Staying on Target_Reducing CV Risk target LDL-C.pptx

Dislipidemia

1. Staying on Target: Reducing CV Risk by Achieving LDL-C Targets With Statin and Nonstatin Therapies  Supported by an educational grant from Novartis Pharmaceuticals Corporation.  Provided by Clinical Care Options, LLC

2. Please feel free to use and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact [email protected] for details About These Slides Slide credit: clinicaloptions.com

3. Faculty Chair Michael Miller, MD, FACC, FAHA Cardiologist & Professor of Medicine Hospital of the University of Pennsylvania Chief of Medicine Corporal Michael J. Crescenz VA Medical Center Philadelphia, Pennsylvania Ty J. Gluckman, MD, MHA, FACC, FAHA, FASPC Medical Director Center for Cardiovascular Analytics, Research, and Data Science (CARDS) Providence Heart Institute Providence Health System Portland, Oregon Faculty

4. Disclosures The faculty reported the following relevant financial relationships or relationships to products or devices they have with ineligible companies related to the content of this educational activity: Michael Miller, MD, FACC, FAHA: consultant/advisor/speaker: 89Bio, Amarin, Ionis. Ty J. Gluckman, MD, MHA, FACC, FAHA, FASPC : has no relevant financial relationships to disclose .

5. Learning Objectives Compare and contrast LDL-C–lowering treatments to select the most appropriate agent for patients with hyperlipidemia Incorporate effects of Lp(a) into risk assessment and treatment strategies for patients with or at risk for ASCVD Implement evidence-based guideline recommendations for establishing and achieving LDL-C targets by appropriately initiating and intensifying therapy Design individualized, optimized treatment regimens to help patients with hyperlipidemia reach LDL-C goals

6. Current Approaches for Hyperlipidemia Management

7. Abnormal Lipids Increase Risk of Myocardial Infarction 36 12 7 10 20 33 20 40 60 80 100 Smoking Fruits/ Veg Exercise Alcohol Psycho- social Lipids All 9 Risk Factors Population Attributable Risk (%) 14 18 90 DM Abdominal Obesity HTN 50 Case-control study of 15,152 patients with acute myocardial infarction and 14,820 controls from 52 countries (INTERHEART study) Yusuf. Lancet. 2004;364:937-952.

8. LDL Is a Causal Agent in ASCVD Tokgözoğlu. Eur Heart J. 2022;43:3198. Observational Epidemiologic Studies Mendelian Randomization and Genetic Analyses Randomized Clinical Trials Animal Experiments LDL-C primary target Lower LDL-C goals LDL-C Causal

9. LDL-C and Atherosclerosis Fernandez-Friera. J Am Coll Cardiol. 2017;70:2979. Generalized (4-6 sites) Intermediate (2-3 sites) Focal (1 vascular site) No atherosclerosis Mean of sites affected 2 Vascular sites 1 Vascular site 0 Vascular sites LDL-C (mg/dL) Atherosclerosis (%) No Atherosclerosis (%) 80 60 40 20 20 40 60 80 100 50-60 (n = 2) 60-70 (n = 9) 70-80 (n = 41) 90-100 (n = 169) 100-110 (n = 214) 110-120 (n = 288) 120-130 (n = 291) 130-140 (n = 275) 140-150 (n = 233) 80-90 (n = 94) 150-160 (n = 163) 11 12 7 24 13 3 1 3 15 21 14 25 19 20 6 6 23 25 9 25 24 8 26 23 12 26 26 100

10. Why LDL Lowering Is Important: Cumulative LDL-C, Yr vs Age Shapiro. J Am Coll Cardiol. 2020;76:1517. Severe hypercholesterolemia from birth (FH) Moderate hypercholesterolemia starting in teens (genetics lifestyle) Modest hypercholesterolemia from adulthood (lifestyle) Threshold for onset of ASCVD Lifelong low LDL-C (genetics, excellent lifestyle, initiation of LDL-lowering therapy at an early age) Cumulative Cholesterol-Yr Age

