Drugs used in Dyslipidemia 

Dr. Divya Krishnan

Calicut medical college

CONTENTS 

Introduction Lipid physiology and lipid metabolism Classification of drugs for dyslipidemias Salient features of different drugs Principles of treatment of dyslipidemias Recent advances Summary

What are Dyslipidemias?

Disorders of lipoprotein metabolism resulting in abnormal plasma concentration of lipoproteins/lipids .

Hyperlipidemias/ Low HDL levels

Hypercholesterolemias

( total cholesterol/ LDL/

Triglycerides)

Dyslipidemias

Primary Secondary

Diabetes

Monogenic Polygenic Myxoedema

Nephrotic syndrome

Alcoholism

Drug induced

Drugs for dyslipidemias

Modify lipid levels in blood.

Can we call these drugs “HYPOLIPIDEMICS”????

Growing interest in drugs for dyslipidemias…..???

Dyslipidemias are important risk factors for atherosclerosis.

Drugs have potential to retard accelerated atherosclerotic process and decrease morbidity and mortality associated with atherosclerosis.

LIPID PHYSIOLOGY

Heterogenous group of compounds related to fatty acids insoluble in water but soluble in non polar solvents.

Simple lipids compound lipids Neutral lipids

TriglyceridesCholesteryl esters

LIPOPROTEINS Macromolecular complexes of lipid and proteins

apoproteins

-provide structural stability

-ligands for receptors

-activate enzymes

unesterified cholesterol

core (TG ,cholesteryl esters)

phospholipids

Classification of lipoproteinsLipoprotein

typeDensity

(g/ml)diameter

(nm)Lipid core Apoprotein Source Function

Chylomicr

on

0.93 100-500

TG>>CHE ApoB48,Apo E

diet Dietary lipid transport

VLDL 0.93-1.006

40-80 TG>>CHE Apo B100Apo E

liver Endogenous lipid transport

IDL 1.006-1.019

30-35 CHE>>TG Apo B100Apo E

VLDL Lipid transport to liver

Source of LDL

LDL 1.019-1.063

20-25 CHE Apo B100 IDL cholesterol transport to

tissues & liver

HDL 1.05-1.120

5-10 CHE ApoAΙ,ApoAп tissues

Removal of cholesterol

from tissuesLipoprotein A /LP(a) : Similar to LDL but with an additional Apo A .

Linked to risk of atherosclerosis

LIPOPROTEIN TRANSPORT

Exogenous pathway Endogenous pathway

LIPOPROTEIN TRANSPORT

Drugs used in Dyslipidemias Part 2

Dyslipidemias

Hypercholesterolemias Hypertriglyceridemias

Combined hyperlipidemias

##low HDL is also part of dyslipidemia

Classification of drugs

First line agents : Lower LDL levels (mainly)

- HMG-CoA reductase inhibitors(statins)

- Bile acid binding resins

- Inhibitors of intestinal cholesterol absorption

Second line agents : Lower VLDL levels

- LPL activators (fibrates)

-VLDL secretion inhibitors(Niacin) Miscellaneous : Gugulipid ,Fish oils

HMGCoA reductase inhibitors(Statins)

- Most effective & best tolerated drugs

History

- First isolated from Penicillium citrinum mould(1972)

