Antihyperlipidemic Drugs

“Antihyperlipidemic drugs are medications used to lower lipid levels in the blood.” Lipids present in the blood are primarily cholesterol and triglycerides.

Topics Covered

• Definitions and types of Lipids

• Lipid Metabolism

• Lipid Metabolism Disorders

• Antihyperlipidemic drugs: Classifications and Mechanism of Action

  • 1. HMG-CoA Reductase Inhibitors (Statins): Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin.

    2. Bile Acid Sequestrants (Resins): Cholestyramine, Colestipol, Colesevelam

    3. Cholesterol Absorption Inhibitors: Ezetimibe

    4. PCSK9 Inhibitors: Alirocumab, Evolocumab.

    5. Fibrates (PPAR-α Agonists): Fenofibrate, Gemfibrozil

    6. Niacin (Nicotinic Acid) Derivatives Niacin (Vitamin B3)

    7. Omega-3 Fatty Acids: Icosapent, Omega 3 acid ethyl esters

    8. CETP Inhibitors (Experimental/Investigational) (Cholesteryl Ester Transfer Protein (CETP) Anacetrapib, Evacetrapib.

Cholesterol is a waxy, fat-like substance found in all the cells in the human body. It's essential for the cell membrane, hormone production, vitamin D synthesis and bile acid formation. Cholesterol is a single substance chemically steroidal in nature. It is insoluble in the blood plasma and travels inside the blood circulation as lipoproteins.

Based on the density of lipoproteins, cholesterol is divided into three types: low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL).

1. LDL is a bad cholesterol and carries cholesterol from the liver to the blood and body tissues. High levels of LDL forms plaque in the arteries (atherosclerosis), increasing the risk of heart disease.

2. HDL is good cholesterol and carries cholesterol from the blood and the body’s tissues to the liver.

3. VLDL is also a bad cholesterol and carries triglycerides in the blood. VLDL support plaque buildup in the artery wall.

4. The fourth cholesterol is chylomicrons. Dietary cholesterol from the intestine enters the blood circulation as chylomicrons.

   Thus, the total cholesterol in blood is LDL, HDL, VLDL.

Metabolism of lipids

A. Lipid metabolism is a complex process. Lipoproteins facilitate the transport of lipids in the bloodstream. Their metabolism involves exogenous (dietary) and endogenous (liver-derived) pathways.

• a. Exogenous (dietary) pathway:

  • i. Digestion and Absorption of Lipids: Dietary lipids are triglycerides, phospholipids, and cholesterol. Bile salts are an emulsifying agent that break down larger lipid droplets into micelles. Pancreatic lipase hydrolyses triglycerides to monoglycerides and free fatty acids. Cholesteryl ester hydrolase breaks down cholesteryl esters into cholesterol. These lipid products are absorbed by enterocytes in the small intestine and reassembled into chylomicrons for transport.

  • ii. Transport of Lipids in Blood: Chylomicron is a lipoprotein that enters blood plasma and transports digested lipids to tissues. Digested lipids in muscles are used to produce energy. Digested lipids in adipose tissues are stored as triglycerides. Unused Chylomicrons enter the liver and are stored.

• b. Endogenous Pathway (Liver-Derived Lipid Transport)

  The liver synthesizes VLDL, which delivers triglycerides to peripheral tissues. VLDL is progressively converted into LDL as it loses triglycerides. LDL delivers cholesterol to cells. Excess LDL can accumulate in arteries, contributing to atherosclerosis.

  • Fatty Acid Oxidation (Lipolysis): Triglycerides in adipose tissue are broken down into free fatty acids and glycerol. Hormone-sensitive lipase (HSL) catalyses this process. Free fatty acids are transported to the liver and muscles, where they undergo beta-oxidation to produce acetyl-CoA, which enters the Krebs cycle to generate ATP.

  • Lipogenesis (Fatty Acid and Triglyceride Synthesis): Excess unused carbohydrates are converted into fatty acids via lipogenesis in the liver. Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) are key enzymes in this process. Fatty acids are then stored as triglycerides in adipose tissue.

• c. Reverse Cholesterol Transport (HDL Function):

  HDL collects excess cholesterol from tissues and transports it to the liver. The cholesteryl ester transfer protein (CETP) helps transfer cholesterol between lipoproteins. The liver excretes cholesterol into bile for elimination.

Disorders of Lipid Metabolism

• Hyperlipidemia: Elevated lipid levels, increasing the risk of cardiovascular disease.

