What’s new in Lipidology, Lessons from “recent guidelines“

What’s new in Lipidology, Lessons from
“recent guidelines“
Dr. Arindam Pande
MBBS (Hons), MD, DM, FESC, FSCAI, FACC (USA), FRCP (Glasg)
Consultant Interventional Cardiologist,
Medica SuperSpeciality Hospital, Kolkata
www.drarindampande.com

Year c. 1503–06,
Location:
Musée du Louvre, Paris
Artist
Leonardo da Vinci
Subject
Lisa Gherardini

* Premature death = under age 70
DALY = Disability Adjusted Life Years; NCDs = noncommunicable chronic diseases.
1. WHO. 2011. Global atlas on cardiovascular disease prevention and control. Geneva: World Health Organization in collaboration with the
World Heart Federation and the World Stroke Organization. 2. WHO. 2016. World Health Statistics 2016: Monitoring health for the SDGs.
Geneva: World Health Organization.
Global Burden of Cardiovascular Disease
Leading cause of death
in the world
• > 17.3 million deaths per year globally
• 10% of the global disease burden
(DALYs)
• Cardiovascular diseases claim
more lives than all forms of cancer
combined
Cardiovascular (CV) Disease1
Top Leading Causes of
Premature Death Globally2*
CVD
Cancer, 27%
Other NCDs, 23%
Respiratory
diseases, 8%
Diabetes, 4%

*”Diseases of the Heart” is defined by the NCHS classification used in compiling the leading causes of death. Includes acute
rheumatic fever/chronic rheumatic heart diseases (I00–I09), hypertensive heart disease (I11), hypertensive heart and renal
disease (I13), CHD (I20–I25), pulmonary heart disease and diseases of pulmonary circulation (I26–I28), heart failure (I50),
and other forms of heart disease (I29–I49, I50.1–I51). “Diseases of the heart” are not equivalent to “total cardiovascular disease,”
which the AHA prefers to use to describe the leading causes of death. Source: National Center for Health Statistics.
1. Mozaffarian D, et al. Circulation. 2015;133(4):e38-360. 2. Vanuzzo D. Intern Emerg Med. 2011;6 Suppl 1:45-51.
Despite Recent Reductions,
Deaths Due to Heart Disease Remain High1
Year
DeathsinThousands
Deaths Attributable to
Diseases of the Heart* (US, 1900-2013)
Deaths due to diseases of
the heart have declined
dramatically over the past 2
decades,
yet the number of deaths
remains high and residual
risk remains1
Residual risk is the risk for
incident CV events or the
progression of CV disease
that persists even with
current standard of care2

1. Keenan TE, et al. Curr Cardiol Rep. 2013;(9):396. 2. WHO. 2011. Global atlas on cardiovascular disease prevention and control. Geneva:
World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization. 3. Sharifi M, et al. Heart.
2016;102(13):1003-1008. 4. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78. 5. Roger VL, et al. Circulation. 2012;125:e2-e220. 6.
Stone NJ, et al. J Am Coll Cardiol. 2014;63:2889-2934. 7. Vanuzzo D. Intern Emerg Med. 2011;6 Suppl 1:45-51.
Multiple Modifiable and Non-modifiable Factors
May Contribute to Cardiovascular Risk
CV = cardiovascular; HeFH = Heterozygous Familial Hypercholesterolemia; HDL = high density lipoproteins; HoFH = Homozygous Familial
Hypercholesterolemia; LDL = low-density lipoproteins; Lp(a) = lipoprotein(a); TG = triglycerides.
Age, Race, Sex4,5
Increased
Cardiovascular
Risk
History of
CV Event6
Smoking2
Lipid Disorders1
(LDL-C, HDL-C, TG, Lp(a))
Type 2 Diabetes,
Metabolic Syndrome2
Obesity2
Genetics3
(e.g., HeFH, HoFH)
Physical Inactivity and
Diet2
Hypertension2
Residual CV risk includes risk from modifiable and non-modifiable risk factors7

Development of CVD in people with T2DM
Early endothelial dysfunction
and vascular inﬂammation
Monocyte recruitment and
foam cell formation
Development of fatty streaks
Atherosclerotic plaque formation
Occlusive thrombus formation
(myocardial infarction/stroke)
ProgressionofCVD
Time
CVD, cardiovascular disease; T2DM, type 2 diabetes mellitus.
Ryden L et al. Eur Heart J 2013;34:3035–3087.
Atherosclerosis is the major pathological
process responsible for CVD in T2DM

