Lipid Management in 2013
Are You
Up to
Date?
October 30, 2007
Carl E. Orringer, MD, FACC
Harrington Chair in
Preventive Cardiovascular Medicine
University Hospitals Case Medical Center
Harrington Heart and Vascular Institute
Associate Professor of Medicine
Case Western Reserve University
School of Medicine
University Hospitals Heart & Vascular Institute
How Increased Concentration of Apo B Containing
Particles Promotes Atherosclerosis
ApoB lipoprotein
particles
Blood
Monocytes bind to
adhesion molecules
Smooth muscle
Inflammatory
response
Modification
Macrophage
Foam cell
ApoB = apolipoprotein B.
1. Tabas I et al. Circulation. 2007;116:1832–1844. 2. Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551–561.
3. Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536–1540. 4. Steinberg D et al. N Engl J Med. 1989;320:915–924.
Atherothrombotic Vascular Disease:
Response-to-Retention Model1
Plaque rupture
Thinning fibrous cap
• Fibrous cap thinning
• Plaque rupture and thrombosis
• Atherothrombotic vascular
disease (eg, MI and stroke)
MI = myocardial infarction.
1. Tabas I et al. Circulation. 2007;116:1832–1844.
Atherosclerosis Progression1–3
Normal Artery
Fatty streak
involving
lipoprotein and
immune cell
infiltration
1. Tabas I et al. Circulation. 2007;116:1832–1844. 2. Hansson GK. N Engl J Med. 2005;352:1685–1695.
3. Jawad E et al. Dis Mon. 2008;54:671–689.
Plaque rupture and
thrombosis (acute
coronary event)
Gradual outward
expansion of
arterial wall
Inward expansion
causing luminal
narrowing (chronic
stable angina)
Lipoprotein Physiology Made Simple
GI Tract
Food is
consumed
1
Adipose
tissue
Food is absorbed
and converted to
transporter particles
3
2
Transporter
3
particles
Liver
4
Disassembles transporter particles
to prevent clogged transport pathways
Assembles key body
maintenance particles,
substrates for hormone assembly
5
5
GI Tract
Refuse eliminated
from the body
8
7
Liver
Accepts refuse
from plasma
Plasma
Energy storage
(starvation)
Muscle
Energy
utilization
Cell membranes,
Salt and H2O balance
Reproductive hormones
Vitamins
6
Particles provided that
eliminate the refuse
Duodenal/
Jejunal
enterocyte
Intestinal
lumen
Glycerol
Phytosterols
Cholesterol
Fatty acids
Bile acids
Phospholipids
Plasma
Lymphatics
A1
B-48
Glucose
Glycerol
A2
A4
CM
C (trace)
E (trace)
Lipoprotein
lipase
Phospholipids
Triglycerides
C E
Micelles
Fatty acids
MTP
NPC1L1
A4
Phospholipids
B-48
CM
CM
Cholesterol
ACAT
ABCG5
ABCG8
FC
CE
Free
fatty acids
To
HDL
Chylomicron
(CM)
Apo B-48
Cholesterol
Surface
Components
Adipose
Tissue
CMR
Muscle
CM remnant
HDL
Apo E
Acetate
B-48
Bile
acids
VLDL remnants
E3
CMR
E3
Liver
Remnant receptor
LDL-Related protein
CM remnants
degradation
E
LDL receptor
C3
C2
VLDL
B-100
Cell membranes
E
C3
C2
VLDL
E
IDL
B-100
SRB1
receptor
Vitamins
CETP
HDL
A1 A2
Hormones
B-100
B-100
CETP
Gallbladder
LDL
FC
Macrophage
Dietary Priorities in Dyslipidemia





