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?
A. Fibrate therapy
B. Initial dietary intervention only
C. Omega-3 fatty acids
D. Statin therapy
E. 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?
A. Aspirin, beta-blocker, ACE inhibitor and statin
B. Aspirin, beta-blocker, diuretic, statin
C. Aspirin, calcium channel-blocker, ACE inhibitor and statin
D. Clexane, ACE inhibitor, diuretic and GTN
E. Clexane, beta-blocker, ACE inhibitor and statinA. 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 µmol/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)
A. Alcoholic cirrhosis
B. Ascending cholangitis
C. Autoimmune hepatitis
D. Drug induced hepatitis
E. Primary biliary cirrhosis
F. 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?
A. Hair loss
B. Impotence
C. Peptic ulceration
D. Pulmonary fibrosis
E. 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?
A. ACE inhibitors
B. Aspirin
C. Beta-blockers
D. Nitrates
E. 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?
A. Creatine kinase
B. Urea and electrolytes
C. ESR
D. 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

26. 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?
A. Anxiety
B. Diarrhoea
C. Flushing
D. Muscle aches
E. 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.

27. 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?
1. Rule out any secondary causes of myopathy or liver
toxicity (physical activity, hypothyroidism, drug
interactions, related diseases).
2. Secondly, it is important to determine whether the
adverse effects are indeed related to statin therapy
by statin dechallenge and rechallenge.
3. 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.

28. 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.

29. 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

30. 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.

31. CURCUMIN (POLYPHENOLIC MOLECULE
THAT CAN BE EXTRACTED FROM TURMERIC)
THE EFFECT OF CURCUMIN ON LIPID LEVEL IN PATIENTS WITH ACUTE CORONARY SYNDROME.
ALWI I1, 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.

32. REFERENCES
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 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
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