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Pharmacotherapy: A Pathophysiologic Approach, 11e

Chapter 31: Dyslipidemia

Dave L. Dixon; Daniel M. Riche

CHAPTER SUMMARY FROM THE PHARMACOTHERAPY HANDBOOK

For the Chapter in the Schwinghammer, Handbook (not Wells Handbook anymore) please go to Chapter 8, Dyslipidemia.

KEY CONCEPTS

KEY CONCEPTS

Lipid abnormalities increase the risk for coronary heart disease (CHD) and cerebrovascular morbidity and mortality.

Low­density­lipoprotein cholesterol (LDL­C) is the primary target for lipid­lowering therapy.

Genetic abnormalities and environmental factors are involved in the development of dyslipidemia.

Therapeutic lifestyle change is first­line therapy for any lipoprotein disorder.

If therapeutic lifestyle changes are insufficient, lipid­lowering agents should be chosen based on which lipid is at an undesirable level and
the degree to which it is expected to increase the risk of atherosclerotic cardiovascular disease (ASCVD).

Statins are the drugs of choice for dyslipidemia because of potency and cost­effectiveness.

If statin monotherapy is insufficient, patients may be treated with evidence­based combination therapy but should be monitored closely for
drug–drug interactions.

Reducing total cholesterol and LDL­C reduces CHD and total mortality.

Lipid­lowering therapies that reduce ASCVD event rates are cost­effective.

Several novel medications including antisense oligonucleotide inhibitors of apoB, microsomal triglyceride transport protein inhibitors,
adenosine triphosphate­citrate lyase (ACL) inhibitors, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used as add­
on therapy or in lieu of statin therapy in select high­risk populations.

PRECLASS ACTIVITY

Preclass Engaged Learning Activity

Watch these YouTube videos to learn about cholesterol basics as well as the physiology of lipoprotein cholesterol and metabolism:

Cholesterol Good and Bad (https://tinyurl.com/yx6a5ufj) by the US National Library of Medicine

Physiology of Lipoprotein Cholesterol (https://tinyurl.com/hcy239y) by Armando Hasudungan

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Chapter 31: Dyslipidemia,
Physiology Dave L. Dixon;
of Lipoprotein Daniel(https://tinyurl.com/pwo856o
Metabolism M. Riche ) by National Heart, Blood, Lung Institute Page 1 / 37
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 on therapy or in lieu of statin therapy in select high­risk populations.
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PRECLASS ACTIVITY

Preclass Engaged Learning Activity

Watch these YouTube videos to learn about cholesterol basics as well as the physiology of lipoprotein cholesterol and metabolism:

Cholesterol Good and Bad (https://tinyurl.com/yx6a5ufj) by the US National Library of Medicine

Physiology of Lipoprotein Cholesterol (https://tinyurl.com/hcy239y) by Armando Hasudungan

Physiology of Lipoprotein Metabolism (https://tinyurl.com/pwo856o) by National Heart, Blood, Lung Institute

INTRODUCTION
Cholesterol, triglycerides, and phospholipids are the major lipids that combine with proteins to be transported as complexes of lipid and proteins
known as lipoproteins. Lipids, such as cholesterol and triglycerides, are insoluble in plasma, which is why the lipoproteins are required for
transportation (Fig. 31­1).1,2

FIGURE 31­1

Intestinal cholesterol absorption and transportation. Cholesterol from food and bile enters the gut lumen and is emulsified by bile acids into micelles.
Micelles bind to intestinal enterocytes and cholesterol, and other sterols are transported from the micelles to the enterocytes by sterol transporters.
Triglycerides (TG) synthesized by absorbed fatty acids (FA) are incorporated into chylomicrons. Chylomicrons are released into lymphatic circulation
and converted to chylomicron remnants (by losing triglyceride), and are then taken up by hepatic LDL­receptor–related protein. (Apo, apolipoprotein;
ABC, ATP­binding cassette; CE, cholesterol ester; FA, fatty acid; NPC1L1, Niemann­Pick C1­Like1 protein; TG, triglyceride.) (Reproduced, with
permission, from Chisholm­Burns MA, Schwinghammer TL, Malone PM, Kolesar JM, Bookstaver PB, Lee KC, eds. Pharmacotherapy Principles &
Practice. 5th ed. New York: McGraw­Hill; 2019.)

There are three major classes of lipoproteins in the serum. These include low­density lipoproteins (LDL), high­density lipoproteins (HDL), and very
low­density lipoproteins (VLDL). VLDL is the primary carrier of triglycerides (TG) in the circulation. Intermediate­density lipoprotein (IDL) is between
VLDL and LDL and is included in LDL­C measurement (Fig. 31­2).3

FIGURE 31­2

Lipoprotein structure, which contains variable amounts of core cholesterol esters and triglycerides and have varying numbers and types of surface
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apolipoproteins.
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low­density lipoproteins (VLDL). VLDL is the primary carrier of triglycerides (TG) in the circulation. Intermediate­density lipoprotein (IDL) is between
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VLDL and LDL and is included in LDL­C measurement (Fig. 31­2).3
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FIGURE 31­2

Lipoprotein structure, which contains variable amounts of core cholesterol esters and triglycerides and have varying numbers and types of surface
apolipoproteins.

Lipid abnormalities increase the risk of coronary, cerebrovascular, and peripheral vascular arterial disease collectively known as
atherosclerotic cardiovascular disease (ASCVD). The ASCVD­risk assessment evaluates a 10­year atherosclerotic cardiovascular disease incident.
Developing a first ASCVD event is defined as nonfatal myocardial infarction or coronary heart disease (CHD) death, or fatal or nonfatal stroke, over a
10­year period. Premature coronary atherosclerosis is the most common and significant consequence of dyslipidemia. The 2014 guidelines from the
American Heart Association (AHA) and American College of Cardiology (ACC) state there is not sufficient evidence to recommend treating to specific
lipid targets but suggests four statin benefit patient populations instead. Low­density lipoprotein cholesterol (LDL­C) is the primary target of lipid
lowering therapy. Methods for risk assessment were also updated, which increases the number of patients that would qualify for therapy. Primary and
secondary CHD prevention measures are provided as well.4–7

There are several subtypes of dyslipidemias, including hypertriglyceridemia, low HDL cholesterol (HDL­C), and diabetic dyslipidemia.
Hypertriglyceridemia can lead to pancreatitis when very high TG levels (>500 mg/dL [5.65 mmol/L]) are seen. High serum triglycerides should primarily
be treated by achieving desirable body weight, consumption of low saturated fat and cholesterol diet, regular exercise, smoking cessation, and
restriction of alcohol.3,4 In patients with borderline­high TG but with accompanying risk factors of established congenital heart disease, family history
of premature CHD, concomitant LDL­C elevation or low HDL­C, and genetic forms of hypertriglyceridemia associated with CHD, lipid­lowering therapy
should be considered.8–10

Low HDL­C is another dyslipidemia subtype that can occur due to insulin resistance, physical inactivity, diabetes, cigarette smoking, high carbohydrate
intake, and some medications. In patients with low HDL­C, the primary target remains LDL­C, but an emphasis on weight loss, increased physical
activity, and smoking cessation are recommended. No randomized controlled trials (RCT) have shown a reduction in ASCVD risk by raising HDL­C
levels.3,11 Hypertriglyceridemia, low HDL­C, and minimally elevated LDL­C characterize diabetic dyslipidemia. Because the primary target is LDL­C in
diabetic dyslipidemia, statins are considered the drugs of choice.3,4,12,13

EPIDEMIOLOGY
Total cholesterol and LDL­C increase throughout life in both men and women. According to AHA estimates, approximately 45% of American adults
aged 20 or older have total cholesterol levels exceeding 200 mg/dL (5.17 mmol/L).14 The prevalence of elevated total cholesterol in adults has remained
the same over the past decade but has improved in children. Westernized societal diets high in cholesterol are a strong contributor to the increase in
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In 2011, CHDIPcaused
is one in every seven deaths in the United States. More than half of individuals at borderline­high risk
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche Page 3 / 37
remain unaware that they have dyslipidemia, and fewer than half of the highest risk persons (those with symptomatic CHD) are receiving lipid­lowering
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treatment. About one­third of treated patients are achieving their LDL­C goal; fewer than 20% of CHD patients are at their LDL­C goal. Estimates from
the National Cholesterol Education Program (NCEP) state that only 26% of patients have an optimal LDL­C (<100 mg/dL [2.59 mmol/L]), and that large
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Total cholesterol and LDL­C increase throughout life in both men and women. According to AHA estimates, approximately 45% of American adults
aged 20 or older have total cholesterol levels exceeding 200 mg/dL (5.17 mmol/L).14 The prevalence of elevated total cholesterol in adults has remained
the same over the past decade but has improved in children. Westernized societal diets high in cholesterol are a strong contributor to the increase in
total and LDL­C cholesterol. In 2011, CHD caused one in every seven deaths in the United States. More than half of individuals at borderline­high risk
remain unaware that they have dyslipidemia, and fewer than half of the highest risk persons (those with symptomatic CHD) are receiving lipid­lowering
treatment. About one­third of treated patients are achieving their LDL­C goal; fewer than 20% of CHD patients are at their LDL­C goal. Estimates from
the National Cholesterol Education Program (NCEP) state that only 26% of patients have an optimal LDL­C (<100 mg/dL [2.59 mmol/L]), and that large
numbers of patients are either untreated or undertreated. Patients at highest risk are less likely to be treated to desirable LDL­C values.15–17 When
patients who are at risk but who have not yet experienced initial cardiovascular (eg, myocardial infarction [MI]) or cerebrovascular (eg, ischemic stroke)
events are treated, it is termed primary prevention. Treatment for those with manifest ASCVD is termed secondary prevention.17 Studies, such as the
Framingham Heart study, show that risk for developing cardiovascular disease is related to the degree of LDL­C elevation in a continuous fashion.3
Hypercholesterolemia, cigarette smoking, hypertension, diabetes, and low HDL­C levels are all additive risk factors for CHD. Risk of MI increases five to
seven times with any pre­existing CHD or previous MI compared to patients with no history of these. Patients with a history of CHD or MI should be
screened, identified, and treated for dyslipidemias. Fifty percent of all MIs and 70% of all deaths due to CHD occur in patients with known CHD.

ETIOLOGY

Genetitc abnormalities and environmental factors are involved in the development of dyslipidemia. The underlying causes of dyslipidemias can be
categorized into two types: primary or secondary. Genetic factors that increase lipid levels can be inherited and cause primary or familial dyslipidemia.
By contrast, lifestyles, diseases, medications, and diet can all lead to abnormal lipid levels and cause secondary or “acquired” dyslipidemia.

Primary or Familial Dyslipidemias

Primary or familial dyslipidemias account for a large number of cases of increased total cholesterol, LDL­C, TGs, or decreased HDL­C. There are certain
familial or genetic defects that can contribute. Genetic disorders can cause an increase or decrease in different lipoproteins. Primary dyslipidemias
result in an increased risk of premature ASCVD due to significant elevations in cholesterol levels. There are different types of familial dyslipidemias,
including hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and disorders of HDL­C metabolism and an excess of lipoproteins.
Two other primary disorders include homozygous familial hypercholesterolemia (HoFH) and heterozygous familial hypercholesterolemia (HeFH).
HeFH is more common with one case per 250 people versus HoFH with one case per one million people. In familial hypertriglyceridemia, TGs are
elevated in the range of 200 to 500 mg/dL (2.26 to 5.65 mmol/L), but at times can be greater than 1,000 mg/dL (11.3 mmol/L). Patients presenting with
TG concentrations greater than or equal to 500 mg/dL (5.65 mmol/L) can have eruptive xanthomas and/or acute pancreatitis. Heterozygous gene
dysfunction usually causes elevations in LDL­C between 250 and 450 mg/dL (6.47 to 11.64 mmol/L), and homozygous patients may present with LDL­C
concentrations above 500 mg/dL (12.93 mmol/L). Tendon xanthomas are thick cholesterol deposits. Xanthelasmas and arcus cornea can also occur,
and these are cholesterol deposits in the eyelids and around the corneal rim.18–21

Secondary or Acquired Dyslipidemias

Secondary or acquired dyslipidemias can accompany genetic disorders or cause lipid imbalances. “The 4D classification” of secondary causes of
dyslipidemia include, diet, drugs, disorder, and diseases.19 Regarding diet, an increase in cholesterol can be caused from excessive alcohol use,
anorexia, weight gain, excessive carbohydrate intake, and high saturated fat intake. Certain medications can also contribute. For example, some
medications that can increase both LDL­C and TGs include atypical antipsychotics, diuretics, beta blockers, glucocorticoids, oral estrogen and
progestin, tacrolimus, and cyclosporine.

Certain metabolism disorders can contribute to cholesterol imbalances. Nephrotic syndrome, renal failure, biliary obstruction, hypothyroidism, and
pregnancy can all potentially contribute. Comorbid conditions or diseases such as hypothyroidism, pregnancy, obesity, polycystic ovarian syndrome
(PCOS), uncontrolled diabetes, liver disease, chronic kidney disease can also play a role.

Although we classify the lipid disorders into primary and secondary dyslipidemias based on etiologies, most dyslipidemias are a result of a
combination of both.4,19

PATHOPHYSIOLOGY
Lipoproteins and Cholesterol
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There are Hill.of
four types Alllipoproteins:
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chylomicrons, UseLDL,
VLDL, • Privacy Policy
and HDL. • Notice
These • Accessibility
lipoproteins vary in content of lipid and protein. The ratio of protein
and lipid in these lipoproteins contribute to the function of each. Chylomicrons contain the most lipid and very little protein. HDL contains the most
protein and a small amount of lipids. The small amount of lipid, and in turn cholesterol, in HDL lipoproteins gives HDL the role of picking up extra
Although we classify the lipid disorders into primary and secondary dyslipidemias based on etiologies, most dyslipidemias are a result of a
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combination of both.4,19
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PATHOPHYSIOLOGY
Lipoproteins and Cholesterol Synthesis

There are four types of lipoproteins: chylomicrons, VLDL, LDL, and HDL. These lipoproteins vary in content of lipid and protein. The ratio of protein
and lipid in these lipoproteins contribute to the function of each. Chylomicrons contain the most lipid and very little protein. HDL contains the most
protein and a small amount of lipids. The small amount of lipid, and in turn cholesterol, in HDL lipoproteins gives HDL the role of picking up extra
cholesterol from the tissue. LDL is not necessarily “bad” cholesterol, but in excess, this generates the problem. We need cholesterol for the
transportation of fats that are absorbed in our diet and delivered to our tissues. Chylomicrons are not normally in plasma during periods of fasting. In
the small intestine, fats are digested and emulsified into micelles. Cholesterol is also absorbed. Fatty acids, cholesterol, and proteins or apoproteins
are packaged and form the chylomicrons. The chylomicrons circulate around the body and deliver lipids and TGs to tissues in need. The remaining
chylomicrons are transported to the liver and bind to LDL receptors. Glucose that has also been absorbed from our diet is delivered to the liver. In the
liver, glucose is converted to pyruvate and then to acetyl­CoA. Acetyl­CoA is eventually converted to cholesterol through 3­hydroxy­3­methylglutaryl­
coenzyme A (HMG­CoA) reductase. HMG­CoA reductase is a target for statins, thus stopping cholesterol synthesis. Glycolysis also synthesizes glycerol.
Combining glycerol and one fatty acid forms monoacylglycerol, and two more fatty acids form triglycerides. Triglycerides and apoproteins are packed
through the Golgi apparatus and form lipoproteins. Lipoproteins contain proteins, apoproteins, TGs, phospholipids, and cholesterol. The liver does
not make all lipoproteins. In fact, only empty HDL and VLDL are made in the liver. VLDL has more TGs and lipids than HDL. VLDL transports these lipids
and TGs to tissues in need of energy or storage. Adipose tissue stores fat, and many tissues use fatty acids for energy. VLDL is transported across
lipase, which changes the VLDL to IDL or intermediate­density lipoproteins. IDL can then be converted to LDL. LDL mainly transports cholesterol to
body tissues, which is why LDL contains the most cholesterol. Tissues need cholesterol to make hormones and maintain cell membrane integrity. Once
LDL gives these tissues cholesterol, it returns to the liver. LDL binds to LDL receptors and is then either recycled to make more lipoproteins or excreted
into the bile. Any excess cholesterol is excreted into the bile, so the body maintains cholesterol balance. HDL or empty HDL plays a role in picking up
any or excess cholesterol and returning it to the liver. The full HDL containing the picked up cholesterol binds to scavenger receptors. They are then
either recycled or excreted depending on how much cholesterol is needed.22

