Familial Hypercholesterolemia
John R. Guyton, M.D.
Director, Duke Lipid Clinic
Durham, NC
Disclosures
• Research grants: Merck, Amgen, Regeneron,
Sanofi, Amarin, Genzyme/ISIS
• Consulting fees: Merck, Regeneron, ...
Case 100. Familial Hypercholesterolemia
Date
Chol
TG
HDLC
LDLC
Non
HDLC While taking
12/04 413 262 58 302 355 No lipid med...
Case 100. Familial Hypercholesterolemia
Date
Chol
TG
HDLC
LDLC
Non
HDLC While taking
11/11 190 86 51 122 139 rosuva 40, ez...
Familial Hypercholesterolemia
• Original definition: Hypercholesterolemia due
to defective LDL receptor function.
• Curren...
FH in Places We Know
Place Populaton FH Patients*
Durham 245,000 500 to 800
Rocky Mount 57,000 115 to 190
Graham 14,000 30...
Dx of FH: Dutch Lipid Clinic Network Criteria
1. LDL-C Points
>325 8
251-325 5
191-250 3
155-190 1
3. 1st deg Points
relat...
Percent of FH Patients Diagnosed*
0 10 20 30 40 50 60 70 80
Mexico
USA
South Africa
Slovakia
UK
Iceland
Norway
Netherlands...
Corneal Arcus
Achilles Tendon Xanthoma
FH – High LDL
FH – High IDL (Intermediate Density Lps)
IDL, Xanthomas, and CAD
1. Tendon xanthomas occur much more
frequently in patients who have both high LDL
and high IDL.
2....
Case 113. Fam’l Hypercholesterolemia, Tendon Pain
Male patient developed angina at age 44, managed
medically. Achilles ten...
Distribution of Lipoprotein(a) Concentrations among
FH Patients Who Did and Did Not Have CHD.
Seed M et al. N Engl J Med 1...
Treatment of Heterozygous FH
• Highly effective statin
• Bile acid sequestrant
• Niacin given at mealtimes
• Ezetimibe
• C...
Lipid Treatment in Familial Hypercholesterolemia
(Presumed LDL Receptor Defect)
• Average 64% LDL-C
reduction (range 56-71...
Young woman first seen in the Duke Lipid Clinic at age 7. Her
pediatrician had noted cutaneous xanthomas at age 4. She had...
Treatment of Homozygous FH
• Usual drugs are only marginally effective.
• LDL apheresis is standard of care.
• New treatme...
Case 115. FH Treatment Initiation in a Young Woman
Young woman whose grandmother had high cholesterol
treated at Duke was ...
CASCADE-FH
 National, patient-led initiative designed to promote
identification of individuals with familial
hypercholest...
Main Objectives
1. Promote the identification and enrollment of individuals
with FH into a national patient-centric clinic...
FH Summary
• FH is underdiagnosed and undertreated.
• Physical exam should evaluate presence of
– Corneal arcus
– Tendon x...
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
Prevention 2014: Familial Hypercholesterolemia
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Prevention 2014: Familial Hypercholesterolemia

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John R. Guyton, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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Prevention 2014: Familial Hypercholesterolemia

  1. 1. Familial Hypercholesterolemia John R. Guyton, M.D. Director, Duke Lipid Clinic Durham, NC
  2. 2. Disclosures • Research grants: Merck, Amgen, Regeneron, Sanofi, Amarin, Genzyme/ISIS • Consulting fees: Merck, Regeneron, Sanofi, Amgen, Novella, Novartis
  3. 3. Case 100. Familial Hypercholesterolemia Date Chol TG HDLC LDLC Non HDLC While taking 12/04 413 262 58 302 355 No lipid meds 5/05 196 90 55 123 141 rosuvastatin 10 mg, ezetimibe 10 mg, niacin-ER 1500 mg, colesevelam 6 tabs 12/05 168 94 47 102 121 same w colesevelam 9 tabs 11/11 190 86 51 122 139 rosuva 40, ezet 10, niacin-ER 2000, colesev 10 tabs Male referred in 12/04 for fam’l hypercholesterolemia at age 58. He had 1st MI at age 24, 2nd MI and 2v. CABG at age 47. Muscle weakness with atorvastatin 80 mg.
