th annual orange county symposium for cardiovascular...
TRANSCRIPT
Objectives
• Review characteristics of the highest
risk patients;
• Identify therapeutic ‘targets’
• Review contemporary ‘goals’ of therapy
12th Annual Orange County Symposium for Cardiovascular Disease Prevention:
Crossroads in Cardiovascular Disease Prevention
EXTREMEASCVD Risk
Management:
Paul D. Rosenblit MD
Emphasis on the
Fundamental Causal
Lipoprotein Particles
Paul D. Rosenblit MD, PhD, FACE, FNLA
Private Practice, Director, & Principal Investigator,
Diabetes/Lipid Management & Research Center
Huntington Beach, CA
Volunteer Clinical Faculty
Clinical Professor of Medicine
(Division Endocrinology, Diabetes & Metabolism)
University of California, Irvine
Co-Director, Diabetes Out-Patient Clinic,
UCI Medical Center, Orange, CA
Faculty Disclosures*
Dr. Paul D. Rosenblit reported the following relevant financial
relationships with commercial interests:
Speaker / Teaching Faculty: Amarin, Amgen, Merck, Esperion
Clinical Research Site Trials: Dexcom, Ionis(Akcea), Lilly, Mylan,
Novo Nordisk, Novartis
Advisory / Consultant: Amarin
* 12 months: July 1, 2019 – June 30, 2020
Management of ‘EXTREME Atherosclerotic
Cardiovascular Disease (ASCVD) Risk
Atherosclerosis Timeline
Modified from Pepine CJ. Am J Cardiol. 1998; 82(suppl.10A):23S-27S
Lesion Growth from Lipid Accumulation
Smooth muscle, collagen
Calcification
ASCVD
Coronary Artery Disease
Carotid Artery Plaque
Atherosclerotic Aortic
Aneurysm
Peripheral Artery Disease
Renal Artery Stenosis)
Thrombus,
hematoma
Inflammation
ASCVD Events
TIA, Angina
Revascularization
(Ischemic HF)
“Hard Events”
Myocardial
Infarction
Ischemic Stroke
CV DeathWilliams MC, Kwiecinski J, Doris M, et al. Low-attenuation noncalcified plaque on coronary computed
tomography angiography predicts myocardial infarction: results from the multicenter SCOT-HEART trial
(Scottish Computed Tomography of the HEART). Circulation 2020;141:1452–1462.
Who?
Subsequent
Event
Majority of Lesions Progressing to Myocardial Infarction are
Non-Obstructive (<70% Stenosis)
Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92(3):657671. doi: 10.1161/01.cir.92.3.657.
FOURIER: Further Cardiovascular OUtcomes Research with PCSK9
Inhibition in Subjects with Elevated Risk: Baseline Characteristics
Characteristic Value
Age, years, mean (SD) 63 (±9)
Male sex 75%
Type of cardiovascular disease
Myocardial infarction 81%
Stroke (non-hemorrhagic) 19%
Symptomatic PAD 13%
Cardiovascular risk factor
Hypertension 80%
Diabetes mellitus 37%
Current cigarette use 28%
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. for the FOURIER Steering Committee and Investigators.
Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22.
https://doi.org/10.1056/NEJMoa1615664.
Inclusion criteria: All patients with established ASCVD on statin therapy
Characteristic Percent
Statin use
High Intensity 69%
Moderate intensity 31%
Low intensity 0.3%
Cardiovascular medicines
ASA, P2Y12 inhibitor or both 92%
Beta Blocker 76%
ACE inhibitor or ARB,
Aldosterone antagonist, or both
78%
FOURIER Further
Cardiovascular OUtcomes
Research with
PCSK9 Inhibition in
Subjects with Elevated Risk
3-Point Composite
‘Hard Outcomes’
(CV Death, Non-
Fatal MI, or Non-
Fatal Stroke)
5-Point Composite
CV Death, Non-
Fatal MI, or Non-
Fatal Stroke,
hospitalization for
unstable angina, or
coronary
revascularization.
FOURIER: Placebo Risk of the Key Secondary Endpoint [3-Point Composite
‘Hard Outcomes’ (CV Death, Non-Fatal MI, or Non-Fatal Stroke)] by Diabetes Status
Extrapolated
10-year risk
40.8%
Median F-U 2.2-yrs
Kaplan-Meier 3-yrs
28%
FOURIER
Inclusion criteria:
1.Clinical ASCVD
2. Max-tolerated
statin
3. Other standard-
of-care pillars of
therapy.
Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, Murphy SA, Kuder JF,
Gouni-Berthold I, Lewis BS, Handelsman Y, Pineda AL, Honarpour N, Keech AC, Sever PS, Pedersen TR.
Lancet Diabetes Endocrinol. 2017 Dec;5(12):941-950. doi: 10.1016/S2213-8587(17)30313-3.
FOURIER: 3-Year Kaplan-Meier 3-Point ASCVD Composite**
Secondary End-Point Outcome [CV Death, Non-Fatal MI, or Non-Fatal Stroke]CRPCKD
Charytan et al. JACC. 2019; 73(23):2961-2670
10.8
9.3
15
8.2
12.6
8.97.9 8.3
12.4
6.6
9.2
7.8
0
2
4
6
8
10
12
14
16
MI <2 yearsago
MI >2 yearsago
>=2 MIs 1 prior MI MultivesselDisease
No MVD
Placebo Evolocumab
Sabatine MS, et al. Circulation. 2018;138:756-766. Bohula ER, et al. Circulation. 2018;138:131–140.
13
7.6
9.5
6.2
0
2
4
6
8
10
12
14
PAD No PAD
Placebo Evolocumab
HR 0.73
(0.59–0.91)
P= 0.004
HR 0.57
(0.38–0.88)
P= 0.0095
PAD
Bonaca MP, et al. Circulation. 2018;137:338–350.
