Emerging Diagnosis and Management Funded by the Kaneka Corporation. Lp(a) and Peripheral Artery Disease
Publisher’s Note The Lp(a) and PAD: Emerging Diagnosis and Management is published by Ascend Media. 401 SW Ward Road, Suite 210, Lee’s Summit, MO 64081 © 2024 American Heart Association, Inc., a 501(c)(3) not-for-profit. All rights reserved. Unauthorized use prohibited. All references and data are as of July 2024.
3 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management 4 ����������������� Contributing Authors 6 ����������������� Defining PAD 8 ����������������� Defining Lp(a) and Why It Matters 10 ����������������� Why Is Lp(a) Important to Measure in Addition to LDL? 11 ����������������� Raising Awareness of Lp(a) 12 ����������������� Intersection of Lp(a) With PAD 13 ����������������� High Lp(a) Is Associated With Increased MALE. 14 ����������������� Approaches to Lowering Lp(a) 15 ����������������� Emerging Experimental Therapies for Lp(a) 16 ����������������� What Can Health Care Professionals (HCPs) Do Now? 18 ����������������� Top Takeaways 21 ����������������� Glossary 22 ����������������� References Contents
Danielle Vlazny, PA-C, MS, CWS, FSVM, is a physician assistant, assistant professor with the Gonda Vascular Center at Mayo Clinic Rochester, Minnesota. She has provided care to vascular patients over the past eight years in outpatient general vascular medicine, thrombophilia, vein clinic, wound care, and inpatient consulting service. In addition, she works on numerous evidence-based medicine and quality improvement projects within the center and teaches at the Mayo Clinic Physician Assistant Program. Disclosures: Professional Services and Activities – Employment: Mayo Clinic Professional Services and Activities – Other Professional Activities: Mayo Foundation for Medical Education and Research Nkechinyere (Nkechi) Ijioma, MBBS, FAHA, FACC, is an interventional cardiologist, and assistant professor of medicine at The Ohio State University. Her research interests include endovascular interventions, acute coronary syndrome, and cardiovascular health equity. Dr. Ijioma currently serves as the program director of Peripheral Vascular Interventions in the Division of Cardiovascular Medicine at The Ohio State University Wexner Medical Center. Disclosures: Professional Services and Activities – Employment: The Ohio State University Wexner Medical Center John Giacona, PA-C, PhD, is a physician assistant at the University of Texas Southwestern Medical Center. Dr. Giacona practices in the Hypertension Section within the Division of Cardiology – Department of Internal Medicine. His research interests include highdensity lipoprotein metabolism, skeletal muscle mitochondrial function, and the autonomic control of blood pressure. Dr. Giacona currently serves as chair of Preventive Cardiology for the Academy of Physician Associates in Cardiology. Reported no disclosures Contributing Authors 4
5 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Geoffrey Barnes, MD, MSc, FAHA, is a cardiologist and vascular medicine specialist at the University of Michigan Frankel Cardiovascular Center. Dr. Barnes is an NIH-funded health services researcher who is active in advancing the care of patients with thrombotic conditions, including peripheral artery disease. He is a leader with several national societies and currently serves as the fellowship director for the University of Michigan Vascular Medicine Fellowship program. Disclosures: Professional Services and Activities – Employment: University of Michigan Professional Services and Activities – Consultant: Acelis Connected Health, Bayer, Janssen Biotech, Inc., AstraZeneca, Pfizer, Anthos, BristolMyers Squibb, Sanofi, Abbott Vascular Financial Support – Grant/Contract: Boston Scientific Corporation Heather Harker Ryan, RN, PhD, CPN, FPCNA, is the clinical nurse educator and nurse scientist for the ambulatory division of the Cambridge Health Alliance in Cambridge, Massachusetts. Her program of research focuses on the identification and treatment of children and families affected by familial hypercholesterolemia. She currently holds leadership positions in a number of national organizations related to nursing leadership and cardiovascular care. Disclosures: Professional Services and Activities – Employment: Cambridge Health Alliance, Massachusetts General Hospital, University of Massachusetts Boston, Boston Children’s Hospital P. Barton Duell, MD, FAHA, MNLA, is an endocrinologist and