The document provides a comprehensive overview of cholesterol, its importance in human health, and the risks associated with high levels, particularly in relation to cardiovascular diseases (CVD). It discusses the body's cholesterol processing, desirable levels, management strategies, treatment options for different age groups, and emerging therapies. Prevention strategies emphasize dietary change and lifestyle modifications as critical measures against hypercholesterolemia and related conditions.

1. CHOLESTEROL 101
Zeena Nackerdien

2. OVERVIEW
What is
cholesterol?
How the body
processes
cholesterol?
Cholesterol
Management
Acute
Treatment
Options
Emerging
Therapies &
Break-
throughs
Prevention
Take-
aways

3. WHAT IS CHOLESTEROL?
Why is it so important?

4. WHAT IS CHOLESTEROL?
WHY IS IT IMPORTANT?
 Heart disease is the leading
cause of death in the USA
 More than 900,000 Americans are
likely to suffer a heart attack or
die from coronary artery disease
this year
 People with high cholesterol are
twice as likely to be among these
individuals than people with lower
levels
 Cholesterol is a key waxy, fat-like
substance used in the human body
to make hormones, vitamin D, and
compounds needed to digest food
 The body makes all the cholesterol
it needs, but some of this sterol
can also be obtained from a diet
The liver is central to
regulating cholesterol
Triggers may reflect
polygenes and/or
an unhealthy lifestyle
USA, United States of America; See Reading List for more detail

5. HOW THE BODY PROCESSES
CHOLESTEROL
Desirable levels of cholesterol

6. HOW DOES THE BODY PROCESS PLASMA
CHOLESTEROL (C)?
Chylomicrons
+ VLDL = Triglyceride-rich compounds
delivering energy-rich
triacylglycerol (TAG) to cells in the body
VLDL - TAG = Remodeled in liver to become LDL
which, in turn, delivers cholesterol
To cells
HDL Is involved in reverse C transport
Cells need C from dietary sources and the liver for membrane synthesis and energy.
However, abnormal levels of plasma lipids and lipoproteins are important risk factors
for metabolic and cardiovascular diseases.
~60-70%
of plasma
cholesterol is
LDL-C
HDL, High-density lipoprotein; LDL, Low-density lipoprotein; VLDL, Very low-density lipoprotein.
See Reading List for more detail.

7. WHAT ARE DESIRABLE LEVELS OF
CHOLESTEROL?
 US Centers for Disease Control and Prevention Recommendations
Less than 200 mg/dL
Total cholesterol
Less than 100 mg/dL
LDL ("bad"
cholesterol)
60 mg/dL or higher
HDL ("good"
cholesterol)
Less than 150 mg/dLTriglycerides
US, United States; LDL, Low-density lipoprotein; HDL, High-density lipoprotein. See Reading List for more detail.

8. “
”
CLINICAL ATHEROSCLEROTIC CVD IS DEFINED AS
ACUTE CORONARY SYNDROME; HISTORY OF MI,
STABLE OR UNSTABLE ANGINA, CORONARY
REVASCULARIZATION, STROKE, OR TIA PRESUMED
TO BE OF ATHEROSCLEROTIC ORIGIN, AND
PERIPHERAL ARTERIAL DISEASE OR
REVASCULARIZATION.Source: Epocrates 2017:Hypercholesterolemia Tx details
https://online.epocrates.com/diseases/17042/Hypercholesterolemia/Treatment-Options
DEFINITION FOR ATHEROSCLEROTIC CVD
Cholesterol levels are included in risk factor assessments for atherosclerotic CVD.
CVD, Cardiovascular diseases; MI, Myocardial Infarction; TIA, Transient Ischemic Attack. See Reading List for more
detail.

9. FRAMINGHAM GLOBAL RISK FACTORS
(INCLUDED QUESTIONS)
 Key ASCVD Risk factor tools are Framingham, MESA, Reynolds, and UKPDS
 Depending on the risk tool, select data from clinical trials (Framingham,
MESA, and UKPDS) were used to calculate 10-year risk of having a heart
attack for adults (20 and older) who do not have heart disease or diabetes
Age Sex Total C HDL-C
Smoker
(in last
month)
Systolic blood
pressure
Is
patient
on high
blood
pressure
medica-
tion?
Calculate = ?
Questions to ask:
ASCVD, atherosclerotic cardiovascular diseases; MESA, Multi-Ethnic Study of Atherosclerosis; Reynolds risk score is a is
a risk equation that includes the conventional CVD risk factors in addition to family history and high-sensitivity C-
reactive protein; UKPDS, United Kingdom Prospective Diabetes Study
See Reading List for more detail.

