This document discusses the history of understanding and managing dyslipidemia and cardiovascular disease risk. Some key points: - Early studies found associations between coffee, smoking and heart disease that were later proved misleading as smokers were more likely to drink coffee. - Diabetes was found to significantly increase cardiovascular risk in the Framingham study. - Autopsies of young soldiers in the 1950s first revealed the prevalence of atherosclerosis. - Later studies through the 1990s established the relationships between serum cholesterol, cardiovascular events and mortality. - Risk factors like inflammation (CRP), calcium scoring, carotid intima-media thickness, and arterial stiffness are now also considered. - Guidelines now recommend tailored stat

1. THE ROLLER COASTER RIDE OF
DYSLIPIDEMIA & CAD MANAGEMENT
Dr Sunil Wadhwa
MD
Senior Consultant
Medicine & Non
Invasive Cardiology
#3,Raghunath Mandir,
Amar Colony,
Lajpat Nagar-4,
New Delhi-110024(INDIA)
VisitingConsultant-National Heart Institute
Metro Heart Institute

3. RED HERRINGS
 Heart patients were advised to
avoid coffee after researchers
found a positive association
between coffee & CHD.
 The association was misleading
 The culprit proved to be cigarette
smoking; smokers were more
likely to drink coffee

4. Smoking Statement Issued in 1956 by
American Heart Association
“It is the belief of the committee that much
greater knowledge is needed before any
conclusions can be drawn concerning
relationships between smoking and death
rates from coronary heart disease.The
acquisition of such knowledge may well
require the use of techniques and research
methods that have not hitherto been applied
to this problem.”
Circulation 1960; vol. 23
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____________________________________________________________
___________________________________________________________

5. CHD Risk by Cigarette Smoking.
Filter Vs. Non-filter. Framingham
Study. Men <55 Yrs.
0
50
100
150
200
250
Total CHD Myocardial
Infarction
Non-Smoker
Reg. Cig. Smoker
Filter Cig. Smoker
14-yr. Rate/1000
119
206
210
59
112
210

6. Diseases of The Heart
Charles K Friedberg MD, WB Saunders Co.
Philadelphia, 1949
“The proper control of diabetes is
obviously desirable even though
there is uncertainty as to whether
coronary atherosclerosis is more
frequent or severe in the
uncontrolled diabetic”
________________________________________________________________
______________________________________________________________

7. Risk of Cardiovascular Events in Diabetics
Framingham Study
Age-adjusted
Biennial Rate Age-adjusted
Per 1000 Risk Ratio
Cardiovascular Event Men Women Men Women
Coronary Disease 39 21 1.5** 2.2***
Stroke 15 6 2.9*** 2.6***
Peripheral Artery Dis. 18 18 3.4*** 6.4***
Cardiac Failure 23 21 4.4*** 7.8***
All CVD Events 76 65 2.2*** 3.7***
Subjects 35-64 36-year Follow-up **P<.001,***P<.0001
_________________________________________________________________
_________________________________________________________________

8. 9
Doubts about
cholesterol as
late as 1989

9. Lifetime Risk of CHD Increases with
Serum Cholesterol-Framingham Study
0
10
20
30
40
50
60
Percent
Men Women
<200 mg
200-239 mg
>240 mg
Framingham Study: Subjects age 40 years
DM Lloyd-Jones et al Arch Intern Med 2003; 1966-1972
34
44
57
19
29
33
Cholesterol
___________________________________________________________________________
_______________________________________________________________________________

10. Q = serum cholesterol quintile.
Kannel WB et al. Am Heart J. 1986;112:825-836.
Multiple Risk Factor Intervention Trial (MRFIT)
N=325,346
Correlation Between Serum
Cholesterol and CVD Mortality-MR-FIT Study
6-YearCVDDeathRatePer1000
0
5
10
15
20
25
30
Q1
(<182)
Q2
(182-202)
Q3
(203-220)
Q4
(221-244)
Q5
(>244)
35-39 years
40-44 years
45-49 years
50-54 years
55-57 years
Serum Cholesterol Quintile (mg/dL)
Untreated Patients

11. THE STORY OF CHOLESTEROL
 Story began in 1951
when Pentagon
dispatched a team of
pathologists to the
combat zone of Korean
War on a grisly mission
to learn from the
bodies of the dead.

