recent advances in dyslipidemia including recent guideline from ADA,AHA

2. Dr. Jeetam Singh Rajput
MLN Medical college

3. Outline
 Introduction.
 Lipid handling in body
 Pathophysiology of atherosclerosis
 Current hypolipidemic drug
 Newer hypolipidemic drug
 AHA/ACC clinical guidelines

4. Introduction
• Dyslipidemia is a disorder of Lipid & lipoprotein
metabolism.
• Three primary abnormality are there
 Elevated triglyceride(TG)
 Elevated LDL cholestrol
 Reduced HDL cholestrol
• It is most important modifiable risk factor for CAD.
• Causes for dyslipidemia
1. Primary dyslipidemia
2. Secondary dyslipidemia

6. SECONDARY DYSLIPIDEMIA
Increased LDL-C Increased TG Low HDL-C
Hypothyroidism Hypothyroidism NAFLD
Renal disease
(Nephrotic syn/CRF)
Renal disease(CRF) CRF
Obstructive liver disease DM(1 & 2) DM(1 & 2)
Cushing syndrome Metabolic syndrome Metabolis syndrome
PCOS HIV HIV
Anorexia nervosa Anorexia nervosa Smoking
DRUG: Gaucher Gaucher
Anabolic steroid Pregnancy DRUG:
Cyclosporin DRUG: Progestin
Progestin Estrogen(OCP’S) Beta blocker
Thiazide BAS Anabolic steroid
SERMs(Tamoxifen) Isotretinoids
Beta blocker PI’s, Corticosteroid
Thiazide, PI’s, Steroids

7. Lipoprotein
• Classified in 7 claases on basis of density
1. HDL
2. VLDL
3. IDL
4. LDL
5. Chylomicron
 TG mainly transported in form of Chylomicron & VLDL.
 Cholestrol mainly transported as cholestrol ester in LDL &
HDL.
Lipoprotein Major surface apolipoprotein
Chylomicron B-48,E,C-I,C-II,A-I,A-II
Chylomicron remnant E
VLDL B-100, E, C-I, C-II,
IDL B-100, E
LDL B-100
Lp(a) B-100, (a)
HDL A-I, A-II, A-IV, C-I, C-II, D, E

8.  Lipoprotein containing apo-lipoprotein B as cofactor they
are atherogenic & which contain apo-lipoprotein A as a
cofactor they are non atherogenic.
 So atherogenic lipoprotein are
 Chylomicron
 Chylomicron remnant
 VLDL
 IDL
 LDL
 Lp(a)
• Only non atherogenic/antiatherogenic/good cholestrol
lipoprotein is
 HDL

11. What does dyslipidemia do:
ATHER
OSCLER
OSIS
Stroke
PVD
Stroke
CAD/MI

13. Classification of Cholestrol & TG level
LIPID Mg/dl
Total cholestrol
Desirable <200
Borderline high 200-239
High >239
LDL Cholestrol
Optimal <70
Normal <100
Near normal 100-129
Borderline high 130-159
High 160-189
Very high >189
HDL Cholestrol
Low(undesirable) <40 male, <50 female
Normal 40-60
High(desirable) >60

14. Journal of clinical lipidology 2015
Triglycerides
Physiological 30-70
Normal <150
Borderline high 150-199
High 200-499
Very high >499

15.  Men>40 and women>50 years of age or post menopausal.
 All patients regardless of age with
 Diabetes mellitus
 Hypertension
 Currently smoking cigarette
 Obesity
 Family H/O CAD <age 60 in first degree relatives
 Inflammatory disease (SLE, RA,Psoriasis etc.)
 Chronic renal failure(eGFR<60ml/min/1.73m2)
 Evidence of atherosclerosis
 HIV infection treated with HAART
Whom to screen for dyslipidemia?

16.  Clinical manifestation of Hyperlipidemia i.e. xanthomas,
premature arcus
 Erectile dysfunction.
• Children with a family H/O hypercholestrolemia or
chylomicronemia.
2012 guidelines of the canadian cardiology society

17. Who should be treated for dyslipidemia ???
• If LDL–C ≥190 mg/dL.
• LDL–C >160 mg/dL and person also has either
 Other evidence of genetic hyperlipidemias.
 Family history of premature ASCVD with onset <55 years in
a first degree male relative or <65 years in a first degree
female relative.
 High sensitivity-C-reactive protein >2 mg/L.
 ABI <0.9.
 Lifetime risk of ASCVD i.e. ASCVD score >7.5
• TG 200-500 then measure NON HDL-C & if
Non HDL-C >190 then consider for drug therapy.