10. FRAMINGHAM: 10-YEAR ASCVD RISK &
CLINICAL EXAMPLES
 High risk: A greater than 20% risk that patient will develop a heart attack or die from coronary disease in the next 10 years.
 Intermediate risk: A 10-20% risk that patient will develop a heart attack or die from coronary disease in the next 10 years
 Low risk: Less than 10% risk that patient will develop a heart attack or die from coronary disease in the next 10 years

High
>20%
 Established
coronary artery
disease
 Cerebrovascular
disease
 Peripheral
arterial disease
 Abdominal aortic
aneurysm
 Diabetes mellitus
 Chronic kidney
disease
Intermediate
10-20%
 Subclinical
coronary artery
disease
 MetS
 Multiple risk
factorsa
 Markedly elevated
levels of a single
risk factorb
 First-degree
relative(s) with
early onset
coronary artery
disease
Lower
<10%
 May include
women with
multiple risk
factors, MetS, or
1 or no risk
factors
Optimal
<10%
 Optimal levels of
risk factors and
heart- healthy
lifestyle
a. Patients with multiple risk factors can fall into any of the 3 categories by Framingham scoring.
b. Most women with a single, severe risk factor will have a 10-year risk ≤10%. See Reading List for more detail.
MetS, Metabolic Syndrome. See Reading List for more detail.

11. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS
(MESA): RISK FACTORS INCLUDED/QUESTIONS
 “The MESA study, which had a multicenter cohort of individuals aged 45 to 84
years with no ASCVD at baseline (N = 6,814), found a 29.3% prevalence of
dyslipidemia” (Jellinger et al, 2017)
Age
(45-85 years)
Sex
Coronary artery
calcification
Race/
Ethnicity
Diabetes
Smoker Genetics
Total C HDL-C
Systolic BP
Lipid-
lowering
drugs
Hypertension
medication
Calculate = ?
BP, blood pressure; C, cholesterol; HDL, High-density lipoprotein; LDL, Low-density lipoprotein. See Reading List for
more detail.

12. MESA RISK CALCULATION OUTCOMES
External validation provided evidence of very good
discrimination and calibration
Harrell’s C-statistic ranged from 0.779 to 0.816 in
validation against existing studies
The difference in estimated 10-year risk between events
and nonevents was approximately 8-9%, indicating
excellent discrimination
Mean calibration found average predicted 10-year risk
within 1/2 of a percent of the observed event rate
The test predicts 10-year risk of a ASCVD event
ASCVD, Atherosclerotic Cardiovascular Diseases; Harrell's C-statistic, Concordance statistic is equal to the area under
a Receiver Operating Characteristic curve. See Reading List for more detail.

13. CHOLESTEROL MANAGEMENT
An evidence-based approach and risk management

14. TREATMENT APPROACH
 Differences exist among various guidelines about treatment details for risk-
stratified patients
 However, guidelines are unanimous in recommending robust statin-based therapies
for high-risk patients and less intensive therapies for lower risk groups
 There are four core components of treatment and, in rare cases, patients may be
referred for experimental therapies
Diet
Exercise
Medications
Dietary
Supplements
Experimental
Therapies
See Reading List for more detail.

15. ACUTE TREATMENT OPTIONS
Summarized options for age-appropriate interventions for patients ± atherosclerotic
cardiovascular diseases (with or without dyslipidemia)
(See Epocrates source in Reading List)

16. TREATMENT (PLUS CLINICAL
ATHEROSCLEROTIC CVD)
 ≤75 years
•High-intensity statin therapy (daily
dose lowers LDL-cholesterol by
≥50%) should be given if there are
no contraindications to high-
intensity therapy.
When high-intensity statin therapy
is contraindicated or not tolerated,
or have characteristics predisposing
to statin-associated AEs, patients
should generally be treated with
moderate-intensity statin therapy
(daily dose lowers LDL-cholesterol
by 30%-50%).
Other characteristics that may
modify the decision to use higher
statin intensities may include, but
are not limited to: a history of
hemorrhagic stroke; Asian ancestry.
+ Lifestyle
changes
+ Lifestyle
changes
AEs, adverse events; CVD, cardiovascular diseases; LDL, Low-density lipoprotein. See Reading List for more detail.