Exp Opin Emerg Drugs 2004;9(2):269–279, N Engl J Med 2005;352:1425–1435. JAMA 2005;294:2437; Lancet 2006;368:1155
LDL-C achieved mg/dL (mmol/L)
WOSCOPS – Pl
AFCAPS - Pl
AFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Pl
LIPID - Rx
4S - Pl
CARE - Rx
LIPID - Pl
CARE - Pl
HPS - Rx
0
5
10
15
20
25
30
40
(1.0)
60
(1.6)
80
(2.1)
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
180
(4.7)
6
Secondary Prevention
Primary Prevention
Rx - Statin therapy
Pl – Placebo
Pra – pravastatin
Atv – atorvastatin
Sim - simvastatin
200
(5.2)
PROVE-IT - Pra
PROVE-IT – Atv
TNT – Atv10
TNT – Atv80
IDEAL-Sim
IDEAL-Atv
ASCOT-PL MEGA-Rx
MEGA-Pl
JUPITER-PlJUPITER-Rosu
▐ ▐ ▐ ▐ ▐ ▐ ▐
▐▐▐▐▐▐
▐

ACC/AHA Guideline (2013)
 Four classes of patients for whom treatment of cholesterol with statins is
recommended:
1. Individuals with established ASCVD
2. Individuals aged between 40 and 75 years with an LDL-cholesterol of at
least 190
3. Individuals aged between 40 and 75 years with diabetes mellitus
4. Individuals with a predicted 10-year ASCVD event rate of 7.5% or above
Stone NJ, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in
Adults. Circulation. 2013;00:000–000

ACC/AHA Guideline (2013):
Controversies..
 The recommendations were based on findings of certain RCTs
 There is no LDL goal to treat as was considered previously
 Non statin therapies are severely de-emphasized
 The guidelines apply only to people between the ages of 40 and 75
because the authors believed there was not enough evidence from
randomized controlled trials to allow development of guidelines outside of
this age range
Raymond C, Cho L, Rocco M, Hazen SL. New cholesterol guidelines: worth the wait? Cleve
Clin J Med. 2014 Jan;81(1):11-9.

The risk calculator
http://my.americanheart.org/professional/StatementsGuidelines/Preventio
nGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

The risk calculator
 The panel deciding upon the use of statins in primary prevention using a
risk calculator despite the fact that none of the studies were so designed
 Risk calculators were not used to determine eligibility for the RCTs upon
which these guidelines were based
 These risk calculators generally over-predict ASCVD risk because of their
use of older data to predict risk (75% to 150%)
 This calculator would make approximately 30 million more Americans eligible
for statin treatment- patients at lower risk would be treated and exposed to
potential side effects of statin therapy
Ades P. A controversial step forward: a commentary on the 2013 ACC/AHA guideline on the treatment of blood
cholesterol to

2018
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/
NLA/PCNA
Guideline on the Management of Blood Cholesterol
Scott M. Grundy, MD, PhD, FAHA, Chair
Neil J. Stone, MD, FACC, FAHA, Vice Chair

Table 4. Very High-Risk* of Future ASCVD Events
Major ASCVD Events
Recent ACS (within the past 12 mo)
History of MI (other than recent ACS event listed above)
History of ischemic stroke
Symptomatic peripheral arterial disease (history of claudication with ABI <0.85, or
previous revascularization or amputation)

Table 4 continued
High-Risk Conditions
Age ≥65 y
Heterozygous familial hypercholesterolemia
History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the
major ASCVD event(s)
Diabetes mellitus
Hypertension
CKD (eGFR 15-59 mL/min/1.73 m2)
Current smoking
Persistently elevated LDL-C (LDL-C ≥100 mg/dL [≥2.6 mmol/L]) despite maximally tolerated statin
therapy and ezetimibe
History of congestive HF

1. LDL goal - 70 mg/dl
2. Non statin drugs – ezitimibe and PCSK9 inhibitors
3. Risk enhancers
4. High risk and very high risk group
5. Management of triglycerides
6. Specific population
1. Older age
2. Children
3. Adolescents
4. Women
5. CKD
6. Inflammatory disease
7. Ethnicity
8. Statin associated side effects
AHA 2013 vs AHA 2018 – what is new?
Key differences of 2013 and 2018 American College of Cardiology/American Heart Association Cholesterol Guidelines

Top 10 Take-Home Messages
2018 Cholesterol Guidelines

Top 10 Take Home Messages
1. In all individuals, emphasize a heart-healthy lifestyle
across the life course.
A healthy lifestyle reduces atherosclerotic cardiovascular disease (ASCVD) risk
at all ages. In younger individuals, healthy lifestyle can reduce development of
risk factors and is the foundation of ASCVD risk reduction.
In young adults 20 to 39 years of age, an assessment of lifetime risk facilitates
the clinician–patient risk discussion (see No. 6) and emphasizes intensive
lifestyle efforts. In all age groups, lifestyle therapy is the primary intervention
for metabolic syndrome.

