Hamid Boulares, Ph.D.Hamid Boulares, Ph.D.

Department of Pharmacology, LSUHSC,

Email: hboulr@lsuhsc.edu

Tel: 568-2304

Lipid Lowering AgentsLipid Lowering Agents

LIPID TRANSPORT - OverviewLIPID TRANSPORT - Overview

Chylomicrons:Chylomicrons: large lipoprotein particles that transport dietary lipids from the intestines to other locations in the body. They are one of the 5 major groups of lipoproteins (chylomicrons, VLDL, IDL, LDL, HDL) which enable fats and cholesterol to move within the water based solution of the blood stream.

Chylomicron remnant:Chylomicron remnant: Once triglyceride stores are distributed, the chylomicron returns APOC2 (but keeps APOE) back to the HDL and thus becomes a chylomicron remnant. APOB48 and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdown.

IDLIDL: intermediate DensityVLDLVLDL: Very low DensityHDLHDL: High Density

LCATLCAT: Lecithin-Acetyl-CoAC-acyltransferase

AtherosclerosisAtherosclerosis

Lipoproteins and Their Structure

SurfaceSurface: monolayer of polar lipids, unesterified cholesterol and apolipoproteins

ApolipoproteinsApolipoproteins: Add stability to structure; act as ligands for cell surface receptors or co-factors for enzymatic reactions

CoreCore: Cholesteryl esters (cholesterol esterified to fatty acid), TG

Characteristics of Lipoproteins

ApoE

VLDL VLDL : endogenous triglycerides; catabolized by lipoprotein lipase (LPL), short half-lifeIDLIDL: cholesteryl esters, converted to LDL by hepatic lipaseLDLLDL: apoB-mediated uptake by LDL receptor, long half-lifeHDLHDL: phospholipids cholesteryl esters, removed by hepatic scavenger receptor Bsecreted to bile, steroid synthesis, VLDL synthesis.

Plasma Lipoproteins: Plasma Lipoproteins: Classes & FunctionsClasses & Functions

Very Low Density Lipoprotein (VLDL)• Synthesized in liver• Transport endogenous triglycerides to peripheral

tissue• 90% lipid, 10% protein• Metabolized by LPL • Apo B-100

•Receptor bindingApo C-II

•LPL activatorApo E

•Remnant receptor binding

Plasma Lipoproteins: Plasma Lipoproteins: Classes & FunctionsClasses & Functions

• Intermediate Density Lipoprotein (IDL)Synthesized from VLDL during VLDL degradationTriglyceride transport and precursor to LDL– Apo B-100

• Receptor binding– Apo C-II

• LPL activator– Apo E

• Receptor binding

Plasma Lipoproteins: Plasma Lipoproteins: Classes & FunctionsClasses & Functions

Low Density Lipoprotein (LDL)– Synthesized from IDL– Cholesterol transport– 78% lipid, 58% cholesterol &

CE– Apo B-100

• Receptor binding

LDL receptorLDL receptor

• Characterized by Michael Brown and Joseph Goldstein (Nobel prize winners in 1985)

• Receptor also called B/E receptor because of its ability to recognize particles containing both Apo B and E

• Activity occurs mainly in the liver

• Receptor recognizes apo E more readily than apo B-100

FYI

Dyslipidemia and atherosclerosis

Many clinical trials demonstrate that increase of LDL levels induce formation of atherosclerosis plaques.

Gordon T et al. Am J Med 1977;62:707-714.

Ris

k o

f C

HD

LDL-C(mg/dL)

0.0

1.0

2.0

3.0

100 160 220 8565

4525

HDL-C

(mg/d

L)

• For any level of LDL-C, HDL-C is inversely related to CHD risk

Slide source: www.lipidsonline.org

Disease Lipid Profile

Prevalence Etiology

Primary Hypercholesterolemia

Familial Hypercholesterolemia LDL 1:500 (+/-) LDL Receptor

Familial Defective ApoB100 LDL 1:100 ApoB100 binding to LDLR

Polygenic Hypercholesterolemia Chol Common unknown

Primary Hypertriglyceridemia

Familial Hypertriglyceridemia TG HDL VLDL

Common VLDL breakdown

VLDL synthesis

Mixed Hyperlipidemia

Familial Combined Hyperlipidemia LDLTG

HDL

1:100 Unknown, dominant inheritance

Disorders of HDL metabolism

Polygenic low HDL HDL Common Obesity, diabetes high carb diets

Familial hypoalphalipoproteinemia HDL 1:100 Unknown, dominant inheritance

Genetic Causes of Dyslipidemia

HypertriglyceridemiaHypertriglyceridemia (VLDL)

Diabetes, oral contraceptives (estrogen), hypothyroidism, hypopituitarism, high sugar diet and high alcohol intake (increased production and decreased clearance of VLDL).

HypercholesterolemiaHypercholesterolemia (LDL)

High cholesterol (fat) diet, hypopitutarism and hypothyroidism (decreased LDL receptors).