Lipid Metabolism and Transport

Cholesterol is water­insoluble so it cannot circulate through blood without help. Lipoproteins are large carrier proteins to help with transport because
they are water­soluble. This allows major lipids to be circulated through the blood. Lipoproteins vary in characteristics depending on the amount of
cholesterol, TG, and apolipoproteins. All lipoproteins also have something called apolipoproteins on its surface. Apolipoproteins are necessary for the
assembly and secretion of lipoproteins. They are also major structural components of lipoproteins that have ligands for binding to receptors or cell
surfaces. These are the cofactors for the activation of enzymes. Apolipoproteins have various functions that transport lipids from sites of absorption to
sites where they are used. Apolipoprotein B containing lipoproteins, known as non­HDL, make up the lipid­delivery pathway. Apolipoprotein A­1 or
HDL participates in reverse cholesterol transport. ApoB containing lipoproteins arise from two sources, one being intestinal ApoB­48 and the other
hepatic ApoB­100 lineage. ApoB containing lipoproteins are secreted from the intestine or liver into the plasma. Apolipoproteins E, C­II, and C­III are
secreted with them. These also may be acquired from HDL. Apolipoprotein remodeling begins, and ApoC­II activates lipoprotein lipase (LPL), which
hydrolyzes the lipoprotein core TGs into free fatty acids. The fatty acids exit and the lipoproteins become smaller and smaller. Remodeling of the ApoB­
100 hepatic lipoprotein, another step by hepatic lipase (HL) is needed to convert IDL to LDL. Most ApoB remnants are recycled to the liver by the LDL­
receptor–related protein (LRP). They can have other metabolic requirements, too. Excess ApoB particles can invade arterial walls and become oxidized.
Once oxidized, they are taken up by macrophage scavenger receptors creating foam cells that lead to atheroma.

ApoA­1 or HDL pathways are believed to protect our bodies from atherogenesis. HDL has two major protective roles in preventing atherogenesis.
Reverse cholesterol transport is the transfer of excess cholesterol from peripheral tissues by HDL. ApoA­1 is secreted from the liver or intestine and is
transported to the cells to remove excess cholesterol. HDL has several cholesterol removing mechanisms. Upregulation of the ATP­binding cassette
transporter or ABCA­1 transporter is triggered by excess cholesterol in the macrophages. ABCA­1 harvests free cholesterol and delivers it to the cell
membrane. The free cholesterol is esterified by lecithin­cholesterol acyltransferase or LCAT. The cholesterol ester moves to the core of the lipoprotein
forming the mature HDL3. Further removal of cholesterol by HDL3 occurs through scavenger receptor class B type 1, or SR­B1 receptors and is acted on
by LCAT, which expands to HDL2. ABCA­1 and SR­B1 are key for cholesterol efflux. HDL2 cholesterol is transferred to ApoB containing lipoproteins. HDL
now has one of three options: HDL triglycerides may be hydrolyzed by HL back into HDL3; HDL2 can return to the liver and through SR­B1 converted
back to HDL3; or HDL2 may be catabolized by the liver. All of these systems work together to maintain cholesterol homeostasis (Figs. 31­3 and 31­4).23

FIGURE 31­3

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Biosynthetic pathway for cholesterol.
Chapter 31: Dyslipidemia, The rate­limiting
Dave L. Dixon; enzyme in this pathway is 3­hydroxy­3­methylglutaryl­coenzyme A reductase (HMG­CoA
Daniel M. Riche Page 5 / 37
reductase).
©2025 (CETP,
McGraw cholesterol
Hill. All Rightsester transferTerms
Reserved. protein;
ofHDL,
Use •high­density lipoprotein;
Privacy Policy • Notice IDL, intermediate­density lipoprotein; LDL, low­density
• Accessibility
lipoprotein; LPL, lipoprotein lipase; VLDL, very­low­density lipoprotein.) (A) Exogenous pathway; (B) Endogenous pathway; (C) Reverse cholesterol
transport. (Adapted from Breslow JL. Genetic basis of lipoprotein disorders. J Clin Invest 1989;84:373.)
by LCAT, which expands to HDL2. ABCA­1 and SR­B1 are key for cholesterol efflux. HDL2 cholesterol is transferred to ApoB containing lipoproteins. HDL
California
now has one of three options: HDL triglycerides may be hydrolyzed by HL back into HDL3; HDL2 can return to the liver and throughNorthstate University
SR­B1 converted
back to HDL3; or HDL2 may be catabolized by the liver. All of these systems work together to maintain cholesterol homeostasis (Figs. 31­3 and 31­4).23
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FIGURE 31­3

Biosynthetic pathway for cholesterol. The rate­limiting enzyme in this pathway is 3­hydroxy­3­methylglutaryl­coenzyme A reductase (HMG­CoA
reductase). (CETP, cholesterol ester transfer protein; HDL, high­density lipoprotein; IDL, intermediate­density lipoprotein; LDL, low­density
lipoprotein; LPL, lipoprotein lipase; VLDL, very­low­density lipoprotein.) (A) Exogenous pathway; (B) Endogenous pathway; (C) Reverse cholesterol
transport. (Adapted from Breslow JL. Genetic basis of lipoprotein disorders. J Clin Invest 1989;84:373.)

FIGURE 31­4

Endogenous lipoprotein metabolism. In the liver, the cholesterol and triglycerides are packed into VLDL particles and sent into the blood. They are
then converted into IDL, which can be cleared by hepatic IDL receptor or metabolized into LDL. LDL can be cleared by LDL receptors or it can enter the
arterial walls and contribute to the development of atherosclerotic plaques and cardiovascular disease. HDL­C is responsible for transporting
cholesterol and phospholipids from the arterial cell wall or other extrahepatic tissues back to the liver. Cholesterol that is returned back to the liver can
then be excreted into the bile. This process is known as reverse cholesterol transport. (Apo, apolipoprotein; CE, cholesteryl ester; FA, fatty acid; HMG­
CoA, β­Hydroxy β­methylglutaryl­CoA; HL, hepatic lipase; LDL, low­density lipoprotein; LPL, lipoprotein lipase; VLDL, very low­density lipoprotein)
(Reprinted, with permission, from Marrs JC. Pathophysiology of Atherosclerotic Cardiovascular Disease. In: Wiggins BS, Saseen JJ, eds. Pharmacist’s
Guide to Lipid Management. 2nd ed. Lenexa, KS: American College of Clinical Pharmacy, 2014:2.)
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cholesterol and phospholipids from the arterial cell wall or other extrahepatic tissues back to the liver. Cholesterol that is returned back to the liver can
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then be excreted into the bile. This process is known as reverse cholesterol transport. (Apo, apolipoprotein; CE, cholesteryl ester; FA, fatty acid; HMG­
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CoA, β­Hydroxy β­methylglutaryl­CoA; HL, hepatic lipase; LDL, low­density lipoprotein; LPL, lipoprotein lipase; VLDL, very low­density lipoprotein)
(Reprinted, with permission, from Marrs JC. Pathophysiology of Atherosclerotic Cardiovascular Disease. In: Wiggins BS, Saseen JJ, eds. Pharmacist’s
Guide to Lipid Management. 2nd ed. Lenexa, KS: American College of Clinical Pharmacy, 2014:2.)

Familial Hypercholesterolemia

Familial hypercholesterolemia is characterized by (a) a selective elevation in the plasma level of LDL; (b) deposition of LDL­derived cholesterol in
tendons (xanthomas) and arteries (atheromas); and (c) inheritance as an autosomal dominant trait with homozygotes more severely affected than
heterozygotes. The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL receptor (LDL­R) or, rarely, a defect of
internalizing the LDL­R complex into the cell after normal binding. This leads to a lack of LDL degradation by cells and unregulated biosynthesis of
cholesterol, with total cholesterol and LDL­C being inversely proportional to the deficit in LDL receptors. Homozygotes (prevalence 1 in 1,000,000) have
severe hypercholesterolemia (650­1,000 mg/dL [16.8­25.9 mmol/L]), with the early appearance of cutaneous xanthomas and fatal CHD generally before
the age of 20 and have essentially no functional LDL receptors. Heterozygotes have only about one­half of the normal number of LDL receptors, total
cholesterol levels in the range of 300 to 600 mg/dL (7.76­15.52 mmol/L), and cardiovascular events beginning in the third and fourth decades of life.

Secondary causes of dyslipidemia exist and that several drugs and conditions may contribute to abnormal lipid levels (Table 31­1). These secondary
forms of dyslipidemia should be managed by addressing the underlying abnormality, including the modification of drug therapy when appropriate.

TABLE 31­1
Secondary Causes of Lipoprotein Abnormalities

Hypercholesterolemia Hypothyroidism
Obstructive liver disease
Nephrotic syndrome
Anorexia nervosa
Acute Intermittent Porphyria
Drugs: progestins, thiazide diuretics, glucocorticoids, beta­blockers, isotretinoin, protease inhibitors, cyclosporine,
mirtazapine, sirolimus

Hypertriglyceridemia Obesity
Diabetes mellitus
Lipodystrophy
Glycogen storage disease
Ileal bypass surgery
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Sepsis
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche Page 7 / 37
Pregnancy
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Acute Hepatitis
Systemic lupus erythematosus
the age of 20 and have essentially no functional LDL receptors. Heterozygotes have only about one­half of the normal number of LDL receptors, total
cholesterol levels in the range of 300 to 600 mg/dL (7.76­15.52 mmol/L), and cardiovascular events beginning in the third and fourth
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Northstate of life.
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Secondary causes of dyslipidemia exist and that several drugs and conditions may contribute to abnormal lipid levels (Table 31­1). These secondary
forms of dyslipidemia should be managed by addressing the underlying abnormality, including the modification of drug therapy when appropriate.

TABLE 31­1
Secondary Causes of Lipoprotein Abnormalities

Hypercholesterolemia Hypothyroidism
Obstructive liver disease
Nephrotic syndrome
Anorexia nervosa
Acute Intermittent Porphyria
Drugs: progestins, thiazide diuretics, glucocorticoids, beta­blockers, isotretinoin, protease inhibitors, cyclosporine,
mirtazapine, sirolimus

Hypertriglyceridemia Obesity
Diabetes mellitus
Lipodystrophy
Glycogen storage disease
Ileal bypass surgery
Sepsis
Pregnancy
Acute Hepatitis
Systemic lupus erythematosus
Monoclonal gammopathy: multiple myeloma, lymphoma
Drugs: Alcohol, estrogens, isotretinoin, beta­blockers, glucocorticoids, bile­acid resins, thiazides, asparaginase,
interferons, azole antifungals, mirtazapine, anabolic steroids, sirolimus, bexarotene

Hypercholesterolemia Malnutrition
Malabsorption
Myeloproliferative diseases
Chronic infectious diseases: human immunodeficiency virus (HIV), tuberculosis
Monoclonal gammopathy
Chronic Liver Disease

Low HDL Malnutrition

Obesity
Drugs: non­ISA beta­blockers, anabolic steroids, probucol, isotretinoin, progestins

Pathogenesis of Atherosclerotic Cardiovascular Disease

The “response­to­injury” hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium, excessive homocysteine,
immunologic attacks, or infection­induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular
interactions that culminate in atherosclerosis. C­reactive protein (CRP) is an acute­phase reactant and a marker for inflammation. Measuring one’s CRP
levels by means of a high­sensitivity CRP may be useful in identifying patients at risk for developing CAD. Lipid abnormalities increase the risk for CHD
and cerebrovascular morbidity and mortality. The eventual outcomes of this atherogenic cascade are clinical events such as angina, MI, arrhythmias,
stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. Atherosclerotic lesions are thought to arise from transport and
retention of plasma LDL­C through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL­C is
chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL­C then recruits monocytes which transform into macrophages
in the artery wall. Macrophages accelerate LDL­C oxidation and apolipoprotein B accumulation and alter the receptor­mediated uptake of LDL­C into
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the artery wall from the usual LDL­R to a “scavenger receptor” not regulated by cell content of cholesterol. Oxidized LDL­C increases plasminogen
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche Page 8 / 37
inhibitor levels (promotion
©2025 McGraw of coagulation),
Hill. All Rights Reserved. induces
Terms ofthe
Useexpression
• Privacyof endothelin
Policy (vasoconstrictive
• Notice • Accessibility substance), inhibits the expression of nitric oxide (a
vasodilator and platelet inhibitor), and is toxic to macrophages if highly oxidized. As oxidation of biologically active lipids proceeds, other lipids
breakdown products of fatty acids and oxysterol are formed, which continue the reaction within the tissue. These events lead to a massive
levels by means of a high­sensitivity CRP may be useful in identifying patients at risk for developing CAD. Lipid abnormalities increase the risk for CHD
and cerebrovascular morbidity and mortality. The eventual outcomes of this atherogenic cascade are clinical events such California Northstate
as angina, University
MI, arrhythmias,
stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. Atherosclerotic lesions are thought to arise
Access fromby:transport and
Provided

retention of plasma LDL­C through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL­C is
chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL­C then recruits monocytes which transform into macrophages
in the artery wall. Macrophages accelerate LDL­C oxidation and apolipoprotein B accumulation and alter the receptor­mediated uptake of LDL­C into
the artery wall from the usual LDL­R to a “scavenger receptor” not regulated by cell content of cholesterol. Oxidized LDL­C increases plasminogen
inhibitor levels (promotion of coagulation), induces the expression of endothelin (vasoconstrictive substance), inhibits the expression of nitric oxide (a
vasodilator and platelet inhibitor), and is toxic to macrophages if highly oxidized. As oxidation of biologically active lipids proceeds, other lipids
breakdown products of fatty acids and oxysterol are formed, which continue the reaction within the tissue. These events lead to a massive
accumulation of cholesterol. The cholesterol­laden macrophages become foam cells; foam cells are the earliest recognized cells of the arterial fatty
streak. Oxidized LDL­C provokes an inflammatory response, which is mediated by a number of chemoattractants and cytokines. The process of aging
may lead to lipoproteins that are more susceptible to oxidation and have longer resident time in the vascular compartment. Repeated injury and repair
within an atherosclerotic plaque eventually leads to fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflammatory cells such
as T­lymphocytes. Maintenance of the fibrous plaque is critical to prevent plaque rupture and subsequent coronary thrombosis.24 An imbalance
between plaque synthesis and degradation may lead to a weakened or vulnerable plaque prone to rupture. The fibrous cap may become weakened
through decreased synthesis of the extracellular matrix or increased degradation of the matrix (Fig. 31­5).

