3. I. OVERVIEW
Coronary heart disease (CHD) is the leading cause of death worldwide.
CHD is correlated with elevated levels of low-density lipoprotein
cholesterol (LDL-C) and triglycerides, and low levels of high-density
lipoprotein cholesterol (HDL-C). Other risk factors for CHD include
cigarette smoking, hypertension, obesity, diabetes, chronic kidney
disease, and advanced age. Elevated cholesterol levels (hyperlipidemia)
may be due to lifestyle factors (for example, lack of exercise or diet
containing excess saturated fats).
4. I. OVERVIEW
Hyperlipidemia can also result from an inherited
defect in lipoprotein metabolism or, more commonly, from a combination
of genetic and lifestyle factors. Appropriate lifestyle changes, along
with drug therapy, can lead to a 30% to 40% reduction in CHD mortality.
Antihyperlipidemic drugs (Figure 22.1) are often taken indefinitely
to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in
select patients and to control plasma lipid levels. [Note: ASCVD includes
CHD, stroke, and peripheral arterial disease.] Figure 22.2 illustrates the
normal metabolism of serum lipoproteins and the characteristics of the
major genetic hyperlipidemias.
5.
6. Figure 22.2
Metabolism of plasma lipoproteins and
related genetic diseases. Roman
numerals in the white circles refer to
specific genetic types of
hyperlipidemias summarized on the
facing page. apo CII = apolipoprotein
CII found in chylomicrons
and VLDL; CM = chylomicron; IDL =
intermediate-density lipoprotein; LDL =
low-density lipoprotein; PCSK9 =
proprotein
convertase subtilisin kexin type 9; TG =
triglyceride; VLDL = very-low-density
lipoprotein.
(Figure continues on next page)
7.
8.
9. II. TREATMENT GOALS
Plasma lipids consist mostly of lipoproteins, which are spherical com
plexes of lipids and specific proteins.The clinically important lipoproteins,
listed in decreasing order of atherogenicity, are LDL, very-low-density
lipoprotein (VLDL) and chylomicrons, and HDL. The occurrence of CHD is
positively associated with high total cholesterol and has an even stronger
correlation with elevated LDL-C. In contrast to LDL-C, high levels of HDL-
C have been associated with a decreased risk for CHD
(Figure 22.3).
10.
11. II. TREATMENT GOALS
According to cholesterol guidelines, the need for antihyperlipidemic
drug therapy should be determined based on an assessment
of risk for ASCVD, in conjunction with evaluation of lipoprotein
levels (for example, LDL-C; Figure 22.4). [Note: Therapeutic lifestyle
changes, such as diet, exercise, and weight loss, may help reduce
cholesterol levels; however, lifestyle modifications do not replace the need
for drug therapy in patients who fall into one of the four statin benefit
groups (see Figure 22.4).]
13. Ill. DRUGS FOR HYPERLIPIDEMIA
Antihyperlipidemic drugs include the statins, niacin, fibrates, bile acid
sequestrants, a cholesterol absorption inhibitor, proprotein convertase
subtilisin kexin type 9 (PCSK9} inhibitors, and omega-3 fatty acids. These
agents may be used alone or in combination. However, drug therapy
should always be accompanied by lifestyle modifications, such as
exercise and a diet low in saturated fats.
14. A. HMG CoA reductase inhibitors
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA} reductase
inhibitors (commonly known as statins} lower LDL-C, resulting in
a substantial reduction in coronary events and death from CHD.
Therapeutic benefits include atherosclerotic plaque stabilization,
improvement of coronary endothelial function, inhibition of platelet
thrombus formation, and vascular anti-inflammatory activity. They are
first-line treatment for patients with elevated risk of ASCVD to reduce
the occurrence of ASCVD events (see Figure 22.4}. [Note: The intensity
of statin therapy should be guided by the patient's absolute risk
for an ASCVD event.]
15. A. HMG CoA reductase inhibitors
1. Mechanism of action: Lovastatin [LOE-vah-stat-in], simvastatin [sim-vah-STAT-in],
pravastatin [PRAH-vah-stat-in], atorvastatin [a-TOR-vah-stat-in], fluvastatin [FLOO-
vah-stat-in], pitavastatin [pit-AV-a-STAT-in], and rosuvastatin [roe-SOO-v a-stat-in] are
competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol
synthesis. By inhibiting de novo cholesterol synthesis, they deplete the intracellular
supply of cholesterol (Figure 22.5). Depletion of intracellular cholesterol causes the cell
to increase the number of cell surface LDL receptors that can bind and internalize
circulating LDL-C. Thus, plasma cholesterol is reduced , by both decreased
cholesterol synthesis and increased LDL-C catabolism. Rosuvastatin and
atorvastatin are the most potent LDL-C lowering statins, followed by pitavastatin,
simvastatin, lovastatin, pravastatin, and fluvastatin. [Note: Because these agents
undergo a marked first-pass extraction by the liver, their dominant effect is on that organ.]
