DIABETIC DYSLIPIDEMIA

Abbas Orabi

Atherogenic ParticlesAtherogenic ParticlesApolipoprotein BApolipoprotein B

Non-HDL-CNon-HDL-CMEASUREMENTS:MEASUREMENTS:

TG-rich lipoproteinsTG-rich lipoproteins

VLDLVLDL VLDLVLDLRRIDLIDL LDLLDL Small,Small,

densedenseLDLLDL

Pathogenesis of the atherosclerotic plaqueLDL Ox-LDL

Scavenger cells within the intima

Foam cells

Growth factors

VSMC fibroblast

Atheromateous plaqueInflammatory cells

Proteolytic enzymesPlaque Rupture

Platelets aggregation

Thrombus

Glagov’s Coronary Remodeling Glagov’s Coronary Remodeling HypothesisHypothesis

NormalVessel

MinimalCAD

Compensatory expansion preserves lumen diameter

Expansion overcome:lumen narrows

SevereCAD

ModerateCAD

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.

Progression

Lipoprotein abnormalities in type 1 diabetes :

Untreated OR poorly treated

VLDL overproduction ( Insulin)

VLDL & chylomicrons impaired clearance ( LPL)

well controlled

Severe Hypertriglyceridemia

Due to :

Nearly, normal lipids profile

Lipoprotein abnormalities in type 2 diabetes :

LDL-cholesterolNormal or slight increase

HDL-cholesterolLow

TriglycerideElevated

HYPERTRIGLYCERIDEMIAHYPERTRIGLYCERIDEMIA

The key characteristic of The key characteristic of diabetic dyslipidemiadiabetic dyslipidemia

Causes of excess VLDL in Causes of excess VLDL in diabetesdiabetes

I Over production I Over production II Impaired clearance:II Impaired clearance:

*Diminished LPL activity*Diminished LPL activity*Abnormal VLDL:*Abnormal VLDL:

LargerLargerMore TGMore TG Apo c & Apo EApo c & Apo E

*competition with chylomicron in *competition with chylomicron in the the common metabolic common metabolic pathwaypathway

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 :

VLDL

Large VLDL-1 SmallVLDL-2

LDL

small LDL

LargeLDL

HDL

Large HDL-2 SmallHDL-3

Pattern B

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 :

HDL contains anti-oxidant enzymes (paraoxanase),

so, reduced HDL may predispose to 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.

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 diabetesHDL in diabetesLower levelLower level

Less formation Less formation Less survivalLess survival

Smaller sizeSmaller sizeCholesterol depleted (CETP)Cholesterol depleted (CETP)TG depletedTG depleted (Hepatic lipase(Hepatic lipase))

PLTPPLTPNascent Nascent HDL2HDL2PLTP

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.

% Change in LDL Cholesterol

Ch

ang

e in

Ath

ero

ma

Vo

lum

e m

m3

Nissen SE, JAMA 2004; 291:1071-80

50% LDL-C reduction

-15-10-5

05

101520

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20

n=502

Both treatment groups

80 mg Atorvastatin or 40 mg PravastatinPATIENTS NEED A 50% LDL-C REDUCTION TO HALT THE

PROGRESSION OF ATHEROSCLEROSIS – “REVERSAL”

To reduce atheroma volume: 53% LDL

reduction in ASTEROID

„ASTEROID“

Nissen SE, JAMA 2006;295:1556-65

To Reach Levels Below 70 To Reach Levels Below 70 mg/dlmg/dl::

To Reach Levels Below 70 To Reach Levels Below 70mg/dlmg/dl::

CholesteroCholesterol l

ReductionReduction80 mg

Atorvastatin51%51%

40 mg Rosuvastatin

53%53%

Ezetimibe + Standard

dose statin

51%51%