Transcript Dyslipidemia and Insulin Resistance – Bad Company

Dyslipidemia and Insulin Resistance Bad Company
James R. Ebert, MD, MPH
March 9th, 2011
Objectives
• Review current recommendations for
treatment of elevated cholesterol in
children and adolescents
• Examine the coexistence of insulin
resistance and lipid abnormalities
• Present recent research on childhood
metabolic syndrome
• But not necessarily in that order
Disclosures
• Nothing to disclose
Why bother to check lipid profiles?
Leading Causes of Death
US 2007
Females
Males
Cardiovascular
Disease, total
401,783
350,236
Cancer
271,079
291,796
Accidents
43,223
80,483
Chronic Lung
Disease
65,841
62,083
Source: CDC/NCHS 2010
7/17/2015
7
Early Appearance of Atherosclerosis:
Bogalusa Heart Study
Prevalence of Fibrous Plaque Lesions
80
Coronary Arteries
Aorta
%
60
40
20
0
16-20
2-15
Age (Years)
Berenson et al, NEJM, 1998
21-25
26-39
2-15 16-20 21-25
26-39
p = 0.001 for trend
CORONARY
ARTERIES
AORTA
Fatty Streaks
Fibrous Plaques
Fatty Streaks
Fibrous Plaques
Body-mass
index
0.33 †
0.24 ‡
0.41 §
0.29 †
Systolic BP
0.31 †
0.17
0.47 §
0.41 §
Diastolic BP
0.14
0.10
0.18
0.24 ‡
Total
cholesterol
0.54 §
0.15
0.26 ‡
0.23
LDL
cholesterol
0.54 §
0.16
0.29 ‡
0.32 †
HDL
cholesterol
-0.03
0.05
-0.14
-0.12
0.23
0.26‡
0.32 †
0.37 †
Triglycerides
†P<0.01.
Berenson et al, NEJM, 1998
‡P<0.05.
§P<0.001
 Defined Risk Factors in adults are
associated with accelerated
atherosclerosis and CVD rates
 Atherosclerosis begins in childhood
 Extent of atherosclerosis in children
correlated with same risk factors as
in adults
Strong JP et al JAMA 1999; Berenson GS et al NEJM 1998; Williams CL et al Circ. 2002
Risk Factors for Coronary Heart
Disease
•
•
•
•
•
•
•
•
•
Hypercholesterolemia
Low HDL-c (<35mg/dL)
Obesity
Hypertension
Diabetes
Smoking
Age
“Y” chromosome
Family history early onset CV disease
10-Year % Probability
of Event
Effect of Multiple Risk Factors on Probability
of CAD: Framingham Study
42
36
30
24
18
12
6
0
SBP 150-160
Cholesterol high
HDL-C low
Diabetes
Smoking
ECG-LVH
Kannel, 2000
40
21
10
6
4
+
-
14
+
+
-
+
+
+
-
+
+
+
+
-
+
+
+
+
+
-
+
+
+
+
+
+
Childhood Metabolic Syndrome
Risk fctrs
Obesity
BP %
Triglycerides
HDL
Glucose mg/dL
Cook, 2003
≥3
Waist circ. ≥ 90th
% for age
and sex
≥ 90th
≥ 110
mg/dL
≤ 40 mg/dL
FG ≥ 110
De Ferranti,
2004
≥3
Waist circ. >75th
% for age
and sex
> 90th
≥ 100
mg/dL
<50 mg/dL F
<45 mg/dL M
FG ≥ 110
Weiss, 2004
≥3
Body mass index
z-score ≥
2.0
> 95th
> 95th %
< 5th %
140-199 2h GTT
Cruz, 2004
≥3
Waist circ. ≥ 90th
% for age
and sex
> 90th
≥ 90th %
≤ 10th %
140-199 2h GTT
Ford, 2005
≥3
Waist circ. ≥ 90th
% for age
and sex
≥ 90th
≥ 110
mg/dL
≤ 40 mg/dL
FG ≥ 110
Goodman,
2007
≥3
Waist circ. ≥ 90th
% for age
and sex
≥ 90th
≥ 110
mg/dL
≤ 10th %
FG ≥ 100
Pathways to Type 2 Diabetes Implicated by Identified Common Variant Associations.
