DRUG SUMMARY TABLE: CHAPTER 20 Pharmacology of Cholesterol and Lipoprotein Metabolism

DRUG CLINICAL APPLICATIONS SERIOUS AND COMMON ADVERSE CONTRAINDICATIONS THERAPEUTIC CONSIDERATIONS
EFFECTS
INHIBITORS OF CHOLESTEROL SYNTHESIS
Mechanism—Inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis → LDL decreases up to 60%, HDL increases ∼10%, triglycerides decrease up to 40%
Lovastatin Shared indications: Myopathy, rhabdomyolysis, Shared contraindications: Statins are drugs of choice for
Pravastatin  Hypercholesterolemia hepatotoxicity, dermatomyositis,  Active liver disease lowering LDL. Atorvastatin and
Simvastatin  Familial systemic lupus erythematosus (shared  Pregnancy and lactation rosuvastatin are the most potent;
Fluvastatin adverse effects); pancreatitis fluvastatin is the least potent.
Atorvastatin
hypercholesterolemia
(pravastatin and rosuvastatin only);
 Serum transaminase Lovastatin, simvastatin, and
Rosuvastatin
 Coronary atherosclerosis hemorrhagic cerebral infarction
elevations
atorvastatin are metabolized by
Pitavastatin  Prophylaxis for coronary (atorvastatin only); acute renal failure  Hypersensitivity to drug
CYP3A4; inhibitors of CYP3A4
atherosclerosis Pitavastatin only:
(rosuvastatin only) increase risk of myopathy; fluvastatin
Pravastatin and simvastatin only:
Abdominal pain, constipation,  Concomitant use of and pitavastatin are metabolized via
 Stroke arthralgia (shared adverse effects); cyclosporine a different cytochrome P450-
Atorvastatin only: musculoskeletal pain, upper mediated pathway; pravastatin and
 Diabetes mellitus type 2 respiratory infection (pravastatin rosuvastatin are not metabolized by
only) cytochrome P450s; consider choosing
a statin not metabolized via P450s in
patients who are concurrently taking
drugs that are metabolized by
cytochrome P450s.
Combination with a bile acid
sequestrant or cholesterol absorption
inhibitor results in additive decrease
in LDL.
Combination with niacin may be
useful in patients with high LDL and
low HDL; however, co-administration
with niacin increases the risk of
myopathy.
Co-administration with gemfibrozil
decreases statin clearance and raises
plasma concentration of statins,
which can induce rhabdomyolysis.
INHIBITORS OF VLDL SECRETION
Mechanism—Inhibit apoB mRNA translation (mipomersen) or apoB lipidation by MTP (lomitapide) to decrease VLDL secretion → at least 25–35% decrease in LDL (both agents) and 15% increase
in HDL (mipomersen)
Mipomersen Homozygous familial Steatosis of liver, anti-glomerular Shared contraindications: Mipomersen is administered as a
Lomitapide hypercholesterolemia (HoFH) basement membrane  FDA approved for HoFH and weekly subcutaneous injection and
tubulointerstitial nephritis, requires physician lomitapide as a daily oral regimen.
angioedema, cancer certification and risk Both agents are co-administered in
Mild increase in liver transaminases, evaluation and mitigation addition to standard medical therapy,
increased hepatic fat, injection site strategy (REMS) including a statin.

INHIBITORS OF BILE ACID ABSORPTION
Mechanism—Bind to bile acids, preventing enterohepatic circulation → LDL decreases up to 28%, HDL increases ∼5%
Cholestyramine Hypercholesterolemia (shared
Colesevelam indication)
Colestipol Pruritus (cholestyramine only)
Diabetes mellitus type 2 (colesevelam
only)
INHIBITORS OF CHOLESTEROL ABSORPTION
Mechanism—Decrease cholesterol transport from micelles into enterocytes by inhibiting uptake through brush border protein NPC1L1 → LDL decreases up to 20%, HDL increases ∼3%, TG
decrease ∼8%
Ezetimibe Primary hypercholesterolemia
Familial hypercholesterolemia
Sitosterolemia (very rare)
Mixed hyperlipidemia
FIBRATES
Mechanism—Agonists of peroxisome proliferator-activated receptor α (PPAR α) → triglycerides decrease up to 50%, HDL increases up to 20%, LDL decreases up to 15%
Gemfibrozil Isolated hypertriglyceridemia
Fenofibrate Hypertriglyceridemia with low HDL
Dysbetalipoproteinemia
reaction, flu-like symptoms,
headache, fatigue, mild
gastrointestinal distress, reduced
vitamin E levels (shared adverse
effects); chest pain, weight loss
(lomitapide only)
Pancreatitis, heart disease
(colesevelam only)
Increase in triglyceride levels,
bloating, dyspepsia, flatulence,
bleeding diathesis secondary to
vitamin K deficiency
Hepatitis, myopathy, rhabdomyolysis
Arthralgia, myalgia
Elevated liver function tests,
myopathy when co-administered with
a statin (shared adverse effects);
 Hepatic impairment
 Serum transaminase
elevations
Lomitapide only:
 Use of CYP3A4 inhibitors
Shared contraindications:
 Hypersensitivity to drug
 Hypertriglyceridemia
Cholestyramine and colesevelam
only:
 Complete biliary obstruction
Hypersensitivity to ezetimibe
Concomitant use with a statin in
pregnancy or while nursing
Active liver disease
Unexplained hepatic transaminase
elevations
Shared contraindications:
 Preexisting gallbladder
disease
Lomitapide may be co-administered
with oral vitamin E supplementation.
