Screening and Treatment of Childhood Dyslipidemia

Magdy El-Masry.
Prof. of Cardiology.
Tanta University.

Should we screen for and treat
childhood dyslipidemia?
Yes , we should screen and treat
childhood dyslipidemia
Dyslipidemia in Children

The Rationale for ASCVD Prevention by Primordial and Primary Strategies
The presence of the high cholesterol in childhood
predicted clinical CVD in adult subjects at 30-50 years of age

Primordial, Primary, and Secondary Prevention of Cardiovascular Disease.
C.A. German et al. Defining preventive cardiology:
A clinical practice statement from the American Society for Preventive Cardiology.
American Journal of Preventive Cardiology 12 (2022) 100432

PEDIATRICS Volume 128, Supplement 5, December 2011
A synopsis of the 2011 pediatric guidelines

→ Selective Screening :
Non-FLP or FLP
→ Selective Screening :
Avg. of 2 FLPs 2w-2m apart

Selective Screening
2-8 years & 12-16 years
WITH:

Interpreting the results of lipid screening in Children
Pediatrics 2011;128 (Suppl 5): S213-S256)

Urgent referrals are recommended for
LDL greater than 190 and
triglycerides greater than 500.

Secondary causes rule
Many diseases have known
secondary causes and one
has to rule them out first
Dyslipidemia
Primary
(Genetic)
Monogenic
Polygenic
Secondary
(Acquired)
4 D’s
Diet
Drugs
Disease
Disorders of
metabolism

Approaches To Dyslipidemia Treatment
in Children and Adolescents
Therapeutic Lifestyle Changes(TLC)
Drug treatment

LDL-C ≥ 130–189 mg/dL with no family history or risk factors/Conditions → Lifestyle changes &Reassess every 6–12 mo

Treatment algorithm of childhood dyslipidemia
Fiorentino, R.; Chiarelli, F. Treatment of Dyslipidaemia in Children. Biomedicines 2021, 9, 1078

Trials in Children
Currently Approval Status
HoFH or severe HeFH from
12 years of age
FH from 12 years of age
Evolocumab
Severe HeFH from 8 years of
age
FH in adults
Alirocumab
Will be tested in paediatric
HeFH in the ORION-16 study.
Primary hypercholesterolemia or mixed
dyslipidaemia in adults
Inclisiran
Novel lipid-lowering drugs
Fiorentino, R.; Chiarelli, F. Treatment of Dyslipidaemia in Children. Biomedicines 2021, 9, 1078

Elevation in TGs
TGs ≥500 mg/dL TG >200–499 mg/dL TG ≥100–200 mg/dL (<10 y) or
≥130–200 mg/dL (>10 y)
TG<100 mg/dL (<10 y) or
<130 mg/dL (>10 y)
*Lifestyle changes
*Counsel on risk of
pancreatitis
*Referral to lipid
specialist
*Fish oil, fibrate/other
medication
*Lifestyle changes 6–12 mo
*Consider omega-3 fish oil
therapy
*Consider referral to lipid
specialist, especially if LDL-C
target achieved
*Lifestyle changes 6–12 mo
*Increase dietary fish content
*Fasting lipid panel every 6 mo
*Continue lifestyle changes
*Fasting lipid panel annually
Criteria for Pharmacotherapy of Dyslipidemia
Pediatrics 2011;128(suppl 5):S213–S256.
Lifestyle changes: diet and physical activity.
Diet: CHILD-1 diet for 3–6 months. If no improvement in lipids, then CHILD-2 Diet.
Physical activity: vigorous activity 60 min/day and screen time (television,texting, computer, etc) limited to
less than 2 hours per day.
N.B. # Fibrates are only indicated in children with severe hypertriglyceridemia (> 500 mg/dl) or at risk of pancreatitis,
who are unresponsive to dietary measures # Icosapent Ethyl: No safety and efficacy studies in pediatrics (<18 years).

Schematic illustration of double filtration plasmapheresis
Christina Taylan1 & Lutz T. Weber
An update on lipid apheresis for familial hypercholesterolemia
Pediatric Nephrology (2023) 38:371–382

Challenges in Dyslipidemia
Management in Pregnant
Women
Should
You
Worry ?
To Treat
or
Not To Treat?
Dyslipidemia in Pregnancy

Dyslipidemia and lipid lowering-therapy {LLT}
in women through the course of life
Lipid-Lowering Therapy in Women of Childbearing Age
There are inherent challenges in the treatment of dyslipidemias during
pregnancy and the postpartum period given the lack of adequate data in
this population and the contraindication of traditional therapeutic agents.

