L9 - Lipid Lowering Drugs

Question 1

What is the purpose of LDL-apheresis therapy in lipid lowering treatment?

Answer 1

LDL-apheresis is a procedure used to remove LDL cholesterol from the blood in patients with severe hypercholesterolaemia, particularly those with homozygous familial hypercholesterolaemia. It is often used when statins and other lipid-lowering drugs are ineffective or not well tolerated. The therapy uses a machine to filter the blood, selectively removing LDL particles and lowering cholesterol levels.

Question 2

What is homozygous familial hypercholesterolaemia (HoFH)?

Answer 2

Homozygous familial hypercholesterolaemia (HoFH) is a genetic disorder characterised by extremely high levels of LDL cholesterol from birth due to mutations in the LDL receptor gene. This condition results in severe cholesterol accumulation, leading to early atherosclerotic cardiovascular disease and often premature death if left untreated. HoFH typically requires aggressive lipid-lowering therapy, such as LDL-apheresis, high-dose statins, PCSK9 inhibitors, or liver transplantation.

Question 3

What is the mechanism of action of statins in lipid-lowering therapy?

Answer 3

Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol synthesis pathway. This leads to a reduction in cholesterol production, particularly in the liver, which in turn increases the number of LDL receptors on liver cells, promoting the clearance of LDL cholesterol from the bloodstream.

Question 4

Why are statins considered a major innovation in the treatment of lipid disorders?

Answer 4

Statins are considered one of the greatest innovations in lipid disorder treatment due to their efficacy in lowering LDL cholesterol, which significantly reduces the risk of cardiovascular diseases, including heart attack and stroke. Statins also have pleiotropic effects, such as improving endothelial function and reducing inflammation, further contributing to their cardiovascular benefits.

Question 5

What are the main indications for statin therapy?

Answer 5

Statins are indicated for the treatment of:

Primary hypercholesterolaemia (high cholesterol levels not caused by another condition)
Combined (mixed) hyperlipidaemia (elevated cholesterol and triglycerides)
Heterozygous/homozygous familial hypercholesterolaemia (genetic disorders leading to very high cholesterol levels)
Primary prevention of cardiovascular (CV) events in high-risk patients (e.g., those with diabetes or hypertension)
Secondary prevention of CV events (post-heart attack or stroke)

Question 6

What is the recommended statin dose for patients with familial hypercholesterolaemia?

Answer 6

In familial hypercholesterolaemia, the high-intensity statin dose, which provides a greater than 40% reduction in LDL cholesterol (LDL-C), is recommended as first-line therapy for both heterozygous and homozygous forms of the condition. This dose is aimed at achieving significant reductions in LDL-C to manage the high cardiovascular risk associated with the condition.

Question 7

What characterises diabetic dyslipidaemia?

Answer 7

Diabetic dyslipidaemia is characterised by:

Predominance of small dense LDL particles, which are more atherogenic.
Elevated fasting and postprandial triglycerides, reflecting poor lipid metabolism.
Elevated LDL cholesterol levels, contributing to plaque formation.
Decreased HDL cholesterol, which normally helps protect against cardiovascular disease.
This lipid profile significantly increases the risk of cardiovascular disease in diabetic patients.

Question 8

Should all diabetic patients take a statin?

Answer 8

Yes, most diabetic patients, especially those with type 1 or type 2 diabetes, are at a higher cardiovascular risk. Statin therapy is commonly recommended for:

Primary prevention in high-risk individuals (those over 40 years or with additional cardiovascular risk factors).
Secondary prevention after cardiovascular events, as it reduces further risk.
However, treatment should be individualised based on factors such as age, comorbidities, and overall cardiovascular risk.

Question 9

What is the mechanism of action of statins?

Answer 9

Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, primarily in the liver. This inhibition leads to:

Reduced cholesterol production, particularly LDL cholesterol.
Increased expression of LDL receptors on hepatocytes, leading to enhanced clearance of LDL cholesterol from the blood.
Statins not only reduce cholesterol levels in the liver but can also affect cholesterol synthesis in other cells, though the liver is the main site of action.

Question 10

What is the role of HMG-CoA reductase in cells?