Top 10
2. In patients with clinical ASCVD, reduce low-density lipoprotein
cholesterol (LDL-C) with high-intensity statin therapy or maximally
tolerated statin therapy.
The more LDL-C is reduced on statin therapy, the greater will be subsequent
risk reduction.
Use a maximally tolerated statin to lower LDL-C levels by ≥50%.

Top 10
3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L)
to consider addition of nonstatins to statin therapy.
• Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and
multiple high-risk conditions.
• In very high-risk ASCVD patients, it is reasonable to add ezetimibe to maximally tolerated statin
therapy when the LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L).
• In patients at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on maximally
tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable,
although the long-term safety (>3 years) is uncertain and cost- effectiveness is low at mid-2018
list prices.

Top 10
4. In patients with severe primary hypercholesterolemia (LDL-C level ≥ 190
mg/dL[≥4.9 mmol/L]) without calculating 10-year ASCVD risk, begin high-
intensity statin therapy without calculating 10-year ASCVD risk.
•If the LDL-C level remains ≥100 mg/dL (≥2.6 mmol/L), adding ezetimibe is reasonable
• If the LDL-C level on statin plus ezetimibe remains ≥100 mg/dL (≥2.6 mmol/L) & the
patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9
inhibitor may be considered, although the long-term safety (>3 years) is uncertain and
economic value is low at mid-2018 list prices.

Top 10
5. In patients 40 to 75 years of age with diabetes mellitus and LDL-
C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin
therapy without calculating 10-year ASCVD risk.
In patients with diabetes mellitus at higher risk, especially those
with multiple risk factors or those 50 to 75 years of age, it is
reasonable to use a high-intensity statin to reduce the LDL-C level
by ≥50%.

Top 10
6. In adults 40 to 75 years of age evaluated for primary ASCVD prevention,
have a clinician–patient risk discussion before starting statin therapy.
Risk discussion should include a review of major risk factors (e.g., cigarette
smoking, elevated blood pressure, (LDL-C), hemoglobin A1C [if indicated],
and calculated 10-year risk of ASCVD);
• the presence of risk-enhancing factors (see No. 8);
• the potential benefits of lifestyle and statin therapies;
• the potential for adverse effects and drug–drug interactions;
• the consideration of costs of statin therapy; and
• the patient preferences & values in shared decision-making.

Top 10
7. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C
levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start
a moderate-intensity statin if a discussion of treatment options favors
statin therapy.
Risk-enhancing factors favor statin therapy (see No. 8).
If risk status is uncertain, consider using coronary artery calcium (CAC) to
improve specificity (see No. 9). If statins are indicated, reduce LDL-C
levels by ≥30%, and if 10-year risk is ≥20%, reduce LDL-C levels by ≥50%.

Top 10
8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to
19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see
No. 7).
Risk-enhancing factors include
• family history of premature ASCVD;
• persistently elevated LDL-C levels ≥160 mg/dL (≥4.1 mmol/L);
• metabolic syndrome;
• chronic kidney disease;
• history of preeclampsia or premature menopause (age <40 yrs)
• chronic inflammatory disorders (e.g., rheumatoid arthritis, psoriasis,
or chronic HIV);
• high-risk ethnic groups (e.g., South Asian);
• persistent elevations of triglycerides ≥ 175 mg/dL (≥1.97
mmol/L);

Top 10
8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5%
to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin
therapy (see No. 7).
Risk-enhancing factors include
and, if measured in selected individuals
• apolipoprotein B ≥130 mg/dL
• high-sensitivity C-reactive protein ≥2.0 mg/L
• ankle-brachial index <0.9 and l
• lipoprotein (a) ≥50 mg/dL or 125 nmol/L, especially at higher
values of lipoprotein (a).
Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5-7.5% (borderline
risk)

Top 10
9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C
levels ≥70 mg/dL- 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD
risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain,
consider measuring CAC.
• If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette
smokers, those with diabetes mellitus, and those with a strong family history of premature
ASCVD.
• A CAC score of 1 to 99 favors statin therapy, especially in those ≥55 years of age.
• For any patient, if the CAC score is ≥100 Agatston units or ≥75th percentile, statin therapy is
indicated unless otherwise deferred by the outcome of clinician–patient risk discussion.