12.2
8.4
10.2
6.2
0
2
4
6
8
10
12
14
Diabetes No Diabetes
Placebo Evolocumab
HR 0.82
0.72–0.93
p=0·0021
HR 0·78
0.69–0.89
p=0·0002)
Sabatine MS, et al. Lancet Diabetes Endocrinol. 2017;5:941-950
Diabetes
MI Proximity Multivessel Disease
10-Year Risk* of 3-Point Composite** Secondary End-Point Outcome
[CV Death, Non-Fatal MI, or Non-Fatal Stroke]
3026
5026
3236
29.642
3547
6829
3728
40.628
36.324
2643
2530
44
0 10 20 30 40 50 60 70 80
Entire Cohort
Hx MI x1
Hx 2 or more MIs
MI, >2 yrs
MI, <2 yrs
MI, <1 yrs
no MVD
Multi-Vessel Disease
Prior Hx MI or stroke
PAD
PAD + MI or stroke
Lp(a) <37
Lp(a) >37
no DM
DM
No Metsyn
MetSyn
no CKD
CKD 2
CKD 3
hsCRP <1
hsCRP 1-3
hsCRP >3 10-Year Risk 2017 AACE
Dyslipidemia Guideline
Low <5%
Moderate 5-10%
High >10-20%
Very-High >20-30%
Extreme >30%
** 10-Year 3-Point Composite MACE Risk(%): Low Moderate High Very High Extreme
FOURIERInclusion criteria
Clinical ASCVD
Rosenblit PD. Extreme atherosclerotic cardiovascular disease (ASCVD) risk recognition.
Current Diabetes Reports. August 2019;19(8):61. https://doi.org/10.1007/s11892-019-1178-6.* Extrapolated
Dreadfully Extreme
Very Extreme
HorrificallyExtreme
FOURIER Analyses: Extrapolated 10-Year 3-Point MACE Composite
(CV death, Nonfatal MI or NonFatal Stroke) Placebo Event Incidence
Inclusion Criteria: All with Hx of ASCVD (MI, or stroke, or PAD)Very High (>20%) Extreme Very
Extreme
Dreadfully
Extreme
Horrifically
Extreme
10-Year 3-Point MACE: >20-30% >30-40% >40-50% >50-60% >60%
Entire Cohort (30.4%)
CRP <1 CRP 1-3 CRP >3
No CKD, CKD stage 2 CKD stage 3
No MetSyn MetSyn
No DM DM
Lp(a) <37 Lp(a) >37
PAD PAD + (MI or Stroke)
Prior MI or Stroke
No Multivessel Disease Multivessel Disease
Hx MI >2 yrs ago Hx MI <2yrs, <1yr
Hx MI x1 Hx ≥2 MIs
Extremely High-, Very High-, and High-risk Patients
Despite Maximally-Tolerated Statin Therapy
High Risk Very High Risk Extremely High Risk
~20% 10-y ASCVD risk 30%-40% 10-y ASCVD risk >45% 10-y ASCVD risk
CVD or FH, but no RFs CVD+ or FH + Risk factors CVD++
CVD with well-controlled CV risk
factors
CVD + diabetes
(no polyvascular disease)
CVD + FH
FH age 40-75 y, no RFs
or well-controlled CV risk factors
CVD + CKD
(excluding hemodialysis)
CVD + Polyvascular disease
CVD + PAD
Acute coronary syndromes (ACS) CVD + Recurrent CVD events
CVD + poorly controlled risk
factors
FH (age 40-75 y) + poorly
controlled CVD risk factors
Robinson JG, Watson KE. Identifying Patients for Nonstatin Therapy. Rev Cardiovasc Med. 2018;19(S1):S1-S8.
ASCVD = Atherosclerotic Cardiovascular Disease
CVD = Cardiovascular Event
FH = Familial Hypercholesterolemia
CKD = Chronic Kidney DiseaseCV RF = Risk Factor
ACS = Acute Coronary Syndrome
PAD Peripheral Artery Disease
Abnormal Lipid
Metabolism
LDL
ApoB
HDL
Triglycerides
Cardio-Renal
Metabolic Risk[Global Risk: ASCVD /
Diabetes / CKD / ESKD /
Heart Failure / Dysrhythmia
All-Cause Mortality]
Overweight / Obesity
Inflammation
Hypertension
Smoking
Physical Inactivity
Unhealthy Eating
Age, Race,
Gender,
Family History
Modified from
Brunzell JD, Davidson MH, Furberg CD, Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL;
American Diabetes Association; American College of Cardiology Foundation.
Diabetes Care. 2008;31(4):811-822 and JACC. 2008;51(15):1513-1524.
Adequately Manage the Cardio, Metabolic, Renal, ±Diabetology:
Risks and Sources of ‘Residual’ Risks
• LDL-C
• TG-rich
remnant Lp-C
• Lp(a)GlucoseBP Lipids
Age Genetics
Insulin ResistanceInsulin Resistance Syndrome
Hypercoagulation
Lipoprotein Sub-Classes
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 801000
Chylomicron
Remnants
VLDL
LDL
HDL2
HDL3
Particle Size (nm)
Density
(g/ml)
Chylomicron
VLDL
Remnants
Lp(a)
IDL
Directly atherogenic
(found in plaque)
pre-β2 HDLpre-β1 HDL
Adapted from
Austin MA, King MC, Vranizan KM, Krauss RM. Circulation. 1990;82(2):495-506.
LDL Fractionation via Gradient
Gel Electrophoresis
High Triglycerides Are
Associated with
LDL Subclass Pattern B,
Elevated Apo B, and
TG-Rich Remnant Cholesterol
(large VLDL, IDL)
Krauss RM, Burke DJ. Identification of multiple subclasses of
plasma low density lipoproteins in normal humans.
J Lipid Res. 1982;23(1):97-104.
Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC,
Krauss RM. JAMA. 1988;260(13):1917-21.
