Adverse media coverage of "statin intolerance" has profound public health implications.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the United States and world-wide, based on data from the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).^1,2 More than 15.5 million Americans have coronary artery disease and every 42 seconds an American will have a myocardial infarction. One-third of those experiencing a coronary event die as a result.³ Statin therapy reduces major adverse cardiovascular events in patients with or at risk for ASCVD and the most recent guidelines from the American College of Cardiology and the American Heart Association (ACC/AHA) recommend moderate to high intensity statin administration in such patients.⁴

Statins have rare serious side effects, such as rhabdomyolysis and hepatotoxicity, and have been associated with increased incidence of diabetes and hemorrhagic stroke. Patients increasingly report symptomatic side effects, such as muscle or joint pain and weakness, preventing them from continuing statin therapy, a condition referred as "statin intolerance."⁵ Evidence on statin intolerance is derived principally from observational studies and reports to regulatory authorities of adverse events that have been attributed to a statin, and not from randomized clinical trials. However, the concept that statin intolerance is a common problem and might outweigh statin-associated benefits has been introduced in the medical literature and emphasized by the public media.^6-8

This has profound public health implications with studies in the United Kingdom, Denmark, and Australia linking adverse media coverage with significantly increased reluctance among physicians to discuss and prescribe statins, and reduced patient adherence to statins. In the UK, an estimated 10% increase in the statin discontinuation rate among patients with or at risk for ASCVD is estimated over the next decade, resulting in an excess of 2,000-6,000 cardiovascular events that could be prevented with statin use.⁹

A recent landmark Lancet publication led by Rory Collins provides an in-depth review of the evidence on statin therapy and the methodological limitations inherent to different study designs.¹⁰ In this Expert Analysis we summarize key points of this review as they pertain to the benefits associated with statin use and provide guidance on how to objectively address the concerns around statin safety.

Statin therapy reduces major adverse cardiovascular events (myocardial infarctions, strokes and death) and all-cause mortality in patients with or at risk for ASCVD.

In a meta-analysis of 27 randomized trials and 174,000 participants, for every ~40 mg/dL LDL-C reduction with statin therapy, the relative risk of major adverse cardiovascular events is reduced by ~20-25%, and all-cause mortality is reduced by 10%. More intense statin regimens yield a 15% further proportional reduction in major adverse cardiovascular events compared to less intense regimens.¹¹ These relative reductions are similar in primary vs. secondary prevention, lower vs. higher-risk, men vs. women, and also similar in other major subgroups. The reduction in all-cause mortality is primarily driven by reductions in deaths due to coronary artery disease (20% relative reduction) and other cardiac causes (10% relative reduction).

Statin therapy is associated with a low risk of muscle injury that in most cases is reversible.

Statin therapy carries a small increase in the absolute risk of muscle injury (defined as muscle symptoms with concurrent elevation of creatine kinase levels), which is estimated at 1 in 10,000 patients per year. Risk of rhabdomyolysis is even less, approximately 2-3 in 100,000 patients per year. Case series of statin-induced muscle injury show complete resolution of muscle pain with discontinuation of statin therapy without deaths and with only 13% of patients requiring hospitalization for rhabdomyolysis.¹²

Statin therapy is associated with rare instances of hepatotoxicity that in most cases is reversible.

Mild asymptomatic elevations of transaminases may be seen in 3% of patients on statin therapy, while the overall risk of drug-induced liver injury (unclear if causal) is estimated as ~1 in 100,000 and the risk of acute liver failure 1 in 1,000,000 patients per year. In a case series of 22 patients with statin-induced liver injury, nine patients were hospitalized, four developed evidence of hepatic failure, four progressed to chronic liver injury (of which three had an autoimmune phenotype of liver injury) and one died.¹³

Statin therapy can result in new-onset diabetes, but the risk for major adverse cardiovascular events remains lower, even in the setting of diabetes.