Top 10
10. Assess adherence and percentage response to LDL-C–lowering
medications and lifestyle changes with repeat lipid measurement 4 to
12 weeks after statin initiation or dose adjustment, repeated every 3 to
12 months as needed.
• Define responses to lifestyle and statin therapy by percentage
reductions in LDL-C levels compared with baseline.
• In ASCVD patients at very high-risk, triggers for adding nonstatin drug
therapy are defined by threshold LDL-C levels ≥70 mg/dL (≥1.8 mmol/L)
on maximal statin therapy (see No. 3).

What about triglyceride ??
2018 Cholesterol Guideline

Hypertriglyceridemia
Recommendations for Hypertriglyceridemia
COR LOE Recommendations
I B-NR
In adults 20 years of age or older with moderate hypertriglyceridemia (fasting or
nonfasting triglycerides 175 to 499 mg/dL [1.9 to 5.6 mmol/L]), clinicians should address
and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes
mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism),
and medications that increase triglycerides.
IIa B-R
In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and ASCVD
risk of 7.5% or higher, it is reasonable to reevaluate ASCVD risk after lifestyle and
secondary factors are addressed and to consider a persistently elevated triglyceride level
as a factor favoring initiation or intensification of statin therapy (see Section 4.4.2.).

Hypertriglyceridemia
Recommendations for Hypertriglyceridemia
IIa B-R
In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides ≥500
mg/dL [≥5.6 mmol/L]) and ASCVD risk of 7.5% or higher, it is reasonable to address
reversible causes of high triglyceride and to initiate statin therapy.
IIa B-NR
In adults with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.7
mmol/L]), and especially fasting triglycerides ≥1000 mg/dL (11.3 mmol/L)), it is
reasonable to identify and address other causes of hypertriglyceridemia), and if
triglycerides are persistently elevated or increasing, to further reduce triglycerides by
implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol,
consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis,
fibrate therapy.

Elderly, should they get any
treatment for cholesterol ??

Primary Prevention in Other Age Groups (Older Adults)
Recommendations for Older Adults
IIb B-R
In adults 75 years of age or older with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8
mmol/L), initiating a moderate-intensity statin may be reasonable.
IIb B-R
In adults 75 years of age or older, it may be reasonable to stop statin therapy when
functional decline (physical or cognitive), multimorbidity, frailty, or reduced life-
expectancy limits the potential benefits of statin therapy.
IIb B-R
In adults 76 to 80 years of age with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8
mmol/L), it may be reasonable to measure CAC to reclassify those with a CAC score
of zero to avoid statin therapy.

What about children and
adolescents ??

Primary Prevention in Other Age Groups (Children and Adolescents)
Recommendations for Children and Adolescents
IIa B-R
In children and adolescents 10 years of age or older with an LDL-C level persistently 190
mg/dL (≥4.9 mmol/L) or higher or 160 mg/dL (4.1 mmol/L) or higher with a clinical
presentation consistent with FH (see Section 4.2.) and who do not respond adequately
with 3 to 6 months of lifestyle therapy, it is reasonable to initiate statin therapy.
IIa B-NR
In children and adolescents with a family history of either early CVD* or significant
hypercholesterolemia,† it is reasonable to measure a fasting or nonfasting lipoprotein
profile as early as age 2 years to detect FH or rare forms of hypercholesterolemia.

Women of child bearing age
group, should they get statin ??

Issues Specific to Women
Recommendations for Issues Specific to Women
I B-NR
Clinicians should consider conditions specific to women, such as premature menopause (age
<40 years) and history of pregnancy-associated disorders (hypertension, preeclampsia,
gestational diabetes mellitus, small-for-gestational-age infants, preterm deliveries), when
discussing lifestyle intervention and the potential for benefit of statin therapy.
I C-LD
Women of childbearing age who are treated with statin therapy and are sexually active
should be counseled to use a reliable form of contraception.
I C-LD
Women of childbearing age with hypercholesterolemia who plan to become pregnant should
stop the statin 1 to 2 months before pregnancy is attempted, or if they become pregnant
while on a statin, should have the statin stopped as soon as the pregnancy is discovered.

What about CKD patients ??