McCarthy MI. N Engl J Med 2010;363:2339-2350.
Insulin Resistance
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•
•
•
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Acanthosis nigricans
Elevated fasting insulin*
Huge spikes during OGGT
FGIR
Other indices (HOMA-IR, QUICKI)
*Laskin, 1993
Acanthosis
Elevated Insulin Levels
• Fasting
– >17 (Dayton CMC lab - with disclaimer)
– >17 if pubertal; >13 if prepubertal (Cincinnati)
• 2 hour sample during standard OGGT
– normal 15-53 (adults–Cincinnati Children’s)
– < 60 (adults–Yeni-Komshian, DiabCare 2000)
• 2 hours after meal
– 7.6 – 26 (adults – Cincinnati Children’s)
“Sally” Age 15
Fasting 30 min
1 hour
BMI 36.6
2 hours
3 hours
4 hours
5 hours
Glucose
mg/dL
98
147
123
110
106
69
85
Insulin
uIU/ml
13.9
257
201
205
162
22.2
17.1
Fasting Glucose/Insulin Ratio
• Fasting Glucose / Fasting Insulin
– Normal - greater than 7
• Correlates with insulin AUC during OGGT
• Correlates with other measures of IR
– QUICKI
{ 1/(log insulin + log glucose) }
– HOMA-IR { (glucose X insulin) / 405 }
• Easy to do
Vuguin, 2001; Silfen, 2001; Keskin, 2005; Yani-Komishian, 2000
Lipoproteins
• Plasma particles that transport lipids
including cholesterol
• Classes
– chylomicrons
– very low density lipoproteins (VLDL)
– intermediate density lipoproteins (IDL)
– low density lipoproteins (LDL)
– high density lipoproteins (HDL)
Lipoprotein
class
Density
(g/mL)
Diameter
(nm)
Protein % Phospho
of dry wt
-lipid %
Triacylglycerol
% of dry wt
HDL
1.063-1.21
5 – 15
33
29
8
LDL
1.019 –
1.063
18 – 28
25
21
4
IDL
1.006-1.019
25 - 50
18
22
31
VLDL
0.95 –
1.006
30 - 80
10
18
50
chylomicrons
< 0.95
100 - 500
1-2
7
84
Composition and properties of human lipoproteins
most proteins have densities of about 1.3 – 1.4 g/mL and lipid aggregates usually
have densities of about 0.8 g/mL
The apolipoproteins
• Major components of lipoproteins
• Classified by letter designation (A thru E)
• Roman numeral suffix describes the order
in which the apolipoprotein emerge from a
chromatographic column
• Responsible for recognition of particle by
receptors
Lipoproteins
• Spherical particles with a hydrophobic
core (TG and esterified cholesterol)
• Apolipoproteins on the surface
• large: apoB (b-48 and B-100) atherogenic
• smaller: apoA-I, apoC-II, apoE
• Classified on the basis of density and
electrophoretic mobility (VLDL; LDL;
IDL;HDL; Lp(a)
Apoproteins of human lipoproteins
• A-I (28,300)- principal protein in HDL
• 90 –120 mg% in plasma; activates LCAT (Lecithin-cholesterol
acyltransferase)
• A-II (8,700) – occurs as dimer mainly in HDL
• 30 – 50 mg %; enhances hepatic lipase activity
• B-48 (240,000) – found only in chylomicron
– <5 mg %; derived from apo-B-100 gene by RNA
editing; lacks the LDL receptor-binding domain of
apo-B-100
• B-100 (500,000) – principal protein in LDL
• 80 –100 mg %; binds to LDL receptor
Apoproteins of human
lipoproteins
• C-I (7,000) – found in chylomicron, VLDL, HDL
• 4 – 7 mg %; may also activate LCAT
• C-II (8,800) - found in chylomicron, VLDL, HDL
• 3 – 8 mg %; activates lipoprotein lipase
• C-III (8,800) - found in chylomicron, VLDL, IDL, HDL
• 8 -15 mg %; inhibits lipoprotein lipase
• D (32,500) - found in HDL
• 8 – 10 mg %; also called cholesterol ester transfer protein
(CETP)
• E (34,100) - found in chylomicron, VLDL, IDL HDL
• 3 – 6 mg %; binds to LDL receptor
• H (50,000) – found in chylomicron; also known as b-2glycoprotein I (involved in TG metabolism)