Framingham Offspring Study: Nuclear Magnetic Resonance, NMR,
Spectroscopy, LDL Particle Numbers (LDL-P) & LDL Cholesterol (LDL-C):
Relationships to Levels of HDL Cholesterol and Triglycerides
Cromwell WC, Otvos JD. Curr Atheroscler Rep. 2004;6(5):381-87.Modified from
Otvos JD, Jeyarajah EJ, Cromwell WC et al. Am J Cardiol. 2002;90(suppl):22i–29i
discordance discordanceconcordance concordance
concordance
discordance
Cromwell WC, Otvos JD, Keyes MJ et al. J Clin Lipidol. 2007;1(6):583-592. Otvos JD, Mora S, Shalaurova I et al. J Clin Lipidol. 2011;5(2):105-13
Framingham Offspring Study (n=3,066) Multi-Ethnic Study of Atherosclerosis, MESA
CHD Event Associations of LDL Particle Numbers (LDL-P) Versus
LDL Cholesterol Content (LDL-C): Concordance and Discordance
Cardiovascular Events in TNT Trial
According to Number of Metabolic Syndrome Components
Deedwania P, Barter P, Carmena R, Fruchart J-C, Grundy SM, Haffner S, Kastelein JJP, LaRosa JC, Schachner H, Shepherd J,
Waters DD. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome:
analysis of the Treating to New Targets study. The Lancet. 2006;368(9539):919–928.
5.3
8.5 8.6
11.5
13.1
17
7.2 7
8.2 8.1
10.3
11.8
0
6
12
18
0 1 2 3 4 5
Atorva 10 Atorva 80
Patients
With
Major
CV
Events*,
%
Number of Metabolic Syndrome Components
Metabolic Syndrome
Components
BP >130/85
FBG ≥100 mg/dL
Fasting TG ≥150 mg/dL
HDL-C
<40 mg/dL in men
<50 mg/dL in women
Waist circumference
>102 cm for men
> 88 cm for women
*Composite of
CHD death,
nonfatal MI,
resuscitated
cardiac arrest, or
fatal or nonfatal
stroke.
Median F-U 4.9 yrs.
Number of CVD Events, in Millions, Prevented by High-risk Tx Regimen of
All in 70th %‘tile of the US Adult Population, in a 10-Year Period,
According to Atherogenic Marker: LDL-C vs. Non-HDL-C vs. Apo B
A Meta-Analysis of CV Risk Markers in 15 independent published analyses
provided a total of 233,455 subjects and 22,950 CV events.
Sniderman AD, Williams K, Contois JH, et. al. Circ. Card. Qual. Outcomes. 2011;4:337-345.
Triglyceride-rich Remnant Cholesterol: Lipoprotein Cholesterol as a
Function of Increasing Levels of Nonfasting Triglycerides.
Lipoprotein
Cholesterol,
mmol/L
mg/dL 88-175 176-263 264-351 352-439 ≥440<88
1 mmol TG/L = 88 mg/dL
5 mmol TG/L = 440 mg/dL
271
332
194
154
116
77
39
0.0
Varbo A, Benn M, Tybjærg-Hansen A,
Jørgensen AB, Frikke-Schmidt R,
Nordestgaard BG. Remnant
Cholesterol as a Causal Risk Factor
for Ischemic Heart Disease. J Am Coll
Cardiol. 2013;61(4):427-36.
mg/dL
Remnant cholesterol is a considerable source of residual
ASCVD risk as TG levels rise above 88 mg/dL (1 mmol/L)
Lipoprotein(a) Is the Most Common Dyslipidemia
Varvel S, McConnell JP, Tsimikas S. Prevalence of Elevated Lp(a) Mass
Levels and Patient Thresholds in 532 359 Patients in the United States.
Arterioscler Thromb Vasc Biol. 2016;36(11):2239-45. doi:
10.1161/ATVBAHA.116.308011
Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of
cardiovascular disease: insights from epidemiology, genetics, and
biology. J Lipid Res. 2016;57(11):1953-75. doi: 10.1194/jlr.R071233
64 million
U.S. residents
have an Lp(a) level
of 60 mg/dL or higher.
Over 3 million
have levels of
180 mg/dL or more,
which confer extremely
high risks.
Tsimikas S. A Test in Context:
Lipoprotein(a): Diagnosis, Prognosis,
Controversies, and Emerging Therapies
J Am Coll Cardiol. 2017;69(6):692-711.
Lipoprotein(a) [Lp(a)]:
Three Inherent Major Pathophysiological Properties
1. Pro-Atherogenic
(Apo B-100-LDL-C)
2. Pro-Inflammatory
(Increased Ox-PL)
3. Pro-Thrombotic
(Anti-fibrinolytic)
Emerging Risk Factors Collaboration.
Lipoprotein(a) Concentration and the
Risk of Coronary Heart Disease, Stroke,
and Nonvascular Mortality.
JAMA. 2009;302(4):412-423.
Clarke R, Peden JF, Hopewell JC, et al.
Genetic variants associated with Lp(a)
lipoprotein level and coronary disease.
N Engl J Med. 2009;361(26):2518-28.
Kamstrup PR, Tybjaerg-Hansen A,
Steffensen R, Nordestgaard BG.
Genetically elevated lipoprotein(a) and
increased risk of myocardial infarction.
JAMA. 2009;301(22):2331-9.
Tsimikas S. J Amer Coll Cardiol. 2017;69(6):692-711.
Lp(a) is an Independent, Causal, Genetic Risk Factor for CVD: The Evidence
CT Chest Scan for Coronary Artery Calcium Score
30 second test
30 2.5 mm slices
Specific-Lipoprotein(a) Apheresis Regressed Coronary Atherosclerosis
(Assessed by Quantitative Coronary Angiography)
Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan RV, Adamova IY, Utkina EA, Konovalov GA, Pokrovsky SN.
Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography.
Atherosclerosis Suppl. 2013 Jan;14(1):93-9. doi: 10.1016/j.atherosclerosissup.2012.10.015.
43.68
48.72
44.31
39.3
0
10
20
30
40
50
60
Baseline 18 months
Change in Diameter Stenosis(%)
Atorva Only Lp(a)-apheresis + Atorva
1.441.45
1.39
1.59
1.25
1.3
1.35
1.4
1.45
1.5
1.55
1.6
1.65
Baseline 18 months
Change in Minimal Lumen Diameter(mm)
Atorva Only Lp(a)-apheresis + Atorva
30 subjects (mean age 53.5 8.3 years, 70% male) with CHD verified by angiography, Lp(a) > 50 mg/dL, and LDL-C 95 mg/dL
(2.5 mmol/L) on chronic statin treatment were prospectively evaluated for 18 months.
