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A. Manavalan
age 55in male or age 65in female first-degree relatives), and
personal history of CVD or noncoronary atherosclerosis
(e.g., abdominal aortic aneurysm, peripheral artery disease,
carotid artery stenosis, etc.).
USPSTF recommends screening for lipid disorders every
5years and with shorter intervals for patients with lipid values that are close to warranting therapy.
Testing Lipid Levels: Fasting vs. Non-fasting
Current guidelines recommend that the lipid panel should be
tested while fasting, i.e., 8–12h of complete diet restriction, in
order to ensure the accuracy and prevent effects of meals on
lipid parameters [5]. In most clinical laboratories, the LDL-c
level is calculated by the Friedewald formula (LDL-c=total
cholesterol − HDL-c− [triglycerides/5]) using fasting samples. The assumption is that the VLDL-c level can be estimated by the level of triglycerides, which, however, is
impacted by the non-fasting state. The calculated LDL-c level
might be inaccurate in individuals with high triglycerides or
low LDL-c levels [6].
However, a fasting test may be inconvenient in clinical
practice and might delay clinical evaluation. Comparisons
between fasting and non-fasting studies have shown that
other than triglyceride levels which are impacted by nonfasting status, other lipid parameters such as total cholesterol
and HDL-c vary little in the general population [7]. Also,
non-fasting LDL-c (calculated) has a similar prognostic value
as fasting LDL-c [8]. Therefore, acquiring a non-fasting lipid
panel test has been suggested for screening.
Assessing Risk forASCVD
The 2019 ACC/AHA guidelines recommend calculating
10-year ASCVD risk and lifetime risk for individuals between
the ages of 40 and 79. This can be performed using the
>20%
“High Risk”
(Class I)
199
Primary Prevention:
Assess ASCVD Risk in Each Age Group
Emphasize Adherence to Healthy Lifestyle
Age 0-19 y
Lifestyle to prevent or reduce
ASCVD risk
Diagnosis of Familial
Hypercholesterolemia→ statin
ASCVD Risk Enhancers:
• Farnily history of premature ASCVD
• Persistently elevated LDL-C >160 mg/
dL (>4.1 mmol/L)
• Chronic kidney disease
• Metabolic syndrome
• Conditions specific to wornen (e.g.,
preeclampsia, premature menopause)
• Inflammatory diseases (especially
rheumatoid arthritis, psoriasis, HIV)
• Ethnicity (e.g., South Asian ancestry)
Lipid/Biomarkers:
• Persistently elevated triglycerides
(
≥175 mg/dL, (≥2.0 mmol/L))
In selected individuals if measured:
• hs-CRP >2.0 mg/L
• Lp(a) levels >50 mg/dL or >125 nmol/L
• apoB >130 mg/dL
• Ankle-brachial index (ABI) <0.9
Age 20-39 y
Estimate lifetime risk
to encourage lifestyleisk to reduce
ASCVD risk
Consider statin if family history
premature ASCVD and LDL-C
>160 mg/dL (>4.1 mmol/L)
<5%
“Low Risk”
Risk discussion:
Emphasize lifestyle
to reduce risk
factors
(Class I)
Chapter 9. Lipids
LDL-C >190 mg/dL (>4.9 mmol/L)
No risk assessment; High-intensity statin
(Class I)
Diabetes mellitus and age 40-75 y
Moderate-intensity statin
(Class I)
Age 40-75 y and
LDL-C >70-<190 mg/dL
(>1.8-<4.9 mmol/L)
without diabetes mellitus
10-year ASCVD risk percent
begins risk discussion
5% - <7.5%
“Borderline Risk”
Risk discussion:
If risk enhancers present
then risk discussion
regarding rnoderate-
intensity statin therapy
(Class llb)
CAC = zero (lowers risk; consider no statin, unless diabetes, family history
intensity statin to reduce
If risk decision is uncertain:
Consider measuring CAC in selected adults:
of premature CHD, or cigarette smoking are present)
CAC = 1-99 favors statin (especially after age 55)
CAC = 100+ and/or
Diabetes mellitus and age 40-75 y
Risk assessment to consider high-intensity statin
>7.5% - <20%
“Intermediate Risk”
Risk discussion:
If risk estimate + risk
enhancers favor statin,
initiate moderate-
LDL-C by 30% - 49%
(Class I)
>75th percentile, initiate statin therapy
(Class IIa)
Age >75 y
Clinical assessment, Risk discussion
Risk discussion:
Initiate statin to reduce
LDL-C ≥50%
F . Algorithm for cholesterol management in primary prevention recommended by the ACC/AHA guidelines
ASCVD risk calculator [9]. This calculator is based on observational data from the Framingham Study and additional
studies on predominantly non-Hispanic white and nonHispanic black residents of the United States. This tool may
over- or underestimate risk in other race/ethnic groups or
non-US populations, particularly in those of South Asian
ancestry. In those individuals with low to intermediate risk
for ASCVD, the presence of risk enhancers should be considered when making decisions about initiating lipid-lowering
therapy (Fig.9.1).