Major lipoprotein classes
• Chylomicrons (derived from diet)
– density <<1.006
– diameter 80 - 500 nm
– dietary triglycerides
– apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/CIII, apoE
– remains at origin in electrophoretic field
Chylomicrons
• Formed through extrusion of resynthesized
triglycerides from the mucosal cells into the
intestinal lacteals
• Flow through the thoracic ducts into the
suclavian veins
• Degraded to remnants by the action of
lipoprotein lipase (LpL) which is located on
capillary endothelial cell surface
• Remnants are taken up by liver parenchymal
cells due to apoE-III and apoE-IV isoform
recognition sites
Major lipoprotein classes
• VLDL
– density >1.006
– diameter 30 - 80nm
– endogenous triglycerides (VLDL=TG/5)
– apoB-100, apoE, apoC-II/C-III
– prebeta in electrophoresis
– formed in the liver as nascent VLDL (contains
only triglycerides, apoE and apoB)
VLDL
• Nascent VLDLs then interact with HDL to
generate mature VLDLs (with added
cholesterol, apoC-II and apoC-III)
• Mature VLDLs are acted upon by LpL to
generate VLDL remnants (IDL)
• IDL are further degraded by hepatic
triglyceride lipase (HTGL) to generate
LDLs
Major lipoprotein classes
• IDL (intermediate density lipoproteins)
– density: 1.006 - 1.019
– diameter: 25 - 35nm
– cholesteryl esters and triglycerides
– apoB-100, apoE, apoC-II/C-III
– slow pre-beta
• Highly atherogenic
Major lipoprotein classes
• LDL (low density lipoproteins)
– density: 1.019 - 1.063
– diameter: 18-25nm
– cholesteryl esters
– apoB-100
– beta (electrophoresis)
Major lipoprotein classes
• HDL (high density lipoproteins)
– density: 1.063-1.210
– diameter: 5-12nm
– cholesteryl esters and phospholipids
– apoA-I, apoA-II, apoC-II/C-III and apoE
– alpha (electrophoresis)
HDLs
• Several subfamilies exist
– Discoidal HDL :
• contains cholesterol, phospholipid, apoA-I, apoA-II,
apoE and is disc shaped;
• Formed in liver and intestine
• It interacts with chylomicra remnants and lecithincholesterol acyl transferase (LCAT) to form HDL3
HDLs
• HDL3
– Composed of cholesterol, cholesterol ester,
phospholipid and apoA and apoE
– Interacts with the cell plasma membranes to remove
free cholesterol
– Reaction with LCAT converts HDL3 to HDL2a (an HDL
with a high apoE and cholesterol ester content)
– Cholesterol ester-rich HDL2a is then converted to
triglyceride-rich HDL2b by concomitant transfer of HDL
cholesterol esters to VLDL and VLDL triglycerides to
HDL
Functions of HDL
•
•
•
•
Transfers proteins to other lipoproteins
Picks up lipids from other lipoproteins
Picks up cholesterol from cell membranes
Converts cholesterol to cholesterol esters
via the LCAT reaction
• Transfers cholesterol esters to other
lipoproteins, which transport them to the
liver (referred to as “reverse cholesterol
transport”)
Lipoproteins (a)- Lp(a)
• Another atherogenic family of lipoproteins(at
least 19 different alleles)
• Consist of LDL and a protein designated as (a)
• The apoA is covalently linked to apoB-100 by a
disulfide linkage
• Contains a kringle protein (tri-looped structure
with 3 intramolecular disulfide bonds –
resembles a pretzel, mimics fibrinogen)
• High risk association with premature coronary
artery disease and stroke
The LDL receptor
• Characterized by Michael Brown and Joseph
Goldstein (Nobel prize winners in 1985)
• Based on work on familial hypercholesterolemia
