Pharmacology of Hyperlipidemia Drugs

Dr. dr. Ratih Dewi Yudhani., M.Sc

Department of Pharmacology – Faculty of Medicine
Universitas Sebelas Maret
December, 2022
 Introduction
• Increasing or decreasing levels of
lipids cause various health effects in the
human body à disorders
• When compared to a lower level of lipids,
a higher amount of lipid accumulation
à causes more health disorders à
hyperlipidemia
• Hyperlipidemia à a group of serious
lipid disorders caused by an abnormally
high level of unwanted lipids in the blood
.

Natesan & Jim-Kin., 2021

 Introduction
Classification of lipid metabolism disorder

Natesan & Jim-Kin., 2021

 Introduction
Cholesterol
§ Component of cell membranes and intracellular organelle membranes
§ Is involved in the synthesis of certain hormones (estrogen, progesterone,
testosterone, adrenal corticosteroids)
§ For synthesis of bile salts à digestion and absorption of fat

Origin of Cholesterol (in the liver)

Hydroxymethyl Glutaryl Co-enzymeA reductase
Acetyl coA à Mevalonic Acid cholesterol
(HMG CoA) reductase
Type of Lipoprotein
Very Low Density Lipoprotein (VLDL)
• Was synthesized in the Liver
• Contain triglycerides (TGs) and some cholesterol
• Account for nearly all TGs in the blood
• Contain Apo B100
• Deliver Triglycerides from the liver to adipose tissues, muscles and body cells

Low Density Lipoprotein (LDL)

• “Bad Cholesterol”
• Were formed from VLDL after removal of most triglycerides
• Contain mainly cholesterol and Apo B100
• Account for 60-70% cholesterol in the blood
• Deliver cholesterol to peripheral tissue
• Greatest contribution to coronary atherosclerosis due to ox-LDL à atherosclerotic
plaque
High Density Lipoprotein (HDL)

• “Good Cholesterol”
• Contain cholesterol
• Some contain Apo AI (cardioprotective effect) and Apo AII
• Account for 60-70% cholesterol in the blood
• Transport cholesterol from peripheral tissue back to the liver à
promotes cholesterol removal
• Anti-atherogenic
Lipid metabolism
in the Liver
Lipid metabolism
in the Liver
Why to treat Hyperlipidemia?

To prevent or slow progression of atherosclerosis

To reduce the risk of Coronary artery Disease

To prolong life
Site of Drugs Action
 Inhibitor HMGCoA Reductase (Statin)
Statin à structural analog with HMGCoA Reductase enzyme
• Prodrugs : Levostatin, Simvastatin
• Active Drugs : Atorvastatin, Fluvastatin, Pravastatin

Mechanism of Action:

§ Competitively inhibit HMGCoa reductase à Inhibit cholesterol synthesis à hepatocytes

synthesize more LDL receptor à hepatocytes will remove more LDL from the blood
§ Most effective in lowering LDL-C
§ Decreased the production of Apolipoprotein B100 à reducing VLDL
§ Decreased the plaque cholesterol content and inflammation at plaque site à direct anti-
atherosclerosis effect
 Clinical Use (Indication) of Statin
§ Effective in reducing LDL, especially when used as combination with other lowing
cholesterol drugs
§ Well tolerated
§ Large clinical trial :
- reduce the risk of Coronary event and mortality in patients with ischemic heart disease
- reduce the risk for ischemic stroke
§ Atorvastatin, Simvastatin, Rosuvastatin --> greater efficacy à In patients with
triglycerides level > 250 mg/dl à also reduce triglyceride and increase HDL-C
§ Atorvastatin à most efficacious agent for severe hypercholesterolemia (lowering LDL-C
> 40-50% within 2 weeks, max reduction in 2-4 weeks
§ Fluvastatin à has less maximal efficacy than others drugs
 Some crucial poins of Statin

§ Statin has high first pass excretion by the liver

§ Statin has greater efficacy when take at night
§ Atorvastatin has the longest half-life
§ Tolerated based among other hypolipidemic drugs
 Adverse Effect of Statin

§ Rash
§ GI tract disturbance à dyspepsia, flatulence, abdominal pain, etc
§ Mild elevation of serum aminotransferases
§ Patient with pre-existing liver disease à might have more severe reaction
§ Increases of creatinine kinase à 10% of patients
§ Severe muscle pain and rhabdomyolisis à few cases
(higher risk especially when use as combination with fibrate)
§ Since Statin is metabolized by Cytochrome P450, drugs or food that inhibit the activity of
thus enzyme à increase the risk of hepatotoxicity and myopathy
§ HMGCoA Inhibitor à teratogenic à avoided in pregnancy
 Bile-Acid Binding Resins
Cholestyramine, Colestipol, Colesevelam

