Dyslipidemia, specially high LDL cholesterol is the key risk factor for cardiovascular diseases. The presentation discusses metabolism and structure of lipoproteins, their screening and interpretation, risk assessment methods, targets for various lipoproteins and its step by step treatment.

1. Overview of Dyslipidemia
Dr S K Agarwal
MBBS, MD, DM, FACC, CBCCT
Consultant cardiologist
Rashid Hospital
skagarwal@dha.gov.ae

2. Magnitude of problem
• The estimated annual incidence of MI is 550,000 new
and 200,000 recurrent attacks
• According to data from 2009-2012, >100 million U.S.
adults ≥20 yrs of age have total cholesterol ≥200
mg/dL; 31 million have ≥240 mg/dL
• 69% of U.S. adults have LDL-C concentrations above
100 mg/dL
• Increasing evidence also points to insulin resistance
—which results in ↑TG & LDL-C and ↓HDL-C
AACE 2017

3. Total cholesterol levels for hunter-gatherers, wild primates, and wild
mammals, generally range from about 70 to 140 mg/dl (corresponding to
low-density lipoprotein levels of about 35 to 70 mg/dl

4. Atherosclerotic Cardiovascular
Disease Risk Factors
Nontraditional risk
factors
Lipoprotein (a)
 Clotting factors
 Inflammation markers
(hsCRP; Lp-PLA2)
Homocysteine levels
Apo E4 isoform
 Uric acid
 TG-rich remnants
Major risk factors
Advancing age
 Total cholesterol
 Non–HDL-C
 LDL-C
Low HDL-C
Diabetes mellitus
Hypertension
Chronic kidney disease
Cigarette smoking
Family history of ASCVD
Additional risk factors
Obesity, abdominal obesity
Family history of
hyperlipidemia
 Small, dense LDL-C
 Apo B
LDL particle concentration
Fasting/postprandial
hypertriglyceridemia
PCOS
Dyslipidemic triad
AACE 2017

5. Atherosclerotic Cardiovascular
Disease Risk Factors
Nontraditional risk
factors
Lipoprotein (a)
 Clotting factors
 Inflammation markers
(hsCRP; Lp-PLA2)
Homocysteine levels
Apo E4 isoform
 Uric acid
 TG-rich remnants
Major risk factors
Advancing age
 Total cholesterol
 Non–HDL-C
 LDL-C
Low HDL-C
Diabetes mellitus
Hypertension
Chronic kidney disease
Cigarette smoking
Family history of ASCVD
Additional risk factors
Obesity, abdominal obesity
Family history of
hyperlipidemia
 Small, dense LDL-C
 Apo B
LDL particle concentration
Fasting/postprandial
hypertriglyceridemia
PCOS
Dyslipidemic triad
AACE 2017

8. Apolipoproteins
B/E receptor ligand *E2:IDL; *E4: Diet ResponsivityapoE
LpL inhibitor; antagonizes apoEapoC-III
LpL activatorapoC-II
Inhibit Lp binding to LDL R; LCAT activatorapoC-I
apoB-48
Structural protein of all LP except HDL
Binding to LDL receptor
apoB-100
Tg metabolism; LCAT activator; diet responseapoA-IV
HL activationapoA-II
HDL structural protein; LCAT activator;RCTapoA-I
Fibrates

9. Cholesterol metabolism
Major sources of Liver cholesterol
Major routes by which cholesterol leaves liver
Ezetimibe
Fibrates
Bile acid
sequestrants
Statins
Lippincott’s Illustrated Reviews-Richard A. Harvey

10. Metabolism of Chylomicrons
Adipokines
TNFα, IL6
Leptin , PAI-1
NPC1L1

11. Role of raised plasma TG and remnant cholesterol in intimal low-
grade inflammation and development of atherosclerosis

12. Metabolism of VLDL, IDL & LDL
LDL receptor deficiency

13. Problem of Residual risk!
Non-HDL revisited
Lipoprotein subclasses and apoB–containing lipoproteins
Non-HDL cholesterol = Total cholesterol-HDL
Remnant cholesterol = Non HDL cholesterol - LDL

15. 15
Patient populations recommended
for plasma lipid screening
Once every five years in patients ≥20 years old
T2DM
Arterial hypertension
Manifest ASCVD
Central obesity
Chronic inflammatory autoimmune disease
CKD
Family history of ASCVD
Offspring of pts with severe disorders of plasma lipids (e.g. FH)
ME 2016
Familial Hypercholesterolemia: Individuals should be screened for FH when there is a family
history of
• premature ASCVD
• Elevated cholesterol levels (total, non-HDL and/or LDL) consistent with FH

