This work mainly deals with cholesterol transport mechanisms, the various types of hyperlipoproteinemias, and the drugs used to combat cholesterol excess. A very precise insight into drugs, their mechanisms, efficacy & adverse effects have been explained. A separate section on NEWER DRUGS for hypercholesterolemia(including drugs in clinical trials) have also been mentioned. A separate category on SITOSTEROLEMIA, their effects & management has been mentioned too. Do go through this and submit your reviews!! Thank You! - RxVichuZ! ;)

1. MANAGEMENT STRATEGIES
FOR DYSLIPIDEMIA &
SITOSTEROLEMIA-
SUMMARIZED CATCHPOINTS
PRESENTED TO: DR.EMILL JAME DAVID
PRESENTER DETAILS:
VISHNU.R.NAIR,
5TH YEAR PHARM.D,
NATIONAL COLLEGE OF PHARMACY(NCP).

2. PURPOSE OF THIS PRESENTATION:
• This presentation aims at providing a precise insight on the do’s and dont’s while
giving specific antihyperlipidemic drugs to a patient
• No further details into dosage, dosage adjustments or other relevant
pharmacological details have been provided
• This presentation is a brief summary on important catchpoints required while
dealing with DYSLIPIDEMIA cases in clinical settings
• Extensive referencing skills are always recommended to get a deeper outlook into
this topic.
HAPPY READING!!

3. GENERAL INTRODUCTION

4. • Chylomicrons(CM)  transport DIETARY TRIGLYCERIDES(TGs) &
CHOLESTEROL
• VLDL  carries endogenous TGs from liver to blood
• In CM  TG content is greater than that of cholesterol
• TGs present in CM  metabolized by LIPOPROTEIN LIPASE(LPL) inside the
walls of blood vessels  free fatty acids formed  utilized by various tissues like
fat & muscle
• Liver surface  contains HEPATIC LIPASE(HL)  metabolizes remaining TGs
 what remain inside CM is CHOLESTEROL  taken up by liver
• To be precise:
a. DIETARY CHOLESTEROL  transported to LIVER
b. Free fatty acids  transported to FAT & MUSCLES.

5. • During high production of TGs inside liver :
- VERY LOW DENSITY LIPOPROTEINS(VLDL) formed  released into
circulation
- MICROSOMAL TG TRANSPORT PROTEIN(MTP)  packs TG & other
components  forms VLDL
- VLDL  contains more TGs than CHOLESTERYL ESTERS(CE)
- TGs  metabolized by LPL
- VLDL  converted to INTERMEDIATE DENSITY LIPOPROTEINS(IDL)
(Remember, that in this condition, the concentration of TG & CE are the same!)
- IDL can have either of the following 2 fates:
a. HL  metabolizes remaining TGs  converted to LDL(that contains only CE!!)
b. Taken up in the liver by LDL-RECEPTORS(LDL-R).

6. - So basically, LDL transports its CE either to various tissues, OR is taken up in
the liver(VIA LDL-R). . .
- PROPROTEIN CONVERTASE SUBTILISIN KIXIN TYPE-9(PCSK-9) is a
PROTEIN  binds to LDL-R  destroys it
- LDL-R  transports TG & CE  sent to lysosome  broken down by
LYSOSOMAL ACID LIPASE.

7. - HDL CHOLESTROL:
a. Formed by taking cholesterol from tissues  helps in its transport to
liver(Process known as REVERSE CHOLESTEROL TRANSPORT)
b. Thus :
• HDL : GOOD CHOLESTEROL!
• VLDL, LDL, IDL: BAD CHOLESTEROLS!!
c. Nascent HDL  secreted by hepatocytes & enterocytes  takes free cholesterol
from tissues & macrophages
d. LECITHIN CHOLESTEROL ACETYL TRANSFERASE(LCAT)  converts free
cholesterol to CE

8. e. MATURE HDL has either of the following 2 fates:
• Taken up by liver through SCAVENGER RECEPTOR SR-B1
• CE  transferred to CMs/VLDL in exchange for TGs by the activity of
CHOLESTERYL TG TRANSPORT PROTEIN(CETP)  VLDL is converted to
LDL  taken up by liver, via LDL-R
f. TG-rich HDL  now acted upon by HEPATIC LIPASE(HL)
- Altered levels of lipoproteins may be secondary to diseases like DM, nephrotic
syndrome, etc
- PRIMARY HYPERLIPOPROTEINEMIA is usually FAMILIAL/GENETIC in
origin.

