Editor's Note: Commentary based on Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins BMJ 2014;349:g3743.

Background

Statins are a cornerstone of preventive pharmacotherapy and are widely utilized over long periods of time. Utilization may increase based on recommendations from the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol treatment guidelines.¹ Therefore, knowledge of the potential risks and benefits of these medications is of high importance to clinicians.

Methods

The authors performed a state-of-the-art review of randomized controlled trials (RCTs), meta-analyses, and systematic reviews of pre-selected non-cardiac effects of statins including: myopathy, diabetes, liver effects, cataracts, dementia and cognition, venous thromboembolism, kidney effects, pancreatitis, erectile dysfunction, chronic obstructive pulmonary disease, cancer, and fatigue.²

Findings/Conclusions

The authors discuss potential mechanisms for each of the non-cardiovascular effects of statins, and thoughtfully weigh the available evidence. They appropriately give the most detailed discussion to myopathy, diabetes, and cognitive effects.

With regards to myopathy, the authors conclude that there is a modest increase in statin-associated myositis (muscle pain with a creatine kinase elevation >10 times the upper limit of normal) and rhabdomyolysis, but not myalgia (muscle pain without CK elevation) with the use of statins. The authors include a discussion of polymorphisms in SLCO1B1, a hepatic ion transporter that regulates uptake of statins, which have been associated with statin myopathy in genome-wide association studies. However, analyses of polymorphisms within clinical trials suggest that the response may be statin-specific, so additional studies are needed.

With regards to diabetes, the author's review of RCTs and meta-analyses confirm the consistent modest increase in the risk of incident diabetes associated with statin therapy, primarily with higher dose statins and in people who are already at high risk of developing diabetes.

The authors include a discussion of cognitive function with statins, and conclude that larger RCTs, including those with pre-specified cognitive function outcomes, have not shown significant adverse effects. A recent systematic review and meta-analysis found a decreased risk of dementia, which needs further investigation.

There is a discussion of liver function testing abnormalities with statins. The authors conclude that transaminase elevations are more likely with higher dose statins and are generally reversible or normalize after continued use. Available data is discussed but no definitive conclusions can be made regarding cataracts, venous thromboembolism, pancreatitis, erectile dysfunction, chronic obstructive pulmonary disease, and fatigue. Cancer risk is addressed, and data confirm no excess risk of cancer with statins. There is mention of the significantly reduced risk of contrast induced nephrotoxicity with high-dose statins. The authors also cite an observational study that reported an increased risk for hospital admission for acute kidney injury, although this study had limitations necessitating additional investigations.

Commentary/Perspective

This well-balanced state of the art review will serve as a great reference for clinicians engaging in the recommended risk/benefit discussion before prescribing statins for patients at risk of atherosclerotic cardiovascular disease (ASCVD).¹ Additional recommendations on statin safety have also been recently published by the National Lipid Association, again highlighting the need for clinicians to be aware of non-cardiovascular effects of statins.³ Assessing potential side effects with statins has historically been challenging, and it is important to note that tolerance is different than safety. To this point, the authors introduce the novel "N of 1" study concept, which has been used in statin myalgia studies with success.⁴ The authors look to the future, and pose important research questions and topics including the use of genetic and clinical markers or models to identify those at higher risk for particular adverse effects, perhaps moving closer to personalized decision making. They identify areas where more research is needed including erectile dysfunction and cataract formation. Finally, the most important conclusion that the authors reach is that for most patients the benefits of statins for atherosclerotic cardiovascular disease risk reduction far outweigh the harms.

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References

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
2. Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ 2014;349:g3743.
3. Jacobson TA. NLA Task Force on Statin Safety--2014 update. J Clin Lipidol 2014;8(3 Suppl):S1-4.
4. Joy TR, Monjed A, Zou GY, et al. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med 2014;160:301-10.

Keywords: American Heart Association, Cholesterol, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Assessment

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