Apolipoprotein B (Apo B)Apolipoprotein B (Apo B)Validity in DMValidity in DM

Apolipoprotein B (Apo B)Apolipoprotein B (Apo B)Validity in DMValidity in DM

Dr. Lamia M Al-NaamaBiochemistry Dept

Basrah Medical College

Dyslipidemia in patients with DiabetesDyslipidemia in patients with Diabetes

High triglyceride (TG) levels TG-rich remnant lipoproteins (VLDL) Altered metabolism of LDL and HDL particles

Absolute levels of LDL cholesterol are commonly not significantly increased, number of LDL particles Predominantly small, dense LDL particles

Low levels of HDL cholesterol (may reduce reverse cholesterol transport)

High triglyceride (TG) levels TG-rich remnant lipoproteins (VLDL) Altered metabolism of LDL and HDL particles

Absolute levels of LDL cholesterol are commonly not significantly increased, number of LDL particles Predominantly small, dense LDL particles

Low levels of HDL cholesterol (may reduce reverse cholesterol transport)

Adapted from Haffner SM Diabetes Care 2003; 26: S83-6and Garvey WT et al. Diabetes 2003; 52: 453-62

Overall LDL cholesterol may also be elevated.

High triglyceride levels manifest as high triglyceride-rich remnant lipoproteins (VLDL) and alter the metabolism of LDL and HDL particles.

Because a mixed dyslipidemic profile increases the risk of developing cardiovascular disease,

it is also referred to as the atherogenic lipid triad or atherogenic dyslipidemia.

Atherogenic dyslipidemia contributes to an increased risk for cardiovascular disease.

Overall LDL cholesterol may also be elevated.

High triglyceride levels manifest as high triglyceride-rich remnant lipoproteins (VLDL) and alter the metabolism of LDL and HDL particles.

Because a mixed dyslipidemic profile increases the risk of developing cardiovascular disease,

it is also referred to as the atherogenic lipid triad or atherogenic dyslipidemia.

Atherogenic dyslipidemia contributes to an increased risk for cardiovascular disease.

Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL and Small LDL and Reduction of HDL

SmallerLDL

HL

Apo AI

Renalclearance

LPL

RemnantsLPL/HL

VLDL

TGTG CETP

Cholesterol

HDL

TGTGLDL

TGTG SmallerHDL

Apo AI: apolipoprotein AI

CETP: cholesteryl ester transfer protein

HL: hepatic lipase

LPL: lipoprotein lipase

TG: triglyceridesAdapted from Haffner SM Diabetes Care 2003; 26: S83-6and Garvey WT et al. Diabetes 2003; 52: 453-62

Diabetes Care 2004;27:S68

“ The mean concentration ofLDL cholesterol in those with type 2 diabetes isnot significantly different from that in those

individuals who do not have diabetes”.

“ ,Howeverqualitative changes in LDL cholesterol may be present. Patients with diabetes tend to have a higher

proportion of smaller and denser LDL particles which are more susceptible to oxidation and may therefore increase

the risk of cardiovascular events”.

“The mean concentration of LDL cholesterol in those with type 2 diabetes is not significantly different from that in those

individuals who do not have diabetes”.

“However, qualitative changes in LDL cholesterol may be present. Patients with diabetes tend to have a higher

proportion of smaller and denser LDL particles which are more susceptible to oxidation and may therefore increase

the risk of cardiovascular events”.

LDL Size Certainly Seems to Matter

Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Small Dense LDL and CHD: Potential Atherogenic Mechanisms

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

Conventional lipid measurements

• Total Cholesterol = VLDL + LDL + HDL

• Friedewald Equation: VLDL = TG/5

• Calculated LDL = TC – (HDL + TG/5)

• Triglycerides

• HDL-C

20 +years of studies: Patients with smaller LDL size have greater

CHD risk at any given level of LDL-C.

20 +years of studies:Patients with smaller LDL size have greater

CHD risk at any given level of LDL-C.

LDLCholesterol

Balance

130 mg/dL 130 mg/dL

Large LDL(Pattern A)

Small LDL(Pattern B)

Higher riskLower risk

But they also have more

particles!www.myheathywiast.org

Apo B

Similar LDLcholesterol

Slower plasma clearance Greater artery uptake & retention Faster oxidation More particles

Cholesterylester

LDL Cholesterol Underestimates the Number of LDL Particles When Levels of Small LDL Are Increased

Larger LDL )phenotype A(More cholesterol/particle

Smaller LDL )phenotype B(Less cholesterol/particle

www.myheathywiast.org

Particle number v/s Lipid level

• Cholesterol is carried into the arterial wall within a LP particle and …

• the number of LP particles determines the likelihood of cholesterol entering and lodging within an arterial wall

