Hyperlipidemia refers to elevated levels of lipids in the blood, including cholesterol and triglycerides. This condition is a major risk factor for cardiovascular diseases, such as coronary artery disease, stroke, and peripheral artery disease. Anti-hyperlipidemic drugs, also known as lipid-lowering agents, are used to manage and reduce high lipid levels to lower the risk of these diseases.
Introduction
Anti-hyperlipidemic drugs are medications aimed at lowering lipid levels in the blood. They target different aspects of lipid metabolism, including the reduction of low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and the increase of high-density lipoprotein (HDL) cholesterol. The primary goals of anti-hyperlipidemic therapy are to prevent atherosclerosis, reduce cardiovascular morbidity and mortality, and improve overall health outcomes.
 Classification of Anti-hyperlipidemic drugs
Anti-hyperlipidemic drugs can be classified into several categories based on their mechanism of action:
1. Statins (HMG-CoA Reductase Inhibitors)
– Examples: Atorvastatin, Simvastatin, Rosuvastatin, Lovastatin
– Mechanism of Action:
– Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis.
– This leads to decreased cholesterol synthesis in the liver, upregulation of LDL receptors, and increased clearance of LDL from the bloodstream.
– Uses: Primary and secondary prevention of cardiovascular events, hypercholesterolemia, mixed dyslipidemia.
– Side Effects: Myopathy, rhabdomyolysis, liver enzyme elevation, gastrointestinal symptoms, increased risk of diabetes.
2. Bile Acid Sequestrants
– Examples: Cholestyramine, Colestipol, Colesevelam
– Mechanism of Action:
– These drugs bind bile acids in the intestine, preventing their reabsorption.
– This depletion of bile acids leads to increased conversion of cholesterol into bile acids in the liver, reducing blood cholesterol levels.
– Uses: Hypercholesterolemia, pruritus associated with partial biliary obstruction.
– Side Effects: Gastrointestinal disturbances (constipation, bloating, nausea), decreased absorption of fat-soluble vitamins and other drugs.
3. Cholesterol Absorption Inhibitors
– Example: Ezetimibe
– Mechanism of Action:
– Ezetimibe selectively inhibits the absorption of cholesterol in the small intestine by targeting the Niemann-Pick C1-Like 1 (NPC1L1) protein.
– This reduces the delivery of cholesterol to the liver, decreasing hepatic cholesterol stores and increasing clearance of LDL from the blood.
– Uses: Hypercholesterolemia (often used in combination with statins), sitosterolemia.
– Side Effects: Gastrointestinal symptoms, increased liver enzymes (when used with statins), myopathy (rare).
4. Fibrates
– Examples: Fenofibrate, Gemfibrozil
– Mechanism of Action:
– Fibrates activate peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates the expression of genes involved in lipid metabolism.
– This leads to increased lipolysis and elimination of triglyceride-rich particles, increased production of HDL, and decreased production of VLDL.
– Uses: Hypertriglyceridemia, mixed dyslipidemia.
– Side Effects: Gastrointestinal disturbances, myopathy (especially when combined with statins), gallstones, liver enzyme elevation.
5. Niacin (Nicotinic Acid)
– Examples: Niacin (Immediate-Release, Extended-Release)
– Mechanism of Action:
– Niacin inhibits lipolysis in adipose tissue, reducing the free fatty acid pool available for triglyceride synthesis in the liver.
– This decreases VLDL and LDL levels and increases HDL levels.
– Uses: Hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia.
– Side Effects: Flushing (reduced with extended-release formulations), gastrointestinal symptoms, hyperglycemia, hyperuricemia, hepatotoxicity.
6. Omega-3 Fatty Acids
– Examples: Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA)
– Mechanism of Action:
– Omega-3 fatty acids reduce hepatic production of triglycerides and increase triglyceride clearance.
– They may also have anti-inflammatory and anti-arrhythmic effects.
– Uses: Hypertriglyceridemia, cardiovascular risk reduction.
– Side Effects: Gastrointestinal disturbances, increased bleeding risk (high doses), fishy aftertaste.
