The State of Dyslipidemia Treatment

USA-145-101385 © 2014 Amgen Inc. All rights reserved. Not for Reproduction.

Table of Contents

Dyslipidemia

Dyslipidemia in Diabetes

Dyslipidemia in Familial Hypercholesterolemia

Dyslipidemia

Mean Blood Cholesterol in the United States Is Among Highest in the World

193 mg/dL

180–193 mg/dL

166 mg/dL

No data

167–179 mg/dL

WHO = World Health Organization. 1 mg/dL=0.0259 mmol/LAdapted from WHO, Mean Blood Cholesterol in Males over 25 Years of Age, 1980–2008. 1. World Health Organization. Global Health Observatory (GHO). World Health Organization website. www.who.int/gho/ncd/risk_factors/cholesterol_prevalence/en/. Accessed October 23, 2014.

Total Cholesterol Levels Increase During Development and Remain Higher Than Those in Hunter-Gatherer Populations

50

40

30

20

10

0

US

Po

pu

lati

on

(%

)

TC Level (mg/dL)2

80 120 160 200 240 280 320 360 400

Cholesterol levelsfor modern hunter-

gatherer populations range from:3 101 mg/dL–146 mg/dL

Distribution of Total Serum Cholesterol Levels in ~34,000 US Adults From NHANES III (1988–1994)

Developmental Period1

Birth Weaned

High fat

Low fat

Breast fed250

200

150

50

0

100

Pla

sm

a T

C (

mg

/dL

)

Fetal Nursing Infant Adult

Formula diet

TC Changes During Fetal Development Through Adulthood

Exact N is not available for Hunter-gatherer data, but is likely in the hundreds.

1. Adapted from Dietschy JM, et al. J Lipid Res. 2004;45:1375-1397. 2. Schwartz LM, Woloshin S. Eff Clin Pract. 1999;2:76-85. 3. Eaton SB, et al. Am J Med. 1988;84:739-749.

This information is meant to inform on levels at different stages of human development

1988-1994 1999-2002 2007-20100

50

100

150

129123

116

In utero (wk)1,c

n = 79

Infants (mo)2

n = 18

Adults (y)3,*

n = 8,174aFormula fed. bBreast fed. cUmbilical cord plasma concentrations*NHANES trends in mean LDL-C serum levels of US adult respondents from 1999-2006, estimates are age adjusted to the 2000 standard US population using the direct method. †Mean Age-adjusted LDL-C levels- approx. 15,000 US adults from NHANES (1988-2010)

1. Parker CR Jr, et al. Metabolism. 1983;32:919-923. 2. Wong WW, et al. J Lipid Res. 1993;34:1403-1411. 3. Cohen JD, et al. Am J Cardiol. 2010;106:969-975. 4. Carroll MD, et al. JAMA. 2012;308:1545-1554

33–34 41–42 4–5 4–5 20–39 40–59 60–740

50

100

150

49

28

48

83

113

124 123

Mea

n L

DL

-C (

mg

/dL

)

Mean LDL-C by Age

LDL-C Levels Rise After Adulthood and Remain Higher Than Those in Early Development

b

Age:

Average LDL-C Levels in the US

Years4,†

a

LD

L-C

(m

g/d

L)

Clinical Guidelines Recommend LDL-C Lowering

1. American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S80. 2. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78. 3. Grundy SM, et al. J. Clin Lipidol. 2013;8:29-60. 4. Reiner Z, et al. Eur Heart J. 2011;32:1769-1818. 5. Stone NJ, et al. J Am Coll Cardiol. 2014;63:2889-2934. 6. Keaney JF, et al. N Engl J Med. 2014;370:275-278.

ADA = American Diabetes Association; AACE = American Association of Clinical Endocrinologists; IAS = International Atherosclerosis Society; ESC = European Society of Cardiology; EAS = European Atherosclerosis Society; AHA = American Heart Association; ACC = American College of Cardiology

AACE Guidelines2

Targets LDL-C level

Targets statin

therapy intensity

ADA Recommendations1

AACE Guidelines2

IASRecommendations3

ESC/EASGuidelines4

ACC/AHAGuidelines5,6

When Compared to Adult Treatment Panel III LDL-C Goals, ~ 48 Million American Adults With High LDL-C Were Not Treated or Not Adequately Treated

71 mil-lion

(33.5%) have high

LDL-C†

66.5% at LDL-C goal levels

without cholesterol-

lowering med-ication†

37 millionare untreated

23 million were treated and at goal‡

11 million were treated, but not at goal‡

Prevalence, Treatment, and Control of LDL-C Based on NHANES 2005-2008*

*Extrapolated from data from 3,996 adults with high LDL-C aged ≥ 20 years in the National Health and Nutrition Examination Survey (NHANES) 2005-2008.†High LDL-C defined as > 160 mg/dL for low-risk adults; > 130 mg/dL for moderate-risk adults; and > 100 mg/dL for high-risk adults or the use of cholesterol-lowering medication. ‡Adult Treatment Panel (ATP) III LDL-C goals: < 160 mg/dL for low-risk adults; < 130 mg/dL for moderate-risk adults; and < 100 mg/dL for high-risk adults.Kuklina EV, et al. Morbidity and Mortality Weekly Report. 2011;60:109-114.

