethnicity, metabolic syndrome, chronic kidney disease, chronic inflammatory conditions, and premature menopause or preeclampsia) is deemed prudent.5

Statin therapy is the most extensively prescribed drug class employed to lower LDL-C and remains the cornerstone of managing elevated LDL-C.7,8 In the past decade, hypercholesterolemia has decreased in prevalence pursuant to widespread statin use. However, overall adherence to statins remains suboptimal; considerable evidence indicates that low adherence (<80%) to statins is linked with poorer outcomes, including death in patients with known ASCVD.8-12 Results of a Kaiser Permanente study found that 15% of patients do not fill their initial statin prescriptions.13 In another cohort study, 2-year adherence rates were 40% for elderly patients with acute coronary syndrome and were significantly lower for patients with chronic coronary artery disease (36%), and those receiving a statin for primary prevention (25%).14 Approximately 50% of patients discontinue statins within 1 year and 70% do so within 2 years.4,8

Many patients who would benefit from these agents are nonadherent due to cost, poor access to care, and AEs.4 When asked why they discontinue statins, patients often report development of statin-associated muscle symptoms.7 The AHA’s Scientific Statement, Statin Safety and Associated Adverse Events: A Scientific Statement from the American Heart Association, indicates that muscle toxicity should not be a primary driver of nonadherence. Approximately 10% of American patients discontinue statins with subjective complaints, usually muscle symptoms without elevated creatine kinase. Yet statin-induced serious muscle injury including rhabdomyolysis occurs in fewer than 0.1% of patients, and the risk of serious hepatotoxicity is roughly 0.001%.15

Statins have been associated with other serious AEs, including new-onset type 2 diabetes. Risk of newly diagnosed statin-induced diabetes is about 0.2% per year of treatment, depending on underlying risk factors.15 Statins may increase the risk of hemorrhagic stroke in patients with cerebrovascular disease, but statins produce a significantly greater reduction in risk of atherothrombotic stroke, total stroke, and other cardiovascular (CV) events. No convincing evidence establishes causal relationships between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendinitis.15 Researchers attribute the disparity between actual AE rates and the number of patients who discontinue statins due to alleged AEs to nocebo effect (undesirable side effects as a result of a patient’s perception that it is harmful rather than as a result of a causative ingredient). When patients and their doctors were aware that statin therapy was used, they reported more muscle-related AEs than when they were enrolled in blinded treatment.16

Statin Resistance

Statin resistance occurs when patients’ LDL-C levels fail to fall despite good adherence.17 Despite this simple definition, it is difficult to determine exactly when statin resistance occurs. Statin-induced LDL-C reduction varies from 5% to 70% among individuals and the time to reach the maximum LDL-C concentration reduction also varies. After adjusting for adherence, many factors influence response, including racial ancestry with Blacks responding less robustly than Whites.17

Differences in drug absorption, drug transport, intrahepatic drug metabolism, drug metabolism within other organs, and drug excretion mechanisms may cause statin resistance.17 Resistance can also occur due to differences in levels of therapeutic target pathways, such as HMG-CoA reductase or various points along the cholesterol biosynthesis and lipoprotein metabolic pathways. Researchers also attribute interindividual variation in statin response to genetic polymorphisms affecting pharmacodynamics (which are poorly understood) and pharmacokinetics.17 Smokers have smaller statin-induced LDL-C decreases than nonsmokers, and patients with hypertension have smaller decreases than those without hypertension. Also, inflammatory cytokines such as IL-1b may disrupt LDL-R feedback regulation and cause statin resistance. Consequently, patients with inflammatory disease may require higher statin doses to achieve target LDL-C levels.17

Mortality Associated With Adherence/Nonadherence

The AHA guideline validates that statins save lives, and studies continue to prove this point. For example, a Veterans Affairs (VA) Health System retrospective cohort analyzed data from adults aged 21 to 85 years who had 1 or more ASCVD events on 2 or more dates in the previous 2 years.18 They were interested in quantifying death of all causes adjusted for demographic and clinical characteristics, as well as adherence to other cardiac medications. All patients had remained on statins of the same intensity for a mean of 2.9 years.18

