ENDOCRINE SOCIETY PRESENTS The Revolution in ......National Lipid Association, he has served on the Lipid Drug Safety Task Force in 2006‐2007 and the Statin Intolerance Panel in

The Revolution in Cholesterol Management: PUTTING PCSK9 INHIBITORS INTO PRACTICE

E N D O C R I N E S O C I E T Y P R E S E N T S

MONDAY, APRIL 3, 20176:00–8:00 AM

Hyatt Regency Orlando Regency Ballroom R

CME CREDITS: 2 AMA PRA

Category 1 Credits™

This activity is supported by an educational grant from

Amgen

Sponsored by

CHAIREliot A. Brinton, MDUtah Foundation for Biomedical Research Director, Atherometabolic ResearchSalt Lake City, UT

AGENDAPCSK9 and the LDL Receptor: Biological and Genetic Underpinnings of Heterozygous FHSergio Fazio, MD, PhD, Oregon Health and Science University

Patient Representative with Heterozygous FH

Diagnosis of Heterozygous FH and Statin TreatmentJohn R Guyton, MD, Duke University Medical Center

CVD Reduction with Non-StatinsHarold Edward Bays, MD, Louisville Metabolic and Atherosclerosis Research Center Inc

Management of Hypercholesterolemia in Diabetes: When to Treat and How Eliot A. Brinton, MD, Utah Foundation for Biomedical Research Director, Atherometabolic Research

LEARNING OBJECTIVESUpon completing this activity, learners will be able to:

• Summarize the biology and genetic underpinnings of dyslipidemia as related to the LDL receptor and PCSK9

• Explain the results of IMPROVE-IT and FOURIER

• Assess the relative strengths and weaknesses of traditional vs newer cholesterol-lowering therapies to treat patients with familial hypercholesterolemia

• Evaluate strategies to optimize patient tolerance of and compliance to statin and ezetimibe treatment in FH and Diabetes Mellitus Type 2

• Incorporate PCSK9-I appropriately for further needed cholesterol lowering in high-risk patients

SYMPOSIUM AGENDA

The Revolution in Cholesterol Management: Putting PCSK9 Inhibitors into Practice Monday, April 3, 2017

6:00 – 6:05 AM Welcome and Introduction Eliot A. Brinton, MD

6:05 – 6:25 AM PCSK9 and the LDL Receptor: Biological and Genetic Underpinnings of Heterozygous FH

Sergio Fazio, MD, PhD

6:25 – 6:35 AM Patient Representative with Heterozygous FH Michael Overstreet 6:35 – 6:55 AM Diagnosis of Heterozygous FH and Statin Treatment

John R. Guyton, MD 6:55 – 7:15 AM CVD Reduction with Non‐Statins Harold Edward Bays, MD 7:15 – 7:35 AM Management of Hypercholesterolemia in Diabetes:

When to Treat and How Eliot A. Brinton, MD 7:35 – 8:00 AM Roundtable Discussion and Q&A

FACULTY Eliot A. Brinton, MD – Program Director Director, Atherometabolic Research Utah Foundation for Biomedical Research Salt Lake City, Utah Sergio Fazio, MD, PhD The William and Sonja Connor Chair of Preventive Cardiology Professor of Medicine and Physiology & Pharmacology Director, Center for Preventive Cardiology Knight Cardiovascular Institute Oregon Health and Science University Portland, OR John R Guyton, MD Professor of Medicine Director, Duke Lipid Clinic Duke University Medical Center Durham, NC Harold Edward Bays, MD, FTOS, FACC, FACE, FNLA Medical Director / President Louisville Metabolic and Atherosclerosis Research Center Louisville KY

FACULTY BIOGRAPHY

Eliot A. Brinton, MD – Program Director Dr. Brinton is President, Utah Lipid Center and Director, Atherometabolic Research, Utah Foundation for Biomedical Research in Salt Lake City, UT. He is President, American Board of Clinical Lipidology and a fellow of the American Heart Association and National Lipid Association. Throughout his 30‐year‐plus career Dr. Brinton has been an investigator in research funded from many sources including grants from the National Institutes of Health (NIH), the Department of Veterans Affairs, the AHA, and industry. His primary

research focus is on mechanisms of human high‐density lipoprotein (HDL) metabolism, including the effects of diet, exercise, estrogen, and insulin resistance. He also has research interests in hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, postmenopausal estrogen replacement, and insulin sensitivity. His areas of clinical expertise include management of dyslipidemia, diabetes mellitus, obesity and insulin resistance, and prevention of atherosclerosis. At the Utah Lipid Center, he runs the only LDL‐Apheresis center between Denver and the West Coast. Dr. Brinton is Associate Editor of the Journal of Clinical Lipidology, Assistant Editor of the Journal of Obesity, and he has served as Editor of Lipids Online, and Section Editor of Current Atherosclerosis Reports. He is on the editorial boards of the Journal of Clinical Endocrinology and Metabolism, Journal of Managed Care Pharmacy, and Clinical Lipidology. Dr. Brinton is a peer reviewer for numerous journals including the American Journal of Cardiology, Archives of Family Medicine, Circulation, and Diabetes Care. He has authored of over 100 articles in peer‐reviewed journals, including Science, the New England Journal of Medicine, JAMA, Circulation, and the Journal of Clinical Investigation. Dr. Brinton has received several scientific awards, including a Clinical Investigator Award from the NIH, a Merit Review Award from the Veterans Administration, and the Robert I. Levy Award of the Kinetics and Metabolism Society (co‐recipient with Jan L. Breslow, MD of The Rockefeller University).

Sergio Fazio, MD, PhD An MD graduate of the University of Rome, Italy, Dr. Fazio continued at the same institution with a fellowship in Metabolic Diseases. In 1985, he undertook a Ph.D. program in Experimental Medicine at the University of Siena, Italy, and completed it at the University of California, San Francisco (UCSF). In 1988 Dr. Fazio joined the Gladstone Institute of Cardiovascular Disease, UCSF, as a postdoc and then as an Instructor in Medicine. In 1993 Dr. Fazio joined Vanderbilt University as an Assistant Professor in

Endocrinology, where he co‐founded the Lipid Clinic and became Director of the Lipid Laboratory. In 1998, he was promoted to Associate Professor. In 1999, he joined the Division of Cardiology to run the Atherosclerosis Research Unit. In 2002, he was promoted to Professor. In 2011 he was appointed the Cornelius Vanderbilt Chair of Cardiovascular Medicine and Chief of the section of Cardiovascular Disease Prevention. Since July 2014 he holds the William and Sonja Connor chair of Preventive Cardiology at the KCVI of OHSU. His clinical interest is the management of dyslipidemic patients. Dr. Fazio’s NIH‐supported research portfolio focuses on the pathogenesis of genetic dyslipidemias, the early cellular events in atherogenesis, and gene therapy approaches to atherosclerosis. He has been an Established Investigator of the American Heart Association and is PI and Co‐PI on several NIH grants. He has published over 200 papers, including original articles, reviews, editorials, and book chapters. He was a charter member of the Study Section AICS of the NIH‐NHLBI from 2006 to 2010. He is member of the American Society for Clinical Investigation and of the Association of American Physicians. He is on the editorial board of Arteriosclerosis, Thrombosis and Vascular Biology and of Circulation Research, and is an associate editor for the Journal of Clinical Lipidology.

John R Guyton, MD Dr. John R. Guyton is Professor of Medicine, Endocrinology Division, and Director of the Lipid Clinic at Duke University Medical Center. Dr. Guyton received his undergraduate degree in Physics from the University of Mississippi and his M.D. from Harvard Medical School. He did his residency in internal medicine under Donald Seldin at University of Texas Southwestern Affiliated Hospitals in Dallas. He then completed a Research Fellowship in Pathology at Harvard Medical School with Morris Karnovsky, conducting research studies in arteriosclerosis. Dr. Guyton moved to Baylor College of Medicine in Houston, where held a Research Career

Development Award and two R01 grants from NIH for studies on lipid deposition in human atherosclerosis. Dr. Guyton has published 135 articles on atherosclerosis and lipid disorders, as well as 24 book chapters. He was active in the founding of the Southeast Lipid Association, the National Lipid Association, and the American Board of Clinical Lipidology. He has served as President of each of these organizations. In the National Lipid Association, he has served on the Lipid Drug Safety Task Force in 2006‐2007 and the Statin Intolerance Panel in 2014. He will begin a new position as editor of the Journal of Clinical Lipidology in September 2017.

