Agents Used in Dyslipidemia 

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Agents Used in Dyslipidemia 

Introduction HMG-CoA Reductase Inhibitors Niacin Fibric Acid Derivatives Bile Acid–Binding Resins Inhibitors of Intestinal Sterol Absorption Future Drugs Combined Drug Therapy Drug Pictures

Introduction Because atherogenesis is multifactorial, therapy

should be directed toward all modifiable risk factors.

Atherogenesis is a dynamic process regression of plaques occur during lipid-lowering therapy.

Preventions have shown significant reduction in mortality from new coronary events and in mortality.

Macrophages take up excess lipid forming foam cells, these collect in the subintimal area.

Foam cells elicit inflammatory response.

Introduction (Cont’d)

These drugs should be avoided in pregnant and lactating women and those likely to become pregnant.

All drugs may require adjustment of doses of warfarin.

Children with familial hypercholesterolemia may be treated after 7 or 8 years of age, when myelination of the CNS is complete

These drugs are rarely indicated before age 16.

Lipoprotein Particles

Classification of lipoprotein particles

Composition Density Size

Chylomicrons TG >> C, CE Low Large

VLDL TG > CE

IDL CE > TG

LDL CE >> TG

HDL CE > TG High Small

Lipoprotein Components of the Blood

Lipoprotein Components FunctionChylomicrons(CM)

Dietary lipids (TGs), Apo CII interactis with LPL of adipocytes, et al. LPL depletes TGs from CMs

Deliver fatty acids (FA) as part of a TG from the gut to cells.

CM remnants TG depleted CM Deliver cholesterol to livers; CM remnants endocytosed by hepatocytes.

VLDL, made by the liver

Apo E, Apo C, B-100, TG & Cholesterol

Delivers TGs from liver to cells

LDL Left after LPL removes TGs from VLDL

Delivers cholesterol from liver to cells

HDL, made by liver

Apo E, Apo C, Cholesterol Scavenges cholesterol from extra-hepatic tissue and returns it to the liver.Activates peripheral LPL

Figure 35–1 Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apoC lipoproteins and apolipoprotein E (apoE) from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apoE are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apoE. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum.

Prevalence (%) of Raised Cholesterol, Iran, 2005

HMG-CoA Reductase Inhibitors

They are also called: Reductase Inhibitors or Statins.

They are analogs of HMG-CoA.

Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin belong to this class.

Statin therapy significantly reduces new coronary events and atherothrombotic stroke.

Currently, statins are initiated immediately after acute coronary syndromes, regardless of lipid levels.

Biosynthesis of Cholesterol

CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA

O

O

OH

CH3 acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA

HMG CoAreductase

CH3

CH3

CH3

CH3

CH3

OH

cholesterol

-OOC-CH2-C-CH2-CH2-OH

OH

CH3 mevalonate

Drug Trade name CompanySales (billion $),

year

Atorvastatin Lipitor Pfizer 12) 2007> (

Clopidogrel Plavix Sanofi-Aventis 5.9) 2005(

Enoxaparin Lovenox or Clexane Sanofi-Aventis

Celecoxib Celebrex Pfizer 2.3) 2007(

Omeprazole Losec/Prilosec AstraZeneca 2.6) 2004(

Esomeprazole Nexium AstraZeneca 3.3) 2003(

Fexofenadine Telfast/Allegra Aventis 1.87) 2004(

Quetiapine Seroquel AstraZeneca 1.5) 2003(

Metoprolol Seloken/Toprol AstraZeneca 1.3) 2003(

Budesonide Pulmicort/Rhinocort AstraZeneca 1.3) 2003(

Leading blockbuster drugs until 2007

Figure 35–3: Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas).

HMG-CoA Reductase Inhibitors (Cont’d)

All statins have high first-pass extraction by the liver.

Their plasma half-lives range from 1 to 3 hr. except for atorvastatin, (14 hr) and rosuvastatin (19 hr).

Statins are most effective in reducing LDL. They increase LDL receptors so:

The catabolic rate of LDL is increased The liver's extraction of LDL precursors (VLDL remnants)

is increased

Modest decreases in plasma triglycerides and small increases in HDL also occur.