Specific Lipoprotein(a) [Lp(a)] apheresis attenuates progression of
CIMT in coronary heart disease patients with high Lp(a) levels
43
27
63
36
-27
-56
-10
-28
-80 -60 -40 -20 0 20 40 60 80
Control
Specific Lp(a) apheresis
Control
Specific Lp(a) apheresis
Regression Progression
17
36
27
30
Ezhov MV, et al. Specific Lipoprotein(a) apheresis attenuates progression of carotid intima-media thickness in
coronary heart disease patients with high lipoprotein(a) levels. Atherosclerosis Supplements 2015;18:163-169.
CIMT= Carotid intima-media thickness
Stable
After 18
months of
therapy
2 years after
study
termination
FOURIER Lipoprotein(a), PCSK9 Inhibition,
and Cardiovascular Risk
O'Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I,
Im K, Lira Pineda A, Wasserman SM, Češka R, Ezhov MV, Jukema JW, Jensen HK,
Tokgözoğlu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS.
Circulation. 2019;139(12):1483-1492.
doi: 10.1161/CIRCULATIONAHA.118.037184
Baseline Distribution of Lp(a)
35% of FOURIER with
Lp(a) >50 mg/dL
120 nmol/L
≈ 50 mg/dL
Percent 3-Point Composite
Hard End Point
CV Event Outcomes
by Achieved
Lp(a) and LDL-C
(above or
below
the medians)
LDL-C <= Median
LDL-C >Median
0
1
2
3
4
5
6
7
8
9
10
Lp(a) > MedianLp(a) <= Median
7.88
6.57
9.43
8.45
LDL-C <= Median LDL-C >Median
CV Death
MI
Stroke
Summary
• Evolocumab significantly reduces Lp(a)
concentration
• Patients starting with higher Lp(a) levels
appear to derive greater absolute benefit
from PCSK9 inhibition.
• Patients who achieve lower levels of
both LDL-C and Lp(a) have the
lowest subsequent risk of CV events.
Cumulative Incidence of Major Adverse Cardiovascular Event
(MACE) According to Concentrations of Lipoprotein(a) [Lp(a)]
among a Secondary Prevention Danish Cohort
Adapted from:
Madsen CM, Kamstrup PR, Langsted A, Varbo A, Nordestgaard BG. Lipoprotein(a)-lowering by 50 mg/dL(105 nmol/L) may be
needed to reduce cardiovascular disease 20% in secondary prevention: A population-based study. Arterioscler Thromb Vasc Biol.
2020;40(1):255-66. doi: 10.1161/ATVBAHA.119.312951
Prospective cohort
study of Individuals
from the Copenhagen
General Population
Study with CVD
at baseline, N = 2,527
4-Point Composite
Lp(a) MACE Risk
(mg/dL) 5-yr 10-yr
≥100 19.3 42
50-99 17.2 33
10-49 15.6 30
<10 13.2 26
Cumulative Incidence
4-Point Composite MACE (%)
= CV death, nonfatal MI,
revascularization (CABG or
PTCA), or ischemic stroke
Modifiable Secondary Causes of Dyslipidemia (↑TG & LDL-C)
• Oral estrogen, tamoxifen, raloxifene
• Protease inhibitors
• Systemic glucocorticoids
• Immunosuppressive drugs
i.e. cyclosporine, sirolimus
• Retinoic acid drugs
• Beta blockers
• Thiazides
• Atypical antipsychotics
• Bile acid sequestrants
• Cyclophosphamide
• L-asparaginase
Lifestyles Contributing to ↑TG
• Lack of aerobic exercise
• Alcohol excess/abuse
• Calorie dense excess,
including high fat; trans fats
increase LDL-C
• Increased simple CHO,
(sugar, fructose intake
Medications Contributing to ↑TGCo-Morbidities Contributing to ↑TG
• Central obesity
• Diabetes mellitus
• Pre-Diabetes
• Insulin Resistance
• Fatty liver disease
• Cushing’s Syndrome
• Pregnancy
• Hypothyroidism
• Chronic Kidney Disease
• Nephropathy, especially
Nephrotic syndrome,
Stage IV, ESKD)
• Chronic Inflammatory
Disorders
• HIV
Evaluate for contributing factors, then modify:
Eliminate, Minimize or Optimize Management
Glycemic Control in Diabetes
Consider pioglitazone for
reduction of insulin resistance
and fatty liver; beta cell
preservation and TG-lowering
(i.e. DM or Pre-DM). [AACE]
If ASCVD, SGLT2i (HF) &/or
GLP-1 RA. [AACE, ADA, EASD]
Fasting TG, >150 (FDA)
Management of Atherogenic Triglyceride-rich Remnant Lipoprotein Cholesterol Particles
Mild-Moderate Hypertriglyceridemia (TG >135-499 mg/dL, Non-HDL-C*, Apo B)
Targeted TG Goal <150 mg/dL (no floor); Targeted-Apo B, Non-HDL-C, LDL-C Goals
(Risk-Dependent)
Pharmaceutical grade EPA= Highly purified, unoxidized, EPA,
(Icosapent ethyl, IPE) high dose, 4 g/day
High/Very High/Extreme ASCVD Risk
Statin
Ezetimibe
Persistently ↑↑ non-HDL-C or
↑↑ LDL-Cconsider
? Lp(a) contribution
Fish oil dietary supplements are NOT a substitute
Focused lab evaluation
& patient follow up as needed
to attain and maintain goals
Cholesterol-Lowering
PCSK9i Fibrate (Fenofibrate)
Niacin
Triglyceride-lowering
ASCVD = atherosclerotic cardiovascular diseaseBG = blood glucoseDHA = docohexaenoic acidEPA = eicosapentaenoic acidGLP-1 RA = Glucagon-like peptide-1 receptor agonistIDL = intermediate density lipoproteinIPE = icosapent ethylLDL =low density lipoproteinNon-HDL-C = Non-high-density lipoprotein PCSK9i = proprotein convertase subtilisin-kexin type 9SGLT2i = Sodium glucose co-transporter-2 inhibitorTG = triglyceridesVLDL = very-low density lipoprotein
If non-HDL-C not at goaladd
BAS, only if on statin
If not at goal, intensity
non-lipid and pharmacologic
measures
Combination therapies are always required
If TG not at goaladd
If TG not at goaladd
Therapeutic Lifestyle Changes
Evaluate Contributing Medications
Optimization of Co-Morbidities
Glycemic Control in Diabetes
Management Secondary Causes
Consider pioglitazone for reduction insulin resistance and fatty liver;
beta cell preservation and TG-lowering (i.e. DM or pre-DM).