Harold Edward Bays MD, FTOS, FACC, FACE, FNLA Dr. Harold Bays is Board Certified in Endocrinology and Internal Medicine, Diplomate of the American Board of Clinical Lipidology, and Diplomate of the American Board of Obesity Medicine. He has served as an Investigator for over 450 Phase I ‐ IV clinical trials regarding treatments for dyslipidemias, obesity, diabetes mellitus, hypertension, and other metabolic and hormonal disorders. As Medical Director and President of Louisville Metabolic and Atherosclerosis Research Center, Dr. Bays has written, or served as a contributing author to over 200 peer review scientific manuscripts and book chapters, as well as over

100 scientific abstracts presented at major scientific meetings. He is a Fellow of the National Lipid Association (FNLA), Fellow of The Obesity Society (FTOS), Fellow of the American College of Cardiology (FACC) and Fellow of the American Association of Clinical Endocrinologists (FACE).

ACCREDITATION STATEMENT

The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation. The Endocrine Society designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

LEARNING OBJECTIVES

Upon completion of this educational activity, learners will be better able to:

Summarize the biology and genetic underpinnings of dyslipidemia as related to the LDL receptor and PCSK9

Explain the results of IMPROVE‐IT and FOURIER

Assess the relative strengths and weaknesses of traditional (statins and ezetimibe) vs newer (PCSK9‐I) cholesterol‐lowering therapies to treat patients with familial hypercholesterolemia (FH)

Evaluate strategies to optimize patient tolerance of and compliance to statin and ezetimibe treatment in FH and Diabetes Mellitus Type 2 (DM2)

Incorporate PCSK9‐I appropriately for further needed cholesterol lowering in high‐risk patients

TARGET AUDIENCE

This continuing medical education activity should be of substantial interest to endocrinologists and endocrine fellows, cardiologists, and other healthcare professionals caring for patients with lipid disorders including familial hypercholesterolemia.

STATEMENT OF INDEPENDENCE

As a provider of continuing medical education (CME) accredited by the Accreditation Council for Continuing Medical Education, the Endocrine Society has a policy of ensuring that the content and quality of this educational activity are balanced, independent, objective, and scientifically rigorous. The scientific content of this activity was developed under the supervision of the Endocrine Society's Special Programs Committee (SPC). The commercial supporter(s) of this activity have no influence over the planning of this CME activity.

DISCLOSURE POLICY

The faculty, committee members, and staff who are in position to control the content of this activity are required to disclose to the Endocrine Society and to learners any relevant financial relationship(s) of the individual or spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose products or services are related to the CME content. Financial relationships are defined by remuneration in any amount from the commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (e.g., stocks, stock options, or ownership interest excluding diversified mutual funds); honoraria or other payments for participation in speakers' bureaus, advisory boards, or boards of directors; or other financial benefits. The intent of this disclosure is not to

prevent CME planners with relevant financial relationships from planning or delivery of content, but rather to provide learners with information that allows them to make their own judgments of whether these financial relationships may have influenced the educational activity with regard to exposition or conclusion. The Endocrine Society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable. The faculty reported the following relevant financial relationship(s) during the content development process for this activity: Harold Edward Bays MD: Consultant, Amgen, Astra Zeneca, Merck & Co.; Investigator, Amarin, Amgen, Astra Zeneca, Merck & Co.; Speaker, Amarin, Amgen, Astra Zeneca, Merck & Co. Eliot A. Brinton, MD: Consultant, Akcea, Amarin, Amgen, Aralez, Arisaph, AstraZeneca, Kastle, Kowa, Merck, PTS Diagnostics, Regeneron, Sanofi‐Aventis; Speaker, Aegerion, Akcea, Alexion, Amarin, Amgen, Janssen, Kowa, Merck, Regeneron, Sanofi‐Aventis; Contracted Research, Amarin, Kowa, PTS Diagnostics Sergio Fazio, MD: Ad Hoc Consultant, Amarin, Amgen, Sanofi, Kowa, Merck & Co. John R Guyton, MD: Principal Investigator, Amarin, Amgen, Regeneron, Sanofi; Investigator, Regeneron; Speaker, Amgen The following SPC member who reviewed content for this activity reported relevant financial relationships: Zahid Ahmad, MD: Research Support, Regeneron, FH Foundation; Consultant, Regeneron; Speaker, Amgen, Genzyme, Sanofi The following SPC member who reviewed content for this activity reported no relevant financial relationships: Connie Newman, MD The following SPC Committee members reported financial relationships: Andrew Ahmann, MD: Research Support, DexCom, Lexicon, Medtronic, Novo Nordisk; Consultant, Dexco, Novo Nordisk, Trividia Health Giuseppe Barbesino, MD: Spouse, employee of Genzyme John Carmichael, MD: Research Support, Novo Nordisk, Chiasma, Novartis, Pfizer, Strongbridge Biopharma; Speaker, Novartis; Advisory Board, Pfizer, Chiasma, Ionis Pharmaceuticals Natalie Cusano, MD: Research Support, Shire; Speaker, Shire Joan Han, MD: Research Support, Rhythm Pharmaceutical Alan Kelly, MD: Speaker, Eli Lilly E Michael Lewiecki, MD: Consultant, Amgen, Merck, Eli Lilly, Radius Health, Shire, Abbvie and Alexion; Speaker, Alexion, Shire; Research Grant Support, Amgen, Eli Lilly, Merck Lisa Nachtigall, MD: Consultant, Ipsen, Novartis, Corcept; Grant Support/Investigator, Chiasma Neda Rasouli, MD: Research Support, Novo Nordisk, Calibra, INTARCIA Therapeutics, GlaxoSmithKline, Bristol Meyer Squibb, AstraZeneca /Amylin, Ionis Pharmaceuticals, Boehringer Ingelheim The Endocrine Society has reviewed these relationships to determine which are relevant to the content of this activity and resolved any identified conflicts of interest for these individuals. The following SPC members reported no relevant financial relationships: Amy Rothberg, MD

Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.

DISCLAIMER

The information presented in this activity represents the opinion of the faculty and is not necessarily the official position of the Endocrine Society. Use of professional judgment: The educational content in this activity relates to basic principles of diagnosis and therapy and does not substitute for individual patient assessment based on the health care provider’s examination of the patient and consideration of laboratory data and other factors unique to the patient. Standards in medicine change as new data become available. Drugs and dosages: When prescribing medications, the physician is advised to check the product information sheet accompanying each drug to verify conditions of use and to identify any changes in drug dosage schedule or contraindications.

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The Endocrine Society has determined that disclosure of unlabeled/off‐label or investigational use of commercial product(s) is informative for audiences and therefore requires this information to be disclosed to the learners at the beginning of the presentation. Uses of specific therapeutic agents, devices, and other products discussed in this educational activity may not be the same as those indicated in product labeling approved by the Food and Drug Administration (FDA). The Endocrine Society requires that any discussions of such “off‐label” use be based on scientific research that conforms to generally accepted standards of experimental design, data collection, and data analysis. Before recommending or prescribing any therapeutic agent or device, learners should review the complete prescribing information, including indications, contraindications, warnings, precautions, and adverse events.

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ACKNOWLEDGEMENT OF COMMERCIAL SUPPORT

This activity is supported by an educational grant from Amgen Inc.

AMA PRA CATEGORY 1 CREDIT™ (CME) INFORMATION

The Endocrine Society designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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PCSK9 and the LDL Receptor: Biological and Genetic Underpinnings of Heterozygous FH

Sergio Fazio, MD, PhD

Sergio Fazio, MD, PhDWilliam and Sonja Connor Professor of Preventive Cardiology

Professor of Medicine, Physiology & Pharmacology Director, Center for Preventive Cardiology

Knight Cardiovascular InstituteOregon Health and Science University

Portland, Oregon

PCSK9 and the LDL Receptor: Biological and Genetic Underpinnings of

Heterozygous FH

Cholesterol Trafficking before PCSK9 (1972-2003)

The Inherited Bases of Metabolic Diseases, 2nd Edition

LDL binds the LDL receptor via apoB

Familial Hypercholesterolemia (Classic Definition): Genetically Inherited High LDL Due to Mutations in

1. LDL receptor (removes LDL from circulation)

Familial Hypercholesterolemia (Classic Definition): Genetically Inherited High LDL Due to Mutations in

1. LDL receptor (removes LDL from circulation)2. ApoB (LDL protein ligand for the LDL receptor)

Cholesterol Trafficking After PCSK9

Qian YW, et al. J Lipid Res. 2007;48(7):1488-1498; Horton JD, et al. J Lipid Res. 2009;50:S172-S177; Zhang DW, et al. J Biol Chem. 2007;282(55):18602-18612.

