Old + Newer agents for dyslipidemia

1. Pharmacotherapy of
Dyslipidemia
Dr. Irfan Ahmad Khan
Senior Resident

2. Introduction
• Dyslipidemia – disorders of lipoprotein metabolism.
– Abnormal plasma cholesterol and/or Triglyceride (TG)
concentrations.
• Major cause of atherosclerosis and related cardiovascular
diseases.

3. Lipoprotein

4. Major lipoprotein classes
Chylomicron
remnants
<1.006 Dietary triglycerides
and cholesterol
TG<CE B-48, E, A-I, A-V, C-I,
C-II, C-III
Product of
Chylomicron
metabolism
apoE-mediated uptake by
liver
A-V
A-IV, A-V
IDL

5. Inhibits LPL activity and
lipoprotein binding to receptors

6. Lipoprotein metabolism
• Transport of Dietary Lipids / Exogenous
Pathway
• Transport of Hepatic Lipids / Endogenous
Pathway
• Reverse Cholesterol Transport

7. +
50%
50%
75%
NPC1L1
ACAT-2 ACAT-2
HL

8. Reverse Cholesterol Transport
ABCA1
TG HL

10. Hyperlipidemia
Primary Secondary
Monogenic Polygenic/multifactorial
Mutation in
apolipoproteins, their
receptors, transport
mechanism, metabolizing
enzyme
Diificult to t/t
• Multiple genetic
• Dietary
• Physical activity
related causes
• DM
• Nephrotic
Syndrome
• Hypothroidism
• Alcoholism
• Drugs
(Corticosteroids,
oral
contraceptives)

11. (I)
(III)
(IIa)

12. Polygenic/Multifactorial
• IIb: Familial Combined (Polygenic)Hyperlipidemia
– Similar to IIa except VLDL ed
– Deficiency of LDL receptors and overproduction of VLDL by liver
• IV: Familial Hypertriglyceridemia
– Overproduction and/ or decreased removal of VLDL

13. Treatment strategies
1. Dietary and lifestyle modification (NCEP-ATP 4 guidelines)
• Aerobic exercise or brisk walking (20-60 min/d for 3-5 days/week)
• Reduce intake of cholesterol(<30% of total calories) and saturated
fats(5-6% of total calories)
• Reduce sugary beverage intake (<36 oz/wk), sweets
• Cessation of alcohol and smoking
2. Drugs
• Individualized approach

14. Drugs for dyslipidemia
A. Well established Anti-dyslipidemic therapies
– HMG-CoA (3-hydroxy-3- methyl glutaryl CoA) reductase inhibitors
– Fibric acid derivatives
– Bile acid sequestrants
– Nicotinic acid
– Inhibitor of dietary cholesterol uptake
B. Newly developed Anti-dyslipidemic therapies
– Proprotein Convertase Subtilisin/Kexin Type 9(PCSK9) inhibitors
– Inhibitor of ApoB Synthesis
– Microsomal Triglyceride Transfer Protein (MTP) inhibitors
– ApoC-III Synthesis inhibitors
– Gugulipid and fish oil derivatives

15. • Most effective, best-tolerated
• Agents included
• Lovastatin
• Pravastatin
• Simvastatin
• Atorvastatin
• Fluvastatin
• Rosuvastatin
HMG-CoA Reductase Inhibitors (statins)

16. MOA
Inhibit HMG-CoA reductase competitively
(HMG-CoAMevalonic acid)
Inhibit biosynthesis of cholesterol
Depletion of cholesterol in hepatocytes
Activates Scap (SREBP cleavage activating protein)
Proteolytic cleavage of SREBP (Sterol regulatory element binding protein)
Translocates to nucleus
 LDL-R expression on hepatocytes
ed hepatic uptake of LDL, IDL & decrease plasma LDL (20-55% )
(Major effect – dose and agent dependent
6% reduction with doubling of dose)

17.  Decrease VLDL by :
• ↓ hepatic VLDL synthesis d/t ↓ in cholesterol  ↓LDL-C(~25%)
 Homozygous familial hypercholesterolemia (LDLR are absent)
 Effect on TGs :
1. If TGs >250 mg/dL - % decrease ~ % decrease in LDL-C
2. If TGs <250 mg/dL - < 25% decrease in TG levels
 in HDL ~15-20% (Rosuvastatin)

18. Pleiotropic effects:
• Improved endothelial function ,  NO
• Increase plaque stability
• Reduce lipoprotein oxidation
• Anti inflammatory role, ↓ CRP
• Reduce platelet aggregation, profibrinolytic activity

19. Pharmacokinetics
• Extensive first pass hepatic metabolism(uptake by OATP1B1)
• Simvastatin, Lovastatin : lactone prodrugs
• t1/2-1-4 hrs taken in evening
Atorvastatin, Rosuvastatin (~20 hrs),
Simvastatin (~12 hrs).
Dosing
• advisable to start each patient on a dose that will achieve the
patient's target goal for LDL-C lowering

