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Abstract

With the release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, emphasis has been placed on using evidence-based intensity of therapy to reduce atherosclerotic cardiovascular disease (ASCVD) risk, rather than focusing on goal cholesterol levels. Before initiating therapy, however, it is critical that physicians and patients discuss 4 key topics: (1) the benefit of ASCVD risk reduction, (2) medication adverse effects, (3) drug–drug interactions, and (4) patient preferences. To facilitate discussion of statin adverse effects, we present here an evidence-based review of the 5 Ms of statin adverse effects: metabolism, muscle, medication interactions, major organ effects, and memory. “Metabolism” represents the small risk of new-onset diabetes that comes with statins, which is highest in those with diabetes risk factors. “Muscle” requires discussion of the wide range of muscle symptoms that occur with statins but emphasizes that these have been no more prevalent than those experienced with placebo in randomized controlled trials (RCTs). “Medication interactions” emphasize that statins interact with numerous medications. Interaction profiles vary widely between statins, and patients should be made aware of the most common interactions with their prescription. “Major organ effects” prompt the physician to review the possibility of a transient transaminitis as well as the recent observation of rare acute kidney injury with statin use. Both are rare and do not require routine monitoring. Finally, “memory” references the recent observational data suggesting statins may contribute to memory loss and confusion, both of which have not been observed in RCTs and resolve with drug cessation. Reviewing these common effects has the possibility to strengthen the doctor–patient relationship and boost both medication adherence and patient satisfaction.

Keywords

statin lipids hypercholesterolemia

Case History

W. Nancy is a 64-year-old white woman with a family history of heart disease (her mother had a myocardial infarction [MI] at age 58), a total cholesterol of 200, triglycerides of 175, low-density lipoprotein cholesterol of 120 mg/dL, and an high-density lipoprotein cholesterol of 45 mg/dL. She is a nonsmoker. She has hypertension with a systolic blood pressure of 130 due to treatment with hydrochlorthiazide 12.5 mg and lisinopril 5 mg daily. She has a fasting blood sugar of 105 mg/dL. She was told that she would benefit from a statin but she questions whether the benefits are worth the possible risks or negative aspects. Her atherosclerotic cardiovascular disease (ASCVD) risk score is 7.6%. She understands she would derive net benefit from a statin based on the new cholesterol guidelines analysis. Nonetheless, she wants a better understanding of possible safety issues and negative aspects. Her physician confirms that risk calculators don’t write prescriptions and she should come into the office to have a discussion of both likely benefits and risks of adverse effects. To organize the discussion of adverse effects, the clinician reviews the 5 Ms associated with statin therapy.

Introduction

Statins are one of the most widely prescribed medications in the United States.¹ They are the drugs of choice for secondary prevention of ASCVD and often used for high-risk primary prevention.² With the release of 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, emphasis has been placed on estimation and treatment based on ASCVD risk, rather than cholesterol level.³ However, a critical step in the implementation of the cholesterol guideline is a discussion between clinicians and patients to address at least 4 key topics: (1) the benefit of ASCVD risk reduction, (2) medication adverse effects, (3) drug–drug interactions, and (4) patient preferences. Thus, the decision to initiate statins in any patient is premature until the clinician reviews the evidence base for statin adverse effects. Moreover, this discussion allows the physician to provide advice on all the ASCVD risk factors since the global risk score is dependent on more than just cholesterol.

This discussion is especially important to put into perspective not only the potential for benefit but also the potential for side effects. We have developed a helpful clinical approach to engaging the patient on this topic. Here, we describe the concept of the 5 Ms of statin adverse effects: metabolism, muscle, medication interactions, major organ effects, and memory (Table 1). By creating a checklist of the 5 Ms at the patient visit, a physician can address the most important side effect concerns for patients. This patient-centered discussion allows the patient to weigh the benefits and the harms—an approach that has the promise to improve medication adherence.⁵

Table 1.