The HMG CoA reductase inhibitors also decrease triglyceride levels and may
increase HDL-C in some patients.
16. Figure 22.5
Inhibition of 3-
hydroxy-3-
methylglutaryl
coenzyme A (HMG
CoA) reductase by
the statin drugs. LDL
= low-density
lipoprotein; VLDL
=very-low-density
lipoprotein.
17. A. HMG CoA reductase inhibitors
2. Therapeutic uses: These drugs are used to lower the risk of
ASCVD events for patients in the four statin benefit groups. Statins are
effective in lowering plasma cholesterol levels in all types of
hyperlipidemias. However, patients who are homozygous for famil ial
hypercholesterolemia lack LDL receptors and, therefore, ben
efit much less from treatment with these drugs.
18. A. HMG CoA reductase inhibitors
3. Pharmacokinetics: Lovastatin and simvastatin are lactones that are
hydrolyzed to the active drug. The remaining statins are all administered
in their active form. Absorption of the statins is vari able (30% to 85%)
following oral administration. All statins are metabolized by cytochrome
P450 (CYP450) isoenzymes in the liver, except pravastatin. Excretion
takes place principally through bile and feces, but some urinary
elimination also occurs. Some characteristics of the statins are
summarized in Figure 22.6.
19.
20. A. HMG CoA reductase inhibitors
4. Adverse effects: Elevated liver enzymes may occur with statin therapy. Therefore,
liver function should be evaluated prior to starting therapy or if a patient has symptoms
consistent with liver dysfunction. [Note: Hepatic insufficiency can cause drug accumu
lation.] Myopathy and rhabdomyolysis (disintegration of skeletal muscle; rare) have been
reported (Figure 22.7). Risk factors for rhabdomyolysis, include renal insufficiency,
vitamin D deficiency, hypothyroidism, advanced age, female sex, and use of drugs that
increase the risk of muscle adverse effects, such as azole anti fungals, protease
inhibitors, cyclosporine, erythromycin, gemfibrozil, or niacin. Simvastatin is metabolized
by CYP450 3A4, and inhibitors of this enzyme may increase the risk of rhabdomyolysis.
Plasma creatine kinase levels should be determined in patients with muscle complaints.
The HMG CoA reductase inhibitors may also increase the effect of warfarin. Thus, it is
important to evaluate the international normalized ratio (INR) when initiating a statin or
changing the dosage. These drugs are contraindicated during
pregnancy, lactation, and active liver disease.
21.
22. B. Niacin {nicotinic acid)
Niacin [NYE-uh-sin] reduces LDL-C by 10% to 20% and is the most
effective agent for increasing HDL-C. It also lowers triglycerides by 20%
to 35% at typical doses of 1.5 to 3 g/day. Niacin can be used in
combination with statins, and fixed-dose combinations of long-acting
niacin with /ovastatin and simvastatin are available. [Note: the addition of
niacin to statin therapy has not been shown to reduce the risk of
ASCVD events.]
23. B. Niacin {nicotinic acid)
1. Mechanism of action: At gram doses, niacin strongly inhibits lipolysis
in adipose tissue, thereby reducing production of free fatty acids (Figure
22.8). The liver normally uses circulating free fatty acids as a major
precursor for triglyceride synthesis. Reduced liver triglyceride levels
decrease hepatic VLDL production, which
in turn reduces LDL-C plasma concentrations.
24.
25. B. Niacin {nicotinic acid)
2.Therapeutic uses: Because niacin lowers plasma levels of both
cholesterol and triglycerides, it is useful in the treatment of familial
hyperlipidemias. It is also used to treat other severe hypercholes
terolemias, often in combination with other agents.
3.Pharmacokinetics: Niacin is administered orally. It is converted in the
body to nicotinamide, which is incorporated into the cofactor nicotinamide
adenine dinucleotide (NAD+). Niacin, its nicotinamide derivative, and
other metabolites are excreted in the urine. [Note: Administration of
nicotinamide alone does not decrease plasma
lipid levels.]
26. B. Niacin {nicotinic acid)
4. Adverse effects: The most common adverse effects of niacin are an
intense cutaneous flush accompanied by an uncomfortable feeling of
warmth and pruritus. Administration of aspirin prior to taking niacin
decreases the flush, which is prostaglandin mediated. Some patients also
experience nausea and abdominal pain. Slow titration of the dosage or
use of the sustained-release formulation of niacin reduces bothersome
initial adverse effects. Niacin inhibits tubular secretion of uric acid and,
thus, predisposes patients to hyperuricemia and gout. Impaired glucose
tolerance and hepatotoxicity have also been reported. The drug should be
avoided in active hepatic disease or in patients with an active pep
tic ulcer.
