Side effect of Statin

Introduction

 Hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA)

inhibitors (commonly known as statins) have been one of the most
widely prescribed groups of drugs in the world since their
introduction to the market more than twenty years ago.
 Currently, there are six statin drugs available on the market:
pitavastatin, atorvastatin, rosuvastatin, pravastatin, simvastatin and
fluvastatin.
 Statins inhibit HMG-CoA, which is a rate limiting step in cholesterol
biosynthesis.
 Statin therapy has been shown to be effective in lowering low
density lipoprotein cholesterol (LDL-C) levels 20-50%, as well as
lowering triglyceride levels 10-20% and causing a possible rise in
serum high density lipoprotein cholesterol (HDL- C) levels (5-10%).
 Recently, concern has been expressed regarding the over-
prescription of statin drugs as well as the potential for
severe adverse effects from statin therapy.
 This has resulted in several a patients ceasing statin
therapy amid questions about the potential risk of long-
term statin use.
 The aim of this article is to the review the current literature
regarding the overall safety of statin therapy
 Musculosceletal

 Nearly all of the statin drugs are associated with

musculoskeletal side effects.
 Myalgia is the most common symptom, and myositis is less
common and associated with a rise in creatine kinase (CK).
 Rhabdomyolysis is the most severe musculoskeletal form
observed, with a rise in CK greater than 10x the upper limit
of normal with associated features including
myoglobinuria, renal impairment and serum electrolyte
abnormalities
 SAMS are typically characterised by muscle pain, weakness and
aches, usually symmetrical and proximal, generally affecting large
muscle groups including the thighs, buttocks, calves and back
muscles.
 While these tend to occur early (within 4-6 weeks after starting a
statin), SAMS have been reported after many years of treatment.
 Symptoms may occur with an increase in statin dose or initiation of
an interacting drug, and are often more common in physically active
individuals.
 SAMS often appear more promptly when patients are re-challenged
with the same statin.
 In most patients, SAMS are not accompanied by marked CK
elevation
 Risk factor for Statin-associated muscle symptoms (SAMS)
 patient factors: very elderly (>80 years), female, low body mass index, Asian
descent
 Other predisposing factors: History of CK elevation or unexplained muscle/
joint/tendon pain, inflammatory or inherited metabolic, neuromuscular/ muscle
defects, previous statin-induced myotoxicity, myopathy on other lipid-lowering
therapy
 Diet/lifestyle: excessive physical activity, overconsumption of grapefruit or
cranberry juice, alcohol or drug abuse
 Concurrent conditions: acute infection, impaired renal or hepatic function,
diabetes, HIV (both the condition and HIV medications such as protease
inhibitors), vitamin D deficiency, organ transplant recipients, severe trauma, biliary
tree obstruction
 Surgery with high metabolic demands
 Genetic factors
 Based on currently available evidence, it is reasonable for patients with mild
musculoskeletal complaints or established mild rises in CK to continue with
statin therapy at lower dosing regimens, with close clinical monitoring.
 Patients with serious adverse effects such as rhabdomyolysis should not
continue with statin therapy, and monotherapy with ezetimibe could be
considered.
 For the spectrum of patients whose circumstances fall in between these
two categories, we would suggest careful clinical assessment to exclude
other causes of myalgia.
 Treatment decisions need to be based on the cardiovascular risk of each
patient. If cardiovascular risk is high then we would suggest rechallenging
with another statin such as atorvatstatin or rosuvastatin with a modified
dosing regimen (such as twice weekly) with close clinical observation.
 Hepatic Dysfunction

 Statin therapy has been associated with elevated

hepatic transaminases in up to 1-3% of patients.
 This usually is dose dependent and occurs within the
first three months of commencing therapy, and is not
usually associated with any long-term hepatic
dysfunction.
 There also appears to be no significant differences
amongst the different statin drugs with regards to
rates of hepatotoxicity.
 The clinical significance of this “transaminitis” is uncertain, with
the vast majority of patients being asymptomatic.
 Cases of hepatic failure due to statin use have otherwise been
exceedingly rare, with case reports providing the primary bulk of
evidence.
 Although it is useful to assess baseline liver function, routine
monitoring of liver function tests is not recommended.
 Patients with mild derangement of LFT’s use can safely continue
statin therapy with close monitoring.
 Statins should not be prescribed, however, in patients with
active hepatitis B virus infection until serum levels of AST, ALT,
GGT, total bilirubin, and ALP have normalized.
 Diabetes Mellitus

 Concordant evidence from RCTs and genetic studies indicate

that statin treatment is associated with a modest increase in the
risk of new-onset DM of approximately one case per 1000
patients per year of exposure but also prevents five new CVD
events.
 In most studies diagnosis of ‘DM’ was based on a laboratory
finding of an HbA1c >6.5 without symptoms; the relevance of
this HbA1c based conversion to diabetes for long-term morbidity
and mortality will require long-term follow-up.
 People with features of the metabolic syndrome or prediabetes
are at significantly greater risk of this adverse effect, although
conversion to DM without statin is also higher.
 Statins have been shown to increase the risk of diabetes
mellitus in that they can disrupt insulin signalling pathways,
affect pancreatic beta cell function and may contribute to
increased insulin resistance.
 Statin therapy is known to be associated with a small
increment in fasting blood glucose levels. Mechanistically,
statins could increase blood glucose by increasing insulin
resistance, possibly mediated by changes in circulating free
fatty acids, impairing beta cell function, or alternative
mechanisms, or a combination of these.
 There is evidence to suggest that some statins are potentially diabetogenic,
and the risk appears to be dose-related.
 However, diabetic patients are one of the groups that benefits most from
statin therapy with regards to cardiovascular risk.
 There is no convincing evidence indicating that statin therapy in diabetics
may contribute to worsening glycaemic control.
 Overall, the cardiovascular protective benefits of statins outweigh the
concerns associated with risk of diabetes mellitus.
 It is important that patients are informed of this risk prior to commencing
therapy and routine monitoring of blood glucose levels is recommended.
 Patients should be reassured that the benefits of statins in preventing CVD
events far outweigh the potential risk from elevation in plasma glucose,
especially in individuals with increased HbA1c.
 Renal

 Statins can influence the kidney in two main pathways.

