Hypercholesterolemia

• elevated LDL-C(low density lipoprotein cholesterol) is a major cause of atherosclerosis
• Reducing the concentration of this lipoprotein stabilises atherosclerotic plaques, and may lead to regression of the atherosclerosis.
•  A moderate reduction of the plasma concentration of this lipoprotein significantly decreases recurrent coronary events\
• Cholesterol and triglyceride are the two major forms of lipid found in the body.
• Both are carried in lipoproteins in the blood. 
• Cholesterol is used mainly in cell membrane formation as well as in bile acids and in steroid hormones
• the lipoproteins carry
  • protein (apoproteins)
  • cholesterol
  • cholesteryl esters
  • triglycerides
  • vitamin E
  • dietary polyphenols
  • co-enzyme Q10

There are five major classes of lipoprotein

Chylomicrons	Triglyceride rich	Atherogenic
VLDL – Very low density lipoprotein
IDL – Intermediate density lipoprotein
LDL – Low density lipoprotein	Cholesterol rich
HDL – High density lipoprotein		Anti-atherogenic

• Intermediate and low density lipoprotein contain the highest proportion of cholesterol while chylomicrons contain little cholesterol.
• Intermediate density lipoprotein and low density lipoprotein (LDL) are the most atherogenic, while high density lipoprotein (HDL) is anti-atherogenic.

• Elevated Triglycerides = elevated VLDL cholesterol
• Elevated Cholesterol =  elevated LDL cholesterol 
• high concentration of HDL cholesterol are not at increased risk of cardiovascular disease
• Hypertriglyceridaemia
  • has strong environmental and genetic causes. 
  • High triglyceride levels can lead to increased CVD risk, pancreatitis and hepatic steatosis 
  • Levels up to 1.7 mmol/L are normal 
  • >10 mmol/L increases risk of pancreatitis and hepatic steatosis.
  • It is important that fasting blood levels are taken, as levels are highest after meals. 
  • After a trial period of diet and exercise, it is recommended that a fasting triglyceride test is repeated.

Secondary dyslipidemia

Causes	Effects on lipid profile
Hypothyroidism Hyperparathyroidism Nephrotic syndrome Cholestasis Anorexia nervosa Cushings syndromes	Increased LDL – C
Type 2 diabetes Obesity Renal impairment Smoking Drug therapy	Increased TG and/or decreased HDL
Alcohol use Oestrogen use (higher dose COCP)	Increased TGHDL- C may increase
Steroids, cyclosporin, higher dose COCP Antipsychotics protease inhibitors beta blockers thiazides Tamoxifen	mainly TG’s

Medications and Dyslipidemia

	LDL Cholesterol	Triglycerides	HDL Cholesterol
Cardiovascular /Endocrine
Amiodarone	↑Variable	↔	↔
β-Blockers***	↔	↑10-40%	↓5-20%
Loop diuretics	↑5-10%	↑5-10%	↔
Thiazide diuretics (high dose)	↑5-10%	↑5-15%	↔
Sodium-glucose co-transporter 2 (SGLT2) inhibitors	↑3-8%	↔↓	↑Variable
Steroid Hormones/Anabolic Steroids
Estrogen	↓7-20%	↑40%	↑5-20%
Select progestins	↑Variable	↓Variable	↓15-40%
Selective Estrogen Receptor Modulators	↓10-20%	↑0-30*	↔
Danazol	↑10-40%	↔	↓50%
Anabolic steroids	↑20%	↔	↓20-70%
Corticosteroids	↑Variable	↑Variable	↔
Antiviral Therapy
Protease inhibitors	↑15-30%	↑15-200%	↔
Direct Acting Antivirals	↑12-27%	↔	↑14-20%
Immunosuppressants
Cyclosporine and tacrolimus	↑0-50%	↑0-70%	↑0-90%
Corticosteroids	↑Variable	↑Variable	↔
Centrally Acting Medications
First Generation antipsychotics	↔	↑22%	↓20%
Second Generation antipsychotics	↔	↑20-50%	↔
Anticonvulsants	↑Variable	↔	↑Variable
Other Medications
Retinoids	↑15%	↑35-100%	↔**
Growth Hormone	↑10-25%	↔	↔↑7%