27. C. Fibrates
Fenofibrate [fen-oh-FIH-brate] and gemfibrozil [jem-Fl-broh-zill] are derivatives of fibric acid
that lower serum triglycerides and increase HDL-C.
1. Mechanism of action: The peroxisome proliferator-activated receptors (PPARs) are
members of the nuclear receptor family that regulate lipid metabolism. PPARs function as
ligand-activated transcription fac tors. Upon binding to their natural ligands (fatty acids or
eicosanoids) or antihyperlipidemic drugs, PPARs are activated. They then bind to
peroxisome proliferator response elements, which ultimately leads to
decreased triglyceride concentrations through increased expression of lipoprotein lipase
(Figure 22.9) and decreased apolipoprotein
(apo) Cll concentration. Fenofibrate is more effective than gemfibrozil
in lowering triglyceride levels. Fibrates also increase HDL-C by
increasing the expression of apo AI and apo All.
29. C. Fibrates
2.Therapeutic uses: The fibrates are used in the treatment of
hypertriglyceridemias. They are particularly useful in treating type Ill
hyperlipidemia {dysbetalipoproteinemia,)in which intermediate density
lipoprotein particles accumulate.
3.Pharmacokinetics: Gemfibrozil and fenofibrate are completely absorbed
after oral administration and distribute widely, bound to albumin. Fenofibrate
is a prodrug, which is converted to the active moiety fenofibric acid. Both
drugs undergo extensive biotransformation and are excreted in the urine as
glucuronide conjugates.
30. C. Fibrates
4. Adverse effects: The most common adverse effects are mild
gastrointestinal {GI} disturbances. These lessen as the therapy progresses.
Because these drugs increase biliary cholesterol excretion, there is a
predisposition to form gallstones. Myositis (inflammation of a voluntary
muscle} can occur, and muscle weakness or tenderness should be
evaluated. Patients with renal insufficiency may be at risk. Myopathy and
rhabdomyolysis have been reported in patients taking gemfibrozil and
statins together. The use of gem fibrozil is contraindicated with simvastatin,
and, in general, the use of gemfibrozil with any statin should be avoided.
Both fibrates may increase the effects of warfarin. Therefore, INR should be
monitored more frequently when a fibrate is initiated. Fibrates should not be
used in patients with severe hepatic or renal dysfunction,
in patients with preexisting gallbladder disease or biliary cirrhosis.
31. D. Bile acid sequestrants
Bile acid sequestrants (resins) have significant LDL-C lowering effects,
although the benefits are less than those observed with statins.
32. D. Bile acid sequestrants
1. Mechanism of action: Cholestyramine [koe-LES-tir-a-meen] , colestipol
[koe-LES-tih-pole], and colesevelam [koh-le-SEV-e lam] are anion-
exchange resins that bind negatively charged bile acids and bile salts in the
small intestine (Figure 22.10). The resin/ bile acid complex is excreted in
the feces, thus lowering the bile acid concentration. This causes
hepatocytes to increase conversion of cholesterol to bile acids, which are
essential components of the bile. Consequently, intracellular cholesterol
concentrations decrease, which activates an increased hepatic uptake of
choles terol-containing LDL-C particles, leading to a decrease in plasma
LDL-C. [Note: This increased uptake is mediated by an up-regulation of cell
surface LDL receptors.]
33.
34. D. Bile acid sequestrants
2. Therapeutic uses: The bile acid sequestrants are useful (often in
combination with diet or niacin) for treating type IIA and type IIB
hyperlipidemias. [Note: In those rare individuals who are homozygous for
type IIA and functional LDL receptors are totally lacking, these drugs have
little effect on plasma LDL levels.] Cholestyramine can also relieve pruritus
caused by accumulation of bile acids in patients with biliary stasis.
Colesevelam is also indicated for type 2 diabetes due to its glucose-
lowering effects.
35. D. Bile acid sequestrants
3. Pharmacokinetics: Bile acid sequestrants are insoluble in water
and have large molecular weights. After oral administration, they
are neither absorbed nor metabolically altered by the intestine.
Instead, they are totally excreted in feces.
