Drugs For Hyperlipidemia

Drugs for Hyperlipidemia
Afnan Atallah, Ph.D.

Al-Quds University
Overview
• Lipids are necessary for human life
• Cholesterol
– Essential for cell membrane
– Precursor to the sterol and steroid compounds
• Triglycerides (TG)
– Composed of 3 fatty acids and glycerol
– Main storage form of fuel, generate high-energy
compound such as ATP, that provides energy
for muscle contraction and metabolic reactions
Hyperlipidemia
Hyperlipoproteinemia
• Increases concentrations of lipids and
lipoproteins
• Hypercholesterolemia; high concentration
of cholesterol
– Atherosclerosis and coronary artery disease
• Hypertriglyceridemia; high concentration of
triglyceride
– Pancreatitis
– Development of atherosclerosis and heart
disease
Coronary Heart Disease (CHD)
• The main cause of premature death in
industrialized countries
• Modifiable risk factors
– Hypertension
– Cigarette smoking
– Low high density lipoprotein (HDL) <40 mg/dl
• Unmodifiable risk factors
– Male gender
– Family history of premature CHD; CHD in
first-degree male relative <55, female <65
– Advance age; Men>45, Women >55
Types of Lipoproteins
Lipid Protein
content Content
Most chylomicron Least
very-low density lipoprotein

(VLDL)
intermediate-density lipoprotein
(IDL)
Least high-density lipoprotein (HDL) Most
Chylomicrons- transport
dietary lipids from the gut to
the adipose tissue and liver
Chylomicron remnants-
produced from Chylomicrons
by lipoprotein lipases in
endothelial cells and
transport cholesterol to the
liver
VLDL-made in the liver and
secreted in to plasma deliver
triglycerides to adipose tissue
in the process get converted
to IDL and LDL
LDL- (bad cholesterol)
delivers cholesterol to
peripheral tissues via
receptors and is
phagocytosed by
macrophages thus delivering
cholesterol to the plaques
(atheromas)
HDL- (good cholesterol)
produced in gut and liver
cells, HDL transports
cholesterol from atheromas
to the liver (reverse
cholesterol transport)
lipoproteins
Lipoproteins Normal Values
mg / dl
Total Cholesterol < 200
LDL < 100
HDL 40-50
Triglycerides < 150

Antihyperlipidemic drugs
 Statins
 Niacin
 Fibrates
 Bile acid sequestrants
 A cholesterol absorption inhibitor
 Proprotein convertase subtilisin kexin type 9
(PCSK9) inhibitors,
 Omega-3 fatty acids.
These agents may be used alone or in
combination.
Drug therapy should always be accompanied by
lifestyle modifications, such as exercise and a
diet low in saturated fats
HMG-CoA
reductase
inhibitors
(STATINS)
Low-Density Lipoprotein
(LDL) Cholesterol High-Density Lipoprotein (HDL) Total Triglyceride
Therapy Concentration Cholesterol Concentration Concentration Other Effects
HMG-CoA ↓20-50% ↑10% ↓10-40% Increase in

reductase hepatic LDL
inhibitors receptors.
Adverse effects: abdominal cramps, constipation, diarrhea, heartburn

Hepatitis, elevate serum levels of hepatic enzymes, Myopathy (Myalgia, Myositis,
Rhabdomyolysis)
HMG CoA reductase Inhibitors
Main Adverse Responses - I.
Myositis and Myopathy (muscle pain)
May be.
– Localized to certain muscle groups, or diffuse.
– Mild to severe/life-threatening (from renal
failure / rhabdomyolysis).
Risk is:
– Dose-related.
–  By drug interactions.
–  By renal or hepatic disease (both are
contraindications), advanced age, etc.
Main Adverse Responses - II.
Hepatotoxicity
• May be asymptomatic
• Requires monitoring as tx. starts
Statins: Main Drug Interactions
• Hepatotoxicity/ myositis risk increased by
co-administration of Niacin
• Gemfibrozil, cyclosporine, erythromycin
increase risk of myopathy and renal
consequences
• Statins increases the effect of warfarin
(INR monitoring)
• Risks vary among the various Statins
• Contraindicated during pregnancy and
lactation
Bile Acid-Binding Resins
 Cholestyramine, Colestipol, Colesevelam
Mechanism of action:
• Moderately effective with excellent safety record
• Large MW polymers containing Cl-
• Resin binds to bile acids and the acid-resin
complex is excreted in the feces
– Prevents enterohepatic cycling of bile acids
– Obligates the liver to synthesize replacement bile
acids from cholesterol
– The levels of LDL-C in the serum are reduced as
more cholesterol is delivered to the liver
Adverse effects:
• GI side effects, constipation, nausea and
flatulence
• Deficiency of fat soluble vitamins
• Interfere with absorption of many drugs
(eg,. Digoxin, warfarin, and thyroid
hormone)
Cholesterol absorption inhibitor
 Ezetimibe:
• Inhibits absorption of cholesterol in the small
intestine by localizing at the brush border of the
small intestine.
• This will reduce hepatic cholesterol and an

increase in LDL-cholesterol uptake into liver cells,
thus decreasing levels in the plasma.
• Alterative to statin in statin-intolerance patients