• Atherosclerosis: Cholesterol buildup in arteries leading to heart disease.

• Metabolic syndrome: A cluster of conditions, including obesity, insulin resistance, and dyslipidemia.

Antihyperlipidemic drugs

“Antihyperlipidemic drugs are medications used to lower lipid levels in the blood.” Lipids present in the blood are primarily cholesterol and triglycerides.

Purpose:

• Reduce the risk of atherosclerotic cardiovascular disease (ASCVD), including heart attacks and strokes.

• By lowering "bad" cholesterol (LDL) and triglycerides, and sometimes raising "good" cholesterol (HDL), these drugs help prevent the buildup of plaque in arteries.

Classification

Antihyperlipidemic drugs are classified based on their mechanism of action as follows:

• 1. HMG-CoA Reductase Inhibitors (Statins): Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin.

• 2. Bile Acid Sequestrants (Resins): Cholestyramine, Colestipol, Colesevelam

• 3. Cholesterol Absorption Inhibitors: Ezetimibe

• 4. PCSK9 Inhibitors: Alirocumab, Evolocumab.

• 5. Fibrates (PPAR-α Agonists): Fenofibrate, Gemfibrozil

• 6. Niacin (Nicotinic Acid) Derivatives Niacin (Vitamin B3)

• 7. Omega-3 Fatty Acids: Icosapent, Omega 3 acid ethyl esters

• 8. CETP Inhibitors (Experimental/Investigational) (Cholesteryl Ester Transfer Protein (CETP) Anacetrapib, Evacetrapib.

HMG-CoA REDUCTASE INHIBITORS (STATINS)

Mechanism of Action

HMG-CoA reductase inhibitors, commonly known as statins, are the most effective and widely used drugs for lowering cholesterol levels. Their mechanism of action involves inhibiting cholesterol biosynthesis and increasing LDL clearance.

• 1. Inhibition of HMG-CoA Reductase: HMG-CoA Reductase catalyses HMG-CoA conversion to mevalonate. Mevalonate is a precursor for cholesterol biosynthesis in the liver. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase to block cholesterol biosynthesis in the hepatocytes (liver).

• 2. Upregulation of LDL Receptors and Increased LDL Clearance: The reduced intracellular cholesterol levels trigger upregulation of LDL receptors on the surface of hepatocytes. These receptors bind to low-density lipoprotein (LDL) particles and facilitate their uptake from the bloodstream into liver cells. This leads to a fall in circulating LDL cholesterol (LDL-C) levels. LDL-C is the primary target in hyperlipidemia treatment.

• 3. Reduction in VLDL and Triglycerides: Statins also reduce the hepatic production of very low-density lipoproteins (VLDL). VLDL are precursors of LDL. This results in a moderate reduction in plasma triglyceride (TG) levels.

• 4. Modest Increase in HDL Cholesterol: Statins have a mild effect in increasing high-density lipoprotein (HDL) cholesterol. This is beneficial for cardiovascular protection.

• 5. Additional Cardioprotective Effects (Pleiotropic Effects): Apart from lipid-lowering properties, statins also exert several beneficial pleiotropic effects, including:

  • a. Anti-inflammatory action (reducing C-reactive protein levels)

  • b. Improvement in endothelial function (enhancing nitric oxide production)

  • c. Reduction of oxidative stress

  • d. Stabilization of atherosclerotic plaques, reducing the risk of plaque rupture and thrombosis

Summary of Pharmacological Effects of Statins in Hyperlipidemia

1. Effect: ↓ Cholesterol synthesis. Outcome: Less hepatic cholesterol production.

2. Effect: ↑ LDL receptor expression Outcome: Enhanced LDL clearance from plasma

3. Effect: ↓ LDL cholesterol. Outcome: Reduced atherogenic risk

4. Effect: ↓ VLDL production Outome: Lower triglyceride levels

5. Effect: ↑ HDL cholesterol Outcome: Cardioprotective effect

Examples of Statins

1. High-potency: Atorvastatin, Rosuvastatin

2. Moderate-potency: Simvastatin. Pravastatin

3. Low-potency: Lovastatin, Fluvastatin.

Pharmacokinetics of statins

• 1. Absorption: Statins are administered orally. Some (e.g., lovastatin) should be taken with food to enhance absorption, while others (e.g., atorvastatin) can be taken without regard to meals. Lovastatin and simvastatin are prodrugs. they are hydrolysed in the GIT to form the pharmacologically active compounds. All statins undergo extensive hepatic first-pass metabolism, which reduces their bioavailability, except for pravastatin, which undergoes minimal metabolism.

