The FH Foundation CASCADE FH RegistryTM Need to insert a slide in this intro section referencing name-brand sponsors and collaboration with DCRI The FH Foundation CASCADE FH RegistryTM

CASCADE FH Registry data to: Evaluate trends in therapy clinical outcomes patient reported outcomes ___improve quality of lige, clinical outcomes, show gaps in care, costs in life years and productivity

https://thefhfoundation.org/fh-research/registry/ CASCADE FH Registry Multicenter US registry to increase awareness, characterize treatment, monitor outcomes in FH Key initiatives of FH Foundation; major data gap in the US CAscade SCreening for Awareness and Detection of FH, national initiative to increase FH awareness, characterize trends in treatment, and monitor clinical and patient-reported outcomes over time https://thefhfoundation.org/fh-research/registry/

CASCADE-FH Registry Design Lipid Clinic Patient Portal Eligibility Clinical or genetic diagnosis of FH Data collection Prospective/retrospective Entered by research staff Abstracted from medical records from routine care Prospective Entered by patient, with follow-up verification by research staff Data captured Demographics Familial hypercholesterolemia diagnosis Cardiovascular history Family history Medications Physical examination Laboratory studies Participating Lipid Clinic, Online Patient Portal we conducted a cross-sectional analysis of 1295 adult FH patients who were enrolled in the CASCADE-FH Registry prospectively through 11 participating lipid clinics between September 2013 and April 2015 (n=436) or for whom retrospective data were abstracted by reviewing historical medical charts (n=859) (Supplementary Figure).24 Institutional review boards at each site reviewed and approved the protocol. Signed informed consent was required for all prospectively enrolled patients, and a waiver was approved for retrospective data abstraction. Clinical and laboratory data obtained locally for routine clinical care were abstracted from patient medical records and entered by trained research staff O’Brien. Am Heart J 2014;167:342

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Preventive Cardiology Inc. Patient Enrollment U Penn deGoma, 356 Thomas Jefferson Duffy, Whellan, 44 Oregon Health & Science University – Shapiro/Duell, 238 Maine MGH Hemphill, 33 Geisinger Boston Childrens Lancaster Anderson, 40 Mayo Kullo, 0 NY (8) NYU Underberg, 5 Rogosin Hudgins, 66 Stanford - Knowles, 108 Chicago Atlantic Ohio State The University of Kansas Moriarty, 504 JHU WVU Neal, 68 CA (28) UCSF NC (4) Nemours Gidding, 36 ULCA- Watson, 3 UC Irvine Wong, 1 GA (10) Duke Baylor Ballantyne, 118 UT Southwestern Ahmad, 312 Vanderbilt Linton, 239 Preventive Cardiology Inc. Baum, 41

Patient Demographic – Clinical Portal

Patient Demographic – Clinical Portal

Diagnostic criteria *MEDPED denotes Make Early Diagnosis, Prevent Early Death; DLCN Dutch Lipid Clinic Network Data are being refined

Insights from initial characterization Patients enrolled in the CASCADE-FH Registry through one of 14 participating lipid centers (n=1565) Excluded patients (n=270) due to: Below 18 years of age (n=202) Homozygous FH (n=43) Missing statin dosage (n=25) Cross-sectional Homozygous FH: genetic diagnosis, untreated LDL-C>500, use of mipomersen or lomitapide Adult patients with heFH eligible for analysis of cardiovascular status and treatment patterns treated at one of 11 lipid centers (n=1295)

Exclusion criteria for initial characterization of of adult HeFH patients Excluded patients not on lipid-lowering therapy or missing entry LDL-C data (n=211) Treated adult patients with heFH eligible for analysis of goal attainment of treated LDL-C<100 mg/dl (n=1084) Excluded patients missing untreated LDL-C data or with the same LDL-C value recorded at both time points (n=432) Treated adult patients with heFH eligible for analysis of goal attainment of ≥50% LDL-C reduction (n=652)

Age at enrollment, years, median (IQR), n=1265 57 Female, % 59 Demographics Age at enrollment, years, median (IQR), n=1265 57 (43-66) Female, % 59 Ethnicity, %   White 80 Black 7 Hispanic 2 Other 10