FIGURE 31­5

Atherogenesis is initiated by the migration of LDL and remnant lipoprotein particles into the vessel walls. These particles undergo oxidation and are
taken up by macrophages in an unregulated fashion, which induces endothelial cell dysfunction. This, in turn, reduces the ability of the endothelium to
dilate the artery and cause a prothrombotic state. Unregulated uptake of cholesterol by macrophages leads to foam cell formation, and thus the
development of atherosclerotic plaques. Macrophages eventually produce and secrete matric metalloproteinases, which degrade the collagen matrix
of the plaques and cause them to be unstable. This can potentially lead to a myocardial infarction. This is a progressive process. (IDL, intermediate
density lipoprotein; LDL, low­density lipoprotein; MMP, matrix metalloproteinase; NO, nitric oxide; SR­B1, scavenger receptor class B type 1)
(Reproduced, with permission, from Chisholm­Burns MA, Schwinghammer TL, Malone PM, Kolesar JM, Bookstaver PB, Lee KC, eds. Pharmacotherapy
Principles & Practice. 5th ed. New York: McGraw­Hill; 2019.)

CLINICAL PRESENTATION

CLINICAL PRESENTATION DYSLIPIDEMIAS

General

Most patients are asymptomatic for years before they develop ASCVD; the initial presentation may be sudden death due to a CHD event.

Many patients with dyslipidemia also present with one or more of the following abnormalities*:
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Atherogenic dyslipidemia
 CLINICAL PRESENTATION DYSLIPIDEMIAS
California Northstate University
General Access Provided by:

Most patients are asymptomatic for years before they develop ASCVD; the initial presentation may be sudden death due to a CHD event.

Many patients with dyslipidemia also present with one or more of the following abnormalities*:

Abdominal obesity

Atherogenic dyslipidemia

Increased blood pressure

Insulin resistance and/or glucose intolerance

Prothrombotic or proinflammatory state

*Patients with three or more of these abnormalities are considered to have the metabolic syndrome

Symptoms of ASCVD

Chest pain

Palpitations

Sweating

Anxiety

Shortness of breath

Loss of consciousness

Difficulty with speech or movement

Abdominal pain

Signs

Abdominal pain

Pancreatitis

Eruptive xanthomas

Peripheral polyneuropathy

Laboratory Tests

Elevated total cholesterol, LDL­C, TGs, apolipoprotein B, hsCRP

Decreased HDL­C

Other Diagnostic Tests

Screenings for manifestations of vascular disease, including carotid ultrasound, coronary calcium score, ankle­brachial index, and heart
catheterization.

TREATMENT
Desired Outcomes

Desired levels2025­2­13
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10:53 and TG
P Your are provided in Table 31­2 for adults and Table 31­3 for children. While abnormalities in these surrogate
IP is
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel
markers may impart an increased risk for ASCVD M. Riche
events, Page 10 / 37
the goal of treatment is to not merely correct lab abnormalities but prevent the development
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
and progression of ASCVD. Thus, the desired outcome is to prevent ASCVD­related morbidity and mortality, including revascularization procedures,
MI, and ischemic stroke. Initiation of lipid­lowering therapies primarily involves the use of those agents shown in RCT to reduce ASCVD risk.20,25
 California Northstate University
TREATMENT Access Provided by:

Desired Outcomes

Desired levels of TC, LDL­C, HDL­C, and TG are provided in Table 31­2 for adults and Table 31­3 for children. While abnormalities in these surrogate
markers may impart an increased risk for ASCVD events, the goal of treatment is to not merely correct lab abnormalities but prevent the development
and progression of ASCVD. Thus, the desired outcome is to prevent ASCVD­related morbidity and mortality, including revascularization procedures,
MI, and ischemic stroke. Initiation of lipid­lowering therapies primarily involves the use of those agents shown in RCT to reduce ASCVD risk.20,25

TABLE 31­2
Classification of Total­, LDL­, HDL­Cholesterol, and Triglycerides in Adults

Total Cholesterol Desirable

<200 mg/dL (5.17 mmol/L) Borderline high
200­239 mg/dL (5.17­6.20 mmol/L) High
≥240 mg/dL (6.21 mmol/L)

Low­Density Lipoprotein Cholesterol Optimal

<100 mg/dL (2.59 mmol/L) Near or above optimal
100­129 mg/dL (2.59­3.35 mmol/L) Borderline high
130­159 mg/dL (3.36­4.13 mmol/L) High
160­189 mg/dL (4.14­4.90 mmol/L) Very high
≥190 mg/dL (4.91 mmol/L)

High­Density Lipoprotein Cholesterol Low (Men)

<40 mg/dL (1.03 mmol/L) Low (Women)
<50 mg/dL (1.3 mmol/L)

Triglycerides Normal
<150 mg/dL (1.70 mmol/L) Borderline high
150­199 mg/dL (1.70­2.25 mmol/L) High
200­499 mg/dL (2.26­5.64 mmol/L) Very high
≥500 mg/dL (5.65 mmol/L)

Table 31­3
Classification of Total­, LDL­, HDL­Cholesterol and Triglycerides in Children

Total Cholesterol Acceptable

<170 mg/dL (4.4 mmol/L) Borderline
170­199 mg/dL (4.4­5.2 mmol/L) High
≥200 mg/dL (5.2 mmol/L)

Low­Density Lipoprotein Cholesterol Acceptable

<110 mg/dL (2.8 mmol/L) Borderline
110­129 mg/dL (2.8­3.3 mmol/L) High
≥130 mg/dL (3.4 mmol/L)

High­Density Lipoprotein Cholesterol Low

<40 mg/dL (1 mmol/L) Borderline
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>45 mg/dL (1.2 mmol/L)
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility

Triglycerides Acceptable
 150­199 mg/dL (1.70­2.25 mmol/L) High
200­499 mg/dL (2.26­5.64 mmol/L) Very high California Northstate University
≥500 mg/dL (5.65 mmol/L) Access Provided by:

Table 31­3
Classification of Total­, LDL­, HDL­Cholesterol and Triglycerides in Children

Total Cholesterol Acceptable

<170 mg/dL (4.4 mmol/L) Borderline
170­199 mg/dL (4.4­5.2 mmol/L) High
≥200 mg/dL (5.2 mmol/L)

Low­Density Lipoprotein Cholesterol Acceptable

<110 mg/dL (2.8 mmol/L) Borderline
110­129 mg/dL (2.8­3.3 mmol/L) High
≥130 mg/dL (3.4 mmol/L)

High­Density Lipoprotein Cholesterol Low

<40 mg/dL (1 mmol/L) Borderline
40­45 mg/dL (1­1.2 mmol/L) Acceptable
>45 mg/dL (1.2 mmol/L)

Triglycerides Acceptable
0­9 years Borderline
<75 mg/dL (0.8 mmol/L) High
75­99 mg/dL (0.8­1.1 mmol/L) Acceptable
≥100 mg/dL (1.1 mmol/L) Borderline
10­19 years High
<90 mg/dL (1 mmol/L)
90­129 mg/dL (1­1.5 mmol/L)
≥130 mg/dL (1.5 mmol/L)

Data from Daniels SR, Benuck I, Christakis DA, et al. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents:
Full report, 2011. National Heart Lung and Blood Institute.

Available at: www.nhlbi.nih.gov/files/docs/guidelines/peds_guidelines_full.pdf

General Approach

A comprehensive approach to treating dyslipidemia and all modifiable major risk ASCVD factors is required to significantly reduce the risk of first
and recurrent ASCVD events. Therapeutic lifestyle change is the first­line therapy for any lipoprotein disorder. A healthy lifestyle should be
implemented in all patients with the general components including a reduction in the percent of calories from saturated and trans fats, increased
intake of soluble fiber, weight reduction if overweight or obese, increased physical activity, and avoiding or quitting tobacco use.25 Additionally,
patients with a diagnosis of hypertension should achieve optimal blood pressure control based on the 2017 ACC/AHA Guidelines for control of
hypertension (see Chapter 30, “Hypertension”).26 Persons with diabetes mellitus, especially those with established ASCVD, should receive glucose­
lowering therapies that have been shown to reduce ASCVD risk (see Chapter 91, “Diabetes Mellitus”).27

If therapeutic lifestyle changes are insufficient, lipid­lowering agents should be chosen based on which lipid is at an undesirable level and the
degree to which it is expected to increase the risk of ASCVD. The decision to initiate lipid­lowering therapy in the management of dyslipidemia should
be based on an individual’s ASCVD risk and not merely plasma levels of atherogenic lipoproteins (such as LDL­C) alone.28 Patients with established
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Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche Page 12 / 37
established ASCVD is more of an art that requires careful consideration of traditional (eg, age, hypertension) and nontraditional (eg, autoimmune
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
diseases, socioeconomic status) risk factors, the risks of lipid­lowering therapy, and patient preference. For patients between 40 and 79 years of age
and no history of ASCVD, the ASCVD Risk Estimator Plus (available at: www.tools.acc.org/ascvd­risk­estimator­plus) should be used to facilitate a
hypertension (see Chapter 30, “Hypertension”).26 Persons with diabetes mellitus, especially those with established ASCVD, should receive glucose­
lowering therapies that have been shown to reduce ASCVD risk (see Chapter 91, “Diabetes Mellitus”).27 California Northstate University
Access Provided by:

If therapeutic lifestyle changes are insufficient, lipid­lowering agents should be chosen based on which lipid is at an undesirable level and the
degree to which it is expected to increase the risk of ASCVD. The decision to initiate lipid­lowering therapy in the management of dyslipidemia should
be based on an individual’s ASCVD risk and not merely plasma levels of atherogenic lipoproteins (such as LDL­C) alone.28 Patients with established
ASCVD are at highest risk and most likely to benefit from select lipid­lowering therapies (such as statins). Risk assessment in patients without
established ASCVD is more of an art that requires careful consideration of traditional (eg, age, hypertension) and nontraditional (eg, autoimmune
diseases, socioeconomic status) risk factors, the risks of lipid­lowering therapy, and patient preference. For patients between 40 and 79 years of age
and no history of ASCVD, the ASCVD Risk Estimator Plus (available at: www.tools.acc.org/ascvd­risk­estimator­plus) should be used to facilitate a
clinician­patient discussion regarding the benefit and risks of lipid­lowering therapy, especially in patients whose 10­year risk is 7.5% or greater (see
Table 31­4). The Risk Estimator is comprised of the patient’s age, gender, race, TC, HDL­C, blood pressure, diabetes status, smoking status, and use of
antihypertensives, statins, and aspirin. Importantly, the Risk Estimator is based on data from large population studies of mostly African­American and
non­Hispanic white men and women. The Risk Estimator can be used for other ethnic groups if they are designated as non­Hispanic white; however,
the Risk Estimator will underestimate the risk of American Indians and Asian Americans of South Asian ancestry, while overestimating the risk of Asian
Americans of East Asian ancestry and some Hispanics (eg, Mexican Americans).28 An estimated lifetime risk for ASCVD can also be performed for
patients between age 20 and 39, yet these results should only be used to justify the need for lifestyle change and not the initiation of lipid­lowering
therapy. Additional tools for ASCVD­risk assessment include high­sensitivity C­reactive protein (hsCRP), apolipoprotein B, and lipoprotein(a) [Lp(a)]
levels that may be obtained to inform decision making in low­intermediate risk patients or those with recurrent ASCVD events despite appropriate
lipid­lowering therapy.28

TABLE 31­4
Key Recommendations to Reduce the Risk of Atherosclerotic Cardiovascular Disease (ASCVD) in Adults

Recommendations (ACC/AHA COR and LOE)

Heart­healthy lifestyle for everyone

Statin Benefit Groups—Patient groups likely to benefit from statin therapy

1. Clinical ASCVDi

a. Very high­riskii
High­intensity or maximally tolerated statin therapy (Class I)
b. Not at very high­risk
Age <75 years: High­intensity statin therapy (Class I)
If high­intensity not tolerated, use moderate­intensity statin therapy (Class I)
Age >75 years: Initiation of moderate­ or high­intensity statin is reasonable (Class IIa)

2. Primary prevention—Severe Hypercholesterolemia (LDL­C ≥190 mg/dL [4.91 mmol/L])

a. Rule out secondary causes of dyslipidemia
b. Age 20­75 years: Maximally tolerated statin therapy (Class I)

3. Primary prevention—Diabetes 40­75 years and LDL­C 70­189 mg/dL (1.81 ­ 4.89 mmol/L)
a. Moderate­intensity statin therapy regardless of 10­year ASCVD risk (Class I)
b. High­intensity statin therapy is reasonable in patients with diabetes and multiple ASCVD­risk factors (Class IIa)
c. It is reasonable to continue statin therapy in adults ≥75 years with diabetes previously taking statin therapy (Class IIa)
d. It is reasonable to initiate statin therapy in adults ≥75 years with diabetes after a discussion of risks and benefits (Class IIb)
e. It is reasonable to initiate statin therapy in adults 20­30 years with diabetes if any of the following apply: (Class IIb)
Long duration of diabetes (≥10 years for type 2 diabetes; ≥20 years for type 1 diabetes)
Albuminuria (≥30 mg/g albumin/mg creatinine [3.4 mg/mmol creatinine])

Estimated glomerular filtration rate <60 mL/min/1.73 m2

Retinopathy
Neuropathy
Ankle­brachial index <0.9
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4. Primary All Rights Reserved. Terms
diabetes, 40­75 of Use
years • Privacy
and LDL­C Policy
70­189 mg/dL• (1.81
Notice • Accessibility
­ 4.89 mmol/L)
1. Emphasize heart­healthy lifestyle and address other risk factors
2. Estimate 10­year ASCVD­risk score based on Pooled Cohort Equation
 Long duration of diabetes (≥10 years for type 2 diabetes; ≥20 years for type 1 diabetes)
Albuminuria (≥30 mg/g albumin/mg creatinine [3.4 mg/mmol creatinine]) California Northstate University
Estimated glomerular filtration rate <60 mL/min/1.73 m2 Access Provided by:

Retinopathy
Neuropathy
Ankle­brachial index <0.9

4. Primary prevention—no diabetes, 40­75 years and LDL­C 70­189 mg/dL (1.81 ­ 4.89 mmol/L)
1. Emphasize heart­healthy lifestyle and address other risk factors
2. Estimate 10­year ASCVD­risk score based on Pooled Cohort Equation
High Risk (≥20%): Initiate high­intensity statin therapy (Class I)
Intermediate Risk (≥7.5% to <20%): If risk enhancersiii present, consider moderate­intensity statin therapy (Class I)
If risk decision is uncertain, consider measuring CAC in selected adults
Consider no statin if CAC = 0 unless patient has diabetes or significant family history of ASCVD
Consider initiating statin therapy if CAC 1­99, especially if age >55 years
Initiate statin therapy if CAC ≥100

Borderline Risk (5% to <7.5%): If risk enhancersiii present, risk discussion regarding moderate­intensity statin therapy (Class IIb)
Low Risk (<5%): Emphasize heart­healthy lifestyle (Class I)

5. Primary prevention—no diabetes, 20­39 years and LDL­C 70­189 mg/dL (1.81 ­ 4.89 mmol/L)
a. Estimate lifetime ASCVD­risk based on Pooled Cohort Equation to encourage lifestyle to reduce ASCVD risk
b. Consider statin therapy if family history of premature ASCVD and LDL­C ≥160 mg/dL (4.14 mmol/L)

iClinical ASCVD includes nonfatal MI, CHD death, and nonfatal and fatal stroke, TIA or peripheral arterial disease presumed to be of atherosclerotic origin.

iiVery high risk include history of >1 major ASCVD events including recent ACS (past 12 months), history of MI, ischemic stroke, or peripheral arterial disease; O R one

major ASCVD event p l u s multiple high­risk conditions: >65 years, familial hypercholesterolemia, history of coronary bypass graft surgery, diabetes mellitus,
hypertension, CKD, current smoking, LDL­C >100 mg/dL (2.59 mmol/L) despite maximally tolerated statin and ezetimibe, or history of heart failure.

iiiRisk Enhancers include: LDL­C 160­189 mg/dL (4.14­4.89 mmol/L), family history of premature ASCVD, metabolic syndrome, chronic kidney disease, chronic

inflammatory conditions (eg, rheumatoid arthritis), premature menopause (before age 40), preeclampsia, high­risk race/ethnicities (eg, South Asian), triglycerides
≥175 mg/dL (1.98 mmol/L), hs­CRP ≥2 mg/L, lipoprotein(a) ≥50 mg/dL (0.5 g/L), apoB ≥130 mg/dL, (1.3 g/L) or ankle­brachial index <0.9.

