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DRUGS FOR DYSLIPIDEMIA

• Dietary fats (mainly triglycerides) are
  broken down by pancreatic lipase into free fatty acids and monoglycerides in
  the small intestine.
• Bile salts emulsify fats, aiding their digestion
  and absorption by forming micelles.
• Free fatty acids and monoglycerides are absorbed by
  intestinal cells (enterocytes), where they are re-esterified into
  triglycerides.

• Chylomicrons: In enterocytes, triglycerides
  are packaged with cholesterol and proteins to form chylomicrons, which are
  transported via the lymphatic system into the bloodstream.
• VLDL (Very Low-Density Lipoproteins): In the
  liver, triglycerides and cholesterol are packaged into VLDL particles,
  which deliver triglycerides to tissues.

• Lipolysis: In tissues, lipoprotein lipase
  breaks down triglycerides in chylomicrons and VLDL into free fatty acids
  and glycerol, which are taken up by cells for energy (via β-oxidation) or
  storage in adipose tissue.
• β-Oxidation: In mitochondria, fatty acids
  are oxidized to produce acetyl-CoA, which enters the Krebs
  cycle for energy production, generating ATP.
• Ketogenesis: In cases of excess acetyl-CoA
  (e.g., fasting), it is converted into ketone bodies in
  the liver, used as an alternative energy source.

• Synthesis: The liver synthesizes cholesterol
  de novo from acetyl-CoA via the HMG-CoA reductase pathway.
• Excretion: Excess cholesterol is converted
  into bile acids and excreted in bile.
• LDL-C and HDL-C: LDL delivers cholesterol to
  peripheral tissues, while HDL (produced in the liver and intestines)
  retrieves excess cholesterol from tissues and returns it to the liver for
  excretion (reverse cholesterol transport).

• Excess dietary fat is stored as triglycerides in
  adipose tissue.
• During fasting or energy needs, stored
  triglycerides are broken down (lipolysis) into free fatty acids and
  glycerol, which are released into the bloodstream for energy production.

 

 

 

1. HMG-CoA Reductase
Inhibitors (Statins)

• Examples: Atorvastatin, Simvastatin,
  Rosuvastatin

2. Bile Acid Sequestrants

• Examples: Cholestyramine, Colesevelam,
  Colestipol

3. Fibrates (Fibric Acid
Derivatives)

• Examples: Fenofibrate, Gemfibrozil

4. Nicotinic Acid (Niacin)

• Examples: Niacin (Vitamin B3)

5. Cholesterol Absorption
Inhibitors

• Example: Ezetimibe
• Mechanism of Action: Inhibits the
  absorption of cholesterol in the small intestine, leading to reduced

6. Omega-3 Fatty Acids

• Examples: Eicosapentaenoic acid (EPA),
  Docosahexaenoic acid (DHA)

7. PCSK9 Inhibitors

• Examples: Alirocumab, Evolocumab

8. Selective Peroxisome
Proliferator-Activated Receptor-Delta (PPAR-δ) Agonists

• Examples: Tesaglitazar

9. Bempedoic Acid

• Mechanism of Action: Inhibits ATP
  citrate lyase (ACL), an enzyme involved in cholesterol synthesis, reducing
  LDL-C levels.

10. CETP Inhibitors
(Cholesteryl Ester Transfer Protein Inhibitors)

• Examples: Anacetrapib, Dalcetrapib
  (investigational drugs)

 

Statins, also known as HMG-CoA
reductase inhibitors, are the most commonly prescribed class of drugs for
the treatment of dyslipidemia, primarily targeting elevated LDL-C (Low-Density
Lipoprotein Cholesterol). They have been extensively studied and proven to
reduce cardiovascular events, morbidity, and mortality in both primary and
secondary prevention of cardiovascular diseases.

• Statins inhibit HMG-CoA reductase, the
  enzyme responsible for the conversion of HMG-CoA to mevalonate, a key
  precursor in the biosynthesis of cholesterol.
• By inhibiting this rate-limiting step in
  cholesterol synthesis, statins lead to a decrease in intracellular
  cholesterol levels in the liver.
• The liver responds by upregulating LDL receptors on
  the hepatocyte surface, which increases the clearance of circulating LDL-C
  from the blood.

• Absorption: Statins are absorbed
  variably after oral administration. The bioavailability of statins is
  generally low due to extensive first-pass hepatic metabolism.
• Metabolism: Most statins are
  metabolized in the liver by the cytochrome P450 (CYP) enzyme system. For
  example:
• Atorvastatin and Simvastatin are metabolized
  by CYP3A4.
• Rosuvastatin and Pravastatin are less dependent on
  CYP enzymes.
• Excretion: Statins and their
  metabolites are mainly excreted via the liver (bile) and to a lesser
  extent via the kidneys.