12. THE STORY OF CHOLESTEROL
 While doing autopsies
for wound ballistics on
2000 dead soldiers ,most
of them were of average
age of 22years,were
vigorous young men
when alive,77% of
soldiers showed some
form of CAD.This was a
shock to the medical
community

14. Libby P. Circulation. 1995;91:2844-2850.
Vulnerable Plaque
• Thin fibrous cap
• Inflammatory cell infiltrates:
proteolytic activity
• Lipid-rich plaque
Lumen Lipid
Core
Fibrous Cap
• Thick fibrous cap
• Smooth muscle cells:
more extracellular matrix
• Lipid-poor plaque
Stable Plaque
Lumen
Lipid
Core
Fibrous Cap
Vulnerable Versus Stable
Atherosclerotic Plaques

16. Small Thrombus

17. ENDOTHELIAL EROSION,LARGE
Nonoccluding THROMBUS

18. ENDOTHELIAL EROSION,LARGE
OCCLUDING THROMBUS

19. DISRUPTIVE PLAQUE

20. DEEP EROSION,SIGNIFICANT
THROMBUS

21. PLAQUE DISRUPTION,LARGE
OCCLUDING THROMBUS

22. Most Myocardial Infarctions Are Caused
by Low-Grade Stenoses
Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.
(Adapted from Falk et al.)
Falk E et al, Circulation, 1995.

23. Trends in mean total serum cholesterol among adolescents 12–17 years of
age by race, sex, and survey year (NHANES: 1988–1994*, 1999–2004 and
2005-2008).
163
165
166
174
159
161
163 163
158
160
154
157
161
162
155
158
140
145
150
155
160
165
170
175
180
NH White Males NH Black Males NH White
Females
NH Black Females Mex. Am. Males Mex. Am. Females
MeanTotalBloodCholesterol
1988-94 1999-2004 2005-2008
Source: NCHS and NHLBI. NH indicates non-Hispanic. Mex. Am. indicates Mexican American.
* Data for Mexican Americans not available.
©2010 American Heart Association, Inc. All rights reserved. Roger VL et al. Published online in Circulation Dec. 15, 2010

24. Trends in mean total serum cholesterol among adults ages ≥20
by race and survey year,
(NHANES: 1988–1994, 1999–2004 and 2005–2008).
206
204
205
203
198
201
198
192
201
180
185
190
195
200
205
210
NH White NH Black Mexican American
MeanSerumTotalCholesterol
1988-94 1999-2004 2005-2008
Source: NCHS and NHLBI. NH indicates non-Hispanic.
©2010 American Heart Association, Inc. All rights reserved. Roger VL et al. Published online in Circulation Dec. 15, 2010

25. NONMODIFIABLE RISK FACTORS
 Ethnicity
 Heredity
 Gender
 Age

26. MODIFIABLE RISK FACTORS
 Obesity
 Physical Inactivity
 Tobacco use
 DM
 Hypertension
 Dyslipidemia

27. Management of Dyslipidemia
Life Style Modification
 Smoking Cessation
 Aerobic exercises
 Wt Loss
 Moderation in alcohol intake
 Diet rich in PUFA lowersTg & LDL- but also lowers
HDL-C.
 Increasing MUFA in diet has no effect on HDL-C
 Consumption of trans-fatty acids is most harmful &
results in reduction of HDL & elevation ofTg & LDL.
 A diet rich in fresh fruits & vegetables is most useful
in raising HDL-C & reducingTg & LDL-C.