Summary of the 5 Ms.^a

The 5 Ms	The Adverse Effect	Patient-Centered Summary
Metabolism	Risk of new-onset diabetes	The risk of new-onset diabetes is low with a slightly higher risk for the most potent statins. This risk is highest in those with diabetes risk factors. Those who progress to diabetes get clear benefit from statins.
Muscle	Risk of muscle symptoms ranging from asymptomatic CK elevations to rhabdomyolysis	Muscle complaints are common symptoms that are not more frequent in trials comparing statins to placebo. In practice, muscle complaints are more common. If clearly related to statin use, change in statin dose or a different statin may prove useful. Severe muscle symptoms can occur, but these are very infrequent and drug–drug interactions are often the cause.
Medication interactions	Statins interact with numerous medications, most commonly macrolide antibiotics and azole antifungals. Certain medications are contraindicated with statins	Patients and physicians alike should be aware that with statins, like many other drugs, drug interactions can occur because some drugs elevate statin concentration. Some statins have more drug–drug interactions than others. Macrolide antibiotics such as clarithromycin and erythromycin can do this for specific statins, including simvastatin, lovastatin, and atorvastatin. Those on multidrug regimens such as transplant patients and those undergoing therapy for HIV need careful evaluation before statins are prescribed.
Major organ effects such as liver and kidney	Statins cause a transaminitis	Baseline liver tests should be done, but routine follow-up is not needed if they are in the normal range. The FDA concluded that serious liver injury with statins is rare and unpredictable in individual patients. Routine monitoring of liver tests does not appear to be effective in detecting or preventing serious liver injury despite minor elevations of transaminases.
Major organ effects such as liver and kidney	Statins are associated with an increased risk of acute kidney injury in observational studies	Although there is an association in observational studies, acute kidney injury due to statins has not been validated in randomized trials.
Memory	Memory loss and confusion have been reported with statin use	Individually reported events have resolved within 3 weeks of stopping the statin. A significant risk of cognitive problems was not seen more commonly in those on statins compared to those taking placebo in 2 large trials.

Abbreviations: CK, creatine kinase; FDA, Food and Drug Administration; HIV, human immunodeficiency virus.

^aFood and Drug Administration continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.⁴

Metabolism

Background

The benefit of statins in the setting of type 2 diabetes mellitus (DM) has been established in randomized placebo-controlled trials (RCTs).⁶ However, recent RCT data analysis has demonstrated that statin use elevated hemoglobin A1c levels and, in susceptible patients with DM risk factors, it hastened the progression to disease. In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, men ≥50 and women ≥60 with high-sensitivity C-reactive protein ≥2 mg/L but who were otherwise healthy were randomly selected to take either 20 mg of rosuvastatin or a placebo.⁷ In addition to a highly significant reduction in the primary end point of MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes, they also reported a hazard ratio of 1.25 for new-onset diabetes (NOD) and higher hemoglobin A1c. The opposite finding occurred in the West Scotland Coronary Prevention Study (WOSCOPS), where the use of pravastatin was associated with a 30% reduction in NOD compared to the use of the placebo among dyslipidemic individuals.⁸

Studies/RCTs/Systematic Reviews

Three meta-analyses used existing RCT data to examine the risk of NOD with statin use. The first study analyzed trials comparing statin to placebo.⁹ Specifically, 13 trials with at least 1000 patients and at least 1-year of follow-up were included. The combined odds ratio for NOD was 1.09 (95% confidence interval [CI] 1.02-1.17) suggesting that, in fact, statins did increase the onset of DM. The authors reported that the absolute risk of NOD was 1 new case for every 255 patients over 4 years of statin use, which translates to less than 1 case in 1000 patient-years. Furthermore, only rosuvastatin showed a statistically significant increase in NOD, while all other associations with individual statins did not reach statistical significance.

The second meta-analysis compared intensive- and moderate-dose statins in 5 RCTs.¹⁰ Once again, an odds ratio of 1.12 for NOD was found in the intensive-dose group, while the absolute risk was 2 in 1000 patient-years. This study also reported fewer than 6.5 major cardiovascular events per 1000 patient-years. Thus, despite the slight increase in NOD in absolute terms, the risks were well outweighed by the benefits. The third meta-analysis was based on 113 698 individuals in placebo-controlled trials and found the same result.¹¹

A reanalysis of the data in JUPITER trial clarified those most likely to develop NOD with statin therapy.¹² The authors identified 4 diabetic risk factors: (1) impaired fasting glucose, (2) body mass index (BMI) ≥30 kg/m², (3) a hemoglobin A1c >6%, and (4) the metabolic syndrome in each patient. Those with at least 1 risk factor did have a high likelihood of developing NOD (hazard ratio 1.28, 95% CI 1.07-1.54, absolute risk 4-5 in 1000). Those with no risk factors had no increased risk of NOD on statin (rosuvastatin) therapy. Nonetheless, even in those with diabetes risk factors, statin therapy prevented 134 vascular events for every 54 new cases of DM.