Prescribing

see medications guide below

First Assess Absolute Cardiovascular Risk

clinically determined high risk

Familial Hypercholesterolaemia (FH):

• Most common inherited cause of premature coronary heart disease (CHD).
• Prevalence: 1 in 250.
• People with diagnosed FH are at clinically determined high risk and should be automatically managed as high CVD risk.
• Individuals with FH should follow Australian guidelines for managing FH.
• FH-specific calculators may be useful.

• Consider Genetics if
  • total cholesterol level above 7.5 mmol/L
  • family history of premature coronary artery disease and death.

Moderate-to-Severe Chronic Kidney Disease (CKD):

• People at Clinically Determined High Risk if Moderate-to-severe CKD:
  • Sustained eGFR <45mL/min/1.73m², or
  • Men with persistent uACR >25mg/mmol, or
  • Women with persistent uACR >35mg/mmol.

for others:

Australian Cardiovascular Disease Risk Calculator (Aus CVD Risk Calculator)

Validated for people without known CVD aged 30 to 79 years who do not already meet high-risk criteria.

Produces estimated 5-year CVD risk scores, expressed as a percentage.

• Key variables:
  • Age (30-79 years)
  • Sex at birth
  • Smoking status
  • Blood pressure (average of last two seated, in-clinic BP measurements)
  • Cholesterol (ratio of total cholesterol to HDL-C)
  • Diabetes status
  • CVD medicines (lipid-modifying(statins), BP-lowering(ACE,bBlockersetc..), and/or antithrombotic(aspirin etc..) medicines)
  • Postcode (to calculate Socio-Economic Indexes for Areas – SEIFA)
  • Medical history of atrial fibrillation- Both paroxysmal and persistent AF are included in the definition of AF
• Diabetes:
  • Type 2 diabetes is independently associated with a two-fold increased risk of developing CVD.
  • The new Aus CVD Risk Calculator includes:
    • Time since diagnosis of diabetes
    • HbA1c
    • eGFR
    • uACR
    • BMI
    • Insulin use
  • Type 1 diabetes: The calculator is not validated for this type.

The risk calculator is not appropriate for assessing patients with already known high CVD risk (eg familial hypercholesterolaemia) for absolute CVD risk.

based on the risk:

Consider Reclassification Factors

Reclassification factors and effect on risk estimates

Factor	Potential to reclassify upward or downward
Ethnicity	↑ or ↓
Family history of premature CVD	↑
Chronic kidney disease	↑
Severe mental illness	↑
Coronary artery calcium score	↑ or ↓

• Ethnicity:
  • First Nations people: Consider reclassifying to higher risk based on clinical, psychological, socioeconomic circumstances, and community CVD prevalence.
    • Close to higher risk threshold:
      • Māori people
      • Pacific Islander people
      • people of South Asian ethnicity (Indian, Pakistani, Bangladeshi, Sri Lankan, Nepali, Bhutanese, or Maldivian ethnicities)
    • Close to lower risk threshold:
      • East Asian ethnicities
        • Chinese
        • Japanese
        • Korean
        • Taiwanese
        • Mongolian
• Family history of premature CVD: Consider reclassifying to higher risk, particularly if close to higher risk threshold
  • defined as
    • coronary heart disease (CHD) or
    • stroke in a first-degree
  • AND
    • female relative aged <65 years or
    • a first-degree male relative aged <55 year

• Chronic kidney disease:
  • Moderate-to-severe CKD (sustained eGFR <45mL/min/1.73m² or persistent uACR >25mg/mmol [men] or >35mg/mmol [women]): Manage as high CVD risk.
  • Non-diabetic with sustained eGFR 45-59mL/min/1.73m² and/or persistent uACR 2.5-25mg/mmol (men) or 3.5-35mg/mmol (women): Consider reclassifying to higher risk.