Secondary HyperlipidemiaSecondary Hyperlipidemia

Classification of Lipoprotein Analysis Results (mg/dl)Classification of Lipoprotein Analysis Results (mg/dl)

Total Cholesterol:<200 desirable

200-239 borderline high>240 high

LDL Cholesterol:<100 optimal

100-129 near/above optimal130-159 borderline high

160-189 high>190 very high

HDL Cholesterol:<40 low>60 high

Triglycerides:<150 normal150-199 high200-499 high

>500 very high

Modes to reduce lipid levelsModes to reduce lipid levels:

1. Therapeutic lifestyle changes.

- improved diet: reduce the intake of saturated fat to < 7% of calories.

- reduce the cholesterol intake to < 200 mg/day.

- weight reduction

- increased physical activity

2. Medication.

Cholestyramine and Colestipol and Colesevelam

Lipid Lowering Drugs:Lipid Lowering Drugs: Anion-Exchange ResinsAnion-Exchange Resins

Sequester bile acids (BA) in the gut hence blocking enterohepatic cycling of BA

Usually used in combination Usually used in combination with a statinwith a statin

Major side effects – bitter taste, nausea constipation

Important interactions – bind polar drugs such as warfarin, digoxin, thyroxine and statins: give 1 hr before resin

STATINSSTATINS

Increased LDLIncreased LDLUptakeUptake

STATINSSTATINS Mechanism of ActionMechanism of Action

HMG CoA reductaseHMG CoA reductase

Lipid Lowering Drugs: Lipid Lowering Drugs: STATINSSTATINS

1. Fungal metabolites: Lovostatin (MEVACOR), Simvastatin (ZOCOR), Provastatin (PRAVACHOL)

2. Synthetic derivatives Fluvastatin (LESCOL), Atorvastatin (LIPITOR) and

Rosuvastatin (CRESTOR)

3. They have short half-lives (~2 hours except atorvastatin at 14h) but but effective with once daily administrationeffective with once daily administration

4. All have slightly higher efficacy if given at nightslightly higher efficacy if given at night

5. All except pravastatin are metabolised through CYP enzymes in the liver which is the source of important drug-drug interactions (e.g. with warfarin)

6.6. Major side effects:Major side effects: Hepatitis and myositis (inflammation of the muscles)

Fatal Rhabdomyolysis with Statins

• The major adverse effect of clinical significance associated with statin use is myopathy

• Rhabdomyolysis; Breakdown of muscle proteins (myoglobin, creatine kinase) that leads to renal toxicity. Symptoms include muscle pain and weakness and dark urine due to muscle catabolism

Reason for Cerivastatin (Baycol) withdrawal from the market (~20-fold greater risk compared to other statins)

• Risk increased by combination with:Risk increased by combination with: – Fibrates especially for gemfibrozil/cerivastatin– Nicotinic acid– Protease Inhibitors (HAART therapy)-Highly Active AntiRetroviral

Therapy

Pleiotropic effects of statins on the vasculature Pleiotropic effects of statins on the vasculature

Clinical Science www.clinsci.org Clin. Sci. (2003) 105, 251-266 Clinical Science www.clinsci.org Clin. Sci. (2003) 105, 251-266

Lipid Lowering Agents: Lipid Lowering Agents: Nicotinic Acid (Niacin)Nicotinic Acid (Niacin)

hepatic VLDL synthesis by inhibiting adipose tissue lipolysis VLDL clearance by LPL activity

• Is the licensed agent with largest impact on HDL (30-50% )

• Lowers lipoproteins VLDL, IDL, LDL (by ~ 30%)

• Usually employed in combination with fibrate, resin or statin

•Major side effectsFlushing – prostaglandin mediatedSkin drying & GI intoleranceExacerbates gout ( uric acid secretion), diabetes (promotes insulin resistance) and peptic ulcers

Lipid Lowering Drugs: Lipid Lowering Drugs: FibratesFibrates

Important interactions

increased risk of myopathy

in dose requirements (~30%) for warfarin- fibrates displace warfarin from albumin

• Act as PPAR ligands- multiple changes • ApoA HDL• LPL• FA uptake and oxidation in

muscle cells• FA oxidation in hepatocytes and

TG synthesis

• Net Effects VLDL (TG), LDL and HDL

• Absorbed efficiently (>90%) when given with a meal but not on an empty stomach

• Main side effects

GI intolerance

1-2% in the incidence of gallstones due to cholesterol synthesis

Gemfibrozil and Fenofibrate

• Novel inhibitor of intestinal cholesterol transporter - inhibits intestinal cholesterol uptake and transport by ~ 50%

• Metabolite has 400x the potency of parent compound and prolongs action by enterohepatic cycling

• No important adverse effects OR significant drug interactions

• Unlike resins does not raise TG -

• synergism with statins

(e.g. ezetimibe/simvastatin, marketed as Vytorin and Inegy)

NPCIL1: Niemann-Pick Cl-like channel 1 protein

Lipid Lowering Drugs: Lipid Lowering Drugs: EZETIMIBEEZETIMIBE

Progression of Drug Therapy Progression of Drug Therapy in Primary Preventionin Primary Prevention

If LDL goal not achieved, intensifyLDL-lowering therapy

If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist

Monitor response and adherence to therapy

• Start statin or bile acid resin or nicotinic acid

• Consider higher dose of statin or add a bile acid sequestrant or nicotinic acid

6 wks 6 wks Q 4-6 mo

• If LDL goal achieved, treat other lipid risk factors

Initiate LDL-lowering drug therapy