9. VARIOUS TYPES OF HYPERLIPOPROTEINEMIAS:
TYPE OF
DISORDER
LP INCREASED TG LEVEL
RISE
CHOLESTERO
L LEVEL RISE
RISK OF
ATHEROSCLER
OSIS
TREATMENT
I CM(Chylomicro
ns)
+++ NO NO NOT
REQUIRED
IIa LDL NO ++ +++ STATINS
IIb VLDL & LDL ++ ++ +++ STATINS,
FIBRATES,
NIACIN
III IDL &
CMR(Chylomicr
on remnants)
++ ++ ++ FIBRATES
IV VLDL ++ NO ++ FIBRATES,
NIACIN
V VLDL & CM ++ NO NO NOT
REQUIRED

10. ANTI-DYSLIPIDEMIC DRUGS

11. • FIRST-LINE DRUGS include:
a. STATINS
b. BILE ACID SEQUESTRANTS
c. INTESTINAL CHOLESTEROL REABSORPTION INHIBITORS
• SECOND-LINE DRUGS include:
a. FIBRATES
b. NIACIN.

12. STATINS

13. • HMG CoA reductase  catalyzes RATE LIMITING STEP in CHOLESTEROL
BIOSYNTHESIS(conversion of HMG CoA to MEVALONATE)
• Statins  competitively inhibit this enzyme  reduce cholesterol synthesis in the
liver  since liver requires cholesterol for bile acid & steroid hormone synthesis
 LIVER responds by INCREASING LDL-receptors on its surface  increases
LDL-uptake from plasma
• STATINS ARE THE MOST POWERFUL LDL-LOWERING AGENTS!!
• Other actions of statins include:
a. Lowering of TG
b. Lowering of IDL
c. Lowering of VLDL
d. Increase of HDL(mild).

14. - Statins have no effect on LIPOPROTEIN(A)
- Most potent statins : PITAVASTATIN, followed by ROSUVASTATIN
- Least potent statins : FLUVASTATIN, LOVASTATIN
- Since activity of HMG CoA reductase is MAXIMUM at night  these drugs are
given at nighttime
- ROSUVASTATIN & ATORVASTATIN can be given AT ANY TIME OF THE DAY,
due to their long t1/2:
a. Half-life of ROSUVASTATIN: 19 hrs
b. Half-life of ATORVASTATIN: 14 hrs
- Longest acting statin: ROSUVASTATIN.

15. - Statins are responsible(to some extent) to lower the risk of stroke & MI due to its
“PLEOTROPIC EFFECTS”, which include:
1. Antioxidant
2. Anti-inflammatory
3. Anti-proliferative.
- STRUCTURAL ANALYSIS OF STATINS:
a. Inactive lactone prodrugs: LOVASTATIN, SIMVASTATIN
b. Active lactone ring: PRAVASTATIN
c. FLUORINE containing congeners: ATORVASTATIN, ROSUVASTATIN,
FLUVASTATIN

16. - All STATINS can be absorbed ORALLY
- Maximum oral absorption observed with FLUVASTATIN
- Food  increases absorption of all statins(except PRAVASTATIN)
- LOVASTATIN & SIMVASTATIN  undergo extensive first-pass metabolism 
administered as PRO-DRUGS
- Drugs administered in active form:
a. Pravastatin
b. Atorvastatin
c. Rosuvastatin
d. Fluvastatin

17. - All statins(except PRAVASTATIN)  metabolized by HEPATIC MICROSOMAL
ENZYMES  have high chances of DRUG INTERACTIONS
- PRAVASTATIN  metabolized by SULFATION(NON-MICROSOMAL) least
chances of drug interactions.
- Major ADRs of statins include:
a. MYOPATHY
b. HEPATOTOXICITY
- Drugs + fibrates(especially GEMFIBROZIL) / NIACIN  high risk of myopathy
- Myopathy  can lead to RHABDOMYOLYSIS  can lead to RENAL
SHUTDOWN
- Avoid statins in PREGNANCY & LACTATION.