If ASCVD, SGLT2I &/or GLP- RA
See table
See table
See table
Management Lipids and Lipoproteins
Simultaneous
Reduce Risk ASCVD and Pancreatitis
Prescription Omega-3 FA (Rx-Om-3)1st Choice: Pure EPA (IPE) 2 g BID
[Rx-grade DHA-EPA mixture, only if IPE is inaccessible)
Dietary Om-3 supplements are NOT a substitute; NOT to be used
Eicosapentaenoic acid-Enrichment
If non-HDL-C not at goaladd
If non-HDL-C not at goaladd
* Non-HDL-C = VLDL-C + LDL-C
Bempedoic acid
If non-HDL-C not at goaladd
GOALS:
Niacin
If non-HDL-C not at goaladd
PDR
Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW, for the
STELLAR Study Group Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin,
Simvastatin, and Pravastatin Across Doses. (STELLAR Trial). Am J Cardiol 2003;92:152-160.
Efficacy of Rosuvastatin, Atorvastatin, Simvastatin, & Pravastatin Across
Doses (STELLAR*): Mean Percentage Change from Baseline LDL-C
-20
-24.4
-29.7-28.3
-35-38.8
-45.8
-36.8
-42.6
-47.8-51.1
-45.8
-52.4 -55
-60
-50
-40
-30
-20
-10
0
10 20 40 80
Prava Simva Atorva Rosuva
Mean
Percent
Change
from
Baseline
in LDL-C
Baseline
LDL-C, mg/dL 189 189 189 188 164 162 155 160 161 158 156 157 163 165
*STELLAR: Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin trial
High-intensity statin Rx
Moderate-intensity statin Rx
Karlson BW, Nicholls SJ, Lundman P, Palmer MK, Barter PJ. Achievement of 2011 European low-density
lipoprotein cholesterol (LDL-C) goals of either <70 mg/dl or 50% reduction in high-risk patients: Results from
VOYAGER. Atherosclerosis 2013;228:265-269.
Therefore, achieving a goal of LDL-C <70 mg/dl is more difficult
than achieving a goal of >50% reduction in LDL-C
Is a High-Intensity Statin for ≥50% LDL-C Reduction Enough?
On Atorvastatin 80 mg/dl:60% achieved >50% reduction30% achieved <70 mg/dL
On Rosuvastatin 40 mg/day:78% achieved >50% reduction42% achieved <70 mg/dL
High-risk patients from the VOYAGER database
[n = 20,539, mean Baseline LDL-C 168.1 (+32.5) mg/dL]
Non-HDL-C
Apo B
Results from the Whole Population VOYAGER: Individual Patient Data Meta-AnalysisHigh-risk patients from the VOYAGER database [n = 20,539, mean Baseline LDL-C 168.1 (+32.5) mg/dL]Change in Lipoprotein/Lipid Levels with Increasing Dose of Each Statin
Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of
comparative efficacy of increasing dose of Atorvastatin versus
Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids
(from VOYAGER). Am J Cardiol. 2010 Jan 1;105(1):69-76. doi:
10.1016/j.amjcard.2009.08.651.
Results from the Whole Population VOYAGER: Individual Patient Data Meta-AnalysisHigh-risk patients from the VOYAGER database [n = 20,539, mean Baseline LDL-C 168.1 (+32.5) mg/dL]
Change in Triglycerides Levels with Increasing Dose of Each Statin
Triglycerides
Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of
comparative efficacy of increasing dose of Atorvastatin versus
Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids
(from VOYAGER). Am J Cardiol. 2010 Jan 1;105(1):69-76. doi:
10.1016/j.amjcard.2009.08.651.
Triglyceride and LDL Cholesterol-Lowering Effects of
Atorvastatin and Simvastatin in Subjects With Hypertriglyceridemia
-26.5
-32.4
-45.8
-26
-16.7
-33.2
-41.4
-27
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Atorvastatin 5 mg Atorvastatin 20 mg Atorvastatin 80 mg Simvastatin 10 mg
TG LDL-CBaseline TG 544 122 660 123 572 114 231 176
Stein EA, Lane M, Laskarzewski P. Comparison of Statins in Hypertriglyceridemia. Am J Cardiol. 1998;81(4A):66B–69B
Combined Ezetimibe and Statin Therapy versus Doubling of Statin Dose
in Patients With Remnant Lipoproteinemia on Previous Statin Therapy
-20.9 -20.1
-33.4
-20.3-24.2 -24.8
-47.8
-23.8
-60
-50
-40
-30
-20
-10
0
TG Non-CHDL-C RLP-C LDL-C
Double Statin dose Statin + Ezetimibe
Nakamura T, Hirano M, Kitta Y, Fujioka D, Saito Y, Kawabata K, et al. A comparison of the efficacy of combined ezetimibe
and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy.