Reduced intake of saturated fat and cholesterol
Increased intake of soluble fiber and plant
sterols/stanols
In overweight and obese patients, reduced
caloric intake to achieve weight reduction
In hypertriglyceridemic patients, same as above
plus reduced intake of simple carbohydrates
Greatest impact of diet tends to be in overweight
or obese patients with atherogenic dyslipidemia
Adding Soluble Fiber to the Diet
 Whole
grains
 Nuts and seeds
 Fruit
 Legumes
Adding Plant Sterols
and Stanols to the Diet
Goal is 2000-2500 mg daily
 Dietary options containing these functional
foods


Margarines
 OJ
 Milk
and non-dairy drinks
 Breads
Mechanism of Action of Plant Sterols/Stanols and Fiber
Intestinal Lumen
Glycerol
Phytosterols
Cholesterol
Fatty acids
Phospholipids
Micelles
Duodenum and Jejunal Enterocyte
Glycerol + 3 FA
Soluble
fiber
Plant sterols
and stanols
Triglycerides
Bile
acids
Mixed Micelles
Microsomal
triglyceride
transfer protein
Chylomicron
NPC1L1
Cholesterol
Phopsho;ipids
Apo B-48
LDL-C Lowering Drug Therapy
Match Drug with Site of Action






Statins
Ezetimibe
Resins
High-dose niacin
Lomitapide
Mipomersin






Microsomal triglyceride
transport protein
Intestinal bile acid
transporter
NPC1L1
Adipose tissue
Apo B
HMGCoA Reductase
LDL-C Lowering Drugs:
Mechanisms of Action
Small intestine
Proximal
Acetyl CoA
NPC1L1
Micelles
Ezetimibe
Distal
Bile
Liver
Intestinal
Bile Acid
Transporter
HMG CoA
reductase
Statin
Cholesterol
FFA
Apo C1,2,3
Tg
Apo E
Apo B
Lomitapide
Mipo VLDL
Niacin
FFA
CE
VLDL
Adipose
Tissue
RLP
Resins
IDL
LDL
What’s New in Lipids in 2013
NCEP ATP 3 transitions to NCEP ATP4
 Update on dietary and drug therapy for
lipid disorders
 Increased emphasis on the metabolic
syndrome
 Questions about role of niacin in treatment
of atherosclerotic vascular disease
 New approaches to LDL-C lowering and
HDL-C raising therapy

NCEP ATP III Approach to
Primary Prevention of CHD



Count traditional risk factors: cigarette smoking;
HBP or on Rx for HBP; HDL-C <40 mg/dl; family
Hx premature CHD in 1st degree relatives
(♂<55, ♀<65); age (males ≥45, females ≥55)
Use Framingham risk scoring to estimate CHD
risk for those with 2 or more risk factors
Manage lipids based upon the principle of
matching treatment intensity to estimated risk
Expert Panel, ATP III. Circulation 2002;106:3143-3421
NCEP/Framingham risk scores: Estimate
of 10-yr Hard CHD risk in men without CHD
Age (y)
Points
20–34
–9
35–39
–4
40–44
0
45–49
3
50–54
6
55–59 60–64
8
10
Total-C
(mg/dL)
20–39
40–49
Points
Age (y)
50–59
<160
160–199
200–239
240–279
? 280
0
4
7
9
11
0
3
5
6
8
0
2
3
4
5
Age (y)
20–39
40–49
50–59
60–69
70–79
0
8
0
5
0
3
0
1
0
1
Nonsmoker
Smoker
Point total:
<0
10-yr risk (%) <1
0
1
1 2
1 1
3
1
4
1
65–69 70–74 75–79
11
12
13
HDL-C (mg/dL)
5
2
60–69
70–79
0
1
1
2
3
0
0
0
1
1
6
2
7 8
3 4
Points
–1
0
1
2
? 60
50–59
40–49
<40
Systolic BP
Points
(mm Hg) Untreated Treated
<120
120–129
130–139
140–159
? 160
9 10 11 12
5 6 8 10
0
0
1
1
2
0
1
2
2
3
13 14 15 16 >17
12 16 20 25 ? 30
Reilly MP, Rader DJ. Circulation. 2003;108:1546-51.
VBWG
ATP III Update 2004:
LDL-C Goals and Cutpoints for Therapy
in Different Risk Categories
Risk Category
LDL-C Goal
Initiate TLC
Consider
Drug Therapy
Very High risk:
ACS, or CHD w/ DM,multiple
CRF
<70 mg/dL
70 mg/dL
> 70 mg/dL
High risk:
CHD or CHD risk equivalents
(10-year risk >20%)
If LDL <100 mg/dl
<100 mg/dL
(optional goal:
<70 mg/dL)
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%)
<100 mg/dL
130 mg/dL
> 130 mg/dL
(100-129 mg/dL:
consider drug Rx)
Moderate risk:
2+ risk factors ( risk <10%)
<130 mg/dL
130 mg/dL
> 160 mg/dL
Lower risk:
0-1 risk factor
<160 mg/dL
160 mg/dL
>190 mg/dL
Grundy S, et al. Circulation 2004;110:227
Step 1:
NHLBI Critical Review
of the Literature
1. What is the evidence that treatment to
specific LDL-C and non-HDL-C goals reduces
outcomes in atherosclerotic cardiovascular
disease in primary and secondary prevention?
2. What is the evidence for efficacy and safety
of statins, resins, fibrates, cholesterol
absorption inhibitors and niacin?
Step 2:
Collaboration of Experts to Translate
Literature Review into Guidelines
American College of Cardiology
Foundation
 American Heart Association
 National Lipid Association

