Vous êtes sur la page 1sur 43

DIABETIC DYSLIPIDEMIA

Abbas Orabi
Atherogenic Particles
Apolipoprotein B
MEASUREMENTS:
Non-HDL-C

VLDL VLDLR IDL LDL Small,


dense
LDL
TG-rich lipoproteins
Pathogenesis of the atherosclerotic plaque
LDL → Ox-LDL

Scavenger cells within the intima

Foam cells

Growth factors

VSMC fibroblast

Atheromateous plaque
Inflammatory cells
Proteolytic enzymes
Plaque Rupture

Platelets aggregation

Thrombus
Historical Model of
Atherosclerosis
Decades Years-Months Months-Days
Healthy Subclinical Symptomatic

Intima
Lumen
Media

Lumen Plaque
narrowing

Adapted from Nissen SE. Am J Cardiol. 2000;86:12H-17H.


Glagov’s Coronary Remodeling
Hypothesis
Progression

Compensatory expansion Expansion overcome:


preserves lumen diameter lumen narrows

Normal Minimal Moderate Severe


Vessel CAD CAD CAD

CAD = Coronary Artery Disease.


Reproduced with permission from Nissen SE. Am J Cardiol. 2000;86:12H-17H; Glagov S, et al. N Engl J Med.
1987;316:1371-1375.
Altered Endothelial Function
Intima
Media
Adventitia

Endothelial Leukocyte Increased endothelial Leukocyte


permeability migration adhesiveness adhesion

Reproduced with permission from Ross R. N Engl J Med. 1999;340:115-126.


Impact of LDL-C Infiltration on
Coronary Artery Inflammation

-C

Reproduced with permission from Hansson GK. N Engl J Med. 2005;352:1685-1695.


Fatty Streak Formation
in Atherosclerosis

Adherence and Adherence


Smooth-muscle Foam-cell T-cell aggregation and entry of
migration formation activation of platelets leukocytes
Reproduced with permission from Ross R. N Engl J Med. 1999;340:115-126.
Formation of Complicated
Atherosclerotic Plaque

Macrophage Formation of Fibrous-cap


accumulation necrotic core formation
Reproduced with permission from Ross R. N Engl J Med. 1999;340:115-126.
Lipoprotein abnormalities in type 1 diabetes :
Untreated OR poorly treated
Severe Hypertriglyceridemia

Due to :
 VLDL overproduction (↓ Insulin)
 VLDL & chylomicrons impaired clearance (↓ LPL)

well controlled
Nearly, normal lipids profile
Lipoprotein abnormalities in type 2 diabetes :
LDL-cholesterol Normal or slight increase

HDL-cholesterol Low

Triglyceride Elevated
HYPERTRIGLYCERIDEMIA

The key characteristic of


diabetic dyslipidemia
Causes of excess VLDL in
diabetes
I Over production
II Impaired clearance:
*Diminished LPL activity
*Abnormal VLDL:
Larger
More TG
Apo c & Apo E
*competition with chylomicron in the
common metabolic pathway
TG

CETP

Hepatic lipases

Small dense LDL


Small dense HDL
Mechanisms of production of small (LDL) and small
(HDL) in type 2 diabetes
Plasma lipoprotein profiles in type 2 diabetes :

↑ Large
VLDL-1
VLDL
↓ Small
VLDL-2

↑ small
LDL Pattern
LDL ↓ Large B
LDL

↓ Large
HDL-2
HDL ↑ Small
HDL-3
LDL density :

↑ Small dense LDL

Small LDL is more atherogenic than large


LDL due to its more susceptibility for oxidation
less affinity to LDLr → increasing residence
time in the plasma.
Ox-LDL :
 Ox-LDL is more atherogenic than Native LDL.

 Prolonged existence in the circulation increases the


likelihood of oxidation :
 Small dense LDL.
 As levels of LDL-C increases so does the half life
of LDL particles (Days rather than hours).
 Glycated Apo B impair LDL clearance.

 HDL contains anti-oxidant enzymes (paraoxanase),


so, reduced HDL may predispose to oxidation.
Atherogenicity of Ox-LDL :
 A ligand for scavenger receptors with production
of “foam” cells.
 Induction of programmed cell death in many cell
types including VSMC, endothelial cells and
macrophages.
 Competitive inhibition of the binding of apoptotic
bodies to macrophages, converting the normally
inflammation-free clearance of apoptotic cells to
a necrotic inflammatory process.
Apo B :
 An elevated apo B concentration is a common
feature of diabetic dyslipidemia.
 Each VLDL contains one apo B molecule.

 Apo B remains associated with the particle until


cleared from the circulation as IDL or LDL.
 LDL account for ≈ 95% of circulating apo B.

 Apo B ≈ [VLDLs, IDLs and LDLs]

 Glycated apo B impairs its interaction with hepatic


LDL receptor (B/E) and slows its clearance.
In the presence of LDL cholesterol – pattern
B – any cholesterol measures will tend to
underestimate the number of LDL particles
present (small dense LDL is relatively
cholesterol depleted).

Apo B ≈ LDL (small & large) + VLDL + IDL.


Thus apo B level may become more widespread
in clinical practice for prediction of CHD risk.
HDL in diabetes
Lower level
Less formation
Less survival
Smaller size
Cholesterol depleted (CETP)
TG depleted (Hepatic lipase)

PLTP
PLTP
Nascent HDL2
HDL density :
 The plasma triglyceride concentration is
negatively correlated with that of large HDL2
and positively correlated with the level of
small HDL3.

 HDL2-relatively depleted has the greater anti-


atherogenic effect.

 HDL3 is rapidly cleared from the circulation


leading to lower serum HDL-cholesterol.
Nissen SE, JAMA
2004; 291:1071-80

Nissen SE, JAMA


2006;295:1556-65

„ASTEROID“
20
Change in Atheroma

15
Volume mm3

10
5
0
-5 50% LDL-C reduction
-10
n=502
-15
-80 -70 -60 -50 -40 -30 -20 -10 0 10 20
% Change in LDL Cholesterol
To reduce atheroma
Both treatment
volume: 53%groups
LDL
reduction in ASTEROID

80 mg Atorvastatin or 40 mg
PATIENTSPravastatin
NEED A 50% LDL-C REDUCTION TO HALT THE
PROGRESSION OF ATHEROSCLEROSIS – “REVERSAL”
:To Reach Levels Below 70 mg/dl

Cholesterol
Reduction
mg 80 51%
Atorvastatin
mg 40 53%
Rosuvastatin
Ezetimibe + 51%
Standard dose
statin