The main maternal metabolic adaptations occurring in pregnancy
Essential for foetal growth and development

Gurleen Kaur, Martha Gulati,Considerations for treatment of lipid disorders during pregnancy and breast feeding, Progress in Cardiovascular Diseases,2022
During pregnancy, all plasma lipids including triglycerides, total cholesterol, and LDL-C rise.
The greatest increase is typically seen in triglycerides, which can increase as much as double or triple prepregnancy levels .
Overall, these physiologic changes are thought to be nonatherogenic as they quickly normalize after delivery .

 Neither triglycerides nor total cholesterol exceeds 250 mg/dL
in normal pregnancies.
 The 2 most common conditions in which lipids should
be addressed during pregnancy are severe hypertriglyceridemia
and familial hypercholesterolemia

 Bile Acid Sequestrants
 Omega-3 FA(Icosapent Ethyl)
Fibrates / Niacin / Ezetimibe
 Statins
Currently, the option of LLT is strictly limited
in pregnant and lactating patients.
Placental transfer of drugs administered to the mother

Drug safety profile
Bile acid sequestrants/resins(Colesevelam) : FDA-approved for treatment of FH
Hormonal contraceptives/therapy :Use of an oral contraceptive containing ethinyl estradiol/norethindrone in patients on
colesevelam was associated with decreased bioavailability of the oral contraceptive .
Oral contraceptives containing ethinyl estradiol/norethindrone should be taken at least 4 h prior to colesevelam.
Pregnancy : Class B, only approved treatment of hyperlipidemia during pregnancy.Not systemically absorbed.
Breastfeeding :
Safe for breastfeeding.
Balla, S., Ekpo, E.P., Wilemon, K.A. et al. Women Living with Familial Hypercholesterolemia: Challenges and Considerations Surrounding Their Care. Curr Atheroscler Rep 22, 60 (2020).
BAS bind to negatively charged bile acids
in the intestine and impede their
absorption . This process depletes the bile
acid pool and disrupts the enterohepatic
circulation of bile acids, thus, increasing
the synthesis of bile acids. Cholesterol is,
therefore, diverted to bile acid synthesis,
thereby reducing circulating LDL-C levels.

Drug safety profile
Statins : FDA-approved for treatment of FH
Hormonal contraceptives/therapy :Limited data on interactions.
One study: induced hormone levels nor efficacy of statin effected
Pregnancy : Class X, limited studies : lipophilic statins(simvastatin/atorvastatin )known to cause holoprosencephaly (HPE)
and the VACTERL.
No known malformations with exposure to hydrophilic statin(rosuvastatin).
Breastfeeding :
Rosuvastatin was detected in the milk of a lactating woman who was started on rosuvastatin 40 mg/day.
Atorvastatin levels in the plasma and the liver of nursing rats were 50% and 40%, respectively, of that in the maternal rat’s
milk .
FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy;
still advises most pregnant patients should stop taking statins. July 20, 2021
For a select few women at high risk for cardiovascular events, statins may provide more benefit than risk, even during pregnancy.
Most women do not have this high risk, however, and should still avoid statins during pregnancy
The labeling of statins has been revised to remove the C/I for use during pregnancy.

Drug safety profile
Ezetimibe: FDA-approved for treatment of FH
Hormonal contraceptives/therapy : No documented interactions
Pregnancy : Class C
Crosses the placenta in animal studies
Breastfeeding :
Maternal breast milk concentration was up to half the level of measured serum concentration.
Ezetimibe might be considered if benefits outweigh the potential risk.

Drug safety profile
Icosapent ethyl(EPA): FDA-approved as an adjunct in adults with elevated triglyceride levels
Hormonal contraceptives/therapy :No documented interactions
Pregnancy : Category C
Breastfeeding :
Studies with omega-3 acid ethyl esters (EPA+DHA) demonstrated excretion in human milk.
Effect of this excretion on the infant is unknown and caution should be exercised when drug is administered to nursing
mothers .
According to safety labels by the FDA, the prescription of omega-3 polyunsaturated
fatty acids should be reserved for patients in whom the benefit from drug therapy
justifies the potential risk to fetus, after a thorough discussion of these risks and
benefits with the patient.
 Fenofibrate might be considered if benefits outweigh the potential risk.
Fibric-acid derivatives could, therefore, be considered after the first trimester if TG levels
remain >500 mg/dL despite the use of omega3 fatty acids and dietary restrictions, and other
treatments options, such as plasmapheresis, are not available.