J Cardiol. 2012;60:12-17. doi.org/10.1016/j.jjcc.2012.02.005
Percent
Reduction
175 173 151 152 6.5 6.6 121 120
Efficacy and Safety of Bempedoic Acid in Patients With
Hypercholesterolemia and Statin Intolerance
-19
-0.4
3.5
-24
-19
-15.5
-30
-25
-20
-15
-10
-5
0
5
TChol TG HDL-C LDL-C Non-HDL-C Apo BSeries 1
Baseline (mg/dL) 246 157 52 159 194 141
Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, Kelly S, Stroes ESG. Efficacy and Safety of Bempedoic
Acid in Patients With Hypercholesterolemia and Statin Intolerance. J Am Heart Assoc. 2019;8(7):e011662.
Effects of PCSK9 Inhibitor (Evolocumab) on Hyperlipidemia.
-28.2
-52
-29
-22
-44-41.8
-12
52.2
-60
-50
-40
-30
-20
-10
0
10
TChol LDL-C VLDL-C Lp(a) Apo B Non-HDL-C TG HDL-C Apo A1
Percent Change in Lipoproteins or Lipids from Baseline
Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM,
Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week
placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809-1819.
doi: 10.1056/NEJMoa1316222.
Change
from
Baseline
(%)
Baseline, mg/dL 176 100.4 20 84, nmol/L 87 124 105 52.6 152.4
Treatment With Bempedoic Acid Alone and in Combination with Ezetimibe Lowers LDL
Cholesterol in Hypercholesterolemic Patients With or Without Statin Intolerance
-20.7
-2.7-4.8
-30
-25-21.3
-24.6
-40.2
-14.3
-7
5
-21.2-18.7
-15.2-12.7 -10.5
-34.3
-12.2
-3.7
-47.7
-42.4
-35.2-37
-25.6
-60
-50
-40
-30
-20
-10
0
10
TChol TG HDL-C LDL-C Non-HDL-C Apo B LDL-P hsCRP
Bempedoic Ezetimibe Bem + EZE
Thompson PD, MacDougall DE, Newton RS, Margulies JR, Hanselman JC, Orloff DG, McKenney JM,
Ballantyne CM.
J Clin Lipidol. 2016 May-Jun;10(3):556-67. doi: 10.1016/j.jacl.2015.12.025.
Percent
Changes
From
Baseline
to
Week 12
in Lipids
and CRP
Baseline (mg/dL) 162-165 151-163 52-54 162-166
-36.6-35.1
-32.7-29.7
-14.2
-8.4 -7.5-6
14 15
-40
-30
-20
-10
0
10
20 Percent Change in TG, Apolipoproteins and Lipoprotein-associated Cholesterol
Effects of Fenofibrate on Atherogenic Dyslipidemia in Hypertriglyceridemic
(HTG) Subjects (n=96): Mean Baseline TG = 480 ±19 mg/dL
Percent
Change
Davidson MH, Bays HE, Stein E, Maki KC, Shalwitz RA, Doyle R; TRIMS Investigators. Effects of fenofibrate on atherogenic
dyslipidemia in hypertriglyceridemic subjects. Clin Cardiol. 2006;29(6):268-273. doi:10.1002/clc.4960290609.
VLDL-C ↓ VLDL-C + ↑ LDL-CFibrate
-33.1
-28.6
-25.8
-17.7
-8.5
-3.6-2.3
-35
-30
-25
-20
-15
-10
-5
0
TG VLDL-C VLDL-TG Non-HDL-C Apo B HDL-C LDL-C
Percent Change in TG, Apolipoproteins and Lipoprotein-associated Cholesterol
Effects of eicosapentaenoic acid ethyl ester (4 Grams) on Atherogenic
Dyslipidemia in Hypertriglyceridemic (HTG) in Subjects randomized 229 diet-
stable patients with fasting TG >500 mg/dl and <2,000 mg/dl ( (n=96): Mean
Baseline TG = 480 ±19 mg/dL
Percent
Change
Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester
(AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized,
double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011 Sep 1;108(5):682-90.
doi: 10.1016/j.amjcard.2011.04.015.
VLDL-C ↓ VLDL-C + ↑ LDL-CEPA ethyl ester
2004 ATP III
Update*:
RCTs that
Provided
Evidence of
Improved
Outcomes when
Targeted LDL-C
was <70 mg/dL
for Highest Risk
Patients
*2004 ATP III Update: Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent
clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39.
PROVE-IT: Cannon CP, Braunwald E, McCabe CH, Rader DJ, et al. Intensive versus moderate lipid lowering with statins
after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. doi: 10.1056/NEJMoa040583.
HPS: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22.
REVERSAL: Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid lowering
therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80.
2004 Evidence* Supportive of Targeted LDL-C Goal <70 mg/dL
Trial Analysis RCT LDL-C, mg/dL,
achieved
Level 1A RCT PROVE-IT * 62
Subgroup Analyses:
Prespecified or
Post-hoc
HPS **
- lowest tertile
- sub-group <100 mg/dL
69
65
Imaging: Coronary IVUS trial,
Percent Arterial Volume (PAV)
changes by linear regression
analysis (LRA)
REVERSAL ***
Mean 73 mg/dL
LRA 8330
Rosenblit PD. Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at ‘Extreme’ ASCVD Risk.
Current Diabetes Reports. 2019;19(12):146:1-18.
2017 AACE
Algorithm:
RCTs that
Provided
Evidence of
Improved
Outcomes when
Targeted LDL-C
was <55 mg/dL
for Highest Risk
Patients
Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. 2017 AACE/ACE Guidelines American Association of
Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular
Disease. Endocr Pract. 2017;23(Supplement 2):1–87.
Rosenblit PD. Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at ‘Extreme’ ASCVD Risk. Current Diabetes Reports.
2019;19(12):146:1-18.
