Hyperlipidemia is a major risk factor for atherosclerosis and related conditions like coronary heart disease and ischemic stroke. It refers to abnormally high levels of lipids in the blood, including cholesterol, triglycerides, and phospholipids. These lipids are transported in the blood within lipoprotein particles like LDL, VLDL, and HDL. Statin drugs are commonly used to lower LDL cholesterol and reduce cardiovascular risk, with fibrates and other drugs also playing a role in treating different lipid abnormalities. Lifestyle modifications focusing on diet and exercise are also important for managing hyperlipidemia.

1. Dr Htet Htet
MBBS, MMedSc
Lecturer
All rights reserved.

2. • HYPERLIPIDAEMIA is a major cause of atherosclerosis and associated
conditions like
• CORONARY HEART DISEASE,
• ISCHAEMIC CEREBROVASCULAR DISEASE,
• PERIPHERAL VASCULAR DISEASE.
Hyperlipidaemia (why it is important?)

3. How?
• Hyperlipidemia Hyperlipoproteinemia
• means abnormally increased plasma lipoproteins
• one of the risk factors for atherosclerosis (deposition
of fats at walls of arteries, forming plaque)

4. • Includes
• Hyperlipidaemia (hypercholesterolaemia)
• Low level of HDL
DYSLIPIDAEMIA
• Can be caused by
• Genetic as well as
• Life style

7. Plasma lipids include: cholesterols, triglycerides and
phospholipids.
Lipids are insoluble in plasma and are transported in protein
capsule known as LIPOPROTEIN

9. Types of lipoproteins
1. Chylomicrons (TGs):
2. VLDL (TGs and cholesterol)
3. IDL (cholesterol, TGs);
4. LDL (cholesterol)
5. HDL (protective)

10. Composition Density Size
Chylomicrons TG >> C, CE Low Large
VLDL TG > CE
IDL CE > TG
LDL CE >> TG
HDL CE > TG High Small

18. Chylomicron remnants
o after LPL mediated removal of dietary triglycerides, chylomicron
remnants still contain dietary cholestrol,
o removed from circulation by the liver by hepatic LDL receptor or LDL
receptor related protein (LRP)
o So LRP is important for plasma lipid metabolism

19. LDL receptor

21. • VLDL synthesized in the liver.
• (Are produced in the liver with triglyceride production is
stimulated by an increased flux of free fatty acids or
• by increased de novo synthesis of fatty acids by the liver. )
• Like chylomicrons, VLDLs travels around the circulatory system
until they associate with lipoprotein lipase, an enzyme bound to
the endothelial surface.

22. • The lipoprotein lipase hydrolyses the triacylglycerol to liberate free
fatty acids which diffuse into the local tissues.
• As triacylglycerol is lost, the VLDL shrinks and
• VLDL are converted to IDL, and eventually to LDL.
• VLDL  IDL  LDL
• are released from the capillary endothelium and reenter the
circulation.
• Virtually all LDL particles in the plasma are derived from VLDL

24. LDL
• almost LDL are derived from VLDL
• Clearance
• Primarily by LDL receptors
• Liver expresses large component of LDL receptors and removes ~ 75%
of all LDL from the plasma
• Therefore, manipulation of hepatic LDL receptor gene expression
is the most effective way to modulate plasma LDL-C levels
Lipoprotein class Major constituent Site of synthesis Mechanism of
metabolism
LDL Cholesteryl esters Product of VLDL
catabolism
Uptake by LDL
receptor (~75%)

25. • LDL becomes arthrogenic when modified by oxidation
• Which is a required step for LDL uptake by scavenger receptors of
macrophages
• This process leads to foam cell formation in arterial lesions.

26. Why is oxidized LDL really the bad guy?
Diaz et al., 1997

29. Why HDL ?
• Are protective lipoproteins, that decrease the risk of CHD
• high level of HDL is desirable
• The protective effect may result from
• Participation of HDL in reverse cholestrol transport (the process by
which excess cholesterol is acquired from cells and transferred to the liver
for excretion. )
• May also protect against artherogenesis
• Anti-inflammatory , Anti-oxidative
• Platelet anti-aggregatory , Anticoagulant , Profibrinolytic activities

33. Statins (HMG CoA reductase inhibitors)
• Most effective
• Best tolerated agent
Mechanism of action
- Competitively inhibit HMG-CoA
reductase, which catalyzes an early, rate
limiting step in cholesterol biosynthesis

34. Mechanism of action
• competitively inhibits HMG CoA reductase enzyme, which
converts HMG CoA to mevalonate
By this way, statins inhibit an early and rate-limiting step
in cholesterol biosynthesis
• due to reduced cholesterol in hepatocyte
 results in increased expression of LDL receptor gene
 increased synthesis of LDL receptors
 greater number of LDL receptors on the hepatocytes
 increased removal of LDL from blood  lowering LDL level.

