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, which is the conversion of HMG-CoA to mevalonate.
• Statins are structural analogs which competitively inhibit HMG-CoA reductase, blocking the conversion to mevalonate and reducing cholesterol biosynthesis in the liver.
• Statin use upregulates LDL receptors on hepatocytes via sterol regulatory element-binding protein (SREBP).
• This upregulation increases LDL recycling while lowering LDL cholesterol and triglycerides and raising HDL cholesterol.
• Lovastatin and simvastatin are prodrugs; atorvastatin, fluvastatin, pravastatin, pitavastatin, and rosuvastatin are active as given.
• The active statins have better maximum efficacy, reducing triglycerides and increasing HDL cholesterol.
• Lab test results while taking Statins include decreased LDL cholesterol, increased HDL cholesterol, and decreased triglycerides.
• Statins can cause decreased C-reactive protein, increased plaque stabilization, anti-inflammatory effects, antioxidant effects, and improved endothelial function of coronary arteries.

Statin Pharmacokinetics

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

Statin Interactions

• Fibrates and nicotinic acid, other lipid-lowering agents, can increase the risk of myopathy when used with statins.
• CYP3A4 inhibitors can impact drug metabolism.
• HIV/HCV protease inhibitors may interact with statins.
• Macrolides (especially erythromycin and clarithromycin) can interact with statins.
• Azole antifungals, cyclosporine, and warfarin may interact with statins.

Statin Side Effects

• Common side effects are headache and gastrointestinal symptoms like constipation, diarrhea, and flatulence.
• Hepatotoxicity can occur due to the cytochrome P450 system being inhibited by certain drugs or foods (e.g., grapefruit juice)
• Statins are teratogenic and should be avoided in pregnancy.
• Mild elevations of serum aminotransferases are common but do not often indicate hepatic damage.
• Muscle pain (myalgia) and weakness are other side effects.
• Myositis, an increase in creatinine kinase (CK) released from skeletal muscle, occurs in about 10% of patients.
• Rhabdomyolysis is a rare but severe side effect that can lead to myoglobinuria, resulting in acute kidney injury (AKI) with increased BUN and creatinine.

Statin Indications

• High-intensity statins are indicated for patients with clinical atherosclerotic cardiovascular disease, LDL cholesterol elevated ≥ 190 mg/dL, or with diabetes and multiple risk factors.
• Low- to moderate-intensity statins are used for the primary prevention of ASCVD in patients aged 40–75 with no history of CVD but with ≥ 1 CVD risk factor and a calculated 10-year ASCVD risk ≥ 10%, and might be considered in those with a risk of 7.5–10%.
• Statins are first-line therapy for hypercholesterolemia which can reduce the risk of mortality in patients suffering from CAD.
• It can be used in a pediatric population and should be taken with the last meal of the day.

Statin Contraindications

• Statins are contraindicated in individuals with hypersensitivity, active liver disease, or muscle disorder.
• They are also contraindicated during pregnancy (teratogenic) and breastfeeding.

Fibrates (Fibric Acid Derivatives)

• Agents in this class include ezafibrate, fenofibrate, and gemfibrozil.
• Fibrates activate peroxisome proliferator-activated receptor alpha (PPAR–α), increasing lipoprotein lipase activity and its synthesis in adipose tissue, leading to clearance of triglyceride rich lipoproteins.
• PPAR-alpha regulates the transcription of genes involved in lipid metabolism.
• In the liver, fibrates stimulate fatty acid oxidation, reducing triglycerides and VLDL synthesis.
• Fibrates decrease the expression of a protein that impedes VLDL clearance (apoC-III) and increase the expression of proteins that increase HDL synthesis (apoA-I, apoA-II).
• Fibrates have little effect on LDL levels (or may even increase them) in some patients.
• These patients may have familial hyperlipoproteinemia, associated with increased levels of both VLDL and LDL
• Fibrates enhance the effect of other drugs (e.g., sulfonylureas, warfarin) by inhibiting hepatic CYP450.
• Lab test results show LDL remains about the same, VLDL is decreased, and HDL is increased.
• Fibrates are a second-line choice in hyperlipidemia, most effective for lowering triglycerides, and are best for treating elevated VLDL and LDL levels, not LDL alone.
• Side effects include nausea, skin rashes, and reduced WBC count or hematocrit, which can potentiate the action of anticoagulants.
• Myopathy may occur, especially in combination with statins, and free myoglobin will induce kidney damage.
• They also may cause the formation of cholesterol gallstones, and reversible increases in LFTs.
• Fibrates are contraindicated in cases of:
• Renal insufficiencyLiver failure
• Gall bladder diseases
• Pregnancy