Late Diagnosis and Treatment Guidelines* 2-11 CASCADE-FH 47 DIAGNOSIS AGE 0 10 20 30 40 50 8-10 Statin 21 ACC/AHA Adult Guidelines 39 CASCADE-FH TREATMENT American Association of Pediatrics 2008 US National Lipid Association 2011 International FH Foundation 2011 European Atherosclerosis Society 2013

Lipids Untreated Total cholesterol mg/dl, n=949 329 LDL-C, n=888 239 Total cholesterol, n=1097 215 LDL-C, n=1084 134 Triglycerides, n=1092 113 HDL-C, n=1096 52 ‘Untreated’ LDL-C: highest documented values prior to initiation of drug therapy or occasionally when a patient was on a drug holiday ‘Treated’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry among patients on LDL-lowering medication(s) ‘Entry’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry, regardless of treatment status ‘Untreated’ LDL-C: highest documented values prior to initiation of drug therapy or occasionally when a patient was on a drug holiday ‘Treated’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry among patients on LDL-lowering medication(s)

Additional CHD Risk Factors   39% 1 38% 2 16% 3+ 7% Diabetes, n=1280 13% Current smoker, n=1272 Hypertension, n=1283 43% Low HDL-C, n=1285 31% Obesity, n=1223 32% BMI, kg/m2, median, n=1223 27 Additional modifiable cardiovascular risk factors defined as diabetes, current smoker, hypertension, and low HDL-C

Cardiovascular Disease ASCVD, n=1273 38% Age at onset, years 52 CHD, overall cohort 36% 51 CHD, men 47% 47 CHD, women 29% 55 Stroke or TIA, n=1282 5% Aortic valve disease, n=1284 3% ASCVD includes any history of CHD, stroke, TIA, peripheral artery disease

Not statin-treated n=326, 25% of overall Statin and Non-Statin Medications   Statin-treated n=969 Not statin-treated n=326, 25% of overall Statin intensity† High 544 (56%) - Low/Moderate 425 (44%) No statin 326 (100%) Statin Rosuvastatin 475 (49%) Atorvastatin 334 (35%) Non-statin Ezetimibe 438 (45%)* 82 (25%) Bile acid sequestrant 141 (15%) 48 (15%) Niacin 135 (14%)* 30 (9%) Fibrate 44 (5%) 20 (6%) Ezetimibe p<0.0001, niacin p=0.0234

Reasons for sub-maximal statin use Statin intolerance or allergy (60%) Patient preference (11%) Physician preference (11%) Pregnancy (3%) Cost (1%) Clinical trial participation (1%) Among the 326 patients not receiving statin treatment, reasons for the lack of statin use included

Combination Therapy & Apheresis   Statin-treated n=969 Not statin-treated n=326 Statin + ezetimibe 438 (45%) - LDL-lowering meds* 196 (60%) 1 428 (44%) 87 (27%) 2 353 (36%) 36 (11%) 3+ 188 (19%) 7 (2%) Apheresis* 37 (4%) 40 (12%) p<0.0001

Treated LDL-C Values & Reduction   Statin-treated Not statin-treated Treated LDL-C* n=959 n=125 <70 mg/dl 58 (6%) 5 (4%) 70-99 mg/dl 194 (20%) 11 (9%) 100-129 mg/dl 238 (25%) 7 (6%) 130-159 mg/dl 153 (16%) 35 (28%) 160-189 mg/dl 113 (12%) 22 (18%) ≥190 mg/dl 203 (21%) 45 (36%) LDL-C reduction* n=576 n=76 ≥50% 257 (45%) 9 (12%) Table 4: Treated LDL-C levels and magnitude of LDL-C reductions compared with untreated levels among adults with heterozygous FH taking LDL-lowering medications P<0.0001 † Chi-square test comparing statin users to statin nonusers. ‡ n=1084 on LDL-lowering therapy for whom treated LDL-C values were available. § n=652 on LDL-lowering therapy for whom untreated and treated LDL-C values were available.