18. Note: NON HDL-C = TC – HDL Cholestrol=LDL+VLDL+IDL
TG >500 consider for drug therapy.
 Individuals with LDL–C ≥190 mg/dL or triglycerides ≥500
mg/dL should be evaluated for secondary cause of
dyslipidemia.
AHA blood cholestrol guideline 2013

19. Treatment goal

20.  *For those at moderate risk, additional testing may be
considered for some patients to assist with decisions about
risk stratification.
 †For patients with diabetes plus 1 major ASCVD risk factor,
treating to a non–HDL-C goal of ,100 mg/dL (LDL-C of ,70
mg/dL) is considered a therapeutic option.
 ‡For patients with chronic kidney disease (CKD) stage 3B
stage 4 the lipid lowering therapy is beneficial but, Stage 5
CKD is a very highrisk condition, but results lipid-altering
therapies have not provided convincing evidence of
reduced ASCVD events in such patients. Therefore, no
treatment goals for lipid therapy have been defined for
stage 5 CKD.
journal of clinical lipidology 2015/AHA guideline 2013

21. Major risk factor for ASCVD

22. Classification of ASCVD(atherosclerotic
cardiovascular disease) :
 Myocardial infarction or other acute coronary syndrome.
 Coronary or other revascularization procedure.
 Transient ischemic attack.
 Ischemic stroke.
 Atherosclerotic peripheral arterial disease
 Includes ankle/brachial index of ,0.90
 Other documented atherosclerotic diseases such as
 Coronary atherosclerosis
 Renal atherosclerosis
 Aortic aneurysm secondary to atherosclerosis
 Carotid plaque, $50% stenosis

23. • For patients at low or moderate risk, lifestyle therapy
should be given a trial of at least 3 mo before initiation of
drug therapy.
• For patients at very high risk and selected patients at high
risk (those unlikely to reach goal with lifestyle alone), drug
therapy may be started concurrently with lifestyle therapy.
• Referral to an RDN is recommended to facilitate dietary
modification and to an exercise specialist for guided
instruction on a suitable exercise program.
Recommendation:

24. • After atherogenic cholesterol targets are achieved with lifestyle
therapies, responses should continue to be monitored at
intervals of 6–12 mo.
• Before initiation of atherogenic cholesterol–lowering drug
therapy, the clinician should discuss with the patient the
treatment objectives, potential ,adverse effects, possible
interactions with other drugs or dietary supplements, lifestyle
and medication adherence, and patient preferences as well as
convey that alternative agents and regimens are available in
the event of side effects.
• First-line cholesterol-lowering drug therapy, unless
contraindicated, is moderate- to high-intensity statin.
• The statin dosage may be increased or the patient switched to
a more efficacious agent, if goal levels of atherogenic
cholesterol are not achieved

25. • Nonstatin drug therapy may be considered for patients with
contraindications for, or intolerance to, statin therapy.
• Combination drug therapy with a statin plus a second (or third)
may be considered for patients who have not attained their
atherogenic cholesterol levels after the maximum tolerated
statin dosage has been reached and for those who have
contraindications or are intolerant to statin therapy.
• If drug therapy is used, at least a 30% reduction in atherogenic
cholesterol should be targeted.
• Response to therapy should be monitored within 4–12 mo.

26. • Patients with very high TG (500 mg/dL), the primary
objective of therapy is to lower the triglyceride level to ,500
mg/dL to reduce the risk of pancreatitis.
• Patients with high TG (200–499 mg/dL), the primary
objective of therapy is to lower levels of non–HDL-C and
LDL-C to reduce risk for an ASCVD event.
• For the level of TG
 TG : 200-499= Statins should be use.
 TG: 500-999= TG lowering agent or Statins may be use.
 TG: >1000 = TG lowering should be consider.
• patients with severe hypercholesterolemia, an alternative goal
is to lower atherogenic cholesterol levels by at least 50%.
• LDL apheresis may be considered for selected patients.