Statins increase risk of type 2 diabetes in a dose-dependent fashion, with an absolute risk excess of 10-20 new cases of diabetes for 10,000 patients per year treated with a typical high-intensity statin.¹¹ Supporting a causal link, genetic variants that reduce activity of HMG-CoA reductase are implicated in diabetes.¹⁴ However, statin therapy prevents major cardiovascular events in 200 of 10,000 secondary prevention patients and 100 of 10,000 primary prevention patients per year.¹¹ New-onset diabetes is accounted for when calculating the net benefit from statin therapy.

Risk for diabetes is higher in patients who have pre-existing risk factors for diabetes, such as obesity, pre-diabetes and features of the metabolic syndrome.¹⁵ In JUPITER (Crestor 20mg Versus Placebo in Prevention of Cardiovascular Events), statin therapy accelerated the average time to diagnosis of diabetes by 5.4 weeks. Patients who developed diabetes while on statin (and remained on statin therapy) had a ~45% lower relative risk of major cardiovascular events compared to those who developed diabetes and did not take a statin. The risk reduction observed in patients who developed diabetes was similar to the risk reduction observed in the entire trial.¹⁶ Lastly, the absolute risk reduction with statin therapy is greater in high-risk patients, such as those with diabetes, despite any increase in incidence of new-onset diabetes.¹¹

Statin therapy is associated with increased risk of hemorrhagic stroke, but it reduces the overall risk of stroke and does not increase mortality in patients with stroke.

Statins increase risk for hemorrhagic stroke, with an absolute risk excess of one to two- hemorrhagic strokes for 10,000 patients per year. Similar to diabetes, the increased incidence of hemorrhagic stroke is taken into account in the estimates of absolute benefits. Statin therapy does not increase mortality in patients with stroke.¹¹ Statin therapy reduces the overall risk of first or recurrent stroke and the net benefit in stroke risk reduction remains despite the small increase in hemorrhagic stroke.¹⁷

Evidence is reassuring on statin therapy and cognitive function.

Cognitive decline and memory loss is commonly attributed to statin therapy. This occurred after the UK Medicines & Healthcare Products Regulatory Agency (2009) and subsequently the FDA (2012) listed the potential for cognitive side effects on the label of all statins. This action was driven by post-marketing individual reports associating statins with memory loss or cognitive impairment, apparently reversible after discontinuation of therapy. However, randomized trials have not shown this.

In a subsequent assessment of FDA surveillance databases, rates of cognition-associated adverse events related to statins were similar to those of other commonly prescribed cardiovascular medications.¹⁸ In a systemic review and meta-analysis of 16 studies evaluating long term cognition and 23,000 patients followed for 3-25 years, there was no association of statin use with incident dementia. In fact, there was a 29% relative reduction in incident dementia documented in high-quality cohort studies of patients treated with statins.¹⁹

A causal link between statin use and perceived muscle pain or weakness, in the absence of muscle injury, has not been established.

As many as 20-25% patients in observational studies have statin intolerance.^6,7 However, these results have not been confirmed in some large-scale observational studies wherein similar rates of muscle-related complaints were observed in patients treated versus not treated with statins (n=5,000-46,000). Furthermore, in randomized controlled clinical trials, statins are equally tolerated with placebo and statin-related muscle pain and weakness occur in no more than 10–20 cases per 10,000 patients annually.

About half of statin trials had run-in phases and a common argument against randomized trials is that run-in phases introduce bias by eliminating patients who have adverse events. Yet, a run-in with active medication occurred in only a few statin trials. Although some patients might have been excluded due to adverse effects soon after initiation of the medication, it is unlikely that use of such a design would prevent the emergence and capturing of side effects for the entire duration of the trial. As a matter a fact, the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial, which included an active run-in, identified increased risk for myopathy with 80 mg of simvastatin daily. Moreover, most statin trials were designed with run-in phases involving the use of a placebo. This design results in improved post-randomization adherence and as a result improved sensitivity to detect any side effects.

