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Progress in primary prevention of atherosclerotic cardiovascular disease: Addressing hyperlipidemia

Publication
Article
Supplements And Featured PublicationsProgress in Addressing Hyperlipidemia in the Primary Prevention Setting

Introduction

Cardiovascular disease (CVD) encompasses various conditions, including heart disease, myocardial infarction (MI), stroke, heart failure, arrhythmia and valvular heart disease. Atherosclerotic CVD (ASCVD) involves the accumulation of plaque in the arteries, leading to arterial narrowing and potentially causing blood clots that can result in heart attack or stroke.1 ASCVD is the leading cause of morbidity and mortality worldwide and the leading cause of death for most racial and ethnic groups in the U.S.2 Among adults 20 years or older, the prevalence of CVD is 48.6%, which accounted for 127.9 million people in 2020. This prevalence increases with age in both sexes.3

Numerous lifestyle factors have a known influence on CVD risk, including nutrition, diet, exercise and physical activity. Additional factors affecting CVD risk are overweight/obesity, type 2 diabetes mellitus, hyperlipidemia (including elevated low-density lipoprotein cholesterol [LDL-C]), hypertension and tobacco use.2

Lowering LDL-C level is an important factor in reducing the risks for various conditions, such as CVD events.4 Statins are the cornerstone of treatment for hyperlipidemia2; however, for some patients, statin therapy alone may not effectively lower LDL-C levels to the desired target,5 and some individuals may face challenges in tolerating statins or escalating their doses because of side effects.6 Therefore, there is a demand for alternative lipid-lowering therapy (LLT) in addition to statins.6 This supplement provides an overview of the evolving treatment landscape for addressing elevated LDL-C levels using nonstatin therapies (PCSK9 monoclonal antibodies [mAbs], Nexletol [bempedoic acid; BA] and Leqvio [inclisiran]).

Hyperlipidemia: Clinical impact and role in ASCVD

Upon sustained exposure to a consistently high LDL-C concentration, LDL particles gradually accumulate and are retained over time in the arterial wall, contributing to the growth and progression of atherosclerotic plaques.4 The total accumulation of atherosclerotic plaque is approximately proportional to an individual’s cumulative exposure to LDL-C and certain other lipoproteins. As atherosclerotic plaque accumulates, it eventually reaches a critical point where plaque disruption can occur, leading to the formation of a thrombus that obstructs blood flow. This obstruction can result in conditions such as unstable angina, MI or death. Once the cumulative plaque burden surpasses this critical threshold, individuals become susceptible to acute cardiovascular (CV) events. The impact of the total plaque burden on the risk of acute coronary syndrome due to plaque disruption can be estimated from the total cumulative exposure of an individual to LDL.4 The risk of MI increases by twofold with each decade of exposure to increased LDL-C levels (higher than the cumulative LDL exposure threshold).4

Lowering LDL-C levels is important for reducing the risk of both primary and secondary ASCVD events in patients with an increased CV risk.4 Primary prevention of CV risk involves measures taken to prevent the development of CV disease in individuals who have not yet experienced a CV event but who have clinical features that place them at a high risk of such events.7 Secondary prevention of CV risk, on the other hand, refers to interventions aimed at reducing the risk of subsequent CV events in individuals who have already experienced a CV event.7

Evolving treatment landscape for hyperlipidemia

Although statins are a first-line therapy for hyperlipidemia, many patients do not reach their LDL-C goals with statins alone.2 For example, according to the results of one study, an American College of Cardiology (ACC)/American Heart Association (AHA) guideline-recommended LDL-C level of less than 70 mg/dL was reached by only 29.3% of patients taking statins.5 Additionally, some patients cannot take statins or experience intolerable side effects with dosage increases; consequently, up to 30% of patients are unable or unwilling to take a statin.8 These side effects most commonly include muscle soreness, aches, cramps, fatigue and weakness.8 Thus, additional options for lowering LDL-C are needed.