ABI, ankle brachial index; ACC/AHA, American College of Cardiology/American Heart Association; ASCVD, Atherosclerotic cardiovascular disease; CAC, coronary artery
calcium; COR, Class of recommendation; hsCRP, high­sensitivity C reactive protein; LDL­C, low­density lipoprotein cholesterol; LOE, Level of evidence; NYHA, New
York Heart Association.

The HMG­CoA reductase inhibitors or “statins” are the drugs of choice for most patients with dyslipidemia.20 A large body of evidence from
randomized, double­blind, placebo­controlled trials has demonstrated the effectiveness of statins on reducing first and recurrent cardiovascular
events, cardiovascular mortality, and all­cause mortality.29 The 2018 ACC/AHA Blood Cholesterol Guideline identified four statin benefit groups where
the data from RCT demonstrate clear evidence that the benefit of statin therapy outweighs the potential risks (Table 31­4).20 Nonstatin lipid­lowering
therapies (such as ezetimibe, bempedoic acid, and PCSK9 inhibitors) play a supportive role in the management of dyslipidemia and are primarily used
in combination with statins when adequate LDL­C lowering cannot be achieved with statins alone, or in patients unable to tolerate the recommended
dose of a statin (Table 31­5).30

TABLE 31­5
Key Recommendations on Role of Nonstatin Therapies to Reduce ASCVD Risk in Adults

Threshold for considering

nonstatin therapies
Recommendations
non­HDL­C
LDL­C (mg/dL)
(mg/dL)
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Terms of Use •tolerated
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Policy • Notice • Accessibility ≥70(1.81 ≥100 (2.59 mmol/L)
a. Consider adding ezetimibe first mmol/L)

b. Consider adding or replacing with PCSK9 inhibitor or adding bempedoic acidiv second
in combination with statins when adequate LDL­C lowering cannot be achieved with statins alone, or in patients unable to tolerate the recommended
dose of a statin (Table 31­5).30 California Northstate University
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TABLE 31­5
Key Recommendations on Role of Nonstatin Therapies to Reduce ASCVD Risk in Adults

Threshold for considering

nonstatin therapies
Recommendations
non­HDL­C
LDL­C (mg/dL)
(mg/dL)

1. Clinical ASCVD without comorbidities on maximally tolerated statin ≥70(1.81 ≥100 (2.59 mmol/L)
a. Consider adding ezetimibe first mmol/L)

b. Consider adding or replacing with PCSK9 inhibitor or adding bempedoic acidiv second

2. Clinical ASCVD with comorbidities on maximally tolerated statin ≥70(1.81 ≥100 (2.59 mmol/L)
a. Consider adding ezetimibe, bempedoic acid, or PCSK9 inhibitor as initial therapy and addition of mmol/L)
another agent if necessary

3. Clinical ASCVD and baseline LDL­C >190 mg/dL (4.91 mmol/L) on maximally tolerated statin ≥70(1.81 ≥100 (2.59 mmol/L)
a. Consider adding ezetimibe, bempedoic acid, or PCSK9 inhibitor as initial therapy and addition of mmol/L)
another agent if necessary

4. Primary prevention and baseline LDL­C >190 mg/dL (4.91 mmol/L) on maximally tolerated statin ≥100 (2.59 ≥130 (3.36 mmol/L)
a. Consider adding ezetimibe, bempedoic acid, or PCSK9 inhibitor as initial therapy and addition of mmol/L)
another agent if necessary

5. Primary prevention (age 40­75 years) with diabetes and baseline LDL­C 70­189 mg/dL (1.81­4.89 ≥100 (2.59 ≥130 (3.36 mmol/L)
mmol/L) on maximally tolerated statin mmol/L)
a. Consider ezetimibe

iComorbidities include diabetes, recent ASCVD event (<3 months), ASCVD event while on a statin, poorly controlled ASCVD­risk factors, elevated lipoprotein(a),

chronic kidney disease, symptomatic heart failure, maintenance hemodialysis, baselines LDL­C >190 mg/dL (4.91 mmol/L), age >65 years, prior MI or
nonhemorrhagic stroke, current daily cigarette smoking, symptomatic peripheral artery disease with prior history of heart attack or stroke, history of
nonmyocardial infarction–related coronary revascularizations, low HDL­C, high­sensitivity C­reactive protein >2 mg/L, or metabolic syndrome.

iiEzetimibe is preferred if <25% additional LDL­C needed, patients <3 months postacute coronary syndrome, cost considerations, patient preference.

iiiPCSK9 inhibitor is preferred if >25% additional LDL­C needed and patient willing to administer subcutaneous injections.

Clinical ASCVD includes nonfatal MI, CHD death, and nonfatal and fatal stroke, TIA or peripheral arterial disease presumed to be of atherosclerotic origin.

ivLong­term cardiovascular outcome data is not yet available for bempedoic acid. Medications with documented cardiovascular benefits, when used in combination

with statins or as mono­therapy, should be preferentially used.

ASCVD, Atherosclerotic cardiovascular disease; LDL­C, low­density lipoprotein cholesterol; non­HDL­C, non­high­density lipoprotein cholesterol; PCSK9, proprotein
subtilisin/kexin type 9.

Data from Reference 20.

Numerous clinical outcome trials have been performed to determine whether lipid­lowering therapies reduce ASCVD risk in primary and secondary
prevention populations. Reducing total cholesterol and LDL­C reduces CHD and total mortality. It is beyond the scope of this chapter to discuss each of
these trials in detail. Table 31­6 summarizes select trials supporting the use of statins and select nonstatins (ezetimibe and PCSK9 inhibitors) to reduce
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Chapter 31:Most of the primary
Dyslipidemia, Daveand secondary
L. Dixon; prevention
Daniel M. Richestudies were double­blinded, randomized, and placebo­controlled, lasting 2 toPage 7 years,
15 /and
37
©2025
most hadMcGraw Hill.patient
sufficient All Rights Reserved.
numbers Terms of Use
to be meaningful. The• body
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of evidence • Accessibility
supporting the role of statin therapy to reduce ASCVD is significant and
meta­analysis data confirms these agents as the first­line therapy in dyslipidemia management.31 As mentioned previously in this chapter, not all lipid­
lowering therapies have translated to reducing ASCVD risk, despite having favorable effects on the lipid profile.
 subtilisin/kexin type 9.

California Northstate University

Data from Reference 20.
Access Provided by:

Numerous clinical outcome trials have been performed to determine whether lipid­lowering therapies reduce ASCVD risk in primary and secondary
prevention populations. Reducing total cholesterol and LDL­C reduces CHD and total mortality. It is beyond the scope of this chapter to discuss each of
these trials in detail. Table 31­6 summarizes select trials supporting the use of statins and select nonstatins (ezetimibe and PCSK9 inhibitors) to reduce
ASCVD risk. Most of the primary and secondary prevention studies were double­blinded, randomized, and placebo­controlled, lasting 2 to 7 years, and
most had sufficient patient numbers to be meaningful. The body of evidence supporting the role of statin therapy to reduce ASCVD is significant and
meta­analysis data confirms these agents as the first­line therapy in dyslipidemia management.31 As mentioned previously in this chapter, not all lipid­
lowering therapies have translated to reducing ASCVD risk, despite having favorable effects on the lipid profile.

TABLE 31­6
Selected Landmark Clinical Trials with Lipid­Lowering Drugs

Follow­Up Control Intervention p­ RRR ARR

Trial N Intervention NNT
(yr) Events (%) Events (%) value (%) (%)

Primary Prevention

AFCAPS/TexCAPS 5 6,605 Lovastatin 20­40 mg 5.5 3.5 <0.001 36.4 2.0 50

WOSCOPS 4.9 6,595 Pravastatin 40 mg 7.8 5.5 <0.001 29.5 2.3 43

CARDS 4 2,838 Atorvastatin 10 mg 9.0 5.8 0.001 37 3.2 32

JUPITER 1.9 17,802 Rosuvastatin 20 mg 2.82 1.59 0.00001 44 1.2 82

Secondary Prevention

HPS 5 20,536 Simvastatin 40 mg 14.7 12.9 0.0003 13 1.8 56

TNT 4.9 10,001 Atorvastatin 10 mg 10.9 8.7 <0.001 22 2.2 45

vs 80 mg

IMPROVE­IT 7 18,144 Ezetimibe + Statin 34.7 32.7 0.016 6 2 50

FOURIER 2.2 27,564 Evolocumab + Statin 11.3 9.8 <0.001 15 1.5 67

ARR, absolute risk reduction; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study32; CARDS, Collaborative Atorvastatin Diabetes Study12;

FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients with Elevated Risk33; HPS, Heart Protection Study34; IMPROVE­IT, Improved

Reduction of Outcomes: Vytorin Efficacy International Trail35; JUPITER, Justification for the Use of Statins in Prevention36; NNT, Number Needed to Treat; RRR,
relative risk reduction; TNT, Treat to New Targets Trial37; WOSCOPS, The West of Scotland Coronary Prevention Study.38

Nonpharmacologic Therapy

Lifestyle modification is the cornerstone of ASCVD­risk reduction and is recommended in all patients, including those receiving lipid­lowering therapy.
Weight and body mass index (BMI) should be determined at each visit and lifestyle patterns to induce a weight loss of 5% to 10% should be discussed in
persons who are overweight or obese. Moderate­to­vigorous intensity physical activity is recommended three to four times per week with each session
lasting 40 minutes on average. All patients should also be counseled to stop smoking and avoid tobacco products altogether.25

It is important to recognize that there is no single diet suitable for every patient. Instead, advise patients to reduce the percent of calories from
saturated and trans fats by following a dietary pattern that emphasizes vegetables, fruits, whole grains, low­fat dairy, poultry, fish, legumes, and nuts;
while limiting the intake of sweets, sugary beverages, and red meat. Plans that closely mirror this dietary pattern and effectively lower LDL­C include
DASH, the USDA Food Pattern, and AHA Diet. Although the Mediterranean­style diet has no consistent effect on LDL­C levels, it has been shown to
reduce major 2025­2­13
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Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche
should be adapted to a patient’s caloric requirements, cultural food preferences, and for other medical conditions (eg, diabetes mellitus).Page 16 / 37
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Individualized diet counseling that provides acceptable substitutions for unhealthy foods and ongoing reinforcement by a registered dietitian are
necessary for maximal effect. It is also important to involve all family members, especially if the patient is not the primary person preparing food.25
lasting 40 minutes on average. All patients should also be counseled to stop smoking and avoid tobacco products altogether.25
California Northstate University
It is important to recognize that there is no single diet suitable for every patient. Instead, advise patients to reduce the percent of calories
Access Provided by: from
saturated and trans fats by following a dietary pattern that emphasizes vegetables, fruits, whole grains, low­fat dairy, poultry, fish, legumes, and nuts;
while limiting the intake of sweets, sugary beverages, and red meat. Plans that closely mirror this dietary pattern and effectively lower LDL­C include
DASH, the USDA Food Pattern, and AHA Diet. Although the Mediterranean­style diet has no consistent effect on LDL­C levels, it has been shown to
reduce major cardiovascular events among persons at high cardiovascular risk when compared to a control diet. Any recommended dietary pattern
should be adapted to a patient’s caloric requirements, cultural food preferences, and for other medical conditions (eg, diabetes mellitus).
Individualized diet counseling that provides acceptable substitutions for unhealthy foods and ongoing reinforcement by a registered dietitian are
necessary for maximal effect. It is also important to involve all family members, especially if the patient is not the primary person preparing food.25

Less than one­third of Americans meet the 2015­2020 Dietary Guidelines for Americans limit of less than 10% of calories from saturated fats.39 In
patients with lipid disorders, the 2013 AHA/ACC Lifestyle Management Guideline recommended only 5% to 6% of total calories from saturated fat.25
This can be achieved by recommending patients limit or avoid fast food, high­fat dairy products, and sweets. Previous dietary guideline
recommendations to limit dietary cholesterol to 300 mg/day was omitted in 2015. However, it is still recommended that individuals limit their daily
dietary cholesterol intake. A dietary pattern low in saturated and trans fats will typically result in a reduction in dietary cholesterol since foods high in
saturated and trans fats are often high in cholesterol. A 12­week trial of lifestyle modification is generally recommended before considering lipid­
lowering therapy in patients without evidence of ASCVD, diabetes, or other high­risk features. Importantly, lifestyle modification alone is inappropriate
for patients with established ASCVD or diabetes given the benefit of statins in these high­risk patients.

Dietary Supplements

Select dietary supplements may be useful to augment diet and lipid­lowering therapy. Increased intake of soluble fiber in the form of oat bran, pectins,
certain gums, and psyllium products can reduce total and LDL­C, but have little or no effect on HDL­C or TG levels. Soluble fiber binds cholesterol and
bile acids in the small intestine, which decrease absorption and reabsorption. Total daily fiber intake should be about 25 g/day, yet most Americans
average only half of the recommended amount.40 Dietary supplements containing fiber may be used to supplement the diet and achieve the
recommended daily intake. An intake of 3 to 12 g/day show reductions in total and LDL­C of 10 mg/dL (0.26 mmol/L) and 12 mg/dL (0.31 mmol/L),
respectively, compared to control.30 It remains unknown if soluble fiber supplements have any impact on cardiovascular morbidity and mortality.
Although seemingly safe, patients should be advised to stay well hydrated to avoid gastrointestinal distress. These products may also be useful in
managing constipation associated with the bile acid sequestrants.

In epidemiologic studies, ingestion of large amounts of oily, cold­water fish (such as salmon) is associated with a reduction in ASCVD risk. Modest
consumption (1­2 servings per week) reduces the risk of cardiovascular death and total mortality.41 The American Heart Association recommends
eating oily fish at least twice a week; however, there are concerns with some types of fish (such as tuna) that often have high levels of environmental
contaminants. There are also concerns about environmental sustainability. Fish oil supplementation is an alternative option that provides a consistent
daily intake of omega­3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplementation significantly reduces TG
levels and VLDL­C, but may increase total cholesterol and LDL­C. Other potentially favorable cardiovascular effects of fish oil supplementation include
antiarrhythmic, antiplatelet, and anti­inflammatory properties. Despite this, a meta­analysis of 10 RCT found no benefit with low doses (less than 2
g/day) of omega­3 PUFA supplementation.42 Still, current recommendations suggest low­dose omega­3 PUFA supplementation is reasonable to
consider in secondary prevention patients with heart failure or at high risk of sudden cardiac death.43 Low dose omega­3 PUFA supplementation is not
recommended in primary prevention patients, especially those with diabetes who do not have established ASCVD.43,44 Additional details regarding
prescription omega­3 PUFA products are further discussed under drug therapy.

Phytosterols, including plant sterols and stanols isolated from vegetable oils, also reduce LDL­C levels. Ingestion of 2 g/day will reduce LDL­C by 5% to
15%, while doses above 3 g/day confer no additional LDL­C lowering.28 The efficacy of plant sterols and plant stanols is considered to be comparable.
The mechanism by which phytosterols reduce LDL­C remains unclear but may decrease the transport of cholesterol in the intestinal brush border
membrane and affect cholesterol uptake via Niemann­Pick C1­Like 1 (NPC1L1) and other transporters. Because lipids are needed to solubilize
stanol/sterol esters, they are usually available in commercial butter­like spreads (such as Benecol®). The presence of plant stanols/sterols is listed on
the food label. Phytosterols should be administered 2 to 4 hours before or after bile acid sequestrants to avoid binding of phytosterols in the gut.
Although phytosterols are generally recognized as safe (GRAS) in the United States, they can cause gastrointestinal distress and should be avoided in
patients with sitosterolemia, a rare genetic disorder characterized by 50­ to 100­fold increase in plant sterol levels and rapid onset of atherosclerosis.45
The effects of long­term phytosterol supplementation on ASCVD risk remains unknown.