Kidney function	Urine ACR (mg/mmol)	eGFR (mL/min/1.73m2)	Recommendation
Normal	Men: <2.5Women: <3.5	≥60	Assess CVD risk using Aus CVD risk calculator.
Impaired kidney function	Men: 2.5–25Women: 3.5–35	45-59	Strongly consider reclassifying risk upwards.
Moderate-to-severe CKD	Men: >25Women: >35	<45	Clinically determined high risk.Do not use Aus CVD risk calculator.Manage as high CVD risk.

• Severe mental illness: Consider reclassifying to higher risk, particularly if close to higher risk threshold.

• Coronary artery calcium (CAC) score:
  • General Recommendations
    • Not recommended for generalized population screening for CVD risk.
  • Specific Situations
    • Do not measure CAC if:
      • History of myocardial infarction or revascularization.
      • Known coronary heart disease.
      • Already known to be at high CVD risk.
    • Consider CAC measurement for reclassifying risk level when treatment decisions are uncertain, such as:
      • When CVD risk is assessed as low or intermediate and other risk concerns are present.
      • When additional information is needed to guide discussions about modifying therapy
  • CAC Measurement:
    • Performed by computed tomography (CT).
    • Provides a score related to calcified plaque in coronary arteries.
    • Results reported as total CAC score (Agatston units) and percentile based on age, sex, and ethnicity.
  • Potential Consequences:
    • Low radiation exposure.
    • Possible clinical and psychological effects of unexpected adverse results.
    • Potential need for further investigations due to incidental findings (e.g., lung nodules).
  • Using CAC Score to Assess CVD Risk
    • Not recommended for population screening due to low yield in low-risk populations.
    • Limited utility for high CVD risk individuals as it won’t change management decisions.
    • Consider CAC measurement if:
      • Risk factors are not fully accounted for by the Aus CVD Risk Calculator.
      • There is reluctance to initiate or adhere to medications.
  • High CAC score (>99 Au) can enhance shared decision-making and promote adherence to preventive treatments.
  • A normal CAC score (zero) warrants repeat testing within 2-5 years to monitor risk changes.

Clinical Applications of CAC Testing

• Not recommended for:
  • Population screening.
  • High-risk individuals.
  • People with known CVD.
• Consider for low or intermediate risk individuals with additional risk factors:
  • Score of zero: May reclassify to low risk.
  • Score >99 Au: May reclassify to higher risk.
  • Repeat testing: Consider in 2-5 years for those with an initial score of zero.
• Special Considerations
  • Younger adults: CAC score of 0 indicates very low 5-year CVD risk but doesn’t rule out non-calcified atherosclerosis.
  • Older adults: CAC score increases with age and may have less discriminative value for those over 75 years.

Practice Points

• Reclassify risk based on CAC score for intermediate risk individuals.
• Explain estimated risk and manage according to current recommendations.
• Repeat CAC test only if management decisions are uncertain.
• Do not repeat if long-term BP-lowering and/or lipid-modifying therapy is already in place.
• Involve the person in management decisions and provide pre-test counseling.
• Clarify CAC report details with the imaging provider if needed.
• Cost of CAC testing varies and is not subsidized by Medicare.

Clinical applications of CAC testing

Clinical situation	CAC testing	Clinical implications
Population screening for CVD	Not recommended	Low yield of CAC scoring in mass population screening
People with high risk of a cardiovascular event in the next 5 years	Not recommended (neither initial nor repeat test)	CAC score would not alter management: preventive treatment indicated.
People with known CVD	Not recommended (neither initial nor repeat test)	CAC score would not alter management: preventive treatment indicated.
CVD risk assessed as low or intermediate in a person with one or more additional risk factors	Can be considered if available and affordable	Detection of CAC may reclassify risk to a higher level.Score of zero may reclassify risk level to low.Score >99 Au (or ≥75 th percentile for age and sex) may reclassify risk level to a higher level.
Change in intensity of preventive treatment is under consideration	Can be considered if available and affordable to inform discussions with patient	CAC score may alter management.
Previous score of zero	Consider re-testing in 2–5 years	CAC score provides additional monitoring of risk.