• Atorvastatin: 14 hours
• Rosuvastatin: 19 hours
• Simvastatin: 2 hours
• Pravastatin: 1.5-2 hours

• LDL-C Reduction: Statins significantly
  reduce LDL-C levels (by 20–60%), depending on the dose and potency.
• Triglyceride Reduction: Statins also
  reduce triglyceride levels by 10–30%.
• HDL-C Increase: Statins modestly
  increase HDL-C levels by 5–10%.
• Pleiotropic Effects: In addition to
  their lipid-lowering action, statins exert several “pleiotropic”
  effects, including:
• Improving endothelial function
• Stabilizing atherosclerotic plaques
• Reducing vascular inflammation
• Decreasing oxidative stress

• Primary prevention of cardiovascular
  events in patients with elevated LDL-C levels.
• Secondary prevention in patients with
  established cardiovascular disease (e.g., post-myocardial infarction,
  stroke).
• Management of dyslipidemia, particularly in
  patients with high LDL-C or mixed dyslipidemia.
• Familial hypercholesterolemia, both
  heterozygous and homozygous, as adjunctive therapy.

• Myopathy and Rhabdomyolysis: Statins
  can cause muscle-related side effects, ranging from mild myalgia to severe
  rhabdomyolysis. Risk is dose-dependent and higher with concurrent use of
  drugs that inhibit CYP3A4.
• Hepatotoxicity: Statins can cause mild
  elevations in liver transaminases. Severe liver injury is rare, but liver
  function tests are recommended at baseline and during treatment if
  clinically indicated.
• New-Onset Diabetes: Statin therapy has
  been associated with a small increased risk of developing type 2 diabetes,
  particularly at high doses.
• Cognitive Effects: Rarely, statins have
  been associated with reversible cognitive effects such as memory loss and
  confusion.

• Active liver disease or unexplained persistent
  elevations in liver enzymes.
• Pregnancy and breastfeeding, as statins can cause
  teratogenic effects.
• Hypersensitivity to any component of the statin
  formulation.

• CYP3A4 Inhibitors: Drugs such as azole
  antifungals (e.g., ketoconazole), macrolide antibiotics (e.g.,
  erythromycin), protease inhibitors (e.g., ritonavir), and grapefruit juice
  can increase statin levels and the risk of myopathy.
• Fibrates: Concomitant use of fibrates,
  especially gemfibrozil, increases the risk of myopathy and rhabdomyolysis.
• Warfarin: Statins may potentiate the
  effect of warfarin, increasing the risk of bleeding.

• Atorvastatin : Moderate-High potency,
  10–80 mg/day
• Rosuvastatin : High potency, 5–40
  mg/day
• Simvastatin : Moderate potency, 10–40
  mg/day
• Pravastatin : Low-Moderate potency,
  10–80 mg/day
• Lovastatin : Low potency, 20–80 mg/day
• Fluvastatin : Low potency, 20–80 mg/day

• Dosing: Statins are generally
  administered once daily, with atorvastatin and rosuvastatin having long
  half-lives that allow for flexibility in dosing time. Simvastatin and
  lovastatin should be taken in the evening for maximum efficacy, as
  cholesterol synthesis is highest at night.
• Monitoring: Liver function tests and CK
  (creatine kinase) levels should be monitored in patients at risk of
  adverse effects, especially those on high doses or with concomitant drug
  interactions.

 

Fibrates, also known as fibric
acid derivatives, are a class of lipid-lowering drugs primarily used to
reduce triglyceride levels and, to a lesser extent, to increase HDL-C
(High-Density Lipoprotein Cholesterol). Fibrates are particularly effective in
patients with hypertriglyceridemia and mixed dyslipidemia.

• Fibrates activate the peroxisome
  proliferator-activated receptor-alpha (PPAR-α), a nuclear
  transcription factor.
• Activation of PPAR-α leads to the following
  metabolic effects:
• Increased lipoprotein lipase (LPL) activity:
  This enhances the hydrolysis of triglycerides in VLDL (Very Low-Density
  Lipoprotein) and chylomicrons, reducing plasma triglyceride levels.
• Decreased production of apoC-III: ApoC-III
  inhibits lipoprotein lipase; thus, its suppression further enhances
  triglyceride breakdown.
• Increased fatty acid oxidation: In the
  liver and muscles, this process reduces the availability of fatty acids
  for triglyceride synthesis.
• Increased HDL-C: Fibrates increase the
  synthesis of apolipoproteins A-I and A-II, which leads to enhanced
  production of HDL particles.

