Anti-Lipids

STATINS

• Most potent oral lipid-modifying agents
• First-Line Therapy for Predominant LDL-C Elevation
• Reductions:
  • LDL-C
  • Triglycerides
• Non-lipid Lowering Properties:
  • Antiplatelet effects
• Potency of Statins
  • More Potent Statins:
    • Atorvastatin
    • Rosuvastatin
    • Simvastatin
  • Less Potent Statins:
    • Fluvastatin
    • Pravastatin

Effectiveness

• Rosuvastatin and Atorvastatin: Most potent
• General Efficacy:
  • A dose lowering LDL by 30-40% results in a 25-30% reduction in cardiovascular events.

Administration Timing

• Cholesterol Synthesis:
  • Predominantly occurs at night.
• Short-acting Statins:
  • Recommended to be taken in the evening or at bedtime.
  • Examples:
    • Lovastatin (Mevacor)
    • Fluvastatin (standard-release)
    • Pravastatin (Pravachol)
    • Simvastatin (Zocor)
• Long-acting Statins:
  • Can be taken any time of the day; choose a time that is easy to remember.
  • Examples:
    • Atorvastatin (Lipitor)
    • Fluvastatin (extended-release)
    • Rosuvastatin (Crestor)

Factors to Consider When Selecting a Statin

• LDL-C-lowering potency
• Potential Drug Interactions:
  • Assess other medications to avoid adverse events and ensure adherence.
• Renal and Liver Function:
  • Adjust dosage as necessary based on organ function.
• Ethnicity:
  • Patients of Asian heritage may require lower doses of rosuvastatin.

• before starting , need baseline
  • BGL
  • liver and muscle biochemistry (ALT and CK) 
  • before initiating statin therapy

Avoid drug interactions

• Medicines that inhibit the CYP P450 enzymes listed in the table below may increase the concentration of the statin, and hence increase the risk of adverse events.

Statin	Metabolised by	Statin concentration may be increased by	Statin concentration may be decreased by
Atorvastatin Simvastatin	CYP3A4 (main)	CYP3A4 inhibitors Azole antifungals (all) Calcium channel blockers (only diltiazem, verapamil) Fluvoxamine Grapefruit juice HIV-protease inhibitor antiretrovirals (all)Macrolide antibacterials (only clarithromycin, erythromycin) Ticagrelor	CYP3A4 inducers Antiepileptics (some eg. carbamazepine, phenytoin) HIV-protease inhibitor antiretrovirals (only ritonavir, tipranavir) Rifampicin St John’s wort
Fluvastatin	CYP2C9 (main) CYP3A4 (lesser extent)	CYP2C9 inhibitors Amiodarone Azole antifungals (only fluconazole, voriconazole) SSRIs (only fluoxetine, fluvoxamine) CYP3A4 inhibitors (see above)	CYP2C9 inducers Rifampicin St John’s wort CYP3A4 inducers (see above)
Pravastatin Rosuvastatin	Not significantly metabolised by CYP enzymes

Adverse effects

• generally well tolerated with the most common adverse effects
  • myalgia
  • transient GI symptoms
  • headache
  • insomnia
  • dizziness

These symptoms are more common with higher doses and may resolve if a different statin is used. 

• Memory Loss
  • No evidence that statis have any positive or negative effect on memory, mental ability or dementia

• STATI-associated Muscles Symptoms (SAMS)
  • Statins have been associated with Nocebo effect – patient experience adverse effects based on the expectation of harm from a treatment
  • Evidence shows that many people who experience muscle symptoms can keep taking their statin at lower dose and upto 90% are able to tolerate a different statin, without problems
  • Myopathy Incidence 1 in 10,000
  • Rhabdomyolysis Incidence 1 in 100,000

Less likely	🡨 SAMS 🡪	More Likely
•       Unilateral •       Nonspecific distribution •       Tingling, twitching, shooting pain, nocturnal cramps or joint pains	NATURE of SYMPTOMS	•       Bilateral •       Large muscle groups (thighs, buttocks, calves, shoulder girdles) •       Muscle aches, weakness, soreness, stiffness, cramping, tenderness or fatigue
Onset before station initiationOnset> 12 weeks after statin initiated	TIMING	Onset 4-6 weeks after statin initiationOnset After statin dosage increase
•       Hypothyroidism •       PMR •       Vit D Def •       Unaccustomed/heavy physical activity •       Medicines: Steroids, antipsychotics, immunosuppressant, antiviral	OTHER CONSIDERATIONS	Risk factors for SAMs •       Medicine or food interactions •       High dose statin therapy •       History of myopathy with other lipid lowering drugs •       Regular vigorous exercise •       Impaired hepatic and renal function •       Substance abuse – EtOH, opiods, Cocaine •       Female •       Low BMI
●        Not Elevated	CK levels	●        Elevated