lipid specialist at the Oregon Health & Science University where he is a professor of medicine in the Center for Preventive Cardiology, Knight Cardiovascular Institute and the Division of Endocrinology, Diabetes, and Clinical Nutrition. He is the director of the Lipoprotein Apheresis Unit and Sterol Analysis Laboratory at OHSU, as well as the co-editor-in-chief of the Journal of Clinical Lipidology. He serves/has served in leadership roles in various organizations including the AHA. He has been involved in numerous phase I-IV research studies related to lipid metabolism and ASCVD risk and has been evaluating and treating patients with elevated Lp(a) for more than 35 years. Disclosures: Professional Services and Activities – Employment: Oregon Health & Science University Professional Services and Activities – Consultant: Esperion Therapeutics Inc., Kaneka Pharma America LLC, Novo Nordisk, Regeneron Pharmaceuticals, Travere Therapeutics, Inc. Professional Services and Activities – Data and Safety Monitoring: Ionis Financial Support – Grant/Contract: Boston Scientific Corporation
Peripheral artery disease refers to peripheral artery obstruction secondary to atherosclerotic disease. Aorta Femoral Iliac Popliteal Posterior Tibial Anterior Tibial Peroneal PVD Arteries Most Commonly Affected by PAD “PAD” is the preferred term for Peripheral Artery Disease, not PVD 6 PAD most commonly affects the lower extremities, but can also affect the upper extremities. PAD Defining
7 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Risk Factors for PAD Older age Smoking Diabetes Hyperlipidemia Family history of PAD PAD is overrepresented in the Black community. Prevalence of PAD Lifetime risk of PAD (80-year horizon) was estimated at: 3, 4, 5 22%Hispanic people 19%White people 29%Black people of PAD are called major adverse limb events (MALE) and may include recurrent limb ischemia and/or amputation. Complications In the U.S., approximately 10-12M age 40+ have PAD.1, 2, 3 people Chronic Kidney Disease (CKD) Hypertension Atherosclerotic disease in another vascular bed
8 • Arterial thrombosis • Inflammation • Endothelial function • Lipid deposition into artery wall High Lp(a) promotes: Lipoprotein(a) – Lp(a) – is composed of an LDL-like moiety that is covalently bound to apolipoprotein(a) – apo(a). Lp(a) Defining and Why It Matters LDL Lp(a) apo(a) 80-90% Genetically determined 6, 7, 8 While not completely defined, Lp(a) is believed to be produced in the liver with proinflammatory and proatherogenic properties. Epigenetic studies show an association between elevated Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD). 9, 10 Lp(a) is: Leading to: • Atherosclerosis • Thrombosis • Calcific aortic stenosis
9 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management An estimated 20-25% of the world’s population has elevated levels of Lp(a).11 Disease/condition Atherosclerosis Thrombosis Aortic Valve Calcification Lp(a) structure & property Molecular mass: 300-800 kDa High carbohydrate content: 28% Apo(a) KIV3-10 KIV1 KIV2 (multiple copies) KV Lipid-rich domain ApoB- 100 a d b c Lp(a) serum level is associated with atherosclerotic cardiovascular diseases including stroke, myocardial infarction (MI), and PAD. Lp(a) is also a significant independent risk factor for PAD and is associated with more severe forms of PAD in specific populations.4 Regulation Genetics Ethnicity/ Race Medical conditions Environment Lp(a) concentration (high variability) Defining Lp(a): and why it matters Continued
10 Elevated Lp(a) is a common independent atherosclerotic cardiovascular disease risk factor that is not measured in the majority of affected patients. The only currently available method to know if someone has elevated Lp(a) is to measure Lp(a) with a simple blood test that is relatively inexpensive. Awareness of the presence of elevated Lp(a) is important, because high Lp(a) increases atherosclerotic cardiovascular disease risk and could inform clinical decision-making regarding risk management. Cascade screening of family members of patients with elevated Lp(a) may identify additional individuals with elevated Lp(a) because of its autosomal codominant inheritance pattern.12 Elevated Lp(a) is an independent risk factor for coronary heart disease (CHD), PAD, cerebrovascular disease, and calcific aortic stenosis. Why Is Lp(a) Important to Measure in Addition to LDL? a) CKD b) Liver disease c) Menopause Lp(a) can be increased by:13 Why would a clinician measure Lp(a)?