Drug safety profile
PCSK-9 inhibitors (Evolocumab/ Alirocumab) : FDA-approved for treatment of FH
Pregnancy : No available data on use in pregnant women.
Unlikely to cross placenta during the first trimester.
Likely to cross placenta in increasing amounts
Breastfeeding :
No data on clinical use during breastfeeding.
Benefit should outweigh risk

Safety comparisons between statins and PCSK9 inhibitors in special populations.
Words in red color outline the future research directions of PCSK9 inhibitors as statin alternative therapy. PCSK9, proprotein convertase subtilisin/kexin type
9; AE, adverse event; eGFR, estimated glomerular filtration rate; RCT, randomized controlled trial. Rev. Cardiovasc. Med. 2022, 23(11), 380

Overview of the safety of PCSK9 inhibitors as statin alternative therapy in statin-limited conditions.
SAMS, statinassociated muscle symptoms; AKI, acute kidney injury; HS, hemorrhagic stroke; HIV, human immunodeficiency virus; NODM, new-onset diabetes mellitus; HCV, hepatitis C
virus; DILI, druginduced liver injury.
• Warrant further analyses to find the beneficiaries of PCSK9 inhibitors regarding the mild degree of statininduced AEs or controversial relationship with statins.
Rev. Cardiovasc. Med. 2022, 23(11), 380

Drug safety profile
Inclisiran: FDA-approved for treatment of FH
Pregnancy : ------
Breastfeeding :
Limited data
We need to wait for the data with new drugs, including PCSK9 inhibitors and especially inclisiran,
which (still hypothetically) might be a very interesting option as it may be used just before the
pregnancy and immediately after with the duration of about 9 months between injections.

Challenges in Conducting Clinical Research Studies in
Pregnant Women
Design and Ethical Difficulties
Due to the lack of evidence-based studies →The
decisions on lipid-lowering therapy in pregnant
patients should be individualized.

Treatment considerations for
dyslipidemias in pregnancy.
Curr Treat Options Cardio Med
(2021) 23: 50
?
First-line: omega-3 fatty acids
and bile sequestrants.
Contraindicated: Statins, niacin,
fibrates, and ezetimibe should all
be discontinued at least 4 weeks
prior to discontinuation of
contraception.
Curr Atheroscler Rep. 2022; 24(7): 493–507.

Dyslipidemia in the Elderly :
To Screen or Not to Screen?
To Treat or Not to Treat?

Aging is associated with an increasing burden of morbidity, especially for CVDs.
The upper figure shows the correlation between age and CV risk, which is explained by an increase in
the number of pathologies such as diabetes and dyslipidemia.
Underneath, the same events are explained from a molecular point of view. Int. J. Mol. Sci. 2022, 23(24), 16033;
from clinical to molecular viewpoint

Aging itself is the strongest
risk factor for nonfatal and fatal ASCVD events
Elderly population = High CV risk

 Many patients are not as worried about dying as
they are about having a potential stroke or an MI
 Do not deny people the right to stay healthy
Taking Action Against Ageism*
*Ageism, also spelled agism , is discrimination against individuals or groups on the basis of their age.

Cardiovascular disease in the elderly: proceedings of the European Society of Cardiology
—Cardiovascular Round Table
European Journal of Preventive Cardiology (2022) 29, 1412–1424

Elderly population should be screened for
 Main CV risk factors :
T2D , HTN , Smoking , Dyslipidemia & Obesity
 Comorbidities : CKD
 Geriatric conditions: Functional Impairment
Screening tool to identify functional impairment :
WHO Integrated Care for Older People (ICOPE)
 Six function assessments: cognitive decline, limited mobility, malnutrition,
visual impairment, hearing loss, and depressive symptoms.
 Dyslipidemia but not hypertension, diabetes is linked to geriatric functional
impairment in community-dwelling elderly.
Vascular Health and Risk Management 2021:17 389–394