Several nonstatin therapies are available for lowering LDL-C, as detailed in Table 1.9-13 Zetia (ezetimibe; EZE), which gained FDA approval in 2002, functions by targeting NPC1L1, the sterol transporter responsible for cholesterol absorption. By inhibiting this transporter at the small intestine, EZE reduces cholesterol absorption, leading to decreased delivery of intestinal cholesterol to the liver. Consequently, hepatic cholesterol stores are decreased, prompting an increase in LDL receptors and facilitating cholesterol clearance from the bloodstream.13 PCSK9 inhibitors are another option for LDL-C lowering. Two types of therapeutic agents targeting PCSK9 are currently approved by the FDA: mAbs and small interfering RNA (siRNA). Under normal conditions, PCSK9 binds to LDL receptors on hepatocyte surfaces, leading to LDL receptor degradation in the liver. PCSK9 inhibitors prevent this binding, increasing the availability of LDL receptors and facilitating LDL clearance, thus lowering LDL-C levels.9,10 The PCSK9 mAbs evolocumab and alirocumab were approved by the FDA in 2015. Both of these mAbs prevent the binding of PCSK9 to LDL receptors in the liver, which induces hepatocytes to increase the number of LDL receptors available to clear LDL from the blood to result in lowered LDL-C levels.9,10 The siRNA inclisiran uses RNA interference to promote catalytic degradation of PCSK9 mRNA in hepatocytes. This process boosts LDL-C receptor recycling and expression on hepatocyte surfaces, increasing LDL-C uptake and thus reducing LDL-C levels in circulation.12 CV outcomes trial data on several nonstatin lipid-lowering agents are described below.

CV Outcomes Trial Data

The mAb PCSK9 inhibitors have been evaluated in CV outcomes trials for the secondary prevention of CV events.14 BA has been evaluated in a CV outcomes trial that enrolled patients who had already experienced a CV event (secondary prevention) and patients who were at high risk of a CV event (primary prevention).7 The effects of inclisiran on CV outcomes are currently being evaluated in clinical trials.15 The results of CV outcomes trials are described in this section.

Alirocumab

ODYSSEY Outcomes (NCT01663402) was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 1,315 sites in 57 countries to determine the efficacy of Praluent (alirocumab) for secondary prevention of CV events in patients who took a high-intensity or the maximally tolerated dose of statin therapy but still required additional LDL-C lowering medication.14 The alirocumab and placebo groups each contained 9,461 patients. The average age of patients was 58.5 (SD, 9.3) years in both the alirocumab and placebo groups and approximately 25% of patients were female. The races of patients in the treatment group were 79.3% White (n = 7,500), 13.2% Asian (n = 1,251), 2.5% Black (n = 235) and 5.0% other (n = 475); the placebo group had a similar composition. Patients were followed for a median of 2.8 years (IQR, 2.3-3.4 years). In the alirocumab group, 9.5% of patients experienced a CV event, compared with 11.1% of patients in the placebo group (HR, 0.85; 95% CI, 0.78-0.93; p-value < 0.001). Patients in the alirocumab group also showed 54.7% lower LDL-C levels than those in the placebo group at 4 years.14

Evolocumab

The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial (NCT01764633) was a randomized, double-blind, placebo-controlled, multinational clinical trial conducted at 1,242 sites in 49 countries.16 This study was performed to examine the efficacy and safety of evolocumab added to moderate- or high-intensity statin therapy for secondary prevention in patients with ASCVD. The primary efficacy end point was the occurrence of major CV events, which were defined as a composite of CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization. The large study population included 13,784 patients in the evolocumab group and 13,780 patients in the placebo group. Patients had an average age of 62.5 (SD, 9.1) years in both groups, and there were approximately 10,400 males (approximately 75.5%) in each of the evolocumab and placebo groups. Also, in both groups, approximately 85% of patients were White. The results showed that the risk of the primary composite end point was significantly lower in the evolocumab group than in the placebo group (9.8% vs. 11.3%, respectively; HR, 0.85; 95% CI, 0.79-0.92; p-value < 0.001). After 48 weeks, the LDL-C level in the treatment group was 59% lower than that in the placebo group (95% CI, 58-60; p-value < 0.001).16

A phase 3, double-blind, randomized, placebo-controlled, multicenter study of evolocumab is currently underway to evaluate whether this mAb can prevent CV events in patients without prior MI and at high risk of a CV event. This long-term primary prevention study, VESALIUS-CV (NCT03872401), includes more than 12,000 patients and is expected to be completed in mid-2025.17

