This PPT contains hypolipidaemic drugs explanation with all recent drugs and with lots of pictures, for better understanding of MBBS and PG students

1. DRUG THERAPY OF
DYSLIPIDAEMIA
Dr. Resu Neha Reddy
2nd year Post Graduate
MD Pharmacology
Osmania Medical College

2. CONTENTS
 LIPIDS
 LIPOPROTEINS
 APOLIPOPROTEINS
 NORMAL LIPOPROTEIN METABOLISM
 LIPOPROTEIN DISORDERS
 PHARMACOTHERAPY OF DYSLIPIDAEMIA
 RECENT APPROACHES
 REFERENCES

3. Ischaemic cerebrovascular & cardiovascular disease  morbidity & mortality

4.  Major cause for ischaemic d/s – Dyslipidaemia  ATHEROSCLEROSIS
 ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVDs)
 Dyslipidaemias  Disorders of lipoproteinmetabolism
 Lipoprotein over-production
 Lipoprotein deficiency

5. LIPIDS
 Heterogeneous groupof compounds
 Insoluble in water
 Stored in body  Source of energy
 Three types : 1) Simple
2) Compound
3) Neutral

6. SIMPLE LIPIDS
 ESTERS of FATTY ACIDS & ALCOHOL
1) Saturatedfattyacids( SFA )
– Lauric& Palmitic acid
- Animalfats& hydrogenatedvegetableoil
4) Trans-fattyacids( TFA )
– Elaidic& Trans-oleicacid
- Hydrogenationof PUFAs& MUFAs
- harmful  RiseLDL-C
 LowersHDL-C
2) Monounsaturatedfattyacids ( MUFA)
- Oleic& Palmitoleic acid( One = bond)
- Olives & nuts  lowersLDL & VLDL
3) Polyunsaturatedfattyacids( PUFA )
- Linolenic& Arachidonic acid
- 2 or more = bonds
- Hypolipideaemiceffect
- Corn,safflower & fishoil

7. COMPOUNDLIPIDS:
 ESTERS of FATTYACIDS & ALCOHOL + OTHERGROUPS
 Sulfolipids & Phospholipids
NEUTRALLIPIDS:
 Non-polar lipids  TG, CH & CE
 TG  Glycerol + 3 OH groupslinked to FA
 CH  Sterol
 Transported intocirculation Solubilisedform LIPOPROTEINS

8. CHOLESTEROL
• C 27 steroid
• important component - cellmembranes
• important precursor molecule- biosynthesis of bileacids
steroidhormones
several fat-solublevitamins

9. CHOLESTEROL STRUCTURE :
 4 Non – Aromatic Rings
 1 Carbon DoubleBond
 1 Side Chain
 Hydroxyl Group

10. LIPOPROTEINS
 Macro molecular assemblies that contain lipids and proteins.
Lipidconstituents include
- free and esterified cholesterol
- triglycerides
- phospholipids
Protein constituents include
- apoproteins
- apolipoproteins

12. TYPES OF LIPOPROTEINS ( LPs )
 Density 5 MAJOR CLASSES
 Diameter
 TG & CE contents

13. (100 - 1000 nm)
(20 – 30 nm) (7 – 20 nm)
(30 – 80 nm)(1.006)
(1.063)

14. LIPOPROTEIN – (a) [( LP(a)]
 Competitive inhibitor of Plasminogen&
receptors
 Fibrinolytic enzyme – PlasminX
 Thrombolysis X
 Smooth m/s cell proliferation+
 PLAQUES
 Greater ATHEROGENICpotential

15. LP( a ) > LDL > VLDL = IDL = CM > HDL
HDL is rather ANTI-ATHEROSCLEROTICLIPOPROTEIN
ATHEROGENICITY

24. REVERSE CHOLESTEROL TRANSPORT

37. LIPOPROTEIN – (a) [( LP(a)]
 Desirable  < 14 mg/dl
 Borderline risk  14 – 30 mg/dl
 High risk  31 - 50 mg/dl
 Very high risk  > 50 mg/dl

