Comprehensive Study Guide on Dyslipidaemia and Antihyperlipidemic Agents

Hyperlipidemia and Plasma Lipid Overview

• Plasma Lipids Transportation: Lipids are water-insoluble and cannot be transported alone in plasma. They are conjugated to proteins to form lipoproteins, which are water-soluble biochemical assemblies.

• Definition of Hyperlipidemia: Metabolic disorders involving elevations in any lipoprotein species (hyperlipoproteinemias or hyperlipidemia). It involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.

• Major Clinical Syndromes:

  • Acute pancreatitis: Often associated with high triglycerides.

  • Atherosclerosis: Correlated with elevated Low-Density Lipoprotein Cholesterol ($LDL-C$) and triglycerides, and lower levels of High-Density Lipoprotein Cholesterol ($HDL-C$).

• Fasting Plasma Lipid Concentrations (12-hour fast): Range from $360-820\,mg/dL$.

• Adult Desirable Lipid Values:

  • Total Cholesterol: Less than $200\,mg/dL$.

  • Triacylglycerol (TAG/Triglycerides): Less than $150\,mg/dL$.

  • Phospholipids (PPL): $125-275\,mg/dL$.

  • Free Fatty Acids (FFA): $8-25\,mg/dL$.

National Cholesterol Education Program Guidelines

• Screening Recommendation: Everyone aged 20 years and older should have blood cholesterol levels measured at least once every 5 years.

• Total Cholesterol Thresholds ($mg/dL$):

  • Desirable: < 200

  • Borderline: $200-239$

  • High Risk: $\ge 240$

• LDL Cholesterol Thresholds ($mg/dL$):

  • Desirable: < 130

  • Borderline: $130-159$

  • High Risk: $\ge 160$

• HDL Cholesterol Thresholds ($mg/dL$):

  • High Risk: < 35

  • Lower Risk/Desirable: $\ge 60$

• Triglycerides Thresholds ($mg/dL$):

  • Desirable: < 150

  • Borderline: $150-199$

  • High Risk: $\ge 200$

Lipoprotein Structure and Classification

• Apolipoproteins (Apo-proteins): Proteins synthesized by the liver that form the protein component of lipoproteins.

• Six Classes and Sub-classes:

  • A: Apo A-I, Apo A-II, Apo A-IV, Apo A-V.

  • B: Apo B-48, Apo B-100.

  • C: Apo C-I, Apo C-II, Apo C-III, Apo C-IV.

  • D, E, and H.

• Separation by Ultracentrifugation (Density/Size):

  • Chylomicrons: Largest, lowest density. Primarily carry dietary TAG (90%).

  • VLDL (Very Low Density Lipoprotein): Produced by the liver; carry endogenous TAG (60%).

  • IDL (Intermediate Density Lipoprotein): Derived from VLDL.

  • LDL (Low Density Lipoprotein): High cholesterol content (50%); "bad cholesterol."

  • HDL (High Density Lipoprotein): Smallest, highest density; primarily protein (50%); "good cholesterol."

• Specific Apolipoprotein Functions:

  • Apo B-100: Found in VLDL, IDL, LDL. Functions: Secretion of VLDL from liver, structural protein, and ligand for LDL receptor ($LDLR$).

  • Apo B-48: Found in Chylomicrons. Function: Secretion of chylomicrons from the intestine.

  • Apo E: Found in Chylomicrons, VLDL, IDL, HDL. Function: Ligand for binding IDL and remnants to the $LDLR$.

  • Apo A-I: Major structural protein of HDL; activates Lecithin-Cholesterol Acyltransferase ($LCAT$).

  • Apo C-II: Found in Chylomicrons, VLDL, IDL, HDL. Function: Activator of Lipoprotein Lipase ($LPL$).

  • Apo C-III: Found in Chylomicrons, VLDL, IDL, HDL. Function: Inhibitor of $LPL$ activity.