• Now, the lipid composition of the principal atherogenic lipoproteins differs substantially amongst individuals

• because the number of particles within any lipoprotein fraction determines the likelihood of any member of that class entering and lodging within an arterial wall

Particle number v/s Lipid level

• Thus, for the same amount of cholesterol measured in 2 individuals, their LP particle number may be different

• Therefore, lipid levels do not automatically match lipoprotein particle levels

• And the risk due to a lipid fraction not same as the risk due to the LP fraction

• Hence, the total number of atherogenic particles is a more important determinant of the risk of vascular disease than the level of any of the conventional lipids (TC, TG etc)

Atherogenic ParticlesAtherogenic Particles

Size (nm)Size (nm)

Density (g/ml)Density (g/ml)

VLDLVLDL

1.0041.0045050

TG-rich LipoproteinsTG-rich Lipoproteins

RLPRLP

2525

1.0131.013

BuoyantBuoyant LDLLDL

2222

1.0231.023

DenseDenseLDLLDL

1919

1.0441.044

Mean EndothelialMean EndothelialPore SizePore Size

For example the amount of cholesterol carried by an LDL particle varies greatly between individuals and can also

change in response to lipid altering Rx.

Report of the thirty person/ten country panel Journal of Internal Medicine, 10 FEB 2006

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty person/ten country panel‐ ‐

So how does one measure the particle number?

1. NMR spectroscopy

2. By measuring apoB

Apolipoprotein B (apoB) is a major structural protein for atherogenic lipoproteins including chylomicron, VLDL, intermediate-density lipoprotein, large buoyant LDL, and small dense LDL.

ApoB is required to transport lipids from the liver and gut to peripheral tissues.

What is Apo B

In general, one molecule of apoB is present on each lipoprotein particle;

The total apo B level represents the total number of atherogenic particles and reflects the atherogenic potential of the whole lipoprotein fraction .

What is Apo B

Why apo B?

•each VLDL, IDL, LDL, and Lp(a) lipoprotein particle contains one molecule of apo B100

•Each chylomicron and chylomicron remnant particle contains one molecule of apo B48 .

•Clinical assays of apoB measure both apo B100 and apo B48 .

•Hence total plasma apo B = (apo B100 +apo B48) represents the total atherogenic particle number

Atherogenic ParticlesAtherogenic Particles

Apolipoprotein BApolipoprotein BMEASUREMENTSMEASUREMENTS::

TG-rich lipoproteinsTG-rich lipoproteins

VLDLVLDL VLDLVLDLRRIDLIDL LDLLDL Small,Small,

densedenseLDLLDL

From Lipids Online: http://www.lipidsonline.org/

Atherogenic ParticlesAtherogenic Particles

Apolipoprotein BApolipoprotein B

Non-HDL-CNon-HDL-CMEASUREMENTSMEASUREMENTS::

TG-rich lipoproteinsTG-rich lipoproteins

VLDLVLDL VLDLVLDLRRIDLIDL LDLLDL Small,Small,

densedenseLDLLDL

From Lipids Online: http://www.lipidsonline.org/

Is apo B better than LDL-C? • Insulin resistance and type 2 diabetes mellitus, MetS, CKD

• Familial combined hyperlipidaemia, (associated with premature coronary artery disease)

• The Quebec Cardiovascular Study, the AMORIS study, the Thrombo Study , the Thrombo Metabolic Syndrome Study, the Northwick Park Heart Study, the Nurses’ Health Study and patients with type 2 diabetes in the Health Professionals’ Follow-up Study

• INTERHEART Study – 52 countries, 30,000 people – value of apo

B/A1 ratio (accounted for over 50% of CV events)

• Hence apo B has entered ESC guidelines for risk estimation and target of Rx

• Insulin resistance and type 2 diabetes mellitus, MetS, CKD

• Familial combined hyperlipidaemia, (associated with premature coronary artery disease)

• The Quebec Cardiovascular Study, the AMORIS study, the Thrombo Study , the Thrombo Metabolic Syndrome Study, the Northwick Park Heart Study, the Nurses’ Health Study and patients with type 2 diabetes in the Health Professionals’ Follow-up Study

• INTERHEART Study – 52 countries, 30,000 people – value of apo

B/A1 ratio (accounted for over 50% of CV events)

• Hence apo B has entered ESC guidelines for risk estimation and target of Rx

What happens on statin Rx? • LDL cholesterol reduced more than apo B

• Thus apo B on statin therapy will be relatively higher than LDL cholesterol

• Thus on treatment apo B should be a more reliable index of the residual risk

• In Studies : AFCAPS/TexCAPS, the Leiden Heart Study and the Thrombo Study on-treatment …