Lipid-lowering Drug Therapy In The Elderly
How old is too old?
Ageism
‘you are too old for that’

Three steps of treating
dyslipidaemia
Int. J. Mol. ci. 2022, 23(16), 9326
Increasing heterogeneity
in biological age
with increasing chronological
age.
•Functional Impairment
•Life Expectancy
•Polypharmacy
Three relevant geriatric
conditions may
influence therapeutic
decision making

What the latest lipid guidelines
say about dyslipidemia in the elderly ?
2018
AHA/ACC
2019
ESC/EAS
2021
ESC
2022
USPSTF

With CVD Without CVD
70 –75 years: treat in the same way as
younger adults.
>75 years: it is reasonable to initiate
moderate/high intensity statins.
 Weigh potential CV risk reduction against
adverse effects, drug–drug interactions,
frailty and patient preferences before
initiating therapy.
Continue high-intensity statins if well-
tolerated
70 –75 years: treat in the same way as
younger adults.
>75 years: clinical assessment, risk
discussion.
 It may be reasonable to stop statins when
functional decline, multimorbidity, frailty or
reduced life-expectancy limits the potential
benefits of statins
Guideline recommendations : AHA/ACC 2018

2021 ESC cardiovascular prevention guidelines : What is new?
 Age-specific risk thresholds in apparently healthy people
 New SCORE for CV risk
classification
(SCORE2 and SCORE2-OP )
SCORE2 :Estimates an individual’s 10-year risk of fatal and non-
fatal CVD events (myocardial infarction, stroke) in apparently
healthy people aged 40–69 years with risk factors
SCORE2-OP : apparently healthy people aged ≥70 years
NB! The SCORE2 charts do not apply to persons with documented
CVD or other high-risk conditions such as DM, FH, or other genetic
or rare lipid or BP disorders, CKD, and in pregnant women.

Treatment of CV
Risk Factors
*Treatment of CV RFs is recommended in apparently healthy people at
very high CV risk (SCORE2 ≥ 7.5% for age under 50 years; SCORE2 ≥ 10%
for age 50-69; years ; SCORE2-OP ≥ 15% for age ≥ 70 years)
*
#
#
SCORE2-OP
SCORE2

• USPSTF Releases Updated Statin Guidelines For Primary Prevention of CVD
• Latest statins guidance keeps more conservative approach to preventing first stroke or heart attack
{Guidelines maintain a relatively higher risk threshold for statin initiation}
The USPSTF recommends that adults without a history of CVD (i.e., symptomatic CAD or ischemic stroke) use a low- to moderate-dose
statin for the prevention of CVD events and mortality when all of the following criteria are met: (1) they are aged 40 to 75 years; (2)
they have 1 or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking); and (3) they have a calculated 10-year
risk of a cardiovascular event of 10% or greater (B recommendation.)

Population Recommendation Grade
1-Adults aged 40 to 75 years
2-who have 1 or more
cardiovascular risk factors
3-and an estimated 10-year CVD risk
of 10% or greater
The USPSTF recommends that clinicians prescribe a statin
for the primary prevention of CVD for adults aged 40 to 75 years
who have 1 or more CVD risk factors (i.e. dyslipidemia, diabetes,
hypertension, or smoking) and an estimated 10-year risk of a
cardiovascular event of 10% or greater.
B
1-Adults aged 40 to 75 years
2-who have 1 or more
cardiovascular risk factors
3-and an estimated 10-year CVD risk
of 7.5% to less than 10%
The USPSTF recommends that clinicians selectively offer a statin
for the primary prevention of CVD for adults aged 40 to 75 years
who have 1 or more CVD risk factors (i.e dyslipidemia, diabetes,
hypertension, or smoking) and an estimated 10-year risk of a
cardiovascular event of 7.5% to less than 10%.
The likelihood of benefit is smaller in this group
than in persons with a 10-year risk of 10% or greater.
C
Adults 76 years or older The USPSTF concludes that the current evidence is insufficient to
assess the balance of benefits and harms of initiating a statin for
the primary prevention of CVD events and mortality in adults 76
years or older.
I
USPSTF Recommendation Summary
Statin Use for the 1° Prevention of CVD in Adults
The U.S. Preventive Services Task Force (USPSTF) assigns one of five letter