Similar conclusions were found in the reanalysis from the Treating to New Targets (TNT) and Incremental Decrease in End-points Through Aggressive Lipid Lowering (IDEAL) secondary prevention trials. These trials compared low-dose (atorvastatin 10 mg or simvastatin 20-40 mg) to high-dose statin (atorvastatin 80 mg).¹³ The study used slightly different DM risk factors: (1) fasting blood glucose >100 mg/dL, (2) history of hypertension, (3) BMI >30 kg/m², and (4) triglycerides >150 mg/dL. Nonetheless, a higher risk of NOD was seen with higher dose statins among patients with 2 to 4 DM risk factors (HR 1.24, 95% CI 1.08-1.42). This was not the case among those with 0 to 1 risk factors (HR 0.97, 95% CI 0.77-1.22).

Summary

Based on the existing data, statins do increase the risk of NOD. Data from RCTs indicate that (1) the risk of NOD, while present, is less than 1 in 1000 patient-years; the risk is higher (2-3 in 1000 patient-years) with more potent statins; (2) those with risk factors for DM are mainly at risk; (3) the substantial benefit of preventing serious cardiovascular outcomes outweighs the risks of a new diagnosis of DM; (4) those that do develop DM would have done so without a statin, which merely accelerates progression to DM; and (5) for those in whom DM does develop, statins are clearly shown to provide net CVD risk reduction.^4,14,15 Indeed, those at the highest risk of experiencing this acceleration to DM are, due to their risk factors, exactly the individuals who benefit the most from statin therapy in terms of ASCVD risk reduction.

Muscle

Background

Muscle side effects have been associated with statins since the introduction of lovastatin in the early 1980s when creatine kinase (CK) level increases were observed in early clinical trials.^16,17 Muscle complaints take numerous forms, and there are currently varying definitions of these side effects. The ACC/AHA/National Heart, Lung, and Blood Institute (NHLBI), The National Lipid Association’s Muscle Safety Expert Panel, and the Food and Drug Administration (FDA) have differed in their definitions of myopathy, myositis, and rhabdomyolysis. A Canadian Working Group Consensus Conference recently worked to integrate and simplify these various definitions.¹⁸ They determined myopathy to refer generally to any disease of muscle, myalgia to describe muscle ache or weakness without elevation of CK, and myositis as muscle symptoms associated with an increase in CK. They determined rhabdomyolysis should be reserved for a CK >10× the upper limit of normal with muscle ache or weakness, which may include myoglobinuria-induced renal damage or require hydration therapy. To define elevations in CK not >10× the upper limit of normal or not associated with symptoms, they added the term hyperCKemia, subdivided into mild grade 1, mild grade 2, moderate, or severe to addresses gradations of muscle breakdown.

Studies/RCTs/Systematic Reviews

Clinical trial data have routinely estimated the rate of muscle complaints associated with statins at 1.5% to 5%. Importantly, the rate of these complaints did not vary between statins and placebo, even in meta-analysis.¹⁹ A major critique of these trial data, however, is that they are likely to underestimate the rate of muscle complaints since trials often exclude patients who have had muscle complaints in the past or have predisposing characteristics.²⁰ As a result, muscle complaints are usually more common in practice, ranging from 5% to 10%.¹⁹ Although surveys have shown an even higher incidence,²¹ these retrospective data cannot differentiate between statin-related discomfort and nonstatin-related discomfort. Again, this is a crucial distinction because in RCTs, a significant number of patients on placebo recorded muscle-related complaints.