• 2. Distribution: Statins are highly protein-bound (>95%), except pravastatin (~50%). Statins are distributed throughout the body, but their primary site of action is the liver, where cholesterol synthesis occurs. Lipophilic statins (e.g., atorvastatin, simvastatin) cross cell membranes more easily and have wider distribution, while hydrophilic statins (e.g., pravastatin, rosuvastatin) tend to remain in plasma.

• 3. Metabolism: Statins are metabolized in the liver by cytochrome P450 (CYP) enzymes, mainly:

  • CYP3A4: Atorvastatin, simvastatin, lovastatin (increased risk of drug interactions).

  • CYP2C9: Fluvastatin, rosuvastatin (fewer interactions)

  • Non-CYP metabolism: Pravastatin is metabolized by sulfation, avoiding CYP interactions.

• Excretion: Statins are primarily excreted in the bile and feces (major route) and to a lesser extent via the kidneys. Hydrophilic statins (e.g., pravastatin, rosuvastatin) have more renal elimination, requiring dose adjustments in kidney disease.

Pharmacological effects

Statins inhibit HMG-CoA reductase, which leads to cholesterol reduction and other pleiotropic benefits. These effects are lipid-lowering effects and non-lipid (pleiotropic) effects.

• 1. Lipid-Lowering Effects

  • a. Inhibition of HMG-CoA Reductase → ↓ Cholesterol synthesis in the liver.

  • b. Upregulation of LDL Receptors → ↑ Hepatic uptake of LDL leading to:

    • i. ↓ LDL cholesterol (by 20–60%).

    • ii. ↓ VLDL and triglycerides (by 10–30%).

  • c. Mild Increase in High-Density Lipoprotein (HDL) (by 5–15%).

• 2. Endothelial and Cardiovascular Effects

  • a. Improved Endothelial Function:

    • i. ↑ Nitric oxide (NO) production → Vasodilation and improved blood flow.

    • ii. ↓ Endothelial dysfunction in conditions like diabetes and hypertension.

  • b. Plaque Stabilization:

    • i. ↓ Lipid accumulation in atherosclerotic plaques.

    • ii. ↓ Risk of plaque rupture and myocardial infarction (MI).

  • c. Anti-Inflammatory Effects:

    • i. ↓ C-reactive protein (CRP), a marker of vascular inflammation.

    • ii. ↓ Levels of inflammatory cytokines (e.g., IL-6, TNF-α).

• 3. Antithrombotic Effects

  • a. ↓ Platelet Aggregation → Reduced risk of thrombosis.

  • b. ↓ Coagulation Factors (e.g., fibrinogen, tissue factor).

• 4. Antioxidant Effects: ↓ Oxidation of LDL, which prevents oxidised LDL formation (a key factor in atherosclerosis).

• 5. Immunomodulatory Effects: ↓ T-cell activation and immune response, beneficial in autoimmune diseases like rheumatoid arthritis and multiple sclerosis.

• 6. Effects on Bone Metabolism: ↑ Bone Formation: Statins may stimulate osteoblast activity, potentially reducing osteoporosis risk.

• 7. Neuroprotective Effects: Possible benefits in Alzheimer’s disease and stroke prevention by reducing neuroinflammation and improving cerebral blood flow.

• Therapeutic uses

Statins are primarily used for their cholesterol-lowering effects, but they have several therapeutic benefits, including:

1. Cardiovascular Disease Prevention – Reduce the risk of heart attacks, strokes, and atherosclerosis.

2. Lowering LDL Cholesterol – Decrease LDL levels, reduce plaque buildup in arteries.

3. Anti-inflammatory Effects – Reduce vascular inflammation.

4. Stroke Prevention – Prevent ischemic strokes by improving blood flow.

5. Diabetes Management – Reduce cardiovascular complications in diabetics.

6. Neuroprotection – Preventing Alzheimer’s disease and cognitive decline.

7. Anti-Cancer Properties – Statins may lower the risk of certain cancers.

8. Chronic Kidney Disease – Reduce cardiovascular risks in kidney disease patients.

Adverse Effects

Statins can cause the following adverse effects:

• Muscle pain (myopathy, rare rhabdomyolysis)

• Liver dysfunction (elevated liver enzymes)

• Increased blood sugar (risk of diabetes)

• Neurological effects (memory loss, confusion)

• Gastrointestinal issues (nausea, diarrhea)

• Headache and dizziness

• Fatigue

Drug interactions

Statins have drug interactions that can increase the risk of adverse effects, particularly myopathy and rhabdomyolysis. The main drug interactions include:

• CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, ketoconazole, ritonavir, grapefruit juice): Increase statin levels, raising the risk of toxicity.

