Drugs for Hyperlipidemia

• Drugs are used to treat hyperlipidemia

Objectives

• Students will be able to list drug groups for hyperlipidemia and provide examples
• They will be able to explain the mechanism of action for each group
• They will also be able to list the major side effects of the different antihyperlipidemic groups
• They will be able to describe the current goals in treating hyperlipidemia

Treatment Options

• Lifestyle changes, such as diet, exercise, and weight reduction are treatment options
• Secondary causes of hyperlipidemia must be excluded before drug therapy is initiated

Treatment Goals

• LDL-C is the primary target in most dyslipidemia management strategies
• Each 1.0 mmol/L absolute reduction in LDL-C is associated with a 20% reduction in the risk of cardiovascular events
• Guidelines on CVD prevention strongly recommend modulating the intensity of the preventive intervention according to the level of the total CV risk

Drugs for Hyperlipidemia

• Statins
• Bile acid binding resins
• Ezetimibe
• Fibrates
• Niacin
• Omega-3 fatty acids
• PCSK9 inhibitors
• Inclisiran
• Bempedoic acid
• Lomitapide
• Evinacumab

Statins

• Atorvastatin and Fluvastatin are statins
• Statins block cholesterol synthesis in the liver
• They decrease LDL cholesterol levels
• They increase plasma HDL levels in some patients
• They reduce TG levels
• Statins reduce CV morbidity and mortality in both primary and secondary prevention, in both genders and age groups
• It slows the progression of coronary atherosclerosis

Statins Mechanism of Action

• Statins block β-hydroxy β-methylglutaryl coenzyme A (HMG-CoA) reductase, thus inhibiting cholesterol synthesis
• This depletes the intracellular supply of cholesterol
• Statins increase LDL receptors that can bind and internalize circulating LDLs, thus increasing catabolism of LDL

Statin Pharmacokinetics

• Statins differ in absorption, bioavailability, plasma protein binding, excretion, and solubility
• Many statins undergo hepatic metabolism via cytochrome P450 isoenzymes
• CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors/competitors
• The degree of LDL-C reduction is dose-dependent
• Interindividual variation exists in LDL-C reduction with the same drug dose due to genetic background impacting cholesterol metabolism, statin uptake, and metabolism in the liver
• Interindividual variations in statin response require monitoring

Statin Intensity

• High-intensity statins lower LDL-C by ≥50%:
  • Atorvastatin 40–80 mg
• Moderate-intensity statins lower LDL-C by 30% to <50%:
  • Atorvastatin 10 - 20 mg
• Low-intensity statins lower LDL-C by <30% on average:
  • Fluvastatin 20–40 mg

Statin Side Effects

• Liver injury (elevation of ALT) is a side effect
  • Progression to liver failure is rare
• Myopathy is the most clinically relevant adverse effect
  • This includes muscular pain and tenderness
• Rhabdomyolysis is a severe form of muscle injury
• There is an increased risk of new-onset diabetes and kidney proteinuria
• Statins are contraindicated in pregnancy and nursing mothers
• Combining statins with gemfibrozil enhances myopathy risk, and should be avoided

Bile Acid-Binding Resins

• Cholestyramine, Colestipol, and Colesevelam are bile acid binding resins
• Colesevelam is better tolerated than cholestyramine
• Bile acid-binding resins cause reduction in LDL-C
• They does not affect HDL-C
• TGs may increase in some predisposed patients
• Bile acid-binding resins reduce glucose levels in hyperglycemic patients
• Bile acid-binding resins are used in the treatment of hypercholesterolemia
• They aren't systemically absorbed, so are very safe
• Bile acid-binding resins are the drugs of choice in children and pregnant and lactating women

Bile Acid-Binding Resins Mechanism

• They bind bile acids in the intestine, preventing their absorption and producing an insoluble complex excreted in feces
• The liver increases cholesterol oxidation by converting cholesterol to bile acids
• This increases cholesterol catabolism and compensatory increase in hepatic LDLR activity This clears LDL-C from circulation and reduces LDL-C levels

Bile Acid Binding Resins, Adverse effects

• Adverse effects: constipation, dyspepsia, and nausea
• The treatment starts with a low dose and ample fluid intake with gradual dose increase
• The resins reduce the absorption of fat-soluble vitamins and increase circulating TG levels in certain patients
• Have major drug interactions with commonly prescribed drugs
• Must be administered 4 h before or 1 h after other drugs
• Colesevelam has fewer interactions and can be taken with statins

Cholesterol Absorption Inhibitors

• Ezetimibe is a cholesterol absorption inhibitor
• It lowers LDL-C
• It inhibits NPC1L1, inhibiting intestinal absorption of dietary and biliary cholesterol in the small intestine
• As a result, there is less cholesterol in the liver
• Upregulating LDLR expression increases clearance of LDL-C from the blood
• Side effects include moderate elevations of liver enzymes and muscle pain