Rhabdomyolysis, the most dangerous of all muscle-related side effects, is exceedingly rare. One death has occurred for every 5.2 million prescriptions for lovastatin, 23.4 million for atorvastatin, 27.1 million for pravastatin, and 8.3 million for simvastatin. Compare this with 1 death for every 316 000 prescriptions for cerivastatin, and it is clear why this drug was pulled from the market. Rhabdomyolysis is uncommon in patients who receive fluvastatin.¹⁹

Older age, female sex, smaller body size, hypothyroidism, and a history of muscular problems all predispose patients to muscle side effects.¹⁹ Although the pathophysiology of muscle symptoms are not well understood, some have suggested that depleted coenzyme Q10 (CoQ10; a downstream product of the enzyme targeted by statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase [HMG-CoA]) and/or vitamin D deficiency may contribute. However, smaller studies have not been conclusive about the value of correcting vitamin D deficiency^22,23 or of adding CoQ10^24,25 for statin muscle complaints. Thus, there is a need for well-designed RCTs to examine these issues critically.

The recent Effect of Statins on Skeletal Muscle Function and Performance (STOMP) trial is the first RCT specifically designed to test a cause–effect relationship between statins and myalgia. Patients came from equal mixes of both genders and 3 age ranges (20-39, 40-54, and older than 55).²⁶ Patients with previous statin use, muscle complaints, or cardiovascular disease were excluded. They were randomized to take either 80 mg of atorvastatin or a placebo for 6 months. Patients on atorvastatin had a significant but mild increase in CK levels of 20.8 ± 141.1 U/L. They also had more study-defined incidents of myalgia (19 vs 10). However, exercise performance was no different between groups. Further insights from this study experience are awaited.

Summary

It is critical that patients understand that a variety of muscle symptoms are experienced commonly and that they may occur more often while on statins. Since myalgias occur in placebo groups of statin RCTs, it is important to be sure that muscle complaints are, in fact, due to the statin. Although some may tolerate mild complaints, especially if episodic, moderate or severe symptoms should prompt a halt to statin use. Cessation generally leads to symptom improvement. The new cholesterol guideline provided a useful approach to those with statin-associated muscle complaints.³ Their algorithm is produced in Table 2.

Table 2.

Management Algorithm for the Evaluation and Treatment of Muscle Symptoms in Statin-Treated Patients.^a

Prior to Initiating Statin Therapy	Severe Muscle Symptoms or Fatigue During Statin Therapy	Mild to Moderate Muscle Symptoms Develop During Statin Therapy
To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline	Promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK, creatinine, and a urinalysis for myoglobinuria.	Discontinue the statin until the symptoms can be evaluated.
		Evaluate the patient for other conditions that might increase the risk of muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, and rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases).
		If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy.
		If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin.
		Once a low dose of a statin is tolerated, gradually increase the dose as tolerated.
		If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed previously.
		If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy or if the predisposing condition has been treated, resume statin therapy at the original dose.

Abbreviation: CK, creatine kinase.

^aAdapted from Stone et al.³

Medication Interactions

Background

Some of the earliest reports of statin adverse effects were observed in the setting of medication interactions, as these were the setting in which statins reached their highest levels.²⁷ In one analysis, 58% of cases of rhabdomyolysis were associated with the use of medications affecting statin metabolism.²⁰ The risk of medication interaction is governed principally by the unique pharmacokinetics of each statin. For convenience, statins can be segregated into 3 major pharmacokinetic classes.

Studies/RCTs/Systematic Reviews

The class with the most interactions is those metabolized by the cytochrome P450 (CYP450) 3A4 system, which includes simvastatin, lovastatin, and atorvastatin. Since so many commonly prescribed drugs interact with this system, it is important to be mindful of those listed in Table 3. Recently, the FDA has added restrictions on dosing for simvastatin and lovastatin, particularly in the setting of commonly used cardiovascular drugs such as verapamil, diltiazem, amlopdipine, ranolazine, and amiodarone (Table 3). Particular awareness should be exercised in patients with organ transplants, as cyclosporine is a potent inhibitor of the 3A4 system, as well as membrane transporters, and so must be used cautiously with all statins.³⁵ Some protease inhibitors are especially strong inhibitors of CYP450 3A4 and so should not be used with statins such as lovastatin and simvastatin.³⁴ Since protease inhibitors themselves can cause dyslipidemias, pravastatin and rosuvastatin are often initial choices, although low-dose atorvastatin can be well tolerated.³⁶ Interactions of atorvastatin related to the 3A4 system may be reduced because some of its metabolism is mediated by OATP1B1.³⁷

Table 3.