11. Statins Remain Mainstay Therapy for Key Risk Groups Silverman. JAMA. 2016;316:1289. Estimated Proportion With Coronary Heart Disease Death or Myocardial Infarction Over 5 Yr Primary prevention trials (n = 8) Control group Intervention group Secondary prevention trials (n = 16) Control group Intervention group Achieved LDL-C Level (mmol-L) 26 26 34 34 28 42 44 28 27 52 41 31 32 23 43 54 36 42 47 33 30 31 46 27 48 23 38 44 30 54 48 36 45 35 29 38 46 45 41 29 32 40 47 35 40 23 52 33 31 30 25 20 18 10 5 1.0 2.0 3.0 4.0 5.0 Statin Therapy in Primary and Secondary Prevention

12. Statin Intensity and LDL-C Reduction Adapted from Grundy. J Am Coll Cardiol. 2019;73:e285. High Moderate Low Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Atorvastatin 10-20 mg Fluvastatin XL 80 mg Fluvastatin 40 mg BID Lovastatin 40 mg Pitavastatin 1-4 mg Pravastatin 40-80 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Fluvastatin 20-40 mg Lovastatin 20 mg Pravastatin 10-20 mg Simvastatin 10 mg  LDL-C on average by ≥50%  LDL-C on average by < 30%  LDL-C on average by 30% to <50%

13. Despite Statin Therapy, Residual Risk Remains Residual CV risk is likely due not only to lipid factors (suboptimal LDL-C, TG) but also other risk factors in suboptimal control such as hypertension, diabetes, or smoking. 1. 4S Group. Lancet. 1994;344:1383. 2. LIPID Study Group. NEJM. 1998;339:1349. 3. Sacks. NEJM. 1996;335:1001. 4. HPS Collaborative Group. Lancet. 2002;360:7. 5. Shepherd. NEJM. 1995;333:1301. 6. Downs. JAMA. 1998;279:1615. 7. Ridker. NEJM. 2008;359:2195. 40 30 20 10 Patients Experiencing Major CHD Events (%) On-treatment LDL-C (mg/dL) N 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/TexCAPS 6 JUPITER 7 CHD Events Occur in Patients Treated With Statins 28.0 19.4 15.9 12.3 13.2 10.2 11.8 8.7 7.9 5.5 10.9 6.8 1.4 0.8 Placebo Statin 117 112 97 93 140 115 55 4444 9014 4159 20,536 6595 6605 17,802 Primary High Risk Secondary

14. Clinical benefits of LDL-C–lowering therapy apply to 4 patient groups Dual goals for all 4 patient groups: 1) percentage reduction in LDL-C and 2) reduction in LDL-C below a specific threshold In general, the intensity of LDL-C–lowering therapy should match the baseline risk of the individual 2018 Blood Cholesterol Guideline Recommendations Grundy. J Am Coll Cardiol. 2019;73:e285. Lloyd-Jones. J Am Coll Cardiol. 2022;80;1366. 4 Key Groups Warranting LDL-C–Lowering Therapy

15. What’s New From the 2022 ACC ECDP on the Role of Nonstatin Therapies to Reduce ASCVD Risk? 01 02 03 04 FDA approved to treat homozygous familial hyperlipidemia in adult and pediatric patients 12 yr or older Addition of Evinacumab FDA approved as adjunct to diet and max tolerated statin for adults with heterozygous familial hyperlipidemia ASCVD who require additional LDL reduction Addition of Inclisiran The goal was to provide practical guidance for HCPs and patients in situations not covered by the 2018 AHA/ACC/ multisociety cholesterol guideline to bridge the next guideline Builds on the 2018 Cholesterol Guideline Monotherapy with 180 mg in statin intolerant patients demonstrated a 24.5% reduction in LDL Addition of Bempedoic Acid Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366.

16. Many LDL-C–Lowering Tools at Your Disposal Bardolia. Front Cardiovasc Med. 2021;8:789931. Statins Bempedoic acid Inclisiran PCSK9 mAbs Ezetimibe LDL-C LDL-C Decreased intestinal cholesterol uptake NPC1L1 Citrate + CoA ATP-CL HMG-CR Cholesterol Reduced cholesterol availability Upregulation of LDL-R PCSK9 mRNA PCSK9 Reduced LDL-R lysomal degradation AcetylCoA

