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Interpreting the ACC-AHA Guidelines on Cardiovascular Interpreting the ACC-AHA Guidelines on Cardiovascular Disease Prevention and Cholesterol ManagementDisease Prevention and Cholesterol Management
Nathan D. Wong, PhD, FACC, FAHANathan D. Wong, PhD, FACC, FAHAProfessor and DirectorProfessor and DirectorHeart Disease Prevention ProgramHeart Disease Prevention ProgramDivision of CardiologyDivision of CardiologyUniversity of California, IrvineUniversity of California, IrvinePast President, American Society for Preventive CardiologyPast President, American Society for Preventive Cardiology
DisclosuresDisclosures
Research contracts to institution from Amgen, Bristol Myers-Squibb, and Regeneron Research contracts to institution from Amgen, Bristol Myers-Squibb, and Regeneron
Consultant, Amgen and Re-Engineering Healthcare, Quinne ManuelConsultant, Amgen and Re-Engineering Healthcare, Quinne Manuel
Nov. 12, 2013Nov. 12, 2013
C-DAYC-DAY Cholesterol?Cholesterol?
Controversy?Controversy?
Confusion?Confusion?
Conundrum?Conundrum?
Courage…...?Courage…...?
I have some bad news for you. While your cholesterol has remained the same, the research findings have changed.
New CVD Prevention Guidelines
1)AHA/ACC Guideline on Cardiovascular Risk Assessment (November)2)AHA/ACC Guideline on Lifestyle Management (November)3)AHA/ACC Guideline on Obesity Management (November)4)AHA/ACC Guideline on Cholesterol Management (November)5)AHA Advisory on Blood Pressure Control (November)6)Guidelines on Hypertension by Members Appointed to JNC-8 (December)7)ASH/ISH Guidelines on Hypertension (December)
NHLBI Charge to the Expert Panel
Evaluate higher quality randomized controlled trial (RCT) evidence for cholesterol-lowering drug therapy to reduce ASCVD risk
Use Critical Questions (CQs) to create the evidence search from which the guideline is developed
• Cholesterol Panel: 3 CQs• Risk Assessment Work Group: 2 CQs• Lifestyle Management Work Group: 3 CQs
RCTs and systematic reviews/meta-analyses of RCTs independently assessed as fair-to-good quality
Develop recommendations based on RCT evidence
•Less expert opinion than in prior guidelines
Recommendation to begin with a global risk assessment using the Pooled Cohort Equations to
estimate 10-year ASCVD Risk(other risk assessment algorithms include the
European SCORE, PROCAM, or Framingham scores)
Preventive cardiology efforts begin with assessment of cardiovascular disease risk
Why Use Risk Scores?
1)Risk functions provide an “economic and efficient method of identifying persons at high cardiovascular risk who need preventive treatment….” (Kannel 1976)2)Intensity of treatment should match a person’s risk (ACC Bethesda Conf, JACC 1996).3)A physician’s estimate is only accurate 24% of the time (Pignone, 2003).4)Can be used to communicate risk in patients and motivate adherence to lifestyle and other therapies.5)Routine use of global risk scores leads to greater use of guideline-based therapy and improved outcomes (Sheridan, 2008).
Risk Category LDL-C GoalInitiate
TLCConsider
Drug Therapy
High risk: CHD or CHD risk equivalents (10-year risk >20%)
<100 mg/dL (optional goal:
<70 mg/dL)
100 mg/dL
100 mg/dL (<100 mg/dL:
consider drug Rx)
Moderately high risk: 2+ risk factors (10-year risk 10% to 20%)
<130 mg/dL (optimal <100
mg/dL)
130 mg/dL
130 mg/dL (100-129 mg/dL:
consider Rx )
Moderate risk: 2+ risk factors (risk <10%)
<130 mg/dL130 mg/dL
160 mg/dL
Lower risk: 0-1 risk factor
<160 mg/dL160 mg/dL
190 mg/dL
Adapted from Grundy SM, et al. Adapted from Grundy SM, et al. CirculationCirculation. 2004;110:227-239.. 2004;110:227-239.
ATP III Update ( 2004 )ATP III Update ( 2004 )
LDL-C Treatment Targets based on 10-year LDL-C Treatment Targets based on 10-year Hard CHD Risk from Framingham Risk ScoreHard CHD Risk from Framingham Risk Score
NHLBI charge to the workgroup: NHLBI charge to the workgroup: To Develop or To Develop or Recommend an Approach to Quantitative Risk Assessment Recommend an Approach to Quantitative Risk Assessment That Could be Used to Guide CareThat Could be Used to Guide Care
Risk Assessment Work Group judged new risk tool was Risk Assessment Work Group judged new risk tool was needed that was needed that was Inclusive of African Americans and with Inclusive of African Americans and with expanded endpoint including expanded endpoint including strokestroke
Sought cohorts representative of the U.S. population as a Sought cohorts representative of the U.S. population as a wholewhole• Community- or population-basedCommunity- or population-based• Whites and African Americans (at a minimum) Whites and African Americans (at a minimum) • Recent follow-up data of at least 10 yearsRecent follow-up data of at least 10 years
10-year follow-up from other ethnicities not available 10-year follow-up from other ethnicities not available at time of developmentat time of development
ASCVD Risk Calculator: Development
Pooled Cohort EquationsPooled Cohort Equations• Atherosclerosis Risk in Communities (ARIC)Atherosclerosis Risk in Communities (ARIC)• Cardiovascular Heath Study (CHS)Cardiovascular Heath Study (CHS)• Coronary Artery Risk Development in Young Adults Coronary Artery Risk Development in Young Adults
(CARDIA)(CARDIA)• Framingham Original and OffspringFramingham Original and Offspring
Hard ASCVDHard ASCVD• CHD death, nonfatal MI, fatal/nonfatal strokeCHD death, nonfatal MI, fatal/nonfatal stroke(but does not include angina, PCI/CABG or other CVD (but does not include angina, PCI/CABG or other CVD
such as HF or PVD)such as HF or PVD) Models tested using traditional RFs + newer markers Models tested using traditional RFs + newer markers
when possiblewhen possible Internal and external validationInternal and external validation
ASCVD Risk Calculator: Development (cont.)