Common Statin Drug–Drug Interactions by Primary Mechanism of Clearance.^a

	CYP450 3A4			CYP450 2C9	OATp1B1
	Simvastatin²⁸	Lovastatin²⁹	Atorvastatin³	Fluvastatin³⁰	Pravastatin³¹	Rosuvastatin³²	Pitavastatin³³
Macrolide antibiotics	CONTRA	CONTRA	INTX
Erythromycin							<1 mg/d
Clarithromycin			<20 mg/d		<40 mg/d
Telithromycin
Azole antifungals (ie, fluconazole)	CONTRA	CONTRA	INTX	INTX^b
Cardiovascular drugs
Amiodarone	<20 mg/d	<40 mg/d	INTX³⁴	INTX³⁴
Dronedarone	<10 mg/d	<20 mg/d	INTX³⁴
Verapamil	<10 mg/d	<20 mg/d	INTX³⁴
Diltiazem	<10 mg/d	<20 mg/d	INTX³⁴
Amlodipine	<20 mg/d
Ranolazine	<20 mg/d	INTX
Antiviral drugs
Protease inhibitors	CONTRA	CONTRA	INTX			INTX
Boceprevir	CONTRA	CONTRA
Telaprevir	CONTRA	CONTRA	Avoid
Efavirenz	INTX³⁴	INTX³⁴	INTX³⁴
Cyclosporine	CONTRA	Avoid	Avoid	<20 mg/d	<20 mg/d	<5 mg/d	CONTRA
Danazol	CONTRA	<20 mg/d
Warfarin	INR should be monitored when stopping or changing any statin

Abbreviations: CONTRA, contraindicated by drug label; CYP450, cytochrome P450; INTX, interaction.

^aDrug–drug interaction as identified by package insert for each statin. Interactions that are possible based on mechanism (and not indicated in the package insert) are referenced individually. We have checked package inserts as of 8-13-13; since changes may occur, we recommend that current manufacturers package inserts be checked before using statins with these drugs. Dosages shown indicate the maximum dose when given concomitantly as recommended by package insert.

^bFluvastatin is specifically limited to 20 mg with fluconazole. Specific limitations with concomitant use of other azoles are not addressed.

Patients should be told that if a new medication is prescribed, there should be a check for drug–drug interactions. Of particular concern to patients in the ambulatory setting are azole antifungals and macrolide antibiotics such as clarithromycin and erythromycin because these drugs can raise statin levels and lead to adverse effects.³⁴ A recent retrospective study of 144 336 patients on 3A4 metabolized statins compared those prescribed erythromycin or clarithromycin to those prescribed azithromycin.³⁸ The results showed a 2.17 (95% CI 1.05-4.53) relative risk of hospitalization with rhabdomyolysis (absolute risk 2 in 10 000) and a 1.56 (95% CI 1.36-1.80) relative risk of all-cause mortality (absolute risk 25 in 10 000). This study is limited by its retrospective nature. However, given the plausibility of interaction between macrolides and certain statins via the 3A4 system, macrolides such as erythromycin and clarithromycin likely put these statin users at unnecessary risk.

Non-3A4 statins have far fewer interactions. Fluvastatin is predominantly metabolized by the 2C9 system, although it should still be stopped temporarily if treatment with an azole antifungal such as fluconazole is required. Pravastatin, rosuvastatin, and pitavastatin have the most favorable interaction profile, as they are primarily metabolized by the OATp1B1 system. It is important to note that cyclosporine can still raise plasma levels of these statins, and concomitant use with pitavastatin is contraindicated by the drug label.³⁴ All statins can interfere with warfarin, and the international normalized ratio should be followed more closely when starting or switching statins.

Summary

Patients need to be made aware of the possible interactions with their statins, particularly of the most commonly prescribed medications, namely, clarithromycin, erythromycin, and azole antifungals. In the new cholesterol guideline, there is emphasis on reviewing potential drug–drug interactions before statins are started. Since patients may receive prescriptions from specialists as well as their primary clinician, they should routinely ask whether any new medication may interact with their statin. In the setting of patients on numerous medications, a statin such as pravastatin or rosuvastatin may be a more prudent choice to reduce the chances of drug–drug interaction. But here is where consultation with the pharmacist to review the potential for drug-drug interactions is worth the extra effort.