17. Intestinal Cholesterol Absorption Inhibitor: Ezetimibe Statins Bempedoic acid Ezetimibe LDL-C LDL-C Decreased intestinal cholesterol uptake NPC1L1 Citrate + CoA ATP-CL HMG-CR Cholesterol Reduced cholesterol availability Upregulation of LDL-R Reduced LDL-R lysomal degradation AcetylCoA Inclisiran PCSK9 inhibitors PCSK9 mRNA PCSK9 Bardolia. Front Cardiovasc Med. 2021;8:789931. Figure reproduced under terms of Creative Commons Attribution License (CC BY). Cannon. NEJM. 2015;372:2387. Daily oral agent, FDA approved for LDL-C lowering Monotherapy achieves ~18% lowering When added to statins achieves additional 23%-24% lowering Not for moderate/severe hepatic impairment

18. IMPROVE-IT: Ezetimibe Efficacy Double-blind, randomized trial of N = 18,144 people hospitalized for ACS within prior 10 days LDL-C 50-100 mg/dL if receiving lipid-lowering therapy LDL-C 50-125 mg/dL if not receiving lipid-lowering therapy Randomized to simvastatin 40 mg monotherapy or simvastatin 40 mg + ezetimibe 10 mg Primary endpoint: 3-point MACE Cannon. NEJM. 2015 ; 372:2387. 3-Component MACE HR: 0.936 (95% CI: 0.89-0.99; P = .016) Event Rate Yr Since Randomization 40 35 30 25 20 15 10 5 1 2 3 4 5 6 7 EZ/Simva: 32.7% (2572 events) Simva: 34.7% (2742 events)

19. PCSK9 Inhibitor mAbs: Alirocumab and E volocumab Statins Bempedoic acid Ezetimibe LDL-C LDL-C Decreased intestinal cholesterol uptake NPC1L1 Citrate + CoA ATP-CL HMG-CR Cholesterol Reduced cholesterol availability Upregulation of LDL-R Reduced LDL-R lysomal degradation AcetylCoA Inclisiran PCSK9 inhibitors PCSK9 mRNA PCSK9 Bardolia. Front Cardiovasc Med. 2021;8:789931. Figure reproduced under terms of Creative Commons Attribution License (CC BY). Alirocumab [PI]. Evolocumab [PI]. FDA approved for LDL-C lowering and to reduce MACE in patients with ASCVD Achieve ~45%-64% LDL lowering Hypersensitivity reactions, diabetes (evolocumab) Dosed SC Q2-4W

20. PCSK9 Inhibitor Monoclonal Antibodies: Impact on MACE 1. Sabatine. NEJM. 2017;376:1713. 2. Goodman. J Am Heart Assoc. 2023;12:e029216. Placebo Alirocumab Patients at Risk, n Yr Since Randomization ODYSSEY Outcomes 2 CHD death, MI, ischemic stroke, UA hospitalization (%) 4126 4116 3854 3872 3646 3715 3471 3574 629 653 HR: 0.83 (95% CI: 0.74-0.94; P = .003) 20 15 10 5 14.2% 12.0% Placebo Alirocumab 1 2 3 4 Mo From Randomization FOURIER 1 CV Death, MI, Stroke, Hosp for UA, or Cor Revasc (%) HR: 0.85 (95% CI: 0.79-0.92; P = .0001) 16 14 12 10 8 6 4 2 14.6% 12.6% Placebo Evolocumab 6 12 18 24 30 36

21. FOURIER-OLE: Lower for Longer Is Better! O’Donoghue. Circulation. 2022;146:1109. 24 48 72 96 120 144 168 12 24 48 72 96 120 144 168 192 216 260 100 90 80 70 60 50 40 30 20 10 Weeks LDL-C (mg/dL) FOURIER-OLE Open-label evolocumab Parent FOURIER Evolocumab vs Placebo Placebo transition to evolocumab 3277 3353 3209 3276 3029 3123 1141 1138 3154 3223 3069 3178 2956 3062 2614 2746 2182 2306 1893 1962 Placebo Evolocumab Randomized to placebo Randomized to evolocumab CV Death, MI, Stroke, Unstable Angina, or Coronary Revascularization (%) HR: 0.85 (95% CI: 0.75-0.96; P = .008) 1 2 3 4 5 3280 3355 2716 2890 2573 2716 1706 1754 3055 3186 2876 3033 Placebo Evolocumab Patients at Risk, n Yr Placebo evolocumab Evolocumab evolocumab 20 10 17.5% 15.4% Evolocumab Evolocumab

