Drugs for Hyperlipidemia - quiz 3

Hyperlipidemia Overview

• Coronary heart disease (CHD) is the leading cause of death worldwide, correlated with abnormal cholesterol levels (dyslipidemia).
• Elevated LDL-C and triglycerides, and decreased HDL-C, are risk factors for CHD.
• Other risk factors for CHD include cigarette smoking, hypertension, obesity, diabetes, chronic kidney disease, and advanced age.

Classification of Hyperlipidemia

• Type I (Familial Hyperchylomicronemia): elevated triglycerides, low-fat diet, and no drug treatment.
• Type IIA (Familial Hypercholesterolemia): elevated LDL-C, normal VLDL, and triglycerides, treated with PCSK9 inhibitors, lomitapide, statin, ezetimibe, and cholestyramine.
• Type IIB (Familial Combined Hyperlipidemia): elevated LDL-C, VLDL, and triglycerides, treated with PCSK9 inhibitors, lomitapide, statin, ezetimibe, and cholestyramine.
• Type III (Familial Dysbetalipoproteinemia): elevated IDL, triglycerides, and VLDL, treated with fenofibrate, icosapent ethyl, niacin, and statin.
• Type IV (Familial Hypertriglyceridemia): elevated VLDL and triglycerides, treated with fenofibrate, icosapent ethyl, niacin, and statin.
• Type V (Familial Mixed Hypertriglyceridemia): elevated chylomicrons, triglycerides, and VLDL, treated with fenofibrate, icosapent ethyl, niacin, and statin.

Dietary Management of Hyperlipidemia

• Multiple options, including TLC diet, Mediterranean diet, and DASH diet.
• Common characteristics: decrease total fat intake, eliminate trans fats, increase soluble fiber, limit alcohol intake, and increase physical activity.

Drugs for Hyperlipidemia

HMG CoA Reductase Inhibitors (Statins)

• Mechanism of action: competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol synthesis.
• Therapeutic use: first-line treatment to reduce the occurrence of ASCVD events in high-risk patients.
• Pharmacokinetics: variable absorption, metabolized by CYP450 isoenzymes, elimination via bile and feces.
• Adverse effects: elevated liver enzymes, myopathy, and rhabdomyolysis, contraindicated during pregnancy, lactation, and active liver disease.

Cholesterol Absorption Inhibitor - Ezetimibe

• Mechanism of action: selectively inhibits absorption of dietary and biliary cholesterol in the small intestine.
• Therapeutic use: adjunct to maximally tolerated statin therapy in patients with high ASCVD risk or statin intolerance.
• Pharmacokinetics: metabolized in the small intestine and liver, elimination via bile and renal.
• Adverse effects: uncommon, do not use in patients with moderate to severe hepatic insufficiency.

Bile Acid Sequestrants

• Mechanism of action: anion-exchange resins that bind negatively charged bile acids and bile salts in the small intestine.
• Therapeutic use: used for type IIA and type IIB hyperlipidemias, and type 2 diabetes.
• Pharmacokinetics: neither absorbed nor metabolically altered, excreted in feces.
• Adverse effects: GI disturbances, may impair the absorption of fat-soluble vitamins, contraindicated in patients with significant hypertriglyceridemia.

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors

• Mechanism of action: inhibition of PCSK9 prevents degradation of LDL receptors, promoting greater clearance of LDL-C from the serum.
• Therapeutic use: used in addition to maximally tolerated statin therapy in patients with heterozygous or homozygous familial hypercholesterolemia.
• Pharmacokinetics: subcutaneous injections administered every two to four weeks.
• Adverse effects: well-tolerated, injection site reactions, immunologic or allergic reactions, nasopharyngitis, and upper respiratory tract infections.

Adenosine Triphosphate-Citrate Lyase (ACL) Inhibitor - Bempedoic Acid

• Mechanism of action: inhibition of ACL, which lowers LDL-C by inhibiting cholesterol synthesis in the liver.
• Therapeutic use: used with max statin therapy in patients with heterozygous familial hypercholesterolemia and ASCVD.
• Pharmacokinetics: oral prodrug, metabolized in the liver, eliminated in the urine.
• Adverse effects: well-tolerated, may exacerbate gout, and cause limb or back pain, muscle spasm, or tendon rupture.

Microsomal Triglyceride Transfer Protein (MTP) Inhibitor - Lomitapide

• Mechanism of action: MTP inhibition leads to a reduction in VLDL release and VLDL-mediated triglyceride secretion.
• Therapeutic use: indicated for homozygous familial hypercholesterolemia, used as an adjunct to other therapies and lifestyle modifications.
• Pharmacokinetics: oral, is both a substrate and inhibitor of CYP3A4.
• Adverse effects: potential for hepatotoxicity, may cause chest pain, fatigue, GI distress, infection, and respiratory issues.