US Adult Population US Adults With High LDL-C

0%

20%

40%

60%

80%

100%

18%

25%

38%

51%

74%

86%

A Substantial Percentage Do Not Achieve LDL-C < 70 mg/dL Despite Maximal Statin Therapy

Individual patient data pooled meta-analysis, N=32,258 of 37 studies, comparing efficacy of various statins in At Risk Groups (VOYAGER).  On multivariate analysis, baseline lipid level (p < 0.0001) and increasing statin dose (p < 0.0001) were strong predictors of achieving treatment goals in high risk patients.  Studies were identified by a comprehensive search of the Cochrane Controlled Trials Registry, Medline (1999-2007), EMBASE (1999-2007) Citeline Trialtrove, and collection of all published research. Maximal intensity included average between two high dose groups of †20 and 40 mg of statin 1 and ‡40 and 80 mg of statin 2. High dose statin per ACC/AHA guidelines = statin 2, 40-80 mg; statin 1, 20-40 mg.

1. Nicholls SJ, et. al. Am J Cardiol. 2010; 105:69-76. 2. Stone NJ, et al. J Am Coll Cardiol. 2014;63:2889-2934.

LD

L-C

> 7

0 m

g/d

L

< 130 mg/dL 130-160 mg/dL > 160 mg/dL

While on Maximal Statin Therapy The Percent of Patients Not Achieving LDL-C < 70 mg/dL By Baseline LDL-C

Maximal Intensity† (20 and 40 mg) of Statin 1

Maximal Intensity‡ (40 and 80 mg) of Statin 2

Baseline LDL-C

Number of High Risk US Adults Achieving LDL-C Levels of < 100 mg/dL or LDL-C Levels of < 70 mg/dL, Respectively

NHANES Administrativeclaims data

EMR NHANES Administrative claims data

EMR0

10

20

30

40

50

60

70

80

90 At goal Not at goal

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

Per

cen

t o

f To

tal

Jones, PH, et al. J Am Heart Assoc. 2012;1:e001800.

High-risk patients were defined as patients older than 18 years with a history of CHD or CHD risk equivalent who had the latest complete lipid panel measurement and were treated with statin monotherapy for > 90 days.EMR = electronic medical record database collected from 40,000 clinicians and 20,000 NP and PA (GE Centricity); Administrative Claims Database of the medical and pharmacy claims for 42MM patients enrolled in a large US managed care plan (Clinformatics DataMart, a product of Optuminsight Life Sciences); NHANES=National Health and Nutrition Examination Survey, a national public health survey conducted by the CDC of a nationally representative sample of 5000 individuals each year across a country.As per NCEP ATP III, the LDL-C goal patients was <100 mg/dL. High-risk patients were also evaluated for the optional goal of LDL-C <70 mg/dL, as per the 2004 update to the NCEP ATP III Guidelines.

Multiple Causes Exist For Failure To Achieve Desired LDL-C• Patients with very high baseline1

• Adherence difficulties2

• Inability to tolerate optimal therapy3

• Limited access to optimal therapy1,4

• Insufficient/limited access to screening5

• Other causes

1. Pijlman AH, et al. Atherosclerosis. 2010;209:189-194. 2. National Cholesterol Education Program (NCEP). Circulation. 2002;106:3143-3421. 3. Cohen JD et al. J Clin Lipidol. 2012;6:208-215. 4. Elis A, et al. Am J Cardiol. 2011;108:223-226. 5. Kuklina EV, et al. CDC Morbidity and Mortality Weekly Report. 2011;60:109-114.

Dyslipidemia in Diabetes

2009-2010 NHANES Data Show Those With Diabetes Are NOT Achieving Desired Lipid Levels

Wong ND, et al. Am J Cardiol. 2013;112:373-379.

Dia

bet

es

Po

pu

lati

on

NO

T

Ach

iev

ing

Des

ire

d L

eve

ls (

%)

LDL cholesterol goal: <70 mg/dL if CHD; <100 mg/dL if > 2 risk factors and Framingham risk score >20% or other previous CVD, diabetes, or chronic kidney disease; <130 mg/dL if 2 risk factors or Framingham risk score 10% to 20%; <160 mg/dL if <2 risk factors and Framingham risk score <10%. Risk factors include age, low HDL cholesterol, hypertension, smoking, and family history. HDL cholesterol normal levels: >40 mg/dL in men and >50 mg/dL in women. Triglyceride normal level: <150 mg/dL.