• Also called B/E receptor due to ability to
recognize particles containing apos B and E
• Activity occurs mainly in the liver
• Receptor recognizes apo E more readily than
apo B-100
Cholesterol sources, biosynthesis
and degradation
• Diet
– only found in animal fat
• Biosynthesis
– primarily synthesized in the liver from acetyl CoA
– biosynthesis is inhibited by LDL uptake by the liver
• Degradation
– only occurs in the liver
– cholesterol is converted to bile acids
Bile acids from cholesterol
• Formed from cholesterol in the liver
• Stored in the gall bladder in bile as bile
salts
• Utilized during digestion of fats and other
lipid substances
Bile acids
• Fat digestion products are absorbed in the
first 100 cm of small intestine
• Primary and secondary bile acids are
reabsorbed almost exclusively in the ileum
returning to the liver by way of the portal
circulation (nearly 100%)
• Less than 500 mg a day escapes
reabsorption and is excreted in the feces
Function of bile salts
• Emulsification of fats due to detergent
activity
• Aid in the absorption of fat-soluble
vitamins (especially vitamin K)
• Accelerate the action of pancreatic lipase
• Keep cholesterol in solution (as micelles)
Frederickson -WHO
classification
Type I: raised chylomicrons, reduced HDL,
absence of lipoprotein lipase; deficiency of
apo CII (hyperchylomironemia). Rare
Type II-A: raised LDL; decreased catabolism of
LDL (receptor deficiency or polygenic)
Type II-B: raised VLDL + LDL; often reduced
HDL; increased production of VLDL +
impaired LDL catabolism
Type III: raised IDL; abnormal apolipoprotein E;
impaired catabolism of IDL; elevated
cholesterol and triglycerides. Rare
Frederickson -WHO classification
Type IV: raised VLDL; often reduced HDL;
impaired VLDL catabolism; dietary
indiscretion
Type V: raised chylomicrons + VLDL;
reduced HDL; reduced lipoprotein lipase +
VLDL hypersecretion. Rare.
Mechanisms of action of drugs
• Bind to bile acids/cholesterol
– inhibit absorption/reabsorption
•
•
•
•
•
•
Inhibit absorption directly
Increase peroxisomal FA oxidation
Stimulate lipoprotein lipase
Inhibit triglyceride lipase
Inhibit HMG CoA reductase
Stimulate microsomal 7-alpha hydroxylase
Drug Classification
• Cholesterol lowering agents
– Bile acid sequestrants
– Absorption blockers
– HMG Co-A reductase inhibitors
Drug Classification
• mixed activity (nicotinic acid)
• triglyceride lowering
– clofibrate
– gemfibrosil
– fenofibrate
Bile acid sequestrants
•
•
•
•
Cholestyramine
Oral, safe, non systemic
Bind to bile acids and inhibit reabsorption
Increase 7-alpha hydroxylase activity
leading to cholesterol degradation
• Decrease plasma LDL
• Problems:
– Abdominal discomfort, bloating, constipation
– Decrease absorption of other drugs
Colesevelam
• Same mechanism of action as colestipol and
cholestyramine
Bile sequestering resins
• drug interactions
(decreased serum
level)
•
•
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•
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•
aspirin
clindamycin
clofibrate
furosemide
glipzide
tolbutamide
phenytoin
imipramine
•
•
•
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•
•
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•
methyldopa
nicotinic acid
penicillin G
propranolol
tetracycline
thiazide diuretics
digoxin
hydrocortisone
phosphate supplements
Ezetimibe
OH
OH
N
F
O
F
EZETIMIBE
Blocks the intestinal absorption of
cholesterol.