Bempedoic acid

CLEAR Outcomes — Primary results in full study population: The Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen (CLEAR) Outcomes trial (NCT02993406)7 was a double-blind, randomized, placebo-controlled trial performed at 1,250 sites in 32 countries to assess the efficacy and safety of BA in managing CV outcomes in patients 18 years or older who were unable or unwilling to take a statin and either had ASCVD (secondary prevention patients) or were at high risk for ASCVD (primary prevention patients).7 The BA group contained 6,992 patients and the placebo group contained 6,978 patients.7 Patients had a mean age of 65.5 years, 48.2% of patients (n = 6,740) were female and 17% (n = 1,190) were Hispanic; 9,764 (69.9%) patients had previously experienced a CV event. Major adverse cardiovascular events (MACE-4; primary end point; defined as nonfatal MI, coronary revascularization, nonfatal stroke and CV death) were reduced by 13.7% in the BA group compared with those in the placebo group; this end point was observed in 819 of 6,992 patients (11.7%) in the BA treatment group and 927 of 6,978 patients (13.3%) in the placebo group (HR, 0.87; 95% CI, 0.79-0.96; p-value = 0.004). After six months, the mean change in LDL-C from baseline in the BA group was -21.7% (baseline 139.0 mg/dL to 107 mg/dL) vs. 0.6% in the placebo group (baseline 139.0 mg/dL to 136.0 mg/dL), for a least-squares mean difference between groups of 21.1%.7

Exploratory analysis of CV outcomes in primary prevention subgroup: To examine the effects of BA on major adverse CV outcomes in the subgroup of primary prevention patients, further exploratory and descriptive analyses of data from CLEAR Outcomes were performed.18 The results of the primary prevention analysis showed that the primary end point, MACE-4, occurred in 5.3% of patients in the BA group and 7.6% of patients in the placebo group (HR, 0.70; 95% CI, 0.55-0.89; p-value = 0.002) — a reduction of 30% in the BA group compared with that in the placebo group. The effects of BA on LDL-C lowering were also examined. After six months, the mean change in LDL-C from baseline in the BA group was 34.0 mg/dL (baseline 142.2 mg/dL) vs. 3.8 mg/dL in the placebo group (baseline 142.7 mg/dL), for a least-squares mean difference between groups of 21.3%.18

Prespecified analysis of total CV events in the full study population: The results of a prespecified analysis to determine the effects of BA on the total incidence of MACE were published in early 2024. BA treatment led to a reduced occurrence of MACE-4 (primary end point) and MACE-3 (key secondary end point; a composite of CV death, MI and stroke) events per 100 patient-years compared with that in the placebo group (MACE-4: 5.0% vs. 6.2%; HR, 0.80; 95% CI, 0.72-0.89; p-value < 0.001; MACE-3: 2.8% vs. 3.3%; HR, 0.83; 95% CI, 0.73-0.93; p-value = 0.002). There was a 20% decrease in the overall incidence of MACE-4 with BA versus placebo.19

Inclisiran

CV outcomes trials of inclisiran are in progress but have not yet been completed.15

Clinical guidelines for the management of hyperlipidemia: Use of nonstatin therapies for primary prevention of ASCVD

2018 and 2019 AHA/ACC Guidelines

The 2018 AHA/ACC Guideline on the Management of Blood Cholesterol and the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease recommend statin therapy in addition to lifestyle modification for select patients (eg, patients with moderately high [≥ 160 mg/dL] or very high [≥ 190 mg/dL] LDL-C or diabetes) and do not provide guidance on the use of nonstatin therapies for primary prevention of ASCVD.2,20

2022 ACC Expert Consensus Decision Pathway

In 2022, the ACC released an expert consensus decision pathway to provide guidance regarding the use of nonstatin therapies. Per the ACC, primary prevention patients with high baseline LDL-C levels (≥ 190 mg/dL) should start with statin therapy in addition to lifestyle modification to achieve a greater than 50% reduction in LDL-C levels to less than 130 mg/dL; patients who do not achieve this target or those with multiple high-risk factors or significant subclinical atherosclerosis may need intensified therapy, possibly including EZE or a PCSK9 mAb.21