Memory

Background

The concern that statins caused cognitive impairment began with case reports of cognitive decline, which were linked to the statins temporally or resolved upon switching or stopping the statin.^40,41 An early meta-analysis of observational studies, however, suggested that statins delayed the onset of cognitive impairment.⁴²

Studies/RCTs/Systematic Reviews

Despite a small case series of 171 patients who self-reported cognitive decline that linked the level of decline to statin potency,⁴³ data from RCTs have not shown an increase in cognitive decline with statin use. Specifically, in the Heart Protection Study, cognitive impairment occurred in 23.7% of those on simvastatin and 24.2% of those on placebo with no significant difference between the groups.⁴⁴ Furthermore, there was no difference in any of the predetermined age groups. In the Prospective Study of Pravastatin in the Elderly (PROSPER), cognitive decline, as assessed by numerous cognitive tasks, declined at the same rate in both treatment and control groups.⁴⁵ Other small-scale RCTs have largely failed to detect an adverse effect of statins on cognition.⁴⁶

On the other hand, some studies have shown a beneficial effect of statins on cognition.⁴⁶ A large cohort study of 3334 patients older than 65 years of age from 4 US communities found that those not taking statins had their scores on the Modified Mini-Mental State Examination fall 0.4 points (on a scale of 100) faster than those on statins, in fact indicating a slight protective effect.⁴⁷

The FDA reviewed the Adverse Event Reporting System database, the published medical literature, including case reports, observational studies, and RCTs to evaluate the effect of statins on cognition.⁴⁸ This data set described persons “over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy.” They noted that there was no specific statin exposure length prior to cognitive symptoms, and importantly, there was no evidence for fixed or progressive dementia.

Independently, the largest and most comprehensive literature review to date recently concluded that the available RCT and cohort data, although low in quality, suggested no increased incidence in Alzheimer disease and no decrease in cognitive performance due to statins.⁴⁹ A smaller systematic review, focusing on RCTs evaluating short-term effects in previously unaffected adults, found no consistent effect on cognitive end points; in the long-term studies (both RCTs and observational studies), statins were found to be beneficial in terms of cognitive outcomes.⁵⁰ Nonetheless, the FDA label on all statins now carries information regarding the possibility of memory symptoms.⁴⁸

Summary

Randomized controlled trials demonstrated no significant difference between statins and placebo in the incidence or rate of cognitive decline. The current cholesterol guideline notes:

In individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy.^{3, p38}

Nonetheless, patients should understand that if cognitive symptoms are found to be attributable to the statin, they should return to baseline within 3 to 4 weeks after stopping the statin.

Major Organ Effects

Background

Given that statins exert powerful inhibition of HMG-CoA in the liver, liver damage has been a major concern with statin treatment. Even in the earliest statin RCTs, an elevation in liver transaminases has been documented with statin use.¹⁶ As a result, physicians checked transaminase levels in patients on statins, and it was not uncommon for statins to be stopped if an elevation from baseline was observed, although the guideline advice was to wait until the transaminases exceed 3× the upper limit of normal.

More recently, concern has been raised regarding acute kidney injury occurring with statin use. In particular, data from the JUPITER trial has been cited to show a risk ratio of 1.19 for acute kidney injury and as high as 1.35 if a doubling of creatinine was considered as part of the diagnosis.⁵¹

Studies/RCTs/Systematic Reviews

Liver

Several important features of statin liver effects have emerged over numerous RCTs.⁵² First, an increase in transaminase levels was rare (<3%) and did not usually differ significantly between treatment and placebo groups as was the case in the Scandinavian Simvastatin Survival Study, the Heart Protection Study, JUPITER, or the Prospective Pravastatin Pooling project.^{7,44,52
–54} Second, statin dose and the incidence of transaminitis are linked: rates of 1% are seen in low- and moderate-dose statins and as high as 2% to 3% in high-dose statins.⁵² Finally, transaminase levels often normalize on their own without having to stop the statin.⁵⁵