18. - Some patients taking STATINS develop DIABETES MELLITUS, but the benefits
(reduced risk of cardiovascular events)  outweigh the risk (of developing DM)
- STATINS are the 1st line drugs for the following conditions:
a. Type IIa
b. Type IIb
c. Secondary hyperlipoproteinemia
- For children with HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA :
a. DOC of age ≥ 8 yrs : PRAVASTATIN
b. DOC of age ≥ 10 yrs: OTHER STATINS(role of PITAVASTATIN here isn’t
justified yet)

19. • Risk of STATIN-INDUCED MYOPATHY is INCREASED by:
a. Old age
b. Renal insufficiency
c. Erythromycin
d. Ketoconazole
e. Fibrates(except BEZAFIBRATE!)
f. Immunosuppressants.

20. • SPECIAL FEATURES OF PRAVASTATIN:
a. Minimum drug interactions(since metabolized by non-microsomal enzymes)
b. Minimum food interactions
c. Minimum risk of myopathy
d. Minimum CNS penetration
e. Reduces fibrinogen levels.

21. INTESTINAL CHOLESTEROL
ABSORPTION INHIBITOR

22. • Drug includes EZETIMIBE
• Drug  inhibits a transporter NPC1L1  prevents intestinal absorption of
cholesterol  reduces cholesterol content of liver  liver responds by increasing
LDL-R synthesis
• Used as MONOTHERAPY/ in combination with STATINS for TYPE IIa & IIb
HYPERLIPOPROTEINEMIA
• Also reduces LDL-C in patients with SITOSTEROLEMIA

23. BILE ACID SEQUESTRANTS

24. • Drugs  bind to BILE ACIDS in intestinal lumen  reduce their absorption 
promotes their excretion through faeces  reduces cholesterol levels in liver 
liver acquires cholesterol from plasma by increasing LDL-R
• Bile acids  inhibit TG production in liver  thus deficiency of bile acids
elevates TG levels
• Bile acid binding agents are used ONLY FOR TYPE IIa
HYPERLIPOPROTEINEMIA(since TGs are normal in this condition)
• Drugs include:
a. Cholestyramine
b. Colestipol
c. Colesevelam.

25. • CHOLESTYRAMINE & COLESTIPOL  available as SACHETS
• SACHETS  mixed with water  kept for sometime(to enhance their
PALATABILITY)  taken with meals
• COLESEVELAM :
a. Available as TABLET
b. Has better patient compliance
• Major ADR : Constipation
• Cholesterol-lowering agent of choice in:
a. Children
b. Pregnancy
c. Lactation.

26. FIBRIC ACID DERIVATIVES

27. • Drugs  activate nuclear receptor PPAR∝(Peroxisome proliferator activated
receptor ∝)  LPL gets activated  effects include:
a. Reduce TG levels
b. Increase HDL levels
• CLOFIBRATE  not used now for the following reasons:
a. High risk of mortality(due to malignancies & post-cholecystectomy
complications)
b. Did not prevent fatal MI

28. • Drugs currently available include:
a. GEMFIBROZIL
b. FENOFIBRATE
c. BEZAFIBRATE
• Fibrates reduce plasma fibrinogen levels
• Important ADRs include:
a. GI distress
b. Elevation of aminotransferases
• Fibrates (except BEZAFIBRATE) + STATINS  high risk of myopathy
• Fibrates  potentiate effects of WARFARIN & OHAs.

29. • Applications of FIBRATES:
a. DOC in Hypertriglyceridemia(Type III & IV)
b. Fenofibrate with other drugs in Type IIb(since fenofibrate has maximum LDL-
lowering action)
• IMPORTANT FEATURES OF FENOFIBRATE:
a. Prodrug
b. Longest t1/2
c. Maximum LDL-C lowering action
d. URICOSURIC in nature can be used in the setting of HYPERURICEMIA

30. NICOTINIC ACID(NIACIN)

31. • Another name of NIACIN is VITAMIN B3
• Drug  inhibits lipolysis in the adipose tissue
• Actions of NIACIN include:
a. Reduces LDL-C
b. Reduces VLDL triglycerides
c. Increases HDL-C
d. Reduces lipoprotein(a)
e. Reduces fibrinogen levels

32. • Major compliance limiting & side-effects of NIACIN include:
a. CUTANEOUS FLUSHING & PRURITUS:
- Niacin  Causes release of PGs  vasodilatory action
- Prevented by pre-treatment with ASPIRIN
- NIACIN should be started at low doses only
b. NIACIN  impairs INSULIN SENSITIVITY  avoid in DIABETICS!!!
c. GI toxicity
d. Hyperuricemia
e. Maculopathy
f. Acanthosis nigricans(dark-coloured skin lesion)
g. Hepatotoxicity

33. • IMPORTANT APPLICATIONS OF NIACIN:
a. Among all hypolipidemic drugs  NIACIN has GREATEST HDL-
INCREASING PROPERTY  useful in patients with high risk of CAD!!
b. Type IIb
c. Type III
d. Type IV disorders.

