approaching to dyslipidemia and Indian guidelines

1. PRACTICAL APPROACH TO MANAGEMENT
OF DYSLIPIDEMIA AND DRUG RESISTANT
DYSLIPIDEMIA
Dr Siva Subramaniyan
PGIMER &Dr.RML Hospital
New Delhi

2. INTRODUCTION
• The estimated annual incidence of MI in US is 550,000 new and 200,000
recurrent attacks. The average age at first MI is 65.1 years for men and 72.0 years
for women.
• Dyslipidemia is a primary, major risk factor for ASCVD and may even be a
prerequisite for ASCVD, occurring before other major risk factors come into play.

3. • Epidemiologic data also suggest that hypercholesterolemia and perhaps coronary
atherosclerosis itself are risk factors for ischemic cerebrovascular accident.
• According to data from 2009 to 2012, >100 million U.S. adults ≥20 years of age
have total cholesterol levels ≥200 mg/dL; almost 31 million have levels ≥240 mg/
dL.

4. • Increasing evidence also points to insulin resistance—which results in increased
levels of plasma triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C)
and a decreased concentration of high-density lipoprotein cholesterol (HDL-C)—
as an important risk factor for peripheral vascular disease , CVA, and ASCVD.

5. • Analysis of 30-year national trends in serum lipid levels shows improvements in
total cholesterol and LDL-C levels.
• This may in part be explained by the steady increase in the use of lipid-lowering
drug therapy (self-reported rate of lipid-medication use, 38%).
• However, 69% of U.S. adults have LDL-C concentrations above 100 mg/dL.
Furthermore, the doubling in prevalence of individuals who have obesity, the
high percentage with elevated TG levels (33%), and the correlation between
obesity and elevated TG point to the need for continued vigilance on the part of
physicians to reduce ASCVD risk.

7. R1. Identify risk factors that enable
personalized and optimal therapy
Major risk factors Additional risk factors Nontraditional risk factors
Advancing age
Total serum
cholesterol level
Non-HDL-C
LDL-C
Low HDL-C
Diabetes mellitus
Hypertension
Chronic kidney disease 3
Cigarette smoking
Family history of ASCVD
Obesity, abdominal obesity
Family history of
hyperlipidemia
Small, dense LDL-C
Apo B
LDL particle concentration
Fasting/postprandial
hypertriglyceridemia
PCOS
Dyslipidemic triad
Lipoprotein (a)
Clotting factors
Inflammation markers
(hsCRP; Lp-PLA)
Homoeysteine levels
Apo E4 isoform
Uric acid
TG-rich remnants

8. • R2. Based on epidemiologic studies, individuals with type 2 diabetes
(T2DM) should be considered as high, very high, or extreme risk for
ACSVD (Grade B; BEL 2).
• R3. Based on epidemiologic and prospective cohort studies,
• individuals with type 1 diabetes (T1DM) and duration more than 20
years or
• with 2 or more major CV risk factors (e.g., albuminuria, chronic
kidney disease (CKD) stage 3/4, initiation of intensive control >5
years after diagnosis), elevation in A1C >10.4%, or insulin resistance
with metabolic syndrome (Grade B; BEL 3).
should be considered to have risk equivalence to individuals with T2DM
Diabetic Individuals

9. R4. The 10-year risk of a coronary event (high, intermediate, or low) should
be determined by detailed assessment using one or more of the following
tools
• Framingham Risk Assessment Tool
• Multi-Ethnic Study of Atherosclerosis (MESA) 10-year ASCVD Risk with
Coronary Artery Calcification Calculator
• Reynolds Risk Score, which includes highly sensitive CRP (hsCRP) and
family history of premature ASCVD)
• United Kingdom Prospective Diabetes Study (UKPDS) risk engine to
calculate ASCVD risk in individuals with T2DM
2) CARDIOVASCULAR RISK

10. • R5. Special attention should be given to assessing women for ASCVD
risk by determining the 10-year risk (high, intermediate, or low) of a
coronary event using-
• the Reynolds Risk Score (www.reynoldsriskscore.org) or
• the Framingham Risk Assessment Tool
WOMEN

11. • R6. Dyslipidemia in childhood and adolescence should be diagnosed
and managed as early as possible to reduce the levels of LDL-C that
may eventually increase risk of CV events in adulthood (Grade A; BEL
1).
CHILDHOOD AND ADOLESCENCE

12. CHILDHOOD AND ADOLESCENCE

13. OTHER LIPIDS
R7. When the HDL-C concentration is greater than 60 mg/dL, 1 risk factor
should be subtracted from an individual’s overall risk profile(Grade B; BEL
2).
R8. A classification of elevated TG should be incorporated into risk
assessments to aid in treatment decisions (Grade B; BEL 2).

