3T’s Formulary Lipid Modification Guideline
Content
Background and scope
Lifestyle Advice and Blood pressure
Primary prevention (non-diabetics)
Primary prevention (Type 2 diabetics)
Secondary prevention
Acute Coronary Syndromes
Initiating and monitoring requirements
Interactions and contra-indications to statins
Background
This guideline represents the consensus view of the 3Ts Formulary Working Group and
offers best practice advice on the care of adults at high risk of developing CVD and/or with
established CVD. The guideline does not, however, override the individual responsibility of
healthcare professionals to make decisions appropriate to the circumstances of the
individual patient, in consultation with the patient and/or guardian or carer.
The guideline addresses the modification of lipids in people with high risk of developing CVD
and those with established CVD. Treatment should be aimed at reducing overall risk. It is
important to stress that a multifactorial approach that addresses all risk factors yields most
benefit.
Scope
Patients (aged 18 years and older) with CVD or without established CVD but who are at high
risk of developing CVD due to a combination of cardiovascular risk factors including raised
blood pressure, hypertension, diabetes, and/or who are overweight or obese.
Lifestyle Advice and Blood Pressure
The following lifestyle issues should be addressed as well as consideration of statin therapy:
Smoking cessation.
Diet – reduce saturated fats, include Mediterranean diet and oily fish twice a week, aim
for body mass index (BMI) of 19 – 25kg/m2, or a minimum of a 10% reduction in body
weight.
Alcohol moderation to within safe limits (up to 21 units per week for men and 14 units per
week for women).
Exercise – aim for a total of 30 minutes of moderate intensity physical activity (eg, brisk
walking) at least 5x a week.
Blood pressure control - Treat if BP consistently over 140/90mmHg to achieve a BP of less
than 140/90mmHg; more aggressive targets apply in patients with chronic kidney disease
and diabetic patients.
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Primary prevention (non-diabetics)
All adults who have a 20% or greater 10-year risk of developing CV disease should be
considered for statin therapy, despite lifestyle intervention.
The decision to treat should follow an informed discussion with the patient about risks and
benefits, taking into account additional factors such as co-morbidities and life expectancy.
A target for total LDL cholesterol is not recommended for patients who are treated with a
statin for primary prevention.
Simvastatin 40mg ON is the 1st line statin for PRIMARY prevention.
If simvastatin 40mg ON is contraindicated or not tolerated or if there are potential
drug interactions, patients may be offered a lower dose or an alternative
preparation, such as Pravastatin 10-40mg ON.
Do NOT exceed simvastatin 20mg ON in non-diabetic patients who are also taking
amlodipine, diltiazem or verapamil.
Primary prevention (Type 2 diabetics)
All People with diabetes aged 40 years or older should usually be considered for
Simvastatin 40mg ON.
Simvastatin 40mg should be considered for people with diabetes younger than 40 years in
those patients with a high cardiovascular risk.
The decision to treat should follow an informed discussion with the patient about risks and
benefits, taking into account additional factors such as co-morbidities and life expectancy.
Consider increasing the dose of Simvastatin to 80mg ON* if the person’s total cholesterol
is not less than 4mmol/L or the LDL-cholesterol is not less than 2mmol/L after 3 months.
For type 2 diabetics with an increased albumin excretion or newly diagnosed CVD,
consider escalation of treatment to a more effective statin (e.g. Atorvastatin 40-80mg).
†
If Simvastatin 40mg ON is contraindicated or not tolerated or if there are potential
drug interactions, patients may be offered a lower dose of Simvastatin or an
alternative, such as Pravastatin 40mg ON or Atorvastatin 10mg-20mg ON.
Higher intensity statins† should not be used routinely in primary prevention except in
those patients with CVD or increased albumin excretion rate.
Do NOT prescribe simvastatin for primary prevention in diabetic patients also taking
amlodipine, diltiazem or verapamil. Switch to atorvastatin 10-20mg ON.
*
See Initiating and monitoring requirements section for details on MHRA drug safety update
on Simvastatin 80mg nocte.
†
Higher intensity statins are statins used in doses that produce greater cholesterol lowering
than Simvastatin 40 mg, for example Simvastatin 80 mg.
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Secondary prevention
Statin therapy is recommended for adults with established CV disease.
Simvastatin 40mg ON is the 1st line statin for SECONDARY prevention
If Simvastatin 40mg ON is contraindicated, not tolerated or if there are potential drug
interactions, patients may be offered an alternative, such as Pravastatin 40mg ON or
Atorvastatin 10-20mg ON or, as a last resort, Simvastatin at a dose less than 40mg ON.
Do NOT prescribe simvastatin for secondary prevention in patients also taking
amlodipine, diltiazem or verapamil. Switch to atorvastatin 10-20mg ON.