2017 Evidence* Supportive of Targeted LDL-C Goal <55 mg/dL
Trial Analysis RCT LDL-C, mg/dL,
achieved
Level 1A RCT IMPROVE-IT * 53.5
Subgroup Analyses:
Prespecified or
Post-hoc
PROVE-IT
TNT
VA Palo Alto Healthcare
JUPITOR
40
54
40
44
Meta-analysis RCT
Statin Trials
8 Statin RCTs
-divided by Quartiles
-divided by Septiles
Q1(<62)mean 49
S1, <50
Imaging: Coronary IVUS trial,
Percent Arterial Volume (PAV)
GLAGOV mean 36.6
Imaging: Coronary IVUS trial, PAV changes
by linear regression analysis (LRA)
REVERSAL ***
Mean 73 mg/dL
LRA 8330
Reduced Outcomes Achieved with LDL-C Level <30 mg/dL
Trial Analysis RCT LDL-C, mg/dL,
achieved
Level 1A RCT FOURIER <30 (median 26)
Subgroup Analysis
Prespecified
or Post-hoc
IMPROVE-IT
FOURIER
<30
<20
<10 (7)
Imaging: Coronary IVUS trial,
Percent Arterial Volume (PAV)
changes by linear regression
analysis (LRA)
8 Statin IVUS trials
GLAGOV
mean 36.6
LRA 9315
LRA 9020
RCTs
that Provided
Evidence of
Improved
Outcomes when
Targeted LDL-C
was <30 mg/dL
for Highest Risk
Patients
Further
Validating
the AACE
Guideline
‘Extreme Risk’
Targeted LDL-C
Goal <55 mg/dL
(No Lower Limit)
Reviewed: Rosenblit PD. Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at
‘Extreme’ ASCVD Risk. Current Diabetes Reports. 2019;19(12):146:1-18.
Post-hoc
Subgroup Analysis
ODYSSEY* (median 8.3
mos. after randomization)
before substitution of PBO
<15
*Schwartz G, Szarek M, Li QH, Chiang CE, Diaz R, Hagstrom E, Huo Y, Jukema YW, Lecorps G, Moryusef A,
Pordy R, White HD, Yusoff K, Zeiher AM, Steg BG. Eur Heart J. Oct. 2019;40(Supp1):Abstract: P1226.
High
<3.0 mmol/L
(<116 mg/dL)
2019 ESC/EASGuidelinesfor the management of dyslipidaemias: lipid modification to reduce cardiovascular risk
European Heart Journal 2019; doi: 10.1093/eurheartj/ehz455
www.escardio.org/guidelines
Treatment Goals for Low-Density Lipoprotein Cholesterol (LDL-C)
Across Categories of Total Cardiovascular Disease Risk
Low
Low Moderate High Very-High CV Risk
•SCORE <1%• SCORE ≥1% and <5%
• Young patients (T1DM <35 years; T2DM <50 years) with
DM duration <10 years (without other risk factors)
Moderate
High
Very-High
• ASCVD (clinical/imaging)
• SCORE ≥10%
• FH with ASCVD or with another major risk
• Severe CKD (eGFR <30 mL/min)
• DM & target organ damage: ≥3 major risk factors;
or early onset of T1DM of long duration (>20 years)
• SCORE ≥5% and <10%
• Markedly elevated single risk factors, in particular, TC >8mmol/L
(310 mg/dL) or LDL-C >4.9 mmol/L (190 mg/dL) or BP ≥180/110mmHg
• FH without other major risk factors
• Moderate CKD (eGFR 30–59 mL/min)
• DM w/o target organ damage, with DM duration ≥10 years
or other additional risk factor
<2.6mmol/L
(<100mg/dL)
Treatment Goal for Targeted LDL-C
<1.8mmol/L
(<70 mg/dL)
<1.4mmol/L
(<55 mg/dL)
<1.0mmol/L
(<40 mg/dL)
LDL-C
reduction
at least
≥50% from
baseline
and
Extreme
Extreme Patients with ASCVD who
experience a 2nd vascular event
(any type) within 2 years while
taking max-tolerated statin therapy
2019
Targeted Apo B, Non-HDL-C, LDL-C:
Numerical Goals for Very High/Extreme Risk
Recent LDL-C
Lowering RCTs
LDL-C Non-HDL-C Apo B
IMPROVE-IT, ACS 53.5 77.2 70.3
ODYSSEY, ACS 53 75 50
GLAGOV 36.6 57.7 43
FOURIER 30 60.5 45.7
Guideline Goals for Atherogenic Lipoprotein Markers (Highest Risk) LDL-C Non-HDL-C Apo B
ACC/AHA 2013 LDL-C ≥50% ↓ NR NR NR
NLA, 2014, 2015, VH Threshold for Therapy + ↓ atherogenic cholesterol ≥50% <70 <90 <80
AACE, 2017, VH <70 <90 <80
AACE, 2017, Extreme <55 <80 <70
AHA/ACC/Multispecialties LDL-C ≥50% ↓ + Threshold for Therapy ≤70 mg/dL NR NR NR
ESC-EAS, 2019, VH <55 <85 <65
ESC-EAS, 2019, VH + Recurrent Events (Extreme) <40 <70 <55
Examples of Intensification of Lipid Lowering Treatment
-30
-50
-65
-60
-75
-85-90
-80
-70
-60
-50
-40
-30
-20
-10
0
ModerateIntensity Statin
High intensityStatin
High IntensityStatin +
Ezetimibe PCSK9i
PCSK9i +Moderate
Intensity Statin+ Ezetimibe
PCSK9i + HighIntensity Statin
+ Ezetimibe
2019 ESC/EAS Guidelinesfor the management of dyslipidaemias: lipid modification to
reduce cardiovascular risk European Heart Journal 2019; doi: 10.1093/eurheartj/ehz455
Average
Percent
LDL-C
Lowering
LDL-C = low-density lipoprotein cholesterol;
PCSK9 = proprotein convertase subtilisin/kexin type 9.