The researchers identified 347,104 eligible adults. As would be expected in the predominately male VA demographic, 1.6% were women.18 More than 80% were White, with varying levels of representation from other demographic groups (next largest group represented African Americans with approximately 10%). Moderate-intensity statin therapy was associated with better adherence than high-intensity statin therapy. Adherence was lower among women, members of all minority groups compared with non-Hispanic White men, and the youngest and oldest of patients compared with patients aged 65 to 74. During the study period, 85,930 (24.8%) study participants died. The researchers compared the most adherent patients (medication possession ratio [MPR] ≥90%) to the least adherent patients (MPR <50%) and found an inverse association between statin adherence and mortality. In unadjusted survival analysis, patients in the least adherent group were 36% more likely to die. They also linked poor adherence to higher LDL-C levels and a greater likelihood of hospitalization for stroke and ischemic heart disease. This demonstrates that strict statin adherence creates a survival benefit.18

Risk Increases, Guidelines Call for Intervention

Once a patient’s ASCVD risk reaches or exceeds the moderate threshold, the AHA guideline now calls for coronary artery calcium (CAC) score to help assess treatment. The guideline also recommends adding nonstatin cholesterol-lowering medications, including ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, for patients at the highest risk of ASCVD.5 Clinicians should discuss more aggressive cholesterol-lowering regimens in patients with established ASCVD. It recommends adding ezetimibe first, then progressing to PCSK9 inhibitors if cholesterol levels remain high.5

The nonstatin lipid-lowering drug ezetimibe inhibits dietary cholesterol absorption by blocking the Niemann-Pick C1-Like 1 protein (NPC1L1). It has a half-life of approximately 22 hours due to enterohepatic circulation; it is metabolized in the small intestine and the liver—not via the cytochrome P450 system—and excreted back in bile as means of elimination.19 When added to a statin, ezetimibe can lower LDL-C up to an additional 15% to 20%, whereas doubling the statin dose lowers LDL-C by 5% to 10%.20 Results of a pooled analysis of 17 double-blind trials of patients who were receiving a statin showed that adding ezetimibe was more likely to reduce LDL-C than adjusting the statin dose.20

Icosapent ethyl has generated global interest. The prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States for elevated triglycerides.21 The study employed icosapent ethyl 4 grams/day. Analysis indicated that icosapent ethyl produced large and significant reductions in multiple ischemic end points, including CV death, myocardial infarction (MI), stroke, coronary revascularization, and hospitalization for unstable angina.21

This study identified a statistically significant 30% relative risk reduction and 2.6% absolute risk reduction in all-cause mortality associated with icosapent ethyl.21 Its overall safety and tolerability profile was virtually identical to that of placebo. The clinical implication is that icosapent ethyl in eligible secondary and primary prevention patients could reduce residual CV risk significantly.21

PCSK9 Inhibitors

The discovery of PCSK9 inhibitors has changed the understanding of lipid metabolism and management of hypercholesterolemia. By means of lysosome degradation, PCSK9 interferes with the natural recycling of the LDL receptor. A clinical trial demonstrated that nonsense mutations in PCSK9 lowered LDL-C and significantly reduced the incidence of coronary heart disease in Blacks and Whites (88% and 47%, respectively).22 Despite substantial evidence that PCSK9 inhibitors reduce LDL-C safely and effectively in levels in patients who respond suboptimally to statins and other therapies, they have been used rarely.23,24 There are currently 2 FDA-approved PCSK9 inhibitors: alirocumab and evolocumab.

Two large CV outcomes trials compared the currently approved PCSK9 inhibitors with placebo. They examined stroke risk in patients with ASCVD and elevated atherogenic lipoproteins that persisted despite statin treatment.25,26 Both trials determined that PCSK9 inhibitors lowered LDL-C by more than 50% below the statin-treated baseline compared with placebo.