39. Dyslipidaemia manifest as :
 TOTAL CHOLESTEROL ( CH )
 LOWDENSITYLIPOPROTEINCHOLESTEROL( LDL-C )
 TRIGLYCERIDE ( TG )
 HIGH DENSITY LIPOPROTEINCHOLESTEROL ( HDL-C)

40. A/K/A HYPERLIPIDAEMIAOR HYPERLIPOPROTEINAEMIA
DYSLIPIDAEMIA PREFERRED  LOWHDL-C

41. TYPES OF DYSLIPIDAEMIAS
 PRIMARYDYSLIPIDAEMIA : Familial Singlegenedefect (Fredericksonclassification)
Multifactorial  Multiple genetic, environmental,
dietary& physical activity
 SECONDARYDYSLIPIDAEMIA : DM, Myxodema
Chronic alcoholism
Hypothyroidism
Nephroticsyndrome
Drugs: Beta blockers,OCPs,

47.  PRIMORDIALPREVENTION- To prevent the development of risk factors rather thantreatingalreadyestablishedrisk
factors.It is a populationbasedapproachthat targets
- Smoking - Healthyeating habits - Wt. management
- CH & glucoselevels - Physical activity - Boodpressure
 PRIMARYPREVENTION– Involvesmanagement of riskfactorsto prevent first ever CHD event.
 SECONDARYPREVENTION- Those who have had a prior CHD event & whose risk factors are treatedmost aggressively.
 150 min/wk of moderateintensityexercise.
MANAGEMENT OF DYSLIPIDEMIA

48. DIETARY RECOMMENDATIONS:
Total calories from fat - < 3 0%
Saturated fat - < 7%
Cholesterol - < 300mg/day
Oily fish t wice a weekor more often
Oils/foods richin α-linolenic acid (soyabean,flaxseed,walnuts)
Sugarybeverages - < 36 oz/week or < 1020 gms/week

49. • PatientsWith CHD  immediately startedwithlipidlowering therapy irrespective of baseline LDL-
C.
• PatientsWithout CHD  lifestyle advice for 3-6 months before drug therapy.
• Before initiating drug therapy, secondary cause of dyslipidemia shouldbe ruledout.
MANAGEMENT OF DYSLIPIDEMIA

50. Pharmacotherapy of Dyslipidaemias
 Therapy that Target Atherogenic Lipoproteins
 Therapy that Target High DensityLipoproteins

51. Therapy that Target Atherogenic Lipoproteins
A) Wellestablished Anti-dyslipidaemic therapies
1) HMG-CoA Reductase Inhibitors (Statins) : Atorvastatin, Simvastatin,
Lovastatin, Pravastatin, Fluvastatin, Rosuvastatin, Pitavastatin.
2) Bile Acid- BindingResins : Cholestyramine, Colestipol, Colesevelam
3) Inhibitorsof Intestinal Cholesterol Absorption : Ezetimibe, Stanol Esters
4) Fibrates ( LPL activators ) : Gemfibrozil, Bezafibrate, Fenofibrate, Ciprofibrate
5) Lipolysis & VLDL Secretion fromAdipose TissueInhibitors : Niacin

53. Therapy that Target Atherogenic Lipoproteins
A) NewlydevelopedAnti-dyslipidaemic therapies
1) Proprotein Convertase Subtilisin/ Kexin Type 9 ( PCSK9 ) Inhibitors :
Alirocumab, Evolocumab, Bococizumab.
2) Apolipoprotein B Synthesis Inhibitor : Mipomersen
3) MicrosomalTrigyceride Transfer Protein( MTP ) Inhibitor : Lomitapide
4) Apolipoprotein C-III Synthesis Inhibitor : Volanesorsen
5) Miscellaneous : Gugulipid& Fishoil derviatives

54. B) Therapy that Target HighDensity Lipoproteins
1) Cholesterol Ester Transfer Protein( CETP) Inhibitors :
Dalcetrapib
Torcetrapib
Evacetrapib
Anacetrapib