22. ATP-Citrate Lyase Inhibitor: Bempedoic Acid Agarwala. Drug Des Devel Ther. 2021;15:1955. Bardolia. Front Cardiovasc Med. 2021;8:789931. Figure reproduced under terms of Creative Commons Attribution License (CC BY). Statins Bempedoic acid Inclisiran PCSK9 mAbs Ezetimibe LDL-C LDL-C Decreased intestinal cholesterol uptake NPC1L1 Citrate + CoA ATP-CL HMG-CR Cholesterol Reduced cholesterol availability Upregulation of LDL-R PCSK9 mRNA PCSK9 Reduced LDL-R lysomal degradation AcetylCoA P rodrug activated in the liver (not active in muscle) Daily oral agent, FDA approved for LDL-C lowering in ASCVD or HeFH Achieves ~17%-18% LDL-C lowering May increase serum uric acid, risk of tendon rupture

23. CLEAR Outcomes: Bempedoic Acid CVOT 4-Component MACE 100 80 60 40 20 Cumulative Incidence (%) Mo Since Randomization 6 12 18 24 30 36 42 48 54 60 HR: 0.87 (95% CI: 0.79-0.96; P = .004) Placebo Bempedoic acid 6 12 18 24 30 36 42 48 54 60 20 15 10 5 Patients at Risk, n Placebo Bempedoic acid 6978 6992 6779 6816 6579 6645 6401 6472 6206 6293 5995 6106 5105 5257 2524 2601 1207 1240 513 556 55 74 N = 13,970 Nissen. NEJM. 2023 ; 388(15):1353. Mo Since Randomization Patients With Event (%) 4-Component MACE (Primary Prevention Subanalysis) HR: 0.70 (95% CI: 0.55-0.89; P = .002) 12 10 8 6 4 2 6 12 18 24 30 36 42 48 54 Placebo Bempedoic Acid

24. PCSK9 mRNA Synthesis Inhibitor: Inclisiran Samuel. Ann Pharmacother. 2022;10600280221105169. Bardolia. Front Cardiovasc Med. 2021;8:789931. Figure reproduced under terms of Creative Commons Attribution License (CC BY). Inclisiran PI. Statins Bempedoic acid Inclisiran PCSK9 mAbs Ezetimibe LDL-C LDL-C Decreased intestinal cholesterol uptake NPC1L1 Citrate + CoA ATP-CL HMG-CR Cholesterol Reduced cholesterol availability Upregulation of LDL-R PCSK9 mRNA PCSK9 Reduced LDL-R lysomal degradation AcetylCoA FDA-Approved for ASCVD or HeFH (adjunct to diet and maximally tolerated statin therapy in patients who require additional LDL-C reduction) Achieves ~48%-52% LDL-C lowering Dosing: SC injection at initiation, 3 mo, then every 6 mo thereafter

25. 20 -20 -40 -80 -100 -60 ORION-10: Clinically Efficacy of Inclisiran in Patients With ASCVD on Maximally Tolerated Statin Therapy Ray. NEJM. 2020;382:1507. Days LDL-C Level (mg/dL) 150 330 510 540 90 270 450 175 100 75 25 150 50 125 Placebo Inclisiran Absolute Change (mg/dL) in LDL-C, ORION-10 Trial Days Change From Baseline (%) 150 330 510 540 90 270 450 Placebo Inclisiran Percentage Change (%) in LDL-C, ORION-10 Trial Patients at Risk, n Placebo Inclisiran 780 781 762 758 745 757 724 737 715 731 698 721 666 691 676 705 Patients at Risk, n Placebo Inclisiran 780 781 762 758 745 757 724 737 715 731 698 721 666 691 676 705

26. Recent and Ongoing Research: Agents Targeting LDL-C Reduction Investigational Agents MK-0616 (o ral macrocyclic peptide inhibitor of PCSK9) Phase II results: 41%-61% lowering of LDL-C 1 Ongoing CVOT: CORALreef Outcomes 2 Obicetrapib (cholesteryl ester transfer protein inhibitor) ROSE, phase II 3 Ongoing CVOT: PREVAIL 4 FDA-Approved Agent Inclisiran (small-interfering RNA agent) Ongoing CVOTs: ORION-4 5 VICTORION-2P 6 1. Ballantyne. J Am Coll Cardiol. 2023;81:1553. 2. NCT06008756. 3. Nicholls. Nat Med. 2022;28;1672. 4. NCT05202509. 5. NCT03705234. 6. NCT05030428.