Treated LDL-C Values ‡ n=1084 on LDL-lowering therapy for whom treated LDL-C values were available.

Magnitude of LDL-C Reduction § n=652 on LDL-lowering therapy for whom untreated and treated LDL-C values were available.

US CASCADE-FH US NHANES High Prevalence of CHD 5-7-Fold Higher US CASCADE-FH US NHANES CASCADE FH median age at diagnosis of CHD: M 47 years, W 55 years AHA Heart Disease and Stroke Statistics 2014 Update: NHANES 2007-2010 prevalence of CHD age 40-59.

Importance of CHD Risk Factors Prevalence Unadjusted OR Adjusted OR Hypertension 43% 5.4 (4.2-6.9) 2.7 (1.9-3.8) Diabetes 13% 4.0 (2.8-5.6) 1.7 (1.0-2.7) Low HDL-C 31% 1.6 (1.3-2.1) 1.5 (1.1-2.1) Smoking 7% 1.6 (1.1-2.5) 1.4 (0.7-2.5)

High Prevalence of CHD (Global) CASCADE-FH Denmark 2012 Canada 2014* UK 2008 Netherlands 2010* Spain 2011* France 2011* Age 57 59 61 51 50 46 LDL-C 239 251 262 259 258 192 TC 389 134 182 - 128 124 194 * Prevalence of ASCVD. Allard Lipids in Health and Disease 2014;13:65. Benn JCEM 2012;97:3956. Beliard Atherosclerosis 2014;234:136. Pijlman Atherosclerosis 2010;209:189. Mata Lipids in Health and Disease 2011;10:94. Hadfield Annals Clin Biochem 2008;45:199.

Treated LDL-C<100 mg/dl Goal attainment UK 2008 CASCADE-FH Netherlands 2010 Treated LDL-C<100 mg/dl Reduction in LDL-C≥50% Pijlman Atherosclerosis 2010;209:189. Hadfield Annals Clin Biochem 2008;45:199.

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Self-reported Quality of Life

FH Understanding (Patient Reported)

Gaps and future plans More patient-centric data needed Limited data on non-White populations, more generalizablity More longitudinal data needed Track effects as PCSK9 are introduced Integrate more historical data Launch patient portal V2.0 More sites, more patients from diverse backgrounds and areas of the country, leverage EHR data Convert retrospective to prospective enrollment Get updated snapshot so we can see what happens within 1 year of FDA approval MEDPED integration

Conclusions High CHD prevalence among adult FH patients Poor LDL goal attainment (<100 mg/dl, >50%) Opportunities to improve care of FH patients: Early diagnosis of FH Early initiation of LDL-lowering therapy Use of high-intensity statin therapy Use of combination therapy Management of other risk factors Careful elicitation of family history Please contribute to the CASCADE-FH Registry!

Acknowledgments Publications Committee and site PIs for CASCADE FH Zahid S. Ahmad, MD* Emily O’Brien, PhD Iris Kindt, MD, MPH Peter Shrader, PhD Joshua W. Knowles, MD, PhD Patrick M. Moriarty, MD Connie B. Newman, MD Yashashwi Pokharel, MD, MSCR Seth J. Baum, MD Linda C. Hemphill, MD Lisa C. Hudgins, MD Catherine D. Ahmed, MBA Samuel S. Gidding, MD Danielle Duffy, MD William Neal, MD Katherine Wilemon, BS Matthew T. Roe, MD, MHS Daniel J. Rader, MD Christie M. Ballantyne, MD MacRae F. Linton, MD P. Barton Duell, MD Michael D. Shapiro, MD University of Pennsylvania Tracey Sikora, Kristen Dilzell Anna Raper, Joyce Ross UT Southwestern Chandna Vasandani Stanford University Aleks Pavlovic Vanderbilt University Misty Hale, Beth Medor Oregon Health & Science University Jill Rose Our FH patients, family, and friends