14. WHEN TO SCREEN?

15. R9. Individuals should be screened for familial hypercholesterolemia (FH)
when there is a F/H of:
• Premature ASCVD (definite myocardial infarction [MI] or sudden death
before age 55 years in father or other male first-degree relative, or
before age 65 years in mother or other female first-degree relative)
• Elevated cholesterol levels (total, non-HDL and/or LDL) consistent with
FH (Grade C; BEL 4).
FAMILIAL HYPERCHOLESTEROLEMIA

16. • R10. Annually screen all adult individuals with T1DM or T2DM for
dyslipidemia(Grade B; BEL 2).
• R11. Evaluate all adults 20 years of age or older for dyslipidemia every
5 years(Grade C; BEL 4).
• R12. In the absence of ASCVD risk factors, screen middle-aged
individuals for dyslipidemia at least once every 1 to 2 years. More
frequent lipid testing is recommended when multiple global ASCVD risk
factors are present(Grade A; BEL 1).
ADULTS

17. • R14. Annually screen older adults with 0 to 1 ASCVD risk factor for
dyslipidemia(Grade A; BEL 1).
• R15. Older adults should undergo lipid assessment if they have
multiple ASCVD global risk factors (i.e., other than age) (Grade C; BEL
4).
• R16. Screening for this group is based on age and risk, but not gender;
older women should be screened in the same way as older men (Grade
A; BEL 1).
OLDER ADULTS

18. • R17. In children at risk for FH (e.g., family history of premature
cardiovascular disease or elevated cholesterol), screening should be at 3
years of age, again between ages 9 and 11, and again at age 18(Grade
B; BEL 3,).
• R18. Screen adolescents older than 16 years every 5 years or more
frequently if they have ASCVD risk factors, have overweight or obesity,
have other elements of the insulin resistance syndrome, or have a family
history of premature ASCVD (Grade B; BEL 3).
CHILDHOOD AND ADOLESCENCE

19. • WHICH SCREENING TESTS ?

20. • R19. Use a fasting lipid profile to ensure the most precise lipid
assessment; this should include total cholesterol, LDL-C, TG, and
non-HDL-C (Grade C; BEL 4, ).
• R20. Lipids, including TG, can be measured in the non-fasting state if
fasting determinations are impractical(Grade D).
FASTING LIPID PROFILE

21. LDL-C
R21. Estimated using the Friedewald equation:
LDL-C = (total cholesterol – HDL-C) – TG/5
however, valid only for values obtained during the fasting state and
becomes increasingly inaccurate when TG levels are greater than 200
mg/dL, and becomes invalid when TG levels are greater than 400 mg/dL
(Grade C; BEL 3).
R22. LDL-C should be directly measured in certain high-risk individuals,
such as those with fasting TG levels greater than 250 mg/dL or those with
diabetes or known vascular disease

22. R23. Measurement of HDL-C should be included in screening tests for
dyslipidemia
R24. The non-HDL-C (total cholesterol minus HDL-C) should be calculated
if moderately elevated TG (200 to 500 mg/dL), diabetes, and/or
established ASCVD
R25. If insulin resistance is suspected, the non-HDL-C should be
evaluated to gain useful information regarding the individual’s total
atherogenic lipoprotein burden
HDL/ NON HDL

23. R26. TG levels should be part of routine lipid screening:
 moderate elevations (≥150 mg/dL) may identify individuals at risk for
the insulin resistance syndrome and
 levels ≥200 mg/dL may identify individuals at substantially increased
ASCVD risk
TRIGLYCERIDES

24. R27. Apo B and/or an apo B/apo A1 ratio calculation and evaluation
may be useful to assess residual risk and guide decision-making in -
 at-risk individuals (TG ≥ 150, HDL-C < 40, prior ASCVD event
 T2DM, and/or the insulin resistance syndrome[even at target LDL-C
levels]) (Grade A; BEL 1).
R28. Apo B measurements (reflecting the particle concentration of LDL
and all other atherogenic lipoproteins) may be useful to assess the
success of LDL-C–lowering therapy(Grade A; BEL 1).
APOLIPOPROTEINS