Recommendations for Assessment of 10-Year Risk of a First Hard ASCVD EventThe race- and sex-specific Pooled Cohort Equations* to
predict 10-year risk of a first hard ASCVD event should be used in non-Hispanic African Americans and non-Hispanic whites, 40 to 79 years of age.
I IIa IIb III
I IIa IIb III Use of the sex-specific Pooled Cohort Equations for non-Hispanic whites may be considered for estimation of risk in patients from populations
other than African Americans and non-Hispanic whites.
*Derived from the ARIC study, CHS, CARDIA study, Framingham original and offspring cohorts.
2013 Prevention Guidelines 2013 Prevention Guidelines ASCVD Risk EstimatorASCVD Risk Estimator
ASCVD Risk EstimatorASCVD Risk Estimator
• Provides 10-year Provides 10-year ASCVD risk for those ASCVD risk for those 40-79 and lifetime risk 40-79 and lifetime risk for those 20-59for those 20-59
• This is intended to This is intended to drive discussions ofdrive discussions ofgreater adherence to greater adherence to heart-healthy lifestyleheart-healthy lifestyle
• Initiates risk Initiates risk discussion with patientdiscussion with patient
• Not an automatic Not an automatic prescription for a statinprescription for a statin
Recommendations for Use of Newer Risk Markers After Quantitative Risk
AssessmentIf, after quantitative risk assessment, a risk-based treatment decision is uncertain, assessment of ≥1 of the following—family history, hs-CRP, CAC score, or ABI—may be considered to inform treatment decision making.†
Routine measurement of carotid intima-media thickness is not recommended in clinical practice for risk assessment for a first ASCVD event.†
I IIa IIb III
†Based on new evidence reviewed during ACC/AHA update of evidence.
I IIa IIb III
No Benefit
If the risk decision is uncertain, the following factors can help inform the treatment decision and revise the risk estimate upward:
1)LDL-C ≥ 160 mg/dl2)Family hx premature ASCVD (prior CAD or stroke in male first degree relative age <55 or female first degree relative <65)3)Increased lifetime risk4)hs-CRP≥ 2 mg/L5)CAC score ≥ 300 or 75th%tile6)ABI < 0.9
Ankle- Brachial Index (ABI)Ankle- Brachial Index (ABI) Measure of lower-extremity Measure of lower-extremity
occlusive peripheral arterial diseaseocclusive peripheral arterial disease
Ankle SBP *Ankle SBP *
ABI < 0.90 is abnormalABI < 0.90 is abnormal
Sensitivity = 90% specificity= 98% for stenosis Sensitivity = 90% specificity= 98% for stenosis >> 50%. 50%.
Can detect asymptomatic diseaseCan detect asymptomatic disease..
Brachial Artery SBP
* dorsalis pedis or posterior tibial artery by doppler probe
ABI
ABI and Total Mortalty ABI and Total Mortalty (ABI Collaboration, JAMA 2008)(ABI Collaboration, JAMA 2008)
Coronary Calcium and Atherosclerosis: Coronary Calcium and Atherosclerosis: Pathology EvidencePathology Evidence
Coronary calcium invariably Coronary calcium invariably indicates the presence of indicates the presence of atherosclerosis, but atherosclerosis, but atherosclerotic lesions do not atherosclerotic lesions do not always contain calcium (1-3).always contain calcium (1-3).
Calcium deposition may occur Calcium deposition may occur early in life, as early as the early in life, as early as the second decade, and in lesions second decade, and in lesions that are not advanced (4-5).that are not advanced (4-5).
Correlates with plaque burden; Correlates with plaque burden; highly sensitive for angiographic highly sensitive for angiographic diseasedisease
1) Wexler et al., Circ 1996; 94: 1175-92, 2) Blankenhorn and Stern, Am J Roentgenol 1959; 81: 772-7, 3) Blankenhorn and Stern, Am J Med Sci 1961; 42: 1-49, 4) Stary, Eur Heart J 1990; 11(suppl E): 3-19, 5) Stary, Arteriosclerosis 1989; 9 (suppl I): 19-32.
Cumulative Incidence of Any Coronary Cumulative Incidence of Any Coronary Event: MESA Study Event: MESA Study
(Detrano et al., NEJM 2008)(Detrano et al., NEJM 2008)
Annual CHD Event Rates (in %) by Calcium Score Events by Annual CHD Event Rates (in %) by Calcium Score Events by CAC Categories in Subjects with DM, MetS, or Neither DiseaseCAC Categories in Subjects with DM, MetS, or Neither Disease
(Malik and Wong et al., Diabetes Care 2011)(Malik and Wong et al., Diabetes Care 2011)
Coronary Heart DiseaseCoronary Heart Disease
Coronary Artery Calcium ScoreCoronary Artery Calcium Score
ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in asymptomatic adults aged 40 and over with diabetes (Class IIa-B)asymptomatic adults aged 40 and over with diabetes (Class IIa-B)
0 1-99 100-399400+
Neither MetS/DM
MetSDM
0.4
1.5 1.9
4
0.20.8
2.1
3.5
0.1 0.41.3
2.2
00.5
11.5
22.5
33.5
4
Annual CHD Event Rate
Can Screening for Atherosclerosis Identify Those Most Likely to Benefit from Lipid-Lowering Therapy?
ACC/AHA 2013 Guideline: IIb-BACC/AHA 2013 Guideline: IIb-B
““..Assessing CAC is likely to be the most useful of the current approaches ..Assessing CAC is likely to be the most useful of the current approaches to improving risk assessment among individuals found to be at intermediate to improving risk assessment among individuals found to be at intermediate risk after formal risk assessment”risk after formal risk assessment”
2010 ACC/AHA Greenland et al. Risk Assessment
Intermediate Risk MESA Subjects
(n=1330)
C-statistics:
FRS alone 0.623FRS+CAC 0.784 (p<0.001)FRS+CIMT 0.652 (p=0.01)FRS+FMD 0.639 (p=0.06)FRS+CRP 0.640 (p=0.03)FRS+FamHx 0.675 (p=0.001)FRS+ABI 0.650 (p=0.01)
Yeboah J et al, JAMA 2012
dd
Lifestyle management remains the cornerstone for reducing cardiovascular disease risk including achieving and maintaining optimal risk factor levels
Critical Question: Among adults, what is the effect of dietary patterns and/or macronutrient composition on CVD risk factors, when compared to no treatment or to other types of interventions?