Answer 10

HMG-CoA reductase is an enzyme involved in the biosynthesis of cholesterol. It is present in various cell types, with a major concentration in the liver, where it controls the rate of cholesterol production. By inhibiting this enzyme, statins reduce cholesterol synthesis, which triggers compensatory mechanisms, such as an increase in LDL receptor activity on liver cells, facilitating greater clearance of LDL cholesterol from the bloodstream.

Question 11

What are the uncommon side effects of statins?

Answer 11

Uncommon side effects of statins include:

Alopecia (hair loss)
Hepatic disorders (liver damage)
Memory loss
Pancreatitis (inflammation of the pancreas)
Sexual dysfunction

Question 12

What are the rare or very rare side effects of statins?

Answer 12

Rare or very rare side effects include:

Myopathy (muscle weakness or pain)
Peripheral neuropathy (nerve damage in extremities)
Tendinopathy (tendon damage or inflammation)

Question 13

What are the frequency-unknown side effects of statins?

Answer 13

Side effects with unknown frequency include:

Depression
Diabetes mellitus, particularly in those at high risk

Question 14

How do lipophilic statins differ from hydrophilic statins in terms of tissue penetration and potential side effects?

Answer 14

Lipophilic statins:
Increased extrahepatic tissue penetration
Increased potential for adverse drug reactions (ADRs) due to widespread distribution in various tissues
Enter cells via passive diffusion, allowing them to be widely distributed
Hydrophilic statins:
Increased hepatoselectivity (tend to act more specifically on the liver)
Require protein transporters (Organic Anion-Transporting Polypeptide) to enter cells, limiting their distribution to the liver

Question 15

How do lipophilic statins enter cells?

Answer 15

Lipophilic statins enter cells via passive diffusion, allowing them to be widely distributed in different tissues.

Question 16

What are the lipophilic statins among the following?

Answer 16

Cerivastatin
Simvastatin
Fluvastatin
Atorvastatin
Q

Question 17

What are the hydrophilic statins among the following?

Answer 17

Pravastatin
Rosuvastatin

Question 18

What are the additional benefits of low or no-intensity statins?

Answer 18

Lower risk of adverse effects
Suitable for patients with contraindications to higher intensity statins
Provides a moderate reduction in LDL cholesterol levels
Lower risk of muscle-related side effects compared to high-intensity statins

Question 19

What are the additional benefits of high-intensity statins?

Answer 19

Greater reduction in LDL cholesterol (greater than 40% reduction)
Proven efficacy in secondary prevention of cardiovascular events
Recommended for high-risk patients, such as those with familial hypercholesterolaemia

Question 20

What are the additional benefits of high-dose statins?

Answer 20

Anti-inflammatory effects
Reduction of the necrotic plaque core
Improvement of endothelial function
Plaque stabilization and potential plaque regression

Question 21

What is the downside of high-dose statin treatment?

Answer 21

Increased risk of statin-associated adverse effects, including muscle pain, liver issues, and other side effects

Question 22

What are the pleiotropic effects of statins?

Answer 22

Statins have multiple beneficial effects beyond lowering cholesterol, such as improving endothelial function, reducing inflammation, stabilising atherosclerotic plaques, and potentially reducing the risk of thrombosis.

Question 23

What are the contra-indications and cautions for statin use?

Answer 23

Elderly: Generally well tolerated, but may experience GI events, renal issues, respiratory disorders, headaches, and musculoskeletal pain.
High alcohol intake/History of liver disease: Increases risk of liver toxicity.
Increased risk of muscle toxicity: Includes patients with a personal or family history of muscular disorders, previous muscular toxicity, and high alcohol intake.

Question 24

How does Ezetimibe work?

Answer 24

Ezetimibe selectively inhibits the Niemann-Pick C1-like 1 (NPC1L1) protein at the brush border of the small intestine. This prevents the absorption of dietary cholesterol into enterocytes, reducing cholesterol levels in the bloodstream.

Question 25

What is the role of ABCG5/G8 and ACAT2 in cholesterol absorption?

Answer 25

ABCG5/G8 transporter actively transfers cholesterol and plant sterols back into the intestinal lumen for excretion.
ACAT2 esterifies absorbed cholesterol (into cholesteryl esters, CE), which is then incorporated into nascent chylomicron particles.
NPC1L1 (Niemann-Pick C1-like 1) protein facilitates the uptake of cholesterol across the brush border membrane into enterocytes.

