1. Kirk Mykytyn, Ph.D. Department of Pharmacology mykytyn.1@osu.edu
Lipid-Lowering Drugs
Kirk Mykytyn, Ph.D.
Department of Pharmacology

2. Learning Objectives
At the end of the module
you will know the mechanisms of action, indications, and major side effects of drugs used in the treatment of disorders of lipid metabolism
At the end of the module you will know the mechanisms of action, indications, and major side effects of drugs used in the treatment of disorders of lipid metabolism

3. Learning Resources
Lilly’s Pathophysiology of Heart Disease, 5th ed. Chapter 5 p and Chapter 17 p
Dr. Mehta’s lecture on Lipid Metabolism
The main learning resource for this module is Lilly’s Pathophysiology of Heart Disease, 5th ed. Chapter 5 p and Chapter 17 p It may also be helpful to review Dr. Mehta’s lecture on lipid metabolism. For further reading on dyslipidemia see chapter 31 of “Goodman and Gilman’s: The Pharmacological Basis of Therapeutics” and chapter 35 of “Katzung’s: Basic and Clinical Pharmacology”. Both of these textbooks are available online from OSU libraries.

4. 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
The pathophysiology this module relates to is hyperlipidemia, which is defined as elevated levels of circulating lipids, specifically cholesterol and triglycerides. Hyperlipidemia is associated with increased risk of atherosclerosis and coronary artery disease, which is the leading cause of death in the United States for men and women. In particular, the risk of disease is correlated with circulating cholesterol levels, as individuals with a serum cholesterol level of 240 mg/dl have a two-fold increased risk for coronary artery disease compared to a person with a level of 200 mg/dl. Cholesterol is primarily transported in the circulation as a component of low-density lipoproteins (or LDL). As these particles mediate cholesterol deposition in arteries it is commonly known as “bad cholesterol”. Thus, reduction of LDL level is the primary goal of lipid-lowering drugs and the higher the overall risk of heart disease, the more aggressive the recommended LDL-lowering therapy. Lowering LDL levels is especially important in patients with additional risk factors for atherosclerosis and coronary artery disease, including; nonmodifiable risk factors including advanced age, male sex and a family history of heart disease (specifically a father or brother before the age of 55 and mother or sister before the age of 65). Modifiable risk factors include cigarette smoking, hypertension, diabetes, and obesity. A final important risk factor is low levels of high-density lipoprotein (or HDL) (recall HDL binds cholesterol in the periphery and transports it to the liver… this lowers the risk of atherosclerosis and so HDL is commonly known as “good cholesterol”).

5. Introduction: Hyperlipidemia
Hyperlipidemia and disease:
Pancreatitis (if extremely elevated TG)
Xanthomas (cholesterol deposits) especially around the eyes or along the Achilles tendon
Hyperlipidemia can also be associated with pancreatitis, which is inflammation of the pancreas, especially when triglyceride levels are abnormally high, and xanthomas, which are cholesterol deposits that are typically seen around the eyes or along the Achilles tendon. Here are two images showing the clinical presentation of xanthomas.

6. Treatment of Hyperlipidemia
Non-Pharmacologic:
Diet
Exercise
Pharmacologic:
Decrease the production of lipoproteins
Increase breakdown or removal
Decrease absorption of lipids
In patients with moderate hyperlipidemia, lifestyle changes, such as diet (and specifically reducing the intake of saturated fats) and exercise can lead to modest decreases in LDL levels and increases in HDL levels. When lifestyle changes fail to achieve target values, pharmacologic agents are used to improve abnormal lipid levels. Lipid-lowering therapies utilize one or more of three general strategies; first, decrease the production of lipoproteins, second, increase the breakdown or removal of lipoproteins, and third, decrease the absorption of lipids.