Familial Hypercholesterolemia (Expanded Definition): Genetically Inherited High LDL Due to Mutations in

1. LDL receptor (removes LDL from circulation)2. ApoB (LDL protein ligand for the LDL receptor)

3. PCSK9 GOF (binds and destroys LDL receptor)

4. LDLR-RAP (positions LDL receptor on apical surface)

Familial Hypercholesterolemia (Expanded Definition): Genetically Inherited High LDL Due to Mutations in

1.LDL receptor (removes LDL from circulation)2.ApoB (LDL protein ligand for the LDL receptor)

3.PCSK9 GOF (binds and destroys LDL receptor)

4.LDLR-RAP (positions LDL receptor on apical surface)

5.Some other genes…… or something

10 consecutive patients I sent to in-house clinical geneticist for genetic testing

Patient PK

54 year old male originally from Western AustraliaHealthy, athletic, symptom freeHis doctor told him it is time to get serious about his cholesterolHe admits he had known about his cholesterol problem since he was in high schoolNever treatedA specialist told him that genetic testing is unnecessary because “You certainly have FH Morocco”Mother affected by hypercholesterolemia, but no evidence of CAD/CVDOne sibling, in good health. Two children, healthy, not screened.He will not take medications

Total cholesterol 368Triglycerides 152HDL 63LDL 275Lp(a) 84

Genetic testing negative

Patient RB

56 year old femaleHealthy, symptom free, works as ED nurseLong history of statin intolerance, now treated with natural therapies, willing to reconsiderMother and two older siblings affected by hypercholesterolemia, but no evidence of CAD/CVD. Three children, healthy, not screened

Total cholesterol 456Triglycerides 78HDL 104LDL 336Lp(a) 14

Genetic testing positive

LDL-C Goal Attainment in FH

FH = familial hypercholesterolemia.Pijlman AH, et al. Atherosclerosis. 2010;209:189-194. Hadfield SG, et al. Ann Clin Biochem. 2008;45:199.

100

10

0

Perc

ent

70

30

Treated LDL-C<100 mg/dL

CASCADE-FH

TheNetherlands

2010

20

90

50

2530

21

60

80

40

UK2008

100

10

0

Perc

ent

70

30

Reduction in LDL-C50%

CASCADE-FH

TheNetherlands

2010

20

90

50 41

6460

60

80

40

UK2008

PCSK9: from Discovery to Clinic

NARC-1 = neural apoptosis-regulated convertase 1; POC = point of care.Seidah NG, et al. Proc Natl Acad Sci USA. 2003;100:928-933. Abifadel M, et al. Nat Genet. 2003;34(2):154-156. Maxwell KN, et al. Proc Natl Acad Sci USA. 2004;101(18):7100-7105. Rashid S, et al. Proc Natl Acad Sci USA. 2005;102(15):5374-5379. Lagace TA, et al. J Clin Invest. 2006;116(11):2995-3005. Cohen JC, et al. N Engl J Med. 2006;354(12):1264-1272. Zhao Z, et al. Am J Hum Genet. 2006;79(3):514-523. Hooper AJ, et al. Atherosclerosis. 2007;193(2):445-448. Chan JC, et al. Proc Natl Acad Sci USA. 2009;106(24):9820-9825. Stein EA, et al. N Engl J Med. 2012;366(12):1108-1118.

• First publicationPOC in patients

• First patients with FH and non-FH treated with PCSK9 mAb

• PCSK9 LOF mutations found with 28% LDL-C and 88% CHD risk

• Humans null for PCSK9 have LDL-C ~15 mg/dL

LDL-C in mice and non-human primates treated with anti-PCSK9 mAb

• PCSK9 (NARC-1) discovered

• PCSK9 GOF mutations associated with ADH

• First subject treated with PCSK9 mAb

• Adenoviral expression in mice

• PCSK9 KO mouse LDL-C

• Plasma PCSK9 binds to LDLR

20122000 201020092008200720062005200420032001 2002

• FOURIER

2017

0

Study Day28 56

0

50

500

100

300

400

200

14 70 8442-70

-60

LDL-C

Mean C

hange (%)

0

-50

-30

-40

150

350

450

250

-10

Total AMG 145 (evolocumab)

Free PCSK9

LDL-C

FreePCSK

9concentration(ng/m

L)FreeAMG145concentration(ng/m

Lx0.01)

Changes in PCSK9 and LDL C levels after a single injectionof Evolocumab

Stein EA & Raal FJ Annu. Rev. Med. 2014. 65:417–31.

160

140

120

100

80

60

40

20

0

Serum PCSK9 levels before and after Injection of PCSK9 inhibitor

Fazio et al, unpublished

Before After

Therapeutic PCSK9 Blockade Reduces Lipoprotein(a) Levels

Stein EA et al. JACC, 2014.

Cardiovascular Outcomes Trialsof PCSK9 Inhibitors

Alirocumab Evolocumab Bococizumab

Sponsor Sanofi/Regeneron Amgen Pfizer

Trial ODYSSEY Outcomes FOURIER SPIRE I SPIRE II

Sample Size 18,000 22,500 12,000 6300

Patients 4-16 weeks post-ACS MI, stroke, or PAD High risk of CV event

Statin Evidence-based RxAtorvastatin 20 mg or

equivalentLipid-lowering Rx

LDL-C 70 mg/dL 70 mg/dL 70-99 mg/dL 100 mg/dL

PCSK9i Dosing Every 2 weeks Every 2 or Every 4 weeks Every 2 weeks

EndpointCHD death, MI,

ischemic stroke, or UA hospitalization

Primary: CV death, MI, stroke, UA hospitalization or coronary revascularizationKey Secondary: CV death,

MI, or stroke

CV death, MI, stroke, or urgent revascularization

Completion March 2018 December 2017 August 2017

Nearly Half of Plasma PCSK9 Associates with LDL

Fan D et al. Biochem 2008. Sun H et al. ATVB 2012.

Tavori H et al. Circ Res 2016

Relative distribution of PCSK9 between LDL and Lp(a)

• Relative distribution between apoB-PCSK9 levels in LDL and Lp(a) was studied separately in each subject.

Conclusion

Heterozygous FH is a relatively common inherited defectIt is most commonly due to mutations in the LDL receptor (LDLR)Even in subjects with LDLR mutation, PCSK9 plays a critical role

in regulating hepatic LDLR levels CVD risk is greatly enhanced in FH subjects due to their life-long

exposure to severe hypercholesterolemiaLDL goal attainment in FH subjects is difficult with inexpensive

statins and other oral agentsNew PCSK9 agents reduce LDL by 50-65% but are expensiveThe biology of PCSK9 is not well understood, and discovery may

lead to alternative approaches to blocking the action of this protein

Diagnosis of Heterozygous FH and Statin Treatment Sergio

John R. Guyton, MD

Practical Points about Diagnosing Familial Hypercholesterolemia and

Using Statin MedicationsENDO Satellite Meeting

April 3, 2017

John R. Guyton, M.D.Duke University Medical Center

Disclosures

• Research grants: Amgen, Regeneron, Sanofi, Amarin

• Honorarium: Amgen

Learning Objectives

• Develop ability to diagnose familial hyperchole-sterolemia consistent with international norms.

• Cite and utilize current guidelines for moderate and intensive statin therapy.

• Recognize and respond to statin intolerance.

• Advise patients on expected benefits of statin and ezetimibe LDL-lowering therapy.

Case 117. Familial HypercholesterolemiaWoman referred to Lipid Clinic in 1995 at age 51 for hypercholesterolemia. Occasional cigarette smoking. No hx ASCVD events or symptoms. Did not “feel well” while taking simvastatin 40 mg/d. Achilles tendon xanthomas.

