Lipid Lowering Therapy (Dawes)

Question 1

What are lipids?

Answer 1

Plasma lipids include cholesterol (steroid synthesis in liver, cell membrane, bile acid), triglycerides (glycerol with three chains), fatty acids, phospholipids.

Chylomicron are lipoprotein particles consists of polar outer layer (soluble) and non-polar lipids core (include cholesterol, triglycerides, apoprotein, etc.).

Question 2

What are the different sub-fractions of cholesterol?

Answer 2

Total cholesterol (mmol/L) include:

• LDL cholesterol (adverse effects) (transfer cholesterol from liver to peripheral tissues)
• HDL cholesterol (beneficial effects) (transfer cholesterol from peripheral tissues to liver)
• VLDL cholesterol (transfer triglycerides to peripheral tissues for energy sources)
• Chylomicron (transport triglycerides)

Triglycerides (mmol/L) have adverse vascular effects, e.g. triglyceride-induced pancreatitis.

Question 3

Why lower cholesterol?

Answer 3

Primary prevention include reduction in vascular events (small (?) effect on mortality)

• (people who haven’t had a defining cardiovascular event yet)

Secondary prevention has large beneficial effects

• ↓CVS mortality, ↓CVS morbidity
• Total cholesterol 1mmol/L reduction → ↓25% vascular events

Question 4

What type of (Clinical assessment) History, Examination, Investigations and treatment would you do for patients high in cholesterol?

Answer 4

Clinical Assessment (Brief)

History of end organ damage? (primary prevention vs secondary prevention)

Examination of BP, xanthoma, xanthelasmata

Investigations include:

• U + Es
• Fasting cholesterol/LDL/HDL/TG
• Glucose
• ECG

Treatment include patients for:

• Primary prevention (low CVS risk needs high number needed to treat for 5 years to prevent one CVS event)
  
  • CVS risk >30% over 10 years (NZ)
  • CVS risk >7.5% over 10 years (US)
• Secondary prevention for angina, MI, CVA, PVD
• Diabetics (high vascular risk)

Question 5

Who should you treat with statin?

Answer 5

Treatment include patients for:

• Secondary prevention for angina, MI, CVA, PVD
• Diabetics (high vascular risk)
• Primary prevention (low CVS risk needs high number needed to treat for 5 years to prevent one CVS event)
  
  • CVS risk >30% over 10 years (NZ)
  • CVS risk >7.5% over 10 years (US)

Question 6

What are the therapeutic “targets”?

Answer 6

Summary

Therapeutic ‘target’ of LDL <1.8mmol/L (linear relationship, as low as possible?)

• Difficult given trial data
• Risk stratify (patients and statin intensity)

Treatment include lifestyle changes, drugs

Question 7

What are some drugs for cholesterol levels?

Answer 7

• Statins (↓TC, ↓LDL, ↑HDL, ↓TGs) include simvastatin 10-40mg nocte, (atorvastatin 10-40mg).
• Fibrates (↓↓TGs, ↑HDL) include bezafibrate 200-400mg od
• Ezetimibe (↓TC, ↓LDL)
• Nicotinic acid (↓TGs)

Question 8

Describe Statins

• Types
• Indications
• Mechanism of action

Answer 8

Statins

Types

It includes simvastatin 10-80mg nocte, atorvastatin 10-80mg

Its indications are:

• Primary prevention (high CVS risk patients, diabetics, familial hypercholesterolaemia
• Secondary prevention (previous MI, angina, CVA, TIA, PVD)

Mechanism Of Action

Statins competitively inhibit 3-hydroxy-3-Methylglutaryl CoA reductase (HMG CoA reductase). Give at night.

1. Reduce cholesterol synthesis in hepatocyte
2. Secondary upregulation of LDL receptor expression hepatocytes (reduce circulating LDL)
   
   • Knock-on effect of blocking HMG CoA reductase is upregulation of LDL
   • Binds the circulating LDL and internalizes it
3. Reduce production of Isoprenoids (in vitro)
   
   • Isoprenoids are involved in inflammation, cell signalling, cell differentiation, cell proliferation, apoptosis, oxidation etc.

Question 9

What are the Side Effects and Drug Interaction of Statin?

Answer 9

Statin side effects include:

• Myalgia
• Myositis (stop if CK x10)
• Rhabdomyolysis (skeletal muscle damge)
• Deranged LFTs (stop if ALT x3)
• Teratogenic (contraindications with pregnancy)

Statin and Myopathy

Incidence of 1 case per 10 000 patients per year. Related to statin concentrations.