• Other risk considerations:
  • Ankle-brachial index: Not recommended as part of CVD risk assessment.
  • High-sensitivity C-reactive protein test: Not routinely recommended.
  • Rheumatoid arthritis: Do not reclassify solely due to its presence.

Manage CVD Risk

Pharmacotherapy

Risk category	Estimated  5‑year CVD risk	Management	Reassessment interval
High	≥10%	Encourage, support and advise a healthy lifestyle.b Prescribe – blood pressure-lowering and – lipid-modifying pharmacotherapy.c	Formal reassessment of CVD risk is not generally required. High-risk status requires clinical management and follow up supported by ongoing communication.
Intermediate	5% to <10%	Encourage, support and advise a healthy lifestyle.b Consider – blood pressure-lowering and – lipid-modifying pharmacotherapy, depending on clinical context.	Reassess risk every 2 years if not currently receiving pharmacotherapy to reduce CVD risk. Assess sooner if close to the threshold for high risk, if CVD risk factors worsen, or new CVD risk factors are identified. For First Nations people, reassess every year as part of an annual health check (or opportunistically) or at least every 2 years.
Low	<5%	Encourage, support and advise a healthy lifestyle.b Pharmacotherapy is not routinely recommended.	Reassess risk every 5 years. Assess sooner if close to the threshold for intermediate risk, if CVD risk factors worsen, or new CVD risk factors are identified. For First Nations people, reassess every year as part of an annual health check (or opportunistically) or at least every 2 years.

Elderly (>74)

• Increasing age, sex and inheritance are key immutable risk factors.
• cannot be placed on the calculator
• side effects increase in the elderly
  • Myopathy can be much more debilitating in the elderly who are at risk of falls.
  • would have to think twice about prescribing primary prevention in a patient over 75yo

• Patients aged >75 years who are already on statins should continue
• Indications to continue treatment with Statin agent in age over 75 years:
  • Coronary Artery Disease
  • High Coronary Calcium Score
  • Ankle brachial index <0.9
  • hs-CRP >2 mg/L
  • Consider continuing agent even without other indications (NNT 83 to avoid 1 MI in 3-4 years – Savarese (2013) J Am Coll Cardiol 62(22):2090-9

Evidence of use in secondary prevention

• The NNT reviewed Statins given for 5 years for heart disease prevention The NNTin patients with known heart disease.
  • Treat 83 to save 1 life
  • Treat 39 to prevent 1 non-fatal heart attack
  • Treat 125 to prevent 1 stroke
  • Conversely treat 10 for 1 harm (muscle damage)
  • Treat 167 for 1 T2DM – Link
• For each 1 mmol/L reduction in LDL-C achieved, there is a 22% relative risk reduction in cardiovascular events over five years

lifestyle modification

Weight Loss Recommendations

Target Measurements

• Waist Measurement:
  • Men: <94 cm
  • Women: <80 cm
• Body Mass Index (BMI): <25 kg/m²

Dietary Guidelines

• Salt Restriction: ≤4 g/day (65 mmol/day sodium)
• Alcohol Intake:
  • Men: ≤2 standard drinks per day
  • Women: ≤1 standard drink per day

Exercise

• Aerobic Exercise:
  • Decreases LDL cholesterol by 10%
  • Increases HDL cholesterol by 5%
• Activity Recommendations:
  • 150 minutes per week of moderate exercise or
  • 75 minutes per week of vigorous exercise
  • Include muscle-strengthening exercises twice weekly
• Suggestions for Activities:
  • Join group classes or clubs for activities such as swimming, walking, cycling, dancing, or gym attendance