Alirocumab

Researchers examined alirocumab’s safety and efficacy in a randomized trial (N = 2341).27 Participants—all at high risk for CV events—were treated with statins at the maximum tolerated dose with or without other lipid-lowering therapy and had LDL-C levels at or exceeding 70 mg/dL. The researchers randomized participants 2:1 to receive subcutaneous alirocumab 150 mg or placebo every 2 weeks for 78 weeks. Percent change in calculated LDL-C level from baseline to week 24 was the primary efficacy end point.27

When compared with placebo, the calculated LDL-C level’s mean percentage change from baseline was −62% (P <.001) at week 24, and the change was sustained over 78 weeks with alirocumab therapy.27 Injection-site reactions were common in alirocumab-treated participants (5.9%). Other AEs that were more likely in alirocumab-treated participants than placebo-treated patients included myalgia (5.4% vs 2.9%). Post hoc analysis determined that the rate of major adverse CV events (death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs 3.3%).27

Therandomized, double-blind, placebo-controlled, ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared alirocumab with placebo in 18,924 high-risk patients with an acute coronary syndrome within the past 1 to 12 months.26 All study participants were receiving high-intensity or maximum tolerated statin dose, but continued to have elevated lipids. The research team adjusted the alirocumab dose in a blinded fashion to target an LDL-C of 25 to 50 mg/dL. They monitored for composite primary end point of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.26

Following patients for a median of 2.8 years, risk of recurrent ischemic CV events was lower among alirocumab-treated participants than in placebo-treated participants.26 Overall, 903 (9.5%) alirocumab-treated participants experienced one of the composite primary end points compared with 1052 patients (11.1%) in the placebo arm. Similarly, fewer alirocumab-treated participants died (334 [3.5%]) than placebo-treated participants (392 [4.1%]). Alirocumab’s absolute benefit on the composite primary end point was most pronounced in patients with baseline LDL-C levels at or exceeding 100 mg/dL. AEs, with the exception of local injection-site reactions, were similar in the 2 groups. Local injection-site reactions occurred in 3.8% of alirocumab-treated participants and 2.1% of placebo-treated participants.26

Researchers have also studied alirocumab in homozygous familial hypercholesterolemia (HoFH), which is associated with extremely high LDL-C levels and early-onset ASCVD despite conventional lipid-lowering treatment.28 In a randomized, double-blind, placebo-controlled, parallel-group, phase 3 study, the researchers evaluated alirocumab’s efficacy and safety with a dose of 150 mg every 2 weeks. They established a primary end point of percent LDL-C reduction from baseline at 12 weeks.28

The researchers randomized participants (N = 69) 2:1 to alirocumab or placebo.28 At baseline, 59 of the 67 patients receiving statins were on high-intensity doses. Fifty participants were on ezetimibe, 10 patients were on lomitapide, and 10 were apheresis patients. Mean baseline LDL-C levels were 295 mg/dL and 259.6 mg/dL in alirocumab and placebo participants, respectively. At week 12, alirocumab-treated patients experienced a 26.9% reduction in LDL-C (difference vs placebo; P <.0001). In the open-label crossover, these results were sustained. Participants experienced no serious AEs, permanent treatment discontinuations, or deaths.28

Evolocumab

Evidence for evolocumab’s safety and efficacy was demonstrated in the FOURIER Study, a double-blind, randomized, placebo-controlled trial. It enrolled 27,564 adult participants (13,784 evolocumab; 13,780 placebo) taking high- or moderate-intensity statin therapy with established CVD who had LDL-C levels at or exceeding 70 mg/dL and/or non−high-density lipoprotein cholesterol at or exceeding 100 mg/dL. The researchers randomized patients to subcutaneous evolocumab (140 mg every 2 weeks [86% of participants] or 420 mg once monthly) or placebo. They followed more than 99% for a median of 26 months. A majority (81%) had history of a previous MI. Approximately 1 in 5 had experienced a nonhemorrhagic stroke, and 13% had symptomatic peripheral arterial disease. Five percent of participants were also taking ezetimibe and most patients were taking at least 1 CV medication. The primary composite end point (time to first occurrence of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) was significantly lower (9.8% vs 11.3%) in evolocumab-treated patients.25,29

A prespecified secondary analysis evaluated evolocumab’s ability to lower LDL-C concentrations progressively over 4 weeks.30 The study team analyzed 25,982 patients from the aforementioned FOURIER trial. Their intent was to elucidate the relationship between achieved LDL-C concentration at 4 weeks and subsequent CV outcomes (composite of CV death, MI, stroke, coronary revascularization, or unstable angina) and 10 prespecified safety events. They followed patients for more than 2 years. Low LDL-C levels were linked to fewer major CV outcomes and reduction in CV events was continued to be realized in those patients with the lowest LDL-C levels. Conversely, participants with very low LDL-cholesterol concentrations were not more likely to have safety issues. The researchers indicate that lowering target LDL-C levels to below those currently recommended may be safe, prudent, and warranted.30