Bile Acid Binding Resins

• Cholestyramine, colestipol, and colesevelam are examples of bile acid binding resins.
• These resins bind bile acids in the intestine, preventing their reabsorption and interrupting enterohepatic circulation, decreasing bile acid absorption.
• By preventing bile acid recycling, resins lower the cholesterol pool and promote the synthesis of high-affinity LDL receptors, increasing removal of LDL from the blood.
• They have little effect on HDL or triglycerides, but in some patients with genetic conditions, resins increase triglycerides and VLDL.
• Lab test results show decreased unbound LDL and slight increases in HDL and triglycerides.
• Bile acid binding resins are used during pregnancy and are administered with statins in hypercholesterolemia
• Additional indications are, digitoxin overdose, pruritus associated with elevated bile acid levels (cholestasis) and bile salt accumulation, and bile acid diarrhea.
• Side effects include gastrointestinal issues (nausea, abdominal bloating and cramping), elevated LFTs, myalgia, and reduced absorption of certain drugs and vitamins.
• Contraindications are hypertriglyceridemia, hypertriglyceridemia-induced pancreatitis, and bowel obstruction.

PCSK-9 Inhibitors

• Alirocumab and evolocumab are PCSK-9 inhibitors.
• Monoclonal antibodies inhibit proprotein convertase subtilisin kexin 9 (PCSK9).
• PCSK9 blocks the LDL-receptor by transporting it to the lysosome for degradation.
• Lead to increased removal of LDL from the blood stream.
• Lab Test - ↓↓↓ LDL, ↑ HDL, ↓ triglycerides
• These include high LDL despite maximally tolerated treatment with statins and ezetimibe, as well as the presence of very high-risk atherosclerotic cardiovascular disease.
• Side effects include myalgia, local reactions at the injection site, and upper respiratory infection/flu-like symptoms.
• These inhibitors are administered every 2 weeks by injection and can be used in monotherapy.

Ezetimibe

• Ezetimibe is a prodrug converted in the liver to an active glucuronide form.
• It inhibits the cholesterol transporter NPC1L1, blocking cholesterol and phytosterol absorption in the GI tract.
• Ezetimibe reduces absorption of cholesterol from diet and bile, and induces a compensatory increase in synthesis of high-affinity LDL receptors, which increases the removal of LDL from blood.
• Lab test results show decreased LDL and slight changes decreases in both HDL and triglycerides.
• It is indicated for hypercholesterolemia and phytosterolemia, or as monotherapy when statins are contraindicated.
• Can be used as combination therapy with a statin when there is not sufficient LDL cholesterol reduction by statins.
• Side effects are rare but in combination therapy, increased liver enzymes (hepatotoxicity), angioedema, diarrhea, and myalgia may occur.
• Coadministration with a statin during active liver disease is contraindicated.

Nicotinic Acid (Niacin)

• Niacin works by blocking hormone-sensitive lipase activity and inhibiting lipolysis and fatty acid release in adipose tissue, which reduces fatty acids and triglycerides in plasma.
• Overall, niacin reduces LDL formation and hepatic VLDL synthesis, increases VLDL clearance, and decreases the catabolic rate for HDL, as well as decreases circulating fibrinogen and increases TPA
• Lab test results show decreases in triglycerides, decreases in LDL synthesis and serum levels, increases in HDL, and a decrease in VLDL.
• It is indicated for hypercholesterolemia, hypertriglyceridemia, low levels of HDL, high LDL cholesterol and lipoprotein levels despite statin and ezetimibe therapy, and when statins are contraindicated.
• Side effects include flushing (reduced by pretreatment with aspirin or ibuprofen), pruritus, nausea, hyperuricemia/gout, and increased LFTs and hypertoxicity.
• It is contraindicated in liver failure, gout, hemorrhage, gastric ulcer and cardiovascular instability.

Combination Therapy

• A change to the diet is the first thing that is advised, but it is often it is insufficient
• Drugs are combined to prevent toxicity and target specific lipoproteins with the desired effect.
• Resins may interfere with the absorption of pravastatin, atorvastatin, and fluvastatin. so statins have to be administered either 1 hour prior to or 4 hours after the resin.
• Combinations of reductase inhibitors with fibrates or niacin increases risk of myopathy.

Lomitapide and Mipomersen

• Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor, which decreases VLDL secretion and LDL accumulation in the plasma, and can cause triglycerides to accumulate in the liver, as well as elevations in transaminases.
• Mipomersen a an antisense oligonucleotide that targets apoB-100, mainly in the liver, and injection site reactions/flu-like symptoms can occur.