- Compactin (Mevastatin) - first to be studied in man

- Lovastatin (from Aspergillus terreus) - first to be

approved for use in humans - Pravastatin , Simvastatin chemically modified

derivatives- Atorvastatin , Fluvastatin , Rosuvastatin , Pitavastatin-

synthetic products

Mechanism of action of statins

Acetyl Co A 3Hydroxy 3 methyl glutaryl CoA

HMG CoAreductase

cholesterol mevalonate

STATINS

Statins (MOA)contd…………………

Statins—effect on plasma lipoprotein levels

LDL levels

TG Levels - 10 – 35% decrease

HDL Levels – 5 -15 % increase

Pleiotropic effects of statins1. Improves endothelial function

2. Decreases vascular inflammation(lowers CRP)

3. Decreases lipoprotein oxidation

4. Stabilisation of atheromatous plaque

5. Decreases platelet aggregation

6. Decreases fibrinogen levels

7. Enhances fibrinolysis

8. Neovascularisation of ischemic tissue

9. Protection from sepsis

10. Immune suppression

11. Inhibition of primordial germ cell migration

Beneficial effects• Antiatherogenic • Alzheimers disease• Prostate cancer

Harmful effects• Contraindication in

pregnancy

Statins-pharmacokineticso Variable absorptiono Extensive first pass hepatic uptake (OATP1B1)

Lovastatin

Pravastatin Simvastatin Atorvastatin

Rosuvastatin

prodrug active prodrug active active

High PPB 50% PPB High PPB High PPB High PPB

Lipophilic hydrophilic lipophilic hydrophilic hydrophilic

T1/2=1-4hrs 1-3hrs 2-3hrs 18-24hrs 18-24hrs

CYP3A4 Sulfate conjugation

CYP3A4 CYP3A4 CYP2C9

Statins-ADR

Headache Nausea & bowel upset Rashes Insomnia (lipophilic drugs) Increase in serum transaminases Muscle tenderness & rise in CPK Myopathy & rhabdomyolysis(rare)

Contraindication

-pregnancy / lactation / children / elderly / liver & kidney disease

Statins-Drug interactions

OATPIBI inhibitors(gemfibrozil) increase statin toxicity

CYP3A4 inhibitors increase toxicity of Lovastatin , Atorvastatin & Simvastatin

CYP2C9 inhibitors increase toxicity of Rosuvastatin & Fluvastatin

Warfarin toxicity with Rosuvastatin(CYP2C9)

Indications for use First choice drugs for 1° & 2° hypercholester-

olemias with or without raised TG levels Drug combinations used in severe / combined

dyslipidemias.

1° prevention of arterial disease in patients with hypercholesterolemias

2° prevention of MI/stroke (initiated soon after an event irrespective of lipid levels)

Tried in Alzheimers disease , prostate cancer

Bile acid binding resins

Oldest & safest MOA----explained with the fig

Cholestyramine , Colestipol ,

Colesevelam

-lower LDL levels (15-25%)

-3-5% rise in HDL

-Increase TG levels

-induces HMGCoA reductase activity

Bile acid binding resins contd…..Adverse drug reactions (mild)

- unpalatable , unpleasant

- bloating , dyspepsia

- constipation

Drug interactions

-interferes with absorption of :-

fat soluble vitamins

thiazides , frusemide

digoxin , warfarin , statins , tetracycline , thyroxine

Colesevelam has less side effects & is devoid of interactions

Bile acid binding resins contd… Indications for use

- Primary hypercholesterolemias.~20% fall in LDL levels.

Monotherapy less popular.Used in combinations for better control of hypercholesterolemias

- Relief of pruritus (cholestasis)

- Bile acid diarrhoea

- Digitalis toxicity

Intestinal cholesterol absorption inhibitors

Inhibit absorption of dietary & biliary cholesterol absorption from intestine-reduced hepatic cholesterol-LDL receptor expression & increased uptake of LDL from plasma.

Plant sterols &stanols

Sitostanol competes with cholesterol for NPC1L1

Sitosterol interferes with cholesterol transfer in the enterocyte

Ezetimibe Inhibits NPC1L1 & inhibits absorption of cholesterol&phytosterol

EZETIMIBE……………Pharmacokinetics

-Poorly absorbed

-Conjugated form gets absorbed & undergoes

enterohepatic circulation.