Red yeast rice is a commonly used dietary supplement in the United States that originates from Chinese medicine. The active ingredient of red yeast
rice is monacolin K, which is chemically identical to lovastatin. This leads some patients to believe red yeast rice is a “natural” statin and, therefore,
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safer
Chapterthan31:
statins currently available
Dyslipidemia, only byDaniel
Dave L. Dixon; prescription;
M. Richehowever, the active ingredient in over­the­counter (OTC) red yeast rice productsPage
vary 17
by /over
37
©2025
120­fold.McGraw Hill. All Rights
Many products containReserved.
little to no monacolin. 46
Terms of UseConversely,
• Privacy Policy • Noticeof•rhabdomyolysis,
case reports Accessibility liver toxicity, and renal failure have raised
concerns about some red yeast rice formulations containing significantly higher levels of monacolin K than described on the label.47 Red yeast rice is
Although phytosterols are generally recognized as safe (GRAS) in the United States, they can cause gastrointestinal distress and should be avoided in
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patients with sitosterolemia, a rare genetic disorder characterized by 50­ to 100­fold increase in plant sterol levels and rapid onset of atherosclerosis.45
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The effects of long­term phytosterol supplementation on ASCVD risk remains unknown.

Red yeast rice is a commonly used dietary supplement in the United States that originates from Chinese medicine. The active ingredient of red yeast
rice is monacolin K, which is chemically identical to lovastatin. This leads some patients to believe red yeast rice is a “natural” statin and, therefore,
safer than statins currently available only by prescription; however, the active ingredient in over­the­counter (OTC) red yeast rice products vary by over
120­fold. Many products contain little to no monacolin.46 Conversely, case reports of rhabdomyolysis, liver toxicity, and renal failure have raised
concerns about some red yeast rice formulations containing significantly higher levels of monacolin K than described on the label.47 Red yeast rice is
not recommended as a suitable alternative to statins. However, if patients choose to take red yeast rice, it is recommended they purchase it from a
reputable supplier and avoid concurrent use with prescription statins.

Pharmacologic Therapy

There are numerous randomized, double­blinded clinical trials demonstrating that reduction of LDL­C reduces ASCVD­event rates in the setting of
primary and secondary prevention.27 Epidemiological studies suggest that every 38 mg/dL (0.98 mmol/L) reduction in LDL­C produces a 21% reduction
in ASCVD event rates over 5 years.48 Additional findings from large prospective cohort studies and Mendelian randomization studies have also
demonstrated a dose­dependent log­linear association between LDL­C and ASCVD risk49 and that lower levels of LDL­C achieve significant reductions
in ASCVD risk. These studies provide a strong rationale for attempting to lower plasma cholesterol and LDL­C in patients at risk for ASCVD.49 It should
be noted, however, that not all lipid­lowering agents that reduce LDL­C have resulted in a reduction in ASCVD events (eg, CETP inhibitors). Thus, LDL­C
lowering alone should not be the sole basis for selecting an appropriate agent.20,28 Lipid­lowering drugs can be broadly divided into agents that
primarily decrease atherogenic cholesterol­containing lipoprotein particles (such as statins) and those that primarily decrease TG levels (such as
fibrates).

Treatment of Specific Dyslipidemia Subtypes

Familial Hypercholesterolemia

Individuals with familial hypercholesterolemia (FH) have a very high lifetime risk of developing ASCVD. Compared to the general population, FH is
associated with a 24­fold higher risk of developing acute MI before age 40.50 FH should be suspected in adults with untreated LDL­C levels of 190 mg/dL
(4.91 mmol/L) or greater or non­HDL cholesterol levels of 220 mg/dL (5.69 mmol/L) or greater who have a family history of high cholesterol or ASCVD in
first­degree relatives. Physical findings (such as xanthomas or corneal arcus) may be present in some patients with FH, but their absence does not rule
out a diagnosis of FH. In clinical practice, one of several validated tools, including the Dutch Lipid Clinic Network, US Make Early Diagnosis Prevent Early
Death (MEDPED), and Simon­Broome Registry, are used to make a formal diagnosis of FH. Genetic testing is available but is only necessary when the
diagnosis is uncertain or if it is needed to obtain prior authorization for select lipid­lowering therapies, such as PCSK9 inhibitors. Approximately 20%
of patients with clinically definite FH will not have an identifiable mutation; therefore, a negative genetic test does not exclude FH.51 Importantly,
cascade screening of all first­degree relatives of diagnosed FH patients is highly recommended as an effective strategy to identify previously
undiagnosed FH patients.

Mipomersen and lomitapide are orphan drugs indicated for use in patients with HoFH and reduce LDL­C levels by ∼25% and ∼40%, respectively.52
Mipomersen is an oligonucleotide inhibitor of apolipoprotein B­100 synthesis administered via subcutaneous injection, while the orally administered
lomitapide is a microsomal triglyceride transfer protein, or microsomal TG transfer protein inhibitor, which reduces the level of cholesterol that the
liver and intestines assemble and secrete into the circulation. Mipomersen is associated with injection site pain and reactions, while both mipomersen
and lomitapide have a black box warning for severe hepatotoxicity and are only available through restricted Risk Evaluation and Mitigation Strategy
(REMS) programs.52 Other treatment options for HoFH patients include LDL apheresis (a process similar to dialysis that removes LDL from the blood)
and liver transplant.50

Hypertriglyceridemia

Elevated TG levels are strongly associated with an increased risk of ASCVD; however, the direct role of TG in the development of ASCVD is debed.53 All
patients with elevated TG levels (see Tables 31­1 and 31­2) should be advised to implement lifestyle interventions that reduce TG levels, including a 5%
to 10% reduction in body weight, reducing consumption of sugar and refined carbohydrates, increasing physical activity, smoking cessation, and
restricting alcohol. Secondary causes of hypertriglyceridemia should also be identified and addressed. Uncontrolled diabetes and chronic kidney
disease are common causes of elevated TG levels, along with certain medications (such as protease inhibitors and atypical antipsychotics). The best
approach to managing
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10:53 Pwhose
YourTGIP levels
is remain elevated after optimizing lifestyle interventions and addressing secondary causes remains
unclear, but
Chapter 31: statins are generally
Dyslipidemia, Dave considered first­line
L. Dixon; Daniel M. given
Richethey can reduce TG levels by up to 30% at higher doses and help achieve desired levels
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37
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LDL­C. The role of TG­lowering therapies such as fibrates and omega­3 PUFA in patients with TG of 200 to 499 mg/dL (2.26 5.64 mmol/L) is less clear.
Clinical trials are underway to determine if fibrates and omega­3 PUFA reduce ASCVD risk in this population.55
Elevated TG levels are strongly associated with an increased risk of ASCVD; however, the direct role of TG in the development of ASCVD is debed.53 All
California
patients with elevated TG levels (see Tables 31­1 and 31­2) should be advised to implement lifestyle interventions that reduce Northstate
TG levels, University
including a 5%
Access Provided by:
to 10% reduction in body weight, reducing consumption of sugar and refined carbohydrates, increasing physical activity, smoking cessation, and
restricting alcohol. Secondary causes of hypertriglyceridemia should also be identified and addressed. Uncontrolled diabetes and chronic kidney
disease are common causes of elevated TG levels, along with certain medications (such as protease inhibitors and atypical antipsychotics). The best
approach to managing patients whose TG levels remain elevated after optimizing lifestyle interventions and addressing secondary causes remains
unclear, but statins are generally considered first­line given they can reduce TG levels by up to 30% at higher doses and help achieve desired levels of
LDL­C.54 The role of TG­lowering therapies such as fibrates and omega­3 PUFA in patients with TG of 200 to 499 mg/dL (2.26 5.64 mmol/L) is less clear.
Clinical trials are underway to determine if fibrates and omega­3 PUFA reduce ASCVD risk in this population.55

Fasting TG levels exceeding 500 mg/dL (5.65 mmol/L) are more commonly associated with pancreatitis and other consequences of
hyperchylomicronemia (such as eruptive xanthomas). At this level of elevated TG, a genetic form of hypertriglyceridemia often coexists with other
causes of elevated triglycerides such as diabetes. Dietary fat restriction is a basic element of treatment as this reduces the synthesis and entry of
additional chylomicrons into the circulation. Lipid­lowering therapies that primarily lower TG levels (such as fibrates, omega­3 PUFA, and niacin) are
recommended as first­line agents.54 Statins may be reasonable first­line options in those patients with an ASCVD risk of 7.5% or greater. If TG levels are
persistently over 500 mg/dL (5.65 mmol/L), it is reasonable to consider adding omega­3 PUFA or fibrate therapy. Success in treatment is defined as a
reduction in triglycerides below 500 mg/dL (5.65 mmol/L) and preventing pancreatitis.

Low HDL Cholesterol

Low HDL­C is a strong independent risk predictor of ASCVD.56 Low HDL­C is defined as less than 40 mg/dL (1.03 mmol/L) for men and less than 50
mg/dL (1.29 mmol/L) for women, but there is no specified goal for HDL­C raising. Low HDL­C may be a consequence of insulin resistance, physical
inactivity, diabetes, cigarette smoking, very high carbohydrate intake, and certain drugs. In patients with low HDL­C levels, the primary target remains
LDL­C. Niacin has the potential for the greatest increase in HDL­C compared to other lipid­lowering therapies and the effect is more pronounced with
regular or immediate­release forms than with sustained­release forms. However, no RCT has resulted in areduction in ASCVD risk by increasing HDL­
C.57,58 Additionally, several CETP inhibitors capable of raising HDL­C levels as much as 135% were evaluated in randomized, placebo­controlled trials
but no additional benefit was found when these drugs were added to background statin therapy.56 Due to the lack of pharmacological agents
demonstrating an improvement in clinical outcomes by focusing on raising HDL­C, lifestyle modification (such as smoking cessation and increasing
physical activity) remains the preferred approach. Although alcohol consumption has been shown to increase HDL­C, it is not acceptable to
recommend this to patients who do not already consume alcohol.

Medications That Primarily Lower Atherogenic Cholesterol

HMG­CoA Reductase Inhibitors (Statins)

Statins (such as atorvastatin) are considered the first­line lipid­lowering therapies for managing dyslipidemia due to robust evidence from multiple
RCTs demonstrating that statins significantly decrease the risk of first (primary prevention) and recurrent (secondary prevention) cardiovascular
events.20,48 Statins significantly reduce LDL­C levels (20%­60%), modestly increase HDL­C (6%­12%) and decrease TG levels (10%­29%).59 Statins
interrupt the conversion of HMG­CoA to mevalonate, the rate­limiting step in de novo cholesterol biosynthesis, by inhibiting HMG­CoA reductase (see
Fig. 31­4). Metabolic studies with statins in normal volunteers and patients with hypercholesterolemia suggest a reduced synthesis of LDL­C, as well as
enhanced catabolism of LDL mediated through LDL receptors, as the principal mechanisms for lipid­lowering effects. Statin selection is primarily
based on the patients individual ASCVD risk and indicated intensity (see Tables 31­4 and 31­7). Currently available products in order of decreasing LDL­
C lowering potency, include rosuvastatin, atorvastatin, pitavastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.59 The plasma half­lives for all
the statins are relatively short (1­3 hours) except for atorvastatin, pitavastatin, and rosuvastatin, which may account for their potency.59 Statins are
generally well tolerated but are not without adverse effects. However, discontinuation rates due to adverse effects in randomized, double­blind,
placebo­controlled trials have often been similar between statin and placebo.60

TABLE 31­7
Intensity of Statin Therapy by Drug and Daily Dose

High­intensity Statin Therapy Moderate­intensity Statin Therapy Low­intensity Statin Therapy

Lowers LDL on average by ≥50% Lowers LDL on average by 30% to <50% Lowers LDL on average by <30%
Atorvastatin 40­80 mg Atorvastatin 10­20 mg Simvastatin 10 mg

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Simvastatin 20­40 mgi Lovastatin 20 mg Page 19 / 37
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Fluvastatin 20­40 mg
Pravastatin 40­80 mg
Lovastatin 40 mg Pitavastatin 1 mg
C lowering potency, include rosuvastatin, atorvastatin, pitavastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.59 The plasma half­lives for all
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the statins are relatively short (1­3 hours) except for atorvastatin, pitavastatin, and rosuvastatin, which may account for their potency.59 Statins are
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generally well tolerated but are not without adverse effects. However, discontinuation rates due to adverse effects in randomized, double­blind,
placebo­controlled trials have often been similar between statin and placebo.60

TABLE 31­7
Intensity of Statin Therapy by Drug and Daily Dose

High­intensity Statin Therapy Moderate­intensity Statin Therapy Low­intensity Statin Therapy

Lowers LDL on average by ≥50% Lowers LDL on average by 30% to <50% Lowers LDL on average by <30%
Atorvastatin 40­80 mg Atorvastatin 10­20 mg Simvastatin 10 mg
Rosuvastatin 20­40 mg Rosuvastatin 5­10 mg Pravastatin 10­20 mg

Simvastatin 20­40 mgi Lovastatin 20 mg

Pravastatin 40­80 mg Fluvastatin 20­40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2­4 mg

iSimvastatin is not recommended by the FDA to be initiated at 80 mg/day due to increased risk of myopathy and rarely rhabdomyolysis.

Boldface type indicates medications that have cardiovascular outcome data from RCTs when given in the specified dose.

FDA, Food and Drug Administration; RCT, Randomized clinical trials.

Statin­associated muscle symptoms (SAMS) are reported by 10% to 25% of statin users and are frequently reported by patients as a reason for statin
discontinuation.61 While various definitions of SAMS exist, the clinical diagnosis of SAMS is based on a subjective clinical assessment. Myalgia is the
most commonly reported muscle­related adverse effect with statin therapy and refers to bilateral muscle achiness, weakness, or cramps affecting
larger muscle groups (such as thighs and back). Myopathy is often used interchangeably with myalgia, but myopathy is a general term used for any
muscle­related symptoms. The most concerning of SAMS is rhabdomyolysis, which is a rapid breakdown of skeletal muscle resulting in creatine kinase
(CK) elevations greater than 10 times the upper limit of normal. The release of myoglobin from damaged muscle tissue may also compromise renal
function and lead to acute kidney injury. Patients presenting with rhabdomyolysis will often describe their urine as dark or “tea­colored” and present
with nausea, vomiting, confusion, coma, cardiac arrhythmias, electrolyte disturbances, and even death. Fortunately, rhabdomyolysis in statin­treated
patients is exceedingly rare occurring in only 0.1% of patients in RCT compared to 0.04% of patients receiving placebo. Rhabdomyolysis is not only
caused by statins but can also be induced by extreme physical exercise, certain metabolism disorders (eg, diabetic ketoacidosis), other drugs (eg,
colchicine), toxins, and infection.