27. The Role of Lipoprotein(a) in ASCVD Risk

28. Additional Risk Factors That Inform ASCVD Risk Risk-Enhancing Factors Family history of premature ASCVD Persistently elevated LDL-C (≥160 mg/dL) Chronic kidney disease Metabolic syndrome Preeclampsia or premature menopause Inflammatory diseases (eg, RA, psoriasis, HIV) South Asian ancestry Persistently elevated triglycerides (≥175 mg/dL) hs-CRP ≥2.0 mg/L Lp(a) ≥50 mg/dL apoB ≥130 mg/dL ABI <0.9 Grundy. J Am Coll Cardiol. 2019;73:e285.

29. Lp(a) and Residual ASCVD Risk Lp(a) levels are genetically determined Normal levels <30 mg/dL (75 nmol/L) 20%-25% have a level ≥50 mg/dL (125 nmol/L) Lp(a) levels not improved with diet and exercise Retrospective analysis of US cohort of >16,000 patients found increased Lp(a) levels independently associated with long-term MACE among people with and without baseline ASCVD Elevated Lp(a) levels increase risk of CVD calcific aortic stenosis www.acc.org/latest-in-cardiology/articles/2023/09/19/10/54/an-update-on-lipoprotein-a. Alhomoud. Pharmacotherapy. 2023;43:1051. Berman. J Am Coll Cardiol. 2024;83;873. LDL Lp(a)

30. Lp(a) Testing: Guidance and Challenges Challenges with routine Lp(a) screening: Lack of reimbursement Lack of treatment options Limited availability of Lp(a) test High cost of testing Lp(a) often used to stratify CV risk Threshold for increased risk is ≥50 mg/dL (≥ 125 nmol/L ) Grundy. J Am Coll Cardiol. 2019;73: e285. Wilson. J Clin Lipidol. 2022;16:e77. Catapano. Atherosclerosis. 2023;370:5. Guidance for Lp(a) Testing Personal history of premature ASCVD Family history of premature ASCVD (<55 yr of age in men, <65 yr of age in women) Primary severe hypercholesterolemia (LDL-C ≥190 mg/dL) Presence of Lp(a) ≥50 mg/dL or ≥125 mmol/L may be used to add statin or ↑ lipid lowering intensity based on projection of future ASCVD risk

31. 220 200 180 160 140 120 100 80 60 40 20 Dallas Heart Study: Lp(a) Levels by Race/Ethnicity Tsimikas .Circulation. 2009;119:1711. 90% 75% Black Female Lp(a) Level (nmol/L)* White Female Hispanic Female *Boxes show medians, 25th and 75th percentile; whiskers specify 10th and 90th percentile. Black Male White Male Hispanic Male

32. Lp(a) Levels and Risk of Aortic Stenosis Kamstrup. J Am Coll Cardiol. 2014;63:470. HR (95% CI) for Aortic Valve Stenosis 5 1 2 3 4 Trend: P <.001 Lp(a) percentile, mg/dL <22 22-66 67-89 90-95 >95 3 (2-4) 11 (7-17) 40 (30-51) 80 (63-95) 124 (104-148)

33. Effects of Approved Lipid-Lowering Therapies on Lp(a) Alhomoud. Pharmacotherapy. 2023;43:105. Therapy Effect on Lp(a) Levels Statins ↑ Ezetimibe Minimal PCSK9 mAbs ↓↓ Inclisiran ↓↓ Bempedoic acid Minimal Nicotinic acid ↓↓ Bile acid sequestrants ↑ Fibric acid derivatives ↑ Omega-3 fatty acids Minimal Lomitapide ↓ Evinacumab Minimal

34. 286 patients with established CVD and Lp(a) levels ≥60 mg/dL (150 nmol/L) randomized to tx group Tsmikas. NEJM. 2020;382:244. NCT04023552. 100% LS Mean Change (%) -20 -40 -60 -80 100 Placebo 20 mg/Q4W 40 mg/Q4W 20 mg/Q2W 60 mg/Q4W 20 mg/QW -6% -35% -56% -58% -72% -80% Lp(a)HORIZON phase III study: Pelacarsen SC injection 80 mg every month vs placebo N = 8323; CVD with Lp(a) levels ≥70 mg/dL Time to occurrence of MACE in 4 yr AKCEA-APO(a)-L Rx : Phase II Study of Effect on Lp(a) Levels