• FFA-Albumin Complex: Adipose tissue source; 99% albumin; carries Free Fatty Acids.

Lipoprotein Metabolism Pathways

• Exogenous Pathway (Chylomicrons):

  • Dietary triglycerides and cholesterol are absorbed into enterocytes.

  • Nascent Chylomicrons (containing Apo B-48) are released into the blood.

  • They receive Apo E and Apo C-II from HDL to become mature chylomicrons.

  • $LPL$ (activated by Apo C-II) hydrolyzes TAG into glycerol and fatty acids for peripheral tissues.

  • Particles shrink, Apo C-II returns to HDL, leaving Chylomicron Remnants for liver uptake.

• Endogenous Pathway (VLDL and LDL):

  • Liver secretes Nascent VLDL (Apo B-100).

  • Becomes mature VLDL in plasma by receiving Apo E and Apo C-II from HDL.

  • TAG is hydrolyzed by $LPL$; VLDL transforms into IDL then LDL.

  • Cholesterol Ester Transfer Protein (CETP): Catalyzes the transfer of phospholipids/TAG to HDL and cholesterol esters from HDL to VLDL.

• LDL Receptor-Mediated Endocytosis:

  • LDL binds to receptors in clathrin-coated pits.

  • Internalized into endosomes; pH drop separates LDL from receptor.

  • Receptors recycle to the membrane; LDL is hydrolyzed in lysosomes to release free cholesterol.

• Reverse Cholesterol Transport (HDL):

  • HDL removes unesterified cholesterol from extrahepatic tissues.

  • $LCAT$: Activated by Apo A-I, esterifies free cholesterol into hydrophobic cholesterol esters that stay inside HDL.

  • HDL transports cholesterol to the liver (for bile acid conversion) or other lipoproteins.

Cholesterol Biosynthesis and Function

• Sources:

  • Endogenous: Synthesized in almost all nucleated cells from Acetyl-CoA ($CH_3CO-S-CoA$) (Liver is the major site).

  • Exogenous: Dietary sources (animal origin only: egg yolk, liver, meat). Typical diet limit: $300\,mg/day$.

• Biological Functions:

  • Production of hormones: Estrogen, Testosterone, Progesterone, Aldosterone, Cortisone.

  • Vitamin D production (via UV rays on skin).

  • Bile acid production (aiding digestion and absorption of vitamins A, D, E, K).

  • Cell membrane Creation and maintenance.

• Biosynthesis Pathway (Cytosol):

  • $Acetyl-CoA \rightarrow Acetoacetyl-CoA \rightarrow HMG-CoA \xrightarrow{HMG-CoA\,Reductase} Mevalonic\,acid \rightarrow Squalene \rightarrow Cholesterol$

• Regulation of HMG-CoA Reductase (Key Enzyme):

  • Feedback inhibition: Cholesterol decreases synthesis.

  • Transcription Control: Cholesterol inhibits the HMG-CoA reductase gene.

  • Hormonal: Insulin stimulates, while Glucagon inhibits the enzyme.

Clinical Classification of Hyperlipidemia

Familial (Primary) Hyperlipidemias (Fredrickson Classification)

• Type I (Familial Hyperchylomicronemia): Increased Chylomicrons. Due to $LPL$ or Apo C-II deficiency. Massive fasting TAG. Treatment: Low-fat diet. No drug therapy effective. (Prevalence: 1 in 1,000,000).

• Type IIA (Familial Hypercholesterolemia): Increased LDL. Block in LDL degradation (receptor defect). Greatly accelerated CHD. Treatment: Diet, Statins, Niacin, Resins. (Prevalence: 1 in 500).

• Type IIB (Familial Combined Hyperlipidemia): Increased VLDL and LDL. Overproduction of VLDL. Treatment: Diet, Statins, Niacin, Resins. (Prevalence: 1 in 100).