Adults With Chronic Kidney Disease
Recommendations for Adults With CKD
IIa B-R
In adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL (1.7 to 4.8 mmol/L) who
are at 10-year ASCVD risk of 7.5% or higher, CKD not treated with dialysis or kidney
transplantation is a risk-enhancing factor and initiation of a moderate-intensity
statin or moderate-intensity statins combined with ezetimibe can be useful.
IIb C-LD
In adults with advanced kidney disease that requires dialysis treatment who are
currently on LDL-lowering therapy with a statin, it may be reasonable to continue
the statin.
III: No
Benefit
B-R
In adults with advanced kidney disease who require dialysis treatment, initiation of
a statin is not recommended.

Statin Safety and Statin-Associated Side Effects ??

Statin Safety and Statin-Associated Side Effects
Recommendations for Statin Safety and Statin-Associated Side Effects
I B-R
In patients at increased ASCVD risk with chronic, stable liver disease (including
non-alcoholic fatty liver disease) when appropriately indicated, it is reasonable
to use statins after obtaining baseline measurements and determining a
schedule of monitoring and safety checks.
IIa B-R
In patients at increased ASCVD risk with severe statin-associated muscle
symptoms or recurrent statin-associated muscle symptoms despite
appropriate statin rechallenge, it is reasonable to use RCT proven nonstatin
therapy that is likely to provide net clinical benefit.

Statin Safety and Statin-Associated Side Effects
Recommendations for Statin Safety and Statin-Associated Side Effects
III: No
Benefit
B-R
Coenzyme Q10 is not recommended for routine use in patients treated with
statins or for the treatment of SAMS.
III: No
Benefit
C-LD
In patients treated with statins, routine measurements of creatine kinase and
transaminase levels are not useful.

How low should we go??

Consistent CV risk reduction independent of baseline LDL-C level
CI, confidence interval; CTT, Cholesterol Treatment Trialists; CV, cardiovascular; LDL-C,
low-density lipoprotein cholesterol; RR, relative risk.
CTT Collaboration. Lancet 2010;376:1670–81.
CTT meta-analysis, N=169,138 in 26 trials
Baseline LDL-C
Events (% per annum)
Statin/Higher Control/Lower RR (CI) per 39 mg/dL reduction in LDL-C
All trials combined
<77 mg/dL 910 (4.1%) 1012 (4.6%) 0.78 (0.61, 0.99)
77 to <97 mg/dL 1528 (3.6%) 1729 (4.2%) 0.77 (0.67, 0.89)
97 to <116 mg/dL 1866 (3.3%) 2225 (4.0%) 0.77 (0.70, 0.85)
116 to <135 mg/dL 2007 (3.2%) 2454 (4.0%) 0.76 (0.70, 0.82)
135 mg/dL 4508 (3.0%) 5736 (3.9%) 0.80 (0.76, 0.83)
Total 10,973 (3.2%) 13,350 (4.0%) 0.78 (0.76, 0.80)
Statin/higher dose better
0.45 0.75 1.0 1.3
Control/lower dose better

JUPITER trial: consistent risk reduction
also at low baseline LDL-C
*Overall in the trial, rosuvastatin reduced LDL-C by 50%, suggesting achieved LDL-C of ≤30 mg/dL in this
subgroup. CI, confidence interval; LDL-C, low-density lipoprotein cholesterol.
Hsia J et al. J Am Coll Cardiol 2011;57:1666–75.
Baseline LDL-C N
HR (95% CI) for
Primary Endpoint
≤130 mg/dL 17,802
≤120 mg/dL 13,972
≤110 mg/dL 9784
≤100 mg/dL 6269
≤90 mg/dL 3687
≤80 mg/dL 2033
≤70 mg/dL 1022
≤60 mg/dL* 511
0.20 0.50 1.00 2.00
Rosuvastatin Superior Rosuvastatin Inferior