25. R 29. Secondary Causes must be ruled out : Common
Causes
• Hypothyroidism
• Nephrosis
• Dysgammaglobulinemia
(SLE,multiple myeloma)
• Progestin or anabolic steroid
treatment
• Cholestic diseases
• Protease inhibitors for
treatment of HIV infection
• Chronic renal failure
• Type 2 diabetes mellitus
• Obesity
• Excessive alcohol intake
• Antihypertensive medications
• Corticosteroid therapy
• Orally administered
estrogens, Oral
contraceptives, pregnancy
Affected lipids: Total cholesterol, LDL-C, TG, VLDL-C

26. R30. Use highly sensitive C-reactive protein (hsCRP) to stratify ASCVD risk
in individuals with-
• a borderline standard risk assessment, or
• in those with an intermediate or higher risk with an LDL-C
concentration less than 130 mg/dL (Grade B; BEL 2).
R31. Measure lipoprotein-associated phospholipase A2 (Lp-PLA2), when it
is necessary to further stratify an individual’s ASCVD risk, especially if
hsCRP elevated(Grade A; BEL 1).
R32. The routine measurement of homocysteine, uric acid, plasminogen
activator inhibitor-1, or other inflammatory markers is not
recommended(Grade D).
ADDITIONAL TESTS

27. APPROACH TO MANAGEMENT OF DYSLIPIDEMIA

28. R33. Coronary artery calcification (CAC) measurement has been shown
to be of high predictive value and is useful in refining risk stratification to
determine the need for more aggressive treatment strategies (Grade B;
BEL 2).
R34. Carotid intima media thickness (CIMT) may be considered to refine
risk stratification to determine the need for more aggressive ASCVD
preventive strategies(Grade B; BEL 2).
ADDITIONAL TESTS…

29. APPROACH TO MANAGEMENT OF DYSLIPIDEMIA
A. Patients with ASCVD
B. Patients undergoing PCI
C. Primary prevention of CVD for DM
D. For patients with CKD
E. Patients with statin intolerance
F. Other pts like hypothyroidism,
- HF,
- inflammatory disease
- elderly, women
- CVA
- HIV

30. ASCVD

31. Cardiovascular Risk Score
• Key Cardiovascular Risk Scoring Tools:
- Framingham,
- MESA,
- Reynolds, and
- UKPDS

32. Major independent risk factors
• high LDL-C,
• polycystic ovary syndrome,
• cigarette smoking,
• hypertension (blood pressure ≥140/90 mm Hg or on hypertensive medication),
• low HDL-C (<40 mg/dL),
• family history of coronary artery disease (in male, first-degree relative younger
than 55 years; in female, first-degree relative younger than 65 years),
• chronic renal disease (CKD) stage 3/4,
• evidence of coronary artery calcification and age (men ≥45; women ≥55 years).

34. Statin For Secondary Prevention
• Current guidelines recommend moderate to high dose of
statins for secondary prevention.
• Atorvastatin has multiple landmark trials for secondary
prevention
Amongst all statins, Atorvastatin has robust evidence for
secondary prevention of ASCVD
Higher dose atorvastatin has shown incremental benefits over
and above those expected with lower dose statins

35. TNT: High Vs Low Dose statin in
Stable CAD
22% risk reduction by 80 mg Vs 10 mg atorvastatin
p<0.001
Waters DD et al. N Engl J Med 2005;352:1425-35
Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD),
nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke
High dose statin is more effective for CV
protection in stable IHD patients

36. CV events in PROVE IT study
Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006
Death/MACEDeath/MI/Urg. Revascu.
↓33%
↓16%
Intensive statin Rx provides more benefits than
moderate statin Rx
PROVE IT trial randomly assigned 4,162 patients who had been hospitalized within the
previous 10 days for ACS to receive pravastatin 40 mg vs intensive regimen of 80 mg
atorvastatin.