• Type III (Familial Dysbetalipoproteinemia): Increased IDL. Mutant Apo E. Xanthomas and vascular disease. Treatment: Niacin, Fibrates, Statins. (Prevalence: 1 in 10,000).

• Type IV (Familial Hypertriglyceridemia): Increased VLDL. Frequently associated with obesity, diabetes, and hyperuricemia. Treatment: Diet, Niacin, Fibrates. (Prevalence: 1 in 100).

• Type V (Familial Mixed Hypertriglyceridemia): Increased VLDL and Chylomicrons. LDL normal or decreased. Treatment: Diet, Niacin, Fibrates, Statins. (Prevalence: 1 in 200).

Acquired (Secondary) Hyperlipidemias

• Causes: Diabetes mellitus, Hypothyroidism, Renal failure, Nephrotic syndrome.

• Drugs: Diuretics, $\beta$-blockers, Estrogens.

• Dietary Factors: Fat intake > 40\%, saturated fat > 10\%, excessive alcohol.

Atherosclerosis Pathophysiology and Manifestations

• Definition: Buildup of plaque (lipid, cellular waste, $Ca^{2+}$, fibrin) inside the arteries.

• Pathology: Endothelial dysfunction and vascular inflammation. Arteries enlarge to compensate for decades (asymptomatic) until severe narrowing occurs.

• Stages:

  • Initial Lesion: Macrophage infiltration.

  • Fatty Streak: Intracellular lipid accumulation.

  • Atheroma/Fibroatheroma: Lipid core and fibrotic/calcific layers.

  • Complicated Lesion: Surface defect, thrombosis, hemorrhage.

• Physical Signs of Hyperlipidemia:

  • Xanthelasma Palpebrarum: Yellowish eye patches.

  • Arcus Senilis: Gray/white peripheral cornea ring.

  • Xanthomata: Yellow cholesterol deposits in tendons, palms, knees.

Management of Hyperlipidemia

Lifestyle Modifications

• Dietary: High vegetables, fruits, whole grains. Low-fat dairy. Fish and legumes for protein. Limit sugar-sweetened beverages and red meats. Saturated/trans fat < 5-6\% of total energy. Sodium < 2,400\,mg/day. DASH diet.

• Physical Activity: 3-4 sessions per week, $40\,minutes$ each, moderate-to-vigorous intensity.

Pharmacological Classes

1. HMG-CoA Reductase Inhibitors (Statins): First-line therapy.

2. Bile Acid Sequestrants (Resins).

3. Niacin (Vitamin B3).

4. Fibric Acid Derivatives (Fibrates).

5. Cholesterol Absorption Inhibitors (Ezetimibe).

6. Omega-3 Fatty Acids.

7. Newer Agents: PCSK9 inhibitors, MTP inhibitors, Antisense oligonucleotides, ATP citrate lyase inhibitors.

HMG-CoA Reductase Inhibitors (Statins)

• Drugs: Atorvastatin (Lipitor), Rosuvastatin (Crestor), Simvastatin (Zocor), Lovastatin, Pravastatin, Fluvastatin, Pitavastatin.

• Mechanism of Action: Structural analogs of HMG-CoA. Competitive inhibition of HMG-CoA reductase.

  • Inhibits de novo cholesterol synthesis.

  • Depletes intracellular cholesterol, leading to increased LDL receptor expression.

  • Enhances LDL uptake from blood.

• Pharmacokinetics:

  • Prodrugs: Lovastatin, Simvastatin, Pitavastatin.

  • Metaolism: Most via CYP3A4 (Atorvastatin, Lovastatin, Simvastatin); Fluvastatin and Pitavastatin via 2C9.

  • Solubility: Lovastatin, Simvastatin, Atorvastatin are lipophilic; Pravastatin, Rosuvastatin are hydrophilic.

• Efficacy (LDL reduction): Rosuvastatin (60%), Atorvastatin (55%), Pitavastatin (43%), Simvastatin (41%).