30. Statins:
 MOA:- HMG CoA inhibitor( rate limiting enzyme in
cholestrol synthesis)
DRUG STARTING DOSE MAXM DOSE BRAND NAME
Lovastatin 20-40 mg daily 80 mg daily Statin,Lostatin,Lovacard,
Lochol, Lovalip
Pravastatin 40-80 mg daily 80 mg daily Pravachol, Pravator,
Simvastatin 20-40 mg daily 80 mg daily Simlip, Starstat
Fluvastatin 20-40 mg daily 80 mg daily Lescol XL 80
Atorvastatin 20-40 mg daily 80 mg daily Atomac, Atorlip, TG-TOR
XTOR, Avas, Lipikind, Avas
Rosuvastatin 5-20 mg daily 40 mg daily Turbovas,Lipirose, Rozustat,
Roseday,Rosulip
Pitavastatin 1-2 mg daily 4 mg daily Pivasta, Pitava

31. Mechanism of action

32. Pleotropic effect of statin:
 Reduction in lipoprotein oxidation.
 Anti inflammatory property.
 Decrease platelet aggregation & formation of thrombi.
 Improvement in endothelial function.
 Antioxidant property.
 Plaque stability.

33. • Dyspepsia
• Headache
• Fatigue
• Muscle & joint pain
• Myopathy, Rhabdomyolysis
Note: Myopathy is precipitated by older age, renal failure,
drug interfere with metabolism of statins.
In the event of muscle symotoms Plasma CK level should
be measure.
• Elevation of ALT & AST
Note: Checked before starting the therapy & after 2-3 mnth of
start of therapy then anually. Change in therapy should be
consider when level of enzyme > 3times normal.
• Associated with risk of diabetes mellitus.
Side effect of statins

34. Contraindication:
 Pregnancy
 Lactation
Potency:
Rosuvastatin ( 39-45% LDL reduction)
>Atorvastatin (39-42%)>Simvastatin(35-41%)>Fluvastatin (25-
35%) >Pravastatin(34%)> Pitvastatin(32%)>Lovastatin(31%)

35. Some important point regarding individual statin:
Atorvastatin:
Long acting, highest LDL-C lowering, antioxidant,
antinflamatory.
Lovastatin:
First clinically used statin, prodrug, extensive FPM.
Simvastatin:
Prodrug, Extensive FPM, greater rise in HDL.
Pravastatin:
CH lowering effect is less,decrease plaque,decrease fibrinogen.
Rosuvastatin:
Most potent, greater reduction in LDL-C.
Pitvastatin:
Latest, no specific advantage.

36. High-Mod-Low intensity statin therapy

38. AHA/ACC guidelines 2013

39. MOA: Increase bile acid excretion , increase LDL receptor.
EXAMPLE:
Bile acid sequestrants:
DRUG STARTING DOSE MAXM DOSE BRAND NAME
Cholestyramine 4 gm daily 32 gm daily Choltran,Choltran
sachet, Questran
Colestipol 5 gm daily 40 gm daily Colestid
Colesevelam 3750 mg daily 4375 mg daily Welchol625

41. SIDE EFFECT:
 Bloating
 Constipation
 Elevated TG
Some important point :
 2nd DOC for dyslipidemia, for statins intolerant patients.
 DOC in children, lactating, pregnant, or could become
pregnant women(b/c do not absorb systemically).
 Used in combination with a statins.
 Hyper-TG limit use.
 Secondary effect on CH synthesis – increase VLDL.

