Statins: HMG-CoA Reductase Inhibitors

Statins (HMG-CoA Reductase Inhibitors)

• HMG-CoA reductase is an enzyme that catalyzes the rate-limiting step in hepatic cholesterol biosynthesis, specifically the conversion of HMG-CoA to mevalonate.
• Statins are structural analogs of HMG-CoA, functioning as competitive inhibitors of HMG-CoA reductase.
• Statins inhibit HMG-CoA reductase, blocking the conversion of HMG-CoA to mevalonate, which reduces intrahepatic cholesterol biosynthesis.
• Statin use upregulates LDL receptors on hepatocytes via sterol regulatory element-binding protein (SREBP).
• The upregulation of LDL receptors increases LDL recycling.
• Statins lower LDL cholesterol and triglyceride levels, and simultaneously increasing HDL cholesterol.
• Lovastatin and simvastatin are prodrugs.
• Atorvastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin are active as given.
• These statins demonstrate better maximum efficacy, decrease triglycerides, and elevating HDL cholesterol, particularly in patients with very high triglyceride levels.
• Lab test results show statins lead to decreased LDL cholesterol, elevated HDL cholesterol, and decreased triglyceride levels.
• Statins decrease C-reactive protein, increase plaque stabilization, increase anti-inflammatory effect and provide antioxidant effects, improve endothelial function of coronary arteries.

Statin Pharmacokinetics

• Atorvastatin has a half-life of 15-30 hours, is metabolized by CYP3A4, and has a bioavailability of ~10%.
• Simvastatin has a half-life of 2-3 hours, is metabolized by CYP3A4 and CYP3A5, and has a bioavailability of ~5%.
• Pravastatin has a half-life of ~2 hours and a bioavailability of ~20%.
• Lovastatin has a half-life of 3 hours, is metabolized by CYP3A4, and has a bioavailability of ~5%.
• Fluvastatin has a half-life of 0.5-2.5 hours, is metabolized by CYP2C9, and has a bioavailability of ~20-30%.
• Pitavastatin has a half-life of 12 hours, is metabolized by limited CYP2C9, and has a bioavailability of ~50%.
• Rosuvastatin has a half-life of 19 hours, is metabolized by limited CYP2C9, and has a bioavailability of ~20%.

Statin Interactions

• Concomitant use of statins with fibrates or nicotinic acid increases the risk of myopathy because both agents can cause myopathy.
• CYP3A4 inhibitors, HIV/HCV protease inhibitors, macrolides (especially erythromycin and clarithromycin), azole antifungals, cyclosporine and warfarin can cause interactions.

Statin Side Effects

• Common side effects are headache and gastrointestinal symptoms like constipation, diarrhea, and flatulence.
• Hepatotoxicity can occur due to the fact that cytochrome P450 systems (CYP3A4 and CYP2C9) normally break down statins, with increased risk when drugs or foods (e.g., grapefruit juice) inhibit this system.
• Statins are teratogenic and should be avoided in pregnancy.
• Mild elevations of serum aminotransferases can occur, which do not necessarily indicate hepatic damage.
• Muscle pain (myalgia) and weakness are common.
• Myositis, indicated by an increase in creatinine kinase (CK) released from skeletal muscle, occurs in about 10% of patients.
• Rhabdomyolysis is a rare but severe side effect which leads to myoglobinuria and can result in acute kidney injury (AKI), with increased BUN and creatinine.

Statin Indications

• High-intensity statins are prescribed
  • For patients with clinical atherosclerotic cardiovascular disease.
  • For patients with LDL cholesterol levels ≥ 190 mg/dL as a first-line treatment.
  • For patients with diabetes mellitus and multiple risk factors.
• Low- to moderate-intensity statins are used for primary prevention of ASCVD
  • For patients aged 40–75 with no prior history of CVD, who have ≥ 1 CVD risk factors.
  • When the 10-year ASCVD risk is ≥ 10%
  • May be considered for patients aged 40–75 with no history of CVD and 10-year ASCVD risk of 7.5–10%.
• Statins serve as first-line therapy for hypercholesterolemia.
• Statin treatment reduces the risk of mortality from CAD.
• Statins can be used in a pediatric population
• Statins should be taken with the last meal before bedtime

Statin Contraindications

• Contraindications include hypersensitivity, active liver disease, muscle disorder and pregnancy or breastfeeding because of teratogenic effects.

Fibrates (Fibric Acid Derivatives)

• Agents include Ezafibrate, fenofibrate, and gemfibrozil.
• Fibrates activate peroxisome proliferator-activated receptor alpha (PPAR-α), which increases lipoprotein lipase activity and its synthesis in adipose tissue
  • PPAR-alpha is a receptor regulating the transcription of genes involved in lipid metabolism.
• Activation of PPAR-α leads to clearance of triglyceride-rich lipoproteins.
• Fibrates stimulate fatty acid oxidation and lowering triglyceride and VLDL synthesis.
• Fibrates decrease the expression of the apoC-III protein, impede VLDL clearance, and increase the expression of apoA-I and apoA-II proteins, increasing HDL synthesis.
• Fibrates have little effect on LDL levels, or even an increase in some patients with familial hyperlipoproteinemia.
• Fibrates also increase VLDL and LDL levels.
• Fibrates enhance the effect of other drugs by inhibiting hepatic CYP450.
• Fibrates cause LDL levels to remain largely unchanged, VLDL levels to decrease, and HDL levels to increase.
• Fibrates are a second-line drug to lower triglycerides and treat hypertriglyceridemia.