Can be used in combination with a statin
PLANT STEROLS
C H3
C H3
H3 C
H3C
C H3
C H3
C H3
C H3
C H2C H3
C H2C H3
C H3
C H3
HO
HO
STIGMASTANO L
BETA SITO STERO L
HMG CoA reductase inhibitors
• The Statins
• Precaution:
• Mild elevation of serum transaminases
• Minor increases in creatine kinase
• Contraindicated during pregnancy
• Available for pediatric use beginning at
age 8
Stein 1999, De Jongh 2002
FIBRIC ACID DERIVATIVES
C H3
C H3
O
(C H2)3 C
C H3
COO H
Cl
C H3
H3C
Cl
C H3
C
O
C H3
O
FENO FIBRATE (TRIC O R)
Triglyceride-lowering
C
C O O Et
C H3
GEMFIBRO S IL (LO PID)
iPrO2C
O
C LO FIBRATE (ATRO MID-S )
NICOTINIC ACID (Niacin)
COOH
A water soluble B vitamin
N
NIC O TINIC AC ID (NIAC IN)
Minimum effective dose – 1.0 gm daily
Sustained release forms are available
Nicotinic acid (Niacin)
• Actions
• dual plasma triglyceride and cholesterol lowering
– decreases VLDL and LDL
• decreases TG lipase in adipose tissue
• increases lipoprotein lipase in adipose tissue
• also decreases Lp(a)
• Side effects
• transient cutaneous flush
• histamine release
• potentiates BP effect of antihypertensives
• Can be used with a statin
Therapeutic Approach
• Diet and exercise come first
• Medications are added as needed if
lifestyle changes are not sufficient
Lichtenstein, 2006; Gidding, 2005
Population-based approach for all
healthy children >2 years of age
• Adequate daily physical activity
• Adequate caloric intake to sustain normal growth
and development
• Dietary cholesterol < 300mg daily
• Total fat < 30% of total calories
– Saturated fat < 10% of total calories
– Trans fat < 1% of total calories
• Emphasize fruits, vegetables, whole grains, fish,
low-fat dairy products
• Avoid sugar-sweetened beverages, food, and
added salt
Lichtenstein, 2006; Gidding, 2005
Targeted approach for children with
elevated LDL, or FH of CVD
• Reduce cholesterol intake to <200mg daily
• Reduce saturated fat intake to <7% of total
calories
• If cholesterol not adequately reduced
within 6 to 12 months, begin
pharmacotherapy if older than 8
Daniels, 2008; McCrindle, 2007
Targets for therapy
• Initial reduction of LDL to <160 mg/dL
– Further reduction to 130 or even 110 in the
presence of
•
•
•
•
•
Strong FH of CVD
Diabetes
Metabolic syndrome/insulin resistance/IGT
Obesity
Other high-risk factors such as elevated Lp(a),
HDL<30
Choice of lipid-lowering
medications
• All statins lower LDL
– Some cost more than others
• Population-based differences in LDLlowering effectiveness may not hold true in
individuals
• Individual patient experiences in reducing
TG or raising HDL may differ from
literature
Choice of medications (cont)
• Kids seem to respond at lower doses than adults
– Might be related to different target choices
• Kids seem to have fewer SE than adults
– Myalgias, elevated CK/transaminases are uncommon
• Although it can be expected that CVD incidence
will eventually be reduced in statin-treated
children, the evidence will not be available for at
least a decade or two
Recent Research - OSCIR
• Increased oxidative stress has been
associated with inflammatory processes
leading to endothelial dysfunction,
atherosclerosis, and CVD.
• Markers for such oxidation include
oxidized LDL (ox-LDL) and 8-iso-PGF2a
• These factors were studied in a sample of
overweight children
Holvoet, 2004; Kim 2006; Urakawa, 2003
Sample
• 277 patients recruited from the Lipid Clinic
• Inclusion criteria
– BMI >=85th%
– Ages 8 through 18
– Elevated fasting glucose, or elevated fasting insulin,
or abnormal fasting lipids
• Exclusion criteria
– Diabetes, inflammatory diseases
– Glucose or lipid lowering medications
– Corticosteroids
Data obtained
• Age, race, sex
• Height, weight, SBP, DBP
• Following a >8 hour fast
– Ox-LDL, 8-iso-PGF2a
– Lipid panel, glucose, insulin
– A large subset also underwent GTT and NMR
particle studies
Results
•
•
•
•
•
•
223 of the 277 completed the testing
Mean age was 12.6 years (6.1 – 18.5)
Median BMI was 33.9 (20.2 – 75.7)
54.7% female
67% Caucasian, 27% AA, 6% Other
No significant sex differences in age,
weight, BMI, or rBMI, or oxidative stress
levels
Results continued
•
•
•
•
57% of children were hypertensive
40% were dyslipidemic
14% had IFG, IGT
2 children were diagnosed with T2DM
Conclusions
• 8-iso-PGF2a levels correlated with standard
measures of insulin resistance (IR), including the
easy to calculate FGIR
• ox-LDL was not correlated with IR, or fasting
levels of glucose or insulin
• ox-LDL was correlated with LDLc, LDLp, total
Cholesterol, and triglyceride levels
• Neither ox-LDL nor 8-iso-PGF2a were correlated
with BMI, rBMI, age, race, or sex in this
significantly obese sample