7. Overview of Lipoprotein Metabolism
Lipoprotein metabolism can be divided into two pathways; the exogenous and endogenous pathways. The exogenous pathway refers to the absorption and transport of dietary fat and cholesterol. Absorption of fat and cholesterol in the intestine is facilitated by bile acids that are synthesized in the liver. Recall that bile acids are synthesized from cholesterol, and represents a catabolism pathway for cholesterol. However, normally greater than 95% of the secreted bile acids are recycled back to the liver through the enterohepatic circulation and so little cholesterol is lost through this process. The solubilized dietary fatty acids and cholesterol are then transported into intestinal enterocytes, where they are converted to triglycerides and cholesterol esters, packaged into chylomicrons and exocytosed into the lymphatic system for transport to the circulation. Within the circulation, chylomicrons can bind to lipoprotein lipase (LPL), which is a lipolytic enzyme expressed on the endothelial surface of capillaries in muscle and fat tissue. Upon binding to LPL, triglycerides in the chylomicron are hydrolyzed to produce free fatty acids (FFAs) and glycerol. The FFAs are then taken up into muscle for ATP biogenesis or adipose tissue for storage. As chylomicrons become depleted of triglycerides, and relatively enriched in cholesterol, they are transformed into chylomicron remnants and taken up by the liver. In the endogenous pathway of lipoprotein metabolism, the liver synthesizes and secretes very-low-density lipoproteins (VLDL) containing cholesterol esters and triglycerides assembled from fatty acids derived from adipose tissue or synthesized de novo. Similar to chylomicrons, VLDL particles can bind to LPL to produce FFAs. Approximately half of the resulting VLDL remnants (which are also known as intermediate-density lipoprotein (IDL)) undergo endocytosis directly by the liver, but the remainder are converted to LDL by hepatic lipase (HL). Importantly, the LDL receptor is the only receptor capable of clearing significant amounts of LDL from the plasma. The half-life of LDL in the circulation is 2-4 days, which is markedly prolonged and explains why LDL cholesterol accounts for 65-75% of total plasma cholesterol. Furthermore, the majority of LDL receptors are expressed on the surface of hepatocytes and so the liver is primarily responsible for the removal of LDL particles from the circulation.

8. 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
The HMG CoA reductase inhibitors, commonly known as statins, are the most effective drugs for reducing LDL cholesterol. They have been shown in numerous clinical trials to significantly reduce mortality after a myocardial infarction. The available agents of this group are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin and pitavastatin. Overall, statins reduce serum LDL levels by 20 to 50%, decrease triglyceride levels by 7 to 30% and increase HDL levels by 5 to 15%. In addition, statins have a number of other pharmacological consequences, or pleiotropic effects, that are also cardioprotective, such as; improving endothelial function, promoting plaque stability, inhibiting platelet aggregation, and suppressing inflammation.

9. HMG CoA Reductase Inhibitors (statins)
This figure shows a detailed diagram of the mechanism of action of statins at the level of a hepatocyte. Note that because statins undergo first-pass extraction by the liver, their dominant effect is on that organ. 1) Statins are competitive inhibitors of HMG CoA reductase, which is the rate-limiting enzyme in the cholesterol biosynthesis pathway. 2) The inhibition of cholesterol synthesis leads to a decrease in the concentration of cholesterol within the cell, which then stimulates expression and synthesis of LDL receptors. 3) This increases the number of LDL receptors on the cell surface, thereby promoting uptake of LDL from the blood, and reducing serum LDL levels. 4) In addition, the decrease in intracellular cholesterol levels leads to a reduction in VLDL synthesis and secretion, which explains the triglyceride-lowering effect of statins. The mechanism whereby statins increase HDL levels is unclear.
Harvey RA. Lippincott’s Illustrated Reviews: Pharmacology. 5th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2012.

10. 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
Here is a summary of the mechanisms of action of statins. With regard to adverse effects, statins are generally well-tolerated and are widely prescribed. The most significant potential adverse effects are rare and include hepatotoxicity and myopathy. Patients with hepatotoxicity may experience fatigue, anorexia and weight loss. More commonly patients are asymptomatic, but routine laboratory studies show an increase in transaminase levels. Symptoms disappear almost immediately after the drug is discontinued, but transaminase levels may remain elevated for weeks. Myopathy typically involves the proximal leg or arm muscles and can range from vague aches to intense myalgias and muscle weakness. Rarely, this can lead to rhabdomyolysis, which is the destruction of muscle that can precipitate renal dysfunction or acute renal failure. Importantly, the incidence of muscle injury is increased by concomitant therapy with certain other drugs, including other lipid-lowering agents, such as niacin and fibric acid derivatives. Statins are contraindicated during pregnancy and in nursing mothers.

11. 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%
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%

12. Overview of Lipoprotein Metabolism
Niacin ǁ
Niacin modifies lipid levels through multiple mechanisms, indicated on this diagram. It decreases activity of an enzyme in adipose tissue called hormone-sensitive lipase, leading to reduced triglyceride catabolism and therefore decreased flux of fatty acids to the liver. This decreases the rate of hepatic triglyceride synthesis and VLDL production. Niacin also enhances the clearance of triglycerides from circulating VLDL by promoting the activity of lipoprotein lipase at adipose and muscle cells. The net effect of these actions is a reduction in serum triglyceride and LDL levels.
Niacin