CASCADE FH Registry Sponsorship

Lipids Untreated Total cholesterol mg/dl, n=949 329 LDL-C, n=888 239 Total cholesterol, n=1097 215 LDL-C, n=1084 134 Triglycerides, n=1092 113 HDL-C, n=1096 52 Entry Total cholesterol, n=1292 224 LDL-C, mg/dl, n=1278 141 Triglycerides, n=1286 HDL-C, n=1291 ‘Untreated’ LDL-C: highest documented values prior to initiation of drug therapy or occasionally when a patient was on a drug holiday ‘Treated’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry among patients on LDL-lowering medication(s) ‘Entry’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry, regardless of treatment status

Not statin-treated (n=326) Statin and Non-Statin Medication   Overall cohort (n=1295) Statin-treated (n=969) Not statin-treated (n=326) Statin intensity† High 544 (42%) 544 (56%) - Low/Moderate 425 (33%) 425 (44%) No statin 326 (25%) 326 (100%) Statin Rosuvastatin 475 (37%) 475 (49%) Atorvastatin 334 (26%) 334 (35%) Non-statin Ezetimibe 520 (40%) 438 (45%)* 82 (25%) Bile acid sequestrant 189 (15%) 141 (15%) 48 (15%) Niacin 165 (13%) 135 (14%)* 30 (9%) Fibrate 64 (5%) 44 (5%) 20 (6%) Ezetimibe p<0.0001, niacin p=0.0234

Combination Therapy & Apheresis   Overall cohort (n=1295) Statin-treated (n=969) Not statin-treated (n=326) Statin + ezetimibe 438 (34%) 438 (45%) - LDL-lowering meds* 196 (15%) 196 (60%) 1 515 (40%) 428 (44%) 87 (27%) 2 389 (30%) 353 (36%) 36 (11%) 3+ 195 (15%) 188 (19%) 7 (2%) Apheresis* 77 (6%) 37 (4%) 40 (12%) p<0.0001

Treated LDL-C Values & Reduction   Overall cohort Statin-treated Not statin-treated Treated LDL-C* n=1,084 n=959 n=125 <70 mg/dl 63 (6%) 58 (6%) 5 (4%) 70-99 mg/dl 205 (19%) 194 (20%) 11 (9%) 100-129 mg/dl 245 (23%) 238 (25%) 7 (6%) 130-159 mg/dl 188 (17%) 153 (16%) 35 (28%) 160-189 mg/dl 135 (13%) 113 (12%) 22 (18%) ≥190 mg/dl 248 (23%) 203 (21%) 45 (36%) LDL-C reduction* n=652 n=576 n=76 ≥50% 266 (41%) 257 (45%) 9 (12%) Table 4: Treated LDL-C levels and magnitude of LDL-C reductions compared with untreated levels among adults with heterozygous FH taking LDL-lowering medications P<0.0001 † Chi-square test comparing statin users to statin nonusers. ‡ n=1084 on LDL-lowering therapy for whom treated LDL-C values were available. § n=652 on LDL-lowering therapy for whom untreated and treated LDL-C values were available.

Coronary Heart Disease

Coronary Heart Disease * Adjusted for age at enrollment, diabetes, current smoking, hypertension, untreated total cholesterol, and low HDL-C. † Median (IQR) shown. For age, OR shown per 10-year increment. For untreated total cholesterol and LDL-C, OR shown per 10-mg/dl increment. For modified CYS, OR shown per 1000-mg/dl*years increment. ‡ Low HDL-C defined as <40 mg/dl for men and <50 mg/dl for women. § Cholesterol-years score was calculated as [untreated total cholesterol * age at initiation of lipid-lowering therapy] + [baseline total cholesterol * (age at enrollment - age at initiation of lipid-lowering therapy)]. Total cholesterol is not adjusted for in multivariable OR. || Statin intensity is defined according to the 2013 ACC/AHA Cholesterol Guidelines.