The decision to treat should follow an informed discussion with the patient about risks and
benefits, taking into account additional factors such as co-morbidities and life expectancy.
Prescribers should consider increasing to Simvastatin 80mg ON if a total cholesterol of
less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L is not attained. In high risk
patients, escalation to Atorvastatin 40mg ON should be considered where targets could
not be achieved with Simvastatin 80mg ON after checking for compliance.
For type 2 diabetics with established CVD, consider escalation of treatment to a more
effective statin (e.g. Atorvastatin 40-80mg).
If Simvastatin 80mg ON is contraindicated, not tolerated or if there are potential
drug interactions, patients may be offered a lower dose of Simvastatin (e.g. 40mg
ON) or an alternative, such as Pravastatin 40mg ON or Atorvastatin 40mg ON.
Acute Coronary Syndromes
People with acute coronary syndrome (ACS) should generally be treated with a higher
intensity statin (a statin which achieves greater lipid lowering than Simvastatin 40mg
daily).
Atorvastatin 80mg ON and Simvastatin 80mg ON are both higher intensity statins, which
are cost-effective in ACS.
There are no lipid targets specified for patients with ACS.
Although there is no guidance on how long patients with ACS should take higher-intensity
statins, patients on high dose statins should be routinely reviewed by their G.P after 3
months of treatment. The recommendations for secondary prevention should be followed
thereafter.
Simvastatin 80mg ON is the 1st line statin for ACS patients.
Atorvastatin 80mg ON may be considered for patients intolerant of or unsuitable±
for Simvastatin 80mg ON.
± Patients unsuitable for simvastatin 80mg include frail elderly patients with low BMI and
patients with impaired renal function.
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Initiating and monitoring requirements
The MHRA published a Drug Safety Update in May 2010 regarding the safety of Simvastatin
80mg. It states that “There is an increased risk of myopathy associated with high-dose (80
mg) Simvastatin. The 80-mg dose should be considered only in patients with severe
hypercholesterolaemia and high risk of cardiovascular complications who have not achieved
their treatment goals on lower doses, when the benefits are expected to outweigh the
potential risks.”
Please note that the risk of myopathy is greater in: elderly patients (>65 years); women;
patients with renal impairment or hypothyroidism; patients who consume large quantities of
alcohol; those with a history of previous muscle problems during treatment with statins or
other lipid-lowering drugs; or those with family history of muscle disorders. Concomitant use
of some medicines may also increase the risk of muscle damage.
General monitoring advice
People who are being treated with a statin should be advised to seek medical advice if
they develop muscle symptoms (pain, tenderness or weakness) If this occurs, creatine
kinase should be measured.
Base line liver enzymes should be measured before starting a statin. LFTs should be
measured within 12 months, but not again unless clinically indicated.
People who have liver enzymes (transaminases) that are raised, but are less than 3 times
the upper limit of normal should not be routinely excluded from statin therapy.
If a patient develops an unexplained peripheral neuropathy, statins should be
discontinued and specialist advice sought.
Primary prevention (non-diabetics)
Assess global cardiovascular risk is essential before starting lipid-lowering therapy
An isolated high total cholesterol without other risk factors may not indicate a need for a
statin, except in potential cases of familial hypercholesterolaemia (total cholesterol > 7.5
mmol/L and a family history of CVD) where treatment is essential
Ideally, cholesterol levels should be measured on two separate occasions and an average
of the results used to calculate CV risk.
For patients aged between 40 and 74 years: risk should be calculated using an approved
CVD risk calculator, for example, Joint British Societies or other Framingham-based CVD
risk tool or QRIsk.
Patients of 75 years or over should be considered at high risk; however the decision to
treat should take into account individual circumstances such as other risk factors, comorbidities and life expectancy.
Statin therapy should be considered for all patients where CVD risk ≥ 20% over the next 10
years.
First line choice: Simvastatin at a dose of 40mg* with the evening meal.
The dose may be reduced in the event of intolerance or an alternative statin such as
pravastatin 10-40mg may be offered.
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Secondary prevention and Primary prevention in Type 2 diabetics
Initiate a statin in all patients with a diagnosis of cardiovascular disease or other
atherosclerotic vascular disease (such as ischaemic stroke or peripheral vascular disease)
or diabetes (>40 years old) or CKD class 4 unless contraindicated.
In diabetics, initiation of a statin may be considered at an earlier age for individuals where
there are multiple cardiovascular risk factors.
First line choice: Simvastatin at a dose of 40mg with the evening meal.
Where Simvastatin 40mg is contraindicated or not tolerated, initiate a lower dose of
Simvastatin or consider an alternative statin, eg Pravastatin 40mg or Atorvastatin 10-20mg
daily.