Researchers conducted a series of trials based on the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) study.31 It evaluated the long-term efficacy and safety with evolocumab. Using data from 1255 patients who received evolocumab for an average of 44 months, evolocumab’s efficacy persisted over 4 years with overall median LDL-C level reductions of 57% (60 mg/dL). Evolocumab lowered LDL-C level by 58% from baseline in patients receiving concurrent statins throughout the study. Adherence to evolocumab was 79% during an average of 44 months of drug exposure in OSLER-1 and no neutralizing antibodies were found in evolocumab-treated patients.31

A newly presented abstract from the 2020 AHA Scientific Session re-examined data from the FOURIER study.32 It evaluated evolocumab’s effect on coronary revascularization, including the need for complex coronary revascularization (eg, multivessel percutaneous coronary intervention [PCI], 3 or more stents). The researchers reviewed blinded FOURIER study data to assess characteristics of coronary revascularization procedures. They found that 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22%, risk of complex revascularization by 29%, and coronary artery bypass grafting by 24%. The researchers concluded that very aggressive LDL-C lowering may reduce coronary atherosclerosis burden, anatomical complexity, and the need for intervention significantly.32

Finally, the guidelines now suggest that clinicians need to begin to monitor and address dyslipidemias much earlier, making the pediatric population a growing area of interest. A 24-week, randomized, double-blind, placebo-controlled trial evaluated evolocumab’s efficacy and safety in patients aged 10 to 17 years with heterozygous familial hypercholesterolemia (HeFH).33 All participants received stable lipid-lowering treatment for at least 4 weeks but had LDL-C levels at or exceeding 130 mg/dL and triglyceride levels of 400 mg/dL or less. The researchers randomized 157 participants in a 2:1 ratio to receive 420 mg evolocumab monthly or placebo. At 24 weeks, the mean percent change from baseline in LDL-C level was a significant −44.5% and −6.2% in the evolocumab and placebo groups, respectively. Participants in the evolocumab and placebo groups experienced similar rates of AEs.33

Other Agents

Lomitapide is an oral FDA-approved adjunct drug for HoFH.34 It binds to and suppresses microsomal triglyceride transfer protein (MTP) inside the endoplasmic reticulum lumen. In the hepatocytes and the enterocytes, suppressing MTP hinders production of lipoproteins that contain apo-B and decreases very-low-density lipoprotein and chylomicrons. While taking lomitapide, patients should adhere to diets with less than 20% in fat calories. Due to a risk of hepatotoxicity, this drug is subject to an FDA-mandated Risk Evaluation and Mitigation Strategy program and chronic transaminase monitoring. Its most common AEs (incidence ≥28%) include diarrhea, nausea, vomiting, dyspepsia, and abdominal pain.34

Bempedoic acid is FDA approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or established ASCVD who require additional LDL-C lowering.35 This adenosine triphosphate-citrate lyase inhibitor is administered orally once daily. The Clear Wisdom Trial, which enrolled 779 patients with ASCVD, HeFH, or both, established its safety and efficacy. All participants had LDL-C levels at or exceeding 70 mg/dL. Bempedoic acid lowered LDL-C levels (–15.1%) significantly more than placebo (2.4%) at week 12. No differences were observed in clinical outcomes, but the trial was not powered to detect a difference.36

Evinacumab is a monoclonal antibody that inhibits angiopoietin-like 3 (ANGPTL3). Loss of function variants of ANGPTL3 show low levels of LDL-C, thus making it a therapeutic target. A phase 3 trial of evinacumab for 65 patients with HoFH demonstrated reductions up to 47% compared with placebo.37 A phase 2 trial of evinacumab in 272 patients with HeFH or refractory hypercholesterolemia showed reduced LDL-C levels up to 56% compared with placebo.38 Evinacumab was approved in February 2021 and is indicated as an adjunct to other LDL-C−lowering therapies for the treatment of adult and pediatric patients aged 12 years and older with HoFH.39