-T1/2=22hrs.Dose -10mg/day

-Excreted in feces

ADR

-Diarrhoea/abd pain/headache

-Allergic rxn ,hepatic dysfunction,myositis(rare)

-Contraindicated in pregnancy

Ezetimibe contd……………Drug interactions

-Bile acid sequestrants inhibit ezetimibe

absorption

Indications Mild hypercholesterolemia when statin is

contraindicated/not tolerated.(~15-20%

decrease in LDL otherwise monotherapy less

efficient than statin Adjunct to statin in hypercholesterolemia

Additive reduction in LDL levels occurs.

Second line agents

Marked reduction in VLDL(TG) Modest fall in LDL & modest rise in HDL

Includes :- Activators of LPL (Fibrates) Inhibitors of VLDL secretion (Niacin)

Fibrates

(Clofibrate) , Gemfibrozil ,Fenofibrate ,

Bezafibrate , Ciprofibrate MOA : Activate PPARα resulting in:- Increase in LPL activity Decrease in Apo CШ FFA oxidation Decreased VLDL synthesis Increased hepatic SREBP Increased Apo AΙ , Apo AЦ

Fall in VLDL (20-50%)

Fall in LDL (10-15%)

HDL rise (10-15%)

FibratesAdditional effects (antiatherogenic)

Decrease fibrinogen levels , factorVЦ Increases fibrinolysis Decrease CRP & vascular inflammation

Inhibit vascular smooth muscle proliferation

Improves glucose tolerance

Pharmacokinetics

Well absorbed

High PPB(95%)

T1/2—Varies

Excreted by kidney

Fibrates ADR

GI distress , headache

Rash , urticaria

Myalgia , fatigue

Hair loss , impotence

Minor elevations in AST , ALP

Myopathy—more when combined with statins

Lithogenicity of bile

Contraindication

Pregnancy , children , kidney disease

Fibrates

Drug interactions Myopathy risk with statins (OATP1B1

inhibition & interference with statin metabolism)

Toxicity of oral anticoagulants(displacement from plasma protein binding sites)

Fibrates…………………Clofibrate - Abandoned

- Doesn’t prevent atherosclerosis

- Risk of gallstones

Gemfibrozil - Higher risk of myopathy with statin

Short t1/2

Bezafibrate - More LDL lowering than gemfibrozil

- Less risk of myopathy with statin

Fenofibrate - More LDL lowering & more HDL

- Raising effect than gemfibrozil

- Less risk of myopathy with statin

- Uricosuric action

Fibrates

Indications for use

- Drug of choice for 1°& 2° severe hyper- triglyceridemia

-Mixed dyslipidaemia (Bezafibrate/fenofibrate)

-Combined with other drugs like statins for resistant dyslipidaemias (fenofibrate preferred)

Nicotinic acid(Niacin) B group vitamin at higher doses reduces plasma

lipids

MOA

Inhibits lipolysis in adipose tissue

decreased FFA for TG & VLDL synthesis in liver

Decreases VLDL(20-50%),LDL (15-25%)

Raises HDL (20-35%) & reduces lipoprotein A & has antiatherogenic properties

NiacinADR

Cutaneous flushing , itching , heat

Dyspepsia , vomiting , diarrhoea , activation of peptic ulcer

Dryness , hyperpigmentation of skin

Liver dysfunction

Precipitation of diabetes

Hyperuricemia

Atrial arrhythmias

Contraindication

Pregnancy , peptic ulcer , diabetes , gout .liver disease

Niacin Drug interactions

-Postural hypotension with antihypertensives

-Myopathy risk with statins

Indications

-Severe hypertriglyceridemias

-Adjunctive drug to statins / fibrates in severe dyslipidaemia-Combined dyslipidemias-Shown to decrease recurrence of MI

Miscellaneous agentsGugulipid : Ayurvedic prep

-Inhibits synthesis & increases excretion of cholesterol- Modest lowering of LDL , TG & rise in

HDL

Fish oils

-lower TG levels but raise LDL

-Antiatherogenic property due to production of 3 series Prostanoids & 5 series LTs