Treatment
In 2013, the American College of Cardiology (ACC) and
American Heart Association (AHA) released updated guidelines for cholesterol management in primary prevention [10].
200
A. Manavalan
Instead of targeting LDL-level goals, which was recommended by the previous Adult Treatment Panel (ATP) III
guidelines [11], the ACC/AHA guidelines promote lipidlowering strategies depending on the ASCVD risk for primary prevention [9, 10]. This recommendation has been
upheld in the ACC/AHA 2019 guidelines for lipid-lowering
therapy in primary prevention [9].
Principles ofTherapy
In the 2019 ACC/AHA guidelines, the initiation and dosage
of lipid lowering therapy in primary prevention is dependent
on a patient’s 10-year ASCVD risk (Fig. 9.1). Patients
20–39years of age are considered to be at low risk for cardiovascular events but may be candidates for statin therapy
based on the presence of risk enhancers such as abnormal
ABI/PVR, elevated coronary artery calcium score, family history, and high-sensitivity CRP, to name a few [12–15]. Statin
therapy may be considered in younger individuals who have
had type 1 diabetes for a duration longer than 20 years or
type 2 diabetes for longer than 10years. In those individuals
with borderline ASCVD risk, coronary artery calcium score
can assist with reassessing risk. The benefit of initiating statin
therapy in those older than 75years is not clear and should
take into account the individual clinical scenario.
All patients with established clinical ASCVD should be
initiated on statin therapy for secondary prevention. Highintensity statin with a goal to lower LDL-C levels to less than
70mg/dL is indicated for patients 76years of age and younger
as this has been shown to decrease cardiovascular events. If
there is intolerance to statin therapy or the target LDL-C
remains unmet, the addition of other agents (ezetimibe,
PCSK9) is recommended to meet the LDL-C goal [9].
Chapter 9. Lipids
201
Treatment Strategies
Lifestyle Modification
Lifestyle modification remains a critical part of cholesterol
management in the AHA guidelines. Lifestyle modifications
include adhering to a healthy diet, regular exercise, abstinence to tobacco products, and controlling body weight [9].
Certain diets such as the DASH diet lower blood pressure
and LDL-c and have been shown to lower LDL-c by 11mg/
dL in adults with LDL-c levels <160mg/dL (high strength of
evidence) [11]. Further, reducing calories from saturated fat
and trans-fat has been shown to lower LDL-c [11]. In general,
it is recommended that all adults consume a healthy plant
based or Mediterranean diet high in vegetables, fruits, nuts,
whole grains, lean vegetable or animal protein such as fish,
and vegetable fiber which has shown to decrease all-cause
mortality compared to standard diets.
Evidence shows that both aerobic physical activity and
resistance training reduce LDL-c and non-HDL-c levels.
Comparing with controls, aerobic physical activity lowers
LDL-c by 3–6mg/dL and non-HDL-c by 6mg/dL (moderate
strength of evidence); resistance training reduces LDL-c and
non-HDL-c by 6–9 mg/dL (low strength of evidence) [11].
The 2019 ACC lifestyle guideline recommends engaging in
150min of moderate-intensity physical activity or 75min of
vigorous-intensity physical activity per week to decrease the
risk of ASCVD [9].
Statins
Statins are the cornerstone and first-line lipid-lowering therapy. Statins act by inhibiting hepatic 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase, which is
the rate-limiting enzyme in cholesterol biosynthesis. This
subsequently leads to upregulation of the LDL receptor,
increased LDL uptake, and reduction of serum LDL-c [16].