The lower the LDL-C achieved, the lower the risk of CV
events
aRCT in patients with stable coronary disease. Major CV Events = death from CHD, nonfatal non-procedure-related MI, resuscitation after cardiac
arrest, or fatal or nonfatal stroke. bRCT of patients with LDL-C <130 mg/dL, high-sensitivity C-reactive protein ≥2.0 mg/L, and no history of CVD
or diabetes mellitus. Major CV events = CV death, MI, stroke, arterial revascularization, or hospitalized UA. ‡post randomization LDL-C. cRCT in
patients with stabilized ACS. Primary composite endpoint of death, MI, stroke, revascularization, and UA requiring hospitalization.
ACS, acute coronary syndrome; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; LDL-C, low-density lipoprotein
cholesterol; MI, myocardial infarction; RCT, randomized controlled trial; UA, unstable angina.
1. LaRosa JC, et al. J Am Coll Cardiol 2007;100:747–52.
2. Hsia J, et al. J Am Coll Cardiol 2011;57:1666–75.
3. Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411–6.
TNT1,a
Rate of major CV events
JUPITER2,b
Time to occurrence of major CV events
PROVE-IT3,c
Hazard ratio of primary endpoint
P for trend <0.0001
0 1 2 3 4
Follow-up (Years)
0.00
0.02
0.04
0.06
0.08
CumulativeIncidence
Placebo
LDL-C >50 rosuvastatin
LDL-C <50 rosuvastatin
*P value for trend across LDL-C
≤40
>40–60
>60–80
>80–100
0.80 (0.59, 1.07)
0.67 (0.50, 0.92)
0.61 (0.40, 0.91)
Lower Better Higher Better
Referent
0 1 2
AchievedLDL-C(mg/dL)
LDL-C (mg/dL)
0
<64
2
4
6
8
10
12
14
64–<77
77–<90
90–<106
≥106
P<0.0001*
%ofPatientsWithMajorCVEvents

Clinical Studies – Evolocumab achieving unprecedented
low levels

Safety issues with such low
level of LDL ???

Cells Acquire Cholesterol from Various Sources
• Cholesterol for cellular physiologic functions can be from intra and/or
extracellular pathways
HDLR = high-density lipoprotein cholesterol receptor; LDL-C = low-density lipoprotein cholesterol; LDL-R = LDL receptor;
LDLRP = LDLR protein; SR-B1 = scavenger receptor class B type 1.
Mc Auley MT, et al. BMC Syst Biol. 2012;6:130. Xie C, et al. J Lipid Res. 2006;47:953-963. Hu J, et al. Nutr Metab (Lond).
2010;7:47. Orth M, Bellosta S. Cholesterol. 2012;2012:292598. Dietschy JM, Turley SD. J Lipid Res. 2004;45:1375-1397.
Figure adapted from Dietschy 2004.
Intracellular concentrations of
cholesterol are tightly regulated
and cells are not dependent on
circulating plasma LDL-C for
cholesterol synthesis.3

The Central Nervous System Synthesizes
Cholesterol De Novo
• The central nervous system
synthesizes cholesterol de
novo1,2
• The blood–brain barrier
prevents the uptake of
systemic lipoprotein
cholesterol1,2
• This segregation ensures that
cholesterol metabolism within
the brain is isolated from
changes in the circulating lipid
levels2
Cholesterol
Brain
SRE-regulated
gene products
Transcription
Acetyl-CoA
Cholesterol
Blood–brain
barrier Blood
Regulation of
neuronal function
Small GTP-binding
proteins
Isoprenoids
Prenylation
Cholesterol
24-hydroxylase
24S-hydroxycholesterol
24S-hydroxycholesterol
SRE
1. Björkhem I, Meaney S. Arterioscler Thromb Vasc Biol. 2004;24:806-815. 2. Katsuno M, et al. Nat Med. 2009;15:253-254.
Figure adapted from Katsuno M et al. 2009.

Safety Events
0
5
10
Neurocog
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
AST/ALT↑ CK↑
LDL-C (mgdL) at 4wks
Non-CV death Hem stroke
Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017
Adj P-values for trend >0.10
for each comparison
% pts
<20
20-49
50-69
70-99
>100
No safety concerns even with LDL <20mg/dl

A Quarter of a Century of Treating LDL-C
LDL‐C(mg/dL)
200
180
160
140
120
100
80
60
40
20
0
1994 1996‐2002 2004‐2005 2015 2017
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School

Summary
• Partial return to identifying lipid lowering goals: For secondary prevention LDL-C ≤
70 mg%. In primary hypercholesterolemia ≤ 100mg%.
• Lowering the use of high-dose statins blindly in majority of patients, emphasize
clinician –patient “risk discussion” in majority of patients requiring primary
prevention before initialing statin therapy.
• For the first time it recommends the use of non statin drugs in those patients
where secondary prevention (or even primary prevention s/a primary
hypercholesterolemia) goals cannot be met.
• For the first time (in perhaps history of Western medicine) the guideline brings
forth the issue of cost, thus preferring ezetimibe (good cost value) over PCSK9
Inhibitors (low cost value).

If we can eradicate Polio………. why not
LDL?

What’s new in Lipidology, Lessons from “recent guidelines“

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