  4. 4. Case 100. Familial Hypercholesterolemia Date Chol TG HDLC LDLC Non HDLC While taking 11/11 190 86 51 122 139 rosuva 40, ezet 10, niacin-ER 2000, colesev 10 tabs 11/13 392 153 56 306 336 rosuva 40, niacin-ER 2000 (?) Male referred in 12/04 for fam’l hypercholesterolemia at age 58. He had 1st MI at age 24, 2nd MI and 2v. CABG at age 47. Muscle weakness with atorvastatin 80 mg. By 2013 the patient had no further ASCVD. He was now a caregiver for his wife with vascular dementia.
  5. 5. Familial Hypercholesterolemia • Original definition: Hypercholesterolemia due to defective LDL receptor function. • Current definition (Eur. Atherosclerosis Society): Hypercholesterolemia caused by mutations affecting key proteins in the LDL receptor endocytic/recycling pathways. • When causative mutation is known, >90% of cases have mutation in LDLR. • Prevalence 1 in 500, perhaps 1 in 300 in all ethnicities worldwide.
  6. 6. FH in Places We Know Place Populaton FH Patients* Durham 245,000 500 to 800 Rocky Mount 57,000 115 to 190 Graham 14,000 30 to 45 Durham/Wake/ Orange Counties 1,300,000 2,600 to 4,300 North Carolina 9,800,000 20,000 to 32,000 * Based on 1/500 to 1/300 and “normal” survival Duke Lipid Clinic 270
  7. 7. Dx of FH: Dutch Lipid Clinic Network Criteria 1. LDL-C Points >325 8 251-325 5 191-250 3 155-190 1 3. 1st deg Points relative Early CHD 1 High LDL-C 1-2 Xanth, arcus 2 2. Phys exam Points Tendon xanthoma 6 Corneal arcus age <45 4 4. ASCVD Points Early CHD 2 Early CerVD or PAD 1 5. Mutational 8 analysis Definiite > 8, Probable 6-8, Possible 3-5, Unlikely <3
  8. 8. Percent of FH Patients Diagnosed* 0 10 20 30 40 50 60 70 80 Mexico USA South Africa Slovakia UK Iceland Norway Netherlands * Based on 1/500 in population. Eur Heart J, 2013
  9. 9. Corneal Arcus
  10. 10. Achilles Tendon Xanthoma
  11. 11. FH – High LDL
  12. 12. FH – High IDL (Intermediate Density Lps)
  13. 13. IDL, Xanthomas, and CAD 1. Tendon xanthomas occur much more frequently in patients who have both high LDL and high IDL. 2. IDL cholesterol is only 10-45 mg/dl in people with a wide range of LDL cholesterol. Nevertheless, high IDL is a risk factor for earlier and more severe CAD. 3. Therefore, we should expect CAD to occur earlier and be more severe when tendon xanthomas accompany high LDLC.
  14. 14. Case 113. Fam’l Hypercholesterolemia, Tendon Pain Male patient developed angina at age 44, managed medically. Achilles tendons 2.5 cm thick. His job in a machine shop requiring squatting every few minutes. He had moderate Achilles tenderness after 6 months, pain interfering with job by 13 months and stopped meds. Initial 264 51 27 226 atorvastatin 40 mg 6 mo 195 112 33 139 atorvastatin, ER-niacin 2000 mg 13 mo 431 170 32 365 meds taken infrequently 10 yr 177 72 42 120 rosuvastatin 20 mg, IR-niacin 2000 mg, ezetimibe 10 mg, cholestyramine 8 g Date Chol TG HDLC LDLC While taking Lakey, Greyshock, Guyton. J Clin Lipidol 2013; 7:178
  15. 15. Distribution of Lipoprotein(a) Concentrations among FH Patients Who Did and Did Not Have CHD. Seed M et al. N Engl J Med 1990;322:1494-1499.