Consume a dietary pattern that emphasizes intake of Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils products, poultry, fish, legumes, nontropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened and nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats.beverages, and red meats.
• Adapt this dietary pattern to appropriate calorie Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions and nutrition therapy for other medical conditions (including diabetes).(including diabetes).
• Achieve this pattern by following plans such as the Achieve this pattern by following plans such as the DASH dietary pattern, the U.S. Department of DASH dietary pattern, the U.S. Department of Agriculture (USDA) Food Pattern, or the AHA Diet.Agriculture (USDA) Food Pattern, or the AHA Diet.
Advise adults who would Advise adults who would benefit from LDL-C or BP benefit from LDL-C or BP
lowering* to:lowering* to:I IIa IIb III
*Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering.
Lipids:Lipids:In general, advise adults to engage in aerobic In general, advise adults to engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3 physical activity to reduce LDL-C and non–HDL-C: 3 to 4 sessions a week, lasting on average 40 minutes to 4 sessions a week, lasting on average 40 minutes per session, and involving moderate- to vigorous-per session, and involving moderate- to vigorous-intensity physical activity.intensity physical activity.
BP:BP:In general, advise adults to engage in aerobic In general, advise adults to engage in aerobic physical activity to lower BP: 3 to 4 sessions a week, physical activity to lower BP: 3 to 4 sessions a week, lasting on average 40 minutes per session, and lasting on average 40 minutes per session, and involving moderate- to vigorous-intensity physical involving moderate- to vigorous-intensity physical activity.activity.
Physical ActivityPhysical Activity
I IIa IIb III
I IIa IIb III
Effect of cardiac rehabilitation in randomized controlled trials Effect of cardiac rehabilitation in randomized controlled trials following a MIfollowing a MI
Oldridge NB et al. JAMA 1988;260:945-950
*p<0.0125*p<0.0125
Cardiac Rehabilitation:Benefits Following a Myocardial Infarction (MI)
Cardiac rehabilitation reduces CV events after a MICardiac rehabilitation reduces CV events after a MI
CV=CardiovascularCV=Cardiovascular
0.76 0.75
1.15
0
0.5
1
1.5
All Cause Death CV Mortality Nonfatal Recurrence
Po
ole
d O
dd
s R
atio
** **
……even modest weight loss (3-5% of body weight) can result in clinically meaningful benefits for triglycerides, blood glucose, glycated hemoglobin, and development of diabetes (type 2)….
. Advise overweight and obese individuals who would benefit from weight loss to participate for ≥6 months in a comprehensive lifestyle program adhering to a lower-calorie diet and in increasing physical activity Prescribe on-site, high-intensity (i.e., ≥14 sessions in 6 months) comprehensive weight loss interventions provided in individual or group sessions by a trained interventionist (dietitian, exercise physiologist, etc.)
What’s New in the Cholesterol Guideline?
1)Focus on ASCVD reduction: 4 Statin Benefit Groups2)New Perspective on LDL-C and/or Non-HDL-C Treatment Goals3)Emphasis on the Clinician-Patient Risk Discussion4)Global Risk Assessment for Primary Prevention5)Safety Recommendations
Critical questions addressed the evidence for LDL-C and non-HDL-C goals primary and secondary prevention and the evidence for reduction in ASCVD events in relation to cholesterol lowering drugs available.
What’s Similar to ATP 3?What’s Similar to ATP 3?
Emphasis on lifestyle measures as crucialEmphasis on lifestyle measures as crucial Focus on treatment of LDL cholesterol Focus on treatment of LDL cholesterol
(LDL-C)(LDL-C) Greatest intensity of treatment for patients Greatest intensity of treatment for patients
at highest riskat highest risk Preference for statins over other Preference for statins over other
medications lowering LDL-C (although this medications lowering LDL-C (although this is greater in the new ACC/AHA Guideline)is greater in the new ACC/AHA Guideline)
4 Statin Benefit Groups4 Statin Benefit Groups
Clinical ASCVD* Clinical ASCVD*
LDL–C LDL–C >>190 mg/dL, Age 190 mg/dL, Age >>21 years21 years
Primary prevention – Diabetes: Age 40-75 years, LDL–C Primary prevention – Diabetes: Age 40-75 years, LDL–C 70-189 mg/dL70-189 mg/dL
Primary prevention - No DiabetesPrimary prevention - No Diabetes††: ≥7.5%‡ 10-year ASCVD : ≥7.5%‡ 10-year ASCVD risk, Age 40-75 years, LDL–C 70-189 mg/dL, risk, Age 40-75 years, LDL–C 70-189 mg/dL,
*Atherosclerotic cardiovascular disease†Requires risk discussion between clinician and patient before statin initiation.‡Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator.
These identified statin benefit groups to not imply that other groups (e.g., those outside the specified age ranges) will not benefit and should not be treated
Individuals Not in a Statin Benefit Group In those for whom a risk decision is uncertain: These factors may inform clinical decision making:
• Family history of premature ASCVD• Elevated lifetime risk of ASCVD• LDL–C ≥160 mg/dL• hs-CRP ≥2.0 mg/L• Coronary artery calcium (CAC) score
≥300 Agaston units• Ankle brachial index (ABI)<0.9
Their use still requires discussion between clinician and patient
Clinician - Patient Risk Discussion Clinician - Patient Risk Discussion Before Statin Rx Especially Primary Before Statin Rx Especially Primary
PreventionPrevention✔Estimate 10 yr
ASCVD Risk (when no CVD)Review other risk factors & risk factor control
✔Review potential for benefit from heart-healthy lifestyle / consider referral to dietitian and exercise physiologist
✔Review potential for - benefit from statins and
potential for adverse effects & drug-drug interactions
✔ Patient Preferences
*Factors if risk decision uncertain: LDL-C ≥ 160, family hx premature ASCVD, increased lifetime risk, hs-CRP≥ 2, CAC score ≥ 300 or 75th% , ABI < 0.9
Summary of Statin Initiation Recommendations to Reduce ASCVD Risk
(Revised Figure)
Summary of Statin Initiation Recommendations to Reduce ASCVD Risk
(Revised Figure)
That’s what it says “one tablespoon full 30 times a day”
Intensity of Statin TherapyIntensity of Statin Therapy
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response.
††Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.including rhabdomyolysis.
High- Moderate- and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)*
High-Intensity Statin TherapyModerate-Intensity Statin
TherapyLow-Intensity Statin
Therapy
Daily dose lowers LDL-C on average, by approximately ≥50%
Daily dose lowers LDL-C on average, by approximately 30% to <50%
Daily dose lowers LDL-C on average, by <30%
Atorvastatin (40†)-80 mgRosuvasatin 20 (40) mg
Atorvastatin 10 (20) mgRosuvastatin (5) 10 mgSimvastatin 20-40 mg‡Pravstatin 40 (80) mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg bidPitavastatin 2-4 mg
Simvastatin 10 mgPravastatin 10-20 mgLovastatin 20 mgFluvastatin 20-40 mgPitavastatin 1 mg
Targets?Targets?
LDL-C achieved mg/dL (mmol/L)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - PlaceboAFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - Placebo
CARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
40(1.0)
60(1.6)
80(2.1)
100(2.6)
120(3.1)
140(3.6)
160(4.1)
180(4.7)
Even
t ra
te (
%)
6
Secondary Prevention
Primary Prevention
Rx - Statin therapyPRA – pravastatinATV - atorvastatin
200(5.2)
PROVE-IT - PRA
PROVE-IT – ATV
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:e-version
TNT – ATV10
TNT – ATV80
LDL cholesterol and benefit in clinical trialsLDL cholesterol and benefit in clinical trialsIs lower better ?Is lower better ?
JUPITERJUPITER
TNTTNT
New Perspective on LDL–C & Non-HDL–C Goals
• Lack of RCT evidence to support titration of drug therapy to specific LDL–C and/or non-HDL–C goals
• Strong evidence that appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit
• Quantitative comparison of statin benefits with statin risk (evaluation of net clinical benefit)
• Nonstatin therapies – did not provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy
TNT: Primary Efficacy Outcome Measure: Major TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events*Cardiovascular Events*
** CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.fatal or nonfatal stroke.LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1430. 2005;352:1425-1430.
HR=0.78 (95% CI 0.69, 0.89); HR=0.78 (95% CI 0.69, 0.89); PP<.001<.001
Pro
po
rtio
n o
f P
atie
nts
Exp
erie
nci
ng
P
rop
ort
ion
of
Pat
ien
ts E
xper
ien
cin
g
Maj
or
Car
dio
vasc
ula
r E
ven
tM
ajo
r C
ard
iova
scu
lar
Eve
nt
00
0.050.05
0.100.10
0.150.15
Atorvastatin 10 mgAtorvastatin 10 mg
Atorvastatin 80 mgAtorvastatin 80 mg Relative Relative risk risk
reduction reduction
22% 22%
00 11 22 33 44 55 66Time (Years)Time (Years)
Mean LDL-C level = 77 mg/dL Mean LDL-C level = 77 mg/dL
Mean LDL-C level = 101 mg/dL Mean LDL-C level = 101 mg/dL
CTT Meta-analysis 26 TrialsCTT Meta-analysis 26 Trials
0.5 0.75 1 1.25 1.5
Statin/more better Control/less better
2.0
2,<2.5
2.5,<3.0
3,<3.5
3.5
Total
910 (14.7%)
1528 (14.0%)
1866 (12.4%)
2007 (12.3%)
4508 (13.0%)
10973 (13.0%)
1012 (16.4%)
1729 (15.9%)
2225 (14.7%)
2454 (15.2%)
5736 (16.5%)
13350 (15.8%)
0.78 (0.61 - 0.99)
0.77 (0.67 - 0.89)
0.77 (0.70 - 0.85)
0.76 (0.70 - 0.82)
0.80 (0.76 - 0.83)
0.78 (0.76 - 0.80)
46
No. of events (% pa)
Statin/more Control/less
2.0
2,<2.5
2.5,<3.0
3,<3.5
3.5
Total
704 (17.9%)
1189 (18.4%)
1065 (20.1%)
517 (20.4%)
303 (23.9%)
3837 (19.4%)
795 (20.2%)
1317 (20.8%)
1203 (22.2%)
633 (25.8%)
398 (31.2%)
4416 (22.3%)
0.71 (0.52 - 0.98)
0.77 (0.64 - 0.94)
0.81 (0.67 - 0.97)
0.61 (0.46 - 0.81)
0.64 (0.47 - 0.86)
0.72 (0.66 - 0.78)
2.0
2,<2.5
2.5,<3.0
3,<3.5
3.5
Total
206 (9.0%)
339 (7.7%)
801 (8.2%)
1490 (10.8%)
4205 (12.6%)
7136 (11.0%)
217 (9.7%)
412 (9.1%)
1022 (10.5%)
1821 (13.3%)
5338 (15.9%)
8934 (13.8%)
0.87 (0.60 - 1.28)
0.77 (0.62 - 0.97)
0.76 (0.67 - 0.86)
0.77 (0.71 - 0.84)
0.80 (0.77 - 0.84)
0.79 (0.77 - 0.81)
More vs less statin
Statin vs control
All trials
Relative risk (CI) permmol/L LDL-C reduction
99% or 95% CI
Proportional effects on MAJOR VASCULAR EVENTS Proportional effects on MAJOR VASCULAR EVENTS per mmol/Lper mmol/L LDL-C reduction, by baseline LDL- LDL-C reduction, by baseline LDL-
CC
Primary prevention 5 to <10% 5-year major CVD riskPrimary prevention 5 to <10% 5-year major CVD riskPer 1 mmol reduction LDL-C with a statin*Per 1 mmol reduction LDL-C with a statin*
*1 mmol/L (39 mg/dl) LDL-C reduction was the average in the primary prevention RCTs excluding JUPITERCTT Collaborators. Lancet 2012; 380: 581-590
• Significantly greater 34% reduction in relative risk of major CVD than higher risk groups
• 17% reduction in total mortality
Primary Prevention Statin TherapyPrimary Prevention Statin Therapy
Thresholds for initiating statin therapy derived Thresholds for initiating statin therapy derived from 3 exclusively primary prevention RCTsfrom 3 exclusively primary prevention RCTs Placebo group 10 yr event rates:Placebo group 10 yr event rates:
JUPITER – 7.6%; MEGA 5.1%; JUPITER – 7.6%; MEGA 5.1%; AFCAPS-TEXCAPS 6.9%AFCAPS-TEXCAPS 6.9%
Guideline Panel’s recommendation:Guideline Panel’s recommendation:As a matter of caution, to avoid over-treating, the As a matter of caution, to avoid over-treating, the
Panel identified those with risk ≥7.5% as a Panel identified those with risk ≥7.5% as a group in which statins provide benefit.group in which statins provide benefit.