Fibrates

• Mechanism of action: peroxisome proliferator-activated receptors (PPARs) agonist, leads to decreased triglyceride concentrations and increased HDL-C.
• Therapeutic use: hypertriglyceridemias, particularly type III hyperlipidemia.
• Pharmacokinetics: completely absorbed, distributed widely, and extensively metabolized, elimination via renal.
• Adverse effects: mild GI disturbances, gallstones, myositis, myopathy, and rhabdomyolysis, especially when taken with statins.

Hyperlipidemia

• Coronary heart disease (CHD) is the leading cause of death worldwide, and it is correlated with abnormal cholesterol levels (dyslipidemia).
• Hyperlipidemia can be caused by lifestyle factors and/or inherited defects in lipoprotein metabolism.
• Other risk factors for hyperlipidemia include cigarette smoking, hypertension, obesity, diabetes, chronic kidney disease, and advanced age.

Normal Metabolism of Plasma Lipoproteins

• Lipoprotein metabolism involves the liver, intestine, and peripheral tissues.
• Chylomicrons (CM) carry dietary triglycerides (TG) from the intestine to the liver.
• Very-low-density lipoproteins (VLDL) carry TG from the liver to peripheral tissues.
• Intermediate-density lipoproteins (IDL) are formed from VLDL and are converted to low-density lipoproteins (LDL).
• LDL carries cholesterol from the liver to peripheral tissues.
• LDL receptors on extrahepatic tissues and the liver mediate the uptake of LDL.
• Chylomicron remnants bind to specific receptors on the liver and are endocytosed.

Frederickson's Classification of Familial Hyperlipidemias

• Type I: Familial hyperchylomicronemia (↑TG, ↑chylomicrons) - no effective drug treatment.
• Type IIA: Familial hypercholesterolemia (↑LDL, ↑TC) - treated with PCSK9 inhibitors, statins, imoitapide, ezetimibe, bempedoic acid, cholestyramine, and niacin.
• Type IIB: Familial combined hyperlipidemia (↑LDL, ↑VLDL, ↑TG, ↑TC) - treated with statins, fibrates, and niacin.
• Type III: Familial dysbetalipoproteinemia (↑IDL, ↑TG, ↑TC) - treated with fenofibrate, icosapent ethyl, niacin, and statins.
• Type IV: Familial hypertriglyceridemia (↑VLDL, ↑TG) - treated with fibrates, niacin, and statins.

Dietary Management of Hyperlipidemia

• Therapeutic Lifestyle Changes (TLC) diet, Mediterranean diet, and DASH diet.
• Common characteristics:
  • Decreased total fat intake
  • Limited saturated fats (≤6%)
  • No trans fat
  • Increased soluble fiber
  • Limited alcohol intake
  • Increased plant stanols and sterols
  • Increased intake of tree nuts and omega-3 fatty acids from marine sources
  • Increased physical activity (↑HDL, ↓LDL)

Hyperlipidemia Guidelines

• 2018 guidelines on the management of blood cholesterol.

Statin Treatment

• Inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG CoA reductase) to lower LDL-C.
• Examples: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.
• Mechanism of action: competitive inhibition of HMG CoA reductase, depleting intracellular cholesterol supply, and increasing LDL receptor binding.
• Therapeutic use: high-intensity LDL lowering, reducing the risk of ASCVD events.
• Pharmacokinetics: variable absorption (30-85%), metabolized by cytochrome P450 (CYP450) isoenzymes, and eliminated in bile and feces.
• Adverse effects: liver enzyme elevation, myopathy, and rhabdomyolysis.

Ezetimibe Treatment

• Inhibits intestinal cholesterol absorption, reducing delivery of intestinal cholesterol to the liver.
• Mechanism of action: selectively inhibits intestinal cholesterol absorption, reducing hepatic cholesterol stores and increasing clearance of cholesterol from the blood.
• Therapeutic use: adjunct to maximally tolerated statin therapy in high ASCVD risk patients.
• Pharmacokinetics: glucuronide conjugation in the small intestine and liver, eliminated in bile and renal excretion.
• Adverse effects: uncommon, do not use in moderate-severe hepatic insufficiency.