SAMS Management

CK > 5 x upper limit of normal   OR CK elevation with muscle weakness	Stop statins for 6-8 weeks until CK in normal range	🡪 Refer urgently if rhabdomyolosis is suspected
		🡪 Symptoms improve	🡪 Resume original statin at lower dose ORSwitch to different statin
			If Symptoms reoccur 🡪 cease till SSx improve, then:
			🡪  switch to low-dose potenet statin (Rosuvastatin) ot Trial intiermittent dosing (once or twice weekly) 🡪  if SSx re occur 🡪 switch to non-statin
		🡪Symptoms continue	🡪Investigate for other causes for Muscle symptoms
CK< 5x ULN	Ceases Statin for 2-4		Then resume Statins

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Ezetimibe

• inhibits the absorption of dietary cholesterol
  • Dose of ezetimibe is 10 mg per day and there is no value in going higher
  • Ezetimibe lowers LDL by approximately 15%. 
  • Combination therapy: 10 mg daily with statin (e.g., Vytorin with simvastatin) or separately. Lowers LDL by an additional 20% compared to statin alone.
  • Side effects:
    • Some individuals develop aches and pains on the usual dose of ezetimibe (10 mg/day)
    • Reducing the dose to 10 mg once per week still produces some lowering of LDL cholesterol but without the adverse effects. 
  • Ezetimibe can further reduce LDL cholesterol in patients on maximum doses of statins. 
  • Adding ezetimibe 10 mg per day can often lead to a synergistic lowering of LDL cholesterol by an extra 20–25%. 
  • Patients who are very sensitive to statin adverse effects can be stabilised on ezetimibe, then given a mini dose of a statin, such as rosuvastatin 2.5 mg every second or third day, with significant benefit. 
  • However, there is no current evidence that ezetimibe reduces the risk of heart attack or stroke, either alone or in combination with statins.

Bile resins (cholestyramine) 

• Cholestyramine 4-8g orally up to 24g daily in divided doses (GI adverse effects leads to non adherence)
• More than 50% of patients cannot tolerate more than 4 g of cholestyramine per day
• One sachet per day is expected to lower the LDL cholesterol by around 10% and it has an additive effect with statin therapy
• Adverse effects: Gastrointestinal side effects often lead to non-adherence.

Fenofibrate

• Fenofibrate 145 g per day
• Usage: Can cause a 5-10% reduction in LDL, primarily used for lowering triglycerides.
• Use with caution when combined with statins. 
• Gemfibrozil
  • has no effect on lowering LDL cholesterol

Nicotinic acid (niacin, vitamin B3)

• Nicotinic acid 250mg oral bd with food up to 1500mg bd or 100mg tds with food 
• increase slowly – no more than 250mg every 4 days
• very rarely used – poorly tolerated (gastritis, glucose intolerance, flushing, higher urate)
• Nicotinic acid at a dose of 3 g per day lowers LDL cholesterol by about 20%, but more than 75% of patients cannot tolerate even half this dose due to severe flushing

PCSK9 Inhibitors

• Monoclonal antibodfy lipid modifying drug
• PCSK9 inhibitors are indicated for:
  • Familial Hypercholesterolemia: Both heterozygous and homozygous forms.
  • Nonfamilial Hypercholesterolemia: In patients with atherosclerotic cardiovascular disease (ASCVD) who require further LDL-C reduction.
  • Statin Intolerance: For patients unable to tolerate statins at any dose.
• Dosage and Administration
  • Alirocumab: Administered at a starting dose of 75 mg every two weeks, with potential titration to 150 mg every two weeks if needed. It can also be given at a higher dose every four weeks.
  • Evolocumab: Administered at a fixed dose of 140 mg every two weeks or 420 mg once a month.
• Recent Changes and PBS Listing
  • As of recent updates, PCSK9 inhibitors have been listed on the Pharmaceutical Benefits Scheme (PBS) in Australia, making them more accessible. General practitioners (GPs) can now prescribe evolocumab in consultation with a specialist, expanding its use beyond the previous restrictions to certain non-GP specialists. The eligibility threshold for patients has also been lowered:
  • New LDL-C Threshold: ≥1.8 mmol/L in the presence of symptomatic ASCVD, reduced from the previous threshold of >2.6 mmol/L. This applies to both familial hypercholesterolemia and nonfamilial hypercholesterolemia patients​​​​.
• Clinical Efficacy and Outcomes
  • Clinical trials such as the FOURIER and ODYSSEY OUTCOMES trials have demonstrated significant benefits of PCSK9 inhibitors:
    • Evolocumab (FOURIER trial): Showed a 59% reduction in LDL-C and a 15% reduction in the risk of major cardiovascular events.
    • Alirocumab (ODYSSEY OUTCOMES trial): Demonstrated a 62% reduction in LDL-C and significant reductions in cardiovascular events, including a 15% reduction in all-cause mortality​​​​.