• apo B was more predictive of the residual risk of vascular events

• LDL cholesterol reduced more than apo B

• Thus apo B on statin therapy will be relatively higher than LDL cholesterol

• Thus on treatment apo B should be a more reliable index of the residual risk

• In Studies : AFCAPS/TexCAPS, the Leiden Heart Study and the Thrombo Study on-treatment …

• apo B was more predictive of the residual risk of vascular events

Thus, advantages of measuring apo B:

• apo B-guided statin therapy should be substantially more

effective than Rx guided by LDL cholesterol

• Enables focus on one rather than several variables

• Non fasting sample

• Measurement standardized by IFCC/WHO

• Indirect measurement of LDL-C requires fasting sample and

direct measurement of LDL-C not standardized.

• apo B-guided statin therapy should be substantially more

effective than Rx guided by LDL cholesterol

• Enables focus on one rather than several variables

• Non fasting sample

• Measurement standardized by IFCC/WHO

• Indirect measurement of LDL-C requires fasting sample and

direct measurement of LDL-C not standardized.

But problems with apo B testing• Test costs ($79.15 v/s $59.20 for an entire conventional lipid

panel)

• Significant lag time in test result reporting

• Poor goal attainment rates on standard therapies, including high-dose statins, with limited evidence for other available interventions and therapeutic effects.

• Discrepant cut off values…….

Drug therapies known to alter advanced lipoprotein analysis parameters, specifically niacin and fenofibrate, have not been shown to additionally reduce cardiovascular risk in recent randomized trials of high-risk patients treated with statin therapy.

• Test costs ($79.15 v/s $59.20 for an entire conventional lipid panel)

• Significant lag time in test result reporting

• Poor goal attainment rates on standard therapies, including high-dose statins, with limited evidence for other available interventions and therapeutic effects.

• Discrepant cut off values…….

Drug therapies known to alter advanced lipoprotein analysis parameters, specifically niacin and fenofibrate, have not been shown to additionally reduce cardiovascular risk in recent randomized trials of high-risk patients treated with statin therapy.

Discrepant apo B cutoffs• The American Diabetes Association (ADA)/American College of

Cardiology (ACC) position statement recommends an apoB goal of <80 mg/dl in highest-risk patients and <90 mg/dl in high-risk patients.

• In contrast, the American Association of Clinical Chemistry (AACC) recommends an apoB goal of <80 mg/dl in high-risk patients and <100mg/dl in moderate risk people.

• The Canadian Cardiovascular Society is in disagreement with the ADA/ACC and the AACC, as they recommend an apoB <80 mg/dl as the primary therapeutic target in high-& moderate-risk patients

• The American Diabetes Association (ADA)/American College of Cardiology (ACC) position statement recommends an apoB goal of <80 mg/dl in highest-risk patients and <90 mg/dl in high-risk patients.

• In contrast, the American Association of Clinical Chemistry (AACC) recommends an apoB goal of <80 mg/dl in high-risk patients and <100mg/dl in moderate risk people.

• The Canadian Cardiovascular Society is in disagreement with the ADA/ACC and the AACC, as they recommend an apoB <80 mg/dl as the primary therapeutic target in high-& moderate-risk patients

Can non HDL-C be a surrogate for apo B ?

• Several large prospective studies have demonstrated that the apo B level is a better predictor of cardiovascular risk than any other lipid measurements .

• In the AMORIS study, apoB was found to be superior to LDL cholesterol as a marker to assess cardiovascular risk, particularly in patients with normal or low LDL cholesterol levels .

• Data from numerous clinical trials with statins have also reported that residual risk is more strongly associated with the apoB level rather than LDL or non-HDL cholesterol levels .

• In the THROMBO study in patients who had recovered from myocardial infarction, higher apoB levels were independently associated with an increased risk of recurrent events, whereas conventional lipid measurements were not .

• Several large prospective studies have demonstrated that the apo B level is a better predictor of cardiovascular risk than any other lipid measurements .

• In the AMORIS study, apoB was found to be superior to LDL cholesterol as a marker to assess cardiovascular risk, particularly in patients with normal or low LDL cholesterol levels .

• Data from numerous clinical trials with statins have also reported that residual risk is more strongly associated with the apoB level rather than LDL or non-HDL cholesterol levels .

• In the THROMBO study in patients who had recovered from myocardial infarction, higher apoB levels were independently associated with an increased risk of recurrent events, whereas conventional lipid measurements were not .

ApoB measurements is better indicator of atherogenic risk than LDL-C.

New guidelines should be advocated by Expert Panels

Like the NCEP or ATP (Adult Treatment Panel) to implement ApoB measurements

A unified cut-off values for Apo B

Conclusion

THANK YOU!!THANK YOU!!