Statins and Diabetes RiskStatins and Diabetes Risk
1) Meta-analysis of 170,255 patients from 76 randomized clinical trials show overall a 9% increased risk for development of incident diabetes among statin users (Sattar, Lancet 2010)
2) Increased risk of diabetes only seen in those with multiple risk factors; obesity, elevated triglycerides, glucose, and hypertension are more strongly related than statins to development of diabetes
3) Many persons on statins have pre-diabetes to begin with; statins may accelerate the progression to diabetes, but on average diabetes occurs 5 weeks later in those on placebo.
4) For every case of diabetes associated with statin use, approximately 5-9 cardiovascular events are prevented
5) Most experts contend the benefits outweigh the risks regarding increases in glucose / A1c.
A moderate intensity statin shows net clinical benefit down to a 10-year ASCVD risk of <5% where NNT is 60-<100 and NNT=100
A 7.5% 10-year ASCVD threshold provides net clinical benefit from NNT of 30 vs. NNH of 33.
Monitoring Statin Therapy: Lipid Monitoring Statin Therapy: Lipid Measurements Still RecommendedMeasurements Still Recommended
Adherence to medication and lifestyle, Adherence to medication and lifestyle, therapeutic response to statin therapy, and therapeutic response to statin therapy, and safety should be regularly assessed. safety should be regularly assessed. This This should also include a fasting lipid panel should also include a fasting lipid panel performed within 4 to 12 weeks after initiation performed within 4 to 12 weeks after initiation or dose adjustment, and every 3 to 12 months or dose adjustment, and every 3 to 12 months thereafterthereafter. Other safety measurements should . Other safety measurements should be measured as clinically indicated. be measured as clinically indicated.
I IIa IIb III
In individuals who have a less-than-anticipated In individuals who have a less-than-anticipated therapeutic response therapeutic response (>=50% on a high intensity (>=50% on a high intensity statin or 30-<50% on a moderate intensity statin)statin or 30-<50% on a moderate intensity statin) or or are intolerant of the recommended intensity of statin are intolerant of the recommended intensity of statin therapy, the following should be performed:therapy, the following should be performed:
Reinforce medication adherence.Reinforce medication adherence.
Reinforce adherence to intensive lifestyle changes.Reinforce adherence to intensive lifestyle changes.
Exclude secondary causes of hyperlipidemiaExclude secondary causes of hyperlipidemia..
I IIa IIb III
Insufficient Response to Statin Insufficient Response to Statin TherapyTherapy
In individuals at In individuals at higher ASCVD risk higher ASCVD risk receiving the receiving the maximum tolerated intensity of statin therapy who maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated continue to have a less-than-anticipated therapeutic response, therapeutic response, addition of a nonstatin addition of a nonstatin cholesterol-lowering drug(s) cholesterol-lowering drug(s) (ideally with proven (ideally with proven efficacy from clinical trials)efficacy from clinical trials) may be considered if may be considered if the ASCVD risk-reduction benefits outweigh the the ASCVD risk-reduction benefits outweigh the potential for adverse effects. potential for adverse effects.
Insufficient Response to Statin Insufficient Response to Statin Therapy May Warrant Non-Statin Therapy May Warrant Non-Statin
DrugDrug
Non-Statin Therapies
1)Ezetimibe –IMPROVE-IT showed additional risk reduction2)Bile Acid Resins3)Niacin (no benefit from AIM-HIGH and HPS2 TRIVE)4)Fibrates (Fenofibrate – no overall benefit from ACCORD Lipid Trial) 5)Therapies for HoFH (Lomitapide, Mipomersin)
Emerging Therapies in Development
1)CETP Inhibitors (Anacetrapib and Evacetrapib)2)PCSK9 Inhibitors
Patients stabilized post ACS ≤ 10 days:LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin 40 mg
Follow-up Visit Day 30, every 4 months
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to Simva 80 mg if LDL-C > 79(adapted per
FDA label 2011)
Improve-IT Study DesignImprove-IT Study Design
*3.2mM **2.6mM
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
90% power to detect ~9% difference
LDL-C and Lipid ChangesLDL-C and Lipid Changes
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 145.1 137.1 48.1 3.8
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
Median Time avg69.5 vs. 53.7 mg/dL
Primary Endpoint — ITTPrimary Endpoint — ITT
Simva — 34.7% 2742 events
EZ/Simva — 32.7% 2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke
7-year event rates
NNT= 50
6% relative risk reduction, but 2% absolute risk reduction
IMPROVE-IT: How Much Really is the IMPROVEment? Expert Analysis Dec 18, 2014
Nathan D. Wong, PHD, F.A.C.C.; Michael Blaha, MD, MPH- http://www.acc.org/latest-in-cardiology/articles
1) Provides the first evidence from a large-scale trial that additional lipid treatment beyond a statin provides further CVD event reduction in high-risk ACS patients 2) Involved exclusively high-risk persons with a recent ACS so may not apply to lower risk persons….implications of this trial beyond the study population should be generalized with caution. 3) A relative risk reduction of 6% (hazard ratio of 0.94) is not impressive, but the high baseline risk resulted in a reasonable NNT of 50; such added therapy is a reasonable option in high-risk ACS subjects 4) Not clear if patients starting at lower LDL-C levels (eg from a high intensity statin) would derive similar benefit
Management of Muscle Symptoms Management of Muscle Symptoms on Statin Therapyon Statin Therapy
• It is reasonable to evaluate and treat muscle symptoms including pain, cramping, weakness, or fatigue in statin-treated patients according to the management algorithm
• To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiating statin therapy
Management of Muscle Symptoms Management of Muscle Symptoms on Statin Therapy on Statin Therapy (con’t)(con’t)
If unexplained severe muscle symptoms or fatigue develop during statin therapy:•Promptly discontinue the statin •Address possibility of rhabdomyolysis with:
CK Creatinine urine analysis for myoglobinuria
Statin Assignment using the 2013 ACC/AHA Cholesterol Guideline Identifies More Persons with Significant CAD versus the 2001 NCEP ATP III Guideline (Johnson and Dowe, JACC 2014)
1)3,076 subjects studied who had CCTA plaque measured2)From the NCEP ATP III Guideline based on LDL-C thresholds for initiating statin use, 59% of subjects with >=50% left main stenosis and 40% with >=50% stenosis of other branches would not have been treated.3) Comparable numbers from the 2013 ACC/AHA Cholesterol Guideline were 19% and 10% 4)The use of targets in the NCEP ATP III caused many with significant stenosis not to be identified for treatment.
