Combined Cascade Screening And Patient Education For Familial Hypercholesterolemia: Genetic Results From A Family Shared Medical Appointment Pilot Study

674 3. Group SSCobotSBR. Risk of fatal coronary heart disease in familial hypercholesterolemia. British Journal of Medicine. 1991;303(6807): 893–896. 4. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. European Heart Journal. 2013;34(45):3478–3490. 5. Umans-Eckenhausen M, Defesche J, Sijbrands E, Scheerder R, Kastelein J. Review of the first 5 years of screening for familial hypercholesterolaemia in the Netherlands. The Lancet. 2001;357(9251): 165–168. 6. Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015. 7. Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 19922010. J Am Heart Assoc. 2014;3(6):e001236. 8. Neil HA, Seagroatt V, Betteridge DJ, et al. Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia. Heart. 2004;90(12):1431–1437. 9. Gagne C, Moorjani S, Brun D, Toussaint M, Lupien PJ. Heterozygous familial hypercholesterolemia. Relationship between plasma lipids, lipoproteins, clinical manifestations and ischaemic heart disease in men and women. European Heart Journal. 1979;34(1):13–24. 10. Beaumont V, Jacotot B, Beaumont JL. Ischaemic disease in men and women with familial hypercholesterolaemia and xanthomatosis. A comparative study of genetic and environmental factors in 274 heterozygous cases. European Heart Journal. 1976;24(3):441–450. 11. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004;160(5):421–429. 12. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97(11):3956–3964. 13. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425–2437.

Abstract won third place Young Investigator Award. 128 Does Body Mass Index Correlate To Lipoproteins And Triglycerides? Findings From DYSIS In 52.916 Statin Treated Patients Dominik Lautsch, Dr scient med, Jean Ferrieres, Univ Prof Dr med, Baishali Ambegaonkar, PhD, Martin Horack, MS, Philippe Brudi, Dr med, Anselm Gitt, Dr med, (Kenilworth, NJ)

Lead Author’s Financial Disclosures: DL is an employee of Merk&Co, Inc. /Merck, Sharp & Dohme, GmbH. Study Funding: The study was funded by Merck&Co, Inc., Kenilworth, NJ. DL, BA, and PB are employees of Merck&Co, Inc. or one of its subsidiaries.

Journal of Clinical Lipidology, Vol 10, No 3, June 2016

Background/Synopsis: It is unclear from exist literature whether LDL choelsterol (LDL-C) correlates to body mass index (BMI), while there is evidence of a common association between BMI, high density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Objective/Purpose: In a representative, real world cohort of 52.916 statin treated patients across the globe we evaluated the correlations between blood lipids and BMI. Methods: DYSIS was a cross-sectional, multicenter study in 30 countries around the world performed in primary care centers. Outpatients were an $45 years of age, treated with statins for $3 months, and had at least one fasting blood lipid profile available within the last 6–12 months while on statins. They were consecutively enrolled. We used SAS 9.3 to calculate the non-parametric Spearman rho correlation between BMI and LDL-C, HDL-C, and triglycerides, respectively. All variables were treated as continuous variables. Using Cochran-Armitage test we determined the trend wise differences between lipoprotein and TG levels per BMI category as defined by the world health organization (WHO). Results: BMI was distributed in DYSIS in the following way: 1.1% of the patients were underweight (BMI,18.5), 33.1% had normal weight (BMI 18.5-24.9), 41.5% overweight (BMI 25.0-29.9), 17.1% suffered from class I obesity (BMI 30.0-34.9), 5.0% from class II obesity (BMI 35.039.9), and 2.1% from class III obesity (BMI $40.0). 45% were female. Mean age was 65.4 years, Statins were administered in all patients whereas the mean simvastatin equivalent dose was 33.5 6 25.1 mg per day. The treated mean LDL-C was 103.21638.26 mg/dl with no significant differences between the BMI categories (p50.5443). Median HDL-C was 47.95 (Interquartile range, IQR 39.83, 58.00). HDL-C values were significantly decreased per higher BMI category (p,0.0001). Median triglycerides were 130.20 (IQR 93.89, 182.46). TG values significantly increased per BMI category (p,0.0001). Spearman rho for LDL-C was 0.00283, for HDL-C -0.14718 and for TG 0.17001. Conclusions: We found a significant correlation between BMI and HDL-C and triglycerides, respectively. This influence ranges around 2-3%. As expected, however, there was no significant correlation or influence between BMI and LDL-C. Our finding was identified in a representative cohort of .50.000 statin treated patients from North America, Europe, the Middle East, Africa and China.