Consider the illustration in Fig. showing two patients with identical CV risk profiles but different clinical trajectories
Both patients A and B are 65-year-old White men with a 10-year ASCVD risk of 8.5% per Pooled Cohort Equation (PCE). Drugs & Aging (2019) 36:687–699
Patient A does not initiate statin therapy, as recommended per the USPSTF, while patient B does initiate statin therapy, as recommended per the ACC/AHA
Patient A goes on to experience a cardiac event 3 years later, starts a statin for secondary prevention, and his CV risk continues to increase each year.
Patient B, with his statin having reduced his ASCVD risk, does not experience a cardiac event.
Patient B’s ASCVD risk continues to increase with age, but not to the degree of patient A, who experienced a cardiac event.
Yet at age 75 years, per the ACC/AHA guidelines, patient B may be considered for statin discontinuation.
Due to age alone, patient B likely meets the risk threshold for statin initiation, but evidence of benefit and accurate CV risk estimation for someone his age is unclear.
USPSTF
recommendation
ACC/AHA
recommendation

Coronary artery calcium in primary prevention
Coronary artery calcium can be a useful adjunct for
identifying statin eligibility in primary prevention of
ASCVD.
Coronary artery calcium (CAC) categories for
considerations for statin therapy.
↑RISK

Age groups Additional considerations Recommendations
30–39 years Long-standing diabetes mellitus (type
1 diabetes, >20 years; type 2 diabetes,
>10 years) and risk factors or
microangiopathy
CAC scoring may be reasonable to
aid in ASCVD risk stratification and
statin treatment shared decision
making.
40–75 years LDL-C level: 70–189 mg/dL Moderate or high intensity statin is
indicated, regardless of CAC score
When decision to initiate statin
therapy has been made
Choose a high intensity statin when
CAC score >100
>75 years When decision to employ a statin for
primary prevention is uncertain
CAC scoring is reasonable to aid in
statin treatment shared decision
making
Coronary calcium scoring recommendations by the National Lipid Association
[J Clin Lipidol. 2021 Jan-Feb;15(1):33–60]

CACS-based algorithm for statin management in asymptomatic patients with various 10-year risk categories for ASCVD.
*Risk-enhancing factors include the following: family history of premature ASCVD; persistently elevated LDL-C levels (=4.1 mmol L1[160 mg
dL1]); metabolic syndrome; chronic kidney disease; history of preeclampsia or premature menopause; chronic inflammatory disorders (e.g.
rheumatoid arthritis, psoriasis or chronic HIV); high-risk race/ethnicity (e.g. South Asian); persistently elevated triglycerides (=2.0 mmol L1[175
mg dL1]); apolipoprotein B=1.3 g L1(130 mg dL1); high-sensitivity C-reactive protein=2.0 mg L1; ankle–brachial index<0.9; lipoprotein(a)>125
nmol L1(50 mg dL1). Journal of Internal Medicine, 2021, 289; 309–324
Coronary Artery
Calcification Score
“CACS”
in primary
prevention
10-year risk categories
for ASCVD Risk { % }

Management of Dyslipidemia in the Elderly :
Top 3 Take Home Points
Absolute risk increases with age :
The CV event rates in elderly subjects are proportionately higher than for younger subjects in primary
and secondary prevention studies
Secondary prevention of events :
The effectiveness of lipid-lowering treatments—and in particular statins—is now certified in the
secondary prevention of events even after the age of 75 and beyond.
Primary prevention :
The opportunity for treatment with statins in primary prevention after the age of 75 continues to
represent an area of uncertainty due to the scarcity of data derived from prospective randomized studies.
Age Matters
but it should not be Used to Discriminate Against the Elderly
• What is the real risk for the patient ?
“Elderly population = High CV risk”
• How much statin will the patient’s body tolerate ?

Research questions in primary prevention with statins among
older people according to the STAREE trial & PREVENTABLE trial
Together, STAREE and PREVENTABLE are anticipated to fill in the knowledge gaps regarding
the benefits and risks of statin treatment in oldest patients in primary prevention;
the outcomes of STAREE shall be available in 2023, and of PREVENTABLE in 2027.
Can statins improve healthy life
expectancy?
Can statins prevent cognitive decline
(dementia)?
Can statins prevent the first heart attack
or stroke in older adults?
Comparison of adverse reactions
between statin and placebo

Screening and Treatment of Childhood Dyslipidemia

Screening and Treatment of Childhood Dyslipidemia

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