HDL-C TGs LDL-C0%

10%

20%

30%

40%

50%

60%

70%

39% 41%

61%

A Substantial Number of People With Diabetes Have High LDL-C

57%

43%

28%

72%

< 100 mg/dL LDL-C

> 100 mg/dL LDL-C

< 70 mg/dL LDL-C

> 70 mg/dL LDL-C

Individuals With DiabetesIndividuals With Diabetes

and Cardiovascular Disease

Ali MK, et al. N Engl J Med. 2013; 368:1613-1624.

Data shown are from 3,355 adults in the National Health and Nutrition Examination Survey (NHANES) with a diagnosis of diabetes from a health care professional, and 97,310 adults who reported having diabetes from the Behavioral Risk Factor Surveillance System (BRFSS) survey. Data is from 2007-2010.

(P<0.001)

Dyslipidemia in Familial Hypercholesterolemia

Familial Hypercholesterolemia Phenotypes

FH Heterozygotes FH Homozygotes

~ 1 in 200 to 1:500 persons worldwide1,4 ~ 1 in 1,000,000 persons worldwide1

1 mutated allele1 2 mutated alleles1

TC: 350 to 500 mg/dL3 TC: > 500 to > 1,000 mg/dL1

LDL-C: 200–400 mg/dL1,2 LDL-C: > 600 mg/dL2

Half the number of LDLR expressed3 LDLR activity absent or dysfunctional3TC = total cholesterol

1. Rader DJ, et al. In: Longo DL, et al, eds. Harrison’s Principles of Internal Medicine. Vol II.18th ed. New York, NY: McGraw Hill Medical. 2012:3145-3161. 2. Robinson JG. J Manag Care Pharm. 2013;19:139-149. 3. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation. 2002;106:3143-3421.4. Nordestgaard BG, et al. European Heart Journal. 2013;34:3478–3490.

Familial Hypercholesterolemia

Mother Father

X

Offspring

FH Heterozygotes FH Homozygote

Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438. Nordestgaard BG, et al. European Heart Journal. 2013;34:3478–3490.

• 1 in 200 to 1:500 in most populations• Half-normal number of LDL receptors• 2-fold increase in plasma LDL

• 1 in 1 million population• Absent or dysfunctional LDL receptors• 6- to 10-fold increase in plasma LDL

67%LDLR

16.7%Others

2.3%PCSK9

14%ApoB

*Autosomal Dominant Hypercholesterolemia. LDLR = LDL receptor; PCSK9 = Proprotein Convertase Subtilisin Kexin Type 9; ApoB = apolipoprotein B Seidah NG, et al. J Mol Med. 2007;85:685-696.

Multiple Genetic Defects Causing Changes in Lipoprotein Metabolism Can Be Associated With Familial Hypercholesterolemia (FH)*

Nordestgaard BG, et al. European Heart Journal. 2013; 34: 3478-3490

Diagnosis of FH in the US is Approximately <1% of Estimated Prevalence

Estimated percent of individuals diagnosed with FH in different countries/territories*

*As a fraction of those theoretically predicted based on a frequency of 1/500 in the general population.  As most countries do not have valid nationwide registries for FH, several values represent informed estimates from clinicians/experts in their respective countries.

Despite Maximal Treatment, A Low Percentage of Patients with HeFH Achieve LDL-C < 100 mg/dL

*NCEP Adult Treatment Panel III Risk Category: Medium Risk: <130 mg/dL (3.4 mmol/L); ≥ 2 risk factors,10-year risk of coronary artery disease ≤ 20%; High Risk: <100 mg/dL (2.6 mmol/L); coronary artery disease or its risk equivalents (atherosclerosis, diabetes, or 10-year risk > 20%).18 week RCT, double-blind parallel group where heterozygous (He) FH patients initiated statin treatment at 20 mg with forced titration to 40 and 80 mg in 1999-2000. N = 623 randomized; p Values were obtained from a logistic regression model . Global population consisted of 31% US patients.**Adults with HeFH were part of a cross-sectional study. 96% were on statin treatment where 34% were on maximum dose. N = 1249 met inclusion criteria. n = 304 patients on maximal therapy; Maximum lipid-lowering therapy was defined as maximum statin doses in combination with ezetimibe. Using outpatient visits to Lipid Clinics after February 2006.

1. Stein EA, et al. Am J Cardiol. 2003; 92:1287-1293. 2. Pijlman AH, et al. Atherosclerosis. 2010; 209:189-194.

In Netherlands Estimates of HeFH Patients On Maximal Lipid Lowering Therapy Achieving

LDL-C < 100 mg/dL**

In a Randomized Global Clinical Trial of HeFH Patients, A Low Percentage Achieved LDL-C Levels

of < 100 mg/dL on Maximal Treatment*

<130 mg/dL <100 mg/dL0%

20%

40%

60%

80%

100% < 100 mg/dL> 100 mg/dL

% o

f P

atie

nts

Ach

ievi

ng

LD

L-C

Go

al

Per

Ris

k C

ateg

ory

Statin 1Statin 2

†p < 0.05, n = 103

n = 37

n = 67

‡p < 0.001, n = 155

14%

86%