Statins

A therapeutic approach to prescribing statins in the general population.

1. Statins Lyndon Woytuck

2. What are we talking about? Physiology of lipids Lipid disorders Statins Indications, MOA, Side effects Other meds

3. Lipoproteins Lipoproteins are composed of varying proportions of cholesterol, TGs, and phospholipids. LDL and HDL carry most cholesterol. Chylomicrons deliver dietary TGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols . Secreted by intestinal epithelial cells. LDL Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modification of IDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis. HDL Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine. Alcohol increases synthesis. VLDL Delivers hepatic TGs to peripheral tissue. Secreted by liver. IDL Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.

4. Cholesterol synthesis Pancreatic lipase degrades dietary triglycerides (TG) in small intestine. Lipoprotein lipase (LPL) degrades TG circulating in chylomicrons and VLDLs. Found on vascular endothelial surface. Hepatic TG lipase (HL) degrades TG remaining in IDL. Hormone-sensitive lipase degrades TG stored in adipocytes. LCAT ( lecithin-cholesterol acyltransferase)—catalyzes esterification of cholesterol. 2⁄3 of plasma cholesterol is esterified CETP (Cholesterol ester transfer protein)—mediates transfer of cholesterol esters to other lipoprotein particles. Rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA to mevalonate.

5. Familial Dyslipidaemia As a GP, what is the recommended drug management for IIa homozygotes? Referral to a specialist centre

6. Question 1 A 52-year-old male who presented with acute chest pain was investigated for acute coronary syndrome. The following fasting result was obtained: Serum Cholesterol 7.1 mmol/L (<5.2) What is the most appropriate primary management for this patient? Fibrate therapy Initial dietary intervention only Omega-3 fatty acids Statin therapy Weight loss programme D. This is hypercholesterolaemia in a patient with acute coronary syndrome and the patient's initial treatment approach would be statin therapy (simvastatin, atorvastatin, rosuvastatin ). Statins have been demonstrated to reduce mortality in both primary and secondary prevention studies and the target cholesterol concentration in this man would be less than 5 mmol /L.

7. Lipid Regulation Primary prevention - Preventative measures for those with high risk of developing CVD Atherosclerotic disease, diabetes mellitus >40, familial hypercholesterolaemia , >75 (particularly smokers or those with hypertension) Those at risk of developing atherosclerotic disease: 10 year risk of ≥20% of CVD benefit most ( [lipid], smoking, BP, gender, age , premature menopause, ethnicity, obesity, [TGs], CKD, low glucose tolerance, FHx ) Secondary prevention – Prevent recurrence of events in those with established CVD Lowering [LDL] and raising [HDL] slows progression of atherosclerosis and may even induce regression What lifestyle modifications can be implemented? Diet, exercise, weight management, alcohol consumption and smoking cessation.

8. What are statins? Statins are used in the primary and secondary prevention of CVD events and reduce total mortality (irrespective of initial [cholesterol]) Statins (HMG-CoA reductase inhibitors) are the most effective drugs available for lowering LDL cholesterol, with reductions in the range of 30 to 60 percent. They also reduce levels of VLDL and increase levels of HDL.

9. Mechanism of Action Statins work by competitively and reversibly inhibiting HMG-CoA reductase, a key enzyme for the synthesis of cholesterol in the liver. After blocking this rate-limiting step, hepatocytes sense the reduced levels of intrahepatic cholesterol and attempt to compensate by synthesizing more LDL receptors on their cell surfaces. This causes increased uptake of plasma LDL, and consequently decreases plasma LDL concentration.

10. Question 2 A patient is discharged from hospital post myocardial infarction. Which combination of medication is most appropriate for the patient to be discharged on? Aspirin, beta-blocker, ACE inhibitor and statin Aspirin, beta-blocker, diuretic, statin Aspirin, calcium channel-blocker, ACE inhibitor and statin Clexane , ACE inhibitor, diuretic and GTN Clexane , beta-blocker, ACE inhibitor and statin A. NICE guidelines on  MI: secondary prevention (CG172)  state that a patient should be discharged post myocardial infarction with: Aspirin ACE inhibitor Beta-blocker A statin. These are prescribed for tertiary prevention, in conjunction with cardiac rehabilitation

11. Indications Atorvastatin (Lipitor), fluvastatin , lovastatin ( Mevacor ), pravastatin ( Pravachol ), simvastatin (Zocor), and rosuvastin (Crestor) Should be considered for all patients: the elderly, symptomatic CVD, coronary heart disease, occlusive arterial disease (PVD, ischaemic stroke, TIA) Diabetes mellitus if >40y, target organ damage, poor glycaemic control, low HDL and high TG, HTN, or FHx of CVD [total cholesterol]:[HDL] >6

