Lipid-Lowering Drugs
Kirk Mykytyn, Ph.D.
Department of Pharmacology
mykytyn.1@osu.edu
Learning Objectives
Learning Resources
1. Lilly’s Pathophysiology of Heart Disease, 5th ed. Chapter 5 p. 127130 and Chapter 17 p. 431-435
2. Dr. Mehta’s lecture on Lipid Metabolism
Introduction: Hyperlipidemia


Definition:
 Elevated levels of circulating lipids, specifically cholesterol and triglycerides
(TG)
Hyperlipidemia and disease:
 Hyperlipidemia (and especially high levels of low-density lipoprotein (LDL))
is correlated with an increased incidence of atherosclerosis and coronary
artery disease (CAD)

Total serum cholesterol level of 240 mg/dl = 2X ↑risk of CAD vs. 200
mg/dl
 Combination with other risk factors

Age/Sex/Family history

Smoking

Hypertension

Diabetes

Obesity

Low HDL levels
Introduction: Hyperlipidemia
Treatment of Hyperlipidemia
Overview of Lipoprotein Metabolism
HMG-CoA Reductase Inhibitors (Statins)


Most effective and best-tolerated agents for reducing LDL
 fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin,
and pitavastatin
  LDL 20-55%,  TG 7-30%,  HDL 5-15%
Other cardioprotective effects
 Improve endothelial function, promote plaque stability, inhibit platelet
aggregation, and suppress inflammation
HMG CoA Reductase Inhibitors (statins)
Harvey RA. Lippincott’s Illustrated Reviews: Pharmacology. 5th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2012.
HMG-CoA Reductase Inhibitors (Statins)
Mechanism of action
 Analog of HMG CoA
 Competitive inhibitor of HMG CoA reductase, the rate limiting step in
cholesterol synthesis
 Reduced hepatic cholesterol results in  LDL receptor expression, which 
the removal of LDL from the blood
 Reduced hepatic cholesterol results in  VLDL synthesis and secretion
Adverse Effects
 Hepatotoxicity (less than 1% of patients)
 Myopathy (2 to 10% of patients) – rarely leads to rhabdomyolysis
 Contraindicated in pregnancy
Niacin


Niacin (nicotinic acid, vitamin B3) is one of the oldest lipid-regulating drugs
and favorably affects virtually all lipid parameters
Most effective agent for raising HDL cholesterol
  LDL 5-25%,  TG 20-50%,  HDL 15-35%
Overview of Lipoprotein Metabolism
Niacin
Niacin
Niacin
Mechanism of action
 Decreases hormone-sensitive lipase (HSL) activity in adipose tissue
  flux of free fatty acid to the liver,  hepatic TG production,  VLDL
secretion
 Enhances lipoprotein lipase (LPL) in adipose and muscle cells
  TG clearance from circulating VLDL
 Increases the half-life of apoAI, the major apolipoprotein in HDL
  HDL levels, without disturbing hepatic retrieval of cholesterol
Adverse Effects
 Transient cutaneous flushing and itching
 Prevented by aspirin, regular use, or timed-release formulations
 Hyperuricemia, impaired insulin sensitivity, hepatotoxicity, and myopathy
Fibrates


Fibric acid derivatives (gemfibrozil and fenofibrate)
Primarily used for reducing TG and increasing HDL serum levels
  LDL 0-20%,  TG 20-50%,  HDL 10-20%
Overview of Lipoprotein Metabolism
Fibrates
Fibrates
Mechanism of action
 Activators of the nuclear transcription factor peroxisome proliferatoractivated receptor α (PPARα)
  LPL expression,  TG clearance from circulating VLDL
  expression apoAI,  HDL levels
Adverse Effects
 Mild GI disturbances
 Gallstones ( biliary cholesterol excretion)
 Myalgia
Bile Acid-Binding Resins

Large, highly positively charged molecules that
bind negatively charged bile acids and bile salts
in the small intestines
  LDL 15-30%,  TG,  HDL 3-5%
Mechanism of action
 Bile acids are prevented from returning to the
liver and are excreted in feces
  hepatic cholesterol conversion to bile acids,
 hepatic cholesterol concentrations,  LDL
receptor expression
 Hepatic cholesterol synthesis also stimulated
  VLDL production,  serum TG levels
Adverse Effects
 Interference with absorption of fat-soluble
vitamins and certain drugs
 GI effects: constipation, nausea, and bloating
Cholesterol Absorption Inhibitors
Treatment Guidelines for Hyperlipidemia
Harvey RA. Lippincott’s Illustrated Reviews: Pharmacology. 5th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2012.
Emerging Therapeutics


Proprotein convertase subtilisin/kexin type 9 (PCSK9) routes LDL and LDL
receptor complexes for degradation in lysosomes
Monoclonal antibodies against PCSK9 block the interaction of PCSK9 with
the LDL receptor, allowing LDL receptor recycling to the cell surface, which
leads to a decrease in circulating LDL
Thank you for
completing this module
Questions?
mykytyn.1@osu.edu