36. D. Bile acid sequestrants
4. Adverse effects: The most common adverse effects are Gl disturbances,
such as constipation, nausea, and flatulence. Colesevelam has fewer Gl
side effects than other bile acid sequestrants. These agents may impair the
absorption of the fat-soluble vitamins (A, D, E, and K), and they interfere
with the absorption of many drugs (for example, digoxin, warfarin, and
thyroid hormone). Therefore, other drugs should be taken at least 1 to 2
hours before, or 4 to 6 hours after, the bile acid sequestrants. These agents
may raise triglyceride levels and are contraindicated in patients with
significant hypertriglyceridemia (greater than 400 mg/dL).
37. E. Cholesterol absorption inhibitor
Ezetimibe [eh-ZEH-teh-mibe] selectively inhibits absorption of dietary and
biliary cholesterol in the small intestine, leading to a decrease in the delivery
of intestinal cholesterol to the liver. This causes a reduction of hepatic
cholesterol stores and an increase in clearance of cholesterol from the
blood. Ezetimibe lowers LDL-C by approximately 18% to 23%. Due its
modest LDL-C lowering, ezetimibe is often used as an adjunct to maximally
tolerated statin therapy in patients with high ASCVD risk, or in statin-
intolerant patients. Ezetimibe is primarily metabolized in the small intestine
and liver via glucuronide conjugation, with subsequent biliary and renal
excretion. Patients with moderate to severe hepatic insufficiency should not
be treated with ezetimibe. Adverse effects are uncommon with the use
of ezetimibe.
38. F. Proprotein convertase subtilisin kexin type 9 inhibitors
predominately produced in the liver. PCSK9 binds to the LDL receptor on
the surface of hepatocytes, leading to the degradation of LDL receptors
(Figure 22.11). By inhibiting the PCSK9 enzyme, more LDL receptors are
available to clear LDL-C from the serum. Alirocumab [al-i-ROK-ue-mab ]
and evolocumab [e-voe-LOK-ue mab] are PCSK9 inhibitors, which are fully
humanized monoclonal antibodies. These agents are used in addition to
maximally tolerated statin therapy in patients with heterozygous or
homozygous familial hypercholesterolemia, or in patients with clinical
ASCVD who require additional LDL-C lowering. When combined with statin
therapy, PCSK9 inhibitors provide potent LDL-C lowering (50% to %70 ).
39. F. Proprotein convertase subtilisin kexin type 9 inhibitors
They may also be considered for patients with high ASCVD
risk and statin intolerance. PCSK9 inhibitors are only available as
subcutaneous injections and are administered every two to four weeks.
Monoclonal antibodies are not eliminated by the kidneys and have been
used in dialysis patients or those with severe renal impairment. PCSK9
inhibitors are generally well tolerated . The most common adverse drug
reactions are injection site reactions, immunologic or allergic reactions,
nasopharyngitis, and upper respiratory tract infections.
41. G. Omega-3 fatty acids
Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty
acids that are predominately used for triglyceride lowering. Essential
fatty acids inhibit VLDL and triglyceride synthesis in the liver. The
omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) are found in marine sources such as tuna, halibut, and
salmon. Approximately 4 g of marine-derived omega-3 PUFAs daily
decreases serum triglyceride concentrations by 25% to 30%, with
small increases in LDL-C and HDL-C.
42. G. Omega-3 fatty acids
Over-the-counter or prescription fish oil capsules (EPA/DHA) can be used
for supplementation, as it is difficult to consume enough omega-3 PUFAs
from dietary sources alone. lcosapent [eye-KOE-sa-pent] ethyl is a
prescription product that contains only EPA and, unlike other fish oil
supplements, does not significantly raise LDL-C. Omega-3 PUFAs can be
considered as an adjunct to other lipid-lowering therapies for individuals
with elevated triglycerides (≥500 mg/dl). Although effective for triglyceride
lowering, omega-3 PUFA supplementation has not been shown to reduce
cardiovascular morbidity and mortality. The most common side effects of
omega-3 PUFAs include Gl effects (abdominal pain, nausea, diarrhea) and
a fishy aftertaste. Bleeding risk can be increased in those who are
concomitantly taking anticoagulants or antiplatelet agents.
43. H. Combination drug therapy
It is sometimes necessary to use two antihyperlipidemic drugs to achieve
treatment goals. Patients with established ASCVD, an elevated 10-year risk
of ASCVD, or those that do not achieve intended LDL-C reductions on
maximally tolerated statin therapy may be considered for combination
therapy. Ezetimibe and PCSK9 inhibitors can be considered for add-on
therapy, since there is evidence that these combinations further reduce
ASCVD events in patients already taking statin therapy. Combination drug
therapy is not without risks. Liver and muscle toxicity occur more frequently
with lipid-lowering drug combinations. Figure 22.12 summarizes some
actions of the antihyperlipidemic drugs.