20. Statins dose (mg) Required to Achieve Various
Reductions in LDL-C from Baseline

21. Adverse effects
• Myopathy:
o Myopathy–rhabdomyolysis–myoglobinuria–renal shut down
o High dose / Old age/ Perioperative period
o Hepatic/ renal dysfunction, Hypothyroidism
o Drugs: fibrates, especially gemfibrozil (OATP1B1 inhibition,
interferes with glucuronidation), erythromycin, cyclosporine,
itraconazole (CYP3A4)
o Fluvastatin (2C9) and pravastatin (unchanged) – less risk of
myopathy
o Niacinenhanced inhibition of skeletal muscle cholesterol
synthesis

22. • Hepatotoxicity :
• Elevation of transaminases.
• Severe hepatitis rare
• Monitoring recommended before starting therapy and at 2-3
months, then annually.
C/I : pregnancy & lactation.
• Pravastatin in children >8 yrs.
• Atorvastatin, Simvastatin and Lovastatin >11 yrs.

23. Use
• DOC for hypercholesterolemia
• Statins + Niacin = ed effectiveness but  risk of myopathy
• Statins + resins = 20-30% greater reduction in LDL-C
• Statins + fibrates = useful when LDL associated with TG
• Atorvastatin and Rosuvastatin : max TG lowering effect
• Statin + resins + Niacin = 70% reduction in LDL-C
• Simvastatin + Ezetimibe = 60% reduction in LDL-C

24. Activators of PPARα – gene transcription regulator (expressed
primarily in liver and brown adipose tissue)
!st generation - Gemfibrozil (600-mg BD, 30 minutes
before morning and evening meals)
2nd generation - Clofibrate (~500 mg QID)
Fenofibrate (~145 mg OD)
Bezafibrate( ~200 mg TDS)
Fibric Acid Derivatives

25. MOA
•  LPL synthesis :  clearance of TG-rich lipoproteins
• Reduce expression of apoC-III (an inhibitor of lipolytic processing
and R-mediated clearance) thereby clearance of VLDL
• Reduce TGs (upto 50%) by stimulation of fatty acid oxidation
• in HDL-C(~15%): stimulation of apoA-I & apoA-II expression
• Misc. effect : inhibition of coagulation and fibrinolysis

26. Therapeutic Uses
• DOC
– Type III familial dysbetalipoproteinemia
– Severe hypertriglyceridemia
– Chylomicronemia syndrome
• Familial hypercholesterolemia type IIa
• Familial combined hypercholesterolemia type IIb
• triglycerides and low HDL-C levels associated with the
metabolic syndrome or type 2 diabetes mellitus

27. Adverse effects
• Abdominal discomfort/ Diarrhea/ Nausea.
• Increased risk of gallstones (clofibrate).
• Prolonged prothrombin time
• Myopathy :
• high risk when combined with statins (followed at 3 months).
• Gemfibrozil : highest incidence.
• Fenofibrate safer: glucuronidated by enzymes that are not
involved in statin glucuronidation
C/I
• Children & pregnant women
• Renal failure

28. • Safest as not absorbed from intestine
• Cholestyramine, colestipol, colesevelam
• MOA:
– Highly positively charged molecules that bind negatively
charged bile acids
– Due to large size, resins are not absorbed and bound bile acids
are excreted in stool
– Pool of bile acids is depleted
Bile Acid Sequestrants

30. • The resin-induced decrease in BA is a/w  in hepatic TG
synthesis. Monitoring (every 1-2 weeks) of fasting TG levels is
needed or their use in such patients should be avoided.
• 12-18% reduction in LDL-C.
• 40 – 60% reduction in LDL-C when used along with statin/ niacin
• 4-5% rise in HDL-C.

31. Therapeutic Uses:
• Heterozygous familial hypercholesterolemia
• Drug of choice for children and females in reproductive age group.
Dose :
• Cholestyramine 4g packet
• Colestipol 5g packet / 1g tab.
• Colesevelam 1.875 g packet/ 625 mg tab. (3 tab.)BD with meal
C/I- Hypertriglyceridemia
Mixed with water or
juice. Ideally, patient
should take resins BBF
and before supper,
starting with one
packet twice daily

32. Adverse effects
• Heart burn, dyspepsia, bloating, gritty sensation (suspending
powder in liquid several hours before ingestion)
• Malabsorption of Vitamin K, folic acid etc.
• Constipation (adequate water intake and psyllium)
• Rarely can cause hyperchloremic acidosis.
D/I:
• Binds to digoxin, warfarin, thyroxine, some statins, furosemide,
thiazides; prevents absorption 1 hr before or 3-4 hrs after
bile acid sequestrants.

33. Niacin (Nicotinic Acid)
• Oldest, effective, inexpensive, often used in combination
• Best agent available for increasing HDL-C (25-30%)
• Lowers TGs (40%), LDL-C (20-25%) in dose of 1.5-3 g/day
• Reduces Lp(a) levels significantly.