Normally, 90% of bile acids (the metabolite of cholesterol) à reasorbed in GI tract à

return to the liver for reuse
Bile-acid binding Resins à large non absorbable polymer that bind bile acid and similar
steroid in intestine to prevent their absorption

Mechanism of Action:
§ Binding to bile acids in the intestinal lumen à inhibit their reabsorption (bile acid
reclycling) à divert hepatic cholesterol to synthesis new bile acid à reduce cholesterol
pool àcompensatory increases LDL receptor in the liver to capture more cholesterol
and synthesize bile acids à increase the removal of LDL from blood
 Clinical Use (Indication) of Resins
§ Resins à modest reduction (15-20%) in LDL-C with little effect on HDL-C and
Triglycerides
§ Use in patient with hypercholesterolemia
§ Can be used to reduce pruritus in patient with cholestasis and bile salt accumulation

o
Bile-Acid Binding Resins Adverse Effect and Drug Interaction
§ GI discomfort à bloating, dyspepsia, nausea, constipation
§ May impaired the absorption of fats, fats soluble vitamins (A, D, E, K), dietary folate
and many drugs (thiazide diuretic, warfarin, digoxin, tetracycline, pravastatin,
Fluvastatin) à these drugs should be given 1 hour before or 4 hours after the resins
 Inhibitor of Cholesterol Absorption (Ezetimibe)
Ezetimibe
Is prodrug à converted in the liver à active glucuronide form
This active form inhibit transporter that mediates GI uptake of cholesterol and
phytosterols

Mechanism of Action:
§ Preventing both absorption of dietary cholesterol and cholesterol excreted in bile acid
à reduce cholesterol in hepatic pool à compensatory increase high-affinity of LDL
receptor à increase removal of LDL from the blood
 Clinical Use of Ezetimibe
§ For hypercholesterolemia and phytosterolemia
§ As monotherapy à 18% reduction of LCL-C
§ In combination with other hypolipidemia drugs à more effective

Ezetimibe Adverse Effect and Drug Interaction

§ Well tolerated
§ When combine with HMGCoA inhibitor à may increase the risk of hepatic toxicity
§ Serum concentration of glucoronic form:
- increased by fibrate
- reduced by cholestiramine
 Niacin (Nicotinic acid)
Niacin reduces LDL-C, Triglycerides, VLDL and increases HDL-C

Mechanism of Action:

§ In liver à Niacin reduces VLDL synthesis and secretion into the blood à preventing
production of LDL à reduces LDL level
§ In adipose tissues à activates signaling pathway that reduces hormone-sensitive
lipase (intracellular lipase system) à inhibit FFA release à decreases FFA and
triglyceride level à reduces LDL formation à decrease LDL-C
§ Niacin à Increases clearance of VLDL by lipoprotein lipase pathway à reduction of
plasma triglycerides concentration
§ Niacin à reduces the catabolic rate of HDL
 Clinical Use of Niacin
§ For hypercholesterolemia
§ For hypertriglyceridemia
§ Mix elevation of LDL-C and TG à in combination with Statin
§ For low level of HDL-C

Niacin Adverse Effect and Drug Interaction

§ Cutaneous Flushing à tolerance with this flushing reaction develops within a few days
§ Dose dependent nausea and abdominal discomfort often occur
§ Pruritus and other skin conditions are reported
§ Moderate elevations of liver enzymes and even severe hepatotoxicity may occur
§ Hyperuricemia occurs in about 20% of patients
 Fibrate
Gemfibrozil, Fenofibrate, Clofibrate

Little of no effect on LDL, reduce VLDL (triglycerides), moderately increasing

HDL

Mechanism of Action:
Activator of Peroxisome Proliferator-Activated Receptor ⍺ (PPAR- ⍺)
§ Increases the activity of endothelial lipoprotein lipase
§ Increases the oxidation of FFA in hepatocytes
§ Decreases VLDL secretion by the liver
§ Moderately increases HDL-level by increasing Apo AI and Apo AII
 Clinical Use of Fibrate
§ For hypertriglyceridemia
§ Mix elevation of LDL-C and TG à in combination with Statin

Fibrate Adverse Effect

The Drug Discovery Development of anti-Hyperlipidemia

• Statins have been shown to be very effective and safe in numerous RCT, and became the
first-line treatment against atherogenic dyslipidemia.
• However, even with optimal statin treatment à 60% to 80% of residual cardiovascular
risk still exists.
• The patients with familial hypercholesterolemia which results in extremely high level of LDL-C and
the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment.