Who to test? 11 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management How should one measure Lp(a)?12 2018 Guideline on the Management of Blood Cholesterol states the relative indications for measurement are family history of premature ASCVD or personal history of ASCVD not explained by major risk factors.14, 15, 16, 17 Lp(a) should be measured with: Those with borderline ASCVD risk to aid in discussion of risk modification therapies Family or personal history of high Lp(a), heart disease, or premature cardiovascular disease Diagnosis of familial hypercholesterolemia (FH) - an inherited condition 18 An isoform-insensitive assay Assay that is traceable to the internationally accepted calibrator (World Health Organization/International Federation of Clinical Chemistry Reference Material SRM-2B) Assay that is reported in nanomoles per liter (nmol/l), when possible. ? Raising Awareness of Lp(a) Once an individual’s Lp(a) levels are tested, do they need to be retested? Although levels are generally stable over time, the levels can vary between labs or may increase after development of certain medical conditions, may decrease after treatment, and may otherwise vary. It may also be helpful to verify results with an outside lab before initiating therapies. If measurements are not uniformly calibrated, one cannot compare measurements generated by different assays.
12 4x Intersection of Lp(a) With PAD A retrospective study showed the prevalence of TransAtlantic Inter-Society Consensus (TASC) II class D and severe calcification of femoropopliteal lesions was higher in patients with high Lp(a) than those with low Lp(a).19 Findings from mechanistic, observational, and genetic studies support the causal role of Lp(a) in CVD, including CHD and PAD.19 MALE is 4 times more common in patients with elevated Lp(a). 21 Lp(a) and Major Adverse Cardiovascular Event (MACE) Elevated Lp(a) levels are independently associated with incident MACE and MALE in patients with PAD treated with revascularization irrespective of LDL-cholesterol (LDL-C) level and statin administration. 12 Higher Lp(a) levels are independently associated with an increased risk of MALE in hospitalized patients.4 Elevated Lp(a) levels are associated with an increased risk of MALE in hospitalized patients.20
High Lp(a) Is Associated With Increased MALE.21 Plasma Lp(a) is independently associated with first and consecutive MALE after iliofemoral endarterectomy. 22 13 33% higher risk of lower extremity revascularization in patients with PAD.23 Elevated Lp(a) incurs a 67.9% Elevated Lp(a) increases risk for MALE postrevascularization in of patients with PAD at 5 years regardless of LDL level and statin use (HR 4.15).21 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management
PCSK9 Inhibitors reduce Lp(a) up to 30%17 Data from trials of monoclonal antibodies directed against PCSK9 demonstrated dramatic LDL-C lowering by an average of 50% to 60%, but also modest Lp(a) lowering of 25% to 30%.28 FOURIER trial: The PCSK9 inhibitor (PCSK9i) evolocumab lowered Lp(a) by a median of 27% at 48 weeks.14, 29 ODYSSEY OUTCOMES trial: 18,924 patients with recent acute coronary syndrome who were taking high-intensity statin demonstrated that the PCSK9i alirocumab reduced Lp(a) by 23% after 4 months.30 ORION-11 (inclisiran) trial:31 The placebo-corrected percentage reduction in Lp(a) levels from baseline to Day 540 was 28.5%. Lipoprotein Apheresis lowers Lp(a) acutely by 50-85%12 14 Approaches for Lowering Lp(a) FDA approved for patients with familial hypercholesterolemia who have ASCVD (such as MI, PAD, CVD) and LDL-C > 100 mg/dl on maximal tolerable drug and lifestyle therapy with or without Lp(a) > 60 mg/dl.12 Indirect evidence suggests that Lp(a) lowering with Lipoprotein Apheresis may be associated with decreased ASCVD risk.24 Results in improved circulation, pain level, and walking distance in those with elevated Lp(a) and severe PAD.25 May reduce CV events in FH patients with elevated Lp(a) ≥60 mg/dL. 26, 27 We currently lack definitive proof that specific pharmacological lowering of Lp(a) reduces adverse cardiovascular outcomes. Many clinicians have the secondary goal of lowering Lp(a) in addition to lowering LDL-C and Apolipoprotein B (ApoB) in high-risk patients, in particular, when recurrent ASCVD events occur despite aggressive LDL-C lowering.12