37. 2) Patients undergoing PCI

38. Loading High dose statin before PCI in ACS
reduces CV events: ARMYDA-ACS
%
5
17
P=0.01
JACC 2007:49:1272-78
171 NSTEACS patients randomized to atorvastatin (80 mg 12 h before PCI, with a further 40-mg pre-PCI or
placebo. All patients received long-term atorvastatin thereafter (40 mg/day). Primary end point : 30-day
incidence of MACE(death, myocardial infarction, or unplanned revascularization)
Among patients with ACS undergoing PCI, pretreatment with atorvastatin 80 mg
improves clinical outcomes, driven mainly by reduction in periprocedural MI

39. ARMYDA-RECAPTURE: loading 80 mg atorvastatin
pre-PCI in those on statin already also reduces CV events
0
3
6
9
12
3.4
9.1
P=0.045
PlaceboAtorvastatin
JACC 2009:54:558-65
383 patients with stable angina (53%) or NSTMI(47%) and chronic statin therapy undergoing PCI were
randomized to atorvastatin reload (80 mg 12 h before PCI , + 40-mg pre-PCI) or placebo. All patients
received long-term atorvastatin thereafter (40 mg/day). Primary end point : 30-day MACE (cardiac death,
myocardial infarction, or unplanned revascularization)
Reloading with high-dose atorvastatin resulted in 50%
reduced risk of MACE at 30 days versus placebo
These findings support strategy of routine reload with high-
dose atorvastatin early before intervention even in the
background of chronic therapy.

40. 3.Primary prevention

41. Major Statin Primary Prevention Trials
Study Patients Cohort Follow
up
Results
ASCOT LLA
*
2532 HT Atorvastatin
10 mg
3.3 yrs 23% risk
reduction
CARDS 2838 DM Atorvastatin
10 mg
3.9 yrs 37% risk
reduction
HPS * 2912 DM Simvastatin
40 mg
5 yrs 33% risk
reduction

42. 4) CKD

43. Dose of statins in patients with CKD
• Atorvastatin: No dose adjustment required
• Rosuvastatin: In patients severe CKD with creatinine clearance < 30 ml/min
(not on hemodialysis), Maximum dose: 10 mg/day
• Pitavastatin: In patients with moderate/severe CKD (GFR: 15-59 ml/min)
Maximum dose: 2 mg/day

44. Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-
analysis
• A meta-analysis of 5 clinical trials head to head comparing atorvastatin vs rosuvastatin
Atorvastatin is better than rosuvastatin for reduction
in proteinuria
Circ J 2012;76:1259-66

45. Effect of pitavastatin on eGFR in CKD patients
(eGFR<60 ml/min/1.73m2)
J Atheroscler Thromb 2010;17:601-609
Pitavastatin 2 mg provides nephroprotective
effects in CKD patients (eGFR 15-59 ml/min)

46. Effect of Pitavastatin on proteinuria
* P <0.01 Vs Control Diabetes Care 2005;28:2728–2732
20 T2DM patients were treated with pitavastatin or placebo for 12 months

47. Even at 1 mg/day dosage, pitavastatin reduces proteinuria in CKD
patients
12-16 week treatment with pitavastatin (n=65) or control (n=40) ** p< 0.01
Am J Cardiol 2011;107:1644 –1649

49. SPECIAL GROUPS
• Children
Universal lipid screening at age 9-11 years. For family history of premature ASCVD,
screen beginning at age 2 years. Treat to non-HDL-C < 145 mg/dL and LDL-C < 130
mg/dL. For familial hypercholesterolemia (FH): Lower LDL-C by at least 50% from
baseline.
• women
Higher lifetime ASCVD risk than men because of greater longevity. Response to
statin therapy similar to men, but drug therapy during pregnancy and nursing
should generally be avoided.

50. • Elderly
Response to statins is similar to younger patients. Consider using moderate-
intensity statins in those age 80 years and above, only after careful patient provider
discussion
• HIV
Increased risk for ASCVD and insulin resistance. HIV positivity should be considered
equivalent to one additional risk factor. Consider drug-drug interactions in lipid
treatment regimens. Pravastatin is safe where as rosu/simava contraindicatedd
• Rheumatoid Arthritis (RA)
• Increased risk for ASCVD. RA should be considered equivalent to one additional
risk factor. LDL-C may be lower during a flare, so check lipids when disease
activity is low. Statins are first-line therapy (IDEAL, TARA STUDY).