1995 340 141 68 243 simvastatin 20 mg

1999 260 79 68 176 2 atorvastatin 10 mg, IR-niacin 500bid

2001 258 73 76 167 2 atorvastatin 10 mg, IR-niacin 750 bid, colesevelam 4 tabs

2014 190 55 89 90 atorvastatin 10 mg, IR-niacin 1000 mg bid, ezetimibe 10 mg, colesevelam 6 tabs

Dat

e

Cho

l

TG

HD

LC

LDLC

Lp(a

)

While taking

Case 117. Familial Hypercholesterolemia

Vascular followup: Amaurosis fugax in October 2002, again in June 2009. Carotid plaques followed by ultrasound. Abdominal and femoral bruits appeared in 2000, abdominal ultrasound normal.

Case 118. Familial HypercholesterolemiaDaughter of previous patient. Lipid Clinic visit in 1996 at age 30 for hypercholesterolemia. No hx ASCVD events or symptoms.

1996 305 111 37 245 colestipol 1 g

Dat

e

Cho

l

TG

HD

LC

LDLC

Lp(a

)

While taking

July 2013. Enrolled in research study of monoclonal antibody to PCSK9.

Familial Hypercholesterolemia

• Original definition: Hypercholesterolemia due to defective LDL receptor function.

• Proposed definition (Eur. Atherosclerosis Society): Hypercholesterolemia caused by mutations affecting key proteins in the LDL receptor endocytic/recycling pathways.

• Practical definition: Severe inherited hypercholesterolemia associated with tissue deposition of cholesterol and early ASCVD.

Dx of FH: Dutch Lipid Clinic Network Criteria

1. LDL-C Points

>325 8251-325 5191-250 3155-190 1

2. Phys exam PointsTendon xanthoma 6Corneal arcusage <45 4

Definite > 8, Probable 6-8, Possible 3-5, Unlikely <3

Achilles Tendon Xanthoma

Corneal Arcus

Dx of FH: Dutch Lipid Clinic Network Criteria

3. 1st deg relative Points

Early CHD 1High LDL-C 1-2Xanth, arcus 2

4. ASCVD Points

Early CHD 2Early CerVDor PAD 1

5. Mutational 8analysis

Definite > 8, Probable 6-8, Possible 3-5, Unlikely <3

Dx of FH: Simon Broome Register Criteria

LDL-C > 190 in adult or >140 in child under age 16PLUS EITHERTendon xanthomas in patient, 1st degree relative, or 2nd degree relative (grandparent, uncle, aunt)ORDNA evidence of deleterious mutation.

Definite FH:

LDL-C > 190, 140 and family hx MI male <50 y.o. female <60 y.o.

Possible FH:

Dx of FH by Dutch Lipid Clinic Criteria in Copenhagen Population Study

Definite > 8 pts 0.20%

Probable 6-8 pts 0.53%

Possible 3-5 pts 6.3%

Benn M et al. JCEM 2012; 97:3956-64.

DNA testing in CHD-free individuals with LDLC > 190 mg/dl

1.7% had a pathogenic FH mutation.

Khera et al. JACC 2016;67:2578.Graham et al. Atherosclerosis 2005;182:331.

Simon Broome “Possible FH”

25-30% had a pathogenic FH mutation.

Distribution of Lipoprotein(a) Concentrations amongFH Patients Who Did and Did Not Have CHD.

Seed M et al. N Engl J Med 1990;322:1494-1499.

P-value <.001

2013 AHA/ACC Four Statin Treatment Groups1. Clinical ASCVD

2. LDL-C > 190 mg/dl

3. Diabetes 40-75 years of age

4. ASCVD risk† calculation > 7.5% over 10 years

Age < 75 high intensity*Age > 75 moderate intensity*

Age > 21 high intensity

Moderate intensity for most

Moderate or high intensity

*High intensity – atorvastatin 80 or 40 mg, rosuvastatin 20 or 40 mg. Moderate – several statins with LDLC lowering 40% to 49%.† Also certain other situations, e.g.,high coronary calcium score.

2015 NLA Recommendations

1. NonHDLC is the primary treatment target.

2. If very-high risk, begin with moderate- or high-intensity statin with nonHDLC and LDLC goals <100 and <70 mg/dl, respectively.

3. In other patients, count number of major risk factors and treat to goals for nonHDLC <130 and LDLC <100 mg/dl.

2017 AACE Lipid GuidelinesCategory Description of risk LDLC

goalNon-HDLC goal

ApoBgoal

Extremerisk

- Progressing ASCVD with LDLC <70- Clinical ASCVD + DM, CKD3/4, HeFH- Premature ASCVD <55 male,<65 female

<55 <80 <70

Very high risk

- Established ASCVD- Diabetes or CKD3/4 with 1+ risk factors- HeFH

<70 <100 <80

High risk - > 2 risk factors & 10 year risk 10-20%- Diabetes or CKD3/4 with 0 risk factors <100 <130 <90

Moderaterisk

< 2 risk factors & 10 year risk <10% <100 <130 <90

Low risk 0 risk factors <130 <160 NR

Statin Intolerance Hierarchy of Evidence

1. N of 1 randomized trial

2. Systematic reviews of randomized trials

3. Single randomized trial

4. Systematic review of observational studies addressing patient-important outcomes

5. Single observational study addressing patient-important outcomes

6. Physiologic studies

7. Unsystematic clinical observations

Users’ guides to medical literature. XXV. Evidence-based medicine. JAMA 2000;284:1290-6.

“4 reasons why RCTs may not be helpful for determining whether a putative harmful agent truly has deleterious effects”

1. Harm rarely a primary endpoint. Unethical to expose patients to harm without benefit.

2. Rare (less than 1%) and serious adverse events may occur over a period of years.

3. Late or legacy effects of treatment are difficult to ascertain (e.g., RAI for thyrotoxicosis).

4. RCT study reports often fail to provide adequate information on harm.

Users’ guides to medical literature. Chapter 14. http://jamaevidence, accessed 4/2/2017.

Side Effects of Statins

Side effect Frequency Comment

Transaminases 0.3-2.5% Often fatty liver, other drugs ALT/AST rarely serious bilirubin rarely occurs

Myopathy 0.1% Hypothyroid, drug interactions(Sx + CK 10x ULN)

Myalgia, stiffness 1% - 5%? Reported by 10-25% of patientsweakness

Cognitive issues ? Reported by ~1% of patients

Lakey et al. J Clin Lipidol. 2016;10:870.

Statin Intolerance

1. Help the patient distinguish between intolerance and safety. Apart from mild promotion of diabetes mellitus, permanent organ damage from statins is very rare.

2. Shared decision-making, but the patient has the final say.

Statin Dosing after Statin-Induced Myalgia

-25%

-45%

-40%

-35%

-28%

5

10

2.5 MTh

2.5

2.5 MWF

Rosuvastatin

-24%

-38%

-33%

-26%

10

5 MTh

5

5 MWF

Atorvastatin

What Insurance Companies Usually Requirefor anti-PCSK9 Prior Authorization

1. Trial of at least 2 statins, one of them at lowest recommended daily starting dose.

2. Addition of ezetimibe 10 mg daily. Sometimes bile acid sequestrant.

3. Anti-PCSK9 for patients who “require additional lowering of LDL cholesterol” –FDA prescribing information.

Anticipated Benefit of LDLC Lowering

1. Older estimate: For every 1% lowering of LDL-C, 1% lowering of occlusive vascular events.

2. Newer estimate: For every 1 mmol/L (38.7 mg/dl) lowering of LDL-C, 20% lowering of occlusive vascular events.

• Implication of #2: Residual risk will remain for some at very high initial risk even if LDL-C approaches zero.

Cholesterol Treatment Trialists’ Collaboration.Lancet 2010; 376:1670.

Learning Objectives

• Develop ability to diagnose familial hyperchole-sterolemia consistent with international norms.

• Cite and utilize current guidelines for moderate and intensive statin therapy.

• Recognize and respond to statin intolerance.

• Advise patients on expected benefits of statin and ezetimibe LDL-lowering therapy.

