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Testing Lipid Levels: Fasting vs. Non-fasting
Current guidelines recommend that the lipid panel should be
tested while fasting, i.e., 8–12 h 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 sam-
ples. The assumption is that the VLDL-c level can be esti-
mated 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].
A fasting test can be inconvenient in clinical practice and
might delay clinical evaluation. Comparisons between fasting
and non-fasting studies have shown that other than triglycer-
ide levels which are impacted by non-fasting 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 for ASCVD
The 2013 ACC/AHA guidelines recommend calculating
10-year ASCVD risk and lifetime risk for patients younger
than 65 using the ASCVD risk calculator [9, 10]. The calcula-
tor is based on the observation data from the Framingham
Study and additional studies on predominantly White and
African-American populations. Therefore, in evaluating
patients of other racial backgrounds, the estimated risk might
need to be adjusted.
The 2013 ACC/AHA guidelines recommend recalculation
of 10-year ASCVD risk every 4–6 years in patients 40–75 years
of age who do not have clinical CVD and adjust treatment
strategies accordingly [9, 10].
D.L. Li
141
Other high-risk features should also be considered while
assessing a given patient’s cardiovascular risk, including fam-
ily history of premature CVD. Additional tests such as high-
sensitivity C-reactive protein (hs-CRP), coronary artery
calcium (CAC) score, and ankle-brachial index (ABI) can
improve the prediction of ASCVD [11–14], especially when
there is uncertainty with respect to initiating treatment
according to ASCVD risk calculator alone.
Treatment
Based on randomized clinical trials, in 2013, the American
College of Cardiology (ACC) and American Heart
Association (AHA) released updated guidelines for choles-
terol management [9, 10]. Instead of targeting LDL-level
goals, which was recommended by the previous Adult
Treatment Panel (ATP) III guidelines [15], the ACC/AHA
guidelines promote lipid-lowering strategies depending on
the ASCVD risk [9, 10].
Patient Population to Treat
In the 2013 ACC/AHA guidelines, four groups have been
identified that clearly benefit from statin therapy in preven-
tion of ASCVD events: (1) patients with clinical atheroscle-
rotic cardiovascular disease, (2) patients with LDL-c levels
≥190 mg/dL, (3) patients with type 1 or 2 diabetes with
LDL-c levels ≥ 70 mg/dL, and (4) patients who have a calcu-
lated 10-year ASCVD risk ≥7.5% and an LDL-c level ≥ 70 mg/
dL [7, 8].
Current evidence from randomized controlled trials fails
to show benefit of statins for patients with (1) end-stage renal
disease on hemodialysis, (2) heart failure (New York Heart
Association Class II–IV), and (3) age ≥ 75 without clinical
CVD. Therefore the current ACC/AHA guidelines do not
have recommendations regarding treatment of hyperlipid-
emia for these three groups of patients [7, 8].
7. L ipids
142
Goals of Treatment
In the 2013 ACC/AHA guidelines, the intensity of choles-
terol management is dependent on a patient’s 10-year
ASCVD risk. For adult patients between 40 and 75 years
of age with (1) clinical atherosclerotic cardiovascular dis-
ease, (2) LDL-c levels ≥ 190 mg/dL, (3) type 1 or 2 diabe-
tes with LDL-c levels ≥70 mg/dL, and (4) a calculated
10-year ASCVD risk ≥7.5%, high-intensity statin therapy
is recommended. For type 1 or 2 diabetic patients with
LDL-c levels ≥70 mg/dL and a calculated 10-year ASCVD
risk <7.5%, moderate-intensity statin therapy is recom-
mended. For patients without the above features but who
have a calculated 10-year ASCVD risk ≥7.5%, moderate-
to high-intensity statin therapy is recommended [9]
(Fig. 7.1).
In comparison, in 2016, the USPSTF updated its recom-
mendations on lipid therapy, which differ from the 2013 ACC/
AHA guidelines regarding statin therapy in primary preven-
tion [16]. The USPSTF guidelines recommended low- to
moderate-intensity statin therapy in patients between the
ages of 40 and 75, without a history of CVD but who have at
least one CVD risk factor (including diabetes) and a 10-year
ASCVD risk ≥10% (B recommendation), and to consider
statin therapy when the 10-year ASCVD risk is between 7.5
and 10% (C recommendation) [16]. The rationale for recom-
mending less aggressive cholesterol management for patients
without clinical ASCVD is that the absolute benefits were
small given the low incidence of cardiovascular events in this
population [17].