Certain risk factors are known to increase the risk of developing SAMS and recognition of these risk factors at the time of statin initiation may minimize
the risk of SAMS. Known risk factors include advanced age, female gender, low body mass index, frequent heavy exercisers, comorbidities (eg, kidney
disease, hypothyroidism), and increased serum statin concentrations due to drug–drug interactions.61 A lower dose might be necessary for patients
with multiple risk factors for SAMS, and once the starting dose is tolerated, the dose can be titrated to the desired potency. Avoiding major drug–drug
interactions is a significant modifiable risk factor for SAMS that pharmacists can directly impact. Nearly 80% of all medications are metabolized in the
liver by the cytochrome P450 system (CYP) with CYP3A4 being the most predominant.62 Statins are no different as nearly all statins, except pravastatin,
are metabolized to some degree by CYP isoenzymes. Lovastatin, simvastatin, and atorvastatin are associated with more significant drug–drug
interactions since they are predominantly metabolized by CYP3A4, while fluvastatin, pitavastatin, and rosuvastatin rely on other CYP isoenzymes (eg,
CYP2C9, CYP2C8, CYP2C19).63 The co­prescribing of medications that compete with or inhibit the same CYP isoenzyme (such as verapamil) can increase
serum statin concentrations and the risk for SAMS. The concurrent use of medications such as gemfibrozil that interfere with statin glucuronidation,
which is responsible for statin clearance, increases the risk of SAMS.

The management of SAMS requires a multifaceted approach. Documentation of the patient’s reported symptoms and determining the probability of
SAMS is an important first step. A Statin Intolerance App (available at: http://www.acc.org/statinintoleranceapp) created by the ACC is a helpful
resource that can be used to determine the possibility of SAMS and provide guidance on managing patients with possible SAMS. Statin therapy should
be generally discontinued in patients with intolerable symptoms. If symptoms resolve, initiate a different statin at a lower dose.61,64 Additionally,
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hydrophilic
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Dyslipidemia, rosuvastatin)
L. Dixon;may be better
Daniel tolerated than lipophilic statins (such as simvastatin). In patients where symptomsPage
M. Riche do not
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improve, Hill. All Rights
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should • Privacy including
be excluded, Policy • Notice and vitamin D deficiency, before a statin rechallenge.64
• Accessibility
hypothyroidism
Alternative dosing strategies (eg, every other day) using statins with long half­lives (atorvastatin, rosuvastatin, and likely pitavastatin) may also be
considered. Nonstatin therapies may be considered in patients who fail multiple statins. While routine CK monitoring is not recommended, a CK
which is responsible for statin clearance, increases the risk of SAMS.
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The management of SAMS requires a multifaceted approach. Documentation of the patient’s reported symptoms and determining
Access Provided the
by: probability of

SAMS is an important first step. A Statin Intolerance App (available at: http://www.acc.org/statinintoleranceapp) created by the ACC is a helpful
resource that can be used to determine the possibility of SAMS and provide guidance on managing patients with possible SAMS. Statin therapy should
be generally discontinued in patients with intolerable symptoms. If symptoms resolve, initiate a different statin at a lower dose.61,64 Additionally,
hydrophilic statins (such as rosuvastatin) may be better tolerated than lipophilic statins (such as simvastatin). In patients where symptoms do not
improve, other potential causes of muscle pain should be excluded, including hypothyroidism and vitamin D deficiency, before a statin rechallenge.64
Alternative dosing strategies (eg, every other day) using statins with long half­lives (atorvastatin, rosuvastatin, and likely pitavastatin) may also be
considered. Nonstatin therapies may be considered in patients who fail multiple statins. While routine CK monitoring is not recommended, a CK
measurement prompted by patient symptoms can be used to exclude rhabdomyolysis and can assist with identifying those with definite myalgia.
Importantly, patients should be reassured that statins are effective and safe, and SAMS is reversible with statin discontinuation.

Other notable adverse effects of statins include mild elevations in serum transaminase levels (primarily alanine aminotransferase [ALT]). Liver
enzymes are not, however, an accurate measure of liver function and there is no causal relationship between statin use and liver failure. Therefore,
routine periodic monitoring of liver enzymes is not required, but liver enzyme tests should be obtained before starting statin therapy to have a
baseline value for comparison if liver enzymes are later discovered to be elevated. Other potential causes for elevated liver enzymes, including
excessive alcohol intake, infection, and select medications should also be evaluated. Statins may be initiated in patients with chronic liver disease,
compensated cirrhosis, and nonalcoholic fatty liver disease; however, statins are contraindicated in patients with decompensated cirrhosis or acute
liver failure.64

Statin use is also associated with a small increased risk of new­onset diabetes.61 This was first observed in the JUPITER (Justification for the Use of
Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, where the number of new­onset diabetes cases was 0.6% higher in those
receiving rosuvastatin 20 mg/day compared to placebo.36 Subsequent meta­analyses of statin trials have also found a modest increase in the number
of new­onset diabetes cases among statin­treated patients compared to placebo, but the absolute risk increase is <1%.65,66 Common attributes of
statin users who develop new­onset diabetes include receiving higher doses of statins and having other risk factors for diabetes, including obesity,
impaired fasting glucose, HbA1c >6% (0.06; 42 mmol/mol Hb) or metabolic syndrome.67 Mechanisms to explain the association between statin use and
new­onset diabetes remains unclear. However, observational data suggest that higher cholesterol levels are protective against developing diabetes.
This may be attributable to changes at the cellular level involving disruption of cholesterol­sensitive cellular functions that affect insulin secretion and
insulin sensitivity.61 Ultimately, the benefit of statin therapy greatly outweighs the risk of new­onset diabetes as statin use in patients at high ASCVD risk
will prevent approximately three ASCVD events for every new case of diabetes.

Cholesterol Absorption Inhibitors

Ezetimibe is a preferred adjunct therapy given it has been shown to modestly reduce the risk of recurrent cardiovascular events in a secondary
prevention population when used in combination with statin therapy.35 The primary lipid­lowering effect of ezetimibe is a modest reduction in LDL­C
of 15% to 24%; with higher reductions achievable when used in combination with statin therapy.35,68 Ezetimibe reduces LDL­C by inhibiting the NPC1L1
protein, an important transporter of cholesterol absorption in the small intestine and hepatocytes.68 Known polymorphisms of NPC1L1 are associated
with lower LDL­C levels and decreased ASCVD risk; thus, providing a rational why ezetimibe reduces ASCVD risk.69 Other than mild gastrointestinal
complaints (such as diarrhea) and postmarketing reports of myalgia and mild ALT elevations when used in combination with statins, ezetimibe is
generally well tolerated. Previous concerns over a potential increased risk of cancer have been nullified given recent prospective clinical trial data
showing there is no increased risk of cancer with ezetimibe use.35 Ezetimibe has no effects on the CYP450 enzyme system; however, concomitant use
with cyclosporine can lead to increased exposure to both ezetimibe and cyclosporine.68

The bile acid sequestrants (BAS), such as colesevelam, modestly reduce LDL­C (13%­20%) and reduce cardiovascular events when used as
monotherapy.70 There is currently no data to determine if the benefits observed with BAS monotherapy translate to its use in combination with statin
therapy. As such, BAS are generally used as adjunct therapy with statins when desired LDL­C levels are not achieved with statins alone. Importantly,
BAS are considered first line during pregnancy since they are not systemically absorbed and pose no risk to the fetus. The primary action of BAS is to
bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids and a markedly increased excretion of
acidic steroids in the feces. This decreases the bile acid pool size and stimulates the hepatic synthesis of bile acids from cholesterol. Depletion of the
hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the number of LDL­R on the hepatocyte membrane.
The increased number of receptors stimulates an enhanced rate of catabolism from plasma and lowers LDL­C levels. The increase in hepatic
cholesterol biosynthesis may be paralleled by increased hepatic VLDL production and, consequently, BAS may aggravate hypertriglyceridemia and
should be avoided in those with TG levels exceeding 300 mg/dL (3.39 mmol/L).30
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One of the main barriers to BAS is their poor tolerability profile. Early BAS (such as cholestyramine) were developed as powders that require mixing
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with water or juice to create a slurry for oral administration. Gastrointestinal complaints of constipation, bloating, epigastric fullness, nausea, and
flatulence are commonly reported with these formulations.30 These adverse effects can be minimized by increasing fluid intake, modifying the diet to
bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids and a markedly increased excretion of
acidic steroids in the feces. This decreases the bile acid pool size and stimulates the hepatic synthesis of bile acids fromCalifornia Northstate
cholesterol. DepletionUniversity
of the
hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the number of LDL­R on Access
the hepatocyte
Provided by: membrane.

The increased number of receptors stimulates an enhanced rate of catabolism from plasma and lowers LDL­C levels. The increase in hepatic
cholesterol biosynthesis may be paralleled by increased hepatic VLDL production and, consequently, BAS may aggravate hypertriglyceridemia and
should be avoided in those with TG levels exceeding 300 mg/dL (3.39 mmol/L).30

One of the main barriers to BAS is their poor tolerability profile. Early BAS (such as cholestyramine) were developed as powders that require mixing
with water or juice to create a slurry for oral administration. Gastrointestinal complaints of constipation, bloating, epigastric fullness, nausea, and
flatulence are commonly reported with these formulations.30 These adverse effects can be minimized by increasing fluid intake, modifying the diet to
increase bulk, and using stool softeners. Tablet forms of BAS (such as colesevelam) are generally better tolerated than resin powders and associated
with lower overall discontinuation rates.71 Other potential adverse effects include impaired absorption of fat­soluble vitamins A, D, E, and K;
gastrointestinal obstruction; and reduced bioavailability of other drugs such as warfarin, levothyroxine, and phenytoin.30 Drug–drug interactions may
be avoided by taking other medications 1 hour before or 4 hours after the BAS.30 Colesevelam is not only approved as a lipid­lowering agent but also as
an antihyperglycemic that modestly lowers glucose levels in patients with type 2 diabetes mellitus.72 Given the better safety and tolerability profile of
ezetimibe, BAS should be reserved only for those patients unable to tolerate ezetimibe who need additional LDL­C lowering despite maximally
tolerated statin therapy.30

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

The PCSK9 inhibitors (e.g. alirocumab) reduce LDL­C by as much as 60% when added to background statin therapy. Inhibiting PCSK9 promotes LDL­R
recycling to the cell surface, which increases LDL­C clearance from the circulation. Both alirocumab and evolocumab are fully human monoclonal
antibodies to PCSK9 and were approved by the FDA in 2015.30 Randomized, double­blind clinical trials have also shown these agents effectively reduce
recurrent cardiovascular events in patients following an acute coronary event and secondary prevention populations when added to background
statin therapy.33,73Alirocumab and evolocumab are both administered by subcutaneous injection. Although this may be a barrier for some patients,
PCSK9 inhibitors can be administered bi­weekly or once­monthly. The most common adverse effect reported are injection site reactions, which can be
minimized by allowing the injection to come to room temperature before use and icing the site before injecting. Some patients may also report “flu­
like” symptoms after the injection. There were initial concerns over a potential increased risk for neurocognitive adverse effects; however, a
randomized trial found no difference in cognitive function between those randomized to evolocumab versus placebo over 19 months of follow­up.74
Furthermore, those patients who reach very low levels of LDL­C (less than 20 mg/dL [0.53 mmol/L]) do not appear to be an increased risk of adverse
events.75 Despite this favorable data, the long­term effects of achieving very low levels of LDL­C with PCSK9 inhibitors remains unknown. Despite their
LDL­C lowering potency and favorable safety profile, PCSK9 inhibitor use has been limited due to their high cost. Although PCSK9 inhibitors should
primarily be used in combination with maximally tolerated statins in high­risk patients unable to achieve desired LDL­C levels with a statin alone,
evolocumab is FDA­approved for use as monotherapy in patients with primary hyperlipidemia (such as heterozygous familial
hypercholesterolemia).30,72

Inclisiran is a small interfering RNA (siRNA) molecule that reduces the production of PCSK9 by inhibiting messenger RNA.76 This novel biological agent,
which pending approved by the FDA, has a sustained effect on LDL­lowering and is given subcutaneously every 3 to 6 months. In Phase 3 clinical trials,
inclisiran reduced LDL­C by an average of 50% when given as add­on therapy in patients who were treated with a high­intensity statin but had not
achieved their LDL­C goal. Similar to alirocumab and evolocumab, inclisiran therapy should be reserved for patients with familial
hypercholesterolemia and those with established ASVCD who do not achieve LDL­C targets despite the use of a high­intensity statin or unable to
tolerate statin therapy. Injection site reactions were uncommon (<3% of study participants), transient, and generally mild. Whether inclisiran use
produces a significant reduction in cardiovascular event rates has not been firmly established.

Adenosine Triphosphate­citrate Lyase Inhibitors

Adenosine triphosphate­citrate lyase (ACL) is a cytoplasmic enzyme responsible for generating acetyl coenzyme A which is needed during the de novo
synthesis of fatty acids and cholesterol. ACL inhibitors prevent cholesterol production upstream from HMG CoA reductase inhibitors (i.e. statins) and
the two therapeutic strategies can be used in combination. Bempedoic acid is an orally administered ACL inhibitor that has been approved for use in
combination with maximally tolerated statin therapy in patients with established ASCVD or familial hypercholesterolemia who require additional LDL­C
lowering. In Phase 3 clinical trials, bempedoic acid produced modest reductions in LDL­C (15­20%) when combined with statin therapy or used as
monotherapy in patients who are unable to tolerate statins.77 It can also be combined with a cholesterol absorption inhibitor (i.e. ezetimibe).
Bempedoic acid plus ezetimibe resulted in a 36% reduction in LDL­C from baseline in a Phase 3 clinical trial.78 Bempedoic acid is generally well
tolerated and does not appear to cause or contribute to muscle symptoms. However, bempedoic acid may cause hyperuricemia and tendon rupture.
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uric acid
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche Page 22 / 37
those
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• Accessibility
in the renal uptake of uric acid from the blood. Though rare, bempedoic acid was associated with an increased risk of tendon rupture or injury (0.5%)
in clinical trials. This uncommon but potentially debilitating adverse effect was not reported in patients who received placebo. Risk factors for tendon
the two therapeutic strategies can be used in combination. Bempedoic acid is an orally administered ACL inhibitor that has been approved for use in
combination with maximally tolerated statin therapy in patients with established ASCVD or familial hypercholesterolemia who require
California additional
Northstate LDL­C
University
lowering. In Phase 3 clinical trials, bempedoic acid produced modest reductions in LDL­C (15­20%) when combined withAccess
statin therapy
Provided by: or used as

monotherapy in patients who are unable to tolerate statins.77 It can also be combined with a cholesterol absorption inhibitor (i.e. ezetimibe).
Bempedoic acid plus ezetimibe resulted in a 36% reduction in LDL­C from baseline in a Phase 3 clinical trial.78 Bempedoic acid is generally well
tolerated and does not appear to cause or contribute to muscle symptoms. However, bempedoic acid may cause hyperuricemia and tendon rupture.
Increased blood concentrations of uric acid were seen in some patients treated with bempedoic acid and this may increase the risk of acute gout in
those with a history of gouty arthritis. Mechanistically, bempedoic acid inhibits the renal tubular organic anion transporter 2 (OAT2), which plays a role
in the renal uptake of uric acid from the blood. Though rare, bempedoic acid was associated with an increased risk of tendon rupture or injury (0.5%)
in clinical trials. This uncommon but potentially debilitating adverse effect was not reported in patients who received placebo. Risk factors for tendon
rupture appear to be age greater than 60 years, concurrent use of corticosteroids or fluoroquinolones, renal failure, and history of tendon disorders.
Until the results of the long­term cardiovascular outcome trial are published, the role of bempedoic acid in the management of dyslipidemia should be
limited.