• Absorption: Fibrates are well-absorbed
  when taken orally, especially when consumed with food, which enhances
  their bioavailability.
• Metabolism: Fibrates are metabolized in
  the liver through glucuronidation and are not significantly metabolized by
  the cytochrome P450 enzyme system.
• Excretion: Primarily excreted via the
  kidneys as glucuronide conjugates. Dosage adjustments are required in
  patients with renal impairment.

• Reduction in Triglycerides: Fibrates
  are particularly effective in reducing plasma triglyceride levels (by
  30–50%).
• Increase in HDL-C: They increase HDL-C
  levels by 10–20%.
• Effect on LDL-C: The effect of fibrates
  on LDL-C is variable. In patients with hypertriglyceridemia, fibrates may
  lower LDL-C by 5–20%, but in some cases, they can increase LDL-C levels,
  especially in patients with very high triglycerides.

• Hypertriglyceridemia: Fibrates are the
  first-line agents for the treatment of severe hypertriglyceridemia,
  especially when the risk of pancreatitis is high.
• Mixed dyslipidemia: In patients with
  elevated triglycerides and low HDL-C, fibrates are used in combination
  with statins.
• Dysbetalipoproteinemia (Type III
  hyperlipoproteinemia): Fibrates are particularly effective in this
  rare genetic disorder characterized by increased triglycerides and
  cholesterol.

• Myopathy and Rhabdomyolysis: Fibrates can
  cause muscle-related side effects, such as myopathy, especially when used
  in combination with statins. The risk of rhabdomyolysis is higher with
  gemfibrozil compared to fenofibrate.
• Gastrointestinal Disturbances: Fibrates may
  cause nausea, abdominal pain, and dyspepsia.
• Cholelithiasis (Gallstones): Fibrates
  increase the cholesterol content of bile, predisposing to gallstone
  formation.
• Hepatotoxicity: Fibrates may cause mild
  elevations in liver enzymes. Severe liver toxicity is rare but can occur.
• Renal Impairment: Fibrates can increase
  serum creatinine levels and should be used cautiously in patients with
  pre-existing renal impairment.

• Severe renal impairment: Fibrates are
  excreted by the kidneys, and their use is contraindicated in patients with
  significant renal dysfunction (e.g., GFR < 30 mL/min).
• Liver disease: Fibrates should not be used
  in patients with active liver disease, including cirrhosis or hepatitis.
• Gallbladder disease: Due to the risk of
  gallstones, fibrates are contraindicated in patients with pre-existing
  gallbladder disease.
• Hypersensitivity: Patients with a known
  hypersensitivity to fibrates should avoid them.

 

• Fenofibrate
• Dose: 54–160 mg once daily.
• Metabolism: Fenofibrate is a prodrug that
  is converted to its active metabolite fenofibric acid.
• Excretion: Primarily excreted in the urine.
• Gemfibrozil
• Dose: 600 mg twice daily.
• Metabolism: Gemfibrozil undergoes extensive
  hepatic glucuronidation.
• Excretion: Mainly excreted in the urine.
• Drug Interactions: Higher risk of myopathy
  when combined with statins compared to fenofibrate.

 

• Bile acid sequestrants (resins) bind bile acids in
  the intestine, preventing their reabsorption.
• This forces the liver to use more cholesterol to
  synthesize new bile acids, thereby reducing the cholesterol pool and
  increasing LDL receptor activity, which lowers circulating LDL-C.

• Cholestyramine
• Colestipol
• Colesevelam

• Decreases LDL-C by 15-30%.
• Slight increase in HDL-C.
• May increase triglycerides (especially
  in patients with hypertriglyceridemia).

• Gastrointestinal issues: Constipation,
  bloating, abdominal discomfort.
• May interfere with the absorption of fat-soluble
  vitamins (A, D, E, K) and other medications (e.g., warfarin, digoxin).

• Primarily used to lower LDL-C in patients with
  hypercholesterolemia.
• Can be combined with statins for additive effects.

• Complete biliary obstruction.
• Severe hypertriglyceridemia (due to
  risk of increasing triglycerides).

• The primary cholesterol absorption inhibitor, Ezetimibe,
  works by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) protein
  in the small intestine.
• This prevents the absorption of dietary and biliary
  cholesterol, reducing the cholesterol delivered to the liver and prompting
  the liver to take up more LDL-C from the bloodstream.

• Ezetimibe (Zetia)

• Decreases LDL-C by 15-20%.
• Minimal effect on HDL-C and triglycerides.
• Often combined with statins for synergistic LDL-C
  reduction.

• Generally well-tolerated.
• Mild gastrointestinal symptoms (e.g., diarrhea,
  abdominal pain).
• Rarely, elevated liver enzymes when used in
  combination with statins.