Since there is controversy on the timing of initiating treat-
ment and the intensity of cholesterol management in patients
without clinical CVD, other factors (e.g., family history, hs-
CRP, CAC score, ABI, etc.) to aid in assessing the ASCVD
risk will likely help guide clinical decisions in a patient with a
borderline calculated ASCVD risk.
D.L. Li
143
Fig. 7.1 Algorithm for cholesterol management recommended by
the ACC/AHA guidelines
Treatment Strategies
Lifestyle Modification
Lifestyle modification remains a critical part of choles-
terol management in the ACC/AHA guidelines. Lifestyle
modifications include adhering to a healthy diet, regular
7. L ipids
144
exercise, abstinence to tobacco products, and controlling
body weight [18].
Certain dietary patterns (e.g., DASH diet, etc.) lower
blood pressure and LDL-c [18]. The DASH diet is high in
fruits, vegetables, low-fat dairy products, whole grains, poul-
try, fish, and nuts. It is low in red meat, sweets, and sugar-
sweetened beverages. The DASH diet has been shown to
lower LDL-c by 11 mg/dL in adults with LDL-c levels
<160 mg/dL (high strength of evidence) [18]. Further, reduc-
ing calories from saturated fat and trans fat has been shown
to lower LDL-c [18]. The total calorie intake for a given indi-
vidual is also critical.
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 3–6 mg/dL and non-HDL-c by 6 mg/dL (moderate
strength of evidence); resistance training reduces LDL-c and
non-HDL-c by 6–9 mg/dL (low strength of evidence) [18].
The 2013 AHA/ACC lifestyle management guideline recom-
mends engaging in aerobic physical activity (moderate to
vigorous intensity, three to four sessions per week, and lasting
40 min per session) to lower LDL-c, non-HDL-c, and blood
pressure [18].
Statins
Statins are the cornerstone and first-line lipid-lowering ther-
apy. Statins act by inhibiting hepatic 3-hydroxy-3-methylglu-
taryl coenzyme A (HMG-CoA) reductase, which is the
rate-limiting enzyme in cholesterol biosynthesis. This subse-
quently leads to upregulation of the LDL receptor and
reduction of LDL-c [19] .
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 30–50% on average; and high-intensity statins
achieve LDL-c reduction by more than 50% [9, 10]. Table 7.1
shows the various options of statins and dosages to achieve
the targeted intensity of statin therapy.
D.L. Li
145
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% [20]. However, a meta-
analysis of multiple RCTs showed no difference in the inci-
dence of muscle-related symptoms between statin-treated
groups and placebo groups, suggesting the muscle symptoms
might not be attributed to statins in many cases [21]. 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 mus-
cles of hands and feet [22]. SAMS often occur early after
starting statin or after increasing the statin dose and generally
resolve within 2 months after discontinuation of the medica-
tion. Searching for contributing factors (e.g., drug interac-
tions, alcohol use, untreated hypothyroidism, etc.), discussion
with the patient about the benefits of statin therapy, reassur-
ance, and trial of alternative statins or reduced dosages are
suggested in this scenario [22].
Statin therapy is associated with elevation of transaminase
levels, which, however, is not indicative of liver injury in the
absence of bilirubin level increase [23]. In many cases the
elevations resolve with continuation of statin therapy.
Significant liver injury is extremely uncommon with statin
Table 7.1 Suggested statin and dose for the appropriate intensity of
therapy
Statin intensities
High intensity
(lower
LDL-c > 50%)
Moderate intensity (lower
LDL-c 30–50%)
Low intensity
(lower
LDL-c < 30%)
Atorvastatin
40 mg, 80 mg
Rosuvastatin
20 mg, 40 mg
Atorvastatin 10 mg, 20 mg
Rosuvastatin 5 mg, 10 mg
Simvastatin 20 mg, 40 mg
Pravastatin 40 mg, 80 mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2 mg, 4 mg
Simvastatin 10 mg
Pravastatin 10 mg,
20 mg
Lovastatin 20 mg
Fluvastatin 20 mg,
40 mg
Pitavastatin 1 mg
7. L ipids
146
use [23]. Routine tests of liver enzymes and liver function are
not indicated following statin therapy [23].