CVD Risk Reduction with Non-Statins

Harold Bays MD, FTOS, FACC, FACE, FNLA

Harold Bays MD, FTOS, FACC, FACE, FNLAMedical Director / President

Louisville Metabolic and Atherosclerosis Research Center(L-MARC Research Center)

CVD Risk Reduction with Non-Statins Endocrine SocietyOrlando Florida

April 3, 2017Disclosures

Dr. Harold Bays and his affiliated research center do not own pharmaceutical stocks or patents. In the past 12 months, Dr. Harold Bays’ research site has received research grants from Amarin, Amgen, Alere, Allergan, Arisaph, AstraZeneca, Bristol Meyers Squibb, Catabasis, Cymabay, Dr. Reddy, Eisai, Elcelyx, Eli Lilly, Esperion, Ferrer/Chiltern, Gemphire, Gilead, GSK, Janssen, Johnson and Johnson, Kowa, Merck, Necktar, Nichi-Iko, Novartis, NovoNordisk, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Selecta, Takeda, and TIMI. In the past 12 months, Dr. Harold Bays has served as a consultant/advisor for Alnylam, Akcea, Amgen, AstraZeneca, Eli Lilly, Esperion, Ionis (ISIS), Janssen, Johnson & Johnson, Merck, Moderna, Novartis, Procter & Gamble, Regeneron, Sanofi, Teva, and Takeda. In the past 12 months, Dr. Harold Bays has served as a speaker for Amarin, Amgen, Astra Zeneca, Eisai, Orexigen, Regeneron, Sanofi and Takeda.

Resins / Bile Acid Sequestrants

Bays HE, Goldberg RB. The Forgotten Bile Acid Sequestrants: Is Now a Good Time to Remember? American Journal

of Therapeutics 14, 567–580 (2007)

NiacinStudy Treatment

n/NControl

n/NPeto OR95% Cl

Peto OR95% Cl

ARBITER-6-HALTS 2/187 9/176 0.25 (0.08, 0.84)Guyton JR et al 1/676 1/272 0.35 (0.02, 7.56)AFREGS 0/71 1/72 0.14 (0.00, 6.92)

ARBITER-2 2/87 2/80 0.92 (0.13, 6.65)

HATS 1/38 5/38 0.24 (0.05, 1.26)

UCSF_SCOR 0/48 1/49 0.14 (0.00, 6.96)

STOCKHOLM 72/279 100/276 0.61 (0.43, 0.88)

CLAS 1/94 5/94 0.25 (0.05, 1.29)

CDP 287/1119 839/2789 0.81 (0.69, 0.94)

TotalTest for heterogeneity: P = 0.24, I2 = 23.0%Test for overall effect: P < 0.0001

0.75 (0.65, 0.86)

Subtotal excluding CDP 0.53 (0.38, 0.73)

0.1 0.2 0.5 1 2 5 10Log scale

Major coronary events: Meta-analysis of niacin monotherapy and in combination with other lipid-altering agents – before AIM HIGH and HPS2-THRIVE

Major coronary events: Meta-analysis of niacin monotherapy and in combination with other lipid-altering agents – before AIM HIGH and HPS2-THRIVE

Bruckert E et al. Atherosclerosis. 2010;210:353-361.

*Highest tertile of TG and lowest tertile of HDL-C. †Heterogeneity by treatment. All measurements in mg/dL. ER=extended release. Guyton JR et al. J Am Coll Cardiol. 2013;62:1580-4. Guyton JR et al. Paper presented at: AHA SS; Nov. 6, 2012; Los Angeles, CA.

Post-hoc Analysis of AIM-HIGH: Niacin ER in Patients with HTG & Low HDL-C

# Patients with CV Events ERN ERN HR(% of Category) Better Worse (95% CI) P-value†

Cholesterol AbsorptionInhibitors

IMPROVE-IT TRIALhttps://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM478550.pdf

http://clinicaltrialresults.org/Slides/AHA2014/Cannon_IMPROVEIT.ppt

Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, JukemaJW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators.. Ezetimibe Added to Statin Therapy after AcuteCoronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97.

Red

uctio

nin

Rat

eof

CV

Even

ts(%

)

0.0 0.5 1.0 1.5 2.0

30

20

10

0

-10

Statin-Mediated CV Risk ReductionCholesterol Treatment Trialists’ (CTT) Meta-analysis50

40

1 mmol/L (39 mg/dL)LDL-C treatment groupdifference reduces risk22% (CTT 2010)

Reduction in LDL-C (mmol/liter)Figure adapted from CTT Collaboration. Lancet. 2005;366:1267-1278; CTT Collaboration. Lancet. 2010;376:1670-1681.

Simvastatin40 mg

Ezetimibe/Simvastatin10/40 mg

IMPROVE-IT Study DesignPatients aged 50 years and stabilized post-ACS 10 days:LDL-C 50-125 mg/dL (or 50-100 mg/dL if prior lipid-lowering therapy)

N=18,144

Standard Medical & Interventional Therapy

Uptitrated tosimvastatin

80 mg ifLDL-C

>79 mg/dL †

Follow-up visit Day 30, every 4 months

Duration: Minimum 2½-year follow-up (at least 5250 events)

Primary Endpoint: CV death, MI, hospital admission for UA,coronary revascularization ( 30 days after randomization), or stroke

†

less than 1 year had their dose decreased to 40 mg in a blinded fashion.ACS=acute coronary syndrome; MI=myocardial infarction; UA=unstable angina.

�

�

– Death due to any cause † , major coronary events, or nonfatal stroke– CHD death † , nonfatal MI, or urgent coronary revascularization †

(PCI or CABG) occurring 30 days after randomization– CV death, nonfatal MI, documented UA requiring hospitalization,

all coronary and non-coronary revascularization † ( 30 days afterrandomization), and nonfatal stroke

†

MI=myocardial infarction; PCI=percutaneous coronary intervention; CABG=coronary artery bypass grafting.

IMPROVE-IT EndpointsTime to First Occurrence

Primary Endpoint– CV Death, nonfatal MI, unstable angina (UA) requiring hospitalization,

coronary revascularization ( 30 days), or nonfatal stroke

Secondary Endpoints

EZ/SimvaN=9067

SimvastatinN=9077

Age(years) 63.6 63.6Female,% 24.5 24.1Diabetes,% 27.1 27.3MIpriortoindexACS,% 21.2 20.7STEMI/NSTEMI/UA,% 28.5/47.4/24.0 28.7/46.9/24.4MediandayspostACStorand(IQR) 5(3,8) 5(3,8)Catheterization/PCIforACSevent,% 88.1/70.4 87.4/69.6Priorlipid-loweringtherapy,% 35.6 35.3MeanLDL-CatACSevent(mg/dL) 93.8 93.8

IMPROVE-IT Key Baseline Characteristics

MI=myocardial infarction; ACS=acute coronary syndrome; STEMI=ST-segment elevation myocardial infarction;NSTEMI=non-ST segment elevation myocardial infarction; UA=unstable angina; rand=randomization; IQR=interquartile range;PCI=percutaneous coronary intervention.

1YearMean LDL-C TC TG HDL-C hs-CRP

EZ/simvastatin 53.2 125.8 120.4 48.7 3.3

Simvastatin 69.9 145.1 137.1 48.1 3.8

Between-groupdifference(mg/dL)

-16.7 -19.3 -16.7 +0.6 -0.5

Mea

nLD

L-C

(mg/

dL)

TC=total cholesterol; TG=triglyceride; hs-CRP=high-sensitivity C-reactive protein; QE=qualifying event; R=randomization;EZ=ezetimibe; Simva=simvastatin.

QE R 1 4 8 12 16 24 36 48 60 72 84 96

65

60

55

50

45

IMPROVE-IT LDL-C and Lipid Changes95

90

85

80

75

70Median Time-Weighted Avg

69.5 vs. 53.7 mg/dL

EZ/SimvaSimva

Time Since Randomization (Months)

8990 8889 8230 7701 7264 6864 6583 6256 5734 5354 4508 3484 2608 1078

9009 8921 8306 7843 7289 6939 6607 6192 5684 5267 4395 3387 2569 1068

NEZ/Simva

Simva

Cum

ulat

ive

%

MI=myocardial infarction; UA=unstable angina, ITT=intention-to-treat; NNT=number-needed-to-treat; EZ=ezetimibe;Simva=simvastatin.