Fish oils (Omega-3 Fatty Acids)

• Lowers Triglycerides (4%: 1 g/day, 10-40%: 2-4g/day)
• Unfortunately raises LDL Cholesterol 5-10%
• Marginal effect on HDL Cholesterol
• Not proven to reduce cardiovascular events

Soluble Dietary Fiber

• Lowers LDL Cholesterol 7% for 10 grams of fiber
• Sources
  • Psyllium, Barley, Beans
  • Oat bran (e.g. cheerios, oatmeal)

Red-yeast rice

• Contains natural HMG-CoA reductase agent (similar to Lovastatin)
  • Produced when rice ferments with yeast
• Currently unregulated and dose not standardized
• Not recommended until standardized dosing available
• May be an alternative for patients not tolerant to Statin medications
  • Example Monocolin K 5-10 mg daily

LDL-C Change		Adverse Effects	CONSIDERATIONS
STATINS Atorvastatin Fluvastatin Pravastatin Rosuvastatin Simvastatin	21-55%	Myalgia, mild transient GI symptoms. headache. sleep disturbance (eg, insomnia, nightmares), dizziness, elevated aminotransferase concentrations.  Rosuvastatin 40mg: proteinurea usually not associated with worsening renal function	Contraindication:Pregnancy  Simvastatin: concurrent use with some CYP3A4 inhibitors (gemfibrozil. cyclosporin or danazol) Rosuvastatin 40 mg: Asian ancestry  Precautions: severe Inter current illness (infection. metabolic disorder), myopathy with other lipid-modifying. renal and hepatic impairment.  Medicine interactions: CYP450 interact ions, cyclosporin, other medicines that cause myopathy eg, nicotinic acid, colchicine  Dosing time:pravastatin and simvastatin: slightly effective taken in the evening
Ezetimibe	18-20%	Headache, diarrhoea.	Precautions: concurrent fenofibrate use, moderate-severe hepatic impairment
Bile acid-binding resins Cholestyramine Colestipol	18-25%	Constipation, abdominal · pain, dyspepsia, flatulence. nausea, vomiting, diarrhoea, anorexia. Adverse effects are dose related, start low, gradually increase	Precautions:TG > 3 rnmol/L, complete biliary obstruction. constipation, diverticular  disease, severe haemorrhoids.Cholestyramine: PKU.  Vitamin supplementation: consider fat-soluble vitamin supplements for higher doses over extended period. Timing: can reduce effect of other medicines; take other medicines at least 1hour before or 4-6 hours after.
Fibrates Fenofibrates Gemfibrozil	5-15%	GI disturbances (eg, dyspepsia. abdominal pain), increased CK concentration (reversible). Myopathy (with concurrent statin use: fenofibrate less risk than gemfibrozil)  Gemfbrozil: headache. dry mouth. Myalgia  Fenofibrate: increased aminotransferase concentration.	Contraindications:severe renal or hepatic impairmentPrimary biliary cirrhosis. gallstones. gall bladder disease. Photosensitivity due to a fibrate Gemfbrozil: concurrent simvastatin or dasabuvir use. Fenofibrate: pancreatitis unless due to hypertriglyceridaemia.concurrent ketoprofen use.  Precautions:fenofibrate: concurrent ezetimibe orthiazolidinedione useSun exposure: avoid skin exposure (use protective clothing. sunscreen). Biochemistry:complete blood count and Liver function at baseline and during treatment: CK at baseline, repeat if clinically indicated.
Nicotinic Acid	15-18%	Vasodilation, hypotension, dyspepsia. diarrhoea, nausea, vomiting. hyperpigmentation. and face & neck flushing.	Contraindications: pregnancy: symptomatic hypotension, recent MI  Precautions: peptic ulcer disease, gout. diabetes. coronary artery disease, CrCI < 30 ml / minute. history of Jaundice or hepatic disease, treatment with antihypertensives.
PCSK inhibitors Alirocumab evolocumab	57-61%	Injection site reaction Nasopharyngitis URTI, pruritis	Precautions: allergic reactions, immunogenicity Alirocumab: severe hepatic impairment Administration: fortnightly or monthly subcutaneous injection
Fish Oil (omega 3 fatty acids)	No change	Mild GI effects	Precautions: concurrent anticoagulation use, high doses may increase bleeding time Dosage:  2-4g daily, omega -3 fatty acids lower TG