Among primary prevention patients aged 40 to 75 years with a 10-year ASCVD risk of less than 7.5%, if LDL-C or non–HDL-C remains high on moderate-intensity statin therapy in addition to lifestyle modification (< 30%-49% reduction in LDL-C or LDL-C ≥ 100 mg/dL), escalation to a high-intensity statin should be considered.21 If an inadequate response persists, adding EZE is reasonable. There is insufficient evidence for use of PCSK9 mAbs, BA or inclisiran for primary prevention of ASCVD or when baseline LDL-C levels are 190 mg/dL or greater, but these medications may be considered for patients with significant subclinical atherosclerosis and diabetes. This expert consensus decision pathway was issued in 2022, prior to the publication of CV outcomes data for patients taking BA for primary prevention (CLEAR Outcomes) in 2023.21

2024 American Diabetes Association Guidelines

For primary prevention of ASCVD in individuals aged 40 to 75 years with diabetes, the ADA recommends a moderate-intensity statin coupled with lifestyle modifications.22 Patients aged 20 to 39 years with diabetes and ASCVD risk factors should initiate statin therapy along with lifestyle adjustments. Individuals who have diabetes and a high CV risk (at least one ASCVD risk factor) and who are aged 40 to 75 years are advised to start high-intensity statin therapy, aiming for at least a 50% reduction in LDL-C levels from baseline or a target of less than 70 mg/dL. In this same age group, but for patients with a higher CV risk (multiple ASCVD risk factors) and an LDL-C of at least 70 mg/dL, adding EZE or a PCSK9 inhibitor to maximally tolerated statin therapy should be considered. For adults 75 years or older who are on statin therapy, treatment continuation is encouraged; a moderate-intensity stain should be considered according to the benefits and risks of treatment. For patients of all ages who are unwilling or unable to take a statin, alternative treatments such as BA may be considered to reduce the risk of CV events.22

Healthcare utilization among patients with ASCVD and impact of prevention of ASCVD events

Healthcare resource utilization (HCRU) is high among patients with ASCVD.23 Zhao and colleagues examined HCRU in commercially insured patients in the U.S. The Truven Health Analytics MarketScan Commercial Claims and Encounters database was used to gather data on HCRU, including information on inpatient and outpatient services, from October 1, 2007, to September 30, 2011. The study population was comprised of 152,290 patients with ASCVD who had data available for at least 12 months before and 24 months after the index date. According to the results, 23% of patients were hospitalized in the first year after being diagnosed with ASCVD and 15% were hospitalized in the second year. Patients had a mean of 22 office visits in the first year and 18 in the second year following diagnosis, with four and six of these visits related to ASCVD, respectively. Moreover, 17% of patients with ASCVD visited the emergency room in the first year after diagnosis, with this number decreasing to 11% in the second year.23

Prevention of ASCVD events is associated with decreased direct medical costs and improved quality of life (QOL) for patients.24,25 Lindner and colleagues predicted the number of ASCVD events that could be prevented based on the risk reduction observed in a previous study. The predicted number of ASCVD events prevented was then used to calculate potential savings in direct medical costs over a 10-year period. National Health and Nutrition Examination Survey (NHANES) data and practice-level data were used for the estimations.24 With improved CVD preventative measures, the 10-year ASCVD risk was predicted to decrease to 10.03%, which represents an absolute reduction of 0.08 percentage points (p-value ≤ 0.01) and a relative risk reduction of 0.79% compared with the baseline risk. Modeling results showed that among the 3,961,384 patients evaluated, 3,169 ASCVD events would be prevented. Given that the average direct 90-day medical cost of a major CV event is estimated at $47,433, avoiding the 3,169 ASCVD events would yield savings of approximately $150 million in direct medical expenses.24

The relationship between the health-related QOL (HRQOL) and ASCVD risk in a national sample of U.S. adults was examined by Nooe and colleagues.25 Pooled cohort equations were derived from 8,978 adults who were aged 40 to 79 years and without CVD. Significant adverse associations (p-value < 0.05) were found between the 10-year ASCVD risk and HRQOL. The authors noted that even in patients without CVD, patients at higher risk have a lower HRQOL.25

Strategies for improving outcomes

There remains room for improvement in uptake of LLT, as shown by the results of an analysis of NHANES data by Gao and colleagues, which demonstrated that although cholesterol screening rates have increased, statin use increased only modestly. NHANES data from 1999 to 2018 were analyzed to examine trends in cholesterol screening and LLT use in the U.S.26 The study population included 50,928 individuals. The analysis showed that cholesterol screening rates were 70.3% in 1999 to 2000 (95% CI, 67.1%-73.3%) but increased to 81.1% in 2017 to 2018 (95% CI, 78.8%-83.2%; p-value = 0.009). Statin treatment, according to 2018 ACC/AHA guidelines, increased from 14.9% in 1999 to 2000 (95% CI, 12.2%-17.9%) to 27.8% in 2017 to 2018 (95% CI, 23.0%-33.2%; p-value < 0.001).26

