DyslipidemiaBrian Lee, MD

Division of Endocrinology & Metabolism

Department of Medicine

Srinakharinwirot University

Basic science

Types of lipids

• Cholesterol

• Fatty acids

• Triglycerides: Fatty acids + glycerol

• Phospholipids: Fatty acids + glycerol + phosphatidic acid

Types of lipids

What are lipoproteins?

• Conjugated particle

– Lipids: cholesterol, triglycerides

– Proteins: apoprotein (apolipoproteins)

• Function: transport lipids and fat-soluble

vitamins

• Lipids do not dissolve in water so they

have to be “packaged.”

Structure of lipoprotein

Outer hydrophobic coat: phospholipids, apolipoproteins, free cholesterol (FC)

Inner hydrophilic core: triglycerides, cholesteryl esters (CE)

What are cholesteryl esters?

• Free cholesterol is confined to the outer coat of

the particle.

• Free cholesterol is converted to cholesteryl

esters by enyzmes called “cholesterol

acyltransferaces.”

• Cholesteryl esters can be packaged into the

inner core of lipoproteins.

• This increases the capacity of lipoproteins,

allowing for more efficient cholesterol transport through the blood stream.

What are apolipoproteins?

• Proteins which form part of the outer coat of

lipoproteins.

• Functions of apolipoproteins:

1.Bind to lipoprotein receptors– ApoB binds to LDL receptors on the liver surface. LDL

particles are then taken up by the liver.

2.Activate/inhibit enzymes involved in

lipoprotein metabolism– ApoC-II activates lipoprotein lipase, which removes

triglycerides from chylomicrons and VLDL.

Major lipid component

Cholesterol:

LDL, IDL, HDL, Lp(a)

Triglyceride:

Chylomicron, VLDL, IDL

Major apolipoprotein

B-100: LDL, VLDL, IDL, Lp(a)

B-48: chylomicron

A-I, A-II: HDL

Lipoprotein metabolism

LPL: lipoprotein lipase, HL: hepatic lipase, FFA: free fatty acid

Exogenous pathway accounts for 25% of cholesterol

Endogenous

pathway: 75% of cholesterol

Reverse cholesterol transport

Role of HDL

Redistribution of

lipids from cells with

excess cholesterol

to cells requiring

cholesterol or to the liver for excretion.

CE: cholesteryl ester, LCAT: lecithin:cholesterol acyltransferase, LDLR: LDL receptor, SR-BI: scavenger receptor

Cholesterol biosynthesis

Enterohepatic circulation of cholesterol and bile acids

Cholesterol

LPLApoCII

FFATG

Chylomicron remnant

LRP1

Enter circulation

Apo B 48

chylomicron

Intestinal cell

MTTP

FFA

NPC1L1 FATPABCG5/G8

FFA + glycerol

TG

cholesterol

cholesterol ester

VLDL

LPL,ApoCII

FFA

IDL

LDL

HL

LD

LR

AP

Peripheral

cell

LDL

HDL

ABCG1

SRB1

XFAMILIAL DYSBETA-LIPOPROTEINEMIA

a | Extracellular proprotein convertase subtilisin kexin 9 (PCSK9; red) binds the low-density

lipoprotein receptor (LDLR; blue), driving internalization of the receptor and its lysosomal

degradation. LDL cholesterol (LDL-C; green) continues to circulate. b | PCSK9-targeted

monoclonal antibodies (mAbs) block the interaction between PCSK9 and LDLR. LDLR, as a

result, remains available to remove LDL-C from the bloodstream and incorporate it into cells.

LDL causes atherosclerosis

Reactive oxygen species (ROS) produced by endothelial cells, smooth muscle

cells (SMCs), and macrophages oxidize LDL in the subendothelial space, at

the sites of endothelial damage, initiating events that result in the formation of

a fibrous plaque. Rupture of fibrous plaque leads to thrombus formation and occlusion of the vessel.

[Non-HDL-C] = [TC] – [HDL-C]

Friedwald’s equation:

[LDL-C] = [TC] – [HDL-C] – [TG]/5includes cholesterol in LDL, IDL, Lp(a)

Approach to Dyslipidemia

• Familial Dyslipidemia

• Secondary Dyslipidemia

• Primary Dyslipidemia

Familial Dyslipidemia

Familial Dyslipidemia

• High cholesterol

– Familial hypercholesterolemia

• High triglycerides

– Familial hypertriglyceridemia

• Combined high cholesterol and triglycerides

– Familial combined hyperlipdemia

– Sitosterolemia

Familial Hypercholesterolemia

Signs of hypercholesterolemia

Dysbetalipoproteinemia

Signs of hypertriglyceridemia

Standing Plasma Test

Secondary Dyslipidemia

Secondary Dyslipidemia

ช>90 cm, ญ>80 cm

Dyslipidemia Guideline

Dyslipidemia Guideline

• Third Report of the National Cholesterol Education Program : Adult Treatment Panel (NCEP ATP III) 2004

• ESC/EAS Guidelines for the management of dyslipidaemias 2011

• American College of Cardiology/American Heart Association 2013

Third Report of the National Cholesterol Education Program : Adult Treatment Panel (NCEP ATP III)

Major Risk Factors

10-year CHD Risk Framingham Score: Men(Sex, Age, Smoking, Chol, HDL, SBP, Tx HT)