Fibrates

• Fenofibrate, bezafibrate, and gemfibrozil are fibrates
• They lower serum triglycerides
• They increase HDL levels
• They are used in the treatment of hypertriglyceridemia
• Fibrates bind to peroxisome proliferator-activated receptor-alpha (PPAR-α)
• They up-regulate lipoprotein lipase (LPL), apo A-I and apo A-II, and down-regulate apo C-III
• Increased LPL expression decreases triglyceride concentrations

Fibrate Side Effects

• Side effects: GI disturbances
• Liver enzymes may become elevated
• Formation of gallstones can occur
• They can cause myopathy and rhabdomyolysis
• Gemfibrozil inhibits the metabolism of statins, which increases concentrations of statins
  • This leads to an increased risk of myopathy
• Fibrates compete with coumarin anticoagulants for binding sites, potentiating the anticoagulant effect
• Fibrates are not for patients with severe hepatic and renal dysfunction and those with gallbladder disease

Niacin

• Niacin, or nicotinic acid has broad lipid-modulating action
• It raises HDL-C
• It reduces LDL-C and TGs
• It is used in hypertriglyceridemia and hypercholesterolemia

Niacin Mechanism and Side Effects

• Niacin inhibits lipolysis in adipose tissue
• This reduces free fatty acid production, which in turn reduces liver triglycerides
• Decreased hepatic VLDL leads to reduced LDL plasma concentrations
• Side effects include skin reactions (flushing), which can be minimized by taking aspirin 30 min before each dose, dyspepsia, hyperuricemia, and liver toxicity
• Niacin and a statin can cause myopathy

Omega-3 Fatty Acids

• Eicosapentaenoic acid (EPA) is an omega-3 fatty acid
• Omega-3 fatty acids are components of fish oil
• They are used to lower triglycerides

PCSK9 Inhibitors

• PCSK9 inhibitors include Evolocumab
• Evolocumab inhibits PCSK9's ability to bind
• PCSK9 binds to LDLR on the surface of hepatocytes, causing LDLR lysosomal degradation and increasing plasma LDL concentrations.
• Antibodies to PCSK9 prevent it from binding the LDLR-LDL complex, preventing LDLR degradation

PCSK9 Inhibitors Continued

• Inclisiran blocks PCSK9 protein synthesis
• Humanized monoclonal antibodies bind free PCSK9, preventing it from binding to the LDL receptor and causing degradation
• As a result, liver clearance of LDL increases, and serum LDL levels lower
• Statin treatment raises levels of circulating PCSK9
• Their best effect occurs in combination with statins
• They are used as adjunctive therapy to maximally tolerated statin
• Administered by subcutaneous injections every 2 weeks or once monthly
• They should not be used in pregnancy
• Side effects include injection site reactions and increased infection risk

ATP-Citrate Lyase Inhibitor

• Bempedoic acid is an inhibitor of ATP-citrate lyase
• It acts by inhibiting hepatocyte cholesterol biosynthesis
• It is an adjunct to diet and maximally tolerated statin therapy and can further lower LDL-C in patients with familial hypercholesterolemia or established atherosclerotic cardiovascular disease
• Bempedoic acid has application in patients who are statin intolerant
• It is administered orally
• Bempedoic acid becomes activated by very-long-chain acyl-CoA synthetase-1 (ASCVL1), which is not expressed in skeletal muscle
  • AS a result, has a lower association with myalgias than statins
• Side effects include Hyperuricemia, increased creatinine, and increased hepatic transaminases

Inhibitor of Microsomal Triglyceride Transfer Protein (MTP)

• Lomitapide inhibits MTP, which is essential for intracellular transfer of triglycerides into triglyceride-rich lipoproteins
• This inhibits the formation of VLDLs in hepatocytes and reduces LDL-C
• Should be used in combination with maximally tolerated statin therapy, always start with statin therapy
• It is approved for adults with familial hypercholesterolemia, and is an adjunct to a low-fat diet and therapies
• It is orally administered
• Significant side effects include diarrhea, vomiting, and abdominal pain as well as elevated ALT and AST

Angiopoietin-like Protein 3 Inhibitor

• Evinacumab inhibits angiopoietin-like protein 3 (ANGPTL3)
• ANGPTL3 regulates lipid metabolism by inhibiting LPL and endothelial lipase (EL)
• Evinacumab inhibition of ANGPTL3 increases LPL and EL activity and decreases LDL-C levels
• It is used as an adjunct to lipid-lowering agents and diet in patients with homozygous FH