Fibrate Side Effects

• Includes nausea, skin rashes, and decreases in WBC count or hematocrit.
• Fibrates potentiate the action of anticoagulants.
• Myopathy may occur, especially in combination with statins, due to free myoglobin inducing kidney damage.
• Cholesterol gallstone formation is a risk, especially in patients with cholelithiasis.
• Elevated liver function tests (LFTs) may be reversible.

Fibrate Contraindications

• Contraindications include renal insufficiency, liver failure, and gall bladder diseases.
• Fibrates should be avoided in pregnancy

Bile Acid Binding Resins

• Examples include cholestyramine, colestipol, and colesevelam.
• Bile acid binding resins bind bile acids in the intestine.
• Bile acid resins are not reabsorbed by the liver, which interrupts enterohepatic circulation, lowering bile acid absorption and increasing bile acid excretion.
• Bile acid binding resins decrease the cholesterol pool and promote LDL receptor synthesis, removing LDL from the blood.
• Affect HDL or triglycerides has little to no effect but may increase triglycerides and VLDL in those with certain genetic conditions.
• Lab tests demonstrate resins lower unbound LDL and slightly increase HDL and triglycerides.

Bile Acid Binding Resin Indications

• Bile acid binding resins can be used in pregnancy.
• Used as combination treatment with statins to treat hypercholesterolemia.
• Used to counter digitoxin overdose.
• Alleviate pruritus associated with elevated bile acid levels/cholestasis and bile salt accumulation.
• Remedy bile acid diarrhea.

Bile Acid Binding Resin Side Effects

• Includes gastrointestinal distress like nausea, abdominal bloating, and cramping.
• May increase liver function tests (LFTs).
• Can incite myalgia and reduces absorption of warfarin, digoxin, and fat-soluble vitamins, thiazide diuretics, pravastatin, and fluvastatin.

Bile Acid Binding Resin Contraindications

• Include hypertriglyceridemia over 300–500 mg/dL.
• Used with Hypertriglyceridemia-induced pancreatitis and bowel obstruction

PCSK-9 Inhibitors

• Considered for patients with homozygous familial hypercholesterolemia.
• Examples are alirocumab and evolocumab.
• PCSK9 inhibitors are monoclonal antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9).
• PCSK9 inhibitors interrupt LDL-receptor transportation to the lysosome for destruction.
• Inhibit of this process leads to increased LDL removal .decreasing blood stream LDL levels.
• Lab tests show they decrease LDL, increase HDL, and decrease triglycerides.
• PCSK9 inhibitors are add-on therapy for patients with high LDL who are already undergoing maximally tolerated treatment with statins and ezetimibe.
• Also used for patients who have very high-risk atherosclerotic cardiovascular disease

PCSK-9 Inhibitors Side Effects

• Include myalgia, local reactions at the injection site, and upper respiratory infection and flu-like symptoms.
• Administered every 2 weeks by injection and can be used in monotherapy

Ezetimibe

• Ezetimibe functions as a prodrug, it is converted in the liver to the active glucuronide form.
• Ezetimibe inhibits cholesterol transporter NPC1L1, which stops absorption in the GI tract of cholesterol and phytosterols.
• Ezetimibe reduces cholesterol absorption from the diet and bile, resulting in reduced cholesterol in the hepatic pool.
• Compensatory increase in synthesis of high affinity LDL receptors increases removal of LDL from blood.
• Lab tests show Ezetimibe is effective at lowering LDL levels, and has little effect on HDL and triglycerides.

Ezetimibe Indications

• Ezetimibe can be used in treatment in hypercholesterolemia and phytosterolemia.
• It is a monotherapy in cases in contraindications or statin intolerance
• Combination therapy (statin and ezetimibe) is used when there is insufficient LDL cholesterol reduction by statins.

Ezetimibe Side Effects

• Side effects for Ezetimibe are rare or well tolerated except for when used in combination therapy.
  • Increased Liver enzymes.
  • Angioedema.
  • Diarrhea.
  • Myalgia.

Ezetimibe Contraindications

• Contraindications for ezetimibe is that it should not be coadministered with a statin during active liver disease.

Nicotinic Acid (Niacin)

• Nicotinic Acid functions through the blockade of hormone-sensitive lipase activity.
• Inhibits lipolysis and fatty acid release in adipose tissue, which causes lowering levels of fatty acids and triglycerides in plasma.
• Niacin reduces LDL formation, causing a decrease in LDL synthesis
• Also reduces hepatic VLDL synthesis .
• Reduces the catabolic rate for HDL, decreases circulating fibrinogen and increases TPA.
• Lab tests indicate Niacin lowers triglyceride, lowers LDL synthesis and serum levels, increases HDL, and decreases VLDL.
• Can be used if statins are contraindicated.

Niacin Side Effects

• Side effects are Flushing and pruritus which are relieved by pretreatment with aspirin or ibuprofen , nausea, hyperuricemia and gout, increased liver function tests and severe liver toxicity.

Niacin Contraindications

• Contraindications include liver failure, gout, hemorrhage, gastric ulcer, and cardiovascular instability.
• Resins interfere with absorption of pravastatin, atorvastatin, and fluvastatin, and should therefore be given at least 1 hour before or 4 hours after the resins.
• A combination of reductase inhibitors with fibrates or niacin increases risk of myopathy.

Lomitapide and Mipomersen

• Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor, decreasing VLDL secretion and accumulation of LDL in the plasma, which can cause accumulation of triglycerides in the liver and elevations of transaminases.
• Mild to moderate injection side reactions and flu-like symptoms can occur, due to Mipomersen, an antisense oligonucleotide that targets apoB-100, in the liver.