55. HMG-CoA Reductase Inhibitors (Statins)
 Development  1976 withdiscovery of Mevastatinby Endoet al. Originally namedCompactin,
fungal metabolite  Penicilliumcitrinum
 Years later, structurally similar compounds  Monascus ruber & Aspergillus terreus  Mevinolin
 Lovastatin ( 2 foldmore potentthanMevastatin)

56. DiscoveredLDL-receptor
1985 Nobel prize in Medicine

57. HMG-CoA Reductase Inhibitors (Statins)
 1985 : Atorvastatin, firstsynthesizedby Bruce Roth while working at Parke-Davis Warner-Lambert
Company ( now Pfizer)
 1990-94 : While researching Lovastatin, Merck scientists synthetically derived Simvastatin 
Fermentationproductof Aspergillusterreus
 Provastatin, identified in bacterium Nocardia autotrophica by researchers of SankyoPharma,
Japan

58. HMG CoA Reductase Regulation
• Allosteric modulation
• Gene regulation
• Proteolysis
• Harmonal regulation
• Competitive Inhibitors

59. Increase : Cholesterol Negative
Bile acids Feedback
Mevalonate
Allosteric modulation

60. Gene regulation
SCAP– SREBP CLEAVAGEACTIVITYPROTEIN
SREBP– STEROLRESPONSEELEMENTBINDINGPROTEIN

61. Proteolysis

62. Harmonal regulation

63. CLASSIFICATION OF STATINS
A. How theyare obtained
Fungal fermentation : Lovastatin, Simvastatin
Synthesis : Atorvastatin, Fluvastatin
B. Livermetabolism
CYP 2C9pathway: Fluvastatin
CYP 3A4 pathway: Otherstatins
C. Physico-chemical properties:
Provastatin  extremelyhydrophilic
Fluvastatin  intermediatecharacteristics
Lovastatin, Simvastatin, Atorvastatin  hydrophobic
D. Specific activity:
Atorvastatin, Cerivastatin, Fluvastatin & Pravastatin  Activeforms
Lovastatin & Simvastatin enzymaticallyhydrolysed Active forms

64. Fungal metabolite  Hexahydronaphthalene ring
Synthetic Heptanoicacid sidechain

65. Competitive Inhibitors

66.  Absorption is variable ( 30 – 85 % ).
 Uptake of statins is mediated by OATP1B1.
 Bioavailability is 5 - 30 %.
 In plasma > 95 % are protein–bound except PRAVASTATIN.
 T ½  1 – 3 hrs , Night , Atorvastatin& Rosuvastatin(14 hrs & 19 hrs)
 Metabolized in liver and excreted in feces.
PHARMACOKINETICS

67. PITAVASTATIN  2 mg
ATORVASTATIN 10 mg
ROSUVASTATIN  10 mg
LOVASTATIN  20 mg
SIMVASTATIN  20 – 40 mg
PRAVASTATIN  20 – 40 mg
FLUVASTATIN  40 mg
LDL  Reduced 20 – 55 %
HDL  Increased 5 – 15 %
TG  Reduced 10 – 35 %

69. Statins – Pleiotropic effect
 PL  Plaque stabilisation
 E  Endothelial dysfunction
 I  Inflammation
 O  Oxidative stress
 TROPIC  Thrombotic effect

70. STATINS : Adverse Effects
 Prolongeduse  LDL reduce -6% Feedbackcompensatory
induction
 Down regulationof LDL receptors
 Myositis  Elevatedserum creatininekinase
 Rhabdomyolysis  (myoglobinuria renalshutdown)
 Lovastatin& Simvastatin crossBBB Sleepdisturbance

71. ADVERSE EFFECTS
Hepatotoxicity Myopathy Not used in pregnancy

72. STATINS : Drug Interactions
 Muscle damage  Gemfibrozil, Niacin, Cyclosporin ( Fluvastatin – Safest )
 CYP3A4 inhibitors  Itraconazole, Cyclosporine, Erythromycin
 Except Fluvastatin& Rosuvastatin increase Statins levels
 CYP3A4inducers  Phenytoin decrease Statins levels
 Grape juice  inhibit intestinal degradation 8-9 foldsincrease
 Lovastatin, Simvastatin & Atorvastatin
 Pravastatin  self conjugation  least interactions