Genetics, Gene Therapy and Atherosclerosis 129 Combined Cascade Screening And Patient Education For Familial Hypercholesterolemia: Genetic Results From A Family Shared Medical Appointment Pilot Study Tina Davis, CRNP, Rolf Andersen, MD, Lars Andersen, BA, Heidi Testa, BSN, Joseluis Ibarra, MD, (Lancaster, PA)

Abstracts

675

Lead Author’s Financial Disclosures: None Study Funding: This study was funded by the Louise Von Hess Foundation.

Background/Synopsis: Familial hypercholesterolemia (FH) remains a significantly underdiagnosed disease.1-4 Cascade screening after identifying an index case to diagnose a greater share of FH patients is widely recommended although rarely executed in the United States.1,5-12 Objective/Purpose: We sought to integrate cascade screening including genetic testing with an educational program into a ‘‘family shared medical appointment’’ format. Here we report our findings of genetic testing as part of our pilot study. Methods: Eight probands diagnosed clinically with heterozygous familial hypercholesterolemia were opportunistically identified at the Preventive Cardiology and Apheresis Clinic of Lancaster General Health. After obtaining consent and blood samples from probands, coordinators awaited contact from and consented thirty two first-degree relatives, who also gave blood samples. All samples received lipid screening and sequencing of exons 1-4, 9-11, and 17 of LDLR, exon 7 of PCSK9, and codon 3500 of exon 26 of APOB. A large-group educational session and individual family breakout sessions were then held and patients’ basic knowledge of FH before and after the program was assessed. The patients’ satisfaction with the program was also assessed at the conclusion of the program. Results: Of 40 total patients, 22 patients received a positive molecular diagnosis. Three of eight probands were heterozygous for mutations in exon 4 of LDLR (c.653delG, c.400T.C, c.502G.A) and one was heterozygous for a mutation in exon 1 (c.97C.T), producing two missense mutations, one frameshift mutation, and one nonsense mutation. One proband was a homozygote for the R3500Q mutation in APOB. Conclusions: C.400T.C has been noted in the Netherlands and Germany, C.653delG in Germany and Canada, c.502G.A in Great Britain and New Zealand, and C.97C.T diffusely throughout Europe. None of the mutations detected in LDLR has previously been reported in the United States. The patient homozygous for R3500Q was clinically diagnosed with heterozygous FH prior to genetic testing, a phenotypic presentation similar to previously described homozygotes. The discovery of an R3500Q Table 1

homozygote adds to five identified in 2010 within Lancaster County, reinforcing the area as a ‘‘hotspot’’ for the mutation.13 The high rate of R3500Q, coupled with the detection of c.653delG and c.400T.C, further underscores the Germanic heritage of the Lancaster area.

References 1. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S1–8. 2. Neil HA, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of underdiagnosis of familial hypercholesterolaemia in routine practice: prospective registry study. BMJ. 2000;321(7254):148. 3. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. European Heart Journal. 2013;34(45):3478–3490. 4. O’Brien EC, Roe MT, Fraulo ES, Peterson ED, Ballantyne CM, Genest J, Gidding SS, Hammond E, Hemphill LC, Hudgins LC, Kindt I, Moriarty PM, Ross J, Underberg JA, Watson K, Pickhardt D, Rader DJ, Wilemon K, Knowles JW. Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. American Heart Journal. 2014;167(3):342–349. 5. Ademi Z, Watts G, Pang J, Sjibrands E, Bockxmeer F, O’Leary P, Geelhoed E, Liew D. Cascade screening based on genetic testing is cost-effective: Evidence for the implementation of models of care for familial hypercholesterolemia. Journal of Clinical Lipidology. 2014;8(4):390–400. 6. Defesche JC. Defining the challenges of FH screening for familial hypercholesterolemia. J Clin Lipidol. 2010;4(5):338–341. 7. Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015. 8. Hadfield SG, Horara S, Starr BJ, et al. Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing Project. Ann Clin Biochem. 2009;46(Pt 1):24–32. 9. Marks D, Thorogood M, Neil SM, Humphries SE, Neil HA. Cascade screening for familial hypercholesterolaemia: implications of a pilot study for national screening programmes. J Med Screen. 2006;13(3):156–159. 10. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR,

LDLR and APOB mutations detected and previous description

Mutation

Exon

Number of carriers detected

Areas in which previously detected

C.400T.C C.653delG C.502G.A C.97C.T APOB R3500Q

4 4 4 1 26

5 6 4 1 1

Germany, Netherlands Germany, Canada UK, New Zealand Turkey, Spain, Italy, France, Russia Diffusely in Europe, USA, Canada, Mexico, Australia, New Zealand, Taiwan, South Korea

heterozygotes heterozygotes heterozygotes heterozygote homozygote, 4 heterozygotes

676 Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. European Journal of Preventive Cardiology. 2015;22(7):849–854. 11. Wonderling D, Umans-Eckenhausen M, Marks D, Defesche J, Kastelein J, Thorogood M. Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands. Seminars in Vascular Medicine. 2004;4(1):97–104. 12. Familial Hypercholesterolemia (FH), Report of a second WHO Consultation: WHO/HGN/FH/CONS/99.2. 13. Shen H, Damcott CM, Rampersaud E, et al. Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish. Arch Intern Med. 2010;170(20):1850–1855.