36. Pharmacokinetics
• Hepatic cholesterol synthesis is maximal between
midnight and 2:00 A.M.
• Thus, statins with short T ½ (all but atorvastatin and
rosuvastatin) should be taken in the evening.
• Atorvastatin, rosuvastatin – have t ½ about ~ 20 hrs, --
• Dose related reduction of cholesterol

37. Therapeutic uses
• Hypercholesterolaemia of any origin
• Primary hyperlipidaemia (raised LDL, total CH level,
with or without raised TG level)
• Secondary hypercholesterolaemia (DM, nephrotic
syndrome)

38. Adverse effects
• Hepatoxicity
• Myopathy , rhabdomyolysis - major adverse effect associated with statin use , risk is
increased with some drugs (eg. Fibrates) especially gemfibrozil – (the drug most
commonly associated with statin induced myopathy)
Pregnancy
•Women who wish to conceive should not take statin
•Women who are taking statin in child bearing years should use highly effective
contraception
•Nursing mothers should avoid statin.

39. Statins
• lovastatin
• Simvastatin
• Atorvastatin
• Fluvastatin
• Rosuvastatin
• Pravastatin

41. • Fibrates bind to PPAR-α and activate
• PPAR-α (peroxisome proliferator-activated receptor α)
• Gene transcription regulating receptor expressed in liver, fat and
muscle
• Activation enhances Lipoprotein lipase synthesis

42. • Fibrates bind to PPAR-α and activate
• 
•  LPL synthesis
• 
• enhanced clearance of
triglyceride rich
lipoproteins
• enhance clearance of VLDL (but VLDL→ IDL → LDL)
• Increases HDL level

43. Pharmacological action
The effects of fibric acid on LP levels differ widely
decreases triglyceride level and used in hypertriglyceridaemia
but
They can cause increase in LDL level (some patients)
Doc for hypertriglyceridaemia ***
LDL level need to be monitored,
If rises, a low dose of statin may be needed
If this combination is used, should be monitored for myopathy

44. • Excretion of fibrates are impaired in renal failure and use
of fibrates is CI in patients with renal failure

45. Therapeutic uses
• Drug of choice for patients with markedly raised TG
level, whether or not CH level are raised.

47. • Generally well tolerated
• GI side effects +
• drug displacement interaction (due to high PPB)
• Esp with oral anticoagulants (wafarin)
• Should monitor PT and reduction of dosage if fibrate is started
• Myopathy syndrome -- Expecially with statins (rare with fenofibrate)
• Increased lithogenecity of bile, increased risk of gall stone formation
• renal failure , hepatic dysfunction (relative CI)
• children, pregnancy (should not be used)

48.  Clofibrate
 Gemfibrozil
 Fenofibrate
 Ciprofibrate
 Benzafibrate

50. • Cholestyramine
• Colestipol
• Colesevelam

51. • bile acid sequestrants are highly positive charged and
• Bile acids are negative charged
• so bile acid sequestrants bind to bile acids
• Because of large size, the resins are not absorbed
• Bound bile acids are excreted in the stool.
• As a result, hepatic cholesterol content decreases
• stimulate the production of LDL receptors
• Increased LDL clearance
• Lowers LDL

53. Therapeutic uses
• Reduction of LDL cholesterol (dose dependent
manner)
• HDL also increased

54. • Should never be taken in dry form
• Available as tablet form

55. • Generally safe, as are not systemically absorbed
• Gritty sensation on taking drug initially especially with powder preparations
• Mild GI symptoms – bloating, dyspepsia
• Interfering absorption of other drugs – eg. Digoxin, wafarin, propanolol
• All drugs should administer 1 hr before or 3-4 hours after.
• Deficiency of fat soluble vitamins