• Fibrates (e.g., gemfibrozil): Higher risk of muscle toxicity and rhabdomyolysis.

• Warfarin: Enhances anticoagulant effects, increasing bleeding risk.

• Calcium channel blockers (e.g., verapamil, diltiazem): Inhibit statin metabolism, increasing drug levels.

• Amiodarone and Dronedarone: Heightened risk of statin-induced myopathy.

• Colchicine: Increased potential for myopathy and neuropathy.

Monitoring and dose adjustments may be needed when combining statins with these drugs.

BILE ACID SEQUESTRANTS (RESINS)

Mechanism of Action of Bile Acid Sequestrants (Resins): Bile acid sequestrants lower cholesterol by:

1. Binding bile acids in the intestine: These resins are positively charged and bind negatively charged bile acids to form resin-bile acid complex. This prevents bile acids reabsorption in the enterohepatic circulation.

2. Increased bile acid excretion: The resin-bile acid complex is excreted in the feces, reducing the bile acid pool.

3. Upregulation of hepatic LDL receptors – The liver converts cholesterol into bile acids to compensate for bile acid loss, which depletes intracellular cholesterol stores in the liver. This increases the number of LDL receptors on hepatocytes, enhancing LDL cholesterol clearance from the bloodstream into liver cells.

4. Reduced LDL cholesterol levels – This overall mechanism decreases plasma LDL cholesterol levels, helping to manage hyperlipidemia.

Since bile acid sequestrants are not absorbed systemically, they have minimal systemic side effects but can cause gastrointestinal issues like bloating, constipation, and indigestion.

Therapeutic Uses of Bile Acid Sequestrants (Resins):

1. Hyperlipidemia: Primarily used to lower LDL cholesterol by increasing bile acid excretion.

2. Primary hypercholesterolemia: Often used as an adjunct to statins or in patients who cannot tolerate statins.

3. Type 2 Diabetes: Some bile acid sequestrants (e.g., colesevelam) help lower blood glucose levels.

4. Chronic diarrhea due to bile acid malabsorption: Useful in post-cholecystectomy diarrhea and short bowel syndrome.

5. Pruritis associated with cholestasis – Binds bile acids, reducing skin itching in liver diseases like primary biliary cholangitis.

6. Digitalis Toxicity: Used as an off-label treatment to bind and eliminate excess digoxin.

These drugs include cholestyramine, colestipol, and colesevelam and are generally safe but can cause gastrointestinal side effects like bloating and constipation.

Adverse effects: Gastrointestinal issues like bloating, constipation, and indigestion.

CHOLESTEROL ABSORPTION INHIBITORS

Mechanism of Action of Cholesterol Absorption Inhibitors: Cholesterol absorption inhibitors selectively inhibit the Niemann-Pick C1-Like 1 (NPC1L1) protein in the small intestine. This protein is responsible for dietary and biliary cholesterol absorption into enterocytes (intestinal cells).

By blocking NPC1L1:

• Less cholesterol is absorbed into the bloodstream.

• Hepatic cholesterol stores decrease, leading to upregulation of LDL receptors on liver cells.

• More LDL cholesterol is cleared from circulation, reducing total LDL-C levels.

Unlike statins, which reduce cholesterol synthesis in the liver, cholesterol absorption inhibitors act at the intestinal level. This makes them useful as monotherapy or with statins for better lipid control.

Pharmacokinetics of cholesterol absorption inhibitors:

• Absorption: Rapidly absorbed in the small intestine, reaching peak plasma levels in 1–2 hours.

• Distribution: Highly protein-bound (~90%) in plasma.

• Metabolism: Undergoes extensive glucuronidation in the liver and intestine, forming an active metabolite.

• Excretion: It enters enterohepatic circulation and is eliminated via bile (hepatic excretion) with minimal renal clearance (~10%).

• Half-life: Around 22 hours, allowing once-daily dosing.

Food does not significantly affect its bioavailability, and it is often used with statins for enhanced lipid-lowering effects.

Adverse effects of cholesterol absorption inhibitors: Cholesterol absorption inhibitors are well-tolerated but may cause the following adverse effects:

• Gastrointestinal issues: Abdominal discomfort, Diarrhea, abdominal pain, and bloating.