16. SCREENING TESTS RECOMMENDED FOR
DETECTING CV RISK
Fasting Lipid Profile-to ensure the most precise lipid assessment;
this include total cholesterol, LDL-C, TG, and non-HDL-C.
non-fasting only if fasting is impractical
LDL-C may be estimated using the Friedewald equation: LDL-C =
(total cholesterol – HDL-C) – TG/5
Non-HDL-C (total cholesterol minus HDL-C) calculate to risk
stratify individuals with moderately elevated TG (200 to 500
mg/dL), DM, and/or established ASCVD
Additional Tests
hsCRP, Lp-PLA2:
routine measurement of homocysteine, uric acid, PAI-1, or other
inflammatory markers is not recommended
AACE 2017

18. Schedule for screening
Adults With Diabetes
• Annually screen all adult individuals with T1DM or T2DM
Children and Adolescents
• In children at risk for FH (e.g., family history of- premature CV disease or elevated
cholesterol), screening should be at 3 yrs of age, again between ages 9 and 11, and again
at age 18
• 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
Young Adults (Men 20-45 Years, Women 20-55 Years)
• Every 5 years as part of a global risk assessment
Middle-Aged Adults (Men 45-65 Years, Women 55-65 Years)
• In the absence of ASCVD risk factors, once every 1 to 2 years. More frequently when
multiple global ASCVD risk factors are present
Older Adults (Older Than 65 Years)
• Annually for adults with 0 to 1 ASCVD risk factor
• older women should be screened in the same way as older men
AACE 2017

19. Feast or famine lipids
Fasting sample must:
• Initiation of therapy
• Met s, DM, FCH
• Pediatric age
• Female sex
standard lipids measured in the fasted state should continue as
the benchmark for risk assessment, diagnosis, and therapy of
lipid disorders, with consideration given to nonfasting samples
in specific clinical circumstances and in the initial screening for
dyslipidemias

20. Secondary Causes of Dyslipidemia
↑ Total cholesterol and LDL-C
• Hypothyroidism
• Nephrosis
• Dysgammaglobulinemia (SLE, multiple myeloma)
• Progestina or anabolic steroid treatment
• Cholostatic diseases of the liver due to abnormal lipoproteins, as in primary biliary
cirrhosis
• Protease inhibitors for treatment of HIV infection
↑ TG and VLDL-C
• Chronic renal failure
• Type 2 diabetes mellitus
• Obesity
• Excessive alcohol intake
• Hypothyroidism
• Antihypertensive medications (thiazide diuretics and b-adrenergic blocking agents)
• Corticosteroid therapy (or severe stress that increases endogenous corticosteroids)
• Orally administered estrogens, oral contraceptives, pregnancy
• Protease inhibitors for treatment of HIV infection
AACE 2017

21. Summary Part I
• Cholesterol metabolism
• Lipoproteins and apolipoproteins
• Mech of action of drugs
• Who need to be screened
• What need to be screened
• Screening schedule
• Fasting vs non fasting
• Secondary causes

22. Framingham SCORE PROCAM (Men) Reynolds (Women) Reynolds (Men)
Sample size 5345 205,178 5389 24,558 10,724
Age, range (y) 30 to 74; M:49 19 to 80; M:46 35 to 65; M:47 >45; M:52 >50; M:63
Mean follow-up (y) 12 13 10 10.2 10.8
Risk factors
considered
Age, sex, total
cholesterol, HDL
cholesterol,
smoking, systolic
blood pressure,
antihypertensive
Medications
Age, sex, total-
HDL cholesterol
ratio, smoking,
systolic blood
pressure
Age, LDL
cholesterol, HDL
cholesterol,
smoking, systolic
blood pressure,
family history,
diabetes,
triglycerides
Age, HbA1C (with
diabetes), smoking,
systolic blood pressure,
total cholesterol, HDL
cholesterol, hsCRP,
parental history of MI
at <60 y of age
Age, systolic blood
pressure, total
cholesterol, HDL
cholesterol, smoking,
hsCRP, parental history
of MI at <60 y of age
Endpoints CHD (MI and
CHD death)
Fatal CHD Fatal/nonfatal
MI or sudden
cardiac death
(CHD and CVD
combined)
MI, ischemic stroke,
coronary
revascularization,
cardiovascular death
(CHD and CVD
combined)
MI, stroke, coronary
revascularization,
cardiovascular death
(CHD and CVD
combined)
URLs for risk
calculators
http://hp2010.nhlbi
hin.net/atpiii/calcul
ator.asp?usertype=
prof
http://www.heartsc
ore.org/pages/welc
ome.aspx
http://www.chd-
taskforce.com/co
ronary_risk_asse
ssment.html
http://www.reynoldsris
kscore.org/
http://www.reynoldsris
kscore.org/
Global Coronary and Cardiovascular Risk
Scores#1