Rhabdomyolysis can induce tubular obstruction causing
tubular injury and ischaemia. Statin therapy can be
associated with a benign proteinuria due to inhibition of
the tubular reabsorption of small molecular weight
proteins.
 The clinical significance of this mild proteinuria is unknown,
as the protein differs from that of other glomerular
diseases.
 There has been no evidence of long-term renal dysfunction
from statin therapy.
 Overall, statins are well-tolerated in patients with CKD with
no significant increase in adverse events.
 The UK-HARP-1 study which investigated the safety of
statin use in the CKD population found no significant
increase in CK levels or LFT derangement.
 Other large trials investigating statin use in this population
have also reported similar findings. It is worth noting that
combination therapy with ezetimibe was associated with
higher rates of myalgia in the SHARP study.
 We would suggest continued statin therapy in patients with CKD
with clinical monitoring for adverse effects similar to non-CKD
patients.
 We would avoid the use of high dose statin therapy or
combination therapy with fibrates or ezetimibe unless patients
have increased cardiovascular risk, or have not achieved
adequate LDL level reduction.
 In the dialysis population we would not suggest commencing
statin therapy in patients with mildly elevated LDL levels.
 Statin therapy should be considered in patients following acute
coronary syndrome or in patients with high cardiovascular risk,
although vigilance is required to monitor for adverse effects.
 Conclusion:
 Statin treatment is not associated with clinically
significant deterioration of renal function.
 Dose reduction based on estimated glomerular filtration
rate may be prudent in patients with severe kidney
dysfunction who are receiving intensive statin regimens
 A protective effect of statins on the kidney cannot be
excluded but further study is merited.
 Malignancy

 The role of statins in malignancy is somewhat clouded by an array of mixed evidence

suggesting both a protective role as well as being a potential risk factor.
 Animal studies have shown the link between high dose statin therapy and liver
tumours in rodent models. However a recent clinical trial showed a reduction in liver
cancers with statin use. Both the Cochrane Re- view of statin therapy in primary
prevention and the Cholesterol Treatment Trialists’ meta analyses have not shown any
increase in cancer risk with statin therapy.
 The Heart Protection study and the West Scotland Coro- nary Prevention Study
(WOSCOPS), which have extended follow-up periods of more than 10 years, have also
not shown any difference in the rates of malignancy with long-term statin therapy. A
recent meta-analysis suggested that long-term statin use reduced the risk of some
haematological malignancies.
 Statin use was associated with a reduction in malignancy risk in post- menopausal
women in the Women’s Health Initiative.
 The sources of evidence will continue to improve once long-term follow-up data of the
early statin trials are published.
 However, it is reassuring that long-term statin therapy appears to be safe for the
majority of patients.
 Neurological

 There have been case reports of statin use associated with peripheral
neuropathy, mood symptoms and irritability.
 Despite some early reports of an increase in haemorrhagic stroke with statin
use, this has not been substantiated in larger clinical trials and the
protective aspects from recurrent ischaemic stroke outweigh these
potential risks.
 There has been some concern regarding cognitive dysfunction in patients on
long-term statin therapy.
 Interestingly, statins have also been shown in some retrospective studies to
reduce the risk of Alzheimer’s disease.
 The mechanisms that may be involved include the interaction with
cholesterol and amyloid processing, as well as the indirect effect via stroke
prevention.
 A recent systematic review did not find any overall increased risk of
dementia with long-term statin use
 Respiratory

 There have been case reports of interstitial lung dis- ease

associated with statin use.
 The mechanism for cellular injury is not well understood,
and patients have usually responded to corticosteroid or
immunosuppressive therapy.
 A recent cohort study did not demonstrate any increased
risk of interstitial lung disease with statin use.
 Statins can safely be prescribed in patients with chronic
respiratory diseases, and routine monitoring of lung
function is not recommended in the absence of symptoms.
 Conclusion

 Hydroxymethyl glutaryl coenzyme A reductase (HMG- CoA) inhibitors, commonly

called statins are one of the most commonly prescribed medications in Asia.
 Statins are the most potent drugs that lower LDL cho- lesterol.

 There is extensive evidence to suggest that statin therapy has significant mortality and
morbidity benefit for both primary and secondary prevention from cardiovascular
disease.
 Myalgia is the most common side effect from statin use with rates from 1-10% of
patients. Rhabdomyolysis is the most serious adverse effect from statin use and is very
rare (less than 0.1%).
 Derangement in liver function tests is common, affecting up to 1% of patients; however
the clinical significance of this is unknown. Some statin drugs are potentially
diabetogenic and the risk appears to increase in those on higher doses.
 Statins have not be proven to increase the risk of malignancy, dementia, mood
disorders, interstitial lung dis- ease and acute interstitial nephritis.
Thankyou