Overview of drugs

Total cholesterol

LDL HDL TG

Statin

Resins - -Ezetimibe - -Fibrates

Niacin

Treatment of hyperlipidemias

Treatment modalities Lifestyle modifications Pharmacotherapy

Treatment plan decided on the basis of :-

lipid profile

risk assessment for CAD

Plasma lipid levels (NCEP-2001)mg/dl

Total cholesterol

LDL HDL TG

Optimal <200 <100<70(CAD)

>40(M)>50(F)

<150

Borderline high

200-239 130-159 - 150-199

high ≥240 160-189 >60 200-499

Very high - ≥190 - ≥500

Risk factors for CAD Men >45, Women>55yrs Family h/o MI/sudden cardiac death before 55yrs in

men & 65yrs in women in first degree relative Smoking HTN High LDL (>160mg/dl) or total cholesterol(>240mg/dl) Low HDL (<40 in men , <50 in women) Obesity

##CAD equivalent : DM / PVD /abdominal aortic aneurysm / symptomatic carotid artery disease

Patient stratification Low risk : 0-1 CAD risk factor Moderate risk : ≥2 CAD risk factors + 10yr

CAD risk < 10% Moderately high risk : ≥2 CAD risk factors

+ 10 yr CAD risk 10- 20 % High risk : CAD / CAD equivalent Very high risk : CAD/CAD equivalent + 1 of

the below ≥2CAD risk factors Single uncontrolled CAD risk factor DM Metabolic syndrome Acute coronary syndrome

NCEP-ATPШ Guidelines

Risk category LDL goal(Mg/dl)

Lifestyle Drug

Very high risk <70 all subjects

All subjects

High risk

<100 All subjects

All subjects

Moderately high risk <130(or < 100)

≥100 ≥130

Moderate risk <130 ≥130 ≥160

Low risk <160 ≥160 ≥190

Drug treatment

Low dose statin(as per target LDL level & cost effectiveness)

Double the dose every six weeks till max dose if inadequate response with low dose

Add another drug (ezetimibe / fibrate /niacin) if needed

Treatment of raised TG levels TG < 150mg/dl – No TG lowering needed .Treat as per LDL

levels TG 200-499 mg/dl ( High)

-lifestyle modification

-treatment of cause if identified

-statin therapy to achieve goal LDL level

-TG lowering drug (fibrate/niacin) considered if:--CAD present/family h/o premature CAD/non HDL≥190/HDL<40/1°hypertriglyceridemias TG > 500mg/dl (Very high)-vigorous measures including TG lowering drugs indicated

Treatment of low HDL

-Total cholesterol: HDL < 3.5 desirable

-Statin therapy targeted at LDL lowers the ratio

-Treatment of metabolic syndrome helps

-Niacin can be added 2 statin therapy

Combined Drug Therapy

Combined drug therapy is useful when:

LDL or VLDL levels are not normalized with a single agent

LDL and VLDL levels are both elevated initially

VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin.

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

Combined Drug Therapy Statins & Resins

synergistic combination in the treatment of hypercholesterolemia.

Niacin & Resins Effective in familial hypercholesterolemia/combined

hyperlipidemias.Resin neutralises acid production by niacin

Statins & Niacin More effective than either agent alone in treating

hypercholesterolemia & combined hyperlipidemia

Combined Drug Therapy

Statins & Ezetimibe Is highly synergistic in hypercholesterolemia.

Statins & Fenofibrate Fenofibrate with certain statins is useful in

combined hyperlipidemias The combination of fenofibrate with

rosuvastatin is particularly effective.

Current status

Future Drugs

CETP inhibitors ( anacetrapib & dalcetrapib )

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

Darapladib inhibits lipoprotein associated

phospholipase A2 (enzyme produced by inflammatory cells & involved in atherosclerosis)

Mipomerson (antisense drug ) directed against Apo B (present in LDL)

Thank you