35. Recent and Ongoing Research: Agents Targeting Lp(a) Reduction 1. O’Donoghue. NEJM . 2022;387:1855. 2. NCT05581303. 3. Nissen. JAMA. 2023;330:2075. 4. NCT06292013. 5. Tsim ikas. NEJM. 2020;382:244. 6. NCT04023552. Investigational Agents Olpasiran Investigational Small-interfering RNA agent Mean 70%-101% reduction 1 Ongoing CVOT: OCEAN(a) 2 Lepodisiran Investigational Small-interfering RNA agent Median 41%-97% reduction 3 Ongoing CVOT: ACCLAIM-Lp(a) 4 Pelacarsen Investigational (aka AKCEA-APO(a)-LRx) Ligand-conjugated antisense agent Mean 35%-80% reduction 5 Ongoing CVOT: Lp(a)HORIZON 6

36. Individualizing and Implementing Therapy to Achieve LDL-C Goals

37. ASCVD Prevention Risk Groups Adapted from Grundy. J Am Coll Cardiol. 2019;73:e285.

38. Secondary Prevention: Clinical ASCVD Adapted from Grundy. J Am Coll Cardiol. 2019;73:e285.

39. Major ASCVD Events ACS within past 12 mo History of MI (other than ACS above) History of ischemic stroke Symptomatic PAD High-Risk Conditions Age ≥ 65 yr CKD (GFR 15-59 mL/min/1.73m 2 ) Coronary bypass or percutaneous intervention Current smoker Diabetes HeFH History of HF Hypertension LDL-C ≥ 100 mg/dL despite maximally tolerated statin + ezetimibe 2 Very high risk 1 ≥2 + Criteria for Defining “Very High–Risk” ASCVD Very high risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366.

40. Patient Population LDL-C, mg/dL Non–HDL-C, mg/dL Adults with ASCVD at very high risk <55 <85 Adults with ASCVD not at very high risk <70 <100 Adults with ASCVD and baseline LDL-C ≥190 mg/dL without FH <70 <100 Adults with ASCVD and baseline LDL-C ≥190 mg/dL with FH <55 <85 Thresholds for Initiation of Nonstatin Therapy in ASCVD Consider addition of nonstatin therapy as needed to achieve desired LDL-C reduction ≥50% reduction in LDL-C on maximal tolerated statin AND . . . Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366. A. pathways B. C. D. IF NO

41. 2022 ACC Expert Decision Pathway Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366. Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy Adults with ASCVD at very high risk 1 2 Threshold reached? Yes Referral to lipid specialist Referral to RD/RDN Consider ezetimibe and/or PCSK9 mAb ≥50% reduction in LDL-C and LDL-C <55 mg/dL on maximal tolerated statin or A. May consider bempedoic acid or inclisiran Threshold reached? Decision for no additional medication No Yes Yes No

42. 2022 ACC Expert Decision Pathway Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy Adults with ASCVD not at very high risk 1 2 Threshold reached? Yes Referral to lipid specialist Referral to RD/RDN Consider ezetimibe ≥50% reduction in LDL-C and LDL-C <70 mg/dL on maximal tolerated statin or B. May consider PCSK9 mAb Threshold reached? Decision for no additional medication No Yes Yes No 3 May consider bempedoic acid or inclisiran Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366.

43. 2022 ACC Expert Decision Pathway Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy Adults with ASCVD with LDL-C ≥190 mg/dL without FH 1 2 Threshold reached? Yes Referral to lipid specialist Referral to RD/RDN Consider ezetimibe and/or PCSK9 mAb ≥50% reduction in LDL-C and LDL-C <70 mg/dL on maximal tolerated statin or C. May consider bempedoic acid or inclisiran Threshold reached? Decision for no additional medication No Yes Yes No 3 May LDL apheresis under care of lipid specialist Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366.

44. 2022 ACC Expert Decision Pathway Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy Adults with ASCVD with LDL-C ≥190 mg/dL with FH 1 2 Threshold reached? Yes Referral to lipid specialist Referral to RD/RDN Consider ezetimibe and/or PCSK9 mAb ≥50% reduction in LDL-C and LDL-C <55 mg/dL on maximal tolerated statin or D. May consider bempedoic acid or inclisiran Threshold reached? Decision for no additional medication No Yes Yes No 3 May consider evinacumab, lomitapide, and/or LDL apheresis for HoFH under care of lipid specialist Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366.