Coronary Heart Disease Characteristic No CHD (N=833) CHD (N=449) Unadjusted OR (95% CI) Adjusted OR Age at enrollment, yrs 53 (36-62) 63 (55-70) 1.75 (1.60-1.92) 1.53 (1.35-1.73) Male 278 (33.7%) 243 (52.3%) 2.15 (1.70-2.71) 2.68 (1.91-3.78) Family history of early MI 356 (57.6%) 227 (70.9%) 1.80 (1.34-2.40) 1.83 (1.25-2.70) Diabetes 59 (7.2%) 108 (23.5%) 3.97 (2.82-5.59) 1.66 (1.01-2.72) Current smoking 47 (5.8%) 41 (9.0%) 1.62 (1.05-2.51) 1.36 (0.74-2.49) Hypertension 233 (28.4%) 316 (68.3%) 5.42 (4.23-6.94) 2.68 (1.91-3.76) Low HDL-C, mg/dl 222 (27.1%) 176 (37.8%) 1.64 (1.29-2.09) 1.53 (1.09-2.14) Obesity 221 (28.1%) 164 (37.6%) 1.54 (1.20-1.98) 1.10 (0.77-1.56) Untreated total cholesterol 324 (298-380) 341 (294-400) 1.02 (1.01-1.04) 1.02 (1.00-1.04) Untreated LDL-C, mg/dl 238 (211-291) 242 (212-297) 1.01 (0.99-1.03) 1.01 (0.96-1.07) Age at FH diagnosis, yrs 43 (25-56) 55 (42-64) 1.46 (1.36-1.57) 0.95 (0.82-1.11) Cholesterol-years, mg*dl/yrs 25393 (16998-33190) 31175 (24790-38445) 1.05 (1.04-1.07) 0.99 (0.97-1.01) Age at initiation of LDL-lowering medication, yrs 36 (22-48) 44 (33-53) 1.35 (1.21-1.51) 0.86 (0.69-1.08) Low/moderate-statin 298 (35.9%) 127 (27.3%) 0.73 (0.54-0.99) 0.76 (0.50-1.15) High-intensity statin 326 (39.3%) 218 (46.9%) 1.15 (0.87-1.52) 1.34 (0.90-1.98) * Adjusted for age at enrollment, diabetes, current smoking, hypertension, untreated total cholesterol, and low HDL-C. † Median (IQR) shown. For age, OR shown per 10-year increment. For untreated total cholesterol and LDL-C, OR shown per 10-mg/dl increment. For modified CYS, OR shown per 1000-mg/dl*years increment. ‡ Low HDL-C defined as <40 mg/dl for men and <50 mg/dl for women. § Cholesterol-years score was calculated as [untreated total cholesterol * age at initiation of lipid-lowering therapy] + [baseline total cholesterol * (age at enrollment - age at initiation of lipid-lowering therapy)]. Total cholesterol is not adjusted for in multivariable OR. || Statin intensity is defined according to the 2013 ACC/AHA Cholesterol Guidelines.

Treated LDL-C≤100 mg/dl

Treated LDL-C≤100 mg/dl * Adjusted for untreated LDL-C, CHD, statin use, and use of >1 LDL-lowering medication † Median (IQR) shown. ‡ OR compared with no statin use.

Treated LDL-C≤100 mg/dl Characteristic LDL-C≥100 (N=816) LDL-C <100 Unadjusted OR (95% CI) Adjusted OR (95% CI) Age at enrollment, yrs 55 (42-65) 60 (49-67) 1.26 (1.15-1.38) 1.23 (1.07-1.41) Male 325 (40.1%) 136 (50.7%) 1.54 (1.17-2.03) 1.28 (0.85-1.93) Coronary heart disease 273 (33.5%) 122 (45.5%) 1.66 (1.26-2.20) 1.36 (0.89-2.09) Family history of early MI 365 (61.9%) 129 (66.5%) 1.22 (0.87-1.72) 1.88 (1.16-3.04) Diabetes 93 (11.5%) 42 (15.8%) 1.44 (0.97-2.14) 1.21 (0.65-2.23) Untreated LDL-C, mg/dl 245 (215-300) 225 (197-270) 0.95 (0.92-0.97) 0.93 (0.90-0.96) Confirmed FH mutation 32 (3.9%) 3 (1.1%) 0.28 (0.08-0.91) 0.16 (0.02-1.20) High-intensity statin 374 (45.8%) 162 (60.4%) 2.95 (1.69-5.15) 4.66 (2.15-10.1) Low/moderate-statin 333 (40.8%) 90 (33.6%) 1.84 (1.04-3.27) 2.29 (1.05-4.95) >1 lipid-lowering medication 407 (49.9%) 171 (63.8%) 1.77 (1.33-2.35) 1.88 (1.25-2.83) * Adjusted for untreated LDL-C, CHD, statin use, and use of >1 LDL-lowering medication † Median (IQR) shown. ‡ OR compared with no statin use.