Evidence-Based Reviews
Statin therapy reduces relative risk of CHD
events in all groups, regardless of
Framingham Risk score
 High-dose statin is more beneficial than
low or moderate dose statin therapy
 Statin therapy is unassociated with
increased risk of cancer
 Statin therapy is the most effective means
of risk reduction in diabetic patients

Restrictions on Simvastatin 80 mg
Use 80 mg daily dose only in those who
have been on that dose for ≥ 12 months
and have not experienced toxicity
 Do not start new patients on 80 mg daily
 Treat patients who require >40 mg with an
alternate lipid-altering therapy
 Switch patients who need to be started on
a drug interacting with simvastatin to an
alternate statin

www.fda.org 6/8/11
Simvastatin Dosing Regulations



Contraindicated: itraconazole, ketoconazole,
posconazole, erythromycin, telithromycin, HIV
protease inhibitors, nefazodone, gemfibrozil,
cyclosporine and danazol
Do not exceed 10 mg daily: diltiazem, verapamil
Do not exceed 20 mg daily: amlodipine,
ranolazine, amiodarone
www.fda.gov 6/8/11, 12/15/11
Hepatic Function Testing in
Patients Receiving Statins




Traditionally ALT and AST have been routinely
measured during statin maintenance therapy
Irreversible hepatic damage due to statins is
extremely rare and likely idiosyncratic (less than
2 per one million patient-years)
There are no data to support routine LFT
monitoring to identify such patients
FDA therefore recommends only baseline
hepatic function studies and follow-up testing as
clinically warranted; routine LFT monitoring is no
longer recommended.
www.fda.gov 2/28/12
Cognitive Adverse Effects of Statins





Occasional patients over age 50 experience notable, but
ill-defined memory impairment that resolves upon
discontinuation of statin therapy
Such memory impairment may occur at any time during
statin therapy
There is no association between statin therapy and
Alzheimer’s dementia
There is no association between memory loss and
specific statin, dose, patient’s age or any specific drugdrug interaction
Consider withdrawing the drug and using alternate
therapies when new memory loss is clinically evident
www.fda.gov 2/28/12
Changes in Blood Glucose in
Patients Receiving Statins




JUPITER reported an increased incidence of
investigator reported diabetes in the rosuvastatin
treated patients
A meta analysis of 13 statin trials reported a 9%
increased risk of incident diabetes
Statin labels have now been revised to reflect
that statin therapy may be associated with a rise
in HgbA1C and fasting plasma glucose
Consensus is that benefits of statin therapy in
appropirate patients far outweighs DM risk
www.fda.gov 2/28/12
The Metabolic Syndrome and
Non-HDL Cholesterol
The Metabolic Syndrome

