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%

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TESTING

Fasting vs Non-Fasting Lipids

• Global consensus (Canada 2016, ESC 2019, ACC 2021): routine non-fasting samples acceptable; repeat fasting only if TG ≥ 4.5 mmol/L or clinical query (e.g., severe HTG).
• Benefits: patient convenience, fewer hypoglycaemic events, smoother laboratory workflow.
• Australia: RACGP endorses the shift; NHFA formal update anticipated 2025. Management thresholds are unchanged.

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Prescribing

if Familial Hypercholesterolaemia (FH) or Moderate-to-Severe Chronic Kidney Disease (Sustained eGFR <45mL/min/1.73m², or Men with persistent uACR >25mg/mmol, or Women with persistent uACR >35mg/mmol) start treatment.

for others: Australian Cardiovascular Disease Risk Calculator (First Assess Absolute Cardiovascular Risk

TARGET

Australian Lipid Targets ( **NHFA 2012; updates pending **)

Setting	LDL-C	Non-HDL-C	TG	HDL-C	HDL : TC
Primary prevention (≥ 5 % absolute risk)	< 2.0 mmol/L	< 2.6 mmol/L	< 2.0 mmol/L	≥ 1.0 mmol/L (M); ≥ 1.2 mmol/L (F)	≥ 0.4
Secondary prevention / Very-high risk	< 1.8 mmol/L (or ≥ 50 % reduction)	< 2.3 mmol/L	< 2.0 mmol/L	same as above	≥ 0.4
Lp(a) (once-off measurement)	Aim < 125 nmol/L (< 0.5 g/L) if available	—	—	—	—

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

Interventions for lowering low-density lipoprotein cholesterol (LDL-C) concentration

		Intervention or drug [NB1]	Approximate reduction in LDL-C concentration [NB2]
Lifestyle modifications		replacing saturated fat with unsaturated fat	5 to 15%27
		increasing the intake of plant sterols to more than 1.5 g/day	5 to 10%28
		losing approximately 10% body weight	5 to 10%29
		increasing aerobic exercise	10%30
		consuming the DASH diet	5%28
Statins	low intensity	simvastatin 10 mgpravastatin 10 to 20 mgfluvastatin 20 to 40 mg	up to 30%25
	moderate intensity	atorvastatin 10 to 20 mgrosuvastatin 5 to 10 mgsimvastatin 20 to 40 mgpravastatin 40 to 80 mgfluvastatin 40 mg twice daily or 80 mg daily	30 to 49%25
	high intensity	atorvastatin 40 to 80 mgrosuvastatin 20 to 40 mg	50% or more 25
Niemann-Pick C1–like transporter (cholesterol absorption) inhibitor		ezetimibe 10 mg	15 to 20%31
PCSK9 inhibitors	monoclonal antibody	evolocumab 140 mg by subcutaneous injection every 2 weeks, or 420 mg once a month	50 to 70%32
	small interfering RNA	inclisiran 300 mg [NB3] by subcutaneous injection initially, then repeated at 3 months, then every 6 months	50%33
DASH = Dietary Approaches to Stop Hypertension; PCSK9 = proprotein convertase subtilisin/kexin type 9NB1: Drug route of administration is oral and frequency is daily, unless specifically stipulated.NB2: Expected reduction in LDL-C concentration may vary by baseline concentration and concomitant therapy.NB3: Inclisiran solution for injection contains inclisiran sodium 300 mg, equivalent to inclisiran 284 mg.

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

MEDICATIONS

HMGCoA Reductase Inhibitors (Statins)

Role:

• First-line therapy for lowering LDL-C.
• Effective, inexpensive, and generally well-tolerated.

Intensity Categories:

• Low, moderate, high — depending on LDL-C lowering potency.

Indication:

• Tailored to baseline LDL-C, target levels, and CVD risk profile.
• “Lower is better” for secondary prevention/high-risk patients.

Adverse Effects:

• Myopathy: CK > 3× ULN, incidence ~1/1000 patient–years.
• Rhabdomyolysis: CK > 10× ULN, rare (~1/100,000 patient–years).
  • Risk ↑ with CYP3A4 inhibitors (e.g. macrolides, azoles, grapefruit).
  • Gemfibrozil + statins → avoid due to high risk.
  • Pravastatin and rosuvastatin not metabolised by CYP3A4 → safer.

Muscle Aches:

• Commonly reported (10–20%) but rarely statin-related.
• Only ~1 in 15 cases confirmed in RCTs.
• Often due to nocebo/drucebo effect.

Management of Statin Intolerance:

• Trial of alternate statin (e.g. pravastatin).
• Dose reduction or intermittent dosing (alternate days/weekly).
• Up to 70% tolerate statins on rechallenge.
• Check and correct vitamin D deficiency if present.

Monitoring:

• Baseline LFTs and CK.
• No need for routine CK/liver monitoring unless symptomatic.

Limitations:

• Many high-risk patients won’t reach LDL-C targets with statins alone.
• Combination therapy often needed.

Ezetimibe

Mechanism:

• Inhibits intestinal cholesterol absorption via NPC1L1 transporter.

Efficacy:

• LDL-C ↓ ~20% (monotherapy).
• LDL-C ↓ ~15% when added to statin.

Clinical Trial (IMPROVE-IT):

• Simvastatin + ezetimibe → 7% ↓ in CV events (modest but significant).

Adverse Effects:

• Flatulence most common.
• Generally well tolerated.

PBS:

• Subsidised as monotherapy- 10 mg daily (if statin-intolerant) or as add-on.
• Fixed-dose combinations available.

PCSK9 Inhibitors

Mechanism:

• Inhibit PCSK9 → preserve LDL receptors → ↑ hepatic LDL clearance.

Agents:

• Evolocumab (PBS-listed)
• Alirocumab (PBS for continuation only)
• Inclisiran (approved, not PBS yet)

Efficacy:

• Evolocumab/Alirocumab: LDL-C ↓ ~60%
• Inclisiran: LDL-C ↓ ~50%

Administration:

• Evolocumab/Alirocumab: s/c every 2 weeks or monthly.
• Inclisiran: s/c at 0, 3, and then every 6 months.

Evidence:

• Evolocumab improves atheroma burden and plaque composition.
• Reduced CV events proportionate to LDL-C lowering.

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.