statins and other newer drugs to treat dyslipidemia all the major categories of hypolypidaemic drugs

1. Lipid Lowering Agents - Statins and Beyond
Dr. VINAY TUTEJA
SMS MEDICAL COLLEGE

2. CONTENTS
LIPID AND ITS METABOLISM
TYPES OF HYPERCHOLESTEROLEMIA
DIAGNOSIS
ANTIHYPERLIPIDEMIC DRUGS

3. LIPID METABOLISM
 Lipids - Esters of fatty acids and alcohols
 Lipoprotein - They are spherical particles that
transport neutral lipids that is TG and CH in blood.

4.  Apolipoprotein : A protein that binds to lipids
 Cholesteryl ester : A compound of cholesterol
and a fatty acid
 Triglycerides : A compound of glycerol &
three fatty acids,
Over 93% of the fat that is consumed in
the diet is in the form of triglycerides (TG).

5.  Cholesterol
• Dietary intake supplies only about 20 –25% of the
cholesterol needed everyday to:
• Build cell membranes
• Synthesize bile acids/salts
• Synthesize hormones of the adrenal glands
aldosterone , cortisol
• Synthesize the sex hormones (Estrone ,
Testosterone)
• The other 75 –80% of our daily need for cholesterol
is synthesized in the liver.

6.  TYPES OF LIPOPROTEINS

7.  Source of Lipids:
I. Endogenous lipids
• Synthesized in the liver
• Liver synthesizes TG and cholesterol , packages
them as VLDLs before releasing them into the
blood
II. Exogenous lipids
• Ingested and processed in the intestine.
• Dietary cholesterol & triglycerides ,packaged into
chylomicrons in the intestine, released into
bloodstream via lymphatics.

9. TYPES OF HYPERCHOLESTEROLEMIA
A.Primary hypercholesterolemia
• Genetically determined
• Frederickson’s Classification

10. B. Secondary hypercholesterolemia
CPG for Managing Dyslipdemia and Prevention of CVD, Endocr Pract.2017 ;23(Suppl2)

11. When to say dyslipidemi

12. CPG for Managing Dyslipdemia and Prevention of CVD, Endocr Pract.2017 ;23(Suppl2)

13. Atherosclerotic Cardiovascular Disease Risk Categories
Garber et al. Endocr Pract. 2017;23:207-238

14. • How to treat
hyperlipidemia?

15. ANTI HYPERLIPDEMIC DRUGS

16.  CETP(Cholesteryl Esteryl Transport Protein) Inhibitors
• Torecetrapib
• Dalcetrapib
• Evecetrapib
• Anacetrapib
 Pcsk9 (Proprotein Convertase Subtilisin / Kexin 9)
Inhibitors
• Bococizumab
• Evolocumab
• Alirocumab
Newer Drugs

17.  Apolipoprotein B synthesis Inhibitor
• Mipomersen
 Microsomal triglyceride transfer protein inhibitor
• Lopitamide

18. STATINS
 Among the biggest selling class of Pharmaceutical
compounds of all time with annual sale in excess of 20.5
Billion US dollars.
 It’s HMG-CoA-Reductase Inhibitors (Rate Limiting)
 Production of this enzyme and of LDL receptors is
transcriptionally regulated by the content of cholesterol in
the cell.
 Drugs
MEVASTATIN
ATORVASTAIN
LOVASTATIN
FLUVASTATINS
PRAVASTATIN
ROSUVASTATIN
SIMVASTATIN
PITAVASTATIN

19. How statins works?

21. 1. Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHAguideline on the treatment of blood cholesterol to reduce athero
sclerotic cardiovascular risk in adults: a report of the AmericanCollege of Cardiology/American Heart Association Task Force1.

22. Adverse effects
 Myopathy - Incidence 1 /10,000

23.  Blood Glucose
• High-dose statins led to statistically significant
increase in blood glucose level - The PROVE-IT–TIMI trial
• JUPITER trial, those randomized to rosuvastatin showed
a significant increase in HbA1c (p=0.001) and in
newly diagnosed diabetes mellitus (relative risk 1.25;
p=0.01).
Circulation: Cardiovascular Quality and Outcomes. 2009;2:279-285
 Sleep
• Significant reductions in average sleep quality were seen
with simvastatin.