Adjunct Management to
Significantly Reduce ASCVD Risk: Rx-grade EPA, non-oxidized, Eicosapentaenoic acid
(Icosapent ethyl) High dose, 4 grams/day:
Secondary Prevention patients: ≥45 years of age, with established clinical
ASCVD as prior MI, ischemic stroke, or PAD,
Primary Prevention patients: ≥50 years of age with diabetes and at least
one additional risk factor, either:
Age: men ≥55 years, women ≥65 years;
HTN (BPsys ≥140 mmHg or BPdias ≥90 mmHg or on anti-HTN’sive med.;
cigarette smoker or stopped smoking within 3 months;
Low HDL-C (≤40 mg/dL for men or ≤50 mg/dL for women);
hs-CRP >3.0 mg/L;
CKD, stage 3,4,± micro- or macroalbuminuria, or retinopathy,
or ABI <0.9 without symptoms of intermittent claudication
“Extreme Risk” Secondary Prevention patients
with multimorbidities, i.e. progressive clinical ASCVD,
including unstable angina or TIA or
established single clinical ASCVD event
in patients with DM, CKD 3/4, or HeFH or
hx of premature ASCVD (<55 male, <65 female)
“High”/“Very High”/“Extreme” ASCVD Risk+ Elevated fasting TG (135-499 mg/dL)
+ LDL-C level 41 to 100 mg/dL
on background of
stable statin dose (±ezetimibe)
Bhatt DL, Steg PG, Miller M, et al. REDUCE-IT Investigators.
Cardiovascular Risk Reduction with Icosapent Ethyl for
Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.
Borow KM, Nelson JR, Mason RP. Atherosclerosis. 2015;242(1):357-366.
Rx-grade EPA, non-oxidized, Eicosapentaenoic acid (icosapent ethyl)
High dose, 4 grams/day.
REDUCE-IT: Primary Composite
Outcome ASCVD Events
TG (216 mg/dL) ≥81 to ≤1401, ↓25%
≥200, ↓25%; <200, ↓29%
>150, ↓26%; <150, ↓34%
TG/HDL ≥200/≤35 ↓32%
TG/HDL <200/>35 ↓25%
Suggests benefit
not related to TG-lowering
Primary Composite Endpoint
Prespecified Total ASCVD Events
TG (216 mg/dL ≥81 to ≤1401, ↓30%
by TG, mg/dL, tertile*
≥81 to ≤190, ↓26% (p=0.0025)
>190 to ≤250, ↓23% (p=0.01)
>250 to ≤1401 ↓40% (p<0.001)
*P (interaction) = 0.17
Suggests possible TG-lowering
component benefit at higher TG
Dose-Dependent MOAs
Reduce ASCVD RiskObjective
REDUCE-IT: Patient’s Qualification
25%
RRR
ASCVD
events
The Fundamental Causal Biomarkers of ASCVD are Apolipoprotein B
(Apo B)-Containing Cholesterol Particles Entering the Arterial Wall
A large concentration or ‘number’ of all atherogenic apo B-containing
cholesterol particles [LDL; Lp(a); andTG-rich lipoprotein remnants
(VLDL-remnants, e.g. IDL, chylomicron remnants),is most predictive of IHD.
Gradient-Driven
Process 1. ↓ Apo B-LDL-C
2. ↓ Apo B-TG-Rich
Lp-C
3. ↓ Apo B-Lp(a)
Pharmacologic EPA* (Rx-grade,
non-oxidized) Enrichment
* Eicosapentaenoic acid
Lowest is Best (i.e. ESC/EAS 2019)
Low risk: <116 mg/dL
Moderate risk: <100 mg/dL
High risk: <70 mg/dL
Very high risk: <55 mg/dL
Extreme risk: <40 mg/dL
↓ TG (VLDL IDL ↑LDL) ↓ Apo B-LDL-C
Lower LDL-C to <50 mg/dL?
Reduce Lp(a) by 50 (or 100 mg/dL)
for 20% (or 40%) 5-yr ASCVD RRR
Lipoprotein [Lp(a)] apheresis
Await potent Apo(a)-lowering Rx
Management: Ultimately, Lower Apolipoprotein B particles
Icosapent Ethyl, 4 grams,
Goldstein JL, Brown MS. Cell 2015;161:161–172.
Ference BA, Ginsberg HN, Graham I, et al. Eur Heart J. 2017;38(32):2459-2472.Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019;380:11–22.
↓ Apo B-LDL-C
Risk-Dependent
Targeted ‘LDL-C’
Goals of Therapy
Agent Target Phase TG-lowering
Potential
Side effects
Fibrates PPARalpha approved ~50% GI, LFTs, creatinine, myositis
Omega-3 Fatty acids Pleiotropic + liver Approved adjunctive for
CVD risk next to statins
~20% Gastrointestinal symptoms
Niacin Liver DGAT & Apo B,
Pleiotropic + liver
EMA: not available
FDA: approved
~30-50% Multiple, flushing, itching &
“Harm” in HPS2-THRIVE
Statins HMG-CoA reductase Approved ~10–20% Gastrointestinal symptoms,
muscle symptoms
Volanesorsen ApoC-III (ASO) EMA: conditional
authorization
FDA: not approved yet
~70–90% ISRs, thrombocytopenia
AKCEA-APOCIII-LRx ApoC-III (GALNac3 ASO) Phase IIa ~60–80% Possibly mild ISRs
Evinacumab ANGPTL3 (monoclonal Ab) Phase III ~50% Not known yet
ONIS-ANGPTL3-LRx ANGPTL3 (ASO) Phase II ~60% Not known yet
ARO-ANG3 ANGPTL3 (siRNA) Phase IIa ~50–60% Possibly mild ISRs
Current and Future TG-lowering agents in Clinical trials.
Modified from
Nurmohamed NS, Dallinga-Thie GM, Stroes ESG. Targeting apoC-III and ANGPTL3 in the treatment of hypertriglyceridemia.
Expert Rev Cardiovasc Ther. 2020 Jun;18(6):355-361. doi: 10.1080/14779072.2020.1768848.
LDL-C Lp(a)TG-Rich Lp-C
Aggressive Lipoprotein Management of Extreme ASCVD
ApoC-III (ASO)
ApoC-III (GALNac3 ASO)
ANGPTL3 (monoclonal Ab)
ANGPTL3 (ASO)
ANGPTL3 (siRNA)
60-80%
Not
Too
distant
future
90-100%
High Intensity Statin +
PCSK9i +
Eztimibe +
Bempedoic acid
IONIS (AKCEA)-APO(a)-LRx =TQJ230
PCSK9i
70-80%
Thank You
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