34. • LPL activity,  clearance of chylomicrons and VLDL
• Inhibit a rate-limiting enzyme of TG synthesis, Diacyl Glycerol Acyl Transferase-2
Inhibits lipolysis of TGs by HS Lipases by inhibiting
adipocyte adenylyl cyclase
Decrease fractional
clearance of
Stimulates expression
of SR-CD36 & ABCA1
1.
2.
3.
4.

35. Therapeutic uses:
• Hypertriglyceridemia and high LDL-C associated with low HDL
• DOC for Familial combined hypertriglyceridemia
• Familial dysbetalipoproteinemia (type 3)
• Severe mixed hypertriglyceridemia(type 4)
• Heterozygous familial hypercholesterolemia (+ resins/statins)
Niacin Starting Dose Maximal Dose
Immediate release 100 mg TDS 1 g TDS
Sustained release 250 mg BD 1.5 g BD
Extended release 500 mg HS 2 g HS

36. Side effects
• Flushing, warmth (PGD2 & E2)
• Pruritus, rashes
• Dyspepsia
• Skin dryness
• Acanthosis nigricans
• Liver dysfunction (flu like fatigue)
• Hyperglycemia, Hyperuricemia
• Risk of myopathy if combined with
statins. (dose not >25% of
maximum)
C/I
• Peptic ulcer disease
• Gout
• DM
• Pregnancy

37. Ezetimibe
• Inhibition of cholesterol absorption by jejunal enterocytes (NPC1L1
transport protein)  decrease in hepatic cholesterol 
upregulation of LDL-R.
• Lowers LDL-C by 15-20%
• HDL-C by ~2% and decrease TGs by ~5%
• 10 mg tablet/day with statins
• Bile-acid sequestrants inhibit absorption of ezetimibeshould not
be co-administered
• ADRs: rare allergic reactions

38. Proprotein Convertase Subtilisin/Kexin Type 9
(PCSK9) inhibitors
• PCSK9: physiological enzyme ligand of LDL-R
Low pH Prevents dissociation

39. • Alirocumab & Evolocumab (Approved in 2015)
– Heterozygous FH
– Lower LDL-C by 50-72% (effect persists for 2-4 weeks after
single S.C. injection)
– Lower PCSK9 activity upto 80%; Reduce Lp(a)
– Alirocumab: 75 mg SC q2weeks; If the LDL-C lowering response
is inadequate, may increase to 150 mg SC q2weeks
– Evolocumab: 140 mg SC q2weeks
• Bococizumab (Phase III)
• PCSK9 also involved in degradation of many receptors that are
also receptors for viruses (human rhinovirus and hepatitis C
virus) viral infections need to be monitored in patients on
PCSK9 inhibitors

40. Inhibitor of ApoB Synthesis: Mipomersen
• Antisense oligonucleotide that inhibits ApoB-100 synthesis in liver
decrease VLDL & LDL-C
• Useful in heterozygous and homozygous FH who lack LDL-R
• 200 mg SC weekly: reduces apoB(33-54%), LDL-C(34-52%),
Lp(a)(24%)
• ADRs: severe injection site reaction, flu-like reactions, headache,
hepatotoxicity
• Approved for t/t of homozygous FH with restriction due to
hepatotoxicity available through restricted Risk Evaluation &
Mitigation Strategy(REMS) program

41. Microsomal Triglyceride Transfer Protein (MTP) inhibitors:
Lomitapide
• Bind and inhibit MTP from transferring TG to apoB in liver
decrease in VLDL & LDL-C
• Useful in homozygous FH who lack LDL-R
• Reduces LDL-C (42-50%)
• Dose: Initially orally 5mg/day 10, 20 40 upto 60 mg
• Approved for t/t of homozygous FH with restriction 
hepatotoxicity available through restricted Risk Evaluation &
Mitigation Strategy(REMS) program

42. ApoC-III Synthesis inhibitors: Volanesorsen
• ApoC-III inhibits LPL reduced lipolysis of TG rich
lipoproteinsTG
• ApoC-III Inhibits hepatic lipase reduced catabolism and uptake
of TG rich lipoprotein remnants
• Phase 3 : hypertriglyceridemia, familial chylomicronemia syndrome

43. Gugulipid
• Developed at CDRI, Lucknow
• MOA: inhibits CH biosynthesis and enhances rate of excretion of CH
• Dose: 25 mg TDS orally
• ADR: Loose stools

44. Fish oil derivatives (Omega-3 Fatty Acids)
• Contains PUFAs: eicosa penta-enoic acid (EPA) and docosa hexa-
enoic acid (DHA)
• TG catabolism, membrane stabilizing and anti-oxidant action
• 4g/day

49. Thank you

50. Disorders of reduced HDL-C
• Gene deletion in APO A5-A1-C3-A4 locus and coding mutation in
APOA1
• Tangier Disease (ABCA1 deficiency)
• Familial LCAT deficiency

51. 2. Therapies that HDL
– Cholestryl ester transfer protein (CETP) Inhibitors:
Dalcetrapib, Torcetrapib, Evacetrapib, Anacetrapib