73. STATINS - Contraindications
 Liver diseases – Elevated SerumTransaminases
 Pregnancy & Lactation  Foetal development

74. BILE ACID BINDING RESINS

75. BILE ACID BINDING RESINS
 BA  Absorptionof dietary fat
 RESINS+BAcomplex 95%not absorbed
 Prevent BA  Entero-hepatic circulation
 Decrease BA  Decrease in CH
 Increase in LDL – R  Decrease LDL– C
 Long term  Decrease of hepaticCH
 Increase HMGCoA Reductase

76. CHOLESTYRAMINE COLESEVELAM
MOA  Chloride ion  negatively chargedBA
Large mol wt polymers, non-absorbable, anionexchangeresin

77. Effectivenessof resins is increasedby administering with statins

78. Preparations :
Cholestyramine  Granular form 16 gms orallybefore foodtwice daily
Colestipol Water or Juice  Hydratefor 2 min
Not Palatable Flavouringagents
Colesevelam  625mg tablets  6 tablets / day
Bettercompliance
Indications :
1) Type II hyperlipoproteinemia
2) Relief of pruritus Partial biliary obstruction (Cholestyramine)
3) May be usedalongwithStatins

79. ADVERSE EFFECTS:
1) Constipation  Highfibre diet
2) Exacerbation  Pre-existing haemorroids, GITdistress
CONTRAINDICATION:
1) Hypertriglyceridemia Resins ↑ TG levels
DRUGINTERACTION:
1) Fat solublevitamins absorption impaired
2) Cholestyramine & Colestipol  Digoxin, Tetracycline, Statin, Thiazide
 Interval of 3 – 4 hrs
COLESEVELAM IS DEVOID OF SUCH DRUG INTERACTIONS

80. Inhibitors of Intestinal Cholesterol Absorption:
EZETIMIBE
 First compoundapproved
 Lowering total & LDL-C
 Inhibit cholesterol absorption
 Enterocytes in small intestine
 Synergisticeffect
 combinedwith Statins ( Simva )  LowersLDL by 20%.

81. NPCILI – NiemannPick C1 like 1 protein

83.  Water insoluble
 Oral administration  Glucoronideconjugation ( Intestine )
 Metabolite( active )  Absorbed Bile
 T1/2  22 hrs ( Entero - hepatic circulation)
 Dose : 10 mg OD
 ADVERSEEFFECT: Allergic reactions – rare,Myopathy( Statin )
 DRUGINTERACTIONS: Resinsinhibit absorptionof ezetimibe
 CONTRAINDICATIONS: Not safe in pregnancy
EZETAMIBE

84.  Inhibit lipid absorption  Intestine
 Present in Margarine spread
 Least absorbable, more safe
 Decrease  CH, LDL - C
PLANT STANOL ESTERS

85.  Structurallysimilarto CH – Differ in side chain
 Without double bond
 More Hydrophobic
 Displace CH frommicelles
 Increase CH excretion
 Dose : 2 gms  Reduce LDL - C by 10 – 15 %

86. PLANT STANOL ESTERS

92. FIBRATES : LPL activators – PPAR α agonist
 Hologenated : 1st generation - Clofibrate
2nd generation– Fenofibrate
- Bezafibrate
- Ciprofibrate
 Non– halogenated: - Gemfibrozil

93. Fibrates
 In 1962, Thorp& waringreportedthat ethyl chlorophenoxyisobutyratelowered
lipid levels in rats
 In 1975, The WorldHealthOrganizationCooperative Trial on Primary Prevention
of Iscaemic Heart Disease using clofibrate
 Despite successful cholesterol lowering
 47%more deaths during treatment withclofibrate
 5%after treatment with clofibrate than the non-treatedhighcholesterol group
 Heart disease  “Unexplained”
 Clofibratewas discontinued in 2002 due to adverse effects