12. Statins are first choice for hypercholesterolaemia and moderate hypertriglyceridaemia Severe hyperlipidaemia not controlled with a maximal dose statin may require ezetimibe or colestyramine , supervised by specialist (discussed later) What medical conditions should be balanced before and with lipid lowering treatment? Before: Hypothyroidism, should receive adequate replacement – may resolve lipid abnormality, untreated it increases risk of myositis During: Hypertension, lowering raised BP; Diabetes, appropriate glycaemic management

13. Cautions and Contra-indications Caution in history of liver disease and contra-indicated in active liver disease or persistently abnormal LFTs Liver enzymes should be measured before treatment and repeated within 3 months and at 12 months, unless signs or symptoms prompt indication Raised serum transaminases <3x upper limit should not be routinely excluded, but >3x should discontinue Advise patients to report myalgia Avoid in acute porphyria (enzyme deficiency in heme production) Contraindicated in pregnancy: must use contraception during and one month after therapy, and during breastfeeding

14. Adverse effects Statins are Cytochrome P450-3A4 substrates: 3A4 inhibitors raise levels and can increase risk of A/E ( eg with cyclosporine A, mibefradil , nefazodone ) inducers like phenytoin lower their effect Muscle toxicity – myalgia, myopathy, and myositis, which can lead to rhabdomyolysis Hepatic dysfunction resulting in persistent elevations in aminotransferases, rarely hepatitis and jaundice, and very rarely hepatic failure GI disturbance and rarely pancreatitis

15. Question 3 A 72-year-old male is discharged from hospital after having suffered an acute myocardial infarction (MI). After discharge he presents with muscle aches and pains. His LFTs show: Bilirubin 12 µ mol /L (0-18 mol /L) AST 130 U/L ( 5-45 U/L) ALT 88 U/L (5-40 U/L) ALP 105 U/L ( 50-110 U/L) GGT 100 U/L (10-70 U/L) Alcoholic cirrhosis Ascending cholangitis Autoimmune hepatitis Drug induced hepatitis Primary biliary cirrhosis Viral hepatitis D. This man has had an MI. He is highly likely to have been discharged on the typical post MI cocktail of drugs including the lipid lowering drugs - statins. The side effect of myalgias is quite common with these agents and deranged LFTs accompany. Hence the diagnosis is likely to be a drug-induced hepatitis, as the AST and ALT are the enzymes most elevated here.

16. Question 4 A 45-year-old male is admitted with a four hour history of chest pain. He is found to have an inferior myocardial infarction and receives thrombolysis. He is discharged some seven days later and amongst the drugs he has been prescribed, he is receiving simvastatin. Is it true or false that the following are typical side effects of statin therapy? Hair loss Impotence Peptic ulceration Pulmonary fibrosis Visual disturbance ALL FALSE Statins are widely used agents and extremely effective in both primary and secondary prevention of myocardial infarction and stroke. Typical side effects of statins include: Muscle aches and pains (myalgia) Headaches Nausea More rarely deranged liver function tests (hepatitis), and Myositis/rhabdomyolysis. The latter is a potentially life threatening but particularly rare complication.

17. Rhabdomyolysis Pathophysiology Associated with lipid regulating drugs, ~1 in 100 000 treatment years May be increased in renal impairment and hypothyroidism Concurrent treatment with drugs that increase plasma statin concentration increase risk of muscle toxicity (Fibrates, nicotinic acid, and immunosuppressants like ciclosporin ) Fibrate and a statin together may increase risk for severe muscle toxicity Caused by injury to skeletal muscle Involves leakage of large quantities of potentially toxic intracellular contents into plasma, with final pathway maybe involving disturbance in myocyte calcium homeostasis Post-injury, plasma myoglobin levels exceed haptoglobin protein binding and can precipitate in glomerular filtrate ( myoglobinuria ). Excess may cause renal tubular obstruction, direct nephrotoxicity (ischemia and tubular injury), intrarenal vasoconstriction, and acute kidney injury (AKI)