Repeat fasting lipid levels within three months of initiation.
Reinforce lifestyle issues and check adherence to medication, as patients often will not
reach targets due to poor compliance.
Consider increasing to simvastatin 80mg daily if a total cholesterol of less than 4mmol/L or
an LDL-cholesterol of less than 2mmol/L is not attained.
Where Simvastatin 80mg is contraindicated or not tolerated, consider a lower dose of
Simvastatin (e.g. 40mg ON) or consider an alternative statin, eg Pravastatin 40mg or
Atorvastatin 40mg daily.
Any decision to increase the intensity of statin therapy should take into account informed
preference, co-morbidities, multiple drug therapy and the benefits and risks of treatment.
Also, cholesterol levels can vary by as much as 10% across the 24 hour period and this
should be taken into account when making prescribing decisions.
Patients should be reviewed annually, with lipid monitoring, to check efficacy, adverse
effects, interactions and concordance.
Acute Coronary Syndrome
Initiate a high-intensity statin in all patients following an acute coronary syndrome during
the hospital admission.
First line choice: Simvastatin at a dose of 80mg daily. The dose may be reduced in the
event of intolerance or drug interactions. (see statin interaction table for details of
potential drug interactions).
Where Simvastatin 80mg daily is considered unsuitable or not tolerated, consider initiating
Atorvastatin 80mg daily.
Repeat fasting lipid levels within three months of initiation.
High intensity statins should be reviewed at 3 months. The recommendations for
secondary prevention should be followed thereafter.
Reinforce lifestyle issues and check adherence to medication.
In patients not achieving an average total cholesterol ≤ 4mmol/L or LDL cholesterol ≤
2mmol/L on high intensity statin - consider referral for specialist advice.
Patients should be reviewed annually, with lipid monitoring, to check efficacy adverse
effects, interactions and concordance.
If statin therapy is contraindicated or not tolerated – consider referral to consultant
cardiologist.
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Interactions and contra-indications to statins
Contra-indication to statin
Solution/Action
Active liver disease or unexplained
persistent elevations of serum
transaminases.
Seek specialist advice from Consultant
Cardiologist/Gastroenterologist.
Pregnancy/lactation
Seek specialist advice from Consultant Cardiologist/ Obs &
Gynae specialist &/or Medicines Management team or
local acute trust Medicines Information department.
Consider switching to another statin &/or seek advice from
the Medicines Information department.
Hypersensitivity to the statin drug or
one of the excipients
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Interacting
drug or food
Statin Drug Interaction Table
Simvastatin
Atorvastatin
prescribing advice
prescribing advice
Rosuvastatin
prescribing
advice
No clinically
relevant
interaction.
No recorded
interaction.
Amiodarone
Increased incidence of
myopathy. Do not exceed
20mg Simvastatin daily*.
Amlodipine
Levels of Simvastatin
No clinically significant
No recorded
No recorded
significantly increased.
interaction with
interaction.
interaction.
Reduce dose to 20mg
atorvastatin reported.
daily (for primary
prevention in nondiabetics)*, or switch to
an alternative statin (for
secondary prevention or
for primary prevention in
diabetics).
Contact HIV specialist pharmacist or HIV consultant before initiating a statin for HIV positive
patients.
Levels of Simvastatin
Levels of Atorvastatin
No recorded
No clinically
dramatically reduced,
reduced (to a lesser extent interaction.
relevant
switch to an alternative
than Simvastatin).
interaction.
statin.
Increased exposure to
Increased exposure to
Increased
Contraindicated in
Simvastatin.
Atorvastatin, reduce dose exposure to
patients taking
Contraindicated with
to 10mg OD or switch to
Pravastatin, begin Ciclosporin.
Simvastatin.
an alternative statin.
with 20 mg of
Switch to an alternative
Pravastatin once
statin.
daily and titrate
to 40 mg with
caution.
Levels of Simvastatin
Levels of Atorvastatin
No interaction is
No interaction is
increased by
increased (to a lesser
expected as
expected as
Clarithromycin or
extent) by Clarithromycin
Pravastatin is not Rosuvastatin is
Erythromcyin. Concurrent or Erythromycin.
significantly
not metabolised
use of either drug with
Withdraw Atorvastatin
metabolised by
by CYP3A
Simvastatin is contraduring treatment with
CYP3A
mechanism, but
indicated. Withdraw
Clarithromycin or
mechanism, but
patient should be
Simvastatin during
Erythromycin. Do not
patient should be warned to be alert
treatment with
exceed doses of 20mg OD warned to be
for signs of
Clarithromycin.
if concurrent treatment is alert for signs of
myopathy.
unavoidable.
myopathy.