94.  # LPL & HL
# hepatic uptake of triglyceride - rich particles

95. FENOFIBRATECLOFIBRATE
BEZAFIBRATE GEMFIBROZIL

96. FIBRATES - PHARMACOKINETICS
 Fibrates are absorbed rapidly & distributedwidely– Liver, kidney, intestine
 T1/2  Gemfibrozil (1.1 hr)
Fenofibrate (20 hr)
Glucoronide conjugation & major  Urine ( C/I in Renal failure )
 Gemfibrozil – negligible

97. Gemfibrozil inhibits OATP1B1  interferes withStatin uptake and metabolism.
Clofibrate 2gm/dayorally Not tolerate Gemfibrozil or Fenofibrate

98. FIBRATES – USES
 LDL – C  Decrease 5 – 15 %
 HDL – C  Increase 10 – 20 %
 TG  Decrease 20 – 50 %
 Type III hyper lipoproteinemia  sensitiveresponders to fibrates
 DOC  severe hypertriglyceridemia
 chylomicronemiasyndrome
 Fenofibrate  Dyslipidaemia+ Gout  Uricosuric effect

99. FIBRATES – ADVERSE EFFECTS
 Lithogenic effect  Clofibrate
 Safein cholecystectomizedpatients
 Myopathy withhighdose statins
 Rashes, urticaria, alopecia, fatigue, headache
 Hepatotoxicity- Rare
 Clofibrate, Bezafibrate, Fenofibrate :
 oral anticoagulants by displacingthemfromalbumin

100. Lipolysis & VLDL Secretion from
Adipose Tissue Inhibitors
NIACIN

101.  Pyridoxine-3-carboxylic acid
 Niacinacts after conversionto NAD( Nicotinamide AdenineDinucleotide )
 Larger doses: 2 – 6 gms / day ( Daily requirement – 15 mg / day )
 Reduces TGlevels within 4-7daysbut takes 3-6wksfor its effectson LDL-C.
↑HDL(30-40%) ↓TG(35-45%)
 Onlylipid lowering agent that reduces LP (a) levels significantly.
 Side effects  limitsits use.
NIACIN

102.  Niacinacts viaGPCR 109A, couplesto Gi
 inhibit adenylylcyclase  ↓ cAMPleading  ↓ hormone sensitive lipase
 prevent TG lipolysis& release of FFA
 Alsoinhibits rate limiting DGAT2 or DAG2
 Promotes LPL activityenhance clearance chylomicrons, VLDL& TG
 RaisesHDL-Cby ↓ fractionalclearance of apoA-1
 In macrophages  stimulatesexpression  scavenger receptors CD36
 cholesterol transporter ABCA1
 reduce cellular cholesterol content
 Half -life : 1 hr  2-3 times daily dosing

104. NIACIN - THERAPEUTIC USES
 DOC  Type II & IV
 Dose : 2 – 4 gms ( max. 6 gms ) in 3 divided doses
 To reduce S/E ( Flushing & itching )  300 mg in 3 divideddoses
 After meals

105. NIACIN– ADVERSE EFFECTS
• Cutaneouseffects : Flushing, pruritus of face & upper trunk, skinrashes
• Dyspepsia( m/c ), nausea, vomiting, diarrhoeaare rare
• Hepatotoxicity ↑serumtransaminases
• Niacin elevates Uric acid levels & reactivates Gout
• Rarely toxic amblyopia & toxic maculopathy
• Atrial tachyarrythimias & atrial fibrillation
• Birthdefects in exp. animals (C/I: pregnancy)
• Insulinresistance  Glucose level monitoring