17. TREATMENT (PLUS CLINICAL
ATHEROSCLEROTIC CVD)
 >75 years
•A moderate-intensity statin. This age group
also represents a characteristic that
predisposes to statin AEs.
+ Lifestyle
changes
AEs, adverse events; CVD, cardiovascular diseases. See Reading List for more detail.

18. TREATMENT (MINUS CLINICAL
ATHEROSCLEROTIC CVD; LDL-C ≥190 MG/DL)
•This group includes include those
who have familial
hypercholesterolemia and are at
high risk on the basis of LDL-Cl
alone. Usually these patients are
treated with high-intensity statin
therapy.
When high-intensity statin therapy
is contraindicated or not tolerated,
moderate-intensity therapy is
indicated
+ Lifestyle
changes
+ Lifestyle
changes
C, cholesterol; CVD, cardiovascular diseases; LDL, Low-density lipoprotein. See Reading List for more detail.

19. TREATMENT (MINUS CLINICAL
ATHEROSCLEROTIC CVD; LDL-C 70-189 MG/DL)
 40-75 years with DM
•For risk ≥7.5% (based on ACC-
recommended ASCVD risk calculator
), high-intensity statin therapy
(daily dose lowers LDL-C by
≥50%) should typically be given
Patients for whom high-intensity
statin therapy are contraindicated
or have an ACC-determined risk
<7.5% may benefit from moderate-
intensity treatment (daily dose
lowers LDL-cholesterol by 30% to
50%)
+ Lifestyle
changes
+ Lifestyle
changes
ACC, American College of Cardiology; C, cholesterol; CVD, cardiovascular diseases; DM, diabetes Mellitus; LDL, Low-
density lipoprotein. See Reading List for more detail.

20. TREATMENT (MINUS CLINICAL ATHEROSCLEROTIC
CVD; LDL-C, 70-189 MG/DL)
 40-75 years without DM
•For risk ≥7.5% (based
•on ACC-recommended ASCVD risk
calculator ), moderate-to-high
intensity stating therapy should be
discussed with the patient, keeping
in mind patient preferences when
emphasizing potential benefits for
ASCVD risk reduction and mentioning
AEs and drug-drug interactions
For an ACC-determined risk of 5% to
<7.5%, or if high-intensity statin
therapy is not well-
tolerated/contraindicated,
moderate-intensity statin therapy
may be a viable option
+ Lifestyle
changes
+ Lifestyle
changes
ACC, American College of Cardiology; ASCVD, Atherosclerotic Cardiovascular Diseases; AEs, adverse events; C,
cholesterol; LDL, Low-density lipoprotein. See Reading List for more detail.

21. TREATMENT (MINUS CLINICAL
ATHEROSCLEROTIC CVD; LDL-C <190 MG/DL)
 <40 or >75 years
•Examine additional factors (e.g., primary
LDL-C ≥160 mg/dL or other evidence of
genetic hyperlipidemia;family history of
premature ASCVD with onset at <55 years of
age in a first-degree male relative or <65
years of age in a first-degree female
relative) and engage the patients in a
discussion about the benefits and risks of
using statins
+ Lifestyle
changes
ASCVD, atherosclerotic cardiovascular diseases; AE, adverse event; C, cholesterol; LDL, Low-density lipoprotein. See
Reading List for mroe detail.

22. TREATMENT (MINUS CLINICAL
ATHEROSCLEROTIC CVD)
 isolated low HDL-cholesterol
•For risk ≥7.5%, moderate-to-high intensity
statin therapy is usually discussed with the
patient with the same considerations as
mentioned in prior treatments. Moderate-
intensity therapy is potentially of use if the
risk is 5% to <7.5%. Where possible,
abdominal obesity, hypertriglyceridemia,
smoking, insulin resistance, or genetic
causes should also be managed.
See Reading List for more detail.

