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
 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.
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 :

Normal or slight increase LDL-cholesterol

Low HDL-cholesterol

Elevated Triglyceride
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
51% mg 80
Atorvastatin
53% mg 40
Rosuvastatin
51% Ezetimibe +
Standard dose
statin