Question 26

What are the indications for ezetimibe?

Answer 26

Adjunct to dietary measures and statin treatment in primary hypercholesterolaemia.
Adjunct to dietary measures and statins in homozygous familial hypercholesterolaemia.
Primary hypercholesterolaemia (if statin is inappropriate or not tolerated).
Used when other treatments are ineffective.

Question 27

What are the common side effects of ezetimibe?

Answer 27

Asthenia
Headache
Runny nose
Sore throat
Diarrhoea (steatorrhoea - increased fat excretion in stools)

Question 28

What are the uncommon side effects of ezetimibe?

Answer 28

Decreased appetite
Arthralgia
Muscle complaints
Nausea

Question 29

What are some rare side effects of ezetimibe?

Answer 29

Constipation
Depression
Dizziness
Dyspnoea
Hepatitis
Myopathy
Pancreatitis

Question 30

What are the contraindications and cautions for ezetimibe?

Answer 30

Hypersensitivity to any component of the formulation
Previous allergic reactions (e.g., rash, angioedema, anaphylaxis)
Concomitant use with a statin in patients with active hepatic disease
Not recommended in patients with moderate to severe hepatic impairment

Question 31

What is the mechanism of action of fibrates?

Answer 31

Fibrates are agonists at the nuclear receptor protein Peroxisome Proliferator-Activated Receptor-α (PPAR-α), which is expressed in muscle, liver, and other tissues. Activation of PPAR-α leads to increased lipolysis and clearance of triglyceride-rich lipoproteins.

Question 32

What are the indications for fibrates?

Answer 32

Fibrates are indicated for:

Mixed hyperlipidaemia (cholesterol and triglycerides) and primary hypercholesterolaemia when statins are contraindicated or not tolerated
Severe hypertriglyceridaemia
Primary prevention of cardiovascular disease in men with hyperlipidaemias if statins are contraindicated or not tolerated

Question 33

How do fibrates lower blood triglycerides?

Answer 33

Fibrates lower blood triglycerides by:

Reducing the liver’s production of very-low-density lipoprotein (VLDL), the triglyceride-carrying particle.
Speeding up the removal of triglycerides from the blood. They also show a modest increase in HDL-C levels but are generally ineffective in lowering LDL-C levels.

Question 34

How do fibrates affect triglyceride-rich lipoproteins and lipoprotein lipase?

Answer 34

Fibrates affect triglyceride-rich lipoproteins by:

Apolipoprotein C-II (apo C-II), which is a cofactor for lipoprotein lipase (LPL), activating LPL.
Lipoprotein lipase (LPL) hydrolyses triglycerides in triglyceride-rich lipoproteins, releasing free fatty acids.
This process leads to the reduction of circulating triglycerides.

Question 35

What are the common and less common side effects of fibrates?

Answer 35

Common side effects:

Constipation, diarrhoea, fatigue, flatulence, gastrointestinal discomfort
Headache, nausea, skin reactions, vertigo, vomiting
Less common (but more serious) side effects:

Atrial fibrillation, angioedema, gallstones
Induction of liver enzymes, myalgia, myopathy

Question 36

What are the contra-indications and cautions for fibrates?

Answer 36

Contra-indications:

History of gall-bladder or biliary tract disease (including gallstones)
Photosensitivity
Cautions:

Risk of myopathy in the elderly
Fibrate/statin combination increases risk of muscle-related side effects (including rhabdomyolysis) and should be used under specialist supervision
Gemfibrozil/statin combination increases risk of rhabdomyolysis considerably and should not be used

Question 37

What are bile acid sequestrants and how do they work?

Answer 37

Bile acid sequestrants (also known as resins) are polycation powders that prevent the reuptake of bile acids from the intestines.
These agents are not absorbed into circulation but instead work by binding to bile acids in the gut and preventing their reabsorption.
The resins are administered by suspending them in water and drinking.
This mechanism leads to a reduction in circulating cholesterol as the liver uses more cholesterol to produce new bile acids, thus lowering blood cholesterol levels

Question 38

What are the indications for bile acid sequestrants (resins)?

Answer 38

Hyperlipidaemias
Primary prevention of coronary heart disease in men aged 35–59 years with primary hypercholesterolaemia that is non-responsive to diet or other measures
Used as an adjunct to other treatments when appropriate or necessary

Question 39

How do bile acid sequestrants (resins) affect LDL receptors and cholesterol levels?

