Statins (patient information)

# Overview
Statins are a class of drug that by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase have revolutionised the treatment of hypercholesteraemia and secondary pathologies such as ischaemic heart disease ,. They are used in primary prevention in those with various hyperlipidaemias and secondary prevention of ischaemic heart disease and ischaemic stroke.

# History
Two Japanese scientists commenced research into inhibitors of HMG-CoA reductase in 1971 reasoning that organisms might produce such products as the enzyme is important in some essential cell wall components. This work lead to the identification of the first clinically useful compound lovastatin(mevinolin)  from a mould in the mid 1970's. This agent was first used in the more severe forms of hypercholesteraemia in the 1980s followed by landmark trials  with simvastatin that showed the potential for cardio-prevention. Cerivastatin was withdrawn in 2001 because of a ten times higher incidence of rhabdomyolysis than the other statins.

# Drugs
- atorvastatin
- fluvastatin
- pravastatin
- rosuvastatin
- simvastatin

# Indications
See current NICE guidelines.
- Primary prevention: dyslipidaemia
- Secondary prevention of ischaemic cardiac events
- Peripheral Vascular Disease

## Undefined Indications
- Secondary prevention of nonfatal ischaemic events with high dose statins (atrovastatin)
Statins in older people
Bandolier give the following statement in their document  - "Statins are effective in older people, and just as effective as in people aged under 65 or 70 years.".  Also, the NLH Q&A Service has answered a number of similar questions . This is suggestive evidence as the definitive clinical trials in primary intervention in the elderly have most certainly not been done and there is little evidence for benefit in women.
- Preventing fractures
- Alzheimers disease (But see below - clinical differences)
- Macular degeneration

# Clinical Differences
Much clinical use of statins reflects marketting rather than the practice of evidenced based medicine. In Quebec by 2003 Atorvastatin had 44% of the market share while simvastatin had  29.9%. In contrast up to the previous year simvastatin had 133,341 of RCT patient-years of follow-up compared to 1457 for atorvastatin .
Rosuvastatin is the most potent inhibitor of HMG-CoA reductase on the UK market. The best evidence base in primary and secondary prevention relates to simvastatin and atorvastatin and as can be seen by the potency chart simvastatin 40mg has similar potency to atorvastatin 10-20mg in lowering LDL cholestrol from a meta-analysis of randomised controlled trials done by Law et al.. Fluvastatin and pravastatin have lower potency. Pravastatin (a natural product) has less potential for interactions with other drugs.Interestingly the relative difference in potency is less in long term studies (greater than 12 weeks) and perhaps this explains the epidemiological observation that mortality and morbidity benefit is not as clearly drug dependant as is the reduction in cholesterol predicted from short term studies.
Although it is too soon to assume that all the benefits of statins 
are due to their actions on cholesterol metabolism alone and on atheroma, the pooled studies have shown on meta-analysis  
, that the reduction in major vascular events is proportional to the reduction in LDL cholesterol levels at 1  year. In contrast population studies of secondary prevention in those over 65 years and long term follow up of RCTs have shown no evidence suggesting better outcome with one statin over another so the issue of which statin is best in the major populations at risk remains unclear.
Recent clinical trials have shown that high dose atorvastatin (80mg) has benefit with selected outcomes after certain acute ischaemic event presentations but the overall marginal benefits against the higher expected toxicity of this dose are unclear as the patient populations in the clinical trials are unrepresentative of usual British populations considered for secondary prevention. Analysis of the raw data from high dose statin trials in acute coronary syndrome has suggested benefit relative to standard statins is restricted to American, and absent in European participants offered aggressive early intervention strategies. High dose atorvastatin after stroke or TIA reduces the incidence of strokes and of cardiovascular events but at 5 year follow up has no mortality benefit and a higher incidence of non fatal haemorrhagic stroke. In patients over 65  years enrolled in the TNT trial while primary events in those on 80mg compared to 10mg atorvastatin were reduced absolutely by 2.3%:
- There was a non significant 0.6% increase in death at the higher dose due to non-cardiovascular mortality
- Treatment-related adverse events were 8.3% on 80mg atrovastatin and 5.2% on 10mg atrovastatin.
There is evidence that simvastatin but not atorvastatin or lovastatin is associated with a reduced incidence of dementia and Parkinson's disease.

## Switching Statins
The only fair clinical trial evidence exists for simvatsatin and low dose atorvastatin. There was no peer reviewed evidence for harm for this swap  although a study from the UK GP database as reported in a press release from the manufacturer of atorvastatin raises concerns. For maximium objective effectiveness you might want to give simvastatin at night. Although fluvastatin has a good safety profile and clinical evidence base, the transfer from another statin to fluvastatin might best be done only when strong clinical indications exist. This recommendation is based on a higher incidence of significant cardiovascular presentations when use of fluvastatin was encouraged by pricing mechanisms in New Zealand, possibly because non equivalent doses were substituted .