  16. 16. Treatment of Heterozygous FH • Highly effective statin • Bile acid sequestrant • Niacin given at mealtimes • Ezetimibe • Currently in trials – monoclonal ab to PCSK9 • Other modalities – fenofibrate, psyllium, plant sterol/stanol esters
  17. 17. Lipid Treatment in Familial Hypercholesterolemia (Presumed LDL Receptor Defect) • Average 64% LDL-C reduction (range 56-71%) • LDL-C fell from mean 353 mg/dl to 126 mg/dl • Mean on-treatment HDL-C 58 mg/dl in men, 72 mg/dl in women • Mean of 3.75 lipid medications 0 100 200 300 400 500 Baseline Recent LDL-C, mg/dl Duke Lipid Clinic, 2006
  18. 18. Young woman first seen in the Duke Lipid Clinic at age 7. Her pediatrician had noted cutaneous xanthomas at age 4. She had 2- yearly visits to NIH from 1996 until 2003. She moved with her family to Utah in 2006 and was provided with the name of a lipid specialist there. Case 114. Homozygous Fam’l Hypercholesterolemia 4 792 84 22 752 no lipid meds 7 577 28 528 simvastatin 10 mg, probucol 250 mg, cholestyramine 1 scoop 9 662 100 36 621 atorva 40, cholestyr 2 scoops 14 485 55 32 442 atorva 80 mg, ezetimibe 10 mg, colesevelam 4 tabs Age Chol TG HDLC LDLC While taking The patient never received LDL apheresis. She died with her first MI at age 23, a few weeks before first scheduled visit with the lipid specialist in 2011.
  19. 19. Treatment of Homozygous FH • Usual drugs are only marginally effective. • LDL apheresis is standard of care. • New treatment options – Lomitapide, inhibitor of microsomal triglyceride transfer protein – Mipomersen, antisense oligonucleotide directed against apoB mRNA.
  20. 20. Case 115. FH Treatment Initiation in a Young Woman Young woman whose grandmother had high cholesterol treated at Duke was seen initially in Duke Lipid Clinic at age 18. She first had high cholesterol measured at age 12. She and her parents with physician advice had elected not to treat until reaching adult age. Initial 264 80 51 217 75 no lipid meds Chol TG HDLC LDLC Lp(a) While taking On physical exam she has no xanthomas, but has a right carotid bruit and bilateral femoral bruits. Dorsalis pedis pulses are normal. Carotid ultrasound (Neurodiagnostic) is pending.
  21. 21. CASCADE-FH  National, patient-led initiative designed to promote identification of individuals with familial hypercholesterolemia  Created and funded by The Familial Hypercholesterolemia Foundation  Study coordination by the Duke Clinical Research Institute (DCRI)  Collaboration between The FH Foundation, the DCRI, lipid specialists, cardiologists, primary care providers, quality improvement personnel, and patients to increase FH awareness, promote optimal disease management, and improve FH outcomes The Familial Hypercholesterolemia Foundation Registry
  22. 22. Main Objectives 1. Promote the identification and enrollment of individuals with FH into a national patient-centric clinical registry using multiple identification pathways including: specialty lipid clinics, electronic healthcare record (EHR) screening, online patient self-enrollment, and family referral 2. Evaluate how individuals with FH are treated, as well as their longitudinal patient experiences, health outcomes, and quality of life; 3. Enhance patient engagement in their disorder by expanding their knowledge via tailored educational initiatives, shared patient communities, health information exchange, and opportunities for enrollment in clinical
  23. 23. FH Summary • FH is underdiagnosed and undertreated. • Physical exam should evaluate presence of – Corneal arcus – Tendon xanthomas (Achilles, also tendons over MP and PIP joints) – Carotid, abdominal, and femoral bruits – Pedal pulses • Laboratory evaluation should include lipoprotein(a) • LDLC targets are applicable and may be difficult to achieve even with combination drug therapy • Advocate family screening and Cascade FH Registry

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