31. LESSONS OF MR-FIT Trial(Multiple
Risk Factor-Intervention Trial (1)
 Intentionally -high risk subjects were selected.
Majority had Obesity, HT, Current smokers, High
Cholesterol diet , to find out if behaviour changes
can reduce CAD>They were divided into “Usual
Care Group” & Special-intervention group”.
 It demonstrated that behaviour of a large group of
men without symptoms of ill health could be
successfully modified & the modifications sustained
for a period of >7 years.
 Surprisingly the trial failed-There were slightly
more deaths in S-I Group, even though statistically
insignificant.

32. LESSONS OF MR-FIT Trial(Multiple Risk
Factor-Intervention Trial (2)
 Dubbed a failure, “vultures” spiraled down to pick at
the fresh carcass of multi-factor CVD
prevention.The dairy, beef, and egg industries and
their advertisers soon made much copy on MRFIT’s
purportedly negative results.The tobacco industry
made nefarious use of them.The hypertension
community suffered for decades from the bad name
given thiazide diuretics(Lowered BP but raised
cholesterol) by the MRFIT results among a small
vulnerable subgroup with ischemic ECG findings.
And for a while, the multi-factor risk prevention
strategy was widely pooh-poohed by those who
never bought its theory in the first place.
 MR-FIT,JAMA(1976),235(8):825-827

33. NONCONVENTIONAL
CARDIOVASCULAR RISK FACTORS
 Coronary Artery Calcium
 C-Reactive Protein
 Lp(a)
 Homocysteine
 Carotid Intima -MediaThickness
 Aortic PulseWaveVelocity
 Other Markers e.g.Fibrinogen,Plasminogen Activator
Inhibitor-1,Platelet Count, Lipoprotein associated
phospholipase A2,NAFLD,Vit D deficiency
Lipid Association of India Expert ConsensusStatement on Management of Dyslipidemia in Indians ,2016,March

34. CORONARY ARTERY CALCIUM
 Total CAC Score as measured using CT,
correlates directly with the total
atherosclerotic burden in the coronaries
 Numerous studies have demonstrated that
CAC score correlates with various ASCVD risk
factors & the risk of CV Events.
 High Risk if CAC score>300 Agatston Unit
 Moderate Risk if CAC score 100-299 Agatston
Unit
Lipid Association of India Expert Consensus Statement on Management of Dyslipidemia in Indians ,2016,March

35. CORONARY ARTERY CALCIUM
LIMITATIONS
 Cost
 Limited availability
 Radiation exposure

36. C-REACTIVE PROTEIN(1)
 Most extensively studied protein biomarker for
inflammation in ASCVD.
 Association between CRP levels & ASCVD is well
established.
 Whether CRP rises non-specifically in response to
the inflammation involved in ASCVD or whether it is
a direct contributor to atherosclerotic progression is
not clear.
 JUPITER Study showed a significant ASCVD risk
reduction with statin in individuals with elevated
CRP despite relatively normal LDL.
Lipid Association of India Expert ConsensusStatement on Management of Dyslipidemia in Indians ,2016,March

37. hs-CRP(2)
 It is important to remember that 50% of all
heart attacks occur among persons without
overt dyslipidemia.
 Elevated levels of hs-CRP is associated with
Recurrent coronary events.
 Many studies have shown that statin therapy
reduces the risk of ACS associated with
elevated CRP even in the absence of
Dyslipidemia
 Measurement of CRP for the targeting of statin therapy in the Primary Prevention of ACS.Ridker et al,NEJM;Vol
344,No 26,June 28,2001,1959-1965

38. C-REACTIVE PROTEIN(3)
Limitations-
 CRP is a nonspecific marker of inflammation.
 Utility is limited to individuals without any
specific cause of active inflammation
 hs-CRP & not conventional CRP is
recommended for ASCVD risk stratification.
 Hs-CRP levels of 2-10mg/L are suggestive of
atherosclerosis. Levels >10mg/L indicates a
non-athersclerotic cause of inflammation &
should not be considered as a marker of
increased ASCVD risk
Lipid Association of India ExpertConsensus Statement on Management of Dyslipidemia in Indians ,2016,March