HMG-CoA Reductase Inhibitors (Cont’d)

Because of marked first-pass hepatic extraction, the major effect is on the liver.

Cholesterol synthesis occurs predominantly at night.

So statins (except atorvastatin & rosuvastatin) should be given in the evening if a single daily dose is used.

Absorption is generally enhanced by food. (except pravastatin).

Rosuvastatin is the most efficacious agent for severe hypercholesterolemia.

HMG-CoA Reductase Inhibitors (Cont’d)

dose-response curves of pravastatin and fluvastatin level off in the upper part of the dosage. Those of other statins are more linear.

Elevations of serum aminotransferase (up to 3 times normal) occur in some patients. Therapy may be continued in such patients.

If levels exceed 3 times normal, medication should be discontinued immediately.

These agents should be used with caution and in reduced dosage in patients with hepatic parenchymal disease, Asians, and the elderly.

Aminotransferase activity should be measured at baseline, at 1–2 months, and then every 6–12 months (if stable).

HMG-CoA Reductase Inhibitors (Cont’d)

Myopathy may occur with monotherapy, but there is an increased incidence if certain other drugs is received.

Genetic variation in an anion transporter is associated with severe myopathy and rhabdomyolysis (with ensuing renal failure) induced by statins.

In all patients, CK (Creatine kinase) should be measured at baseline.

If muscle pain or weakness appears, CK should be measured immediately and the drug discontinued if it is elevated significantly.

The myopathy usually reverses promptly upon cessation of therapy.

Reductase inhibitors should be temporarily discontinued in the event of serious illness, trauma, or major surgery.

Niacin (Nicotinic Acid, Vit. B3)

Niacin (but not niacinamide) decreases VLDL, LDL and Lp(a).

It is the most effective agent for increasing HDL.

Niacin inhibits VLDL secretion, in turn decreasing production of LDL.

Increased clearance of VLDL via the LPL pathway contributes to reduction of triglycerides.

Fibrinogen levels are also reduced, and tissue plasminogen activator increases.

Niacin (Nicotinic Acid, Vit. B3) (Cont’d)

Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose.

Aspirin 30 min. beforehand blunts this PG mediated effect.

Niacin should be avoided in most patients with severe peptic disease.

Acanthosis nigricans (rare side effect) contraindicates use of niacin (associated with insulin resistance).

Niacin (Nicotinic Acid, Vit. B3) (Cont’d)

Reversible elevations in aminotransferases up to twice normal may occur.

Liver function should be monitored at baseline and at appropriate intervals.

Rarely, niacin is associated with arrhythmias, mostly atrial, and a reversible toxic amblyopia.

Patients should be instructed to report blurring of distance vision.

Niacin may potentiate the action of antihypertensive agents, requiring adjustment of their

Fibric Acid Derivatives (Fibrates)

Gemfibrozil and fenofibrate decrease levels of VLDL and, in some patients, LDL as well.

Fibrates function primarily as ligands for the nuclear transcription receptor, PPAR-α.

Fibrates up-regulate LPL, apo A-I and apo A-II, and down regulate apo CIII, an inhibitor of lipolysis.

This increases oxidation of fatty acids in liver and striated muscle.

Fibrates are useful for decreasing VLDL.

Figure 35-4: Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins.

Fibric Acid Derivatives (Fibrates) (Cont’d)

Only modest reductions of LDL occur in most patients.

In combined hyperlipidemia, LDL often increases.

HDL cholesterol increases moderately.

These agents potentiate the action of coumarin anticoagulants.

Risk of myopathy increases when fibrates are given with reductase inhibitors.

The use of fenofibrate with rosuvastatin appears to minimize this risk.

Fibric Acid Derivatives (Fibrates) (Cont’d)

Cholesterol gallstones may increase so should be used cautiously in biliary tract disease, women and obese patients.

Fibrates are useful drugs in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia.

They also may be of benefit in treating the hypertriglyceridemia that results from treatment with viral protease inhibitors.

Bile Acid–Binding Resins

Colestipol and cholestyramine are useful only for isolated increases in LDL.

In patients who also have hypertriglyceridemia, VLDL levels may be further increased by resins.

This may require the addition of niacin.

Resins bind bile acids in the intestinal lumen and prevent their reabsorption.