A. Manavalan
202
T . Suggested statin and dose for the appropriate intensity of
therapy
Statin intensities
High-intensity
(lower
LDL-c>50%)
Atorvastatin
40–80mg
Rosuvastatin
20–40mg
Moderate-intensity
(lower LDL-c
30–49%)
Atorvastatin 10–20mg
Rosuvastatin 5–10mg
Simvastatin 20–40mg
Pravastatin 40–80mg
Lovastatin 40mg
Fluvastatin 80mg
Pitavastatin 1–4mg
Low-intensity (lower
LDL-c<30%)
Simvastatin 10mg
Pravastatin 10–20mg
Lovastatin 20mg
Fluvastatin 20–40mg
The type and dose of statin determine their potential for
LDL-c reduction. Low-intensity statin therapy reduces LDL-c
by less than 30%; moderate-intensity statins lower LDL-c by
30–49% on average; and high-intensity statins achieve LDL-c
reduction by more than 50% [ACC 2019 guidelines]. Table9.1
shows the various options of statins and dosages to achieve
the targeted intensity of statin therapy.
Statin-associated muscle symptoms (SAMS, including
muscle pain and aching, cramps, and weakness) are the most
commonly reported adverse effects of statins. The incidence
has been estimated to be about 10% [17]. However, a metaanalysis of multiple RCTs showed no difference in the incidence of muscle-related symptoms between statin-treated
groups and placebo groups, suggesting the muscle symptoms
might not be attributed to statins in many cases [18]. SAMS
are usually manifested by pain and weakness of the large
muscle groups such as the bilateral thighs, buttocks, back, and
shoulders; cramping usually occurs unilaterally in small
muscles of hands and feet [19]. SAMS often occur early after
starting statin or after increasing the statin dose and generally
resolve within 2months after discontinuation of the medication. Searching for contributing factors (e.g., drug interactions, alcohol use, untreated hypothyroidism, vitamin D
Chapter 9. Lipids
203
deficiency, etc.), discussion with the patient about the benefits
of statin therapy, reassurance, and trial of alternative statins
or reduced dosages are suggested in this scenario [19].
Statin therapy may be associated with elevation of transaminase levels, which, however, is not indicative of liver
injury in the absence of bilirubin level increase [20]. In many
cases the elevations resolve with continuation of statin therapy. Significant liver injury is extremely uncommon with
statin use [20]. Routine tests of liver enzymes and liver function are not indicated following statin therapy [20].
Statin use mildly increases the risk of new-onset diabetes
(odds ratio 1.12, 95% confidence interval: 1.06–1.18 in the
meta-analysis) [21], but the cardiovascular protective effect
of statins far outweighs this risk in the majority of cases.
Fibrates
By activating peroxisome proliferator-activated receptor-α
(PPAR-α), fibrates primarily decrease triglycerides and raise
HDL-c levels. They are commonly used to treat dyslipidemia
with elevated triglycerides, when triglyceride levels exceed
500 mg/dL. In the follow-up of the ACCORD Lipid Trial
participants, it was noted that the use of fenofibrate resulted
in a decrease in cardiovascular events in men with diabetes
and triglycerides >204mg/dL and HDL-c <34mg/dL, while
use in women led to slightly increased risk of both myocardial
infarction and stroke (HR 0.84 vs. 1.3) [22]. While these
results remain unexplained, it is thought to be due to the
smaller number of female participants in the ACCORD
Trials as well as a lower rate of events in the placebo group.
While no sex differences were noted in participants of the
FIELD study, no significant decrease in cardiovascular events
were noted in the fenofibrate arm, possibly due to a high rate
of statin use among the placebo group [23]. A recent systematic review and meta-analysis comparing statins and fibrate
monotherapy revealed no difference in cardiovascular events
in both groups with less serious side effects in the statin
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A. Manavalan
group. However, most of the 19 eligible randomized trials
included were designed to assess short-term lipid outcomes,
making it difficult to be certain about comparisons for longterm outcomes [24].
Fish Oil
Omega 3 fatty acids are valuable adjuncts in decreasing
serum triglyceride levels. Icosapent ethyl (Vascepa), when
added to statin therapy in patients with elevated triglycerides
who suffered from diabetes mellitus or established cardiovascular disease, had a 25% risk reduction in major adverse
cardiovascular events [25]. Vascepa was FDA approved in
2019 as adjunctive therapy to statins for individuals with
clinical ASCVD or diabetes with two risk factors who have a
triglyceride level >150mg/dL and <500mg/dL.
Other Non-statin Medications
The 2019 ACC expert consensus documents recommend nonstatin therapies in adjunct to statin therapy in patients with
clinical ASCVD who have suboptimal LDL-c lowering after
lifestyle modification and maximally tolerated statin therapy
[9]. The potential adjunctive therapy options include ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK
9) inhibitors [9].