Synergistic effect with all statins since colchicine can also cause myopathy. Increased surveillance
for signs of myopathy required when combination is unavoidable.
Levels of Simvastatin
Increased exposure to
No recorded
No recorded
significantly increased.
Atorvastatin.
interaction.
interaction.
Reduce dose to 20mg
Use the lowest possible
daily (for primary
dose of atorvastatin and
prevention in nonmonitor patient.
diabetics)*, or switch to
Antiretrovirals
(proteus inhibitors.)
Carbamazepine
Ciclosporin
Clarithromycin and
Erythromycin
Colchicine
Diltiazem
Increased exposure to
Atorvastatin, use lowest
possible dose.
Pravastatin
prescribing
advice
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Danazol
Fibrates
Fusidic acid
Grape fruit juice
Imidazole and
triazole antifungals
Verapamil
Warfarin (or
coumarins)
an alternative statin (for
secondary prevention or
for primary prevention in
diabetics).
Increased exposure to
Increased exposure to
No recorded
No recorded
Simvastatin.
Atorvastatin.
interaction
interaction
Contraindicated with
Reduce dose or switch to
Simvastatin.
an alternative statin.
Switch to an alternative
statin.
Increased risk of rhabdomyolisis when fibrates are used with statins. Concurrent use of a fibrate
and a statin should only be undertaken only under specialist supervision.
Increased risk of
Increased risk of
No recorded
No recorded
rhabdomyolysis
rhabdomyolysis
interaction.
interaction.
Significantly increased
Modestly increased
No recorded
No recorded
exposure to Simvastatin,
exposure to Atorvastatin,
interaction.
interaction.
avoid grapefruit juice.
avoid large quantities of
grapefruit juice.
Significant increased
Increased exposure to
No clinically
No clinically
exposure to Simvastatin
Atorvastatin (to a lesser
relevant
relevant
when used with azole
extent) when used with
interaction.
interaction.
antifungals. Increased
azole antifungals.
surveillance for muscle
Increased surveillance for
toxicity required. Consider muscle toxicity required.
suspending Simvastatin
Consider suspending
treatment for short
Simvastatin treatment for
courses of azole
short courses of azole
antifungals
antifungals
Levels of Simvastatin
Increased exposure to
No recorded
No recorded
significantly increased.
Atorvastatin.
interaction
interaction
Reduce dose to 20mg
Use the lowest possible
daily (for primary
dose of both drugs if used
prevention in nonconcurrently.
diabetics)*, or switch to
an alternative statin (for
secondary prevention or
for primary prevention in
diabetics).
Monitor INR before
Monitor INR before
No increased
Monitor INR
starting treatment &
starting treatment &
monitoring
before starting
regularly during
regularly during treatment, required.
treatment &
treatment, especially with especially with dose
regularly during
dose changes
changes.
treatment,
especially with
dose changes
*Doses higher than 20mg in these combinations are classed as ‘off-label’ use.
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References
National Institute for Health and Clinical Excellence (NICE). Lipid modification. Cardiovascular risk
assessment: the modification of blood lipids for the primary and secondary prevention of
cardiovascular disease. Clinical Guideline 67. May2008.
http://guidance.nice.org.uk/CG67/NICEGuidance/pdf/English
National Institute for Health and Clinical Excellence (NICE). Type 2 Diabetes- newer agents (partial
update of CG66). Clinical Guideline 87. May 2009. http://guidance.nice.org.uk/CG87
National Institute for Health and Clinical Excellence (NICE). Guidance on the prevention,
identification, assessment and management of overweight and obesity in adults and children
Clinical Guideline 43, 2006
NPC patient decision aid. Statins: standard doses 2009
http://www.npci.org.uk/therapeutics/cardio/cdlipids/resources/pda_Lipids.pdf
What is the place in therapy of simvastatin 80mg/day in the light of recent MHRA guidance?
MeReC Extra No 46 August 2010
MHRA. Drug Safety Update May 2010;3(10):7–8
Lipid-modifying treatment MeReC Bulletin Volume 19 No 3 December 2008
SEARCH Study Collaborative Group. Study of the effectiveness of additional reductions in
cholesterol and homocysteine (SEARCH):Characteristics of a randomized trial among 12 064
myocardial infarction survivors. Am Heart J 2007;154:815–23
Stockley’s drug interactions http://www.medicinescomplete.com/mc/stockley/current/
Summary of Product Characteristics for the individual statins:
(http://www.medicines.org.uk/emc/)
MHRA. Drug Safety Update August 2012; 6(1):S1
UKMi North West: MHRA recommendations on simvastatin interactions: What are the
implications for patients taking amlodipine?
Approved by 3T’s Formulary Working Group: December 2012
Review Date: December 2014
Number of pages: 9
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