Emerging Therapies

As we look forward, small interfering RNA (siRNA) molecules appear to be the next generation of PCSK9-antagonizing drugs, with the first candidate being inclisiran.4 Inclisiran is a PCSK9-specific siRNA that prevents translation of PCSK9 messenger RNA. That action decreases PCSK9 concentrations, thus lowering LDL-C levels. The ORION clinical development program has 12 clinical trials underway or completed.4 In ORION-10 and ORION-11, inclisiran was evaluated in patients with ASCVD or ASCVD equivalents, finding approximately a 50% reduction in LDL-C values compared with placebo. AEs were similar between inclisiran and placebo, with the exception of injection-site reactions for inclisiran-treated patients.40

Conclusions

Guidelines and consensus recommend aggressive lipid-lowering therapy for patients at high risk for cardiovascular disease. Statins remain the cornerstone of treatment with the addition of ezetimibe to help patients reach their target LDL-C levels. Continued re-evaluation of LDL-C levels and the addition of newer therapies, such as PCSK9 inhibitors, will allow patients with continued elevated LDL-C levels to reach recommended levels and reduce cardiovascular risk.

Author affiliation: John Lindsley, PharmD, BCPS, is clinical pharmacy specialist, Cardiac Care Unit, Johns Hopkins Hospital, Baltimore, MD.

Funding source: This activity is supported by educational funding provided by Amgen.

Author disclosure: Dr Lindsley has no relevant financial relationships with commercial interests to disclose.

Authorship information: Analysis and interpretation of data; concept and design; critical revision of the manuscript for important intellectual content; drafting of the manuscript.

Address correspondence to: jlindsl1@jhmi.edu

Medical writing and editorial support provided by:Jeannette Y. Wick, RPh, MBA, FASCP

REFERENCES

1. Cardiovascular diseases. World Health Organization. May 17, 2017. Accessed December 27, 2020. www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

2. Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. doi: 10.1161/CIR.0000000000000659

3. Khavjou O, Phelps D, Leib A. Projections of cardiovascular disease prevalence and costs: 2015–2035. Prepared for the American Heart Association 2016. Accessed December 27, 2020. heart.org/idc/groups/heart-public/@wcm/@adv/documents/downloadable/ucm_491513.pdf

4. German CA, Shapiro MD. Small interfering RNA therapeutic inclisiran: a new approach to targeting PCSK9. BioDrugs. 2020;34(1):1-9. doi: 10.1007/s40259-019-00399-6

5. 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [Erratum in: J Am Coll Cardiol. 2019;73(24):3237-3241]. J Am Coll Cardiol. 2019;73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003

6. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-125. doi: 10.1111/j.1472-8206.2004.00299.x

7. Ward NC, Page MM, Watts GF. Clinical guidance on the contemporary use of proprotein convertase
subtilisin/kexin type 9 monoclonal antibodies. Diabetes Obes Metab. 2019;21(suppl 1):52-62.
doi: 10.1111/dom.13637

8. Krähenbühl S, Pavik-Mezzour I, von Eckardstein A. Unmet needs in LDL-C lowering: when statins won’t do! Drugs. 2016;76(12):1175-1190. doi: 10.1007/s40265-016-0613-0

9. Rasmussen JN, Gislason GH, Rasmussen S, et al. Use of statins and beta-blockers after acute myocardial infarction according to income and education. J Epidemiol Community Health. 2007;61(12):1091-1097. doi: 10.1136/jech.2006.055525

10. Bouchard MH, Dragomir A, Blais L, Bérard A, Pilon D, Perreault S. Impact of adherence to statins on coronary artery disease in primary prevention. Br J Clin Pharmacol. 2007;63(6):698-708. doi: 10.1111/j.1365-2125.2006.02828.x

11. Ho PM, Magid DJ, Masoudi FA, McClure DL, Rumsfeld JS. Adherence to cardioprotective medications and mortality among patients with diabetes and ischemic heart disease. BMC Cardiovasc Disord. 2006;6:48. doi: 10.1186/1471-2261-6-48

12. De Vera MA, Bhole V, Burns LC, Lacaille D. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014;78(4):684-698. doi: 10.1111/bcp.12339

13. Cheetham TC, Niu F, Green K, et al. Primary nonadherence to statin medications in a managed care organization. J Manag Care Pharm. 2013;19(5):367-373. doi: 10.18553/jmcp.2013.19.5.367

14. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 2002;288(4):462-467. doi: 10.1001/jama.288.4.462

15. Newman CB, Preiss D, Tobert JA, et al; American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association [Erratum in: Arterioscler Thromb Vasc Biol. 2019;39(5):e158]. Arterioscler Thromb Vasc Biol. 2019;39(2):e38-e81. doi: 10.1161/ATV.0000000000000073

16. Gupta A, Thompson D, Whitehouse A, et al; ASCOT Investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389(10088):2473-2481. doi: 10.1016/S0140-6736(17)31075-9

17. Reiner Z. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis. 2014;24(10):1057-1066. doi: 10.1016/j.numecd.2014.05.009

18. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2019;4(3):206-213. doi: 10.1001/jamacardio.2018.4936

19. Phan BA, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag. 2012;8:415-427. doi: 10.2147/VHRM.S33664

20. Ambegaonkar BM, Tipping D, Polis AB, Tomassini JE, Tershakovec AM. Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. Atherosclerosis. 2014;237(2):829-837. doi: 10.1016/j.atherosclerosis.2014.10.105

21. Bhatt DL. REDUCE-IT. Eur Heart J. 2019;40(15):1174-1175. doi: 10.1093/eurheartj/ehz179

22. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi: 10.1056/NEJMoa054013

23. PCSK9 inhibitors grew steadily in the dyslipidemia market last year. Pharmaceutical Technology. Updated February 26, 2018. Accessed January 22, 2021. pharmaceutical-technology.com/comment/pcsk9-inhibitors-grew-steadily-dyslipidemia-market-last-year/

24. Are PCSK9 inhibitors about to take off? PharmaTimes online. May 27, 2019. Accessed January 22, 2021. pharmatimes.com/web_exclusives/are_pcsk9_inhibitors_about_to_take_off_1289184

25. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664

26. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. doi: 10.1056/NEJMoa1801174

27. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. doi: 10.1056/NEJMoa1501031

28. Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: the ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020;76(2):131-142. doi: 10.1016/j.jacc.2020.05.027

29. Repatha. Prescribing information. Amgen Inc; 2020. Accessed February 24, 2021. pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/repatha/repatha_pi_hcp_english.pdf

30. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):1962-1971. doi: 10.1016/S0140-6736(17)32290-0

31. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term low-density lipoprotein cholesterol-
lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol. 2017;2(6):598-607. doi: 10.1001/jamacardio.2017.0747

32. Oyama K, Furtado R, Fagundes A Jr, et al. Abstract 14770: Reduction with evolocumab in complex coronary disease requiring revascularization: insights from the FOURIER Trial. Circulation. 2020;142:A14770. Accessed December 27, 2020. ahajournals.org/doi/10.1161/circ.142.suppl_3.14770

33. Santos RD, Ruzza A, Hovingh GK, et al. Evolocumab in pediatric heterozygous familial hypercholesterolemia. N Engl J Med. 2020;383(14):1317-1327. doi: 10.1056/NEJMoa2019910

34. Juxtapid. Prescribing information. Amryt Pharma; 2020. Accessed February 24, 2021. juxtapidpro.com/prescribing-information

35. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: the CLEAR Wisdom Randomized Clinical Trial [published correction appears in JAMA. 2020;323(3):282]. JAMA. 2019;322(18):1780-1788. doi: 10.1001/jama.2019.16585

36. Raal FJ, Rosenson RS, Reeskamp LF, et al; ELIPSE HoFH Investigators. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383(8):711-720. doi: 10.1056/NEJMoa2004215

37. Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med. 2020;383(24):2307-2319. doi: 10.1056/NEJMoa2031049

38. Evkeeza. Prescribing information. Regeneron Pharmaceuticals, Inc; 2021. Accessed March 8, 2021. regeneron.com/sites/default/files/Evkeeza_PI.pdf

39. Ray KK, Wright RS, Kallend D, et al; ORION-10 and ORION-11 Investigators. Two phase 3 trials
of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507-1519. doi: 10.1056/NEJMoa1912387

download issueDownload Issue : Hyperlipidemia: Effective Disease Management to Decrease Economic and Quality of Life Burden