51. • Thyroid disease
subclinical and overt hypothyroidism
- subclinical with abs+, smoker, elderly, severe dyslipidemia
- overt with CAD and without CAD
• CVA
ischemia and haemorrhagic CVA
• HF
Ischemia and non ishemic HF (CORONA, GISSI HF study)

52. R47. A comprehensive strategy to control lipid levels and address
associated metabolic abnormalities and modifiable risk factors is
recommended primarily using lifestyle changes patient education with
pharmacotherapy as needed to achieve evidence based targets (Grade A,
BEL 1)
TREATMENT

53. R48. Recommended reasonable and feasible approach to fitness therapy:
exercise programs that include(Grade A, BEL 1) -
• at least 30 minutes of moderate-intensity physical activity [consuming
4-7 kcal/min] 4 to 6 times weekly, with an expenditure of at least 200
kcal/day);
• suggested activities include
• brisk walking,
• riding a stationary bike,
• water aerobics,
• cleaning/scrubbing,
• mowing the lawn, and sporting activities
Life style Changes: Physical Activity

54. R49. Daily physical activity goals can be met in a single session or in
multiple sessions throughout the course of a day (10 minutes minimum
per session) (Grade A, BEL 1).
R50. In addition to aerobic activity, muscle-strengthening activity is
recommended at least 2 days a week(Grade A, BEL 1) .
Life style Changes: Physical Activity..

55. R51. For adults, a reduced-calorie diet consisting of (Grade A, BEL 1)
• fruits and vegetables (combined ≥5 servings/day),
• grains (primarily whole grains),
• fish is recommended
R52. For adults, the intake of saturated fats, trans-fats, and
cholesterol should be limited (Grade A, BEL 1)
R53. Primary preventive nutrition consisting of healthy lifestyle habits
is recommended in all healthy children (Grade A, BEL 1)
Life style Changes: Medical Nutrition Therapy

56. R54. Tobacco cessation should be strongly encouraged and
facilitated(Grade A, BEL 1)
Life style Changes: Smoking Cessation

57. R56. Recommended as the primary pharmacologic agent(Grade A; BEL 1).
R57. For clinical decision making, mild elevations in blood glucose levels
and/or an increased risk of new-onset T2DM associated with intensive
statin therapy do not outweigh the benefits of statin therapy for ASCVD
risk reduction(Grade A; BEL 1).
R58. In individuals within high-risk and very high-risk categories, further
lowering of LDL-C beyond established targets with statins results in
additional ASCVD event reduction and may be considered(Grade A; BEL 1).
STATINS

58. R59. Target a reduced LDL-C treatment goal of <70 mg/dL: (Grade A;
BEL 1).
• Very high-risk individuals with established coronary, carotid, and
peripheral vascular disease, or
• diabetes, who also have at least 1 additional risk factor,
R60. Extreme risk individuals should be treated with statins to target an
even lower LDL-C treatment goal of <55 mg/dL(Grade A; BEL 1).
Statins…

59. R61. Fibrates should be used to treat severe hypertriglyceridemia (TG
>500 mg/dL) (Grade A; BEL 1).
R62. Fibrates may improve ASCVD outcomes in primary and secondary
prevention when TG concentrations are ≥200 mg/dL and HDL-C
concentrations <40 mg/dL(Grade A; BEL 1).
Fibrates

60. • Omega-3 Fish Oil
R63. Prescription omega-3 oil, 2 to 4 g daily, should be used to treat
severe hypertriglyceridemia (TG >500 mg/dL). (Grade A; BEL 1).
Dietary supplements are not FDA-approved and generally are
not recommended for this purpose.
• Niacin
R64. Niacin therapy is recommended principally as an adjunct for
reducing TG (Grade A; BEL 1).
R65. Niacin therapy should not be used in individuals aggressively
treated with statin due to absence of additional benefits with well-
controlled LDL-C(Grade A; BEL 1).
Other Drugs

61. • Bile Acid Sequestrants
R66. Bile acid sequestrants may be considered for reducing LDL-C and
apo B and modestly increasing HDL-C, but they may increase TG(Grade A;
BEL 1).
• Cholesterol Absorption Inhibitors
R67. Ezetimibe may be considered as monotherapy in reducing LDL-C and
apo B, especially in statin-intolerant individuals (Grade B; BEL 2).
R68. Ezetimibe can be used in combination with statins to further reduce
both LDL-C and ASCVD risk (Grade A; BEL 1).
Other Drugs…