• Hepatotoxicity: Elevated liver enzymes, especially when combined with statins.

• Myopathy: Muscle pain or weakness, increased risk when used with statins.

• Headache & fatigue: Common but mild side effects.

• Allergic reactions: Rash or angioedema in rare cases.

Regular monitoring of liver function and muscle symptoms is recommended, particularly when used with statins.

PCSK9 inhibitors

Work by blocking proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that regulates low-density lipoprotein receptors (LDL-R) on liver cells.

Mechanism of Action PCSK9 inhibitors:

1. PCSK9 normally binds to LDL receptors (LDL-R) on hepatocytes, leading to their degradation.

2. PCSK9 inhibitors prevent this binding, allowing LDL-R to the liver surface.

3. More LDL receptors remain available, increasing the clearance of LDL cholesterol (LDL-C) from the bloodstream.

4. Results in a significant reduction in LDL-C levels, lowering the risk of atherosclerosis and cardiovascular diseases.

These drugs are mainly used in hypercholesterolemia, especially in high-risk patients not responding to statins.

Mechanism of action of Fibrates (PPAR-α Agonists)

Fibrates are PPAR-Alpha (Peroxisome Proliferator-Activated Receptor Alpha) agonists that regulate lipid metabolism. Their mechanism of action includes:

1. Activation of PPAR-α – Stimulates nuclear receptors primarily in the liver and muscle, leading to changes in gene expression.

2. Increased Lipoprotein Lipase (LPL) Activity – Enhances the breakdown of triglycerides (TGs) into free fatty acids, reducing serum TG levels.

3. Reduced Hepatic VLDL Production – Lowers the synthesis and secretion of very low-density lipoproteins (VLDL), further decreasing TGs.

4. Increased HDL Cholesterol – Upregulates Apolipoprotein A-I and A-II, leading to elevated high-density lipoprotein (HDL) levels.

5. Enhanced Fatty Acid Oxidation – Reduces lipid accumulation in the liver by promoting β-oxidation of fatty acids.

6. Modulation of Inflammatory and Thrombotic Processes – Fibrates have mild anti-inflammatory and antithrombotic effects, potentially benefiting cardiovascular health.

Fibrates are mainly used to lower triglycerides and increase HDL, making them useful in conditions like Hypertriglyceridemia.

Mechanism of Action of Niacin

Niacin (nicotinic acid) and its derivatives work primarily by modifying lipid metabolism. Their mechanism of action includes:

1. Inhibition of Lipolysis: Niacin inhibits lipase in adipose tissue, reducing the breakdown of triglycerides into free fatty acids. This decreases the hepatic production of VLDL and subsequently lowers LDL levels.

2. Increase in High-Density Lipoprotein (HDL) Levels: Niacin enhances apolipoproteins A1 levels, which helps increase HDL cholesterol, promoting reverse cholesterol transport.

3. Inhibition of Triglyceride Synthesis: Niacin suppresses diacylglycerol acyltransferase 2 (DGAT-2), a key enzyme in triglyceride synthesis, leading to lower VLDL and triglyceride levels.

4. Anti-Inflammatory and Antioxidant Effects: Niacin has additional vascular benefits, including reducing oxidative stress and endothelial inflammation, contributing to its cardioprotective effects.

Due to these actions, niacin is used in dyslipidemia management, particularly for increasing HDL and lowering triglycerides. It is not preferred due to flushing, hepatotoxicity, and other side effects.

Mechanism of Action of Omega 3 fatty acids

Omega 3 fatty acids exert their effects by modifying lipid metabolism, reducing inflammation, and influencing cell membrane function. Their key mechanisms of action include:

1. Triglyceride Reduction – Omega-3s (especially EPA and DHA) inhibit diacylglycerol acyltransferase, reducing triglyceride synthesis and increasing beta oxidation of fatty acids.

2. Inhibition of VLDL Synthesis – Decrease (VLDL) production in the liver, lowering circulating triglycerides.

3. Anti-Inflammatory Effects – Omega-3s inhibit arachidonic acid metabolism and promote the production of anti-inflammatory resolvin and protectins

4. Improved Endothelial Function – Enhance nitric oxide production, leading to vasodilation and improved blood flow.

5. Antiarrhythmic Effects – Stabilize cardiac ion channels, reducing the risk of arrhythmia.

6. Platelet Aggregation Inhibition – Decrease platelet adhesion and aggregation, reducing thrombosis risk.

These mechanisms contribute to their cardiovascular benefits, particularly in reducing triglycerides and inflammation.