45. Primary Prevention: Severe Hypercholesterolemia Adapted from Grundy. J Am Coll Cardiol. 2019;73:e285.

46. ACC ECDP: Thresholds for Initiation of Nonstatin Therapy Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366. Patient Population LDL-C, mg/dL Non–HDL-C, mg/dL Adults without ASCVD and baseline LDL-C ≥190 mg/dL <100 <130 Consider addition of nonstatin therapy as needed to achieve desired LDL-C reduction ≥50% reduction in LDL-C on maximal tolerated statin AND . . . E. IF NO

47. 2022 ACC Expert Decision Pathway Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy Adults without ASCVD with LDL-C ≥190 mg/dL 1 2 Threshold reached? Yes Referral to lipid specialist Referral to RD/RDN Consider ezetimibe and/or PCSK9 mAb ≥50% reduction in LDL-C and LDL-C <100 mg/dL on maximal tolerated statin or E. May consider bempedoic acid or inclisiran Threshold reached? Decision for no additional medication No Yes Yes No 3 Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366. May consider evinacumab, lomitapide, and/or LDL apheresis for HoFH under care of lipid specialist

48. Primary Prevention: Diabetes Mellitus Adapted from Grundy. J Am Coll Cardiol. 2019;73:e285.

49. ASCVD Risk Estimator Plus. tools.acc.org/ASCVD-Risk-Estimator-Plus/. Estimating Cardiovascular Risk in DM to Determine Statin Intensity

50. Additional Risk Factors That Inform DM Risk Diabetes-Specific Risk Enhancers Long duration (≥10 yr for type 2 diabetes or ≥20 yr for type 1 diabetes) Albuminuria (≥30 mcg of albumin/mg creatinine) eGFR <60 mL/min/1.73 m 2 Retinopathy Neuropathy ABI <0.9 Grundy. J Am Coll Cardiol. 2019;73:e285.

51. Increase to high-intensity statin therapy if goal not met OR a) the 10-yr ASCVD risk is 7.5%-19.9%, b) there are DM risk enhancers, and/or c) there is subclinical atherosclerosis Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366. Patients With DM, but No ASCVD and an LDL-C <190 mg/dL 10-yr ASCVD risk <7.5%, no DM risk enhancers, and no subclinical atherosclerosis 1 2 Moderate-intensity statin therapy 30%-49% reduction in LDL-C and LDL-C <100 mg/dL (non–HDL-C <130 mg/dL) GOAL HOW TO GET THERE 10-yr ASCVD risk ≥20% 1 2 High-intensity (or maximally tolerated) statin therapy ≥50% reduction in LDL-C and LDL-C <70 mg/dL (non–HDL-C <100 mg/dL) GOAL HOW TO GET THERE May consider ezetimibe

52. Primary Prevention: No ASCVD, SH, or DM Adapted from Grundy. J Am Coll Cardiol. 2019;73:e285.

53. ASCVD Risk Estimator Plus. tools.acc.org/ASCVD-Risk-Estimator-Plus/. Estimating Cardiovascular Risk for Those Without DM

54. Using Coronary Calcium to Refine CV Risk Assessment CAC: marker of subclinical atherosclerosis, total plaque burden, and ASCVD risk Increasing risk of ASCVD with CAC burden, independent of coronary artery stenosis Imaging of CAC, noninvasive and low cost; may identify patients at very high risk at an early point before a clinical event Primary prevention patients with CAC ≥1000 identified as group for combination lipid-lowering therapy However, markers that equate to very high risk still undefined Grundy. Circulation. 2019;139:e1082. Mach. Eur Heart J. 2020;41:111. Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366.  my.clevelandclinic.org/health/diagnostics/ 16824-calcium-score-screening-heart-scan

55. Primary Prevention Patients Who May Benefit From CAC Grundy. J Am Coll Cardiol. 2019;73:e285. CAC Measurement Candidates Who Might Benefit From Knowing Their CAC Score Is Zero Patients reluctant to initiate statin therapy who wish to understand their risk and potential for benefit more precisely Patients concerned about need to reinstitute statin therapy after discontinuation for statin-associated symptoms Older patients (men, 55-80 yr of age; women, 60-80 yr of age) with low burden of risk factors who question whether they would benefit from statin therapy Middle-aged adults (40-55 yr of age) with PCE-calculated 10-yr risk of ASCVD 5.0% to <7.5% with factors that increase their ASCVD risk, although they are in a borderline risk group