62. • PCSK9 Inhibitors
R69. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
should be considered for use in combination with statin therapy for LDL-C
lowering in individuals with FH(Grade A; BEL 1).
R70. PCSK9 inhibitors should be considered in patients with clinical
cardiovascular disease who are unable to reach LDL-C/non-HDL-C goals
with maximally tolerated statin therapy. (Grade A; BEL 1).
They should not be used as monotherapy except in statin-intolerant
individuals
Other Drugs…

63. R71. Combination therapy of lipid-lowering agents should be considered
when the LDL-C /nonHDL-C level is markedly increased and monotherapy
(usually with a statin) does not achieve the therapeutic goal (Grade A; BEL 1).
Combination Therapy

64. INDIANS

65. INDIA
• The burden of atherosclerotic cardiovascular disease (ASCVD) in India is
alarmingly high and is a cause of concern.
• Indians
a) are at high risk of developing ASCVD,
b) usually get the disease at an early age,
c) have a more severe form of the disease and
d) have poorer outcome as compared to the western populations
• Access to health care is also not optimal in India, and the treatment of ASCVD
remains expensive
Lipid Association of India Expert Consensus Statement on Management of
Dyslipidemia in Indians 2016

66. Epidemiology of Dyslipidemia in India
• The available evidence suggests that dyslipidemia is steadily rising among Indians,
a trend which is opposite to what is observed in western populations
• Prevalence of hypercholesterolemia varies from 10-15% in rural to 25-30% in
urban populations
• When compared with the western populations, Indians and migrant South Asians
tend to have higher triglyceride levels and lower HDL cholesterol levels but the
total cholesterol levels are generally lower than in the US or the UK populations

67. Cardiovascular Risk Stratification in Indians
• In patients with established ASCVD, treatment decisions pertaining to the use of
preventive cardiovascular therapies are relatively straight forward as all patients
require aggressive risk reduction.
• Patients requiring primary prevention of ASCVD have wide heterogeneity in the
likelihood of developing ASCVD and necessitates some form of risk stratification.
• CV risk stratification is required so that the intensity of preventive therapies can be
appropriately matched with the individual’s risk of developing a CV event.

68. INDIAN DYSLIPIDEMIA
Lipid Association of India Expert Consensus Statement on Management of
Dyslipidemia in Indians 2016

69. ATHEROGENIC DYSLIPIDEMIA
Low HDL
High TG
High Lp(a)
High LDL is very uncommon
Apo B: Apo A1 is the best biomrker

70. Lipid screening at 20 years of age

71. ACC/AHA risk
calculator
• Not validated in
Indians
• 10 year risk only
• Only conventional
risk factors
• Needs computer

72. Coronary calcium
• Both LDL-C and HDL-C were found to be
independent predictors of CAC
• CAC score >400 had 100% specificity

73. CIMT
 For 0.1 mm increase in CIMT the future risk of MI increased by 10-15%
 A 10% reduction in LDL-C per year accounted for a reduction of CIMT by 0.73
 presence of carotid plaques is a marker of already existing ASCVD

74. Aortic stiffness

75. Lp(a)
 more common among
CAD patients with existing
family history
 Lp(a) levels in Asian
Indian newborns were
significantly higher than
in Chinese in Singapore
 Level > 20 mg/dL
indicates increased
ASCVD risk in Indians
Lipid Association of India Expert Consensus Statement on Management of
Dyslipidemia in Indians 2016

76. • presence of obesity
and/or metabolic
syndrome in an
individual who is
otherwise at low 10-
year risk of ASCVD
should indicate high
lifetime ASCVD risk.
Obesity/ MetS

77. • A 5-μmol/L tHcy increment elevates CAD risk by as much as
cholesterol increases of 0.5 mmol/L (20 mg/dL)
• Very high prevalence of hyperhomocystinemia (>15 µmol/L) in 75% of
subjects in India, which was strongly correlated with cobalamin
deficiency
• impaired cobalamin status appears more important than folate
deficiency among Asian Indians
HOMOCYSTEINE
Lipid Association of India Expert Consensus Statement on Management of
Dyslipidemia in Indians 2016