0 1 2 3 4 5 6 7Time Since Randomization (Years)

35

30

25

20

15

10

5

0

IMPROVE-IT Primary Efficacy EndpointCV Death, Nonfatal MI, UA Requiring Hospitalization, Coronary Revascularization

( 30 days), or Nonfatal Stroke (Protocol-Defined ITT Population)40

73717455

68016799

63756327

58395729

42844206

33013284

19061857

Subjects at risk

EZ/Simva 9067Simva 9077

Hazard ratio, 0.936 (95% CI, 0.887-0.988); p=0.016NNT=50

EZ/Simva (32.7%; 2572 events)Simva (34.7%; 2742 events)

Cum

ulat

ive

%

Cum

ulat

ive

%

p=0.570 1.030 (95% CI, 0.930-1.141); p=0.570 p=0.711 1.032 (95% CI, 0.873-1.219); p=0.711

New, Relapsing, or ProgressingMalignancy, Excluding Non-melanotic

Skin Cancers Any Death Due to Malignancy


1

0

2

3

5

4

EZ/SimvaSimva

87298772

85468548

83298312

79057867

60056036

48444884

28552905

Subjects at risk


Hazard ratio, 1.032 (95% CI, 0.873 – 1.219);Hazard ratio,


5

0

10

20

15

EZ/SimvaSimva

82458324

78797916

75507578

70617090

52555305

41814218

24262429

Subjects at risk


Hazard ratio, 1.030 (95% CI, 0.930 – 1.141);Hazard ratio,

Similar Rates of Cancer AEs and Cancer DeathsProtocol-Defined ITT Population

PCSK9 Inhibitors

Currently Available PCSK9 InhibitorsAlirocumab Evolocumab

FDA approval July 2015 August 2015

Indication

Adjunct to diet and max tolerated statin for adults with HeFH, or clinical

ASCVD, who require additional lowering of LDL-C

Adjunct to diet and max tolerated statin for adults with HeFH, or clinical

ASCVD, who require additional lowering of LDL-C, HoFH pts on

other LTT

Dosing 75 – 150 mg SC Q2W140 mg or 420 mg SC Q2W; 420 mg

SC monthly for HoFH

How suppliedSingle-dose pre-filled pens and pre-filled glass syringes that deliver –75 mg/mL or 150 mg/mL solution

Single-use pre-filled syringe or SureClick® autoinjector that deliver –

1mL of 140 mg/mL solution

Side effects Nasopharyngitis, injection site reactions; hypersensitivity reactions

Nasopharyngitis, injection site reactions; hypersensitivity reactions

HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous FH. LLT = lipid lowering therapy.Evolocumab - Repatha. Drugs@FDA FDA Approved Drug Products. August 2015. http://www.accessdata.fda.gov/Alirocumab - Praluent. Drugs@FDA FDA Approved Drug Products. July 2015. http://www.accessdata.fda.gov/ Accessed September 8, 2015.

The effect of alirocumab/evoloumab on CV mortality and morbidityhas not been established.

Efficacy and Safety of Combining Alirocumab With Atorvastatin or Rosuvastatin Versus Adding Ezetimibe,

Doubling Statin Dose or Switching Statin Therapy in High Cardiovascular Risk Patients: ODYSSEY OPTIONS I and II

Harold Bays,1 Michel Farnier,2 Daniel Gaudet,3 Robert Weiss,4 Juan Lima Ruiz,5Gerald F. Watts,6 Ioanna Gouni-Berthold,7 Jennifer G. Robinson,8 Peter Jones,9Randall Severance,10 Maurizio Averna,11 Elisabeth Steinhagen-Thiessen,12 Helen M. Colhoun,13 Jian Zhao,14 Yunling Du,14 Corinne Hanotin,15 Stephen Donahue14

1Louisville Metabolic and Atherosclerosis Research Center (L-MARC), Louisville, KY, USA; 2Point Médical, Dijon, France; 3ECOGENE-21 Clinical Trial Center and Dept of Medicine, Université de Montréal, Chicoutimi, Quebec, Canada; 4Maine Research Associates, Auburn, ME, USA; 5Lipid and Vascular Research Unit, University Hospital Vall d'Hebron, Barcelona Spain; 6Lipid Disorders Clinic, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia; 7University of Cologne, Center for Endocrinology, Diabetes and Preventive Medicine (ZEDP), Cologne, Germany; 8University of Iowa, Iowa City, IA, USA; 9Baylor College of Medicine, Houston, TX, USA; 10Radiant Research - Phoenix SE, ChandLer, AZ, USA; 11Università di Palermo – Policlinico “P. Giaccone”, Palermo, Italy; 12Charité – Universitaetsmedizin Berlin Campus Virchow Klinikum, Berlin, Germany; 13University of Dundee, Dundee, Scotland; 14Regeneron Pharmaceuticals, Inc. Tarrytown, NY, USA; 15Sanofi, Paris, France

Study Designs of OPTIONS I and II

Treatments in OPTIONS II shown in italics.†75 mg Q2W to 150 mg at W12 if W8 LDL-C 70 or 100 mg/dL (depending on CV risk).ClinicalTrials.gov identifier: NCT01730040 (OPTIONS I), NCT01730053 (OPTIONS II).Bays H at al. Oral Presentation at AHA 2014; November 15-19, 2014; Chicago, Illinois

Double-Blind Treatment Period (24 Weeks)

ATV 80 mg or RSV 40 mg

EZE + ATV 40 mg or RSV 20 mg

RSV 40 mg (OPTIONS I only)

Alirocumab† + ATV 20 mg or RSV 10 mgAlirocumab dosed as single 1 mL auto-injection using a prefilled pen for self-administration

EZE + ATV 20 mg or RSV 10 mg

ATV 40 mg or RSV 20 mg

Alirocumab† + ATV 40 mg or RSV 20 mgAlirocumab dosed as single 1-mL auto-injection using a prefilled pen for self-administration

Follo

w-u

p Pe

riod

(8 W

eeks

)

entry statin:ATV 20 mg

(OPTIONS I)or

RSV 10 mg (OPTIONS

II)

entry statin:ATV 40 mg

(OPTIONS I)or

RSV 20 mg (OPTIONS II)

N=47

N=47

N=47

N=57

N=55

N=57

N=45

R

R

AssessmentsW0 W8 W16

Primary endpoint (calculated LDL-C % change

from baseline) Safety analysis

(all groups)

W4 W12 W24

Per-protocol dose if W8 LDL-C70 or 100 mg/dL (depending on CV risk)

Screening period(2-6 weeks)

N=53

N=53

N=54

N=49

N=48

N=48

-44.1

-54.0

-20.5 -22.6-5.0 -4.8 -21.4

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

Alirocumab Significantly Reduced LDL-C in Patients on an Entry Statin of ATV 20 Or 40 mg or RSV 10 mg

Intent-to-treat (ITT) analysis. LS mean difference *P<0.0001; †P=0.0004; ns = not significant alirocumab versus comparator.Level of statistical significance: 0.01 (OPTIONS I) and 0.0125 (OPTIONS II) following Bonferroni adjustment for multiplicity.‡ Dose at W12 if W8 LDL-C 70 or 100 mg/dL (depending on CV risk) among patients with at least one injection after Week 12.

Statin dose at randomization from 20 to 40, or 40 to 80 mg/day in OPTIONS I, and from 10 to 20, or 20 to 40 mg/day in OPTIONS II.Bays H at al. Oral Presentation at AHA 2014; November 15-19, 2014; Chicago, Illinois.

+ Alirocumab 75/150 mg Q2W‡ + EZE 10 mg/day Double statin dose/day RSV 40 mg/day

OPTIONS I

LS

mea

n (S

E) %

cha

nge

from

bas

elin

e

Entry statin =ATV 20 mg


55 53 53 46 46 47 45n=

8.0% haddose at W12

20.9% had dose at W12

LS mean (SE)vs ezetimibe -23.6 (6.6)†

vs double statin -39.1 (6.4)*

LS mean (SE)vs ezetimibe -31.4 (6.1)*

vs double statin -49.2 (6.1)*vs rosuvastatin -32.6 (6.0)*

OPTIONS II

-50.6

-36.3

-14.4 -11.0-16.3 -15.9

Entry statin =RSV 10 mg


48 47 48 53 50 52



LS mean (SE)vs ezetimibe -36.1 (6.1)*

vs double statin -34.2 (5.9)*

LS mean (SE)vs ezetimibe -25.3 (10.1)

vs double statin -20.3 (10.1)

77.8

60.1

43.1 43.6

31.3 29.9

79.2 77.2

50.354.2

1610.2

42.2

0

10

20

30

40

50

60

70

80

90

100

ITT analysis. Combined estimate for odds ratio *P<0.0001; †P=0.0018; ‡P=0.0004 alirocumab versus comparatorLevel of statistical significance according to the hierarchical testing procedure: 0.01 (OPTIONS I) and 0.0125 (OPTIONS II).