39. LIPOPROTEIN(a) or Lp(a)
 Lp(a) is a genetically modified form of LDL
particle.
 Lp(a) appears to be an important ASCVD risk
factor for Indians as Indians tend to have high
prevalence of raised Lp(a).
 A level of >20mg/dL indicates increased
ASCVD risk in Indians
Lipid Association of India Expert ConsensusStatement on Management of Dyslipidemia in Indians ,2016,March

40. HOMOCYSTEINE
 Elevated Homocysteine is a risk factor for
CAD,Stroke,PVD & DVT.
 Homocysteine estimation in asymptomatic
individuals is not recommended.
 Currently there is no evidence to show that
lowering Serum Homocysteine levels withVit
B12 & Folic Acid reduces the risk of ASCVD
Lipid Association of India ExpertConsensus Statement on Management of Dyslipidemia in Indians ,2016,March

41. Carotid Intima-Media
Thickness(CIMT)
ADVANTAGES
 Compared with CAC,CIMT is simpler to perform
 More widely available
 Completely safe
DISADVANTAGE
 Accuracy for ASCVD risk prediction is inferior to that
of CAC

42. AORTIC PULSE WAVE VELOCITY
 Aortic PWV is a measure of arterial stiffness.
 Usually carotid-femoral & brachial-ankle PWV are
measured.
 It is more useful in the workup of hypertensive
subjects but its role in CAD is uncertain at present

43. Tailored Treatment v/s Treat-to
Target
 Treat-toTarget means achieving the goal as
per recommendation of NCEP-Guidelines i.e.
 Serum Cholesterol
 Triglycerides
 LDL
 HDL
 TailoredTreatment means treating a patient
based on 10 year CHD Risk score. It is better &
saves more lives.
 Optimising statin treatment for Primary Prevention of CAD. RodneyA Hayward et alAnn Intern Med 2010,152:69-
77

44. ACC 10 year
CHD RISK
CALCULATOR

47. ACC Recommendation for Primary
Prevention
 Low to moderate dose statin is recommended
for adults between 40-75 years of age if there is a
presence of 1 or more cvd risk factors-
 LDL>130mg/Dl
 And/or HDL<40mg/Dl
 DM
 HT
 Smoking
 10 year CVD risk>10%

48. LDL-Is Lower,the better?
 Clinical data has suggested a linear relation between LDL
lowering & ASCVD risk reduction.
 There is ample evidence to suggest that more aggressive lipid
lowering therapy effectively reduces CV events than does a less
aggressive lipid lowering therapy.
 Targets inVERY HIGH RISK PATIENTS<70mg/dL.
 In HIGH RISK GROUP<100mg/dL.
 Reducing LDL levels lower than recommended targets further
reduces ASCVD risk-thus Lower LDL the better.
 Large scale trial shows that individuals with very low LDL are
generally healthy & have low ASCVD risk
 Levels<50mg is safe & do not cause increase in the risk of
cancer,hemorrhagic stroke or neurocognitive dysfunction.
 LDL should be the primary target of therapy

49. Non-HDL Cholesterol
 Non HDL=Sr Cholesterol-HDL
 NonHDL-C is particularly informative in Diabetics.
 It is a co-primary target,as important as LDL-C,for
lipid lowering therapy.
 It doesn’t require fasting sample.
 Normal level is<130mg/dL
 In all individuals,the Non-HDL-C levels should be
kept within 30mg/ dL of LDL-C

50. TRIGLYCERIDE
 ElevatedTg is associated with increased risk of
ASCVD,independent of LDL levels
 HighTg+High small dense LDL+Low
HDL=Atherogenic Dyslipidemia.
 KeepTg<150mg/dL, preferably <100mg/dL.
 In patients with raisedTg secondary causes of
elevatedTg should be ruled out e.g. Alcohol
intake,DM,Hypothyroidism,Nephrotic
Syndrome,,CKD,Obstructive Liver Disease,Drugs
e.g. Steroids,BB,Protease inhibitors for HIV
 Statin should be the first drug in all the patients
with highTg. Only whenTg is not sufficiently
lowered,a non-statin should be added.