A 48 year old white woman with diabetes and microalbuminuria has a lipid panelTC 197; TG 300; HDL-C 42; LDL-C 95
Her BMI is 34; weight up 4 lbsSystolic BP 134. A1c 8.4%. Non-smoker
In addition to adherence to an optimal lifestyle what is the next step to reduce her risk for heart attack and stroke?
Question 1
A. Moderate intensity statin; no followup lipids needed
B. No need to use the risk estimator; she has diabetes
C. Moderate intensity statin, regular lipid follow-ups to determine adherence and response to therapy.
D. US guidelines don’t allow a non-statin to be added.E. Time spent on adherence not useful; missing 25% of doses per month not likely to affect potential for benefit
Question 1
Answer C. She’s in a statin “benefit” group.
Why not an LDL-C or non HDL-C? The evidence points to proper intensity of therapy
Why not high intensity statin therapy? She has only a 3.1% 10 year risk. Had she been a smoker, her risk would be 9.3%. Then appropriate measures to aid tobacco cessation as well as a more intensive dose of statin if tolerated would have been appropriate.Her A1c is elevated. Can a bile acid sequestrant be used? YesNon-statins can be used in any of the high risk groups if it is felt that optimal adherence to statin therapy gives a less than anticipated response.
Question 1
79 yo man had acute MI & received a stent to his LAD. Home on atorvastatin 40 mg daily &usual 2o prevention Rx TC 150; TG 150; HDL-C 45; LDL-C 75; Non HDL-C 105
Which of these is a true statement? A. Getting under 70 will provide an outcomes difference for him
B.Statin dose should be atorva 80 mg/day or rosuva 40 mg/d
C.Guidelines recommend lipids monitored periodically to assess adherence to statin/lifestyle; also for safety issues
D. No need to have lipids checked. It's a set it and go on strategy
Question 2
Answer is C. Since he is over 75, use of 40 mg atorvastatin would be reasonable, even though there is data to support high dose statin after age 75.
The issue of competing comorbidities, multiple medications, and greater potential for side-effects with a high-intensity statin affect the decision here. What is crucial is to monitor lipids periodically and discuss safety issues.
After checking lipids 4-12 weeks after the statin is started, they should be checked 3-12 months regularly with the interval dependent on how likely the patient is to have problems with adherence or safety issues
Question 2
60 yo overweight white man with diabetes and hypertension for past 10 years on metformin. He is a non-smoker. He comes in 25 minutes into an acute ST elevation anterior MI and has a PCI with a drug eluting stent placed in his LAD. His lipid panel on admission shows: TC 168 TG 220 HDL 30 LDL 94 His non HDL-C was 138. He was on simvastatin 10 mg daily.
Post MI, he is given aspirin, clopidogrel, lisinopril, and a long acting beta blocker. He is discharged on atorvastatin 20 mg daily. Four weeks later, his LDL-C has fallen to 70 mg/dl.
He has met LDL-C targets of <100 and 70 or less for primary and secondary prevention. Is his care optimal?
Question 3
An example of how fixed “targets” can give less than optimal Rx
Although he attained the LDL-C target of <100 mg/dl, he needed a higher intensity statin. When he had an LDL-C of 94, this 60 yo man with diabetes and hypertension should have been on a moderate intensity statin.
After an acute coronary event, he now merited as a first consideration, a high intensity statin. The evidence based choice is atorvastatin 80 mg daily. In the PROVE-IT trial, those with acute MI randomized to a high intensity statin (atorvastatin 80 mg/d)) had improvement in outcomes as compared to those on a moderate intensity statin (pravastatin 40 mg/d) Cannon C et al N Engl J Med 2004;350:1495-504.
Question 3
FH is more common than many well FH is more common than many well known genetic diseasesknown genetic diseases
• 1:300 – 1:500 worldwide
• Autosomal dominant• 620,000 FH patients in
US • Average LDL is 220
mg/dl• 20 fold increased risk
of coronary heart disease
• Causes 20% of MIs before age 45 and 5% before age 60
Hopkins et al. J. Clinical Lipidology. 2011Goldberg et al. J. Clinical Lipidology. 2011
FH exposes people to very high cholesterol from birth, thus reaching a threshold for CHD earlier in life
FH exposes people to very high cholesterol from birth, thus reaching a threshold for CHD earlier in life
Cumulative exposure (cholesterol yrs) by age:FH vs unaffected (healthy) individuals
Cumulative exposure (cholesterol yrs) by age:FH vs unaffected (healthy) individuals
Adapted from Horton et al. J Lipid Res. 2009;50:S172-S177
10
5
01 20 40 60 80
Age (years)
Cho
lest
erol
yea
r sc
ore
(g/d
L-ye
ars)
Threshold for CHD: reached by age 40 for those with HeFH and
age 20 for HoFH, > 70 yrs in healthy
individuals
Healthy individualsHeterozygous FH
Homozygous FH
Da Vinci’s Mona Lisa: FH ?Da Vinci’s Mona Lisa: FH ?
Xanthelasma ??? ???