Answer 39

Negative effect on LDL receptors
Positive effect on cholesterol synthesis
They bind bile acids and cholesterol, reducing cholesterol reabsorption, which increases hepatic cholesterol synthesis to compensate. This ultimately leads to an increase in LDL receptor expression and a reduction in LDL levels in the blood.

Question 40

What are the mechanistic consequences of bile acid sequestrants?

Answer 40

Bind bile acids, preventing their reabsorption in the intestine.
Promote hepatic conversion of cholesterol into bile acids.
Increase liver LDL-receptor activity, leading to enhanced clearance of LDL-cholesterol from the blood.

Question 41

What are the side effects of bile acid sequestrants?

Answer 41

Gastrointestinal issues: Constipation, bloating, indigestion, and flatulence.
Malabsorption of fat-soluble vitamins: A, D, E, K.
Potential increase in triglycerides in some patients.
Discomfort due to reduced bile acid circulation.

Question 42

What are the contraindications and cautions for bile acid sequestrants?

Answer 42

Contraindicated:

History of bowel obstruction.
Severe hypertriglyceridaemia.
Cautions:

May affect absorption of negatively charged drugs, such as:
Thiazide diuretics (e.g. hydrochlorothiazide).
Loop diuretics (e.g. furosemide).
Beta blockers (e.g. propranolol).
Cardiac glycosides (e.g. digoxin).
Anticoagulants (e.g. warfarin).

Question 43

What are the contraindications and cautions for bile acid sequestrants related to drug administration?

Answer 43

Cautions:
Administration timing: Other medications should be taken at least 1 hour before or 3 hours after bile acid sequestrants to prevent interactions and ensure proper absorption.

Question 44

What are the contraindications and cautions related to fat-soluble vitamins in bile acid sequestrant therapy?
A:

Answer 44

Caution: Bile acid sequestrants may reduce the absorption of fat-soluble vitamins (A, D, E, K). Supplementation of these vitamins may be required during treatment.

Question 45

What are the contraindications and cautions related to hepatic phosphatidic acid phosphatase activation in bile acid sequestrants?

Answer 45

Caution: The activation of hepatic phosphatidic acid phosphatase in bile acid sequestrant therapy promotes hepatic triglyceride (TG) synthesis, leading to an increase in plasma triglyceride (TG) levels. This can be problematic in patients with hypertriglyceridaemia.

Question 46

What are the contraindications and cautions related to the reduction of intracellular cholesterol in bile acid sequestrants?

Answer 46

Caution: The reduction of intracellular cholesterol caused by bile acid sequestrants can lead to activation of HMG-CoA reductase (HMGCR), which increases cholesterol synthesis.
Solution: This loss of cholesterol-lowering efficacy can be overcome by adding a statin, which inhibits HMGCR and further reduces cholesterol synthesis.

Question 47

What is the mechanism of action of Orlistat?

Answer 47

Orlistat inhibits gastric and pancreatic lipases, which are enzymes that break down triglycerides in the intestine, thereby reducing the absorption of dietary fats.

Question 48

What are the brand names and dosages of Orlistat?

Answer 48

Prescription form: Xenical (120mg, Roche)
Over-the-counter form: Alli (60mg, GSK)

Question 49

How does Orlistat prevent fat digestion?

Answer 49

Orlistat prevents fat digestion by binding to gastric and pancreatic lipases in the gastrointestinal tract. This inhibition reduces the breakdown of triglycerides (TG) into fatty acids (FA), thereby preventing their absorption into the body.

Question 50

What effect does Orlistat have on the formation of micelles in the intestine?

Answer 50

By inhibiting lipases, Orlistat reduces the breakdown of triglycerides, which in turn reduces the formation of micelles that are needed for the absorption of fatty acids and fat-soluble vitamins.

Question 51

What are the indications for Orlistat?

Answer 51

Orlistat is used as an adjunct in obesity treatment for individuals with a Body Mass Index (BMI) of 30 kg/m² or more, or for those with a BMI of 28 kg/m² or more when accompanied by other risk factors, such as type 2 diabetes, hypertension, or hypercholesterolaemia. It is used alongside a mildly hypocaloric diet.

