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