This document discusses the treatment of dyslipidemia. It begins by introducing lipids and lipoproteins, and their association with atherosclerosis. It then describes the structure and function of various lipoproteins. The main treatments discussed are statins, bile acid sequestrants, fibrates, niacin, and ezetimibe. Statins work by inhibiting cholesterol biosynthesis and are the first-line treatment. Bile acid sequestrants work by binding bile acids to reduce cholesterol absorption. Fibrates activate lipoprotein lipase and lower triglycerides. Niacin increases HDL and reduces triglycerides and LDL. Ezetimibe inhibits intestinal cholesterol absorption.

1. TREATMENT OF DYSLIPIDEMIA
DR CHINTAN DOSHI

2. INTRODUCTION
• Lipids are insoluble molecules that are essential for
membrane biogenesis and maintenance of
membrane integrity
• For transport the aqueous media of the blood,
nonpolar lipids, such as cholesteryl esters and
triglycerides, are packaged within lipoproteins
• Increased concentrations of certain lipoproteins in
the circulation are associated strongly with
atherosclerosis

3. LIPOPROTEIN
• Macromolecular aggregates that transport
triglycerides and cholesterol in the blood.
• Microscopic spherical particles
• 7-100 nm in diameter

4. STRUCTURE
 lipoprotein
↙ ↓ ↘
surface hydrophobic apolipoproteins
monolayer core
↓ ↓
 Unesterified cholesteryl ester
Cholesterol triglycerides
 phospholipid

6. Lipoprotein Lipid contained Function
Chy. TG >> CHE Dietary TG transport
Chy. rem. CHE >> TG Dietary CH transport
VLDL TG >> CHE Endogenous TG
transport
LDL CHE Transport CH to
tissues and liver
HDL Phospholipid, CHE Removal of CH from
tissues

7. METABOLISM
• ApoB – CONTANING LIPOPROTEIN
• Deliver fatty acids in the form of triglycerides
 muscle tissue→ ATP biogenesis
 adipose tissue → storage.
• TYPES
 Chylomicrons-
• Formed in intestine
• Transport dietary TGs
 Very low density LP ( VLDL)-
• Formed in liver
• Transport endogenous TGs

8. INTRAVASCULAR METABOLISM
Chylomicrons/ VLDL
↓
Activated by ApocII transferred from HDL
↓
can bind to LPL (lipoprotein lipase) , enzyme on
endothelium of capilleries in muscle /fat
↓
Hydrolysis of TGs into free FA , glycerol

9. CONTD…
• LPL activity depends on fed/ fasting state
In fasting state: FA taken by muscle for energy
In fed state: FA stored in adipose tissue.

10. PATHO-PHYSIOLOGY
Increase risk of cardiovascular mortality:
• ↑ LDL-C
• ↓ HDL-C
Clinically, dyslipidemias can be divided into:
• Hypercholesterolemia
• Hypertriglyceridemia
• Hyperlipidemia
• Disorder of HDL metabolism

11. Hyperlipoproteinaemias can be:
• Secondary: associated with diabetes,
myxoedema,nephrotic syndrome, chronic
alcoholism,drugs (corticosteroids)
• Primary: due to genetic defect

13. Pharmacotherapy
• First line Lipid lowering agents:
1. HMG-Co A Reductase Inhibitors (Statins) :
 Lovastatin
 Simvastatin
 Fluvastatin
 Pravastatin
 Atorvastatin
 Rosuvastatin
 Pitavastatin

14. Contd....
2. Bile Acid-Binding Resins:
 Cholestyramine
 Colestipol
 Colesevelam
3. Inhibition of Intestinal Absorption of
Cholesterol:
 Stanol esters
 Ezetimibe

15. Contd....
• Second line lipid lowering agents:
1. Activators of Lipoprotein Lipase (Fibrates):
 Gemfibrozil
 Bezafibrate
 Fenofibrate
 Clofibrate
2. Inhibitor of VLDL secretion and Lipolysis:
 Niacin (Nicotinic acid)

16. Contd.....
• Miscellaneous agents :
 Gugulipid
 Fish oil derivatives
• New Drugs (CETP Inhibitors):
 Torcetrapib
 Anacetrapib

17. •Statins

18. M/A:
• Competitively
inhibits HMG-
CoA reductase
which cause
conversion of
HMG-CoA to
mevalonate,
early and rate-
limiting step in
cholesterol
biosynthesis

19. ACTIONS
Effect of statins on TG level
• Low intracellular levels of CH also decrease VLDL
• Moderate lowering of TGs level about 30-35%
Effect on HDL-C level:
• Increase 5% to 10%
Effect on LDL-C level:
• Lower by 20% to 55%, depending on the dose and statin
used
• LDL-C is reduced by 6% (from baseline) with each doubling
of the dose