130 Treatment Of A Patient Homozygous For Familial Defective Apolipoprotein B-100 With Evolocumab: A Case Study Rolf Andersen, MD, Heidi Testa, BSN, Tina Davis, CRNP, Joseluis Ibarra, MD, Lars Andersen, BA, (Lancaster, PA)

Lead Author’s Financial Disclosures: None Study Funding: None Background/Synopsis: Familial defective apolipoprotein B (FDB) is an autosomal co-dominant disorder of lipid metabolism characterized by elevated LDL-C and generally considered to be a type of familial hypercholesterolemia (FH).1-4 In contrast with autosomal dominant hypercholesterolemia caused by mutations in LDLR, most cases of FDB identified to date result from a single mutation in APOB known as R3500Q.5,6 R3500Q appears frequently among genetically confirmed cases of FH in many European nations.7-11 To date, relatively few patients homozygous for R3500Q have been detected, and the phenotypic data and therapeutic responses of these patients occurred before the release of monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9).12-17 Objective/Purpose: Here we report the first known case study of the use of PCSK9 inhibitors in a patient homozygous for R3500Q. We sought to determine the effect of PCSK9 therapy on the subject’s lipid profile. Methods: We retrospectively analyzed the patient’s electronic health record to determine the patient’s lipid levels before and after the addition of PCSK9 inhibitor evolocumab to statin/ezetimibe therapy. We further examined the subject’s cardiovascular medical history, recorded lipid values, social history, family history, genetic status, and concomitant medications. Results: The subject is a male aged 40 with a history of premature ST-elevated myocardial infarction at age 37 followed by three coronary artery bypass grafts, as well as non-ST-elevated myocardial infarction at age 39. The subject is a current every day smoker with a family history of premature coronary artery disease. Prior to treatment, the subject displayed a maximum LDL-C of 318 mg/dL which was reduced to 180 mg/dL with atorvastatin 80 mg daily and

Journal of Clinical Lipidology, Vol 10, No 3, June 2016 Table 1 Homozygous FDB subject lipid levels pre- and posttreatment with evolocumab 140 mg/mL

Lipid values

80 mg atorvastatin 10 mg 80 mg atorvastatin ezetimibe 140 mg/mL Off 10 mg evolocumab treatment ezetimibe

LDL-C (mg/dL) 318 Non-HDL-C (mg/dL) 334 Triglycerides (mg/dL) 87 HDL-C (mg/dL) 44 VLDL-C (mg/dL) 16

180 197 83 44 17

108 125 85 39 17

ezetemibe 10 mg daily. Based on these lipid levels, the subject was phenotypically diagnosed with heterozygous FH. The subject was placed on 140 mg/mL evolocumab following its approval as indicated for prior ASCVD requiring additional lipid-lowering therapy as well as heterozygous FH. The subject’s LDL-C then dropped from 180 mg/dL to 108 mg/dL, a reduction of 40%. After beginning evolocumab therapy, the subject received genetic testing demonstrating his status as homozygous for R3500Q. Conclusions: Similar to FDB homozygotes previously described, the subject presented with lipid levels lower than those typically displayed by patients homozygous for mutations in LDLR, leading to his initial identification as a heterozygote. The disparity between phenotypic and genotypic diagnosis in the case of this subject demonstrates the increasing relevance of genetic testing to dyslipidemia, as a diagnosis of homozygous FDB/FH qualifies the subject for an increase in evolocumab monthly dosage as well as other adjunct therapies such as mipomersen sodium and lomitapide. While the subject did not reach NLA lipid goals for patients with prior ASCVD, there was an observed 40% reduction in LDL-C after treatment with evolocumab 140 mg/mL.18 This may be due to enhanced LDLR-metiated uptake of VLDL and IDL particles as well as larger LDL particles as previously described in an FDB homozygote.13

Works Cited 1. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S1–8. 2. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. European Journal of Preventive Cardiology. 2015;22(7):849–854. 3. Innerarity TL, Mahley RW, Weisgraber KH, et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990;31(8):1337–1349.