24.  Liver
• A meta-analysis of randomized, double-blind, head-to-
head, statin comparisons showed more LFT elevations
with higher dose statins.
 Interaction with Fibrates –
• Gemfibrozil , amplify the risk of rhabdomyolysis on
statins.
1)Pranav Sikka, K. K. Saxena Statin Hepatotoxicity: Is it a Real Concern?
Heart Views. 2011 Jul-Sep; 12(3): 104–106
2)Wiggins BS1, Saseen JJ Gemfibrozil in Combination with Statins-Is It Really Contraindicated?
Curr Atheroscler Rep. 2016 Apr;18(4):18

28. CHOLESTEROL ABSORPTION
INHIBITOR
 EZETIMIBE
• Inhibits the luminal cholesterol uptake by
inhibiting cholesterol transport protein Nieman Pick
C1 like 1 protein.
• Dosage -10 mg orally once a day
• ↓ LDL-C 10-18%

29. Mechanism 0f action

30.  Despite the established cholesterol-lowering benefits of
ezetimibe, significant controversy exists with respect to
ezetimibe’s vascular and clinical benefit.

31. FIBRATES
 These are ligands for peroxisome proliferator
activated receptors (PPARs) increase expression of
lipoprotein lipase .
 Activating Lipoprotein lipase, hence increasing
hydrolysis of TG in chylomicrons and VLDL particles
 Dosage: 150mg once a day
 Produce a modest decrease in LDL ( 10%) and
increase in HDL (~ 10%).But, a marked decrease in
TGs (~ 30%).

32. MECHANISM OF ACTION:

33.  Adverse effects
• GIT disturbances.
• Gall stones increased billiary cholesterol
excretion.
• Muscle pain and myopathy , specially when
combined with statins
• Potentiate effects of oral anticoagulants
• Contraindicated in pregnancy, lactating women,
renal and hepatic dysfunction, gall stones.

35. NICOTINIC ACID
 Vitamin B3
 Lipid-lowering properties require much higher
doses than when used as a vitamin.
• Vitamin dose -15-35 mg/day;
• Antihyperlipidemic activity 1-2 g, 3xtimes
day
 Effective, inexpensive, often used in
combination with other lipid-lowering agents

36.  Mechanism of action:

38.  Adverse effects
• Skin flushing
• Pruritus
• Abdominal discomfort
• Hepatotoxicity (rare but may be severe),
• Nausea
• Peptic ulcer
• Atrial fibrillation
• Glucose intolerance
Flushing can be diminished by taking an 350mg
aspirin about 30min before niacin

39. BILE ACID SEQUESTRANTS
 They sequester bile acids in the GIT.
 Prevent their reabsorption and enterohepatic
recirculation.
 Drugs - Cholestyramine,
Colestipol
Colesevelam
 Dosage - 1.875 g (3 tablets) PO q12hr with
meals

40. MECHANISM OF ACTION

41.  THERAPUTIC USES:
• Type IIA and IIB hyperlipidemias (along with
statins when response to statins is inadequate or
they are contraindicated).
• Useful for Pruritus in biliary obstruction (↑ bile
acids).
• Second generation BAS such as colesevelam and
colestimide have a glucose-lowering effect

42. ,
MD, PhD Franklin J. Zieve etal. Results of the glucose-lowering effect of WelChol study (GLOWS): A randomized, double-blind,
placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes.
clinthera.2007.01.003
,

43. CETP INHIBITORS (Cholesteryl
Esteryl Transport Protein) Inhibitors
 Drugs
• Torcetrapib
• Dalcetrapib
• Evacetrapib
• Anacetrapib
 CETP transfers cholesteryl ester from HDL to
VLDL or LDL .
 Inhibition of this process results in higher HDL
levels and reduces LDL levels

44.  Mechanism of action

45. TORCETRAPIB:

46. DALCETRAPIB

47. EVACETRAPIB:

48. ANACETRAPIB
• REVEAL STUDY: CETP Inhibitor Anacetrapib Meets
Primary End Point

49. APOLIPOPROTEIN B SYNTHESIS
INHIBITORS
• Antisense oligonucleotides
• ↓ LDL-C 21%, TC 19%, apo B 24%, and non-HDL-C 22%
in patients with HoFH.
• Dosing of 200 mg per week subcutaneously
 MIPOMERSEN

50.  MECHANISM OF ACTION

52. ADVERSE EFFECTS
• Can cause increases in transaminases (ALT,AST).
• Causes increase in hepatic fat (steatosis) with or
without concomitant elevated transaminases,
which may be a risk for progressive liver
diseases.
• Only available through REMS program ( Risk
Evaluation and Mitigation Strategy )