Optional < 70

100

Therapeutic Lifestyle Changes

Atorva Fluva Pitava Lova Prava Rosuva Vytorin† Simva %↓ LDL-C

----- 40 mg 1 mg 20 mg 20 mg ----- ----- 10 mg 30%

10 mg 80 mg 2 mg 40 or 80 mg 40 mg ----- ----- 20 mg 38%

20 mg ----- 4 mg 80 mg 80 mg 5 mg 10/10 mg 40 mg 41%

40 mg ----- ----- ----- 10 mg 10/20 mg 80 mg 47%

80 mg ----- ----- ----- 20 mg 10/40 mg ----- 55%

----- ----- ----- 40 mg 10/80 mg ----- 63%

Relative LDL-lowering Efficacy of Statin and Statin-based Therapies*

Atorva=Atorvastatin; Fluva=Fluvastatin; Pitava=Pitavastatin; Lova=Lovastatin; Prava=Pravastatin; Rosuva=Rosuvastatin; Simva=Simvastatin.

FDA Simvastatin warning 2011

•Maintain patients on simvastatin 80 mg only if they have been taking this dose for 12 or more months without evidence of muscle toxicity.

•Not start new patients on simvastatin 80 mg.

FDA Simvastatin warning 2011

• Contraindicated with simvastatin:

• Itraconazole • Ketoconazole • Posaconazole (New) • Erythromycin • Clarithromycin • Telithromycin • HIV protease inhibitors • Nefazodone • Gemfibrozil • Cyclosporine • Danazol

Do not exceed 10 mg simvastatin daily with:Verapamil Diltiazem

Do not exceed 20 mg simvastatin daily with:Amiodarone Amlodipine

American College of Cardiology/American Heart Association 2013

Recommendations for Statin Therapy

Clinical ASCVD : history of MI, stable or unstable angina, coronary

revascularization, stroke, or TIA presumed to be of atherosclerotic

origin, and peripheral arterial disease or revascularization

No Clinical ASCVD

10-y ASCVD risk parameterSex, Age, Race, Chol, HDL, SBP,

Tx HT, DM, Smoking

No T1 or T2DM Age 40-75 years

Focus on ASCVD Risk Reduction: 4 statin benefit groups

• Individuals with clinical ASCVD

• Individuals with primary elevations of LDL-C ≥ 190 mg/dL

• Individuals 40-75 y with diabetes with LDL-C 70-189 mg/dL

• Individuals without clinical ASCVD or diabetes who are 40-75 y with LDL-C 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher

Characteristics predisposing to statin adverse effects (should be careful for higher intensity statin)

• > 75 years of age

• Multiple comorbidities including impair renal or hepatic function

• Unexplained ALT elevation > 3 ULN

• Used drugs affecting statin metabolism

• History of hemorrhagic stroke

• Asian ancestry

Regularly monitor adherence to lifestyle and drug therapy every 3-12 mo once statin adherence has been established

• If less than-anticipated therapeutic response – Reinforce improved adherence to lifestyle and drug

therapy (class I, level A)

– Evaluated for secondary causes of hypercholesterolemia if indicatd (class I, level A)

– Increase statin intensity, or if patient is receiving maximally tolerated statin intensity, consider addition of nonstatin therapy shown in RCT to reduced ASCVD events in selected high risk patients (class Iib, level C)

Summary of Statin Safety Recommendations (1)

• Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are < 40 mg/dL

• Individuals receiving statin therapy should be evaluated for new-onset diabetes mellitus (0.1 and 0.3 excess causes of diabetes per 100 statin treated individuals)

• Healthy lifestyle habits should be encouraged to prevent progression to diabetes (class I, level B)

Summary of Statin Safety Recommendations (2)

• Baseline measurement of ALT should be perform before initiating statin therapy

• Baseline measurement of CK is reasonable for individuals believed to be an increase risk for adverse muscle events eg. concomitant drugs Rx that may increase the risk for myopathy

• Do not routinely monitor ALT or CK unless patient is symptomatic (class I, level A)

If muscle symptoms develop during statin Rx

• Discontinue the statin

• Evaluating CK (may consider Cr, myoglobinuria in severe case)

• Evaluate other conditions that might increase the risk for muscle symptoms ( hypothyroid, rheumatologic diseases, reduce hepatic or renal function )

• If the symptoms resolve, rechallenge with the same dose of statin or lower

• If the symptoms recur, discontinue statin and rechallenge with progressively lower doses of the same or a different statin

Safety of Fibrates (1)

• Gemfibrozil should not be initiated in patients on statin therapy because of an increase risk for muscle symptoms and rhabdomyolysis

• Fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefit from ASCVD risk reduction or triglyceride lowering when TG are > 500 mg/dL, are judged to outweight the potential risk for adverse effects.

Safety of Fibrates (2)

• Renal status should be evaluated before fenofibrate initiation, within 3 months after initiation, and every 6 months thereafter.

• Fenofibrate should not be used if eGFR < 30 mL/min per 1.73 m², is present.

• If eGFR is between 30 and 59 mL/min per 1.73 m², the dose of fenofibrate should not exceed 54 mg/day.

What do we change the practice after the new ACC/AHA guildeline ?

• Treat the risk not the cholesterol level

• Focus on ASCVD risk reduction : 4 statin benefit groups

• Use appropriate maximally tolerated dose of statins

• A new perspective on LDL-C and non HDL-C treatment goals

• Global risk assessment for primary prevention

Summary : Drugs used to treat hyperlipidemia