Ezetimibe: Ezetimibe selectively inhibits cholesterol
absorption in the small intestine. In combination with maximally tolerated statins, ezetimibe has been shown to produce an additional 24% reduction of LDL. Ezetimibe in
combination with statin therapy also significantly reduced
ASCVD events (13% reduction in myocardial infarction,
21% reduction in ischemic stroke, and 10% reduction in
death from cardiovascular causes) in patients with established ASCD [26].
Bile acid sequestrants: Bile acid sequestrants (BAS) act by
binding to bile constituents and disrupting enterohepatic circulation of bile acids. This subsequently leads to increased
bile acid production and intrahepatic cholesterol flux, result-
Chapter 9. Lipids
205
ing in upregulation of LDL receptors, and reduction of
LDL-c level. Bile acid sequestrants might be considered as
adjunctive therapy if a patient is intolerant of ezetimibe and
has a triglyceride level >300 mg/dL.However, the effect of
BAS on ASCVD risk reduction remains unclear [27].
PCSK 9 inhibitors: PCSK 9 is a serine protease that binds
to the hepatocyte LDL receptor and facilitates its degradation. Inhibition of PCSK 9 therefore increases hepatocyte
LDL receptors by preventing their degradation. This enhances
hepatic LDL uptake and decreases LDL-c levels. Monoclonal
antibodies to PCSK 9, evolocumab and alirocumab, have
been shown to lower LDL-c levels by 50–70% from baseline.
When used on a background of statin therapy, they significantly reduce the risk of cardiovascular events by 15–20%
[28, 29]. Both these drugs were approved by the US Food and
Drug Administration (FDA) in 2015 for the treatment of
familial hypercholesterolemia and for secondary prevention
in patients with established ASCVD and inadequate response
or intolerance to statin monotherapy. Inclisiran, a long-acting
RNA interference (RNAi) agent that inhibits PCSK 9 protein synthesis, has been noted to decrease LDL levels by 50%
on the background of statin therapy in phase 3 trials; however, the number of cardiovascular events was too small to
draw meaningful conclusions with regard to ACSVD risk
reduction and cardiovascular outcome trials are ongoing [30].
The FDA recently approved the use of inclisiran as add-on
therapy to statins in eligible patients. The main side effects
related to PCSK9 inhibitor use are related to injection site
reactions. New-onset diabetes and nasopharyngitis are also
known to occur.
Bempedoic acid: Bempedoic acid is a pro-drug that is activated in the liver to inhibit ATP-citrate lyase. This enzyme
lies upstream from HMG CoA reductase; its inhibition
results in decrease in cholesterol synthesis in hepatocytes.
However, this drug remains inactive in skeletal muscle and is
not associated with myopathy. In a recent clinical trial, the
addition of bempedoic acid on the background of statin or
ezetimibe therapy resulted in 14% reduction in LDLc levels
[31]. Cardiovascular outcome data is not yet available. While
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A. Manavalan
there are no specific contraindications to therapy, side effects
include uricemia and gout, and this may be exacerbated in
those with preexisting disease.
Monitoring After Initiating Therapy
The current ACC/AHA guidelines recommend repeating the
lipid panel 4–12weeks after starting statin therapy or adjusting statin dose and every 3–12months thereafter, in order to
monitor adherence and response to statin therapy [9].
Clinical Pearls
• Hyperlipidemia, or dyslipidemia, is defined as increased
levels of lipids, including cholesterol and triglycerides.
• USPSTF strongly recommends screening for lipid disor-
ders in men ≥35years of age and women ≥45years of age.
Screening is also recommended in men between the ages
of 20 and 35 or women aged 20 and 45 with multiple risk
factors for atherosclerotic cardiovascular disease.
• Statins remain the first-line therapy for hyperlipidemia,
reducing the level of LDL-c and cardiovascular events.
• Four groups were identified to benefit from lipid lowering
therapy: patients with clinical ASCVD, patients with
LDL-c ≥190mg/dL, patients between the ages of 40 and 75
with type 1 or type 2 diabetes, and patients with a calcu-
lated 10-year ASCVD risk ≥7.5%.
• The ACC/AHA recommends that the intensity of lipid
management be tailored to the individual’s 10-year
ASCVD risk.
• For those individuals with established ASCVD, LDL-C
goal of <70 mg/dL is recommended through the use of
high-intensity statin monotherapy or in combination with
other lipid lowering agents.
Don’t Miss This!
• SAMs can occur in about 10% of patients.
• Be familiar with new effective drugs, including PCSK 9
inhibitors, Vascepa, and Bempedoic acid.
Chapter 9. Lipids
207
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