Reduction in Treated LDL-C≥50%

Reduction in Treated LDL-C≥50% * Adjusted for current age, gender, untreated LDL-C, family history of premature MI, statin use, and use of >1 LDL-lowering medication † Median (IQR) shown. ‡ OR compared with no statin use.

Reduction in Treated LDL-C≥50% Characteristic ↓LDL-C<50% (N=386) ↓LDL-C≥50% (N=266) Unadjusted OR (95% CI) Adjusted OR (95% CI)* Age at enrollment, yrs 55 (40-65) 57 (45-66) 1.12 (1.02-1.23) 1.26 (1.09-1.45) Male 131 (34.0%) 117 (44.2%) 1.53 (1.11-2.11) 1.26 (0.82-1.94) Coronary heart disease 112 (29.0%) 89 (33.5%) 1.23 (0.88-1.72) 0.63 (0.39-1.02) Family history of early MI 152 (53.5%) 145 (71.1%) 2.13 (1.46-3.13) 1.90 (1.25-2.89) Diabetes 37 (9.7%) 28 (10.5%) 1.10 (0.65-1.84) 0.78 (0.38-1.60) Untreated LDL-C, mg/dl 230 (208-270) 265 (224-324) 1.10 (1.07-1.12) 1.06 (1.03-1.10) Confirmed FH mutation 10 (2.6%) 13 (4.9%) 1.93 (0.83-4.47) 0.71 (0.24-2.11) High-intensity statin 142 (36.8%) 170 (63.9%) 3.22 (1.34-7.74) 3.55 (1.26-9.99) Low/moderate-statin 177 (45.9%) 87 (32.7%) 1.77 (0.71-4.39) 1.83 (0.65-5.16) >1 lipid-lowering medication 150 (38.9%) 179 (67.3%) 3.24 (2.33-4.49) 1.79 (1.18-2.72) * Adjusted for current age, gender, untreated LDL-C, family history of premature MI, statin use, and use of >1 LDL-lowering medication † Median (IQR) shown. ‡ OR compared with no statin use.

Patient Reported Data

United States: Data from the CASCADE-FH Registry LDL-C Levels & Treatment Patterns Among Adults with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE-FH Registry BACKUP SLIDES

Study Design ‘Untreated’ LDL-C: highest documented values prior to initiation of drug therapy or occasionally when a patient was on a drug holiday ‘Treated’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry among patients on LDL-lowering medication(s) ‘Entry’ LDL-C: most recent values available at the time of inclusion into the CASCADE-FH Registry, regardless of treatment status

Study Design More details about analysis?

United States: Data from the CASCADE-FH Registry LDL-C Levels & Treatment Patterns Among Adults with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE-FH Registry Emil M. deGoma, MD University of Pennsylvania on behalf of the CASCADE-FH Registry

Study Objectives Describe clinical and lipid characteristics Assess treatment patterns and LDL-C values Characterize association between patient characteristics and prevalent CHD Quantify association between patient characteristics and LDL-C goal attainment, treated LDL-C<100 mg/dl or ↓LDL-C>50%

FH History Age at FH diagnosis, years, n=1232 47 (31-59) FH diagnosis before age 30, % 22 Age at initiation of LDL-lowering medication, years, n=677 39 (25-50) Medication before age 30, % 17 Family history of early MI, %, n=938 45

High Prevalence of CHD (US) Age 57 40 50 45 LDL-C 239 TC 402 224 256 134 - 172 116 *Prevalence of ASCVD. Stone Circ 1974;49:476. Hopkins Am J Cardiol 2001;87:547. Elis Am J Cardiol 2011;108:223.