7. PCSK9 Inhibitors
– Examples: Alirocumab, Evolocumab
– Mechanism of Action:
– PCSK9 inhibitors are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that promotes the degradation of LDL receptors.
– Inhibition of PCSK9 increases the number of LDL receptors on hepatocytes, enhancing the clearance of LDL from the bloodstream.
– Uses: Hypercholesterolemia, particularly in patients with familial hypercholesterolemia or those who do not achieve adequate LDL reduction with statins.
– Side Effects: Injection site reactions, allergic reactions, neurocognitive effects (rare).
8. Other Emerging Therapies
– Examples: Bempedoic acid, Lomitapide, Mipomersen
– Mechanism of Action:
– Bempedoic acid: Inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase, reducing cholesterol synthesis.
– Lomitapide: Inhibits microsomal triglyceride transfer protein (MTP), reducing the secretion of VLDL and chylomicrons.
– Mipomersen: An antisense oligonucleotide that inhibits the synthesis of apolipoprotein B-100, a component of LDL and VLDL.
– Uses: Hypercholesterolemia, particularly in patients with familial hypercholesterolemia.
– Side Effects: Bempedoic acid (gout, tendon rupture), Lomitapide (gastrointestinal symptoms, liver enzyme elevation), Mipomersen (injection site reactions, flu-like symptoms, liver enzyme elevation).
 Mechanisms of Action of Anti-hyperlipidemic drugs
– Statins: Inhibit cholesterol synthesis in the liver, upregulate LDL receptors, increase LDL clearance.
– Bile Acid Sequestrants: Bind bile acids in the intestine, increase conversion of cholesterol to bile acids, reduce cholesterol levels.
– Cholesterol Absorption Inhibitors: Inhibit cholesterol absorption in the intestine, reduce hepatic cholesterol stores, increase LDL clearance.
– Fibrates: Activate PPAR-α, increase lipolysis and elimination of triglycerides, increase HDL production, decrease VLDL production.
– Niacin: Inhibit lipolysis in adipose tissue, reduce VLDL and LDL levels, increase HDL levels.
– Omega-3 Fatty Acids: Reduce hepatic triglyceride production, increase triglyceride clearance, have anti-inflammatory effects.
– PCSK9 Inhibitors: Inhibit PCSK9, increase LDL receptor numbers, enhance LDL clearance.
– Emerging Therapies: Various mechanisms targeting cholesterol and triglyceride metabolism.
 Uses of Anti-hyperlipidemic drugs
– Primary and Secondary Prevention of Cardiovascular Events: Statins, PCSK9 inhibitors, ezetimibe.
– Hypercholesterolemia: Statins, bile acid sequestrants, ezetimibe, PCSK9 inhibitors, emerging therapies.
– Hypertriglyceridemia: Fibrates, omega-3 fatty acids, niacin.
– Mixed Dyslipidemia: Statins, fibrates, niacin.
– Familial Hypercholesterolemia: PCSK9 inhibitors, lomitapide, mipomersen, bempedoic acid.
 Side Effects of anti-hyperlipidimics
– Statins: Myopathy, rhabdomyolysis, liver enzyme elevation, gastrointestinal symptoms, increased risk of diabetes.
– Bile Acid Sequestrants: Gastrointestinal disturbances, decreased absorption of fat-soluble vitamins and other drugs.
– Cholesterol Absorption Inhibitors: Gastrointestinal symptoms, increased liver enzymes (when used with statins), myopathy (rare).
– Fibrates: Gastrointestinal disturbances, myopathy (especially when combined with statins), gallstones, liver enzyme elevation.
– Niacin: Flushing, gastrointestinal symptoms, hyperglycemia, hyperuricemia, hepatotoxicity.
– Omega-3 Fatty Acids: Gastrointestinal disturbances, increased bleeding risk (high doses), fishy aftertaste.
– PCSK9 Inhibitors: Injection site reactions, allergic reactions, neurocognitive effects (rare).
– Emerging Therapies: Bempedoic acid (gout, tendon rupture), lomitapide (gastrointestinal symptoms, liver enzyme elevation), mipomersen (injection site reactions, flu-like symptoms, liver enzyme elevation).