Lowering of LDL levels is dose-
dependent.
Increase HDL modestly.
Second-line agents for lipid
reduction; used mainly to treat
hypercholesterolemia in young
patients and patients for whom
statins alone do not provide sufficient
LDL reduction.
Increase triglyceride levels.
Significant bloating and dyspepsia
limit patient adherence.
Decrease absorption of fat-soluble
vitamins; bleeding may result due to
vitamin K deficiency; bind certain
drugs, such as digoxin and warfarin.
Modest LDL reduction; small effect
on HDL and triglycerides (TG).
Often combined with a statin to
prevent a compensatory increase in
hepatic cholesterol synthesis.
Ezetimibe is rapidly absorbed by
enterocytes and circulates
enterohepatically.
Ezetimibe levels are increased by
cyclosporine and fibrates.
Ezetimibe can increase plasma
concentrations of cyclosporine.
Drugs of choice for
hypertriglyceridemia.
 pancreatitis, serum creatinine  Hepatic dysfunction Bezafibrate and ciprofibrate are
elevation (fenofibrate only)  Severe renal impairment available in Europe.
Abdominal discomfort Used in combination with statins for
 Nursing mothers
combined hyperlipidemia or when
 Hypersensitivity to drug
HDL cholesterol is decreased;
Gemfibrozil only:
however, there is an increased risk of
 Concomitant use with myopathy when combined with
repaglinide or simvastatin statins.
Fenofibrate has fewer GI and
myopathy adverse effects than
gemfibrozil.
Fibrates increase warfarin levels.
NIACIN
Mechanism—Reduces free fatty acid release from adipose tissue and increases plasma residence time for apoAI → triglycerides decrease up to 45%, LDL decreases up to 20%, HDL increases up
to 30%
Niacin Isolated low HDL Hepatotoxicity, rhabdomyolysis Active liver disease Decreases LDL and triglyceride;
Low HDL with mildly elevated LDL or Flushing, abdominal discomfort Active peptic ulcer increases HDL.
TG Arterial bleeding Flushing occurs during first few
Familial combined hyperlipidemia Hypersensitivity to niacin weeks of use and can be prevented
by pretreatment with NSAID; flushing
limits use.
Hyperuricemia may precipitate gout.
Niacin use is associated with impaired
insulin sensitivity.
OMEGA-3 FATTY ACIDS
Mechanism—Regulate nuclear transcription factors including SREBP-1c and PPARα to reduce triglyceride biosynthesis and increase fatty acid oxidation → reduce plasma triglycerides by up to
50%
EPA Hypertriglyceridemia Increased low-density lipoprotein Hypersensitivity to omega-3 fatty Lovaza® is a prescription-strength
DHA cholesterol acids formulation of eicosapentaenoic acid
GI discomfort (EPA) and docosahexaenoic acid
(DHA).
PCSK9 INHIBITORS
Mechanism—Bind to PCSK9 in plasma, thereby promoting antibody complex-mediated degradation; reduced PCSK9 levels decrease the rate of LDL-R degradation, leading to net increase in the
rate of LDL-C clearance and a 50–72% decrease in LDL-C levels
Evolocumab Shared indication: Hypersensitivity reaction (including Hypersensitivity to any component of Subcutaneous injection every 2
Alirocumab  Heterozygous familial vasculitis) drug weeks (every 4 weeks for
hypercholesterolemia (HeFH) Nasopharyngitis, upper respiratory evolocumab in HoFH).
or clinical ASCVD requiring tract infection, injection site reaction, Discontinue treatment for serious
additional lowering of LDL-C influenza, back pain, myalgia, hypersensitivity reactions.
Evolocumab only: diarrhea (shared adverse effects);
 Homozygous FH (HoFH) dizziness, hypertension (evolocumab
only); elevated liver enzymes
(alirocumab only)