18. Rhabdomyolysis The classic symptomatic triad is Myalgia, Generalized weakness and Darkened urine , but many non-specific presentations Management in statin-induced rhabdomyolysis Fluid resuscitation, initiated as soon as possible Institution of measures to prevent of AKI and acute renal failure (ARF) – Urinary alkalization, mannitol, loop diuretics Correction of electrolyte, acid-base, and metabolic abnormalities Dialysis, if indicated Use of free-radical scavengers and antioxidants (clinical utility remains unclear) Discontinuance of all inciting myotoxic agents Prevention If myopathy is suspected and creatine kinase is markedly elevated >5x upper limit or muscular symptoms are severe then statin should be discontinued In patients at high risk of muscle effects, a statin should not be started if CK is elevated Patients at high risk of myopathy: personal or FHx of muscular disorders, history of muscular toxicity or liver disease and the elderly

19. Question 5 A 65-year-old female presents with a recent history of muscle aches and pains. She has a history of ischaemic heart disease for which she has recently been treated. Which of the following agents is most likely to be responsible for her presentation? ACE inhibitors Aspirin Beta-blockers Nitrates Statins E. Statins are lipid lowering therapies which have been demonstrated to reduce cardiovascular risk substantially. However, a common side effect of this treatment is myalgia. This can be exacerbated by certain agents such as macrolides, fibrates and hypothyroidism. A rarer but potentially lethal side effect is rhabdomyolysis where there is severe muscle infiltration and destruction that can cause renal failure.

20. Question 6 A 55-year-old man presents with a recent history of muscle aches and pains for 2 weeks, mainly affecting his thighs and which is particularly bad when he climbs stairs. He has type 2 diabetes and high blood pressure. He started simvastatin 40mg PO once at night a month ago. He has 5/5 power in both legs. Which is the single most appropriate investigation? Creatine kinase Urea and electrolytes ESR LDH A. When starting a statin, patients should be made aware of the risks of developing a myopathy and advised to report any muscle weakness or pain as soon as it develops. In this event, it is important to measure the CK promptly. If it is more than 5 times the upper limit or if myopathy is suspected on clinical grounds (as in this case), then treatment should be discontinued. If symptoms resolve and levels of CK return to normal, then the statin could be tentatively reintroduced, or an alternative could be considered.

21. Example of a drug KD is a 32 year old female, found to have a high lipid profile two years ago on a regular check. She has a family history of hyperlipidaemia and she has tried adjusting her diet and going to the gym on a regular basis since finding out about her health. She has recently had genetic testing for familial hypercholesterolaemia and was found to be heterozygous. What management would you recommend at this point? STATIN therapy for primary prevention of cardiovascular event

22. Example of a drug KD is prescribed Atorvastatin at 10mg daily, to increase in 4 weeks to 40mg once daily with re-evaluation to consider further increase (up to maximum 80mg od). (10mg is the usual preventive dose used in primary hypercholesterolaemia or combined hyperlipidaemia.) What should you be cautious about when starting atorvastatin? What should you warn KD about when starting statin therapy? Be aware of comorbid hypothyroidism, unbalanced diabetes, or hypertension. Liver enzymes should be measured before treatment and repeated within 3 months and at 12 months, unless signs or symptoms prompt indication. Adequate contraception must be used during therapy, and one month after. Contraindicated while breastfeeding. Advise patients to notify you of myalgia or weakness and screen for history of muscular disorders.

23. Other atherosclerosis modifying meds Bile acid binding resins prevent reabsorption of bile: Cholestyramine Colestipol Nicotinic acid is also an option for secondary prevention. It inhibits mobilization or peripheral FFAs flushing. May also be used to further lower TG or LDL concentration: Niacin Vitamin B3 Fibrates enhance oxidation of FFAs. Potentiates warfarin A. Added to statin therapy if TGs are high after the [LDL] has been reduced adequately: Gemfibrozil Clofibrate Fenofibrate If statins are contra-indicated or not tolerated, a fibrate or bile acid sequestrant may be considered for primary or secondary prevention Fibrates and Niacin can also cause myopathy These drugs should NOT be used in combination with statins for primary prevention of CVD – increased risk of side effects including rhabdomyolysis Gemfibrozil should NOT be used with a statin (rhabdomyolysis) Consider dose adjustments if total [cholesterol] <4mmol/L or LDL <2mmol/L is not achieved with initial treatment

24. Question 7 A 44-year-old patient with familial hypercholesterolaemia is being treated with high dose nicotinic acid, a derivative of vitamin B3 (niacin). What are the main side effects expected with this treatment? Anxiety Diarrhoea Flushing Muscle aches Skin rash on neck C. Nicotinic acid can increase HDLc and reduce LDlc . Co-administration of another medication ( laropiprant ) may improve flushing S/E. Anxiety, diarrhoea and skin rashes on sun exposed sites are all features of niacin deficiency (pellagra). Niacin and its derivatives work as cofactor in cellular reactions, including the metabolism of fatty acids and steroid hormones. Niacin is an important antioxidant protecting the liver against free radical damage. Niacin is required for synthesis of the histone proteins which are bound to DNA and facilitate DNA storage, replication and repair. Niacin may have a role in the regulation of blood sugar concentrations, although this is poorly understood.