Requires 3 or more
Waist circumference >35”♀ or 40”♂
 Fasting glucose 100-125 mg/dl
 BP ≥130/85 or on anti-HBP meds
 HDL-C < 50 mg/dl♀ or <40 mg/dl ♂
 Triglycerides ≥ 150 mg/dl

Increased risk for type 2 DM and CHD
 LDL-C is not a good CHD risk predictor in
these patients

The Metabolic Syndrome
A Growing Cardiometabolic
Phenotype in the U.S.
1994 – 2002
2003 – 2010
∆ (%)
MetS
23.7%
34.0%
+10.3
High TG
27.0%
33.0%
High TG and low HDL-C
2.1%
4.8%
Type II diabetes mellitus
7.9%
10.7%
+6.0
+2.7
+2.8
Impaired fasting glucose
6.1%
25.9%
+19.8
Obesity
19.8%
33.7%
+13.9
Ramjee V, et al. J Am Coll Cardiol. 2011;58:457-463.
The Heterogeneity of Lipoprotein Particles
Density (g/ml)
0.95

IDL
1.006
Chylomicron
Remnants
1.02
LDL
1.06
1.10
Chylomicrons
VLDL
HDL2
Lp(a)
HDL3
n-H
o
N
1.20
5
s(
e
l
c
10
20
40
DL
rti
a
P
1
oB
ap
m
ul
c
e
ol
)
cle
i
t
ar
p
/
e
Non-HDL-C= cholesterol
concentration in all
apo B-containing
particles
60
Diameter (nm)
80
1000
Understanding
Non-HDL Cholesterol
HDL
Cholesterol
+
Usually Anti-atherogenic
Total Cholesterol
LDL
Cholesterol
+IDL-C
+RLP-C
+Lp(a)-C
+
VLDL
Cholesterol
Pro-atherogenic
Non-HDL-Cholesterol
Address only when Tg = 200-499 mg/dl



Non-HDL-C = Total cholesterol – [HDL-C]; or
[LDL-C] + [VLDL-C]
Goal for non-HDL-C is <30 mg/dl above LDL-C
goal because desirable Tg is <150 mg/dl
When non-HDL-C is >30 mg/dl above LDL-C
goal, more intensive lipid therapy is warranted
Tg/5
Appears on all UH lipid profiles
when triglycerides are 200-499
Treatment of the
Metabolic Syndrome



Treatment of choice is diet and cardiovascular
exercise to achieve IBW
Medical therapy is used when diet and exercise
does not achieve goals
Goals of lipid therapy depend upon serum
triglycerides:



Tg <200: Achieve LDL-C goal
Tg 200-499: Achieve LDL-C goal, then non-HDL-C
goal
Tg ≥500: Lower Tg to <500; then achieve LDL-C goal
and then non-HDL-C goal
Niacin Therapy: Does it Help?
Lipid Effects of Niacin
Raises HDL-C
 Lowers triglycerides
 In high doses lowers LDL-C
 Lowers Lp(a)

Earlier Studies on Niacin
Reduced risk of non-fatal MI in post MI
men in pre-statin era
 Reduced angiographic CAD progression in
combination with statin therapy
 Reduced CIMT when used in combination
with a statin

AIM-HIGH: Niacin Plus Statin
to Prevent Vascular Events






3414 subjects, age ≥ 45 yrs with established ASCVD
(documented CHD, cerebrovascular or carotid disease or
symptomatic PAD)
Documented atherogenic dyslipidemia (LDL-C ≤ 160 mg/dl;
HDL-C ≤ 40 mg/dl in men or ≤ 50 mg/dl in women; and
triglycerides ≥ 150 mg/dl or ≤ 400 mg/dl)
All patients received simvastatin to achieve LDL-C 40-80
mg/dl and if necessary, ezetimibe 10 mg daily
Subjects randomized to receive Niacin E-R 2000 mg daily,
or if not tolerated,1500 mg daily; or placebo
Primary outcome: Composite endpoint of CHD death, nonfatal MI; ischemic stroke; hosp. for NSTE ACS; or symptomdriven coronary or cerebrovascular revascularization
Study enrollment began September 2005
AIM-HIGH:
Study Prematurely Terminated