15 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Antisense Oligonucleotide (ASO) a. Pelacarsen - may lower Lp(a) by about 80% CETP inhibitor a. Obicetrapib - may lower Lp(a) by about 45% Small interfering RNA (siRNA) a. Olpasiran - dose-dependent reduction with ASCVD 32 b. SLN360 – dose-dependent reduction of Lp(a) 33 c. Lepodisiran – dose-dependent, long-duration reductions in serum Lp(a) concentrations 34 Emerging Experimental Therapies for Lp(a)
16 What Can Health Care Professionals (HCPs) Do Now? Shared Decision-Making 35 Relative indications for measuring Lp(a) are family history of premature ASCVD or personal history of ASCVD not explained by major risk factors. Verify insurance coverage of testing and treatments. Discuss new therapies in development. Intensify management of all other ASCVD risk factors, including LDL-C and non-HDL-C elevation. If measured, the Lp(a) level can be used as a risk-enhancing factor in this scenario.12
17 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Diet and exercise have not been shown to reduce Lp(a) levels.5, 12 Treat modifiable risk factors Medical therapy and lifestyle changes include targeting diabetes (enhanced glucose control), smoking cessation, treating HTN and/or high LDL-C, sustained weight loss, and increasing physical activity.6 Initiate or increase statin intensity if elevated Lp(a), even if LDL-C is at goal. Lp(a) lowering is difficult, but proven therapies for ASCVD prevention should be implemented. Lp(a) levels are 80-90% genetically influenced. 6 Cascade screening of family members of a patient with high Lp(a) will identify elevated Lp(a) in family members. This allows affected family members to learn they have a hidden ASCVD risk factor, and provides an opportunity for them to intensify ASCVD preventive interventions.12 Follow the Guidelines 2019 AHA/ACC primary prevention of CVD.6 An Lp(a) ≥50 mg/dL or ≥125 nmol/L is considered a risk-enhancing factor.12
18 Top Takeaways Lp(a) is largely determined by genetics. Lp(a) is elevated in approximately 20% of the general population. Elevated Lp(a) is overrepresented in the Black community. Lp(a) elevation is known to drive atherosclerosis and intravascular inflammation, increasing the risk for ASCVD and PAD. Patients with elevated Lp(a) have worse outcomes related to PAD and high incidence of MALE. Patients with PAD are candidates for screening for Lp(a) elevation. Lipoprotein Apheresis is currently the sole FDA-approved treatment for lowering Lp(a), only in individuals with clinically diagnosed Familial Hypercholesterolemia with documented coronary or peripheral artery disease and LDL-C levels greater than 100 mg/dL.36 Therapies to reduce Lp(a) levels are in development. 1 2 3 4 5 6 7
19 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Notes:
20 Notes:
21 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Glossary Apo(a) . . . . . . . Apolipoprotein(a) ApoB . . . . . . . . . . . . . . . . Apolipoprotein B ASCVD . . . . . . . Atherosclerotic Cardiovascular Disease CHD . . . . . . . . Coronary Heart Disease CKD . . . . . . . . Chronic Kidney Disease FH . . . . . . . . . Familial Hypercholesterolemia HCP . . . . . . . . Health Care Professionals HoFH . . . . . . . . Homozygous Familial Hyperlipidemia LDL-C . . . . . . . . Low Density Lipoprotein Cholesterol Lp(a) . . . . . . . . Lipoprotein(a) (pronounced L-P-little-A) 36 MACE . . . . . . . . Major Adverse Cardiovascular Event MALE . . . . . . . . Major Adverse Limb Event PAD......... Peripheral Artery Disease PVD......... Peripheral Vascular Disease PCSK9 inhibitors . . . PCSK9 Monoclonal Antibody siRNA . . . . . . . . Small Interfering RNA TASC . . . . . . . TransAtlantic Inter-Society Consensus For more information on Lp(a), scan the QR code to download Lp(a): A Toolkit for Health Care Professionals. Lp(a):A Toolkit for Health Care Professionals Novartis is proud to support the American Heart Association’s Lp(a) Awareness and Testing Initiative.
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About Lipoprotein (a) | Heart Disease, Family Health History, and Familial Hypercholesterolemia | CDC
This publication was funded by the Kaneka Corporation.
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