57. Niacin (Nicotinic acid)
One of the oldest drug used to treat dyslipidaemia

58. • Adipose tissue,
• Stimulates Gi adenylate cyclase pathway
• Inhibit cAMP production
• Decrease HSL (hormone sensitive lipase activity)
• TAG lipolysis 
•  release of free fatty acids
• liver
• May inhibit rate limiting enzyme of triglyceride
synthesis, DGAT2 (diacylglycerol acyltransferase-2)

60. Adverse effects
• Flushing , heat, itching
• Dyspepsia

61. • Patients with any history of PU should not take niacin
because it can reactivate ulcer.
• Most common, serious side effect – is hepatotoxicity
• Should be used with caution in DM patients as it can cause
insulin resistance and severe hyperglycaemia

62. Therapeutic uses
• Indicated for hypertriglyceridaemia and elevated LDL-C
• useful for patients with hypertriglyceridaemia and low
HDL-C levels

63. Precaution
• concurrent use of Niacin and Statin can cause myopathy

65. Ezetimibe
• MOA
• Inhibits luminal cholesterol uptake by jejunal enterocytes, by
inhibiting the transport protein (NPC1L1)

66. Pharmacological action
• By inhibiting the dietary cholesterol absorption
• Reduction in incoporation of cholesterol into chylomicrons
• Reduced cholesterol content of chylomicrons
• Diminish the delivery of cholesterol to liver by chylomicron remnants
• May decrease artherogenesis directly (CR are very arthrogenic)
• Due to reduced delivery of intestinal cholesterol to the liver
• Increased expression of LDL receptors,
• Enhance LDL clearance

67. Uses
• Can be used alone or together with statins
Statins, which inhibit cholesterol synthesis – tends to increase intestinal
absorption
Ezetimibe, which inhibits intestinal cholesterol absorption – enhances
cholesterol synthesis
Dual therapy with these two classes of drugs prevent both enhanced
choelsterol synthesis induced by ezetimibe and the increase in cholesterol
absorption induced by statins

68. Pharmacokinetics
• Should not be given together with bile acid sequestrants
• Because may inhibit absorption of ezetimibe,
• Otherwise, no significant DI reported.

69. Adverse effects
• Since all statins are CI in pregnancy and nursing women,
combination products containing ezetimibe and statin
should not be used by women in child bearing years with
out contraception.

72. Summary
• Patients with any type of dyslipidaemia are at risk of developing
atherosclerosis-induced vascular disease.
1. Maintain ideal body weight
2. Eat diet low in saturated fat and cholesterol
3. Regular exercise
• Are cornerstone of managing dyslipidaemia

73. • Although absence of dyslipidaemia, type II DM and metabolic
syndrome
• To assess their future risk of vascular disease event, patients
should be titrated to achieve target lipid values.
• Statin therapy should be the first line choice
• If not adequately controlled with statin alone, add second
line

74. • On addition of another drug
• Should discuss about untoward effects although
they are rare and serious
• Hepatotoxicity
• Rhabdomyolysis
• Renal failure

75. REFERENCE:
• Tripathi, KD. 2008. Antitubercular drugs, in Essentials of
Medical Pharmacology. 6th Edition. India: Jaypee Brothers
Medical Publishers (P) Ltd.
• Thomas, P.B. 2011. Drug Therapy of
Hypercholesterolaemia and Dyslipidaemia, in Goodman &
Gilman’s Pharmacological Basis of Therapeutics. 12th
Edition, edited by Laurence Brunton, Bruce Chabner, Bjorn
Knollman. United States: The McGraw-Hill Companies, Inc.

76. Signs and symptoms of
hypercholesterolaemia &
some interesting facts

77. A xanthoma :
is a deposition of yellowishcholesterol-rich
material in tendons or other body parts in
various disease states.
They are cutaneous manifestations
of lipidosis in which there is an accumulation
of lipids in large foam cells within the skin.
They are associated with hyperlipidemias,
both primary and secondary types.

78. Xanthelasma
• Xanthelasma (or xanthelasma palpebrarum) is a sharply
demarcated yellowish deposit of fat underneath the skin, usually
on or around theeyelids

79. Xanthoma striatum palmare
is a cutaneous condition characterized by xanthomas of the
palmar creases which are almost diagnostic
for dysbetalipoproteinemia