New classes of lipid-lowering drugs have been developed

 The newest hyperlipidemia drugs
PCSK9 Inhibitor

PCSK-9 (Pro-protein convertase subtilisin/kexin type 9)

is a serine protease à plays a central role in cholesterol
metabolism in the liver by enhancing the degradation of LDLRs

PCSK-9 Inhibitor à enhancing the recycling of LDL-C receptor

à increasing the expression of LDL-C receptor at hepatocytes

PCSK9 inhibitor à recently showed promising results of

significant LDL-C lowering in familial hypercholesterolemia
(FH) patients from the long-term phase III clinical trials

FH à a genetic disorder caused by a mutation in LDL receptor gene,

apolipoprotein B (ApoB), or PCSK9 gene with the prevalence of 1 in
300 to 500 people for heterozygous form and 1 in 1,000,000 people for
the more severe homozygous form.
These genetic defects à the significant elevation of blood LDL-C levels
à the early development of Atherosclerotic cardiovascular disease
with higher mortality Ahn & Choi., 2015
 The newest hyperlipidemia drugs
PCSK9 Inhibitor

Pre-Clinical Study

§ In mice with lacking PCSK9 à The reduced accumulation

of cholesteryl esters in the lesion of aortic atherosclerosis.
By comparison, overexpression of PCSK9 induced an excess
burden of atherosclerosis
§ In LDLR deficient mice à knock down or overexpression of
PCSK9 had no significant effects on the cholesteryl ester
accumulation and the size of atheromatous plaque

Clinical Study

§ In clinical trial (77 patients) with heterozygous familial

hypercholesterolemia à alirocumab reduced LDL-C by 29% to 43%
for 150 to 300 mg injection at every 4 weeks and by 68% for 150
mg injection at every 2 weeks
 The newest hyperlipidemia drugs
Microsomal triglyceride transport protein (MTP) inhibitor

• MTP à transfers TG, phospholipids and cholesteryl esters to the ApoB in endoplasmic reticulum
and has a critical role in the synthesis of VLDL and chylomicrons in liver and intestine
• Inhibition of MTP à the decreased synthesis and secretion of VLDL in the liver by inhibiting the
lipidation of ApoB.
• inhibition of MTP in enterocytes à the reduction in plasma TG level by reducing dietary fat
absorption through chylomicron.
• An orally active small molecule inhibitor of MTP à lomitapide, was developed and it has been
approved for the treatment of homozygous familial hypercholesterolemia
 The newest hyperlipidemia drugs
Antisense oligonucleotide against ApoB

• ApoB à the major structural protein of atherogenic lipoproteins à a key role in the assembly and secretion
of VLDL from the liver
• Mipomersen à a synthetic 20 nucleotide antisense oligonucleotide which can bind to ApoB mRNA via
complementary sequence interactions à Hybridization of mipomersen to the target ApoB mRNA creates a
substrate for RNase H1 à the decrease of the ApoB mRNA level and the production of ApoB
• Frequent adverse effects associated with mipomersen à injection site reactions, flu-like symptoms and
hepatic enzyme elevation
• There is still concern for regular monitoring of hepatic function is requested in the patients receiving
mipomersen
MTP Inhibitor &
Antisense oligonucleotide against ApoB

Mechanism of Actions
 The newest hyperlipidemia drugs
Apolipoprotein A1 (ApoA1) mimetics

• The high serum level of HDL-C is a well-known protective factor of ASCVD

• ApoA1 à the major apolipoprotein component of mature HDL.
• ApoA1 à took cholesterol from macrophages in atherosclerotic lesions via ATP-binding cassette A1 (ABCA1)
à triggering reverse cholesterol transport.
• The central role of ApoA1 in comprising HDL-C makes it as an attractive target for modifying ASCVD risk.
ApoA1 mimetics are a class of drugs that is designed to mimic the effect of ApoA1 and HDL-C to reverse the
progression of atherosclerosis
References
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29(6), 596-604
Liao CJ, Huang PS, Chien HT, Lin TK, Yeh CT, Lin KH, 2022. Effects of Thyroid Hormones on Lipid Metabolism
Pathologies in Non-Alcoholic Fatty Liver Disease. Biomedicines, 10(6), 1232
Lipid Transport, Storage, and Utilization. https://openoregon.pressbooks.pub/nutritionscience/chapter/5e-
lipid-transport-storage-util/
Ahn CH, Choi SH. 2015. New Drugs for Treating Dyslipidemia: Beyond Statins. Diabetes Metab J;39:87-94