• Used to reduce LDL-C in patients with hypercholesterolemia.
• Often prescribed as an add-on therapy
  to statins when additional LDL-C lowering is needed.

• Severe hepatic impairment.
• Hypersensitivity to the drug or any of
  its components.

• PCSK9 inhibitors are monoclonal antibodies that
  target proprotein convertase subtilisin/kexin type 9 (PCSK9).
• PCSK9 normally binds to LDL receptors on liver
  cells, promoting their degradation.
• By inhibiting PCSK9, these drugs increase the
  number of LDL receptors available to clear LDL-C from the
  bloodstream, thereby reducing LDL-C levels.

• Alirocumab 
• Evolocumab 

• Significant reduction in LDL-C by
  50-60%.
• Moderate reduction in triglycerides and increase in
  HDL-C.
• Additive effect when combined with statins or other
  lipid-lowering agents.

• Injection site reactions (as they are
  given subcutaneously).
• Flu-like symptoms, such as upper respiratory tract
  infections.
• Rare reports of cognitive effects, such as
  confusion or memory issues.

• Familial hypercholesterolemia (heterozygous
  or homozygous).
• Atherosclerotic cardiovascular disease patients
  who require additional LDL-C lowering despite statin therapy.
• Patients intolerant to statins.

• Hypersensitivity to the drug or its
  components.
• Pregnancy and breastfeeding (use with
  caution, as the effects have not been well-studied).

• Given by subcutaneous injection every
  2–4 weeks, depending on the drug and dosage.

• Mechanism: Reduces VLDL and LDL
  synthesis in the liver, while increasing HDL-C.
• Effects: Lowers LDL-C and
  triglycerides, significantly increases HDL-C.
• Adverse Effects: Flushing,
  hyperglycemia, hyperuricemia (gout), hepatotoxicity.

• Examples: Eicosapentaenoic acid (EPA),
  Docosahexaenoic acid (DHA)
• Mechanism: Reduce hepatic triglyceride
  synthesis.
• Effects: Primarily reduce
  triglycerides, with minimal effects on LDL-C and HDL-C.
• Adverse Effects: GI discomfort, fishy
  aftertaste, increased risk of bleeding.

4. Bempedoic Acid

• Mechanism: Inhibits ATP citrate lyase
  (ACL), an enzyme involved in cholesterol biosynthesis.
• Effects: Lowers LDL-C by 15-20%.
• Adverse Effects: Muscle pain, elevated
  uric acid levels, potential increase in liver enzymes.

• Mechanism: Small interfering RNA
  (siRNA) that targets PCSK9 mRNA, reducing PCSK9 synthesis in the liver.
• Effect: Significantly reduces LDL-C (up
  to 50%) by increasing LDL receptor availability.
• Administration: Subcutaneous injection
  every 6 months.
• Adverse Effects: Injection site
  reactions, nasopharyngitis.

• Mechanism: Inhibits ATP citrate lyase
  (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol
  biosynthesis pathway.
• Effect: Lowers LDL-C by 15–20%, often
  used as an adjunct to statins.
• Adverse Effects: Increased uric acid
  (risk of gout), muscle pain, elevated liver enzymes.

• Mechanism: Monoclonal antibody against
  angiopoietin-like 3 (ANGPTL3), a regulator of lipid metabolism.
• Effect: Reduces LDL-C, triglycerides,
  and HDL-C, particularly effective in patients with homozygous familial
  hypercholesterolemia.
• Administration: Intravenous infusion
  every 4 weeks.
• Adverse Effects: Flu-like symptoms, GI
  discomfort.

• Mechanism: Inhibits microsomal
  triglyceride transfer protein (MTP), reducing VLDL and LDL particle
  formation.
• Effect: Dramatic reduction in LDL-C
  (40-50%), primarily used in patients with homozygous familial
  hypercholesterolemia.
• Adverse Effects: GI disturbances, liver
  enzyme elevation, hepatotoxicity.

• Mechanism: Antisense oligonucleotide
  targeting apolipoprotein B (apoB) mRNA, reducing LDL-C synthesis.
• Effect: Lowers LDL-C (up to 25%), used
  for homozygous familial hypercholesterolemia.
• Adverse Effects: Injection site
  reactions, flu-like symptoms, liver toxicity.

• Examples: Evinacumab, investigational
  drugs targeting ANGPTL3.
• Mechanism: Inhibit angiopoietin-like 3
  (ANGPTL3), which regulates lipid metabolism, leading to reductions in
  LDL-C, triglycerides, and HDL-C.
• Effect: Significant reductions in LDL-C
  and triglycerides, especially in patients with genetic lipid disorders.