78. CRP
 significant ASCVD risk reduction
with statin in individuals with
elevated CRP despite relatively
normal LDL-C
 A value of > 2 mg/l of hs-CRP
indicates increased ASCVD risk.
 When the value is >10 mg/L, it
usually indicates a non-
atherosclerotic cause of
Inflammation
 But Quality control and proper
standardization of hs-CRP is
challenging in India

79. Risk factors
NO LDL NO CRP
NO HOMOCYSTEINE
CAC
Aortic stiffness
CIMT
Lp(a)
MertS

80. JBS3: Lifetime ASCVD risk calculator
Estimate lifetime risk
Validated in indians
Non-conventional risk factors
<30% = LOW RISK
30-44% = MODERATE RISK
>45% = HIGH RISK

81. Identify
High Risk
patients
Assess
Risk factors
Estimate
Lifetime risk
The Indian Approach

85. Treatment of drug-resistant hypercholesterolemia

86. • Statins are the preferred therapy for most patients requiring treatment of
dyslipidemia and in particular those with an elevated LDL-C.
• If after treatment with the maximal tolerated dose of statin the patient has not
achieved the LDL-C goal – drug resistant dyslipidemia
• However, some patients, including young individuals with severe
hypercholesterolemia such as occurs in familial hypercholesterolemia, are unable
to sufficiently lower their LDL-C to values with the use of these drugs. These
individuals remain at high risk for cardiovascular events.

87. PCSK9 ANTIBODIES
• Evolocumab
• Alirocumab

88. LDL apheresis
• LDL apheresis, which is approved by the United States Food and Drug
Administration, has been recommended by some experts for these individuals.
Patients who might be potential candidates include:
- those with coronary artery disease (CAD) and LDL-cholesterol levels greater than
200 mg/dL after standard therapy,
- those without established CAD, but at high risk due to an LDL-cholesterol level
greater than 300 mg/dl after dietary and pharmacologic intervention,

89. - particularly those who have additional risk such as first-degree relatives with
premature CAD, high lipoprotein (a), or high-risk medical condition.
- Individuals with homozygous familial hypercholesterolemia (FH) usually are
treated with LDL apheresis.

90. PARTIAL ILEAL BYPASS SURGERY
The efficacy of partial ileal bypass surgery was best assessed in the POSCH trial. The
study population consisted of 838 patients, with an average age of 51 years, who
had survived a first myocardial infarction. The mean follow-up period was 9.7 years.
The following benefits were noted in those treated with surgery compared to the
controls
- A 23 percent reduction in the serum total cholesterol concentration (181 versus
236 mg/dL [4.71 versus 6.14 mmol/L]).
- A 38 percent reduction in serum LDL-cholesterol.
- A nonsignificant reduction in overall mortality and mortality due to coronary heart
disease.
- A significant 35 percent reduction in the combined end point of death due to
coronary heart disease and confirmed nonfatal myocardial infarction.
-A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7,
and 10 years consistently showed less disease progression in the surgery group

91. LIVER TRANSPLANTATION- Liver transplantation is a procedure that has been used
in familial hypercholesterolemia (FH) homozygous patients to provide the
functional hepatic low density lipoprotein (LDL) receptors that these patients lack.
Multiple case reports of children as young as five years of age have demonstrated
that successful transplantation leads to normalization of low density lipoprotein
cholesterol (LDL-C) levels beginning as early as five days after surgery.
PORTOCAVAL SHUNT

92. LOMITAPIDE
• In December of 2012, the United States Food and Drug Administration (FDA)
approved the use of lomitapide for patients with homozygous familial
hypercholesterolemia (FH).
• Lomitapide is an inhibitor of microsomal triglyceride transfer protein, which
transfers triglycerides onto apolipoprotein B as part of the assembly of very low
density lipoprotein within the liver.
• lomitapide carries a Boxed Warning regarding a serious risk of liver toxicity, as its
use is associated with liver enzyme abnormalities.
• Embryotoxic and severe diarrhea can occur

93. • In a study of six patients with homozygous FH lomitapide (at doses ranging
between 0.03 and 1.0 mg per kilogram of body weight per day) decreased low
density lipoprotein cholesterol (LDL-C) by 51 percent and apolipoprotein B by 56
percent from baseline values