Question 52

What are the common and less common side effects of Orlistat?

Answer 52

Common side effects include abdominal pain, which can be minimised with reduced fat intake, anxiety, and diarrhoea (steatorrhoea), as well as other gastrointestinal disorders.
Less common or unknown frequency side effects include anorectal haemorrhage, cholelithiasis (gallstones), and diverticulitis.

Question 53

What are the contraindications and cautions for using Orlistat?

Answer 53

Contraindications include cholestasis (reduced or blocked bile flow from the liver) and chronic malabsorption syndrome.
Caution should be exercised as Orlistat may impair the absorption of fat-soluble vitamins (A, D, E, and K).

Question 54

What is Bempedoic acid and its mechanism of action?
A:

Answer 54

Bempedoic acid is a first-in-class drug, approved for use in the United States in February 2020 and in the European Union in April 2020.
It competitively inhibits adenosine triphosphate-citrate lyase (ACL), an enzyme involved in liver cholesterol synthesis.

Question 55

How is Bempedoic acid activated and what is its mechanism of action in cholesterol synthesis?

Answer 55

Bempedoic acid is a prodrug, activated to the thioester with coenzyme A by the enzyme ACSVL1 (Very long-chain acyl-CoA synthetase) in the liver.
The activated form inhibits ATP citrate lyase, an enzyme involved in cholesterol biosynthesis in the liver.
This action occurs upstream of HMG-CoA reductase, the enzyme targeted by statins.

Question 56

What are the indications for Bempedoic acid?

Answer 56

Primary hypercholesterolaemia or mixed dyslipidaemia in patients who have not responded adequately to other appropriate measures.
It can be used in combination with a statin, or with a statin and other lipid-lowering therapies, or with other lipid-lowering therapies alone.
It is also used alone if a statin is contraindicated or not tolerated.

Question 57

What are the side effects of Bempedoic acid?

Answer 57

Common or very common:

Anaemia
Gout
Hyperuricaemia
Pain in extremity
Frequency not known:

Diarrhoea
Muscle spasms
Nausea
Interactions:

Increases plasma levels of statins, with the effect being most pronounced with simvastatin and pravastatin.

Question 58

What are the contra-indications/cautions for Bempedoic acid?

Answer 58

Increases plasma levels of statins, which can lead to potential adverse effects of the statins.
The effect is most pronounced with simvastatin and pravastatin (mechanism not confirmed).

Question 59

What is the mechanism of action of PCSK9 inhibitors like Evolocumab?

Answer 59

PCSK9 inhibitors, such as Evolocumab, bind to PCSK9 and prevent it from binding to LDL receptors (LDLRs) on the liver surface.
In the absence of PCSK9, more LDLRs are available on the liver cells, allowing for more efficient removal of LDL from the blood.

Question 60

What condition is associated with gain-of-function mutations in the gene for PCSK9?

Answer 60

Familial hypercholesterolemia is associated with gain-of-function mutations in the gene for PCSK9, leading to reduced LDL removal from the bloodstream.

Question 61

What is Repatha and how does it work?

Answer 61

Repatha is a brand name for Evolocumab, a PCSK9 inhibitor.
It works by binding to PCSK9, preventing it from binding to LDL receptors (LDLRs) on the liver. This allows more LDL receptors to remain on the liver surface, enhancing the liver’s ability to clear LDL (low-density lipoprotein) cholesterol from the bloodstream.

Question 62

What are the indications for Repatha (Evolocumab)?

Answer 62

Primary hypercholesterolemia
Combined (mixed) hyperlipidaemia
Homozygous familial hypercholesterolaemia
Established atherosclerotic cardiovascular disease (CVD)
In all cases, Repatha is used in combination with a statin, statin and other lipid-lowering therapies, other lipid-lowering therapies, or alone if a statin is contraindicated or not tolerated.

Question 63

How is Repatha administered?

Answer 63

The recommended starting dose of Repatha is 140 mg every 2 weeks or 420 mg every month.
It is administered subcutaneously into the thigh, abdomen, or upper arm.
The dose can be adjusted depending on the patient’s underlying disease.

Question 64

hat are the common side effects of Repatha (Evolocumab)?