Leonardo da Vinci, in addition to his art is famed for his remarkable efforts in scientific work including investigations of atherosclerosis. Indeed, careful clinical examination of the Mona Lisa reveals a yellow irregular leather-like spot at the inner end of the left upper eyelid and a well-defined swelling on the right hand beneath the index finger, probably signifying the first case of this disease.www.powerofthegene.com
Died in 1516 @ age 37 suddenly , cause unknown
FH is a “Winnable battle”
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
The FHF national patient registryThe FHF national patient registry
“What’s measured improves”Peter F. Druker
Long term goal is to have 90% of FH patients DIAGNOSED and TREATED
LDL ApheresisLDL Apheresis
FDA approvedFDA approved Dextran sulfate adsorption (DSA)Dextran sulfate adsorption (DSA) Heparin-mediated extracorporeal precipitation (HELP)Heparin-mediated extracorporeal precipitation (HELP)
60-80% LDL reduction60-80% LDL reduction
Largest observational study - 72% event reductionLargest observational study - 72% event reduction
Small RCTs- regressionSmall RCTs- regression
Potential vascular benefitsPotential vascular benefits Endothelial functionEndothelial function Reduction in inflammatory markers (CRP, VCAM, MCP-1)Reduction in inflammatory markers (CRP, VCAM, MCP-1)
Mehta P, Baer J, Nell C, Sperling LS. Current Treatment Options in CV Mehta P, Baer J, Nell C, Sperling LS. Current Treatment Options in CV Medicine 2009,11:279-288Medicine 2009,11:279-288
Plasma Line
LIPOSORBER®
Column
Plasma Pump
LDL apheresisLDL apheresis
Blood With
drawal
Blood Pump
Heparin Pump
Blood Return
PlasmaSeparator
RegenerationPump
Re-PrimingSolution
RegenerationSolution
Waste Line
s
Time averaged LDLTime averaged LDL
Time
LDL-C
Time Average
Diet Therapy
LIPOSORBER® Treatment
Pre
Post
Diet & Drug Therapy
Drug Lomitapide Mipomersen Proprotein convertase subtilisin/kexin type9
PCSK9 mAb
DeliveryOral (pill)
Injection (subq every week)
Injection (subq every 4 weeks)
Action MTP inhibitorAnti-sense ApoB oligonucleotide
Antibodies to PCSK9
LDL-C Effect in statin Rx HoFH
40-50% 25% 50-70%
Availability REMS* REMS* In research trials
Monitor Liver Ftn Tests Liver Ftn Tests
ConcernsHepatotoxicityDrug interactions
HepatotoxicitySite injection rxnFlu symptoms
Antibody development
Cost $300,000/pt/yr $300,000/pt/yr Not available
New Therapies to Lower LDL-CBeyond Underlying Statin Therapy (courtesy P. Wilson)
*REMS= Risk Evaluation and Mitigation Strategies
The Role of PCSK9 in the Regulation The Role of PCSK9 in the Regulation
of LDL Receptor Expressionof LDL Receptor Expression
For illustration purposes only
Impact of PCSK9 mAb Impact of PCSK9 mAb
on LDL Receptor Expressionon LDL Receptor ExpressionFor illustration purposes only
LAPLACE-2: LDL-C Response at Mean of Weeks LAPLACE-2: LDL-C Response at Mean of Weeks 10 and 1210 and 12
82All treatment differences versus placebo and ezetimibe were statistically significant (P<0.001). No notable differences were observed between the mean of weeks 10 and 12 and week 12 alone. LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly. Vertical lines represent 95% CIs.
Placebo Q2WPlacebo QM
Ezetimibe QD + Placebo Q2WEzetimibe QD + Placebo QM
Evolocumab Q2WEvolocumab QM
Evolocumab Q2W & QM: 63 to 75% reductions in LDL-C versus placebo Ezetimibe: 17 to 24% reductions in LDL-C versus placebo
Mea
n P
erc
ent
Ch
ang
e fr
om
Bas
elin
e i
n L
DL
−C
Atorvastatin 10 mg
Atorvastatin 80 mg
Rosuvastatin5 mg
Rosuvastatin40 mg
Simvastatin40 mg
GAUSS-2 in Statin Intolerant Pts: GAUSS-2 in Statin Intolerant Pts: Evolocumab Mean LDL-C % ChangeEvolocumab Mean LDL-C % Change
83
BL Week 2 Week 4 Week 6 Week 8 Week 10 Week 12
-80
Study drugadministrationBiweekly SC
-60
-40
-20
0
Day 1
Mea
n P
erc
ent
Ch
ang
e in
LD
L-C
fro
m B
ase
lin
e -18%
-56%
1: Ezetimibe (N = 51) 2: Evolocumab 140 mg Q2W (N = 103)
Study Week
Treatment Difference vs Ezetimibe
Average at weeks 10 and 12 -37%P<0.001At week 12 -38%
BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted.
1) High risk subjects for cardiovascular disease whose LDL-C was suboptimal despite maximally tolerated statin and/or other lipid-lowering therapy.
2) Follow-up: 78 weeks. Subjects (N=2,341) with LDL-C >70 mg/dL, 18% of whom had heterozygous familial hypercholesterolemia (HeFH)
3) Randomized to alirocumab 150 mg Q2W SC or matching placebo.4) Mean baseline LDL-C was 123 mg/dL and 122 mg/dL, respectively. The primary endpoint was
percent LDL-C reduction from baseline at 24 weeks.
28-36% of Guideline-Recommended Patients Not on Statins: ACC NCDR PINNACLE Registry (Maddox et al., JACC 2014)
Kaiser Permanente (KP) is utilizing the 2013 ACC/AHA Cardiovascular Risk and Cholesterol Guidelines in an effort to prevent more heart attacks and strokes
KP is pivoting from a focus on LDL <100 to an emphasis on statin use rates in members of the four statin benefit groups outlined in the new guidelines
August 2014 - KP Southern California (KPSC) region made available to providers at the point of care the ACC/AHA 10-year ASCVD risk estimator (A-Risk), with variables filled in automatically – A summary page of their electronic health record shows for example: "ASCVD risk 17%, start atorvastatin 40 mg daily…” also on the summary page is the last lipid panel result and date, and a medication list with dates of last refill
Pay for Performance? What Pay for Performance? What should we measure? should we measure?
On treatment LDL ? Should be be penalized if our patient does not reach On treatment LDL ? Should be be penalized if our patient does not reach LDL-C<100?LDL-C<100?
% reduction of LDL from baseline?% reduction of LDL from baseline?
Appropriate intensity of statin used?Appropriate intensity of statin used?