Dose at W12 if W8 LDL-C 70 or 100 mg/dL (depending on CV risk) among patients with at least one injection after Week 12.¶Statin dose at randomization from 20 to 40, or 40 to 80 mg/day in OPTIONS I, and from 10 to 20, or 20 to 40 mg/day in OPTIONS II.Bays H at al. Oral Presentation at AHA 2014; November 15-19, 2014; Chicago, Illinois

OPTIONS IIOPTIONS I

Com

bine

d es

timat

e fo

r pr

opor

tion

of p

atie

nts

achi

evin

g L

DL

-C g

oal o

f <70

mg/

dL (%

)





>60% of Patients Receiving Alirocumab on Background Statin Achieved LDL-C <70 mg/dL

8.0% haddose at W12




*

†‡

*

*

*

*

+ Alirocumab 75/150 mg Q2W‡ + EZE 10 mg/day Double statin dose/day RSV 40 mg/day

UA = unstable angina.www.clinicaltrials.gov. Accessed June 21, 2016.

PCSK9 Inhibitor CV Outcomes Trials

Evolocumab(AMG 145)

Alirocumab(SAR236553 / REGN727)

Bococizumab (RN 316)

Sponsor Amgen Sanofi / Regeneron PfizerTrial FOURIER ODYSSEY Outcomes SPIRE 1 SPIRE 2Sample size 27,564 18,600 17,000 11,000

Patients MI, stroke, or PAD 4-52 weeks post-ACS High risk of CV event

Statin Atorvastatin 20 mgor equivalent

Evidence-basedmedical Rx

Lipid-loweringRx

LDL-C mg/dL (mmol/L)

70( 1.8)

<70(<1.8)

70- 100(1.8-2.6)

100(2.6)

PCSK9i dosing Q2W or Q4W Q2W Q2W

Endpoint

1°: CV death, MI, stroke, revascularization,

or hospitalization for UA Key 2°: CV death,

MI, or stroke

CHD death, MI, ischemic stroke, or hospitalization

for UA

CV death, MI, stroke,or urgent

revascularization

Completion 12/2017 12/2017 6/2018 3/2018

What About Costs?PCSK9 Inhibitor US

Prescribing Information Indications

• [PCSK9 INHIBITOR] is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C*

• The effect of [PCSK9 INHIBITOR] on cardiovascular morbidity and mortality has not been determined

PCSK9 = proprotein convertase subtilisin/kexin type 9.

* Evolocumab also indicated to treat homozygous FH.

Overall Conclusions of Non-Statins

• Resins (bile acid sequestrants) are used infrequently due to adverse effects, and potential drug interactions

• Niacin is used infrequently due to modest improvement in lipid levels, adverse effects, and lack of convincing CVD benefits when added to statins

• Cholesterol absorption inhibitors (e.g., ezetimibe) modestly lowers LDL-C and modestly reduces ASCVD risk (albeit without an approval to reduce ASCVD risk)

• PCSK9 inhibitors dramatically reduce LDL-C levels, with one study demonstrating moderate reduction in ASCVD (but not yet approved to reduce ASCVD risk)

Management of Hypercholesterolemia in Diabetes: When to Treat and How

Eliot A. Brinton, MD

Eliot A. Brinton, MD, FAHA, FNLAImmediate Past-President, American Board of Clinical Lipidology

Director, Atherometabolic ResearchUtah Foundation for Biomedical Research

President, Utah Lipid CenterSalt Lake City

[email protected]

Duality of Interest

Dr. Brinton has received:

• Research funding: Amarin, Aurora Foundation, Kowa,National Institutes of Health

• Honoraria as consultant/advisor: Akcea, Alexion,Amarin, Amgen, Aralez, Arisaph, AstraZeneca, Kastle,Kowa, Merck, PTS Diagnostics, Regeneron, SanofiAventis

• Honoraria as speaker: Akcea, Alexion, Amarin, Amgen,Boehringer Ingelheim, Janssen, Kastle, Kowa, Lilly,Merck, Novo Nordisk, Regeneron, Sanofi Aventis

HDL

LDL

IDL

VLDL

Ath

erog

enic

Lipo

prot

eins

Non

–HD

L-C

(lip

id);

Apo

B (p

rote

in)

Intermediate-density lipoprotein– Formed from VLDL with loss of TG– TG CE– Also known as a VLDL remnant

Low-density lipoprotein – Formed from IDL with loss of TG– CE >> TG– Main plasma cholesterol carrier

High-density lipoprotein– Removes cholesterol from peripheral tissues– Other anti-athero effects

Lp(a)Lipoprotein (a)

– Formed from LDL plus Apo (a)– Very atherogenic/pro-oxidative

Very-low-density lipoprotein– Made in the liver– TG >> CE– Takes lipids from the liver to periphery

Non–HDL-C (& Apo B) Include All Atherogenic Lipoproteins

Non–HDL-C = Cholesterol Component

Non–HDL-C = TC – HDL-C

CE=cholesterol ester

Apo B = Protein

Component

Non–HDL C Is Stronger than LDL Cin Predicting CHD Risk

To Fast or Not to Fast?

Fasting Lipid Panel

• Better accuracy for TG

• TG cutoffs are based onfasting values

• Slightly better for LDL C

• Easy to get before visit

• Allows fasting glucose test,best for Metabolic Synd.

Non Fasting Lipid Panel

• Can get on any visit

• Accuracy: Non HDL C good,TG OK (but differs), LDL Creasonable

• Good prediction of CVD (butdirect comparison lacking)

• A1c OK for DM2 risk

Bottom line: fasting panel is generally betterbut non fasting is generally easier

ASCVD Risk Assessment in DM1 & DM2

DM1• Assume high ASCVD risk if > 40 y/o (women men)• Even higher risk if other risk factors: smoking, +FHx,

LDL C, HTG, low HDL C, central obesity, MetSyndDM2• Assume high lifetime ASCVD risk even before Dx(i.e. at onset of MetSynd), women men

• Assume high 10 y risk if > 40 y/o• Even higher risk if other risk factors: smoking, +FHx,

LDL C, Non HDL C, ApoB, HTG, low HDL C,central obesity, MetSynd

Statins Work Equally Wellin Patients With or Without Diabetes

Event Rate (No DM) Event Rate (DM)

Statin Statin Control Statin Control

HPS* (w/ CHD) Simva 40 20% 26% 33% 38%

CARE§ Prava 40 19% 25% 29% 37%

LIPID¶ Prava 40 12% 15% 19% 23%

PROSPER Prava 40 13% 16% 23% 18%

ASCOT-LLA¶ Atorva 10 5% 9% 10% 11%

TNT Atorv 10 v 80 8% 10% 14% 18%

* CHD death, nonfatal MI, stroke, revascularizations§ CHD death, nonfatal MI, CABG, PTCA¶ CHD death and nonfatal MI

CHD death, nonfatal MI, stroke£ CHD death, nonfatal MI, resuscitated cardiac arrest, stroke

Patients with Diabetes Have High ResidualCVD Risk Despite Statin Monotherapy

( non DM w/o statin)Event Rate (No DM) Event Rate (DM)

Statin Statin Control Statin Control

HPS* (w/ CHD) Simva 40 20% 26% 33% 38%

CARE§ Prava 40 19% 25% 29% 37%

LIPID¶ Prava 40 12% 15% 19% 23%

PROSPER Prava 40 13% 16% 23% 18%

ASCOT-LLA¶ Atorva 10 5% 9% 10% 11%

TNT Atorv 10 v 80 8% 10% 14% 18%

* CHD death, nonfatal MI, stroke, revascularizations§ CHD death, nonfatal MI, CABG, PTCA¶ CHD death and nonfatal MI

CHD death, nonfatal MI, stroke£ CHD death, nonfatal MI, resuscitated cardiac arrest, stroke

Degree of CHD is by Degree and Duration LDL C Lowering

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020). Cannon CP, et al. AHA, November, 17 2014.