56. Lloyd-Jones. J Am Coll Cardiol. 2022;80:1366. Patients Without ASCVD or DM and an LDL-C <190 mg/dL 10-yr ASCVD risk of 5.0%-19.9% 1 Moderate-intensity statin therapy 30%-49% reduction in LDL-C and LDL-C <100 mg/dL (non–HDL-C <130 mg/dL) GOAL HOW TO GET THERE 10-yr ASCVD risk ≥20% 1 2 High-intensity (or maximally tolerated) statin therapy ≥50% reduction in LDL-C and LDL-C <70 mg/dL (non–HDL-C <100 mg/dL) GOAL HOW TO GET THERE May be reasonable to consider ezetimibe 2 Increase to high-intensity statin therapy

57. Cost Considerations Discuss out-of-pocket costs Discuss Benefits/Risks of Therapy Discuss risk reduction Discuss safety of therapy Recommend statins Consider combination and/or nonstatin therapy when appropriate Setting the Stage for Shared Decision-making: 2018 Blood Cholesterol Guideline Checklist Assess ASCVD Risk Assign to statin treatment group Use decision tools to explain risks Lifestyle Modifications Review lifestyle habits Endorse healthy habits and provide resources/referrals Grundy. J Am Coll Cardiol. 2019;73:e285.

58. Engaging Patients in Shared Decision-making: 2018 Blood Cholesterol Guideline Checklist Grundy. J Am Coll Cardiol. 2019;73:e285. Use teach-back method to gain insights in what the patient learned Invite the patient to ask questions Inquire about patient preferences and values Discuss barriers to adherence Collaborate in developing the treatment and follow-up plan

59. Navigating Financial Access Barriers needymeds.org. ssa.gov/medicare/part-d-extra-help. medicare.gov. nafcclinics.org. Find links and information for active copay and medication assistance programs at needymeds.org Commercially or Privately Insured Medicare Part D Uninsured Formulary review Before prescribing To recommend/choose alternative agent Collaborating to follow step-therapy Prior authorization, peer to peer, and appeals Copay assistance cards Find free clinics in your area National Association of Free & Charitable Clinics: nafcclinics.org Formulary review Before prescribing To recommend/choose alternative agent Assist in applying for Extra Help Plan for coverage gap Find and assist with preparing medication assistance application Plan for open enrollment Important for patients to review and select best plan each year during open enrollment (October 15 - December 7)

60. Responses to Perceptions of Key Barriers to PCSK9i Use* McCormick. J Manag Care Spec Pharm. 2020;26:1517. Percentage 90 15 30 45 60 75 P = .72 P = .70 P = .09 P = .003 P = .63 67 72 72 78 72 44 6 11 56 17 High copays charged to patients Inadequate or incomplete documentation in prior authorization paperwork Excessive prior authorization documentation requirements and associated burdens Insufficient evidence that PCSK9i therapies are cost-effective Insufficient evidence that PCSK9i therapies reduce risks of major cardiovascular events Providers (n = 18) Payers (n = 18) *Pooled ratings of 4 (agree) and 5 (strongly agree) on a Likert scale.

61. Impact of Social Determinants of Health Social determinants of health have tremendous affect on an individual’s health regardless of age, race or ethnicity 40% 10% 30% 20 % SDoH Impact 20% of a person’s health and well-being is related to access to care and quality of services The physical environment, social determinants and behavioral factors drive 80% of health outcomes Socioeconomic Factors Physical Environment Health Behaviors Health Care Education Job Status Family/ Social Support Income Community Safety Tobacco Use Diet & Exercise Alcohol Use Sexual Activity Access to Care Quality of Care Figure adapted from aha.org/landing-page/addressing-social-determinants-health-presentation.

62. clinicaloptions.com Go Online for More CCO Coverage of Hyperlipidemia! On-demand webcast  to watch later at your convenience  ​ ClinicalThought commentaries  including a discussion of unmet needs in hyperlipidemia and healthcare professionals’ compelling questions from the symposium