13. 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
Here is a summary of the mechanisms of action of niacin. Additionally, niacin also increases the half-life of apoAI, the major apolipoprotein in HDL. The increase in plasma apoAI increases plasma HDL concentrations and presumably augments reverse cholesterol transport. The major adverse effects of niacin are cutaneous flushing and itching. The flushing involves the release of prostaglandins D2 and E2 within the skin and can be prevented by pretreatment with aspirin or another non-steroidal anti-inflammatory drug. These adverse effects usually disappear after several weeks of niacin use or with use of a timed-release formulation. Additional important adverse effects include hyperuricemia, which may precipitate gout, impaired insulin sensitivity, which may precipitate diabetes in patients at risk. So niacin should be used with caution in diabetic patients. Hepatotoxicity can also occur and manifest with elevated serum transaminases. Rare cases of myopathy have been reported and the incidence is increased when niacin is prescribed concurrently with a statin.

14. 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%
The fibric acid derivatives, or fibrates, include gemfibrozil and fenofibrate. They are primarily used for reducing serum triglyceride levels and increasing serum HDL levels. Their effect on LDL cholesterol is more variable and less beneficial than other lipid-altering drugs.

15. Overview of Lipoprotein Metabolism
Fibrates exert their effects by binding to and activating peroxisome proliferator-activated receptor alpha (which is abbreviated as PPAR alpha). PPAR alpha is a nuclear receptor expressed in hepatocytes, skeletal muscle, macrophages, and the heart. Upon binding of fibrate, PPAR alpha activates transcription of lipoprotein lipase. As shown on this diagram, the fibrate-induced increase in lipoprotein lipase enhances the clearance of triglycerides from circulating VLDL. This increased catabolism of VLDL may actually raise the circulating LDL level, especially in patients with baseline hypertriglyceridemia.
Fibrates

16. Fibrates Mechanism of action
Activators of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPARα)
 LPL expression,  TG clearance from circulating VLDL
 expression apoAI,  HDL levels
Adverse Effects
Mild GI disturbances
Gallstones ( biliary cholesterol excretion)
Myalgia
Here is a summary of the mechanisms of action of fibrates. Additionally, fibrates also increase hepatic production of apoAI, thereby increasing plasma HDL. Fibrates are generally well tolerated, with gastrointestinal discomfort the most common potential adverse effect. Fibrates increase biliary cholesterol excretion and so may contribute to gallstone formation. Rare adverse effects include muscle pains, and when used in combination with a statin the risk of rhabdomyolysis is increased.

17. 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
The bile acid-binding agents or sequestrants are large, highly positively charged molecules that bind noncovalently to negatively charged bile acids in the small intestine. The group includes the resins cholestyramine and colestipol and the hydrophilic polymer colesevelam. These drugs possess similar efficacy and reduce LDL levels 15 to 30%. They can lead to increases in HDL levels but can also increase triglyceride levels. The way bile acid-binding agents work is by forming a complex with bile acids that cannot be reabsorbed in the small intestine and is therefore excreted in the stool. This loss of bile acids causes hepatocytes to increase bile acid synthesis, leading to a decrease in hepatocyte cholesterol concentration. Similar to the effect of statins, LDL receptor expression is stimulated in response to the lower hepatocyte cholesterol levels, enhancing LDL clearance from the circulation. However, unlike statins, new hepatic cholesterol production is also stimulated. The boost in cholesterol synthesis augments VLDL production, resulting in increased serum triglyceride levels. Thus, bile acid-binding agents should be used with caution in patients with hypertriglyceridemia. As bile acid-binding agents are not absorbed systemically, they have little potential for serious toxicity. However, significant GI distress, including constipation, nausea and bloating can limit patient adherence. Bile acid-binding agents can also decrease absorption of fat-soluble vitamins and certain drugs, including digoxin and warfarin. This interaction can be eliminated by administering the sequestrant at least one hour before or four hours after other drugs. Currently, bile acid-binding agents are used mainly for treatment of hypercholesterolemia in young patients less than 25 years of age and in patients for whom statins alone do not provide sufficient plasma LDL reduction.