5/26/11: US FDA reports early termination of trial
due to lack of benefit of niacin vs. placebo when
added to that achieved with simvastatin or
simvastatin plus ezetimibe
Small, unexplained increase in ischemic strokes in
niacin arm vs. placebo (28 strokes [1.6%] versus 12
strokes [0.7%] in niacin versus placebo arms.

Role that niacin played in these strokes is uncertain as 9
of the strokes in the niacin group occurred in subjects
who d/c’d niacin 2 months to 4 years before their strokes
HPS-2 THRIVE
25,673 pts in UK, China and Scandinavia
with established atherosclerotic vascular
disease
 All received simvastatin ± ezetimibe to
lower TC to ≤ 135 mg/dl.
 Patients randomized to receive niacin 2g
daily + laropiprant 40 mg daily and
followed for major vascular events for
medain follow-up of 4 years

HPS-2 THRIVE Results
No benefit on MVE of adding Niacinlaropiprant to aggressive LDL lowering
regimen
 Increased incidence of serious adverse
events (myopathy) in Chinese patients

European Heart Journal doi:10.1093/eurheartj/eht055
Newer Drugs for LDL-C Lowering
and HDL-C Raising
 CETP
inhibitors
 PCSK9 inhibitors
Basic HDL Metabolism
Small Intestine
VLDL, Remnant particles
Apo A1
Phospholipids (PL)
CE
TG
Liver
FC
Pre-β HDL
SR-B1
Lecithin
cholesteryl
Acyltransferase
(LCAT)
LDL -R
Bile
CE
FC
Apolipoproteins
PL
ABC A1
transporter
TG
CE
HDL-3
Macrophage
LCAT
CE
ABC G1
PL
transporter
TG
Apo B
TG
CE
VLDL, LDL
Fecal
elimination
CETP
CE
TG
CE
HDL-2
FC
Effect of CETP Inhibition
Small Intestine
Apo A1
Phospholipids
Liver
FC
Pre-β HDL
SR-B1
Lecithin cholesteryl
acyltransferase
Apolipoproteins
LDL -R
FC
Lipoprotein PL
lipase
Bile
CE
ABC A1
transporter
CE
TG
HDL-3
LPL
CE
Macrophage
LCAT
ABC G1
transporter
TG
CETP
Apo B
CE
TG
VLDL, LDL
Fecal
elimination
CE
TG
FC
HDL-2
CE
↑HDL-C
↓LDL-C
CETP inhibitors

Torcetrapib


Improved lipids, increased mortality
Dalcetrapib

No reduction in events post MI
Anacetrapib
 Evacetrapib

Mutations Causing Familial Hypercholesterolemia
-
LDL particles
Apo B
4
2
1
Hepatocyte
Lysosomal
degradation
Cholesterol 7 alpha
hydroxylase
 LDL-R
Cholesterol
5
Bile
+
 PCSK9
+
Sterol
Regulatory Element
Binding Protein
Statin
3
1. Abnormal # or
function of LDL-R
2. Defective apo B
3. PCSK9 overexpression
4. Abnormality of LDL
adaptor protein (ARH)
5. Chol 7 alpha OH ase ↓
PCSK9 Inhibitors
Subcutaneously administred
 Dosing is every 2 or every 4 weeks
 Reduces LDL-C by about 60-70%
 Has been shown to lower LDL-C in statin
intolerant patients, patients with FH
 Ongoing trials assesing safety and efficacy
in reducing CHD events