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) [24], 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 have been used not uncommonly to treat
dyslipidemia with elevated triglycerides. However, multiple
studies to date failed to show efficacy in reducing cardiovas-
cular events or all-cause mortality in type 2 diabetic patients
[25–27]. While a subgroup analysis from a more recent study
showed benefits of fenofibrate (RR 0.73, CI 0.56–0.95) in
diabetic patients with triglycerides >204 mg/dL and
HDL-c < 34 mg/dL, it also showed that fenofibrate increased
myocardial infarction and stroke in female diabetic patients
(RR 1.30, CI 1.01–1.68) [25].
Combination of Statins and Other Non-statin
Medications
The 2016 ACC expert consensus documents recommend non-
statin 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
[28]. The potential adjunctive therapy options include ezeti-
mibe, bile acid sequestrants, and proprotein convertase sub-
tilisin/kexin type 9 (PCSK 9) inhibitors. Niacin and fibrates,
on the other hand, are no longer recommended [28].
Ezetimibe: Ezetimibe selectively inhibits cholesterol absorp-
tion by the small intestine. In combination with statins, ezeti-
mibe has been shown [29] to produce an additional 23–24%
reduction of LDL and further reduce ASCVD events in
patients with clinical CVD.
D.L. Li
147
Bile acid sequestrants: Bile acid sequestrants (BAS) act by
binding to bile constituents and disrupting enterohepatic cir-
culation of bile acids. This subsequently leads to increased
bile acid production and intrahepatic cholesterol flux, result-
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, there is no
evidence for additive benefits of BAS as an adjunctive ther-
apy to statins [28].
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 and thus reduces
LDL-c level. Monoclonal antibodies to PCSK 9, evolocumab
and alirocumab, as monotherapies or in combination with
statins, have been shown to further lower LDL-c levels by
50–70% from baseline and reduce the risk of cardiovascular
events [30, 31]. Both were approved by the US Food and
Drug Administration (FDA) in 2015 to treat familial hyper-
cholesterolemia and to achieve ASCVD secondary preven-
tion as an adjunct to statins. Inclisiran, a long-acting RNA
interference (RNAi) agent that inhibits PCSK 9 protein syn-
thesis, has recently been tested in phase 1 trials, manifesting a
robust and prolonged effect on LDL-c reduction as well [32].
While PCSK 9 inhibitors are exciting and powerful new
agents for lowering LDL-c, their long-term efficacy and
safety remain to be tested.
Monitoring After Initiating Therapy
The current ACC/AHA guidelines recommend repeating
the lipid panel 4–12 weeks after starting statin therapy or
adjusting statin dose and every 3–12 months thereafter, in
order to monitor adherence and response to statin ther-
apy [9, 10].
7. L ipids
148
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 ≥35 years of age and women ≥45 years of age.
Screening is also recommended in men between the ages
of 20 and 35 or women aged 20–45 with multiple risk fac-
tors for atherosclerotic cardiovascular disease.
• Statins remain the first-line therapy for hyperlipidemia,
reducing the level of LDL-c and cardiovascular events.
• Fibrates effectively reduce the triglyceride level and, how-
ever, have failed to show cardiovascular benefits in multi-
ple clinical trials.
• Four groups were identified to benefit from statin therapy:
patients with clinical CVD, patients with LDL-c ≥ 190 mg/
dL, patients between the ages of 40 and 75 with type 1 or
type 2 diabetes, and patients with a calculated 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.
Don’t Miss This!
SAMs can occur in about 10% of patients.
Be familiar with new effective drugs, including PCSK 9
inhibitors (and inclisiran, a long-acting RNA interference
agent).
References
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serum cholesterol and risk of premature death from coronary
heart disease continuous and graded? Findings in 356,222 pri-
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