42. NOTE: Usually employed in combination with fibrate, statins.
Most effctive HDL-C raising pharmacological agent.
MOA: dec VLDL & fibrinogen & TG(40%), Inc HDL.
INDICATION : Elevated LDL-C, & TG.
SIDE EFFECT:
 Cutaneous flushing.
 GI upset
 Elevated – glucose, uric acid , LFT
PREPARATION:
Nicotinic acid:
PREPARATION STARTING DOSE MAXM DOSE BRAND
Immidiate release 100 mg tid 1 gm tid Niaspan100
Sustained/Extende
d release
250 mg bid 1.5 gm bid Nialip250/375

43. MOA: Increase LPL, decrease VLDL synthesis.
INDICATION: Elevated TG.
SIDE EFFECT:
 Dyspepsia
 Myalgia
 Gall stone , Elevated transaminases.
EXAMPLE:
Fibric acid derivatives:
DRUG STARTING DOSE MAXM DOSE BRAND NAME
Gemfibrozil 600 mg bid 600 mg bid Gempar300
Triglyd600,
Normolip300
Fenofibrate 145 mg qd 145 mg qd TG Chek160,
Trichek, Fenolip
Bezafibrate 200 mg bid 200 mg bid Beza XL 400

44. NOTE:
 Less favourable effect on clinical outcome, improvement in
microvascular outcome.
FENOFIBRATE:
 Reduce fibrinogrn level.
 Commonly used in combination with statins(myopathy).
GEMFIBROGIL: Increase risk of myopathy with statin.
BEZAFIBRATE: No myopathy.
INTERACTION:
 Increase risk of myositis on statins.
 Reduction dose(30%) requirement for patients on warfarin.

45. EZETIMIBE:
TRADE NAME:
Ezetib10mg, Ezitimide 10mg, Ezedoc 10mg.
DOSE: 10 mg daily.
 Inhibit CH absorption from intestine by binding to NPC1L1
transporter in intestine.
 Indicated for elevated LDL-C.
 Unlike resin it causes fall in TG.
 Causes elevation in transaminases.
Cholestrol absorption inhibitor:

46. Omega-3 fatty acid :
 Causes increase catabolism of TG.
 Indicated in elevated TG.
SIDE EFFECT:
 Dyspepsia
 Fishy odor to breath.
DRUG STARTING DOSE MAXM DOSE BRAND NAME
Omega-3 acid ethyl
ester
4 gm daily 4 gm daily MAX-OMEGA300/200
Multivite FM Omega
Icosapent ethyl 4 gm daily 4 gm daily Vascepa 1gm

49. PCSK9 INHIBITOR:
 Inhibit proprotein convertase subtilisin/kexin type 9.
 Increase LDL receptor density on hepatocyte.
 Prevent LDL receptor degredation.
1. ALIROCUMAB
 Brand name – Praluent
 Dose 1. starting dose : 75 mg s/c twice weekly.
2. maxm dose : 150 mg s/c twice weekly.
INDICATION:
 Adjunct to diet & maximally tolerated statin therapy.
 Adult with hetrozygous familial hypercholestrolemia.
 Clinical ASCVD.
 Who require additional lowering of LDL-C.

50. SIDE EFFECT:
 Nose throat irritation
 Injection site reaction & bruising
 Flue like symptoms
 Diarrhoea, muscle pain
NOTE: Alirocumab is first PCSK9I to be approved in july
2015

51. 2. EVOLOCUMAB:
 Brand name : Repatha
 Dose: 420 mg s/c once monthly.
 FDA approval in 27 aug 2015.
 Indication & side effects are same as that of Alirocumab.
3. BOCOCIZUMAB:
 Yet not approved by FDA.

52.  Brand name: Kynamro.
 DOSE: 200 mg s/c weekly.
 Decrease formation of apo-B containing lipoprotein
including LDL-C(40-50%)
 Also decrease Lp(a) concentration.
 Approved for homozygous familial hypercholestrolemia &
minimising need lipid apheresis.
 SIDE EFFECT:
1. Influenza like illness.
2. Injection site reaction .
3. Hepatic steatosis.
Apo B Inhibitor- MIPOMERSEN

53. MTTP Inhibitor- LOMITAPIDE
 Brand name: Juxpid
 Dose: 5 mg daily to 60 mg daily.
 Inhibit TG transfer to Apo-B48 & Apo B100 in intestine &
liver cells respectively.
 Lead to decrease formation chylomicron & VLDL, decrease
VLDL lead to decrease level of LDL.
 FDA approval in 2012 for homozygous familial
hypercholestrolemia.
SIDE EFFECT:
1. Increased stool frequency.
2. Hepatic steatosis, elevated tranaminases.