Drug That Primarily Lower Triglycerides

Fibric Acid Derivatives (Fibrates)

Although fibrates, such as gemfibrozil, have been shown to reduce cardiovascular events when used as monotherapy, there is less evidence to support
their use in combination with statin therapy.53,54 Fibrates are primarily used in patients with TG levels that exceed 500 mg/dL (5.65 mmol/L) to reduce
the risk of acute pancreatitis. The two available fibrates, gemfibrozil and fenofibrate, are potent TG­lowering therapies (20%­50%), but may cause a
modest reciprocal rise in LDL­C in patients with severely elevated TG levels.55 Plasma HDL­C concentrations may rise 10% to 15% or more with fibrates.
Gemfibrozil increases the activity of LPL and reduces to a lesser extent the synthesis or secretion of VLDL from the liver into the plasma. Fenofibrate
increases LPL activity and reduces apoprotein C­III (an inhibitor of LPL) by activating peroxisome proliferator­activated receptor α (PPARα), which
regulates the expression of genes involved in the regulation of lipids and other metabolic processes.

Fibrates are generally well tolerated, but gastrointestinal complaints and transient elevations in transaminase levels have been reported.79 Both
gemfibrozil and fenofibrate require dose adjustments for significant renal impairment and fenofibrate has been reported to worsen renal function,
although this is usually transient and self­limiting.20,80 Muscle­related adverse effects can occur with both gemfibrozil and fenofibrate alone but is
more common when used in combination with statins to manage complex dyslipidemia or elevated TG levels. Gemfibrozil, and its glucuronide
metabolite, has potent effects on CYP450 enzymes (such as CYP3A4), intestinal, hepatic, and renal transporters making it highly prone to significantly
increase serum statin concentrations and the risk of SAMS.63 For this reason, current guidelines do not recommend gemfibrozil to be initiated in
patients receiving statin therapy; fenofibrate is favored instead.20 Fenofibrate and gemfibrozil and may enhance the formation of gallstones, but this
occurs rarely.81 Fibrates may potentiate the effects of warfarin and the international normalized ratio (INR) should be monitored very closely with this
combination.82

Omega­3 Polyunsaturated Fatty Acids (PUFA)

High doses of omega­3 fatty PUFA (2­4 g/day of EPA/DHA) significantly reduce TG and VLDL cholesterol levels (20%­50%) with lesser effects on other
lipoproteins.55 The mechanisms by which omega­3 PUFA reduce TG levels include increasing hepatic oxidation of free fatty acids, increasing LDL
hydrolysis by activating PPARα and inhibiting apoprotein C­III. The omega­3 PUFA formulations approved by the FDA for treating TG levels of 500
mg/dL (5.65 mmol/L) or greater include an omega­3­acid ethyl ester of EPA/DHA (Lovaza®), omega­3­carboxylic acid of EPA/DHA (Epanova®), and ethyl
ester of EPA only (Vascepa®). DHA and EPA have different effects on LDL­C as EPA prevents LDL oxidation and promotes LDL clearance, whereas DHA
does not; however, the clinical significance of this remains unclear.83 Prescription omega­3 PUFA products contain approximately 1 g of EPA/DHA per
capsule, whereas the EPA/DHA content of OTC “fish oil” supplements is often less than 300 mg per capsule and are not regulated by the FDA. Unless
patient affordability is an issue, prescription omega­3 PUFA are preferred to minimize pill burden and ensure product quality. Randomized clinical
trials of omega­3 PUFA have shown mixed results due to the lack of generalizability due to the population studied, the background lipid­lowering
therapy used, and dose taken.55,83 The recently published REDUCE­IT study, a landmark trial, evaluated the effects of icosapent ethyl (4g/day), a high­
potency EPA derivative, used as add­on therapy to statins.84 At baseline, patients enrolled in the REDUCE­IT study had a median TG level of 216 mg/dL
(2.44 mmol/L) and the majority had a history of ASCVD. Icosapent ethyl reduced the rate of ischemic events by 25% and significantly reduced the risk of
cardiovascular death when compared to placebo. However, icosapent ethyl also increased the risk of hospitalization for atrial fibrillation or flutter. The
REDUCE­IT study was released shortly after the 2018 ACC/AHA guidelines were published and, thus, icosapent ethyl was not discussed or
recommended. Future guidelines should bring clarity to the role of icosapent ethyl for the treatment of hypertriglyceridemia in patients at high risk of
ASCVD events.
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Chapter 31: Dyslipidemia,
Gastrointestinal complaintsDave
(suchL.
asDixon; Daniel
abdominal M.and
pain Riche
“fishy burps”) are common with OTC omega­3 PUFA products but may be minimized Pageby23 / 37
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
refrigerating the capsules. However, they should not be kept frozen in the freezer. Caution is advised in patients with known sensitivities or allergies to
fish or shellfish. Drug–drug interactions are minimal with omega­3 PUFA, although caution is advised when used concomitantly with antiplatelet
potency EPA derivative, used as add­on therapy to statins.84 At baseline, patients enrolled in the REDUCE­IT study had a median TG level of 216 mg/dL
(2.44 mmol/L) and the majority had a history of ASCVD. Icosapent ethyl reduced the rate of ischemic events by 25% and California Northstate
significantly University
reduced the risk of
cardiovascular death when compared to placebo. However, icosapent ethyl also increased the risk of hospitalization forAccess
atrialProvided
fibrillation
by: or flutter. The
REDUCE­IT study was released shortly after the 2018 ACC/AHA guidelines were published and, thus, icosapent ethyl was not discussed or
recommended. Future guidelines should bring clarity to the role of icosapent ethyl for the treatment of hypertriglyceridemia in patients at high risk of
ASCVD events.

Gastrointestinal complaints (such as abdominal pain and “fishy burps”) are common with OTC omega­3 PUFA products but may be minimized by
refrigerating the capsules. However, they should not be kept frozen in the freezer. Caution is advised in patients with known sensitivities or allergies to
fish or shellfish. Drug–drug interactions are minimal with omega­3 PUFA, although caution is advised when used concomitantly with antiplatelet
agents or anticoagulants since omega­3 PUFA may prolong bleeding time.

Niacin

Niacin (nicotinic acid) increases HDL­C (5%­30%), and lowers TG (20%­50%) and LDL­C (5%­20%). Despite these favorable changes in the lipid profile,
niacin has not been shown to improve cardiovascular outcomes in patients on background statin therapy with relatively well­controlled lipids at
baseline.57,58 Niacin primarily lowers TG levels by inhibiting lipolysis with a decrease in free fatty acids in plasma and decreased hepatic esterification
of TG. It also significantly raises HDL­C by reducing its catabolism and selectively decreasing hepatic removal of HDL apoA­I but not the removal of
cholesterol esters, thereby increasing the capacity of retained apoA­I to augment reverse cholesterol transport in isolated hepatic cells. Niacin also
reduces the hepatic synthesis of VLDL, which, in turn, leads to a reduction in the synthesis of LDL. However, the modest decrease in serum LDL­C levels
is dose­dependent.

Niacin has many adverse drug reactions that frequently limit its use. Cutaneous flushing and itching appear to be prostaglandin mediated and can be
reduced by administering aspirin 325 mg given shortly before niacin ingestion.85 Flushing seems to be related to rising plasma concentrations of niacin
and the use of immediate­release formulations; taking the dose with meals and slowly titrating the dose upward may also minimize these effects.
Extended­ or sustained­release products may minimize these complaints in some patients. The only legend form of niacin, Niaspan® (Abbott), is an
extended­release form of niacin with pharmacokinetics intermediate between immediate­ and sustained­release products that are sold as food
supplements rather than legend products. In controlled trials, Niaspan® is reported to have fewer dermatologic reactions and has a lower risk for
hepatoxicity.85 Potentially important laboratory abnormalities occurring with niacin therapy include elevated liver function tests, hyperuricemia, and
hyperglycemia. With less than 3 g/day, the degree of liver function test elevation is generally not marked and often transient, and a temporary
reduction in dosage frequently corrects the problem. Pre­existing gout and diabetes may be exacerbated by niacin; these patients should be
monitored more closely and their medication titrated appropriately.86,87 Niacin is contraindicated in patients with active liver disease and active peptic
ulcer disease. Concomitant alcohol and hot beverages may magnify flushing and pruritus with niacin and they should be avoided at the time of
ingestion. Nicotinamide should not be used in the treatment of hyperlipidemia, as it does not effectively lower cholesterol or TG levels.

Special Populations

Older Adults

Dyslipidemia is an independent risk factor for ASCVD in older adults (greater than 65 years old), as it is in the younger patient.88 The attributable risk,
which is the difference in absolute rates of cardiovascular events between segments of the population with higher or lower serum cholesterol levels,
increases with age. Drug therapy in principle differs little from younger patients, and older patients respond to lipid­lowering therapies as well as
younger patients. The gain in life expectancy may be small depending on the age at the start of treatment and the magnitude of LDL­C reduction. The
benefits of moderate­to­high intensity statin therapy in older adults for secondary prevention is quite clear, while the benefit of statins in older adults
for primary prevention is more controversial.88 This is especially true in individuals greater than 75 years of age since this age group is poorly
represented in RCTs.20 Primary prevention in younger patients requires about 2 years before reduction in ASCVD risk is apparent, and this lag time
should be taken into consideration, along with life expectancy, in patient selection for statin therapy in older adults. To help address this gap in the
evidence, the ongoing Statin Therapy for Reducing Events in the Elderly (STAREE) trial (NCT02099123) is evaluating the efficacy of atorvastatin 40
mg/day for primary prevention in those 70 years or older without diabetes.

The risks of statin therapy in older adults must also be considered. Changes in body composition, renal function, and other physiologic changes of
aging may make older patients more susceptible to the adverse effects of lipid­lowering drug therapy.88 Older adults are more prone to developing
SAMS and the effects of SAMS on the risk of falls and functional status remains unclear.83 There is also concern regarding the potential negative effects
of statins on cognitive function; however, data from meta­analyses has suggested statins are not associated with adverse cognitive effects.89,90 Statin
use has also been associated with increased risk of cataracts, which is highly prevalent among older adults, yet a meta­analysis found no clear evidence
Downloaded 2025­2­13 10:53 P Your IP is 91
showing
Chapter statins increase theDave
31: Dyslipidemia, risk ofL.cataracts. Older
Dixon; Daniel M. adults
Riche are also more likely to develop type 2 diabetes and the impact of statin therapy on new­
Page 24 / 37
onset diabetes in older adults is a concern warranting further study.
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility

Children
The risks of statin therapy in older adults must also be considered. Changes in body composition, renal function, and other physiologic
California changes
Northstate of
University
aging may make older patients more susceptible to the adverse effects of lipid­lowering drug therapy.88 Older adults areAccess
more prone
Provided by:to developing

SAMS and the effects of SAMS on the risk of falls and functional status remains unclear.83 There is also concern regarding the potential negative effects
of statins on cognitive function; however, data from meta­analyses has suggested statins are not associated with adverse cognitive effects.89,90 Statin
use has also been associated with increased risk of cataracts, which is highly prevalent among older adults, yet a meta­analysis found no clear evidence
showing statins increase the risk of cataracts.91 Older adults are also more likely to develop type 2 diabetes and the impact of statin therapy on new­
onset diabetes in older adults is a concern warranting further study.

Children

While cardiovascular events rarely occur in those under 18 years of age, the process of atherosclerosis often begins during childhood.92 Early
identification and management of risk factors is critical for primordial prevention of ASCVD. Dyslipidemia in children can develop from secondary
causes, similar to adults, or may present as primary dyslipidemia (such as FH). Universal lipid screening is recommended between age 9 and 11 as this
is a stable time for lipid assessment before the onset of puberty, which decreases cholesterol levels 10% to 20%.92 Lipid screening before age 9 is only
recommended in children with a significant family history of premature ASCVD, known first­degree relatives with dyslipidemia, or other cardiovascular
risk factors (such as diabetes, obesity, or hypertension).92

Drug therapy in children is not recommended until the age of 10 years or older and the guidelines for initiation of therapy and acceptable levels of
cholesterol and lipoproteins are quite different that adults (see Table 31­3).92 Children younger than 10 years should only receive drug therapy if they
have a genetic lipid disorder (such as FH) or high­risk ASCVD condition (such as diabetes); these children should be referred to a pediatric lipid
specialist.92 Lifestyle interventions are generally the mainstay of therapy, yet children with FH will often require drug therapy. Pravastatin may be used
in children as young as 8 years old, while all other statins are indicated for use in children 10 years of age and older.92 Start with the lowest available
statin dose and titrate every 3 months as necessary to achieve treatment goals. Appropriate contraception strategies are recommended in females
taking statins who are sexually active. Ezetimibe and BAS also have data suggesting they are safe and effective to use in children 10 years or older. At
this time, evolocumab is the only PCSK9 inhibitor with safety and efficacy data in children 13 years or older with HoFH.93 The safety and efficacy of
fibrates and omega­3 PUFA have not been established.

Women

The leading cause of death in women is ASCVD and as many women as men die of ASCVD annually. This is mostly due to a longer average life
expectancy and a higher lifetime risk of ischemic stroke than men.94 Age is an important factor when estimating cardiovascular risk in women as most
ASCVD events occur in postmenopausal women. The decline in estrogen levels that occurs during menopause is associated with increased
cardiovascular risk, yet hormone replacement therapy is not recommended as studies have shown it does not reduce cardiovascular risk.95,96 Other
age­related changes, including increases in blood pressure and LDL­C, play a significant role as well in both women and men. Women have been
underrepresented in RCT of lipid­lowering therapies; however, a meta­analysis of 27 RCTs found statin therapy is equally effective in men and
women.97 Nonstatin therapies also appear to be equally effective except for fenofibrate, which is associated with an increased ASCVD risk in women
when combined with simvastatin.98 This finding was not, however, observed in another RCT comparing fenofibrate to placebo.99 The clinical
significance of this subgroup finding remains unknown.

Pregnancy is associated with a progressive rise in cholesterol and TG levels, yet dietary therapy is the mainstay of treatment, with emphasis on
maintaining a nutritionally balanced diet as per the needs of pregnancy.100 If the patient is very high risk or has FH, a BAS may be considered during
pregnancy since there is no systemic drug exposure.100 Statins are pregnancy category X and contraindicated due to potential teratogenic effects.
Women of childbearing age who are on statin therapy and are sexually active should use a reliable form of contraception to prevent pregnancy.
Women who plan to become pregnant should discontinue the statin 1 to 2 months before pregnancy is attempted. Ezetimibe and niacin are pregnancy
category C drugs but no data are available in humans. Increased intake of omega­3 PUFA, particularly DHA, during pregnancy is important for fetal
brain development; however, prescription omega­3 PUFA products are pregnancy category C.101 There is currently no information on the safety of
PCSK9 inhibitors in pregnant women.

Patients with Diabetes

Diabetes is a major risk factor for ASCVD and persons with diabetes are at greater risk of morbidity and mortality following an ASCVD event.20 The
dyslipidemia commonly found in persons with diabetes is often characterized by hypertriglyceridemia, low HDL­C, and modestly elevated, but dense,
LDL­C that are highly atherogenic.102 Despite the modest elevation in LDL­C observed in these patients, statins are the first­line therapy given the
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significant body of evidence from RCT demonstrating that statins reduce ASCVD events and mortality in persons with diabetes.20 However,Page individual
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche 25 / 37
risk among those with diabetes who have no history of ASCVD is not homogenous, so the 10­year
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility ASCVD­risk score may be used to determine the
appropriate statin intensity (see Table 31­4).20 High­intensity statin therapy is preferred in those with diabetes and a history of ASCVD (secondary
prevention) given these patients are at very high risk of recurrent ASCVD events.
Patients with Diabetes California Northstate University
Access Provided by:

Diabetes is a major risk factor for ASCVD and persons with diabetes are at greater risk of morbidity and mortality following an ASCVD event.20 The
dyslipidemia commonly found in persons with diabetes is often characterized by hypertriglyceridemia, low HDL­C, and modestly elevated, but dense,
LDL­C that are highly atherogenic.102 Despite the modest elevation in LDL­C observed in these patients, statins are the first­line therapy given the
significant body of evidence from RCT demonstrating that statins reduce ASCVD events and mortality in persons with diabetes.20 However, individual
risk among those with diabetes who have no history of ASCVD is not homogenous, so the 10­year ASCVD­risk score may be used to determine the
appropriate statin intensity (see Table 31­4).20 High­intensity statin therapy is preferred in those with diabetes and a history of ASCVD (secondary
prevention) given these patients are at very high risk of recurrent ASCVD events.