34. MISCELLANEOUS DRUGS

35. • PROBUCOL:
- Has antioxidant action
- Inhibits LDL oxidation
- Reduces levels of both HDL & LDL
• GUGULIPID:
- Developed by Central Drug Research Institute, Lucknow
- Causes modest reduction in LDL
- Slight increment in HDL-C
- ADR: Diarrhea.

36. NEWER DRUGS

37. CETP INHIBITORS:
• CETP  required for exchange of TG & CE between HDL & apo-B rich
lipoproteins  leads to formation of TG-rich HDL  acted upon by HEPATIC
LIPASE(HL)
• CETP inhibitors  increase HDL-C levels
• The following CETP-inhibitors failed the clinical trials :
a. Torcetrapib(due to excessive mortality rates)
b. Dalcetrapib (due to reduced efficacy)
c. Evacetrapib(due to reduced efficacy)
• ANACETRAPIB  currently undergoing clinical trials.

38. MTP INHIBITORS:
• Drug includes LOMITAPIDE
• Drug  inhibits Microsomal triglyceride transport protein(MTP)  prevents
VLDL assembly & its production in liver
• Indicated for FAMILIAL HOMOZYGOUS HYPERCHOLESTEROLEMIA

39. MIPOMERSEN:
• Antisense oligonucleotide
• Drug  targets MESSENGER-RNA for apo-B rich lipoproteins
• FDA-approved for FAMILIAL HOMOZYGOUS HYPERCHOLESTEROLEMIA
• Given subcutaneously ONCE A WEEK
• Black-box warning by FDA on drug usage: RISK OF LIVER DISEASE.

40. PCSK-9 INHIBITORS:
• Proprotein convertase subtilisin kixin type-9  protein, that binds to LDL-R 
Transports LDL-R to lysosomes, causing their degradation
• PCSK-9 inhibitors  prevent LDL-R destruction  reduce LDL-C levels
• Monoclonal antibodies are used
• Include:
a. ALIROCUMAB
b. EVOLOCUMAB
* Approved for FAMILIAL HYPERCHOLESTEROLEMIA(as adjunct to diet &
maximally tolerated statin therapy)

41. AVASIMIBE:
• Drug  inhibits ACAT-1( Acyl coenzyme A: cholesterol acyl transferase-1) 
prevents formation of cholesterol ester from cholesterol  prevents cholesterol
deposition in arterial wall.

42. SITOSTEROLEMIA: A BRIEF
INSIGHT

43. • In normal individuals  <5% of dietary plant sterols (eg SITOSTEROL) are
absorbed through GIT
• Plant sterols  excreted through bile  leads to fecal excretion
• Thus, in normal individuals  levels of plant sterols are kept very low in tissues
• In SITOSTEROLEMIA  elevated levels of plant sterols & cholesterol occurs,
due to the following reasons:
a. Increased intestinal absorption
b. Reduced biliary excretion
• SITOSTEROLEMIA is an AUTOSOMAL RECESSIVE DISORDER
• Caused by mutation in the following genes:
a. ABCG5
b. ABCG8

44. • Increased levels of hepatic sterols  causes DOWNREGULATION of LDL-R on
hepatocytes  leads to high levels of LDL-C
• Due to incorporation of plant sterols in membranes  patients can experience
the following clinical episodes:
a. Tendon xanthoma
b. Premature atherosclerotic disease
c. Hemolysis
d. Splenomegaly
• STATINS are ineffective in these conditions
• Only effective agents include:
a. Ezetimibe
b. Bile acid sequestrants.

45. CHOLESTEROL TRANSPORT & SITES OF
ACTION OF NEW ANTI-DYSLIPIDEMIC DRUGS:

46. THANK YOU!!!!  