51. HDL-C
 HDL is a class of heterogenous lipoproteins that are
the only anti-atherogenic lipid particles in blood.
 Cardio-protective effects of HDL-C have been
attributed to its role in-
 reverse cholesterol transport
Effect on endothelial cells
Its antioxidant activity.
 It is increasingly been recognized that the
concentration of HDL subclasses & the kinetics of
HDL metabolism & not the absolute value of HDL
may be the primary determinants of its anti-
atherogenic effects.

52. HDL-C
 A Canadian cohort study showed that low as well as
very high levels of HDL-C were associated with
increased risk of death from both CV & non-CV
causes,compared with intermediate HDL-C levels.
 This suggests that there is a U shaped HDL-C
mortality curve
 Low HDL level is defined as
Men<40mg/dL
Women<50mg/dL
 Patients with low HDL are 3 times more likely to die
after an Acute Coronary Event.

53. PHARMACOTHERAPY
OF DYSLIPIDEMIA

54. Coronary Primary Prevention
Trial(CPPT)
 Cholestyramine (Bile binder) v/s Placebo.
 Expected 25% reduction in cholesterol levels but
got just 6-7% reduction & that too in controlled
conditions.
 Although, the drug appeared to absorb bile acid
effectively ,the liver compensated to some extent
by stepping up the manufacture of cholesterol.
 Most of the participants refused to take 6
packets/day of drug in view of discomforting
abdominal side effects.
 LESSON-Body has a tremendously effective
mechanism for maintaining blood cholesterol
levels.

55. WHO-Clofibrate Trial
 Objective was to reduce Cholesterol levels by 30%
but achieved just 9% reduction.
 Reduction in non-fatal MI but no reduction in fatal
MI.
 Excess deaths in the treatment group due GB
Stones,Cholecystectomy,Increased cancers of liver
& digestive system.

56. Management of Dyslipidemia
Pharmacotherapy
 STATINS-even though are used primarily to lower
LDL-C but also raise HDL-C by 5-15%.Due to their
profound risk reduction by various
mechanisms,statins should be used as the 1st line
agents in patients with low HDL-C, whether or not
LDL-C is elevated.
 NIACIN-Niacin is the most effective HDL-C raising
pharmacological agent however HPS2-THRIVE
Study & AIM-HIGH study failed to show any benefit
in CV risk reduction , rather there was some harm
with niacin therapy.Currently it is not
recommended for clinical use as a HDL-C raising
agent.

57. Management of Dyslipidemia
Pharmacotherapy
 FIBRATES-are used in patients in combination with
statins who continue to have highTg in spite of
optimum statin therapy.
 They can be used as a 1st line therapy only ifTg
levels >500mg/dL & LDL-C is normal since the
primary aim in such patients is to prevent attack of
Acute Pancreatitis & not prevention of CAD.

58. CETP INHIBITORS
 If Cholesteryl-esterTransfer Protein(CETP) is
not produced in people due to
mutation>High HDL levels>However CETP
inhibitors e.g.Tor cetra pib(Pfizer) & Dal
ctera pib(Roche) were a failure in clinical
trials.
 Trials with Ana cetra pib & eva cetra pib are
underway.

60. PCSK9 Inhibitors
 New kid on the block.
 PCSK9=Proprotein convertase
subtilisin/kexin type 9 inhibitors e.g.
Evolocumab,Alirocumab.
 FOURIERTrial-Pts of atherosclerotic CVD
&already receiving statins were given Inj
Evolocumab 140mg every other week.
 Results-15-20% reduced risk of MI,Stroke,CV
deaths & hospitalization over a period of 2.2
years.

61. PCSK9 Inhibitors 2
 In many patients LDL was reduced to
22mg/dl.They pushed the LDL levels that
almost approached those of newborns.
 These findings show that patients with
atherosclerotic CVD benefit from lowering of
LDL levels below current targets.
 Proves LDL is LOWERTHE BETTER
 Cost is a concern. Annual cost of Rx is $
14100(Rs 92000/-) per annum

62. THANK YOU