Answer 64

Arthralgia (joint pain)
Back pain
Hypersensitivity reactions
Increased risk of infection
Nausea
Skin reactions

Question 65

What are the uncommon side effects of Repatha (Evolocumab)?
A:

Answer 65

Influenza-like illness
Injection site infection

Question 66

What are the rare or very rare side effects of Repatha (Evolocumab)?

Answer 66

Angioedema (swelling of deeper layers of the skin, often around the eyes and lips)

Question 67

What are the contraindications for Repatha (Evolocumab)?

Answer 67

Hypersensitivity to the active substance or to any of the excipients in the formulation.

Question 68

What is Inclisiran and how does it work?

Answer 68

Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) that targets and limits the production of PCSK9. By inhibiting PCSK9, Inclisiran increases the number of LDL receptors on liver cells, which enhances the uptake of LDL-cholesterol from the blood and effectively lowers LDL-cholesterol levels.

Question 69

How does Inclisiran work at the molecular level?

Answer 69

Inclisiran is a long-acting, synthetic siRNA that is conjugated to triantennary N-acetylgalactosamine carbohydrates. This allows it to bind to liver asialoglycoprotein receptors, which facilitates its rapid uptake specifically into hepatocytes. Inside the hepatocytes, Inclisiran binds to the RNA-induced silencing complex (RISC), which then catalytically cleaves the PCSK9 mRNA, leading to its degradation. As a result, less PCSK9 is produced, which allows more LDL-C receptors to be recycled to the hepatic membrane, increasing LDL-C uptake and lowering its blood levels.

Question 70

What are the indications for Inclisiran?

Answer 70

Inclisiran is indicated for the treatment of primary hypercholesterolaemia or mixed dyslipidaemia. It can be used in combination with a statin, or with a statin and other lipid-lowering therapies, or with other lipid-lowering therapies alone if a statin is contraindicated or not tolerated.

Question 71

What are the side effects of Inclisiran?

Answer 71

Common: Injection-site reactions
Uncommon: Myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhoea, and dizziness.

Question 72

What are the contraindications and cautions for Inclisiran?

Answer 72

Contraindications: Hypersensitivity to the active substance or any of the excipients.

Question 73

What is the current approach to treating hyperlipidaemia, and what are the options available?
A:

Answer 73

First-line treatment: Statins are the “drug of choice” for hyperlipidaemia, though they come with potential side effects.
Second-line treatment: Ezetimibe is commonly used after statins.
Alternative options:
PCSK9 inhibitors and small interfering RNAs are newer therapies and are primarily used as adjuncts or alternatives in statin-intolerant patients or when other therapies fail.
These newer therapies represent the next generation of lipid-controlling treatments.
Diet and lifestyle should always be the first step in managing hyperlipidaemia.

Question 74

Statins (e.g. Atorvastatin, Simvastatin, Rosuvastatin)

Answer 74

Mechanism of Action:
Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway in the liver. This results in reduced cholesterol synthesis and an increase in LDL receptor activity, leading to enhanced clearance of LDL cholesterol from the bloodstream.
Indications:
Primary hypercholesterolaemia
Combined (mixed) hyperlipidaemia
Familial hypercholesterolaemia (heterozygous and homozygous)
Primary and secondary prevention of cardiovascular events in patients at high risk
Contraindications:
Active liver disease
Pregnancy and breastfeeding
History of statin-induced myopathy or rhabdomyolysis
Side Effects:
Common: Myalgia, gastrointestinal symptoms (e.g., constipation, nausea), headache
Serious: Rhabdomyolysis, liver dysfunction, cognitive impairment
Other: Increased risk of diabetes (in at-risk patients), elevated liver enzymes

Question 75

Ezetimibe

Answer 75

Mechanism of Action:
Ezetimibe inhibits the Niemann-Pick C1-like 1 (NPC1L1) protein on the brush border of enterocytes in the small intestine, preventing cholesterol absorption. This reduces the amount of cholesterol available for incorporation into chylomicrons, lowering plasma cholesterol levels.
Indications:
Adjunctive therapy with statins for primary hypercholesterolaemia
Homozygous familial hypercholesterolaemia
When statins are not tolerated or inappropriate
Contraindications:
Hypersensitivity to the drug
Moderate to severe hepatic impairment when combined with statins
Side Effects:
Common: Diarrhoea, abdominal pain, fatigue, headache
Less common: Liver enzyme elevation, muscle pain
Rare: Myopathy, pancreatitis