23. PRIMARY LIPID-LOWERING
DRUG CLASS
Primarily LDL-C 21-55% by competitively
inhibiting rate- limiting step of cholesterol
synthesis in the liver, leading to upregulation
of hepatic LDL receptors
Effects on TG and HDL-C are less pronounced
( TG 6-30% and  HDL-C 2-10%)
 Liver function test prior to therapy and as clinically
indicated thereafter
 Myalgias and muscle weakness in some patients Potential
for drug-drug interaction between some
 statins and CYP450 3A4 inhibitors, cyclosporine, warfarin,
and protease inhibitors
 Myopathy/rhabdomyolysis in rare cases; increased risk
with co-administration of some drugs (see
 product labeling)
 Simvastatin dosages of 80 mg are no longer recommended.
 Do not exceed 20 mg simvastatin daily with amlodipine or
ranolazine
 Plasma elevations of rosuvastatin may be higher among
Asian persons than other ethnic groups
 New-onset diabetes is increased in patients treated with
statins; however, it is dose-related, occurs primarily in
patients with MetS, appears to be less common with
pravastatin and possibly pitavastatin, and occurs overall
to a lesser extent than the associated decrease in ASCVD
HMG-CoA reductase inhibitors (statins:lovastatin,
pravastatin, fluvastatin, simvastatin,
atorvastatin, rosuvastatin, pitavastatin)
MAIN CONSIDERATIONS
METABOLIC EFFECT
{
ASCVD, Atherosclerotic Cardiovascular Diseases; C, cardiovascular diseases;
HDL, High-density lipoprotein;
LDL, Low-density lipoprotein; MetS, metabolic syndrome; TG, Triglycerides.
See Reading List form more detail.

24. PRIMARY LIPID-LOWERING
DRUG CLASS
.
Cholesterol absorption inhibitors (ezetimibe)
MAIN CONSIDERATIONS
METABOLIC EFFECT
{
Primarily  LDL-C 10-
18% by inhibiting intestinal absorption of
cholesterol and decreasing delivery to the liver,
leading to upregulation of hepatic LDL receptors
 Apo B 11-16%
In combination with statins, additional LDL-C
25%, total LDL-C 34-61%
In combination with
fenofibrate,  LDL-C 20-22% and
 apo B 25-26% without reducing HDL-C
 HDL-C
 Myopathy/rhabdomyolysis (rare) Myopathy/
rhabdomyolysis (rare)
 When co-administered with statins or fenofibrate,
risks associated with those drugs remain (e.g.,
myopathy/ rhabdomyolysis, cholelithiasis)
Apo B, Apolipoprotein B; HDL, HIgh-density lipoprotein; LDL, Low-density lipoprotein. See Reading list for more detail.

25. PRIMARY LIPID-LOWERING
DRUG CLASS
.
PCSK9 (Proprotein convertase subtilisin/kexin
type 9) inhibitors (alirocumab, evolocumab)
MAIN CONSIDERATIONS
METABOLIC EFFECT
{
LDL-C 48-71%,  non-HDL-C 49-
58%, Total-C 36-42%, Apo B 42-
55% by inhibiting PCSK9 binding with LDLRs,
increasing the number of LDLRs available to
clear LDL, and lowering LDL-C levels
 Requires sub-Q self-injection, and refrigeration is
generally needed.
 Adverse reactions resulted in discontinuation in 2.2%
overall, 1.2% more than placebo for evolocumab, and
5.3% overall, 0.2% more than placebo for alirocumab.
Overall levels of adverse reactions and discontinuation
very low.
 Adverse reactions with significantly different rates
between drug and placebo were local injection site
reactions (1.9% greater for alirocumab vs. placebo, 0.7%
greater for evolocumab vs. placebo) and influenza (1.2%
greater for alirocumab vs. placebo, 0.2% for evolocumab
vs. placebo). The most common adverse reactions with
similar rates for drug vs. placebo were for the following:
 Alirocumab (4-12%; most common to least
common): nasopharyngitis, influenza, urinary tract
infections, diarrhea, bronchitis, and myalgia;
 Evolocumab (2-4%; most common to least
common): Nasopharyngitis, back pain, and upper
respiratory tract infection.
Sub-Q, sub-cutaneous. See Reading List for more detail .