Strategies for improving the outcomes of patients with hyperlipidemia include educational initiatives for both healthcare providers and patients and quality improvement initiatives at the health system level.27,28

Healthcare provider education

Clinical inertia occurs when a clinician does not initiate or intensify therapy when a treatment goal is not met.27 One way that this challenge can be overcome is by educating clinicians on changes in practice guidelines through continuing education programs. Providing education outreach visits in which a trained individual provides face-to-face education and feedback on clinician performance can also be used to facilitate provider training and education.27

Patient education

Shared decision-making can function as an important component of hyperlipidemia treatment. Clinicians should discuss treatment options with patients, ensuring that they understand the overall clinical benefits of comprehensive CV risk reduction and assisting them in navigating medical misinformation.27

Education can be provided on risk reduction strategies including eating a healthy diet, implementing exercise regimens, eliminating tobacco, limiting alcohol and managing weight and other medical conditions.28 Risk calculators are available for determining a patient’s risk of developing ASCVD.29 This tool enables physicians to forecast the 10-year risk and predict the impact of various treatments on risk.29

Improving adherence to therapy is another important goal of patient education. Adherence to statin therapy remains lower than 70% in patients who require LLTs.30 A retrospective, observational database study conducted from January 1, 2021, to February 8, 2023, showed that among patients taking nonstatin LLTs, 49% adhere to PCSK9 inhibitors, 51% adhere to alirocumab and evolocumab and 70% adhere to inclisiran.31 The various barriers to LLT adherence are described in Table 2, along with potential strategies for addressing these challenges.32

Systems level

Quality improvement initiatives at the health systems level can include implementation of financial incentives for practices that substantially lower the 10-year ASCVD risk of their patients.33

Clinical pathways can be developed based on recent and emerging data from CV outcomes trials, such as CLEAR Outcomes.7,34 The results of recent studies show that CV risks can be reduced in primary prevention patients with appropriate treatment. Targeting patients at higher risk with more intensive therapies can improve health and reduce economic impacts.34

Conclusions

Strategies for primary prevention of ASCVD involve addressing risk factors, including hyperlipidemia. Nonstatin LLTs such as PCSK9 inhibitors, BA and inclisiran can be used to help lower LDL-C levels. Identifying treatment barriers as well as implementing education strategies for both patients and providers can help patients achieve goal LDL-C levels and reduce their risk of developing ASCVD.


