Statin adverse effects: Sorting out the evidence

THE BOTTOM LINE: Physicians should carefully evaluate the anticipated cardiovascular risk for patients who have had a hemorrhagic stroke to determine whether statin therapy would be beneficial.

Other serious adverse effects: Which reports are accurate?


Statin use has been associated with a number of other serious AEs. Some reports appear to be accurate; others do not hold up after a close look at the evidence.

Malignancy. A potential link between statins and an increased risk of malignancy has been considered for years. A large trial (N=5804) from 2002 found a correlation between pravastatin and an increased risk of new cancer diagnoses compared with placebo (HR=1.25; 95% CI, 1.04-1.51; P=.02).³⁷ But a 10-year follow-up did not substantiate this finding, and it is now believed that the original result may have been due to chance.³⁸ Numerous other meta-analyses and systematic reviews have found no link between statin use and malignancy.^39-41

Cataracts. Potential ocular effects have been widely studied and debated in recent years. Observational studies reporting an association between statin use and cataracts have had conflicting results, with some showing statins as protective^42-45 and others finding an increased risk.^46,47 However, a recent propensity-score matched analysis found that statin users do indeed have an increased risk of developing cataracts.⁴⁸ The authors concluded that for primary prevention, the risk-benefit equation for statin use should include this added risk.⁴⁸

In addition, a review of the databases of the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, and the FDA from 1987 to 2008 indicates that statin therapy may also cause diplopia, ptosis, and ophthalmoplegia.⁴⁹

Peripheral neuropathy. Despite case reports of statin-induced peripheral neuropathy, the NLA’s Neurology Expert Panel states that statins do not appear to cause this condition. If a patient receiving statin therapy develops peripheral neuropathy, a full work-up for other causes should be initiated before considering a modification of statin therapy, the panel advises.²⁸

Statins have also been linked to headache and dizziness, respiratory symptoms, gastrointestinal problems, and rash, among other AEs (TABLE 3).⁵⁰

Which drug? Potential differences in statins


The meta-analysis with >240,000 participants evaluated patients taking 7 different statins (atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, and simvastatin), looking at AEs of the drugs both collectively and individually.4 As noted earlier, the overall discontinuation rate due to AEs for all statins was 5.7%. Discontinuation rates for each agent were not reported.⁴

A recent propensity-score matched analysis found that statin users have an increased risk of developing cataracts.The researchers did report, however, that atorvastatin and rosuvastatin had the highest discontinuation rates; atorvastatin and fluvastatin had the highest incidence of transaminase elevations (OR, 2.6 and 5.2, respectively); and pravastatin and simvastatin appeared to be the best tolerated and safest statins, with the lowest discontinuation rates. However, higher doses of simvastatin (>40 mg/d) significantly increased the risk of CK and transaminase elevations (OR, 4.1 and 2.8, respectively),⁴ as well as the risk of rhabdomyolysis at the highest dose.^15,16

Are statins safe for these patients?

When considering statin therapy, there are some patient populations that warrant particular concern:

Women of childbearing age. Statins are contraindicated in women who are pregnant or breastfeeding,¹ and should not be initiated in women who are trying to conceive.

Children and adolescents (ages 8-18 years). Statins have been shown to be safe and effective for children and adolescents with familial hyperlipidemia. No effect on growth or maturation has been seen.⁵¹ As with adults, however, higher statin doses and the use of concomitant interacting drugs increase the risk of AEs.

Asians. The new ACC/AHA guideline suggests taking Asian ancestry into consideration when prescribing statins because Asians may be more sensitive to medications metabolized by the CYP450 system.¹ However, there are no reports of an increased risk of AEs in Asian patients on statins.⁵² (To read more about statin use in particular patient populations, see “Statin therapy: When to think twice,” J Fam Pract. 2013;62:726-732.)

Patient factors that increase risk

Risk factors for statin-induced AEs include:¹

• multiple and/or serious comorbidities (eg, hypothyroidism, impaired renal or hepatic function, rheumatic disorders)
• unexplained ALT elevation >3 times the 
upper limit of normal
• history of prior statin intolerance or concomitant use of drugs that affect statin 
metabolism
• age >75 years
• preexisting muscle disorders
• low vitamin D levels.


If a patient who would clearly benefit from statin therapy develops an AE requiring discontinuation, a retrial—with the same drug or a different statin—is generally recommended once the symptoms resolve.¹

Statins have been shown to be safe and effective for children and adolescents with familial hyperlipidemia.CASE › The risk of elevated serum transaminases, insulin resistance, cognitive impairment, and neuropathy associated with statin use is minimal, and further evaluation revealed that Mr. L’s recent symptoms had other causes. The elevated transaminases were due to fatty liver disease, the cognitive impairment was secondary to sleep apnea (both linked to his obesity), and the tingling in his hands was the result of carpal tunnel syndrome caused by his exercise regimen.