The role of nonstatin therapies in persons with diabetes is complex but has become clearer in recent years. In the Improved Reduction of Outcomes:
Vytorin Efficacy International Trial (IMPROVE­IT) the benefit of adding ezetimibe to simvastatin was significantly enhanced in those with diabetes
compared to patients without diabetes.103 The addition of evolocumab to background statin therapy in the Further Cardiovascular Outcomes Research
With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial was equally effective in those with, and without, diabetes.104 Given the mixed
dyslipidemia associated with diabetes, there has been considerable interest in the potential of fibrates to reduce ASCVD risk. However, in the Action to
Control Cardiovascular Risk in Diabetes (ACCORD) the combination of fenofibrate and a statin in patients with type 2 diabetes did not reduce the rate of
fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke compared to simvastatin alone.98 Subgroup analyses from two RCTs
have suggested a potential benefit with fenofibrate in those with TG levels >204 mg/dL (2.31 mmol/L) and HDL­C <34 mg/dL (0.88 mmol/L), but this has
not been evaluated in a prospective RCT.98,99 Additionally, fenofibrate appears to reduce the progression of diabetic retinopathy, as well as the need
for laser treatment.105 The BAS colesevelam is FDA­approved to improve both glycemic and lipid control, but it can exacerbate hypertriglyceridemia,
which is commonly observed in those with diabetes.55 Niacin modestly increases fasting plasma glucose (∼4%­5%) and HbA1c levels (∼0.25%).86 As
such, niacin should not be routinely used in persons with diabetes especially given the lack of evidence to support its use.

Patients with Kidney Disease

Dyslipidemia is highly prevalent among patients with kidney disease.106 The dyslipidemia pattern in patients with kidney disease includes
hypertriglyceridemia, slightly elevated total cholesterol and LDL­C and low HDL­C levels.106 These abnormalities are thought to be caused by a
deficiency in apolipoprotein C­II, perhaps as a result of sustained use of heparin during hemodialysis and depletion of LPL, carbohydrate­induced
obesity and hypertriglyceridemia, loss of carnitine during hemodialysis, use of acetate buffer (acetate is a precursor to fatty acid synthesis) during
hemodialysis, and decreased LCAT activity during hemodialysis.107 Dialysis does not correct the lipid abnormalities. Renal transplantation may correct
lipid abnormalities in some patients; however, in others, the use of transplantation­related medications, such as corticosteroids and cyclosporine may
aggravate lipid abnormalities.107

Statins effectively reduce LDL­C in patients with kidney disease, yet the cardiovascular event reduction is less robust in patients kidney disease.106
Notably, rosuvastatin failed to prevent cardiovascular events in a RCT of patients undergoing hemodialysis suggesting statins should not be initiated in
this population.108 Statins are generally continued, however, in patients who are on statins before progressing to end­stage renal disease and
requiring dialysis.106 Moderate­intensity statins are generally preferred in patients with kidney disease to minimize the risk of adverse effects (such as
SAMS).106 Kidney transplant recipients are at considerably high risk of future cardiovascular events and should receive statin therapy; however,
appropriate statin selection is important given the potential for drug–drug interactions with antirejection therapies (such as cyclosporine).106
Ezetimibe may also be used in combination with statin therapy based on RCT evidence showing this combination reduces cardiovascular events
compared to placebo in patients at various stages of advanced kidney disease.109 Current guidelines do not advocate for routine use of other nonstatin
therapies at this time given the paucity of efficacy data and safety concerns.106

Patients with Chronic Inflammatory Disorders and HIV

It is well established that the chronic inflammation and immune activation seen with chronic inflammatory disorders (eg, rheumatoid arthritis, lupus)
and human immunodeficiency virus (HIV) accelerate the development and progression of atherosclerosis. These nontraditional risk factors are not
included in the ASCVD­risk estimator, but they should be considered when assessing individual ASCVD risk. After a 3­ to 6­month trial of lifestyle
interventions, these patients should have their 10­year ASCVD risk estimated. In those with a 10­year ASCVD risk of 5% or greater, it is reasonable to
initiate moderate­intensity statin therapy.

In addition to considering statin therapy, there are additional considerations with the treatments used for chronic inflammatory disorders and HIV.
Long­term use2025­2­13
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10:53 therapy,
P Your IPforisexample, has been shown to mediate atherosclerosis progression and development in patients with HIV.
Chapter
With that31: Dyslipidemia,
said, Dave L. (eg,
many antiretrovirals Dixon; Danielinhibitors)
protease Page 26 / 37
M. Riche can significantly increase TG levels. Anti­inflammatory therapies (eg, tociluzimab,
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
methotrexate) used in the management of rheumatoid arthritis have produced mixed results in terms of their effects on lipid levels and ASCVD risk.
included in the ASCVD­risk estimator, but they should be considered when assessing individual ASCVD risk. After a 3­ to 6­month trial of lifestyle
California Northstate University
interventions, these patients should have their 10­year ASCVD risk estimated. In those with a 10­year ASCVD risk of 5% or greater, it is reasonable to
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initiate moderate­intensity statin therapy.

In addition to considering statin therapy, there are additional considerations with the treatments used for chronic inflammatory disorders and HIV.
Long­term use of antiretroviral therapy, for example, has been shown to mediate atherosclerosis progression and development in patients with HIV.
With that said, many antiretrovirals (eg, protease inhibitors) can significantly increase TG levels. Anti­inflammatory therapies (eg, tociluzimab,
methotrexate) used in the management of rheumatoid arthritis have produced mixed results in terms of their effects on lipid levels and ASCVD risk.

PATIENT CARE PROCESS

Patient Care Process for the Management of Dyslipidemias

Collect

Patient characteristics (eg, age, race, gender, pregnant)

Patients history: Past medical (eg, HTN), family (eg, early­onset coronary heart disease), social

Current medications (including over­the­counter [OTC]) and prior lipid­lowering medication use

Socioeconomic factors that may affect access to treatment or other aspects of care

Lifestyle assessment: smoking status, exercise, diet, and alcohol intake

Symptoms indicative of ischemic injury (eg, chest pain)

Objective data

Height, weight, BMI, and blood pressure

Lipoprotein concentrations (eg, Total Cholesterol/LDL­C/HDL­C/Triglycerides)

Labs (eg, AST/ALT, urinalysis, TSH, glucose, Serum Creatinine, and BUN at baseline)

Assess

Potential secondary causes (eg, diabetes mellitus, alcohol abuse, renal dysfunction, liver disease, drug­induced, thyroid disorder)

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needs of specific P Yourpopulations
IP is such as children/adolescents, pregnant or menopausal women, older adults, ethnic/racial
Chapter 31: Dyslipidemia, Dave L. Dixon; Daniel M. Riche Page 27 / 37
groups, or high­risk conditions/residual risks (eg, patients with rheumatoid arthritis or residual risk despite statin and lifestyle therapy)
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Presence of high­risk comorbid conditions: diabetes mellitus, peripheral arterial disease, coronary artery disease, chronic kidney disease,
carotid artery stenosis, abdominal aortic aneurysm
 Labs (eg, AST/ALT, urinalysis, TSH, glucose, Serum Creatinine, and BUN at baseline)
California Northstate University
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Assess

Potential secondary causes (eg, diabetes mellitus, alcohol abuse, renal dysfunction, liver disease, drug­induced, thyroid disorder)

Special needs of specific patient populations such as children/adolescents, pregnant or menopausal women, older adults, ethnic/racial
groups, or high­risk conditions/residual risks (eg, patients with rheumatoid arthritis or residual risk despite statin and lifestyle therapy)

Presence of high­risk comorbid conditions: diabetes mellitus, peripheral arterial disease, coronary artery disease, chronic kidney disease,
carotid artery stenosis, abdominal aortic aneurysm

Dyslipidemia­related complications (eg, heart disease, stroke)

Ten­year atherosclerotic cardiovascular disease (ASCVD)­risk assessment (only if primary prevention)

Current medications that may contribute to dyslipidemia

LDL­C reduction based on statin benefit group, if applicable (see Table 31­4)

Appropriateness and effectiveness of current lipid­lowering therapy (if any)

Plan*

Tailored therapeutic lifestyle changes (eg, diet and nutrition)

Drug therapy regimen including specific lipid­lowering medication, dose, route, frequency, and duration; specify the continuation and
discontinuation of existing therapies (see Table 31­4)

Monitoring parameters including efficacy (eg, lipid panel, cardiovascular events), safety (medication­specific adverse effects), and time frame
(3­month initial follow­up intervals, followed by 6­12 month intervals once at goal)

Patient education (eg, purpose of treatment, dietary and lifestyle modification, drug therapy)

Self­monitoring of weight, exercise, diet, drug adherence/adverse effects

Referrals to other providers when appropriate for coordination of care (eg, physician, dietician)

Implement*

Provide patient education regarding all elements of the treatment plan, including self­management training

Use motivational interviewing and coaching strategies to maximize adherence

Schedule follow­up and time frame to achieve goals of therapy

Follow­up: Monitor and Evaluate

Determine response to lipid­lowering therapy and weight­loss goals

Presence of medication­induced adverse effects (eg, elevated transaminases or myalgia on statins)

The occurrence of cardiovascular (CV) events

Patient adherence to treatment plan using multiple sources of information

* Collaborate with patient, caregivers, and other healthcare professionals.

EVALUATION OF THERAPEUTIC OUTCOMES

Short­term evaluation of therapy for dyslipidemia is based on a complete lipid panel obtained 4 to 12 weeks after initiation or following a dose
adjustment of lipid­lowering therapy to evaluate therapeutic response.20 This is especially important with statin therapy given there are numerous
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Riche statins that give rise to variable response to therapy. Long­term evaluationPage
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37
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a repeat lipid panel obtained every 3 to 12 months to ensure adherence to lipid­lowering therapy and maintenance of desired levels of LDL­C. It20

should be noted that although total cholesterol (TC) HDL­C, and TG levels are directly measured, LDL­C is typically estimated using the Friedewald
equation, LDL­C = TC – HDL­C – (TG/5) (or LDL­C = TC – HDL­C – (TG/2.2) when lipid levels are all expressed in mmol/L), which does not provide an
 California Northstate University
EVALUATION OF THERAPEUTIC OUTCOMES Access Provided by:

Short­term evaluation of therapy for dyslipidemia is based on a complete lipid panel obtained 4 to 12 weeks after initiation or following a dose
adjustment of lipid­lowering therapy to evaluate therapeutic response.20 This is especially important with statin therapy given there are numerous
pharmacokinetic and pharmacodynamic differences among statins that give rise to variable response to therapy.110 Long­term evaluation is based on
a repeat lipid panel obtained every 3 to 12 months to ensure adherence to lipid­lowering therapy and maintenance of desired levels of LDL­C.20 It
should be noted that although total cholesterol (TC) HDL­C, and TG levels are directly measured, LDL­C is typically estimated using the Friedewald
equation, LDL­C = TC – HDL­C – (TG/5) (or LDL­C = TC – HDL­C – (TG/2.2) when lipid levels are all expressed in mmol/L), which does not provide an
accurate estimate of VLDL­C.111 As such, the Friedewald equation can underestimate LDL­C in patients with high TG levels as well as those with very low
LDL­C levels. Given VLDL­C concentrations are typically small in comparison to LDL­C, the inaccuracy of VLDL­C has previously been accepted. However,
given the increased prevalence of obesity, metabolic syndrome, and diabetes, more patients have elevated levels of VLDL­C. Useful alternatives in these
patients include non­HDL­C (TC minus HDL­C) and direct LDL­C measurements, which are more accurate than estimated LDL­C using the Friedewald
equation.111 A nonfasting lipid panel is generally acceptable, except in patients with hypertriglyceridemia, where a fasting lipid panel is preferred to
minimize interference from chylomicrons.112 Routine safety monitoring of hepatic function and CK levels is not recommended in statin­treated
patients, but these may be obtained if the patient has signs or symptoms suggestive of liver or muscle injury.20 Patients taking niacin, on the other
hand, should have hepatic function tests performed at baseline, after each dosage increase, and every 6 months thereafter while taking a stable
dose.20 Periodic monitoring of A1c is warranted in persons with diabetes receiving niacin and patients treated with statins who are at high risk for
developing diabetes.20

In patients treated with lipid­lowering therapy for secondary prevention, symptoms such as angina or intermittent claudication may improve over
months to years. If patients have xanthomas or other external manifestations of dyslipidemia, these lesions should regress with therapy.50 Modifiable
risk factors such as hypertension, smoking, exercise and weight control, and glycemic control in persons with diabetes should also be monitored and
evaluated.20,28 Dietary therapy is an important part of treating dyslipidemia and a dietitian should be consulted to perform an initial evaluation with
periodic follow­up thereafter if the goals of therapy are not achieved.25 Use of food diaries and recall surveys enable the collection of information
about diet in a systematic manner and may improve patient adherence to dietary recommendations.

POSTCLASS ACTIVITY

Postclass Engaged Learning Activity

Watch the video entitled “Strategies for Optimizing Statin Therapy: Focus on Drug Interactions” from Pharmacy Times by Mary Bridgeman. This 14­
minute video provides a detailed overview of potential drug–drug interactions that can occur with statin therapy through the CYP3A4 pathway.
Create a table of the strong CYP3A4 inhibitors and inducers, the effect each would have on a patient’s statin concentrations, and what potential side
effects could occur from those interactions. This information will help students be prepared to participate in the PLAN and FOLLOW­UP steps in the
patient care process.

Link to video: https://bit.ly/2OaHiWG

ABBREVIATIONS

Apo apolipoprotein

ASCVD atherosclerotic cardiovascular disease

ALT alanine transaminase

AST aspartate transaminase

ATP adenosine triphosphate

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BAS bile acid sequestrants
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BMI body mass index
 ALT alanine transaminase
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ATP adenosine triphosphate

BAS bile acid sequestrants

BMI body mass index

BUN blood urea nitrogen

CE cholesterol ester

CETP cholesterol ester transfer protein

CHD coronary heart disease

CKD chronic kidney disease

CVD cardiovascular disease

DHA docosahexaenoic acid

EPA eicosapentaenoic acid

HbA1c glycosylated hemoglobin A1c

HDL­C high­density lipoprotein­cholesterol

HIV human immunodeficiency virus

HMG CoA β­hydroxy β­methylglutaryl coenzyme A

HTN hypertension

IDL­C intermediate­density lipoprotein­cholesterol

LCAT lecithin­cholesterol acyltransferase

LDL­C low­density lipoprotein­cholesterol

LPL lipoprotein lipase

LRP LDL­receptor­related protein

NPC1L1 Niemann­Pick C1­like1

OTC over­the­counter

PCOS polycystic ovarian syndrome

PSCK9 proprotein convertase subtilisin/kexin type 9

PUFA polyunsaturated fatty acid

RCT randomized controlled trial

SAMS 2025­2­13 10:53 P Your

Downloaded statin­associated
IP is muscle symptoms
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TC total cholesterol
 California Northstate University
PUFA polyunsaturated fatty acid
Access Provided by:

RCT randomized controlled trial

SAMS statin­associated muscle symptoms

T2DM type 2 diabetes mellitus

TC total cholesterol

TG triglyceride

TSH thyroid stimulating hormone

UA urinalysis

VLDL­C very low­density lipoprotein­cholesterol

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