References

1. American Heart Association. What is cardiovascular disease? January 10, 2024. Accessed February 4, 2024. https://www.heart.org/en/health-topics/consumer-healthcare/what-is-cardiovascular-disease
2. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e563-e595. doi:10.1161/CIR.0000000000000677
3. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke
statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147(8):e93-e621. doi:10.1161/CIR.0000000000001123
4. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156. doi:10.1016/j.jacc.2018.06.046
5. Wong ND, Young D, Zhao Y, et al. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011-2012. J Clin Lipidol. 2016;10(5):1109-1118. doi:10.1016/j.jacl.2016.06.011
6. Toth PP, Patti AM, Giglio RV, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018;18(3):157-173. doi:10.1007/s40256-017-0259-7
7. Nissen SE, Lincoff AM, Brennan D, et al; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353-1364. doi:10.1056/NEJMoa2215024
8. Cheeley MK, Saseen JJ, Agarwala A, et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. 2022;16(4):361-375. doi:10.1016/j.jacl.2022.05.068
9. Repatha. Prescribing information. Amgen, Inc.; 2023. Accessed February 23, 2024. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Repatha/repatha_pi_hcp_english.pdf
10. Praluent. Prescribing information. Regeneron Pharmaceuticals; 2023. Accessed February 23, 2024. https://products.sanofi.us/praluent/praluent.pdf
11. Nexletol. Prescribing information. Esperion Therapeutics; 2023. Accessed February 23, 2024. https://pi.esperion.com/nexletol/nexletol-pi.pdf
12. Leqvio. Prescribing information. Novartis Pharmaceuticals Corporation; 2023. Accessed November 6, 2023. https://www.novartis.com/us-en/sites/novartis_us/files/leqvio.pdf
13. Zetia. Prescribing information. Organon & Co.; 2023. Accessed February 22, 2024. https://www.organon.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf
14. 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
15. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(suppl):1507-1519. doi:10.1056/NEJMoa1912387
16. Sabatine MS, Giugliano RP, Keech A, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
17. ClinicalTrials.gov. Effect of evolocumab in patients at high cardiovascular risk without prior myocardial infarction or stroke (VESALIUS-CV). February 22, 2024. Accessed February 28, 2024. https://clinicaltrials.gov/study/NCT03872401
18. Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023;330(2):131-140. doi:10.1001/jama.2023.9696
19. Nicholls SJ, Nelson AJ, Lincoff AM, et al. Impact of bempedoic acid on total cardiovascular events: a prespecified analysis of the CLEAR Outcomes randomized clinical trial. JAMA Cardiol. doi:10.1001/jamacardio.2023.5155
20. Grundy SM, Stone NJ, Bailey AL, et al. 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. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
21. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al; Writing Committee. 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
22. American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: standards of care in diabetes-2024. Diabetes Care. 2024;47(suppl 1):S179-S218. doi:10.2337/dc24-S010
23. Zhao Z, Zhu Y, Fang Y, Ye W, McCollam P. Healthcare resource utilization and costs in working-age patients with high-risk atherosclerotic cardiovascular disease: findings from a multi-employer claims database. J Med Econ. 2015;18(9):655-665. doi:10.3111/13696998.2015.1041966
24. Lindner SR, Balasubramanian B, Marino M, et al. Estimating the cardiovascular disease risk reduction of a quality improvement Initiative in primary care: findings from EvidenceNOW. J Am Board Fam Med. 2023;36(3):462-476. doi:10.3122/jabfm.2022.220331R1
25. Nooe A, Edwards MK, Addoh O, Loprinzi PD. Convergent validity of the ACC/AHA pooled cohort equations in associating with health-related quality of life among adults in the United States. Health Promot Perspect. 2016;7(1):42-46. doi:10.15171/hpp.2017.08
26. Gao Y, Shah LM, Ding J, Martin SS. US trends in cholesterol screening, lipid levels, and lipid-lowering medication use in US adults, 1999 to 2018. J Am Heart Assoc. 2023;12(3):e028205. doi:10.1161/JAHA.122.028205
27. Dixon DL, Sharma G, Sandesara PB, et al. Therapeutic inertia in cardiovascular disease prevention: time to move the bar. J Am Coll Cardiol. 2019;74(13):1728-1731. doi:10.1016/j.jacc.2019.08.014
28. American Heart Association. Reduce your risk of ASCVD. December, 2022. Accessed February 2, 2024. https://www.heart.org/-/media/Files/Health-Topics/Cholesterol/Reduce-ASCVD-risk.pdf
29. ASCVD Risk Estimator Plus. American College of Cardiology. Accessed February 23, 2024. https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/
30. Colantonio LD, Rosenson RS, Deng L, et al. Adherence to statin therapy among US adults between 2007 and 2014. J Am Heart Assoc. 2019;8(1):e010376. doi:10.1161/JAHA.118.010376
31. Niu X, Popadic BA, Ma, X, et al. Six-month adherence among early inclisiran initiators vs. anti-PCSK9 mAbs users: a retrospective analysis of US claims databases. Poster presented at: American Heart Association Scientific Sessions 2023; November 11-13, 2023; Philadelphia, PA.
32. Desai NR, Farbaniec M, Karalis DG. Nonadherence to lipid-lowering therapy and strategies to improve adherence in patients with atherosclerotic cardiovascular disease. Clin Cardiol. 2023;46(1):13-21. doi:10.1002/clc.23935
33. Borden WB, Wang J, Jones P, et al. Reducing cardiovascular risk in the Medicare Million Hearts Risk Reduction Model: insights from the National Cardiovascular Data Registry PINNACLE Registry. Circ Cardiovasc Qual Outcomes. 2022;15(4):e007908. doi:10.1161/CIRCOUTCOMES.121.007908
34. Abrahams T, Nelson AJ, Nicholls SJ. How will our practice change after the CLEAR Outcomes trial? Curr Atheroscler Rep. 2024;26(3):83-89. doi:10.1007/s11883-024-01188-5
























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