20. Contd....
Potential cardioprotective effects other than LDL
lowering:
• Pleiotropic effects
Endothelial Function:
• Enhances endothelial production of the
vasodilator nitric oxide
• Improved endothelial function after a month of
therapy

21. Contd....
Plaque Stability:
• Inhibit monocyte infiltration into the artery wall
• Inhibit macrophage secretion of matrix
metalloproteinases in vitro

22. Inflammation:
• Antiinflammatory role
• Decreased levels of C-reactive protein
Coagulation:
• Reduce platelet aggregation and reduce the
deposition of platelet thrombi

23. Contd....
Lipoprotein Oxidation:
• Oxidative modification of LDL appears to play
a key role in mediating the uptake of
lipoprotein cholesterol by macrophages
• Statins reduce the susceptibility of
lipoproteins to oxidation

24. • Oral administration: 30%- 85%
• Extensive first-pass hepatic uptake
• All statins, except rosuvastatin are metabolized
primarily by CYP3A4
• Atorvastatin, Pravastatin, and Rosuvastatin uptake
is mediated by the organic anion transporter 2
(OATP2)
• Half-lives : 1 to 4 hours, except in the case of
Atorvastatin and Rosuvastatin,about 20 hour
• 70% of statin metabolites are excreted by the liver
with subsequent elimination in the feces
Pharmacokinetics:

25. ADMINISTRATION
• Because HMG-CoA reductase activity is
maximum at midnight
• all statins are administered at bed time to
obtain maximum effectiveness
• not necessary for atorvastatin and
rosuvastatin, which have long plasma t½.

26. Adverse Effects
Hepatotoxicity
• Elevation in hepatic transaminase
Myopathy:
• Incidence of myopathy is quite low (0.01%),
• risk of myopathy and rhabdomyolysis increases in
proportion to plasma statin concentrations
Sleep Disturbances :
• Lipophilic agents like lovastatin and simvastatin

27. Contraindication:
• Liver disease
• Pregnancy and during lactation

28. • Primary hyperlipidemias: type IIa, IIb and V
• Secondary hypercholesterolaemia ( diabetic,
nephrotic syndrome etc.)
• In severe drug-resistant dyslipidaemia (e.g.
heterozygous familial hypercholesterolaemia),
ezetimibe is combined with statin treatment.
Uses

29. Lovastatin
• It is the first clinically used statin
• is lipophilic and given orally in the precursor
lactone form.
Simvastatin
• Same as lovastatin except more potent

30. Pravastatin
• Initiated with a 20- or 40-mg dose that may be
increased to 80 mg
• Hydroxy acid, it is bound by bile-acid
sequestrants, which reduces its absorption
Fluvastatin
• Same as Pravastatin

31. Atorvastatin
• This newer and most popular statin
• is more potent and appears to have the highest
LDL-CH lowering efficacy at maximal daily dose of
80 mg.
• has additional antioxidant property.
Rosuvastatin
• another newer, commonly used and potent statin

32. Pitavastatin
• latest and dose-to-dose the most potent
statin.
• no specific advantages compared to other
statins have been demonstrated

33. Bile Acid-Binding Resins
Mechanism of action:
Resins bind bile acids
Prevents their enterohepatic circulation
Faecal excretion of bile salts and CH is
increased

34. Contd....
Hepatocytes to up-regulate 7α-Hydroxylase
Increase bile acid synthesis, Decrease hepatic
cholesterol concentration
Stimulating the production of LDL receptors,
increase in hepatic LDL receptors expression,
increases LDL clearance
lowers LDL-C levels

35. Contd....
Adverse Effects :
• Bloating and dyspepsia
• Constipation (prevented by adequate daily water
intake
• rare instances of hyperchloremic acidosis (as
administrated in chloride form)
Contraindication:
• Severe hypertriglyceridemia

36. Disadvantages:
• Unpalatable
• Inconvenient
• Have to be taken in large doses
• Because of flatulence and other
g.i.disturbances have poor patient
acceptability

37. •Activators of
Lipoprotein Lipase
(Fibrates)

38. Mechanism of action

39. Contd.....
Pharmacokinetics:
• Absorbed rapidly and efficiently (>90%) when given with
a meal but less efficiently when taken on an empty
stomach
• 95% plasma protein bound exclusively to albumin
• Half-lives: ranging from 1 hour (gemfibrozil) to 20 hours
(fenofibrate)
• Glucuronide conjugation
• Excretion-urine