18. Cholesterol Absorption Inhibitors
Ezetimibe
Selective inhibitor of cholesterol uptake at the brush border of epithelial cells in the small intestine
Acts by competitively inhibiting the Niemann-Pick C1-like 1 transporter protein
 absorption of dietary and biliary cholesterol
 LDL 15-20%,  TG 0-5%,  HDL 1-2%
Plant Sterols/Stanols
Similar in molecular structure to cholesterol, naturally present in fruits and vegetables, block absorption of cholesterol
Some foods come fortified with plant sterols (ex. Benecol)
The final class of agents is the cholesterol absorption inhibitors, which reduce cholesterol absorption in the small intestine. Although this includes reduced absorption of dietary cholesterol, the more important effect is reduced reabsorption of biliary cholesterol, which comprises the majority of intestinal cholesterol. The first of these agents, Ezetimibe, decreases cholesterol transport into enterocytes by selectively inhibiting a brush border transporter protein named Niemann-Pick C1- like 1. At therapeutic concentrations, ezetimibe reduces intestinal cholesterol absorption by about 50%, without reducing the absorption of triglycerides or fat-soluble vitamins. By inhibiting cholesterol uptake, ezetimibe results in reduced chylomicron production and therefore less cholesterol delivery to the liver. The reduced cholesterol content stimulates compensatory hepatic production of LDL receptors, which augment clearance of circulating LDL. Used alone at standard dosage, ezetimibe reduces LDL cholesterol concentrations by up to about 20%. When combined with statin therapy, more protent LDL lowering ensues. The reason for this is the reduction in hepatic cholesterol content due to inhibition of cholesterol absorption leads to a compensatory increase in hepatic cholesterol synthesis that partially offsets the benefits of reducing absorption. By combining ezetimibe with a statin, the compensatory increase in hepatic cholesterol synthesis is prevented. This approach reduces LDL cholesterol concentrations by an additional 15% compared with the effect of the statin alone. Unlike bile acid-binding agents, ezetimibe is absorbed systemically, yet side effects from ezetimibe therapy are rare. Importantly, the addition of ezetimibe to a statin regime does not appear to significantly increase the risk of statin-associated myopathy. A second type of cholesterol absorption inhibitor is plant sterols and stanols that are naturally present in vegetables and fruits, which can be consumed in larger amounts from nutritional supplements. Additionally, some foods come fortified with plant sterols and stanols, such as Benecol, a margarine-like spread. Plant sterols and stanols are similar in molecular structure to cholesterol but are substantially more hydrophobic. They increase the excretion of cholesterol in the stool but are poorly absorbed themselves. Dosages of 2 to 3 grams of plant sterols/stanols per day results in a reduction in plasma LDL concentrations of approximately 15%. The mechanism of action for plant sterols/stanols is identical to ezetimibe.

19. Treatment Guidelines for Hyperlipidemia
This figure presents treatment guidelines for hyperlipidemia. Note that diet and exercise are integral to all treatments of hyperlipidemia. Further note that statins are the first-line pharmacologic therapy and the remaining agents presented in this module can be used in combination with statins for further LDL lowering or to resolve additional dyslipidemia. However, combination drug therapy is not without risks. Liver and muscle toxicity occur more frequently with lipid-lowering drug combinations.
Harvey RA. Lippincott’s Illustrated Reviews: Pharmacology. 5th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2012.

20. 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
Although statins are the cornerstone of treatment for hyperlipidemia, some patients are intolerant to these drugs, with up to 7% of patients on statins reporting myalgias. Additionally, a large proportion of very high-risk patients are unable to achieve acceptable LDL lowering, even with the use of high potency statins. Thus, there is a need for additional treatment approaches. Although you will not be tested on this information, I would like to tell you about a promising new therapeutic target, which is proprotein convertase subtilisin/kexin type 9 or PCSK9. The PCSK9 protein regulates the expression of LDL receptors on the cell surface in the liver. Specifically, after LDL receptors bound to LDL particles are internalized, PCSK9 binds to the LDL receptor and directs it to the lysosome for degradation, thereby decreasing the number of LDL receptors at the cell surface and increasing circulating plasma LDL cholesterol. This is illustrated in the left panel of the figure. Interestingly, gain of function mutations in PCSK9 have been linked to autosomal dominant hypercholesterolemia and premature cardiovascular disease while loss of function mutations are associated with reduced LDL cholesterol plasma levels and protection from coronary heart disease. Notably, patients with loss of function mutations in PCSK9 do not have any obvious concomitant deleterious phenotypes. Therefore, PCSK9 inhibition offers a promising supplement or alternative to statin therapy in the reduction of LDL cholesterol. Currently, there are two fully human monoclonal antibodies (Evolucumab and Alirocumab), which have completed late stage clinical trials and shown good tolerability, safety and efficacy. Their mechanism of action is illustrated in the right panel in the figure. The antibody binds to PCSK9, preventing it from directing the LDL receptor to the lysosomes. Rather, the LDL receptor is recycled back to the cell surface where it can bind to and internalize additional LDL particles, thereby reducing LDL cholesterol plasma levels.

21. Lipid Lowering Drugs Quiz

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