↑ incidence SLC01B1 (chromosome 12) (defect transporter so more statin remain in circulation)

• Encodes organic anion-transporting polypeptide OATP1B1
• Mediates hepatic uptake of drugs

Drug interactions

• Simvastatin has interaction with drugs undergoing CYP3A4 metabolism, e.g. amiodarone, verapamil, diltiazem, erythromycin.
• Statin also has interaction with fibrate.
• Tertogenic

Question 10

What are the endpoint class effect of Statin in CV?

Answer 10

Effect of Statins on CV Endpoints (Class Effect)

Meta-analysis of 14 outcome trials (included 90,056 and all major statins) shows per mmol/L reduction in LDL:

• Total mortality ↓12%
• Major vascular event ↓21%

There is no evidence of XS cancer deaths and 5-year risk of rhabdomyolysis <1:10,000

Question 11

What are the Pleiotropic Effects of statin?

Answer 11

Statins And “Pleiotropic Effect”

Non-cholesterol-lowering (beneficial) effects are ?clinically important due to decreased isoprenoids. Observations (in vitro) shows:

• Anti-thrombotic
• Anti-inflammatory
• Immune modulation

Some benefits occurring before ↓cholesterol.

Question 12

Describe Fibrates

• Introduction
• Indications
• Side Effects

Answer 12

Fibrates

Introduction

Fibrates include bezafibrate 200-400mg od. They can ↓↓trigylcerides 30-50% (↓LDL, ↑HDL).

Indications include:

• Isolated hypertriglyceridaemia (>10mmol/L) (other treatments include diet, exercise, weight loss, ↓alcohol, ↑DM control)
• Combined therapy with statins (resistant hypercholesterolaemia problems)

Mechanism of Action

It is PPARα agonist, which stimulates peroxisome proliferator-activated receptor α (nuclear).

• Liver and skeletal muscle lipid metabolism
  
  • ↓hepatic VLDL production
  • ↑hepatic VLDL clearance
  • ↑skeletal muscle FA storage
• Activate lipoprotein lipase
  
  • Breaks down TGs
• Anti-proliferative/anti-inflammatory effects?

Side Effects

• GI upset (diarrhoea, nausea)
• Deranged LFTs
• Myositis (↑ risk with concurrent statin)

Question 13

Describe Ezetimibe

• Mechnaism of action
• Side Effects
• Indications

Answer 13

Ezetimibe

Mechanism of Action

Ezetimide is relatively new (intestinal glucuronidation to glucuronide). Low efficacy as monotherapy (10mg od). Use with statin.

Mechanism is by blocking NPC1L1 channel:

• Reduce cholesterol absorption (from intestinal lumen to enterocyte)
• ↓ intestinal delivery of cholesterol to liver
• ↑ expression of hepatic LDL receptors
• Enterohepatic circulation

Side Effects

• Abdominal pain
• Diarrhoea (more cholesterol in stool)

Combination Therapy Of Ezetimibe and Statin

This is dual inhibition approach of ezetimibe and statin, which inhibits cholesterol production and absorption.

Question 14

Describe Nincotinic acid

• Mechanism of action
• Side effects

Answer 14

Nicotinic Acid (Niacin)

Introduction

Nicotinic acid is vitamin B3 (niacin), rarely used. Dose of 25-500mg od.

• It can ↓triglycerides, ↑ HDL
• Use as combination therapy with statin or fibrate

Side effects include GI intolerance, flushing (prostaglandin synthesis causing cutaneous vasodilation), dry skin.

Mechanism of Action

• Reduced FA mobilization from the periphery (inhibit HM74 receptor)
• Reduced hepatic triglyceride/VLDL production (inhibit DGAT2 receptor)
• Reduced HDL degradation (inhibit catabolic receptor)

Question 15

Describe Bile Acid binding Resins

Answer 15

Bile Acid Binding Resins (Sequestrants)

Mechanism of Action

Bile acid binding resins are uncommonly used now in “statin era”

It includes cholestyramine, which bind bile acids, so stop enterohepatic circulation.

• →↓absorption of exogenous cholesterol
• →↑conversion of endogenous cholesterol to bile acids in hepatocytes
• ↑ hepatic LDL expression

It is given orally (sachets), but unappetising.

Side Effects

• It is not systemically absorbed.
• It has lots of GI side effects including nausea, bloating, constipation/diarrhoea.
• It impairs fat-soluble vitamin A,D,E,K absorption
• It interferes drug absorption (digoxin, warfarin, thiazides, T4)