25. Example of a drug KD is found at 3 months to have markedly elevated liver function tests and her physician thinks it is prudent to modify therapy in order to avoid drug induced liver complications. What management is indicated for KD? Rule out any secondary causes of myopathy or liver toxicity (physical activity, hypothyroidism, drug interactions, related diseases). Secondly, it is important to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge . If symptoms do not resolve, it is advisable to restart with the same statin at a lower dosage or to switch to another statin. The selection of the new statins should favor molecules metabolized via different pathways.

26. Example of a drug KD discontinues atorvastatin for 4 weeks with resolution of liver enzyme elevations, but then is changed to rosuvastatin therapy. Again, after 3 months, she has elevated liver transaminases. What pharmacotherapy could be used for KD? Unconventional dosing (every-other-day or weekly administration) of statins with longer half-lives; although it has not been established that the cardiac risk reduction would be the same. Non-statin lipid-lowering drugs (ezetimibe, bile acids sequestrants , and fibrates) alone or in combination in statin-intolerant patients must be limited to selected patients after careful consideration of individual global cardiovascular and lipid targets. In low-risk individuals the use of herbal supplements effective in reducing LDL-C can be considered.

27. Example of a drug For those who cannot tolerate statin therapy, you can discontinue atorvastatin and start fibrate therapy. Fibrates are first line therapy only in those whose serum TG >10mmol/L. KD is prescribed gemfibrozil 1.2g daily in 2 divided doses. Gemfibrozil is indicated in hyperlipidaemias of type IIa , IIb , III, IV, and V and for primary prevention in men with hyperlipidaemia who have not responded adequately to diet and other measures

28. Red yeast rice RYR is made from yeast ( Monascuspurpureus ) grown on rice. It is a dietary staple in some Asian countries. Processed red yeast rice supplements include red yeast rice extract (RYRE), which is any extract of red yeast rice, and Xuezhikang , an alcohol extract of red yeast rice. RYR contains several compounds known as monacolins, which block the production of cholesterol. One of these, monacolin K, has the same structure as the drugs lovastatin and mevinolin . Studies suggest that RYR use may lead to a 10-33% reduction in LDL cholesterol. This is a moderate effect, compared to the statins. Information on the long-term safety of RYR is limited at this time.

29. Curcumin ( polyphenolic molecule that can be extracted from turmeric ) The effect of curcumin on lipid level in patients with acute coronary syndrome. Alwi I 1 ,  Santoso T ,  Suyono S ,  Sutrisna B ,  Suyatna FD ,  Kresno SB ,  Ernie S . The effects of curcumin on total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride in acute coronary syndrome patients. interventional multi- centre randomized double blind controlled trial to evaluate the effects of curcumin administration at escalating doses (low dose 3 times 15 mg/day, moderate dose 3 times 30 mg/day, and high dose 3 times 60 mg/day) on total cholesterol level, LDL cholesterol level, HDL cholesterol level, and triglyceride level in ACS patients. The effects of curcumin on total cholesterol level and LDL cholesterol level for the 75 ACS patients participating in that RCT, there was a trend that the lower the dose of curcumin, the higher the effect of reduction. For HDL cholesterol level, there was also a trend that the lower the dose of curcumin, the higher the effect of increase in HDL cholesterol level. However, for triglyceride the pattern was not the same, and the group of moderate-dose curcumin shoed the minimal effect of increase, followed by the low-dose curcumin and finally the high-dose curcumin that showed the highest effect of increase. the administration of low-dose curcumin showed a trend of reduction in total cholesterol level and LDL cholesterol level in ACS patients.

30. References BMJ OnExamination http://my.onexamination.com/ BNF 57 March 2009 Oxford Assess and Progress, Clinical Medicine FIRST AID FOR THE USMLE STEP 1 2014 TAO LE, VIKAS BHUSHAN, et al. https://medcomic.com/blog/statins/ http://www.anaesthetist.com/physiol/basics/metabol/cyp/Findex.htm http://emedicine.medscape.com/article/1007814-overview http://www.mayoclinic.org/drugs-supplements/red-yeast-rice/background/hrb-20059910 Acta Med Indones .  2008 Oct;40(4):201-10. http://www.ncbi.nlm.nih.gov/pubmed/19151449 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138147/