• Therapeutic Benefits: Plaque stabilization, improved endothelial function, inhibition of platelet thrombi, anti-inflammatory.

• Side Effects:

  • Hepatic: Elevated liver enzymes (discontinue if > 3 \times upper limit). Monitor LFTs.

  • Muscle: Muscle pain (10-15%). Rare myopathy or life-threatening rhabdomyolysis.

  • Monitoring: Check Creatine Kinase (CK) at baseline and if symptoms occur.

  • Other: Cognitive impairment (rare), increased $HbA1c$/fasting glucose.

• Drug Interactions: Fibrates (Gemfibrozil) increase rhabdomyolysis risk. Niacin (> 1\,g/day) increases myopathy risk. Grapefruit juice increases levels of 3A4-dependent statins (> 1\,liter/day).

• Contraindications: Active liver disease, pregnancy (Category X), nursing mothers.

Bile Acid Sequestrants (Resins)

• Drugs: Cholestyramine, Colesevelam, Colestipol.

• Mechanism of Action: Large MW anion-exchange resins that bind negatively charged bile acids in the intestine.

  • Excretion of resin-bile acid complex in feces decreases bile acid concentrations.

  • Hepatocytes increase conversion of cholesterol to bile acids.

  • Increases hepatic LDL uptake.

• Pharmacokinetics: Not absorbed; totally excreted in feces.

• Efficacy: Reduces LDL (15-26%), raises HDL (3-6%). May increase TAG.

• Therapeutic Uses: Combination therapy for Type IIA/IIB; digitalis toxicity; pruritus from biliary stasis; glucose lowering in Type 2 Diabetes (Colesevelam).

• Side Effects: GI distress (constipation, nausea, flatulence). Malabsorption of fat-soluble vitamins (A, D, E, K).

• Interactions: Binds neutral/cationic/anionic drugs (Digitalis, Thiazides, Warfarin, Tetracycline, Aspirin, Statins). Dose other drugs 1-2 hours before or 4-6 hours after resin.

• Contraindications: Significant hypertriglyceridemia (> 400\,mg/dL).

Niacin (Vitamin B3 / Nicotinic Acid)

• Note: Nicotinamide alone does not lower lipid levels.

• Mechanism of Action: Strong inhibition of lipolysis in adipose tissue. Reduces free fatty acids available to the liver for TAG synthesis. Reduced VLDL production leads to reduced LDL-C.

• Efficacy: Lowers TG (20-50%), Lowers LDL (15-26%), Raises HDL (15-35%).

• Side Effects:

  • Niacin Flush: Cutaneous flush and pruritus (prostaglandin-mediated). Minimized by Aspirin ($325\,mg$) 30-60 min before, or using extended-release forms.

  • Metabolic: Hyperuricemia (inhibits uric acid secretion; exacerbates gout). Impaired carbohydrate tolerance (hyperglycemia).

  • Hepatic: Reversible elevation of liver enzymes.

Fibric Acid Derivatives (Fibrates)

• Drugs: Fenofibrate, Gemfibrozil.

• Mechanism of Action: Ligands for nuclear transcription receptor $PPAR-\alpha$ (Peroxisome Proliferator-Activated Receptor-alpha).

  • Increases expression of $LPL$, decreasing TAG.

  • Decreases Apo C-III (LPL inhibitor).

  • Increases Apo A-I and A-II, raising HDL.

• Pharmacokinetics: Long half-life (20 hours for Fenofibrate; 1.5 hours for Gemfibrozil). Primarily renally excreted as glucuronide.

• Efficacy: Lowers TG (30-55%), Raises HDL (18-22%). LDL effect variable.

• Side Effects: GI disturbances. Gallstones (biliary cholesterol excretion). Myositis/Myopathy (high risk when combined with Gemfibrozil + Statins).

