Anti-Lipids
STATINS
Most Potent Oral Lipid-Modifying Agents
First-Line Therapy for elevated LDL-C (low-density lipoprotein cholesterol).
Lipid Reduction: Lowers LDL-C and triglycerides.
Non-lipid Benefits: Antiplatelet properties.
Potency of Statins:
- More Potent: Atorvastatin, Rosuvastatin, Simvastatin.
- Less Potent: Fluvastatin, Pravastatin.
Effectiveness:
- Rosuvastatin and Atorvastatin are the most potent statins.
- Lowering LDL by 30-40% reduces cardiovascular events by 25-30%.
Administration Timing:
- Cholesterol synthesis mainly occurs at night.
- Short-acting statins (e.g., Lovastatin, standard-release Fluvastatin, Pravastatin, Simvastatin) should be taken in the evening or at bedtime.
- Long-acting statins (e.g., Atorvastatin, extended-release Fluvastatin, Rosuvastatin) can be taken any time, based on patient preference.
Factors to Consider When Choosing a Statin:
- LDL-C-lowering potency.
- Potential Drug Interactions: Assess current medications to avoid adverse effects.
- Renal and Liver Function: Adjust doses based on organ function.
- Ethnicity: Patients of Asian descent may need lower doses of rosuvastatin.
Baseline Tests Before Statin Therapy:
- Baseline blood glucose levels (BGL).
- Liver and muscle biochemistry (ALT, CK).
Avoiding Drug Interactions:
- Statins metabolized by the CYP P450 system may interact with other drugs, altering their concentration and increasing the risk of side effects.
- Atorvastatin and Simvastatin: Metabolized mainly by CYP3A4. Concentration increased by inhibitors (e.g., azole antifungals, certain calcium channel blockers, macrolide antibacterials, grapefruit juice) and decreased by inducers (e.g., rifampicin, St. John’s wort).
- Fluvastatin: Metabolized by CYP2C9, with interactions similar to those for CYP3A4.
- Pravastatin and Rosuvastatin: Not significantly metabolized by CYP enzymes.
| 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 | ||
Common Adverse Effects:
- Generally well-tolerated.
- Frequent side effects: Myalgia, gastrointestinal symptoms, headache, insomnia, dizziness.
- These are more common with higher doses and may resolve with dose adjustment or switching statins.
Memory Concerns:
- No strong evidence suggests that statins affect memory, cognition, or dementia risk.
Statin-Associated Muscle Symptoms (SAMS):
- Nocebo effect: Patients may experience muscle symptoms due to expectations of harm.
- Many patients tolerate a lower dose or switch to a different statin. Up to 90% can continue treatment without problems.
- Myopathy incidence: 1 in 10,000.
| 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 | |
Additional Therapies:
Ezetimibe:
- Inhibits absorption of dietary cholesterol.
- Standard dose: 10 mg per day (no benefit in increasing the dose).
- Lowers LDL cholesterol by approximately 15%.
- Combination Therapy:
- Used with statins (e.g., simvastatin) for an additional 20% LDL reduction.
- Side Effects:
- Some patients experience muscle aches on 10 mg/day; reducing the dose to once a week may alleviate symptoms while still providing LDL reduction.
- Uses:
- Can be added to statin therapy for further LDL lowering.
- Beneficial for patients sensitive to statin side effects; statin doses can be minimized with ezetimibe.
- No current evidence that ezetimibe alone or in combination reduces heart attack or stroke risk.
Bile Acid Resins (Cholestyramine):
- Dose: 4-8 g orally, up to 24 g daily in divided doses.
- More than 50% of patients cannot tolerate more than 4 g/day due to gastrointestinal side effects.
- Lowers LDL cholesterol by about 10% per sachet.
- Often used in combination with statins.
- Side Effects: Gastrointestinal symptoms leading to poor adherence.
Fenofibrate:
- Standard dose: 145 mg per day.
- Primarily lowers triglycerides, with a 5-10% reduction in LDL cholesterol.
- Use with caution when combined with statins due to increased risk of side effects.
Gemfibrozil:
- No significant effect on LDL cholesterol.
Nicotinic Acid (Niacin, Vitamin B3):
- Dose: Start at 250 mg twice daily with food, increase slowly up to 1500 mg twice daily.
- Often poorly tolerated due to side effects (gastritis, glucose intolerance, flushing, high uric acid levels).
- At 3 g/day, lowers LDL cholesterol by about 20%, but most patients cannot tolerate even half this dose due to flushing.
PCSK9 Inhibitors:
- Indications:
- Familial hypercholesterolemia (heterozygous and homozygous).
- Nonfamilial hypercholesterolemia with ASCVD requiring further LDL reduction.
- Statin intolerance.
- Dosage:
- Alirocumab: 75 mg every 2 weeks, up to 150 mg if needed, or 300 mg every 4 weeks.
- Evolocumab: 140 mg every 2 weeks or 420 mg once a month.
- PBS Eligibility:
- Familial hypercholesterolemia (both heterozygous and homozygous forms).
- Non-familial 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.
- LDL-C Threshold:
- LDL-C ≥ 1.8 mmol/L: In the presence of symptomatic ASCVD, the threshold has been lowered from the previous >2.6 mmol/L.
- This applies to both familial and nonfamilial hypercholesterolemia patients.
- PBS Listing:
- GPs can prescribe PCSK9 inhibitors (evolocumab and alirocumab) in consultation with a specialist.This has expanded the availability of these drugs, previously limited to non-GP specialists.
- Clinical Efficacy:
- Evolocumab (FOURIER trial): 59% LDL-C reduction, 15% reduction in cardiovascular events.
- Alirocumab (ODYSSEY OUTCOMES trial): 62% LDL-C reduction, 15% reduction in all-cause mortality.
Fish Oils (Omega-3 Fatty Acids):
- Lowers triglycerides by 4% at 1 g/day, 10-40% at 2-4 g/day.
- May increase LDL cholesterol by 5-10%.
- Minimal effect on HDL cholesterol.
- No proven reduction in cardiovascular events.
Soluble Dietary Fiber:
- Lowers LDL cholesterol by 7% for every 10 grams of fiber consumed.
- Sources include psyllium, barley, beans, and oat bran (e.g., oatmeal, Cheerios).
Red Yeast Rice:
- Contains natural HMG-CoA reductase inhibitors, similar to lovastatin.
- Produced from rice fermented with yeast.
- Not recommended due to lack of regulation and standardized dosing.
- Potential alternative for statin-intolerant patients if standardized dosing becomes available.
| 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 |