Bile Acid Sequestrants

• Bind negatively charged bile acids and salts in the small intestine, increasing fecal excretion of bile acids, and reducing hepatic cholesterol stores.
• Examples: colesevelam, cholestyramine.
• Mechanism of action: anion-exchange resins that bind bile acids and salts, increasing the excretion of bile acids, and reducing hepatic cholesterol stores.
• Therapeutic use: modest LDL-C lowering, used for type IIA and type IIB hyperlipidemias.
• Pharmacokinetics: not absorbed or metabolized, eliminated in feces.### Bile Acid Sequestrants
• Colesevelam:
  • Mechanism of action: binds bile acids in the gut, increasing their excretion and reducing their return to the liver, which leads to increased conversion of cholesterol to bile acids, thereby reducing plasma LDL-C
  • Therapeutic use: indicated for type 2 diabetes, and as an adjunct to diet and exercise to reduce LDL-C
  • Pharmacokinetics: not absorbed systemically, side effects include GI disturbances, flatulence, and nausea
• Cholestyramine:
  • Mechanism of action: binds bile acids in the gut, increasing their excretion and reducing their return to the liver, which leads to increased conversion of cholesterol to bile acids, thereby reducing plasma LDL-C
  • Therapeutic use: indicated for hypercholesterolemia and pruritus caused by bile acid accumulation
  • Pharmacokinetics: not absorbed systemically, side effects include GI disturbances, flatulence, and nausea

PCSK9 Inhibitors

• Alirocumab:
  • Mechanism of action: inhibits PCSK9, a protein that degrades LDL receptors, leading to increased LDL receptor expression and reduced LDL-C
  • Therapeutic use: indicated as an adjunct to diet and maximally tolerated statin therapy for adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease
  • Pharmacokinetics: administered subcutaneously every 2-4 weeks, side effects include injection site reactions, hypertension, and nasopharyngitis
• Evolocumab:
  • Mechanism of action: inhibits PCSK9, a protein that degrades LDL receptors, leading to increased LDL receptor expression and reduced LDL-C
  • Therapeutic use: indicated as an adjunct to diet and maximally tolerated statin therapy for adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease

ACL Inhibitors

• Bempedoic Acid:
  • Mechanism of action: inhibits ACL, a cholesterol synthesis enzyme, leading to reduced LDL-C
  • Therapeutic use: indicated as an adjunct to diet and maximally tolerated statin therapy for adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease
  • Pharmacokinetics: administered orally, side effects include GI disturbances, upper respiratory tract infections, and muscle spasms

MTP Inhibitors

• Lomitapide:
  • Mechanism of action: inhibits MTP, a protein involved in triglyceride-rich lipoprotein secretion, leading to reduced LDL-C
  • Therapeutic use: indicated as an adjunct to diet and other therapies for adult patients with homozygous familial hypercholesterolemia
  • Pharmacokinetics: administered orally, side effects include hepatotoxicity, chest pain, fatigue, and GI disturbances

Fibrates

• Gemfibrozil:

  • Mechanism of action: activates PPAR-α, leading to increased lipoprotein lipase expression and reduced triglycerides
  • Therapeutic use: indicated for hypertriglyceridemia, type III hyperlipidemia, and to prevent pancreatitis
  • Pharmacokinetics: administered orally, side effects include GI disturbances, myositis, and increased risk of gallstones### Fibrates

• Should not be used in patients with severe hepatic or renal dysfunction

• Should not be used in patients with preexisting gallbladder disease or biliary cirrhosis

Niacin (Nicotinic Acid)

• Inhibits lipolysis in adipose tissue, reducing production of free fatty acids
• Decreases TG synthesis by 20-30%, and reduces LDL-C by 10-20%
• Most effective agent for increasing HDL-C
• Used in treatment of familial hyperlipidemias
• Can be used with statins
• Not indicated for CV benefits or reduction of ASCVD
• Adverse effects: flushing, nausea, and abdominal pain

Omega-3 Fatty Acids

• Found in marine sources such as tuna, halibut, and salmon
• Inhibits VLDL and TG synthesis in the liver
• Used as an adjunct to other lipid-lowering therapies for individuals with elevated TG (>500mg/dL)
• Has not been shown to reduce CV morbidity or mortality
• Adverse effects: GI effects, fishy aftertaste, and increased bleeding risk with anticoagulants

Icosapent Ethyl (EPA only)

• Does not raise LDL-C unlike other fish oil supplements
• Reduces the risk of CV events in secondary prevention patients or high-risk primary prevention patients
• Adverse effects: GI effects, and increased risk of bleeding with anticoagulants

Combination Drug Therapy

• Ezetimibe, PCSK9 inhibitors, and icosapent ethyl can be considered for add-on therapy for patients on maximally tolerated statin therapy
• Combination therapy may increase liver and muscle toxicities