40. Contd....
Adverse Effects:
• Gastrointestinal side effects
• Minor increases in liver transaminases and alkaline
phosphatase
• Clofibrate use has been associated with increased risk of
gallstone formation
Contraindication:
• Renal and Liver failure
• Children and during pregnancy

41. Uses
• Drugs of choice for treating hyperlipidemic subjects
with type III hyperlipoproteinemia
• Subjects with severe hypertriglyceridemia
(triglycerides >1000 mg/dl) who are at risk for
pancreatitis
• High triglycerides and low HDL-C levels associated
with the metabolic syndrome or type 2 diabetes
mellitus

42. Gemfibrozil
 fibric acid derivative
 promotion of fibrinolysis
 LDL composition may be altered
 Gemfibrozil + statin-increases risk of myopathy
 600 mg BD taken before meals

43. Bezafibrate
• alternative to gemfibrozil in mixed
hyperlipidaemias
• Not associated with myopathy

44. Inhibitor of VLDL secretion and
Lipolysis
• Niacin, nicotinic acid (pyridine-3-carboxylic acid)
• Water-soluble B-complex vitamin that functions as a
vitamin only after its conversion to NAD or NADP
• Hypolipidemic effects of niacin require larger doses than
are required for its vitamin effects
• Best agent available for increasing HDL-C

45. Contd....
Mechanism of action:
Stimulates GPCR on adipocytes
Decrease adipocyte hormone-sensitive lipase
activity
Decreased flux of free fatty acid to the liver
Decrease the rate of hepatic triglyceride synthesis
and VLDL production

46. Contd....
Decrease TG and LDL
Increase the half-life of apoAI, the major
apoprotein in HDL
Increase plasma apoAI increase plasma HDL
Augments reverse cholesterol transport

47. • It also reduces lipoprotein Lp (a), which
is considered more atherogenic.

48. Adverse effects
Cutaneous vasodilator:
• flushing, heat and itching
• minimized by
a. starting with a low dose taken with meals
b. sustained release (SR/ER) tablet
c. Aspirin
d. Laropiprant

49. Contd.
• Dyspepsia,vomiting and diarrhoea
• Peptic ulcer is aggravated
• Hepatotoxicity
• Hyperglycemia and precipitation of diabetes
mellitus
• Hyperuricemia and gout
• Atrial arrythymia
• Contraindicated during pregnancy and in
children

50. USE:
• Patients with both hypertriglyceridemia and
low HDL-C levels
• pancreatitis associated with severe
hypertriglyceridaemia
• reduce recurrences of MI and overall mortality
• Used in high risk case only

51. •Ezetemibe

52. Contd....
Mechanism of action:
Inhibits a specific transport process in jejunal
enterocytes, which take up cholesterol from the lumen
Transport protein is NPC1L1
Inhibiting intestinal cholesterol absorption
Reduction in the incorporation of cholesterol into
chylomicrons

53. Contd....
Diminishes the delivery of cholesterol to the
liver by chylomicron remnants
Decrease atherogenesis directly

54. Cond....
Effects on Lipoprotiens:
• Reduces LDL-C levels by 15% to 20%
• Fasting triglyceride levels decrease about 5%
• HDL-C levels increase about 1% to 2%
Pharmacokinetics:
• Very poor aqueous solubility
• Absorbed partly after conjugated with glucuronic
acid
• Secreted in bile, undergo enterohepatic
circulation, excreted in faeces
• Plasma half life: 22 hrs

55. Contd.....
Adverse effect:
• hepatic dysfunction
• rarely myositis
Contraindication:
• Pregnant and women who are breastfeeding
• Liver dysfunction

56. Use:
• Monotherapy or in combination with statin to treat
hyperlipoproteinaemias
Combination Therapy (Ezetimibe Plus Statins)
• Statins, which inhibit cholesterol biosynthesis,
increase intestinal cholesterol absorption
• Ezetimibe, which inhibits intestinal cholesterol
absorption, enhances cholesterol biosynthesis
• Further reduction of 15% to 20% in LDL-C with
combined therapy
• Highest simvastatin dose (80 mg), plus ezetimibe (10
mg), average LDL-C reduction was 60%

57. New Drugs (CETP Inhibitors):
• Cholesteryl ester transfer protein (CETP) is a
plasma glycoprotein synthesized by the liver
• Mediates the transfer of cholesteryl esters
from HDL-C to LDL-C and VLDL-C during
‘reverse cholesterol transport’
• Inhibitors of this protein, torcetrapib,
anacetrapib, raise HDL-CH and lower LDL

58. • Torcetrapib was found to increase
cardiovascular events like angina, MI, heart
failure and death

59. •Thank you