Meaningful discussion between clinician & patient (informed clinical decision Meaningful discussion between clinician & patient (informed clinical decision making)………making)………
NCQA will retire the measure focusing on LDL-C treatment targets in persons NCQA will retire the measure focusing on LDL-C treatment targets in persons with ASCVD and align with the latest guidelines focusing on statin therapy in with ASCVD and align with the latest guidelines focusing on statin therapy in patients with established ASCVD and not on LDL-C control or screening.patients with established ASCVD and not on LDL-C control or screening.
Synopsis of RecommendationsSynopsis of Recommendations
1. Encourage adherence to a healthy lifestyle (provide support 1. Encourage adherence to a healthy lifestyle (provide support for medical nutrition therapy and physical activity counseling)for medical nutrition therapy and physical activity counseling)
2. Statin therapy recommended for adult groups demonstrated 2. Statin therapy recommended for adult groups demonstrated to benefitto benefit
3. Statins have an acceptable margin of safety when used in 3. Statins have an acceptable margin of safety when used in properly selected individuals and appropriately monitoredproperly selected individuals and appropriately monitored
4. Engage in a clinician-patient discussion before initiating 4. Engage in a clinician-patient discussion before initiating statin therapy – especially for primary prevention in patients statin therapy – especially for primary prevention in patients with lower ASCVD risk – includes discussion of global risk with lower ASCVD risk – includes discussion of global risk reduction, benefits and risks of treatment, and patient reduction, benefits and risks of treatment, and patient preferencespreferences
Stone NJ, et al. Ann Int Med. 2014 [epub ahead of print]
Synopsis of RecommendationsSynopsis of Recommendations
5. Use the newly developed pooled cohort 5. Use the newly developed pooled cohort equations for estimation 10-year ASCVD riskequations for estimation 10-year ASCVD risk
6. Initiate proper intensity of statin therapy6. Initiate proper intensity of statin therapy
7. Evidence is inadequate to support treatment to 7. Evidence is inadequate to support treatment to specific LDL-C or non-HDL-C goalsspecific LDL-C or non-HDL-C goals
8. Regularly monitor patients for adherence to 8. Regularly monitor patients for adherence to lifestyle and statin therapylifestyle and statin therapy
Stone NJ, et al. Ann Int Med. 2014 [epub ahead of print]
ClinicalJudgment
“Evidence-Based” Not “Evidence-Bound”
Three Key Dimensions
“Evidence-Based” Not “Evidence-Bound”
Three Key Dimensions
Scientificevidence
Patient preference
“Clinical practice guidelines such as these should not take the place of sound clinical judgment. These guidelines should enable a discussion between a patient and their health care provider about the best way to prevent a heart attack or stroke, based on the patient’s personal health profile and their preferences”
John Gordon Harold, MD, MACC
ACC Past President
Thank You!
American Society for Preventive Cardiology: www.aspconline.org
UCI Heart Disease Prevention Program
www.heart.uci.edu
Microsomal Triglyceride Transfer Protein Microsomal Triglyceride Transfer Protein (MTP)(MTP)
• MTP is an intracellular lipid-transfer protein found in the lumen of the endoplasmic reticulum (ER) responsible for binding and shuttling individual lipid molecules between membranes1
• Normal concentrations and function of MTP are necessary for the proper assembly and secretion of apo B-containing lipoproteins in the liver and intestines2
1. Hussain M, et al. Journal of Lipid Research. 2003:44;22-32.2. Liao W, et al. Journal of Lipid Research. 2003:44;978-985.
Liver Cell
ER
Lumen
Cytoplasm
MTP
IntestinalEpithelial Cell
ER
Lumen
Cytoplasm
MTP
©2013 Aegerion Pharmaceuticals, Inc.
MTP Inhibitors – Mechanism of ActionMTP Inhibitors – Mechanism of Action
MTP inhibitorsMTP inhibitors1,2 1,2
Prevent the assembly of apo B-containing lipoproteins in hepatocytes Prevent the assembly of apo B-containing lipoproteins in hepatocytes and enterocytes. This inhibits the synthesis of VLDL and chylomicrons. and enterocytes. This inhibits the synthesis of VLDL and chylomicrons.
The inhibition of the synthesis of VLDL and intestinal chylomicron The inhibition of the synthesis of VLDL and intestinal chylomicron secretion lowers plasma lipids.secretion lowers plasma lipids.
1. Wetterau JR, et al. Science. 1998:282;751-754. 2. Hussain MM, et al. Nutrition Metabolism. 2012:9;14. ©2013 Aegerion Pharmaceuticals, Inc.
Phase 2 Study DesignPhase 2 Study Design
6 Patients
4 weeks 4 weeks 4 weeks
Key Inclusion Criteria:- Patients aged 18-40 yrs.- Clinical Diagnosis of HoFH and one of the following
- documented functional mutation in both LDL receptor alleles OR - skin fibroblast LDL receptor activity <20% normalOR - TC >500 mg/dl + TGs <300 mg/dl + both parents with TC >250mg/dl
4 weeks
Cuchel, M. et al. NEJM 2007; 356:148-56.
• Single arm, open label study• 16-week treatment duration - lomitapide as monotherapy (no background lipid-lowering
therapies)• Dose escalated from a low starting dose (mean doses at each of the four titration steps
were: 2.0, 6.7, 20.1, and 67.0 mg/day)• Low-fat diet (prescribed diet of <10% energy from fat)
Lomitapide0.03 mg/kg
Lomitapide 0.3 mg/kg
Lomitapide0.1 mg/kg
Lomitapide1.0 mg/kg Washout
4 weeks
©2013 Aegerion Pharmaceuticals, Inc.
Phase 2 HoFH Study: EfficacyPhase 2 HoFH Study: Efficacy51% Reduction in LDL-C51% Reduction in LDL-C
Cuchel, M. et al. NEJM 2007; 356:148-56.
51% Reduction
p<0.001
Mean Dose (mg): 2.0 6.7 20.1 67.0
©2013 Aegerion Pharmaceuticals, Inc.
Antisense Oligonucleotides and Antisense Oligonucleotides and Apo B Synthesis InhibitionApo B Synthesis Inhibition
Brautbar A and Ballantyne CM. Nat Rev Cardio 2011;8:253.
Mipomersen and LDL Lowering in Mipomersen and LDL Lowering in Homozygous FHHomozygous FH
Baseline LDL-C: 405 mg/dl
n=17n=34
Raal F. Lancet 2010;375:998-1006.
200mg SC/Q week