Genetic LifelongLower LDL C

(~5 years)

Rx ~4 7 yLower LDL C

LDL C Decrease (mg/dL)

CHDRelative

RiskReduction(%

)

Degree of CHD is by Degree and Duration LDL C Lowering

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020). Cannon CP, et al. AHA, November, 17 2014.

Genetic LifelongLower LDL C

(~5 years)

Rx ~4 7 yLower LDL C

LDL C Decrease (mg/dL)

CHDRelative

RiskReduction(%

)

3 4x benefit with lifelong vs short “Rx”is rationale for lifelong statins for DM2

Statin IntoleranceStatin

% Patients with muscle complaints (N=832)

Pravastatin 40 mg 10.9Atorvastatin 40–80 mg 14.9Simvastatin 40–80 mg 18.2Fluvastatin XL 80 mg 5.1

Muscle Symptoms on High DoseStatin Therapy (PRIMO)Observational, multi adjusted data N=7900

Bruckert, E. Cardiovasc Drugs & Ther. 2005;19:403 14.*Barilla, D. Biopharmaceutics & Drug Dispos. 2004;25:51–59.

Due to 1st pass hepatic extraction, fluvastatin XL hassystemic statin levels muscle exposure*

Fluva XL 80 may be worth trying in patients reportingtotal/near total statin intolerance from muscle pain

New Onset DM2with Statin Therapy

P = 0.019

Sattar N, et al. Lancet 2010; 375: 735-42

N=877, Observational data. Barkas, F. J Clinical Lipidology (2016) 10, 306–313.

Additive Effect of Fasting Glucose & Statin Intensity on Risk of New-Onset DM2

Waters, DD. J Am Coll Cardiol 2011;57:1535-1545

Pitavastatin Does Not Increase New Onset DM2 (by OGTT)

Months since randomisationNo. at Risk

556534

ControlPitavastatin

500475

405385

350320

277263

190178

123124

77101

4268

1530

523

Cum

ulat

ive

Inci

denc

e R

ate

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42 48 54 60 66 72

HR 0.82 (95% CI: 0.68-0.99)p=0.041 (Stratified log-rank test)

Pitavastatin

Control

Median follow up 2.8 years (range 2-6 years)Average pitavastatin dose 1.3mg

J-PREDICT. Design: Yamazaki, T. Diabetol Int (2011) 2:134–140. Results Late Breaking Studies 73rd ADA 2013, Chicago, IL

IGT patientsN=975 > 6mo f/u

Pitavastatin Has Neutral Glycemic Effect(3 mo-2y f/u; prava, < atorva, others)

DM risk• R

• R

Intestinally ActingLDL C Lowering Agents

• Bile acid sequestrants

• Cholesterol absorption inhibitors(ezetimibe)

~3x Benefit in DM2(?)


Ezetimibe Does Not Increase Risk of New-Onset DM2 (Despite further LDL-C)


Ezetimibe Does Not Increase Risk of New-Onset DM2 (Despite further LDL-C) Statin + Intestinally Acting Agent

(CAI or BAS) = 2 to 3 Statin Doublings

Intestinally Acting Lipid MedsSummary/Overview

• Both BAS and CAI– LDL receptors (like sta ns)– LDL C 2 3 statin dose doublings

• CAI– Easy (one small pill, once daily, few side effects)– Proven ASCVD w/ sta n– Greater benefit in DM2(?)– Now generic, price soon

• BAS– Hard (many large pills vs gritty powder, 1 3 x daily, GI sidee ects, may drug absorp on)

– Contraindicated if TG >400 mg/dL– Proven ASCVD w/o sta n (likely w/ sta n)– Glucose in DM2 (DM2 prevention??)– Inexpensive generic

Please see the full Prescribing Information provided at this presentation.

Phase 3, Placebo-Controlled Clinical Trial Program Included 3499 Randomized Patients: 100% on Maximally Tolerated Statins1

Maximally tolerated statin: highest tolerated dose of atorvastatin, rosuvastatin, or simvastatin.ASCVD=atherosclerotic cardiovascular disease; HeFH=heterozygous familial hypercholesterolemia; T2DM=type 2 diabetes mellitus.1. Alirocumab Prescribing Information. Sanofi/Regeneron Pharmaceuticals, 2015; 2. Data on file, Sanofi/Regeneron Pharmaceuticals.

90% of Patients Were High CV Risk1

Of which 11%had DM22


54%of non-FH

patients had clinical ASCVD1

36%of patients had HeFH1

10%Had DM2

Only

DM2 in ~31% of all PCSK9-I subjects







54%of non-FH



10%Had DM2

Only

DM2 alone(w/o HeFH or prior ASCVD)

~10% of patients studied but not an indication for PCSK9-I

regardless of ASCVD risk!


10%Had DM2

Only






54%of non-FH



DM2 alone(w/o HeFH or prior ASCVD)

~10% of patients studied but not an indication for PCSK9-I

regardless of ASCVD risk!

DM2 in 21% of indicated

patients

but

LDL C Predicts CVD

LDL C Predicts CVD w/ All LDL R Based Rx Can LDL-C be Too Low?• Abetalipoproteinemia & HoHypobeta. (LDL C <25 mg/dL)

– Autosomal recessive LoF MTP, or apo B gene mutations– Apo B cont. lipos (chylos, VLDL, LDL) very low/absent– Neurological/ophthalm sequelae Rx w/ fat soluble vits/EFFA– Malabsorption Sx reduced by low fat diet + MCT oil– Hepa c steatosis and AST/ALT (no hep. fibrosis)– ASCVD

• Heterozygous PCSK9 LoF (LDL C ~60 100)—N 100s– PCSK9 ~1/2 nl– ASCVD– Normal neurological and reproductive function

• Homozygous PCSK9 LoF (LDL C ~10 20)—N=3– PCSK9 absent– Normal neurological and reproductive function

• PCSK9 I mAb LDL C < 25: no evidence for harmAfter Lee J, J Inherit Metab Dis 37:333, 2014; Cohen, JC. NEJM 2006;354:1264-72 and Sabatine MS. Am Heart J 2016;173:94-101.

Can LDL-C be Too Low?• Abetalipoproteinemia & HoHypobeta. (LDL C <25 mg/dL)

– Autosomal recessive LoF MTP, or apo B gene mutations– Apo B cont. lipos (chylos, VLDL, LDL) very low/absent– Neurological/ophthalm sequelae Rx w/ fat soluble vits/EFFA– Malabsorption Sx reduced by low fat diet + MCT oil– Hepa c steatosis and AST/ALT (no hep. fibrosis)– ASCVD

• Heterozygous PCSK9 LoF (LDL C ~60 100)—N 100s– PCSK9 ~1/2 nl– ASCVD– Normal neurological and reproductive function

• Homozygous PCSK9 LoF (LDL C ~10 20)—N=3– PCSK9 absent– Normal neurological and reproductive function

• PCSK9 I mAb LDL C < 25: no evidence for harmAfter Lee J, J Inherit Metab Dis 37:333, 2014; Cohen, JC. NEJM 2006;354:1264-72 and Sabatine MS. Am Heart J 2016;173:94-101.

Probably not!

±

±

•

•

Summary: ASCVD RiskManagementby Cholesterol Lowering in DM1 & DM2DM1• Statins in most/all if > 40 y/o (women men)• Consider statin adjuncts (ezet & PCSK9 I) if LDL C/Non HDL C

above goal:– 2o prev: <70/<100– 1o prev: <100/<130

DM2• Statins inmost/all at any age (female male, even children/

adolescents) due to lifetime CVD risk vs e cacy,safety & cost of statins

• Consider statin adjuncts (ezet & PCSK9 I) if LDL C/Non HDL Cat or above goal:– 2o prev: <70/<100– 1o prev: <100/<130

DM1 or DM2• Extra aggressive Rx needed if DM + FH

Documents

ENDOCRINE SOCIETY PRESENTS The Revolution in ......National Lipid Association, he has served on the Lipid Drug Safety Task Force in 2006‐2007 and the Statin Intolerance Panel in