Question 76

Fibrates (e.g. Fenofibrate, Gemfibrozil)

Answer 76

Mechanism of Action:
Fibrates activate peroxisome proliferator-activated receptor-alpha (PPAR-α), which increases the expression of genes involved in lipid metabolism, particularly enhancing the breakdown of triglycerides by lipoprotein lipase (LPL). They also increase HDL cholesterol levels but have a minimal effect on LDL cholesterol.
Indications:
Mixed hyperlipidaemia (high triglycerides and cholesterol)
Severe hypertriglyceridaemia
Primary prevention of cardiovascular disease in men with hyperlipidaemias who cannot tolerate statins
Contraindications:
Hepatic or renal impairment
Gallbladder disease (e.g., gallstones)
Concurrent use with statins (increases risk of muscle toxicity)
Side Effects:
Common: Gastrointestinal discomfort (e.g., nausea, diarrhoea), fatigue
Serious: Myopathy, liver enzyme elevation, gallstones
Other: Increased risk of rhabdomyolysis with statin combination

Question 77

Bile Acid Sequestrants (e.g. Cholestyramine, Colestipol)

Answer 77

Mechanism of Action:
These resins bind to bile acids in the intestine, preventing their reabsorption. The liver compensates by converting more cholesterol into bile acids, leading to increased LDL receptor expression on hepatocytes and enhanced clearance of LDL cholesterol from the bloodstream.
Indications:
Primary hypercholesterolaemia
Adjunctive therapy in cardiovascular disease prevention
Contraindications:
Biliary obstruction
History of gallstones or other gastrointestinal disorders
Interaction with negatively charged drugs (e.g., warfarin, thiazide diuretics)
Side Effects:
Common: Constipation, bloating, nausea, flatulence
Serious: Impaired absorption of fat-soluble vitamins (A, D, E, K)
Other: May impair absorption of other medications

Question 78

PCSK9 Inhibitors (e.g. Evolocumab, Alirocumab)

Answer 78

Mechanism of Action:
PCSK9 inhibitors bind to PCSK9, a protein that normally promotes the degradation of LDL receptors. By preventing PCSK9 from binding to LDL receptors, these drugs increase the number of LDL receptors on hepatocytes, leading to greater clearance of LDL cholesterol.
Indications:
Primary hypercholesterolaemia
Homozygous familial hypercholesterolaemia
Established atherosclerotic cardiovascular disease
In combination with statins or other lipid-lowering therapies
Contraindications:
Hypersensitivity to the drug
Side Effects:
Common: Injection site reactions, back pain, flu-like symptoms
Serious: Rare risk of angioedema, hypersensitivity reactions
Other: Nasopharyngitis

Question 79

Small Interfering RNA (siRNA) - Inclisiran

Answer 79

Mechanism of Action:
Inclisiran is a synthetic siRNA that targets and degrades the mRNA for PCSK9, leading to reduced synthesis of PCSK9 and increased LDL receptor expression in the liver. This results in enhanced clearance of LDL cholesterol from the bloodstream.
Indications:
Primary hypercholesterolaemia
Mixed dyslipidaemia
In combination with statins or as a monotherapy when statins are not tolerated
Contraindications:
Hypersensitivity to the drug
Side Effects:
Common: Injection-site reactions, myalgia, headache
Uncommon: Fatigue, nausea, back pain
Serious: Potential for liver enzyme elevation, though rare

Question 80

Summary Comparison

Answer 80

Statins are the most widely used and effective for reducing LDL cholesterol, with potential side effects like muscle pain and liver toxicity.
Ezetimibe is often used in conjunction with statins to further lower LDL when statins alone are insufficient or not tolerated.
Fibrates are particularly effective for lowering triglycerides but are not effective for reducing LDL cholesterol. They also increase HDL cholesterol.
Bile acid sequestrants are an older therapy that lowers LDL cholesterol by promoting its conversion into bile acids, but they are limited by gastrointestinal side effects and drug interactions.
PCSK9 inhibitors and siRNA (Inclisiran) are newer therapies that work by increasing LDL receptor availability in the liver, providing a more targeted approach to lowering LDL cholesterol. They are particularly useful for patients with familial hypercholesterolaemia or those who cannot tolerate statins.