106. Proprotein Convertase Subtilisin / Kexin Type 9 ( PCSK9 )
Inhibitors :

120. PCSK9 Inhibitors
 LDL– R degradationis reduced  Genetic loss -of -function of PCSK-9
 ASCVDreducedto 88 %
 Approvedin 2015 HeterozygousFH ( lifestylecontrol+ Statins )
1) EVOLOCUMAB 140mg-2weeksor 420mgmonthlyS.Croute,
ReduceLDL& apo B  50 – 72 %
1) ALIROCUMAB T1/2– long, 2 – 3 weeks after one injection,No A/E
2) BOCOCIZUMAB PhaseIII  HeFH& HoFH

121. Apolipoprotein B Synthesis Inhibitor : MIPOMERSEN

122. MIPOMERSEN( approved by FDAin Jan2013 )
DOSE: 200 mg subcutaneouslyonce weekly
MOA: Antisense apolipoprotein B synthesis inhibitor
P/K: Tmax: 3 to 4 hours
Distribution: highlyproteinbound (90%)
Metabolism: endonucleases
Half-life: 1 to 2 months
PREGNANCY: CategoryB – not known to cause harmin animals,
no datain humans

123.  ApoB  mainprotein  Atherogenic lipoprotein
 AntiSence Oligonucleotide ( ASO) # apo B-100synthesisin liver
REDUCE : ApoB  33 – 54 %
LDL-C 34 – 52 %
Lp ( a )  24 %
ADVERSE EFFECTS:
 Severe injection site reactions 72 – 97 %
 Flu – like reaction  25 – 29 %
 Headache 15 – 31 %
 Liver enzymeelevation 3 – 17 %
USES:
TypeII HeFH& HoFH
LackLDL-R
Do not reposndto Statins& PCSK9Inhibitors

124. Microsomal Trigyceride Transfer Protein ( MTP ) Inhibitor :
LOMITAPIDE

125. LOMITAPIDE
USES:Adjunctto lipidloweringmedicationsandlow-fatdietin patientswithHoFH
DOSE: Initially:5 mgorallydailywithoutfood
Titrationschedule:5mgx 2 weeks, 10 mgdailyx 4 weeks, 20 mgdailyx 4 weeks,
40mgdailyx 4 weeks, 60 mgdailymaximum. Increasebasedonsafetyandtolerability
MOA: Microsomaltriglyceridetransferproteininhibitor
P/K: Tmax:6 hours
Distribution:highlyproteinbound(99.8%)
Metabolism:CYP3A4
Half-life:approximately40 hours
PREGNANCY: CategoryX – knownteratogeninratsandferrets(fetalmalformation)

126. Mipomersen (Kynamro) Lomitapide (Juxtapid)
BlackBox Warning Riskof heptaotoxicity Riskof hepatotoxicity
REMSprogram
(RiskEvaluation& Mitigation
Strategy)
- To ensureawarenessof hepatotoxicityrisk,needfor
patientmonitoring,anddiagnosisof HoFH
- Followmonitoringrecommendations
- Prescribertraining, certification, priorauthorization
- Pharmacycertification
- To ensureawarenessof hepatotoxicityrisk,need
forpatientmonitoring,anddiagnosisof HoFH
- Followmonitoringrecommendations
- Prescribertraining, certification, prior
authorization
- Pharmacycertification

127. Apolipoprotein C-III Synthesis Inhibitor : Volanesorsen
ApoC III  Proinflammatory protein Liver  Component of all LPs ( plasma )
# LPL  Prevents lipolysisof TG  Increase TG
# HL Reduce catabolism, Hepaticuptakeof TG-richLPs
Preventing formationof Apo C III  AntiSence Oligonucleotide ( ASO)

129. ApolipoproteinC-III Synthesis Inhibitor : Volanesorsen

130. Gugulipid
( Commiphorawightii)
 Drug developed  Central Drug ResearchInstitute, Lucknow
 Orally # CH synthesis
 IncreasesCH excretion
 Dose : 25mgtablet thrice daily
 Reduce  Total CH, LDL-C, TG
 Increase  HDL-C
 S/E : Loose stools ( NO teratogenic or Carcinogenic effect )