94. MIPOMERSEN
• is an antisense oligonucleotide complementary to the coding region for human
apolipoprotein B (apo B) mRNA. Through direct binding to apo B mRNA,
mipomersen inhibits apo B production. Apo B is the major structural component
LDL particles, and its metabolic precursors VLDL and IDL.
• In January of 2013, FDA approved the drug for use in patients with homozygous
familial hypercholesterolemia . There was no specification that LDL apheresis or
liver transplantation had to be instituted first.
• The efficacy and safety of mipomersen was evaluated in a study of 51 patients
with homozygous familial hypercholesterolemia (FH), 12 years of age or older
(mean age 30 to 33 years), who were being treated with maximal dose statin
therapy .

95. • The patients were randomly assigned in a 2:1 manner to either mipomersen 200
mg subcutaneously weekly (or 160 mg for body weight <50 kg) or placebo.
• The mean serum LDL-C prior to initiation of therapy was
425 mg/dL (11.0 mmol/L).
• After 26 weeks of treatment, patients taking mipomersen had a significantly
greater lowering of LDL-C (mean -24.7 versus -3.3 percent with the mean attained
serum cholesterol being 330 mg/dL [8.4 mmol/L])

96. • Gene therapy- Gene therapy, supplying the normal LDL receptor gene for the
treatment of familial hypercholesterolemia (FH), has been tested in mice and
human subjects
• CETP inhibition- significantly raise HDL-C levels. Some of these, such as
anacetrapib and TA-8995, have been shown to lower LDL-C levels by about 40 to
45 percent. However, studies showing clinical benefit have not been reported and
other CETP inhibitors have not been found to be of clinical benefit or were
associated with adverse outcomes.

97. • Antibody removal of resistin — Resistin is an adipose tissue-derived serum protein
(adipokine) that is increased in obesity and is positively correlated with atherosclerotic
cardiovascular disease.
• In-vitro studies of its function have demonstrated that resistin is able to down-regulate
LDL-receptor expression, potentially by increasing the expression of PCSK9. These studies
also showed that antibody-immunoprecipitation removal of resistin in human serum
from obese individuals leads to an increase in LDL-receptors.
• ETC-1002 — ETC-1002 is a novel, small molecule regulator of lipid and carbohydrate
metabolism . In a 12-week study of 177 individuals with LDL-C between 130 and
220 mg/dL (3.4 to 5.7 mmol/L) and not taking statin therapy who were randomly
assigned to three doses of the drug or placebo, there was an approximate 27 percent
reduction in LDL-C at the highest dose . HDL-C and triglycerides were relatively
unchanged and the safety profile appeared favorable.

98. SUMMARY
• For patients with heterozygous FH who, after six months of dietary and optimal
drug therapy, have an LDL-C above 300 mg/dL , and have no established
cardiovascular disease, or above 200 mg/dL in the presence of established
cardiovascular disease - low density lipoprotein (LDL) apheresis
• it is reasonable to begin such therapy with LDL-C values as low as
160 mg/dL (4.10 mmol/L) in patients with evidence of advanced atherosclerotic
cardiovascular disease. In addition, it is reasonable to consider the use of LDL
apheresis in selected patients with even lower LDL-C levels who have
documented progression of their atherosclerotic disease

99. • For patients with homozygous FH who are on maximal medical therapy and have
the following LDL-C values, either LDL-apheresis or liver transplantation . The
decision between the two should be based on issues of availability, patient
preference, and expertise in performing liver transplantation (including operative
mortality)
•LDL-C ≥160 mg/dL in children (age less than 18 years) with established
atherosclerotic CVD
•LDL-C ≥250 mg/dL in children without established atherosclerotic CVD
• LDL-C ≥160 to 190 mg/dL in adults with established CVD
•LDL-C ≥190 mg/dL in adults without established CVD

100. • FH patients without cardiovascular disease who do not achieve LDL-C
<200 mg/dL or those with established disease who do not achieve an LDL-C
<160 mg/dL (4.10 mmol/L) after optimal drug therapy and LDL
apheresis, lomitapide or mipomersen can be added. For patients who are not
candidates for or refuse LDL-apheresis or liver transplantation, lomitapide or
mipomersen should be considered as additional pharmacologic therapy.
• Ileal bypass and portocaval shunt should not be used except in unusual
circumstances.