Figure 35–2 Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.

Bile Acid–Binding Resins (Cont’d)

Excretion of bile acids is increased up to tenfold by resins.

This enhances conversion of cholesterol to bile acids in liver.

LDL receptors are also up-regulated, particularly in liver.

The resins have no effect in homozygous familial hypercholesterolemia (no receptor exist) but may be useful in heterozygotes.

Bile Acid–Binding Resins (Cont’d)

The resins are used in treatment of patients with primary hypercholesterolemia (20% reduction in LDL cholesterol in maximal dosage).

Resins may be helpful in relieving pruritus in patients who have cholestasis.

Because the resins bind digitalis glycosides, they may be useful in digitalis toxicity.

Resins should be taken with meals. They lack effect when taken between meals.

Digitalis structure

Bile Acid–Binding Resins (Cont’d)

Common complaints are constipation and bloating, usually relieved by dietary fiber or mixing psyllium with the resin.

Resins should be avoided in patients with diverticulitis.

Any additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption.

Inhibitors of Intestinal Sterol Absorption

Ezetimibe is a selective inhibitor of cholesterol and phytosterols absorption and reduces LDL.

A transport protein (NPC1L1) is the target of the drug.

It is effective even in the absence of dietary cholesterol (inhibits reabsorption of cholesterol in the bile).

Plasma concentrations are increased by fibrates and reduced by resins.

Inhibitors of Intestinal Sterol Absorption (Cont’d)

The effect of ezetimibe on cholesterol absorption is constant over the dosage range of 5–20 mg/d.

Therefore, a single daily dose is used.

Average reduction in LDL cholesterol is 18%.

Ezetimibe is synergistic with reductase inhibitors.

The combination decreases LDL 25% beyond that achieved with the reductase inhibitor alone.

Figure 35–2 Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.

Future Drugs

A new class of drugs, cholesterylester transfer protein (CETP) inhibitors, looks promising for raising HDL.

Two CETP inhibitors, anacetrapib and dalcetrapib, are in Phase III trials.

These drugs can lower LDL while increasing HDL to an extent not possible with existing HDL-raising therapies.

One or both of these drugs may receive FDA approval as early as 2012.

Future Drugs (Cont’d)

Cholesteryl ester transfer protein (CETP), is also called plasma lipid transfer protein.

It facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins.

It collects triglycerides from VLDL or LDL and exchanges them for cholesteryl esters from HDL and vice versa.

Future Drugs (Cont’d)

Other novel cholesterol-lowering drugs are in the pipeline.

Antisense drugs, (mipomersen), inactivate messenger RNA, thereby suppressing the activity of a bad gene.

Mipomersen, is directed against apolipoprotein B, a substance that is linked to elevated LDL.

Future Drugs (Cont’d)

Darapladib is a second novel drug which inhibits lipoprotein-associated phospholipase A2 (Lp-PLA-2)

It is an enzyme produced by inflammatory cells and is involved in the atherosclerosis.

Combined Drug Therapy

Combined drug therapy is useful when: VLDL levels are significantly increased during treatment

of hypercholesterolemia with a resin.

LDL and VLDL levels are both elevated initially.

LDL or VLDL levels are not normalized with a single agent.

An elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias.

Combined Drug Therapy

Statins & Resins This synergistic combination is useful in the treatment

of familial hypercholesterolemia.

Niacin & Resins Controls VLDL levels during resin therapy of disorders

involving both increased VLDL and LDL levels.

Niacin & Statins This regimen is more effective than either agent alone

in treating hypercholesterolemia.

Combined Drug Therapy

Statins & Ezetimibe Is highly synergistic in hypercholesterolemia.

Statins & Fenofibrate Fenofibrate with certain statins is useful in

elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin

is particularly effective. Some other statins may interact unfavorably owing

to effects on cytochrome P450 metabolism.

Strategy for Controlling Hyperlipidemia

Serum Cholesterol Cellular CholesterolLDL-R

Conversion to hormones withincells or storageas granules

HMG CoA reductase

STATINSDiet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption

BILE ACIDSEQUESTRANTS

Lipoproteincatabolism

FIBRATES

Ezetimibe

SummaryIn English

Thank youAny question?