# Toxicity
The safety profile for currently marketed statins is well characterised and very similar in terms of events reported to adverse reaction databases. There is some randomised controlled trial data on meta-analysis suggesting differential toxicity. On this evidence atorvastatin may more commonly produce any adverse effects perhaps because of the number of recent trials using very high dose (80mg) which is associated with diarrhoea, abdominal pain, or nausea compared to lower doses of the drug or say 80mg simvastatin. Fluvastatin is lowest in producing any adverse effect. Statin therapy increased the risk of adverse effects by 39% (OR = 1.4; 95% CI, 1.09-1.80) with number needed to harm of 197) compared with placebo. Thus treating 1000 patients with a statin would prevent 37 cardiovascular events, and 5 adverse events would be observed.
All statins are contraindicated in pregnancy and breastfeeding. There are isolated reports of congenital abnormalities in the babies of women who took statins during early pregnancy.
There is very little real evidence for a number of popular concerns in terms of absolute risk including:
- Lens opacities
- Sleep disturbance
- Mood disorders
- Dementia
- Cancer (the association may be with excess LDL cholesterol reduction)
- Peripheral neuropathy eg relative risk of 37 (95% CI 1876), absolute risk 01%.

## Monitoring
PRODIGY suggestions are::
- Before starting treatment a baseline lipid profile should be established (TC, LDL-C, HDL-C and TG).
- Baseline tests for creatine kinase (CK), AST or ALT, creatinine (if also using a fibrate).  Thyroid stimulating hormone (TSH) are also recommended to exclude hypothyroidism as a secondary cause.
- 8-12 weeks after the start of treatment OR an increase in dose check lipid levels (non-fasting TC and HDL-C) and liver function tests (AST or ALT).  These same tests are required at an annual test.  NOTE. If LDL-C or TG levels are needed a fasting sample must be used.
If muscle symptoms suspected check CK levels.

## Myopathy
Statins are very safe drugs.  However there is a risk of myopathy (which does not always show the expected characteristic rise in creatine kinase.  Myopathy sometimes, rarely, includes severe rhabdomyolysis (incidence less than 5/100,000 patient years with current statins and lower at typical secondary prevention doses in clinical use)  .

### Factors aggravating toxicitiy
There is a correlation with dose.  All the present statins have an acceptible profile but it is important, particularly at the higher ends of the dosage range of each statin to give full consideration of this issue. All agents are more likely to be toxic in those with renal impairment and possibly hypothyroidism.  Active liver disease is a contra-indication as are porphyria and pregnancy.
Combination of a statin with a fibrate is regarded as significantly more likely to produce muscle damage, although both classes of drug are known to produce this side effect on their own. Gemfibrozil in particular should not be used in combination with a statin. Nicotinic acid at therapeutic doses used to treat hypercholesteraemia has also been associated with this problem when given with a statin. Both simvastatin and atrovastatin have the potential for increased plasma levels when given with certain cytochrome modifying drugs such as clarithromycin.
Such interactions are most likely to be significant at the higher end of each drug's dosage range and in those with particular phenotypes.  The role of statins in modulating the response to infection is unclear and advice has been given that simvastatin should be withheld during course of certain anti-microbial agents.

## Other Side Effects
Headache, altered liver function tests, paraesthesia (a burning neuropathy seems characteristic), abdominal pain, flatulence, non-specific changes in bowel habit, nausea and vomiting are known. Rash and allergic reactions are rare. There is presently no evidence that prophylactic use of coenzyme Q10 is useful. Indeed the coenzyme Q10 issue (it is most certainly depleted with chronic statin therapy) is a rea
son why the outcomes of statin trials must be evaluated in terms of total mortality and morbidity over long periods of time, as they have been, rather than using short term cardiovascular and lipid surrogates.
Analysis shows that with atorvastatin, fatal stroke is increased in diabetics with advanced renal failure needing haemodialysis and there is no net gain from using the drug . Such associations are not completely implausible and clinicians would be wise to be aware of them.

# Pharmacology
There is a strong suspicion that statins may do more than inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Indeed they may
- act as anti-inflammatory agents
- prevent in vivo oxidation
- modulate cellular immunity
- modulate endothelial action
- increase nitric oxide bioavailability
These effects might be modulated by interference with isoprenoid synthesis or specific actions of some statins to block cell adhesion receptors. Currently much interest is in the epidemiological correlation of about a 15% reduction in severe sepsis and mortality from infection .

## Statin Withdrawal
An increased frequency of cardiac events in those undergoing coronary bypass surgery has been associated with peri-operative statin withdrawal .