Smoking Cessation

• Quit Smoking: Essential for overall cardiovascular health

Diet

• Fat Replacement:
  • Replace saturated fat with carbohydrates and foods rich in mono- or polyunsaturated fats
  • Increase intake of high-fiber foods
• Avoid Trans Fats:
  • Avoid baked goods containing trans fatty acids, such as pies, pastries, cakes, and biscuits
• Mediterranean Diet:
  • Vegetarian-like diet high in nuts, olive oil, vegetables, and pasta cooked al dente
  • High intake of fish

Omega-3 Fatty Acids

• Fish Oil:
  • Effective in lowering triglycerides
  • No effect on LDL cholesterol at usual therapeutic doses
  • Very high doses may increase LDL cholesterol

TARGETS

total cholesterol	<4.0 mmol/L
HDL-C	≥1.0 mmol/L
LDL-C primary prevention	<2.0 mmol/L
LDL-C secondary prevention	<1.8mmol
non-HDL-C	<2.5 mmol/L
TG	<2

MEDICATIONS

HMGCoA Reductase Inhibitors (Statins)

• First-line therapy for lowering LDL cholesterol.
• Effectiveness: Lowers LDL by 30-40%. Doubling the dose reduces LDL by an additional 5-10%.
• Monitoring: Check lipid levels 4-8 weeks after starting or adjusting the dose. Maximum response is expected within 4 weeks.
• Non-fasting blood samples are acceptable and may improve adherence (European guidelines/NPS).
• Fasting sample required if triglycerides (TG) are elevated (NPS).

Ezetimibe

• Monotherapy: 10 mg daily, used if statin intolerant. Lowers LDL by 15-20%.
• Combination therapy: 10 mg daily with statin (e.g., Vytorin with simvastatin) or separately. Lowers LDL by an additional 20% compared to statin alone.

Bile Acid Sequestrants (Cholestyramine)

• Dosage: 4-8 g orally, up to 24 g daily in divided doses.
• Adverse effects: Gastrointestinal side effects often lead to non-adherence.

Nicotinic Acid (Niacin, Vitamin B3)

• Dosage: 250 mg orally twice daily with food, up to 1500 mg twice daily or 100 mg three times daily with food. Increase slowly (no more than 250 mg every 4 days).
• Usage: Rarely used due to poor tolerance (gastritis, glucose intolerance, flushing, higher urate levels).

Fenofibrate

• Dosage: 145 mg daily.
• Usage: Can cause a 5-10% reduction in LDL, primarily used for lowering triglycerides. Use with caution when combined with statins.

Resistant LDL-C Management

1. Titrate statin to the maximum tolerated dose.
   • Dose increases at intervals of 4-8 weeks.
2. If targets are not met:
   • Consider adding a second agent (e.g., ezetimibe, bile acid sequestrant).
3. Persistent elevated LDL-C despite statin + bile acid sequestrant:
   • Consider adding nicotinic acid or fenofibrate as outlined above.

Treatment of Isolated Hypertriglyceridemia (VLDL Cholesterol)

First-line: Lifestyle Modifications

• Diet: Rich in mono- and polyunsaturated fats, low glycaemic index carbohydrate foods.
• Caloric restriction: Leading to weight reduction.
• Exercise: Regular physical activity.

Second-line: Pharmacotherapy

• Marine omega-3 fatty acids (Fish oil)
  • Dosage: 1.2 to 3.6 g daily of omega-3s.
  • Capsules:
    • 1 g capsule contains 300 mg of omega-3 (minimum 4 capsules/day).
    • 1.5 g capsule contains 450 mg of omega-3 (minimum 3 capsules/day).
  • Concentrated liquid: 2.7 g/5 ml (~2 ml/day minimum).
• Fenofibrate
  • Dosage: 145 mg orally daily.
• Gemfibrozil
  • Dosage: 600 mg orally twice daily.