132. Fish oil derivatives – Omega-3 Fatty Acids
 Contains PUFA  EPA
DHA
 Prophylaxis High-risk Hyperlipidaemic+ CAD
 Membrane stabilising
 Antioxidant action
 Formulated withVit E
 EPA& Icosapent ethyl  1gm capsule
 T1/2 – 50 – 80 hrs

133.  The protectiveroleof PON1inatherosclerosis.
 Circulatingmonocytesare activatedinanoxidantand
inflammatoryenvironmentandbecomemacrophages.
 Thisenvironmentalsopromotestheoxidationof LDL
particles,whichareinternalizedintothemacrophages
thatbecomefoamcells.
 PON1hydrolyzesoxidizedlipidsinLDL,reversingthis
lipoproteinto itsnaturalstatus-inhibiting
atherosclerosis.
 PON1,by inhibitingMCP-1,isanti-inflammatoryand
favorscholesteroleffluxfrommacrophages.

134. COMBINATIONDRUGTHERAPY USES
BA RESIN+ FIBRATE TypeII
A/E  Cholelithiasis
BA RESIN+ NIACIN TypeIIa& IIb
Adv Reducegastricirritationby Niacin
STATIN+ BA RESIN ReduceLDL-C TypeIIa
D/I Before1 hr or after4 hrs
BARESIN+ NIACIN TypeIIa& IIb
STATIN+ NIACIN TypeIIa& IIb
STATIN+ EZETIMIBE Synergisticcombination
TypeIIa
STATIN+ FBRATE A/E  Myopathy
STATIN+ ANTI– PCSK9 Mab Synergisticcombination
TypeIIa

135. Cholesterol Ester Transfer Protein ( CETP ) Inhibitors

136. CETP Inhibitors
• HumanCETP deficiency  IncreasedHDL-C
• CETP activity inversely correlatedto HDL-C
• Reductionin CETP  Markedreductionin CH burdenin TG rich particles
• DecreasingCETP activity  InhibitedAtherosclerosis in animal models

137. Failed:
Torcetrapib- failed in 2006 excess deaths in Phase III clinical trials.
Dalcetrapib- development halted in May 2012 whenPhase III trials failed to showclinicallymeaningful efficacy
Evacetrapib- development discontinued in 2015 due to insufficient efficacy
Succeeded:
Anacetrapib- In 2017, the REVEALtrail ( RandomizedEValuationof the Effects of Anacetrapib through Lipid
Modification ) basedon more than 30,000 participantsshowed a modest benefit of the addition of anacetrapibto
statin therapy. Despite the successful trial, Merckhalted the development of the drug. [11]

138. RECENT APPROACHES
• RecombinantApo A-1 Milano(variant of apoproteinA-1) infusioncausedregressionof atherosclerosisin animal
models.Expensiveto produce& must be givenby I.V route but strategycontinuesto be a focusof interest.
• Drugsinhibiting squalene synthesis,MTP inhibitors and drugsthat alter apo B are beinginvestigated.
• SqualenesynthesisinhibitorsTAK-475,Zaragozicacid& 107393RPRare beinginvestigated.
• ORION-1describes - Inclisiran– targetsPCSK9 mRNA & Blocks

139. Two bags of fresh frozen plasma: The bag on the left was obtained from
a donor with hyperlipidemia, while the other bag was obtained from a donor with normal serum
lipid levels.

140.  Goodman & Gilman’sThePharmacologicalBasisof Therapeutics13thed.
 BertramG Katzung Basic& ClinicalPharmacology14th ed.
 Rang& Dale’sPharmacology8th ed.
 Lippincott’s IllustratedReviewsPharmacology5th ed.
 KD Tripati Essentialsof MedicalPharmacology7th ed.
 R S Satoskar PharmacologyandPharmacotherapeutics25th ed
 Sharma& Sharma’s Principlesof Pharmacology3rd ed.
 Dr S K Srivastava Pharmacologyfor MBBS1st ed.
 Images – web,KaplanUSMLEstep1 Biochemistry,FirstAidfor theUSMLE
REFERENCES

141. THANK YOU