1. Drugs used in Dyslipidemia
Dr. Divya Krishnan
Calicut medical college

2. 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

3. What are Dyslipidemias?
 Disorders of lipoprotein metabolism resulting in
abnormal plasma concentration of
lipoproteins/lipids .
Hyperlipidemias/ Low HDL levels
Hypercholesterolemias
( total cholesterol/ LDL/
Triglycerides)

4. Dyslipidemias
Primary Secondary
Diabetes
Monogenic Polygenic Myxoedema
Nephrotic syndrome
Alcoholism
Drug induced

5. Drugs for dyslipidemias
 Modify lipid levels in blood.
Can we call these drugs
―HYPOLIPIDEMICS‖????

6. 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.

7. 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
Triglycerides
Cholesteryl
esters

8. LIPOPROTEINS
 Macromolecular complexes of lipid and proteins
apoproteins
-provide structural stability
-ligands for receptors
-activate enzymes
unesterified cholesterol
core (TG ,cholesteryl esters)
phospholipids

10. Classification of lipoproteins
Lipoprotein
type
Density
(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 B100
Apo E
liver Endogenous
lipid transport
IDL 1.006-
1.019
30-35 CHE>>TG Apo B100
Apo 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 tissues
Lipoprotein A /LP(a) : Similar to LDL but with an additional Apo A.
Linked to risk of atherosclerosis

11. LIPOPROTEIN TRANSPORT
Exogenous pathway Endogenous pathway

12. LIPOPROTEIN TRANSPORT

13. Drugs used in Dyslipidemias
Part 2

14. Dyslipidemias
Hypercholesterolemias Hypertriglyceridemias
Combined hyperlipidemias
##low HDL is also part of dyslipidemia

15. 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

16. 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

17. Mechanism of action of statins
Acetyl Co A 3Hydroxy 3 methyl glutaryl CoA
HMG CoA
reductase
cholesterol mevalonate
STATINS

18. Statins (MOA)contd…………………

19. Statins—effect on plasma lipoprotein levels
LDL levels

20.  TG Levels - 10 – 35% decrease
HDL Levels – 5 -15 % increase

21. Pleiotropic effects of statins
1. 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

22. Statins-pharmacokinetics
o Variable absorption
o Extensive first pass hepatic uptake (OATP1B1)
Lovastatin Pravastatin Simvastatin Atorvastatin Rosuvastati
n
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

23. 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

24. 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)

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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.

32. 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)

33. 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%)

34. Fibrates
Additional 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

35. 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

36. Fibrates
Drug interactions
 Myopathy risk with statins (OATP1B1
inhibition & interference with statin
metabolism)
 Toxicity of oral anticoagulants(displacement
from plasma protein binding sites)

37. 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

38. 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)

39. 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

40. 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

41. 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

42. Miscellaneous agents
Gugulipid : 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

43. Overview of drugs
Total
cholesterol
LDL HDL TG
Statin
Resins
- -
Ezetimibe
- -
Fibrates
Niacin

44. Treatment of hyperlipidemias
Treatment modalities
 Lifestyle modifications
 Pharmacotherapy
Treatment plan decided on the basis of :-
lipid profile
risk assessment for CAD

45. 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

46. 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

47. 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

48. 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

49. 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

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

51. 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

52. 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.

53. 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

54. 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.

55. Current status

56. 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)

57. Thank you