Familial Hypercholesterolemia Foundation The FH Foundation is a patient-centered nonprofit organization dedicated to education, advocacy, and research of Familial Hypercholesterolemia

Cumulative LDL Exposure & CHD Baum J Clin Lipidol 2014;:542. Adapted from Horton JD, et al. J Lipid Res. 2009; 50 (Suppl):S172-S177.

CASCADE FH Registry data to: Evaluate trends in therapy clinical outcomes patient reported outcomes ___improve quality of lige, clinical outcomes, show gaps in care, costs in life years and productivity

Title Goes Here # of Enrolling Sites: 18 Total Patients Enrolled: 2561 CASCADE FH Registry # of Enrolling Sites: 18 9 sites in progress Total Patients Enrolled: 2561 # of Patients Enrolled via Patient Portal: 349 # of Patients Enrolled via Clinical Sites: 2212 R:1415 / P:797 Title Goes Here

CASCADE Site Enrollment Numbers

Limitations and Next Steps Limited generalizability based on 11 lipid centers Increase number of participating centers Leverage large electronic health databases Obstacles to optimal treatment remain unclear Update data fields to capture additional detail Cross-sectional study design Prospective follow-up is ongoing Our analysis of the diagnosis, management, and outcomes of adult FH patients from 11 lipid specialty centers may not be generalizable to the broader US FH population. To our knowledge, the only published study to examine FH patients in a community setting is a 2012 Danish analysis of 502 FH patients identified from the large Copenhagen General Population Study.2 Despite similar median untreated lipid levels, mean ages, and prevalence rates of CHD (Supplementary Table 2), the Danish cohort exhibited higher on-treatment LDL-C levels compared with the CASCADE-FH Registry (182 vs 134 mg/dl). This suggests that our findings restricted to experienced lipid clinics may well underestimate the existing treatment gap in the US. Increasing the number of institutions participating in the CASCADE-FH Registry (as of August 2015, 17 sites are actively enrolling) along with efforts to leverage large electronic health databases to identify patients with FH will yield more generalizable results. The latter approach, which includes the FH Foundation’s FIND (Flag, Identify, Network, Deliver) FH initiative and the Electronic Medical Records and Genomics (eMERGE) Network, may help identify a larger number and more diverse cohort of FH patients. While our study identified suboptimal use of high-intensity statin or combination therapy, the reasons for not pursuing these treatments, particularly in younger individuals, remain uncertain. Despite universal recommendations for statin therapy in adult FH patients,1, 3, 8, 10 1 out of 4 patients in our study were not taking statins at the time of registry enrollment, largely due to statin intolerance. The high proportion of statin non-users in the CASCADE-FH Registry may reflect referral bias to participating specialty lipid centers. Because of the cross-sectional nature of our data, associations between various characteristics and prevalent CHD or LDL-C goal attainment are hypothesis-generating and do not establish causality. Finally, despite the high prevalence of CHD at baseline, our data may in fact underestimate the burden of CHD among adults with FH due to survival bias.

Results: Diagnostic Criteria n = 876 US FH Patients Age (yrs) 53 (17) Female 57% BMI (kg/m2) 28(6) Ethnicity/Race 78% white 6% black 3% Hispanic 12% other Age at FH diagnosis (yrs) 43 (19) Prior CHD 38% Family history of MI 45% Tendon Xanthomas 18% Pre-treatment LDL-C (n = 444, mg/dL) 269 (87) Data shown as mean (SD) unless otherwise indicated BMI body mass index, FH familial hypercholesterolemia, CHD coronary heart disease, MI myocardial infarction, LDL-C low density lipoprotein-cholesterol

CASCADE FH Patient registry: Diagnostic criteria were divided into non-exclusive categories: “clinical diagnosis” MEDPED* Simon-Broome DLCN* other *MEDPED denotes Make Early Diagnosis, Prevent Early Death; DLCN Dutch Lipid Clinic Network