• Contraindications: Severe renal/hepatic disease, preexisting gallbladder disease.

Cholesterol Absorption Inhibitors (Ezetimibe)

• Mechanism of Action: Blocks the transporter protein NPC1L1 (Niemann-Pick C1-Like 1) in the brush border of enterocytes.

  • Inhibits intestinal uptake of cholesterol and phytosterols.

  • Reduces cholesterol delivery to the liver, leading to increased clearance of blood cholesterol.

• Efficacy: Lowers LDL (18-20%). Synergistic with Statins.

• Pharmacokinetics: Glucuronidated to active form. Peak in 12-14 hours.

• Interactions: Fibrates increase ezetimibe levels and risk of cholelithiasis.

Omega-3 Fatty Acids

• Drugs: Lovaza ($DHA$ and $EPA$), Vascepa (pure $EPA$), Epanova (omega-3-carboxylic acids).

• Mechanism of Action: Inhibits VLDL and TAG synthesis in the liver.

• Efficacy: Lowers TG (25-45%). Lovaza and Epanova may raise LDL-C; Vascepa (Icosapent) does not significantly raise LDL-C.

• Source Types: $\alpha$-linolenic acid (ALA-plants), Eicosapentaenoic acid (EPA-marine), Docosahexaenoic acid (DHA-marine).

Newer and Specialized Lipid-Lowering Medications

• PCSK9 Inhibitors: Evolocumab (Repatha), Alirocumab (Praluent).

  • MOA: Monoclonal antibodies bind to PCSK9, preventing it from mediating the degradation of LDL receptors. Increases receptor recycling to the cell surface.

  • Efficacy: Significant LDL reduction (up to 60%). Weekly/biweekly SubQ injection.

  • Inclisiran: Small interfering RNA (siRNA) that inhibits the translation of PCSK9 mRNA.

• MTP Inhibitor: Lomitapide (Juxtapid).

  • MOA: Inhibits Microsomal Triglyceride Transfer Protein, preventing VLDL assembly in the liver and Chylomicron assembly in the intestine.

  • Indication: Homozygous familial hypercholesterolemia ($HoFH$).

  • Warning: Black box for hepatotoxicity (fatty liver); REMS program.

• Apolipoprotein B Antisense Oligonucleotide: Mipomersen (Kynamro).

  • MOA: Binds to Apo B-100 mRNA, promoting its degradation via RNase H. Inhibits synthesis of VLDL/LDL.

  • Indication: $HoFH$.

• ATP Citrate Lyase Inhibitor: Bempedoic Acid.

  • MOA: Inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway.

• Gene Therapy: Alipogene tiparvovec for lipoprotein lipase deficiency ($LPLD$).

Alternative Dietary Supplements

• Red Yeast Rice (RYR): Contains Monacolin K, same structure as Lovastatin. Reduces LDL by 10-33%.

• Garlic: May slightly lower blood cholesterol and blood pressure; effects observed in short-term studies (1-3 months), but long-term efficacy is not confirmed.

Questions & Discussion

• Q1: Associated with decreased atherosclerosis risk? (C) HDL.

• Q3: Drug likely to increase TG and VLDL as monotherapy? (B) Cholestyramine.

• Q4: Drugs to avoid in pregnancy? Statins (e.g., Pravastatin) and Resins (malabsorption concerns). Statins are Cat X.

• Q5: Gemfibrozil mechanism? (D) Increased triglyceride hydrolysis by lipoprotein lipase.

• Q6: Gemfibrozil toxicity? (B) Cholelithiasis.

• Q7: Alcohol effects on lipids? (E) Increased triglycerides.

• Q8: Exacerbates gout? (D) Niacin.

• Q9: Monitoring for Atorvastatin? (B) Alanine and aspartate aminotransferase ($ALT/AST$).

• Q10: Ezetimibe mechanism? (C) Decreased gastrointestinal absorption of cholesterol.