53. Microsomal triglyceride transfer
protein (MTTP) INHIBITORS
 LOMITAPIDE
• FDA Aproved_ dec 2012
• Dosage: Cap 5mg to 60mg once daily
• ↓ Up to LDL-C 40%, TC 36%,apo B 39%, TG 45%,
and non HDL-C 40%

54.  MECHANISM OF ACTION MTTP INHIBITOR
MTTP INHIBITOR
•Inhibits the microsomal triglyceride transfer protein which is
necessary for VLDL assembly and secretion in the liver.

56. PCSK9 INHIBITORS
 A new era of lipid lowering therapy
 PCSK9 is a secreted serine protease that binds to
the extracellular domain of the LDL receptor
and targets the LDL receptor to the lysosomal
compartment for degradation.
 Consequently, PCSK9 prevents recycling of the LDL
receptor to the cell surface, thereby attenuating
LDL clearance
 Drugs - Bococizumab , Evolocumab ,Alirocumab
Inclisiran

57. Mechanism of action

58. • Bococizumab is a monoclonal antibody that
inhibits PCSK9, a protein that interferes with the
removal of LDL.
• Failed in phase 3 clinical trial due to higher level of
immunogenicity and higher rate of injection site
reactions and no benifits over placebo.
BOCOCIZUMAB

60. ALIROCUMAB
• It is a human monoclonal antibody
• FDA aproved_ july 2015
• Dosage: 75 mg SC every 2 weeks
may increase to 150 mg SC q2weeks
• Common side effects: nasopharyngitis, influenza, UTI
, diarrhea, bronchitis, and myalgia

62. Evolocumab
• Evolocumab is a humanized monoclonal antibody
• FDA APROVED _ August 2015
• Dosage 140 mg subcutaneously every 2 weeks
or
420 mg subcutaneously once a month
• It cost about $14,300 USD per year

64.  Inclisiran
• Long-acting, synthetic, small-interfering RNA
molecule directed against PCSK9 .
• Subcutaneously delivered
• Comleted phase 2 clinical trial
• A single 300-mg injection of inclisiran plus statin
therapy achieved a mean 51% reduction in LDL
cholesterol and a second subcutaneous 300-mg
dose resulted in a 57% reduction in LDL

66. Uses of PCSK9 INHIBITORS
• PCSK9 inhibitors should be considered for use in
combination with statin therapy for LDL-C lowering
in individuals with FH.
• PCSK9 inhibitors should be considered in individuals
with clinical cardiovascular disease who are unable
to reach LDL-C/non-HDL-C goals with maximally
tolerated statin therapy.
•They should not be used as monotherapy except In statin
intolerant individuals.

67.  Take Home Message
Statins are wonder drugs that
have shaped the treatment of
hypercholesterolemia and
associated cardiovascular
diseases.
• Beyond statins many new agents
with promising results have
emerged but they are not in reach

68. MCQ
Q. White woman with diabetes 48 yr of age Total cholesterol
180 mg/dl, HDL cholesterol 55mg/dl,Systolic blood pressure
130 mm Hg ,Non smoker with calculated 10-yr risk of CHD
or stroke 1.8%, which of the following are to be started?
1. Atorvastatin 80mg
2. Rusovastatin 40mg
3. Atorvastatin 10mg
4. Fibrates

70. Q. Which of the lipid lowering agents have
additional benefits in diabetes mellitus?
1 . Statins
2. CETP inhibitors
3. Bile acid sequestrants
4. Pcsk 9 inhibitors

71. Q Torcetrapib a CETP inhibitor having
promising antilipid effects was withdrawn
from trials for which of the following reasons?
1. High cost
2. No change in incidence of ASCVD
3. Hypertension
4. None of these

72. Q. Which of the following is a synthetic PCSK9
inhibitor?
1. Bococizumab
2. Inclisiran
3. Evolocumab
4. Alirocumab

73. Q. Skin flushing is a side effect of which of the
following?
1. Bile acid sequestrants
2. CETP inhibitors
3. Statins
4. Niacin

74. Q. PCSK 9 causes which of the following effects
in liver?
1. Increases LDL receptors
2. Decreases LDL receptors
3. Can cause both
4. Has no effects on LDL receptors