26. OTHER PRIMARY LIPID-LOWERING DRUG
CLASSES
Bile acid
sequestrants
(cholestyramine,
colestipol,
colesevelam
hydrochloride)
Fibric acid
derivatives
(gemfibrozil,
fenofibrate,
fenofibric acid
Niacin
(nicotinic acid)
MTP
Inhibitor
(lomitapide)
MTP, Microsomal triglyceride transfer protein Inhibitor; See Reading List for more detail.

27. EMERGING THERAPIES &
BREAKTHROUGHS
CETP inhibitors, Sebelipase alpha,…

28. SELECT EMERGING THERAPIES
 Over 1 year, anacetrapib (a CETP inhibitor), substantially reduced LDL-C
levels in clinical trial participants with heterozygous familial
hypercholesterolemia, and was well tolerated
 The rare disorder, lysosomal acid lipase deficiency, causes cirrhosis and severe
dyslipidemia. Sebelipase alpha therapy appears promising for some of these
patients
CETP, member of a class of drugs that inhibit cholesterylester transfer protein. See Reading List for more detail.

29. 2016 BREAKTHROUGHS IN
ATHEROSCLEROSIS RESEARCH
See Reading List for more detail.

30. PREVENTION
Primary and secondary strategies

31. PRIMARY & SECONDARY STRATEGIES
Primary
• Except for a genetic predisposition, the condition is mainly
preventable
• Therefore, a low-fat diet and reasonable amount of aerobic
exercise will impact the prevalence of hypercholesterolemia,
obesity and CV disease
Secondary
• Lowering of dietary total and saturated fat, weight loss, aerobic
exercise, and addition of plant stanols/sterols to the diet leads to
reduced LDL-C and an increase in HDL-C
• Patients should also be assessed for other CV risk factors, such as
smoking and diabetes, with the aim to manage these risk factors.
See Reading List for more detail.

32. TAKEAWAYS
Conclusions and reading lists

33. CONCLUSIONS
 Lowering cholesterol is useful as a measure to reduce the risk of heart disease
in people who are at high risk for this disease or other form of atherosclerosis
 Benefit/risk profiles of lipid-lowering medications within the context of other
medications/comorbidities should be discussed on a case-by-case basis
 Since changing cholesterol levels may not always alter risks for these
ailments, patients are wise to use a holistic approach in order to maintain
health e.g., include a balanced diet and exercise

34. READING LIST…
 US National Institutes of Health. National Heart, Lung and Blood Institute.
https://www.nhlbi.nih.gov/health/health-topics/topics/hbc. Accessed May, 2017.
 Cholesterol, Lipoproteins, and the Liver.
https://courses.washington.edu/conj/bess/cholesterol/liver.html.
 American College of Cardiology slide deck. 2013; https://www.acc.org/tools-and-practice-
support/clinical-toolkits/prevention. Accessed May, 2017.
 US Centers for Disease Control and Prevention. Division for Heart Disease and Stroke Prevention.
Cholesterol Fact Sheet. 2017;
https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_cholesterol.htm. Accessed May, 2017.
 Epocrates (An Athenahealth company) 2017;
https://online.epocrates.com/diseases/17032/Hypercholesterolemia/Risk-Factors. Accessed May,
2017.
 American Association for Clinical Chemistry. LabTestsOnline. Lipid Profile. 2017;
https://labtestsonline.org/understanding/analytes/lipid/tab/test/. Accessed May, 2017.
 Bjorkhem I, Meaney S. Arterioscler Thromb Vasc Biol. 2004;24(5):806-815.
 Brænne I, Kleinecke M, Reiz B, et al. Eur. J. Hum. Gen. 2016;24(2):191-197.
 Clayton PT. Arch Dis Child. 1998;78(2):185-189.
 Damen JAAG, Hooft L, Schuit E, et al. BMJ. 2016;353.
 Khera AV, Kathiresan S. Nat Rev Genet. 2017 (advance online publication).
 Quehenberger O, Dennis EA. NEJM. 2011;365(19):1812-1823.

35. READING LIST
 Jellinger PS, Handelsman Y, Rosenblit PD, et al. Endocr Pract. 2017;23(Suppl 2):1-87.
 Tang WH, Hazen SL. Nat Rev Cardiol. 2017;14(2):71-72.
THIS SLIDE DECK IS FOR INFORMATIONAL PURPOSES ONLY.
PLEASE CONSULT A PHYSICIAN FOR ANY MEDICAL CONDITION.