The CRISP (Computed Tomography Perfusion to Predict Response to Recanalization in Ischemic Stroke Project) trial specifically assessed the effect of lovastatin on health-related quality of life in 430 older adults, showing no differences across a wide battery of tests, and no differences in reported muscle pain.²⁰ In two randomized, blinded studies with cross-over design, 120-511 patients with reported statin intolerance were randomized to receive a statin and then placebo or placebo and then a statin. While 36-43% of study participants reported muscle symptoms when on statin but not on placebo, 27-29% of them reported muscle symptoms when on placebo but not on statin.^21,22 These results indicate that, even among highly selected patients with reported statin intolerance, their symptoms commonly are not due to statin therapy.

Conclusions: The ultimate role of shared decision making in initiation of statin therapy and the ethical responsibility of media towards public health.

In this expert analysis, we summarized the benefits and adverse effects associated with statin therapy. Objectively, current best evidence is very clear: the absolute benefit from reduction of cardiovascular events outweighs the absolute risk of adverse events, which are mostly reversible. The extensive evidence base means that it is unlikely for large absolute excesses in other serious adverse events to be discovered, and thus the balance of benefits versus harms associated with statin therapy is unlikely to substantially change in the future. However, each patient deserves to weigh the risk/benefit ratio based on his/her personal values and self-reported health status, including symptom burden (from either the disease or medical treatments), functional status, and health-related quality of life. Initiation of statin therapy should be based on shared decision making between clinicians and patients.

Clinicians should offer statin therapy to patients with or at risk for ASCVD and objectively share with them safety and efficacy data. If a primary care provider is not sure about the ASCVD risk of the patient, s/he should refer the patient to a cardiovascular disease specialist. Patients who develop symptoms possibly related to statins may be referred to lipid specialists to further examine evidence for a causal association of the symptoms with statin use and explore alternative risk reduction approaches. Last but not least, the media have an ethical responsibility to public health and should proceed with extreme caution when making unfavorable statements about established medical treatments.

References

1. Centers for Disease Control and Prevention (CDC). Leading Causes of Death. 2015;2016.
2. World Health Organization (WHO). The top 10 causes of death. 2014;2016.
3. Writing Group M, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38-360.
4. 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.
5. Guyton JR, Bays HE, Grundy SM, et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol 2014;8:S72-81.
6. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123.
7. Redberg RF, Katz MH. Healthy men should not take statins. JAMA 2012;307:1491-2.
8. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharmacol 2015;8:201-10.
9. Matthews A, Herrett E, Gasparrini A, et al. Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data. BMJ 2016;353:i3283.
10. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016. [Epub ahead of print]
11. Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
12. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med 2005;165:2671-6.
13. Russo MW, Hoofnagle JH, Gu J, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 2014;60:679-86.
14. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015;385:351-61.
15. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol 2011;57:1535-45.
16. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-71.
17. Sett AK, Robinson TG, Mistri AK. Current status of statin therapy for stroke prevention. Expert Rev Cardiovasc Ther 2011;9:1305-14.
18. Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med 2013;159:688-97.
19. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 2013;88:1213-21.
20. Santanello NC, Barber BL, Applegate WB, et al. Effect of pharmacologic lipid lowering on health-related quality of life in older persons: results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study. J Am Geriatr Soc 1997;45:8-14.
21. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90.
22. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015;238:329-35.

Keywords: American Heart Association, Arthralgia, Cause of Death, Cholesterol, Cognition, Cognition Disorders, Coronary Artery Disease, Creatine Kinase, Dementia, Diabetes Mellitus, Type 2, Homocysteine, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver Failure, Liver Failure, Acute, Metabolic Syndrome, Myocardial Infarction, Phenotype, Primary Prevention, Rhabdomyolysis, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Stroke, Tomography, Dyslipidemias

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