55.  Thyroid hormone analog with minimal non hepatic tissue
uptake.
 No long term or large study done so far.
 No clinical hyper/hypo thyroidism.
 S/E: Elevated liver enzyme.
Thyromimetic- EPRORITOME

56. Lipid apheresis:
 Selective removal of LDL, VLDL, Lp(a).
 Little pr no effect on other plasma component( HDL, alb,IgG)
Indication:
Familial hypercholestrolemia
Note:- After diet and maximum tolerated drug therapy for
6month 1)LDL level >200 with CAD
2)LDLlevel >300 without CAD
then Lipid apheresis/LDL apheresis is indicated.

57. 1. Best predictor for future risk of cardiovascular events
among following is:
a) hsCRP
b) Lipoprotein a
c) Homocysteine
d) Interleukin 6

58. Ans; A hsCRP
CRP when measure d by high senstivity assay strongly and
indepenly predict risk of MI, Stroke, PAD,
hsCRP+ TC:HDL-C > hsCRP > TC:HDL-C > Apo B > S.
Amyloid A > LDL-C > TC > IL-6 > Homocysteine > lip(a)

59. 2. The protein which has structural homologywith
plasminogen and is responsible for MI & stroke
a) HDL
b) Lp(a)
c) LDL
d) Homocysteine

60. Ans : B Lp(a)
It is an LDL like plasma lipoprotein consisting of a
cholestrol rich LDL particle with one molecule of Apo-
B 100 and an additional protein Apo(a) apolipoprotein.
It has structural homology to plasminogen but lack any
fibrinolytic activity.

61. 3.Which of the following increases the susceptibility to
coronary artery disease:
a) Type V Hyperlipoproteinemia
b) Von willebrands disease
c) Nephrotic syndrome
d) SLE

62. Ans. C Nephrotic syndrome
Hyperlipidemia in nephrotic syndrome is a consequences of
increased hepatic lipoprotein synthesis LDL & Cholestrol
increased in majority of patients ,this hyper lipidemia may
accelerate atherosclerosis and progression of renal disease
….…harrision’s
Hyperlipidemia type V not associated with increased LDL
This disorder does not appear to increase risk of CHD either
because large TG rich lipoporotein are not atherogenic or
because only normal amount of LDL can be generated
……………….harrison’s

63. 4. All of the following are diatery goal are recommended for
patient with high risk of CHD except
a) Saturated fat < 7% of total cal
b) Total cholestrol < 250 mg/d
c) Polyunsaturated fat upto 10% of total calorie
d) Salt intake < 6 gm/d

64. Ans. B. Total cholestrol<250mg/d
NCEP- ATP –III Guidelines
Nutrition Recommended intake
Saturated fat < 7% of total calories
Polyunsaturated fat Upto 10% of total calories
Carbohydrate Up to 20% of total calories
Fibre 20-30 gm/d
Protein Approximately 15% of total calories
Cholestrol < 200 mg /d
Salt < 6gm/d

65. 5. Predisposing factor for CAD include all except:
a) Homocysteinemia
b) Increase Lipoprotein B
c) Increase Fibrinogen
d) Increase plasminogen activator inhibitor 1

66. 6. After an attack of ACS the lipid profile of the pt will be as
follow:
a) Increase TG & VLDL, Decrease – HDL , LDL, TC
b) Decrease – LDL,VLDL, TG & Increase – HDL
c) Increase – LDL, VLDL, TC & Decrease – HDL, TG
d) All increase

67. 7. Reverse Cholestrol transfer done by:
a) HDL with the help of Apo-A
b) HDL with the help of Apo –B
c) HDL with the help of Apo –C
d) HDL with the help of Apo-E

68. 8. A 64 yr old pt of CHD on statin complaining of
Myalgia & decrease urine output what should be next
line of management
a) Reassure the patient continue with same drug
b) Stop the statin and admit the patient
c) Decrease the dose of statin & measure CK level
d) Shift patient to another hypolipidemic drug

69. 9. Which of the following statin do not require bed time
dosing
a) Lovastatin
b) Simvastatin
c) Fluvastatin
d) Rosvastatin

70. 10. Which of the following combination should be avoided:
a) Atorvastatin + fenofibrate
b) Rosuvastatin+ fenofibrate
c) Simvastatin+ gemfibrozil
d) Simvastatin+ fibroic acid