23. Risk categories
ESC 2016 ACC 2013------ATP III
Very high-risk Subjects with any of the following:
• Documented CVD, clinical or unequivocal on imaging.
Clinical includes previous MI, ACS, PCI, CABG and other
arterial revascularization procedures, stroke and TIA and
PAD. Unequivocally documented CVD on imaging such as
significant plaque on CAG or carotid ultrasound.
• DM with TOD such as
proteinuria or with a major risk factor such as smoking, HT
or dyslipidaemia.
• Severe CKD (GFR <30 mL/min/1.73 m2).
• A calculated SCORE ≥10% for 10-year risk of fatal CVD
1. Patients with any form of
clinical ASCVD
2. Patients with primary LDL-
C levels of ≥190 mg/dl
3. Patients with DM, 40 -75
years of age, with LDL-C
levels of 70-189 mg per dL
4. Patients without diabetes,
40 -75 years of age, with an
estimated 10-year ASCVD
risk ≥ 7.5%
(10-year risk >20%)
High-risk Subjects with:
• Markedly elevated single risk factors, in particular
cholesterol >310 mg/dL (e.g. in familial
hypercholesterolaemia) or BP ≥180/110 mmHg.
• Most other people with DM (some young people with
type 1 diabetes may be at low or moderate risk)
• Moderate CKD (GFR 30–59 mL/min/1.73 m2).
• A calculated SCORE ≥5% and <10%
2+ risk factors
(10-year risk 10% to 20%)
Moderate-risk SCORE is ≥1% and <5% for 10-year risk of fatal CVD 2+ risk factors (10 year risk
<10%)
Low-risk SCORE <1% for 10-year risk of fatal CVD 0-1 risk factor
https://www.framinghamheartstudy.org/risk-functions/coronary-heart-disease/hard-10-year-risk.php
#2
ESC 2016 and ACC AHA 2013 / 2014 guidelines

24. Treatment targets and goals for
CVD prevention
primary
Target:
LDL-C
Very high-risk: LDL-C <70 mg/dL or a reduction of at least
50% if the baseline is between 70 and 135 mg/dL
High-risk: LDL-C <100 mg/dL or a reduction of at least
50% if the baseline is between 100 and 200 mg/dL
Low to moderate risk: LDL-C <115 mg/dL
secondary
targets:
Non-HDL-C
100, 130 and 145 mg/dL for very high-, high- and
moderate-risk subjects, respectively
HDL-C no target, but >40 mg/dL in men and >48 mg/dL in women
indicates lower risk.
TG no target but <150 mg/dL indicates lower risk and higher
levels indicate a need to look for other risk factors.
ESC 2016
#3

25. My cholesterol !!!!
What happened???
Oh no, nothing with your cholesterol level, our levels changed yesterday !

26. Treatment Recommendations
Lifestyle changes
Physical Activity:
• fitness therapy ( 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)
• muscle-strengthening activity is recommended at least 2 days a week
Medical Nutrition Therapy
• Reduced-calorie diet of fruits and vegetables (combined ≥5
servings/day), whole grains, fish, and lean meats
• plant stanols/sterols (~2 g/ day) and soluble fiber (10-25 g/day)
• Limited intake of saturated fats, trans-fats, and cholesterol
Primary preventive nutrition consisting of healthy lifestyle habits is
recommended in all healthy children
Smoking Cessation
Pharmacologic Therapy
#4

28. 30 gm/day

29. Omega-3 Content of Frequently Consumed Seafood Products
SEAFOOD PRODUCT
OMEGA-3s PER 3
OUNCE COOKED
PORTION
Herring wild (Atlantic & Pacific), Salmon farmed (Atlantic),
Salmon wild (King), Mackerel wild (Pacific & Jack) ♥♥♥♥♥ >1,500 milligrams
SEAFOOD PRODUCT
Salmon canned (Pink, Sockeye & Chum) Mackerel canned (Jack),
Mackerel wild (Atlantic & Spanish), Tuna wild (Bluefin)
♥♥♥♥ 1,000 to 1,500 milligrams
Salmon wild (Sockeye, Coho, Chum & Pink), Sardines canned,
Tuna canned (White Albacore), Swordfish wild , Trout farmed
(Rainbow), Oysters wild & farmed, Mussels wild & farmed
♥♥♥
500 to 1,000 milligrams
Tuna canned (Light), Tuna, Wild (Skipjack), Pollock wild (Alaskan),
Rockfish wild (Pacific) clams wild & Farmed, Crab wild (King,
Dungeness & Snow), Lobster wild (Spiny), Snapper wild, Grouper
wild, Flounder/Sole wild, Halibut wild (Pacific & Atlantic), Ocean
Perch wild, Squid wild (Fried), Fish Sticks (Breaded)
♥♥ 200 to 500 milligrams
Scallops wild , Shrimp wild & Farmed, Lobster wild (Northern),
Crab wild (Blue), Cod wild, Haddock wild Tilapia farmed , Catfish
farmed, Mahimahi wild, Tuna wild (Yellowfin), Orange Roughy
wild , Surimi Product (Imitation Crab)
♥ < 200 milligrams