Ezetimibe+Simvastatin (Vytorin®)
Nicotinic acid (Niacin; vitamin B3)
• At “high doses”…
– niacin strongly inhibits lipolysis in adipose tissue,
thereby reducing production of free fatty acids
Reduces the metabolism or catabolism of
Cholesterol and Triglycerides
• Effective in lowering triglyceride, total serum
cholesterol, and LDL levels
• Increases HDL levels
• Mainly used + statin for combined, severe,
refractory hypercholesterolemia +
hypertriglyceridemia
Adverse effects :
• Cutaneous dilator – flushing, itching (shortly
after dose)
– Several strategies to handle
• Wait for tolerance to develop
• Small divided doses
• Aspirin premedication (if not contraindicated)
• Use sustained release prep instead (NIASPAN)
• Hepatotoxicity
• Hyperglycemia
• Potentiates gout (decrease uric acid secretion)
• Severe GI distress ( by antacids)
Niacin: DDIs
•  Risk of statin-induced myopathy
• Antagonizes effects of all antidiabetic
drugs: insulin, oral hypoglycemic agents
Fibric acid derivatives
• Fenofibrate, Gemfibrozil
• These are PPAR α (peroxisome proliferator-activated

receptors) activators.
• PPAR α:
– Nuclear receptor that is involved in metabolism of
carbohydrates and fats.
– This increase in the synthesis of lipoprotein lipase
thereby increases the clearance of triglycerides.
Fibric acid derivatives :
Adverse effects :
• Gall stones due to increase biliary
cholesterol excretion
• Myopathy, myositis (higher risk with
statins)
• GI disturbances
• Potentiate the effect of
– Warfarin (INR is required)
– Oral hypoglycemic agents
– Oral antithyroid drugs
• Contraindicated in patients with hepatic or
renal dysfunction, or in patients
preexisting gallbladder disease
Proprotein convertase subtilisin kexin type 9
inhibitors (PCSK9)
Proprotein convertase subtilisin kexin type 9
inhibitors (PCSK9)
 PCSK9: is an enzyme predominately produced in the
liver.
 Binds to the LDL receptor on the surface of hepatocytes,
leading to the degradation of LDL receptors
 PCSK9 inhibitors: Alirocumab and evolocumab
 More LDL receptors are available to clear LDL-C from the
serum.
 Combination with statin therapy, PCSK9 inhibitors provide
potent LDL-C lowering (50% to 70%)
 Available only 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.
 Generally well tolerated.
 The most common adverse drug reactions are injection site
reactions, immunologic or allergic reactions, nasopharyngitis,
and upper respiratory tract infections.
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.
 Over-the-counter or prescription fish oil capsules (EPA/DHA) can be used for
supplementation
 Icosapent ethyl is a prescription product that contains only EPA
 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
 The most common side effects of omega-3 PUFAs:
 GI effects, fishy aftertaste. Bleeding risk can be increased
Site of action :Drugs for Hyperlipidemia
Drugs Indication Effects On Adverse
Lipid Profile Effects
Cholestyramine Elevated LDL ↓ LDL(20%) GI problems

Colistipol Pregnancy and ↑ TGs (~5%) (bloating,
Colesevelam Children constipation)
Niacin Elevated LDL, ↓ TG (40%) Flushing of face

Low HDL and ↓ LDL (15%) & Pruritus
Elevated TG ↑ HDL (25%) Hyperglycemia
Gemfibrozil Elevated TG ↓ TG (50%) Myositis

↓ LDL (10%) Gall stones
↑ HDL (15%)
HMG-CoA Elevated LDL ↓ LDL (30%) Hepatotoxicity

Reductase ↑ HDL (8%) Myositis
Inhibitors ↓ TG (20%)

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Drugs for Hyperlipidemia

Afnan Atallah, Ph.D.

very-low density lipoprotein

LDL < 100

Triglycerides < 150

HMG-CoA ↓20-50% ↑10% ↓10-40% Increase in

Adverse effects: abdominal cramps, constipation, diarrhea, heartburn

• This will reduce hepatic cholesterol and an

• Alterative to statin in statin-intolerance patients

• These are PPAR α (peroxisome proliferator-activated

Cholestyramine Elevated LDL ↓ LDL(20%) GI problems

Niacin Elevated LDL, ↓ TG (40%) Flushing of face

Gemfibrozil Elevated TG ↓ TG (50%) Myositis

HMG-CoA Elevated LDL ↓ LDL (30%) Hepatotoxicity

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