30. 6
4
2
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
A Randomized, Controlled, Crossover Trial
The Almond magic Circulation. 2002;106
Change in lipids from controls
(in %)
LDL HDL Total:HDL LDL:HDL Apo B:A1 Ox LDL
Half: <0.018 0.034 0.004 <0.001 0.01 -----
Full: <0.001 0.047 <0.001 <0.001 <0.001 <0.001

31. #5 Drug therapy

32. Practical approach to reach LDL goal
ESC 2016
Starting
#5a

33. Relative LDL-lowering Efficacy of
Statin and Statin-based Therapies
Atorva Fluva Pitava Lova Prava Rosuva Vytorin* Simva %↓ LDL-C
----- 40 mg 1 mg 20 mg 20 mg ----- ----- 10 mg 30%
10 mg 80 mg 2 mg 40or80 mg 40 mg ----- ----- 20 mg 38%
20 mg ----- 4 mg 80 mg 80 mg 5 mg 10/10 mg 40 mg 41%
40 mg ----- ------ ----- ----- 10 mg 10/20 mg 47%
80 mg ----- ------ ----- ----- 20 mg 10/40 mg ----- 55%
----- ----- ------ ----- ----- 40 mg ----- 63%
Source: US FDAWeng TC, et al. J Clin Pharm Ther 2010;35:139
#5b

34. 34
Recommendations for the pharmacological
treatment of hypercholesterolaemia
Recommendations Class Level
Prescribe statin up to the highest recommended dose or
highest tolerable dose to reach the goal. I A
In the case of statin intolerance, ezetimibe or BAS or these
combined, should be considered. IIa C
If the goal is not reached, statin combination with a
cholesterol absorption inhibitor should be considered. IIa B
If the goal is not reached, statin combination with a bile acid
sequestrant may be considered. IIb C
In patients at very high-risk, with persistent high LDL-C
despite treatment with maximal tolerated statin dose, in
combination with ezetimibe or in patients with statin
intolerance, a PCSK9 inhibitor may be considered.
IIb C
ESC 2016

39. CKx2wks
Monitor CK

41. Principal mechanisms involved in statin-induced
myopathy

44. 44
Recommendations for lipid-lowering
therapy in patients with ACS
Recommendations Class Level
Initiate or continue high dose statins early after admission
(1-4 d) in all ACS patients without contraindication or history
of intolerance, regardless of initial LDL-C values.
I A
Lipids should be re-evaluated 4–6 wks after ACS to see whether target
of LDL-C <70 mg/dL or a reduction of at least 50% (if the baseline is
between 70 - 135 mg/dL) have been reached and whether there are
any safety issues. The therapy dose should then be adapted
accordingly.
IIa C
If the LDL-C target is not reached with the highest tolerable
statin dose, ezetimibe should be considered in combination
with statins in post-ACS patients
IIa B
If the LDL-C target is not reached with the highest tolerable statin dose
and/or ezetimibe, PCSK9 inhibitors may be considered on top of lipid-
lowering therapy; or alone or in combination with ezetimibe in statin
intolerant patients or in whom a statin is contra-indicated.
IIb C

53. Fasting TG
EPA/DHA
AHA Triglyceride Guidance
Miller et al. Circ 2011; 123: 2292

55. Impact of fibrates on macrovascular events
risk according to lipoprotein phenotype
N Engl J Med 2010

56. • An atherogenic lipoprotein
containing apo(a) and apoB.
• 20-30% of people have levels
suggesting C-V risk.
• Black subjects have Lp(a)
normal range twice as high
as white and Asiatic subjects.
• Apo(a) sequence similar to plasminogen, and Lp(a)
interferes with spontaneous thrombolysis.
• Lp(a) levels highly genetic, resistant to diet and drug
therapy, although niacin may help.
• PCSK9 has shown good results
Apo(a)
-S-S-
Lipoprotein(a), or Lp(a)
“LDL”

57. Statin effect in other diseases
• Statin and gallstones
• Statin and open angle glaucoma
• Statin and VTE
• Statin in very low LDL post MI
• Statin and sepsis
• Statin and NAFLD
• Statin and H pylori

59. slideshare.net/sanjeevkagarwal
Thank you
Best Wishes