True hepatotoxicitiy in statin use is remarkably rare. In a retrospective study of 23 000 patients on statins, only 62 had transaminitis greater than 10 times the upper limit of normal.⁵⁶ Only 16 of these were determined to be related to statin use and 13 of those due to medication interactions. Furthermore, 10 of these patients were rechallenged with the same or different statin with no increase in transaminases. Given the lack of evidence pointing to true hepatotoxicity, it has been suggested that rather than causing actual damage to hepatocytes, which would be observable on pathology, statins merely increase membrane permeability to transaminases, mimicking cellular damage.⁵²

Kidney

Use of a higher strength of statins did not increase the risk of renal injury among MI survivors in 2 RCTs.⁵⁷ The primary prevention trial JUPITER did report an increased relative risk of acute kidney injury with 20 mg of rosuvastatin, but the difference was not statistically significant and small in absolute terms: of 8901 patients treated with statins and 8901 patients given placebo, 19 had acute kidney injury in the statin group and 16 in the placebo group.⁵¹

Given the rarity of these events, it was suggested that only large retrospective studies would be able to detect differences. A study of 225 992 statin users in England and Wales showed that statins were associated with a hazard ratio of between 1.50 and 2.19 of developing acute renal failure and showed a dose–response effect.⁵⁸ However, the incidence of these events was 1 to 3 per 10 000 person-years. Another large retrospective trial used rigorous propensity matching to determine the risk of acute renal failure with statin use.⁵⁹ This study was even larger: 673 410 individuals on high-dose statins were compared to an equal number of propensity-matched controls on low-dose statins. There was a significant 34% increase in the rate of hospitalization for acute kidney injury in the first 120 days of high-dose statin treatment. However, at most, the absolute risk was 1.2 per 1000 patients. Furthermore, despite propensity score matching, the high-dose statin group had a significantly higher rate of patients with congestive heart failure, which points out that propensity matching mitigates, but does not eliminate, confounding.

Conversely, the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, a prospective randomized, target-based, and open label trial showed a renoprotective effect for statins.⁶⁰ The study was performed in Greek patients with known coronary heart disease and less than 75 years of age. Patients not on statins had a 5.2% decrease in their creatinine clearance (CrCl), while those on statins had 4.9% increase in CrCl, and those using atorvastatin had a 12% increase in CrCl.

Summary

Despite prior concern over major organ system adverse effects with statins, particularly hepatic and renal complications, RCT data do not confirm these fears. In the case of hepatic toxicity, the data suggest that changes in liver transaminases, while dose dependent, represent a clinically insignificant transaminitis, and, in fact, severe liver reactions are likely due to medications interactions rather than statin toxicity. As a result, the FDA no longer recommends routine monitoring of liver transaminases for those with normal baseline liver function tests unless clinically indicated.⁴

Similarly, concern over acute kidney injury is not supported by large RCTs, and statins, particularly atorvastatin, have been shown to be renoprotective. Even if acute kidney injury was directly due to statins, the incidence of these events is so low, and their clinical importance is so unclear that the well-supported cardiovascular benefit of statins outweighs the risk. Patients should be counseled that major organ concerns are minor issues.

Finally, robust evidence from 27 randomized trials has demonstrated that after a median of 5 years of statin therapy, there is no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).⁶¹ These concerns should not limit the use of statins in groups where benefit has been clearly documented.

Medication Adherence: The Sixth M

Medication adherence is a complex problem and is a function of numerous factors: economics, incentives, physician education, patient education, protocol of care, and technology.⁶² Adherence and persistence remain major problems for preventative cardiovascular medications, including statins,³¹ and this shortcoming is not without cost. Medication nonadherence across the health care system costs an estimated US$290 billion annually.⁶²

Nonadherence to statins and other cardiovascular medications likely contributes significantly to this figure. A meta-analysis of 376 162 patients across 20 studies showed that adherence to cardiovascular medications was 57% after 2 years.⁶³ In particular, adherence was lower among those receiving these medications for primary prevention compared to secondary prevention: 57% versus 76%. Such nonadherence contributes clearly to poorer outcomes. A retrospective study demonstrated that nonadherence to secondary prevention medications after 1 year was associated with a 19% increase in a combined outcome of cardiovascular death, MI, or stroke.⁶⁴

Despite the multifactorial nature of medication nonadherence, there are settings in which adherence is high. Clinical trials, such as the Scandinavian Simvastatin Survival Study, maintained 90% adherence rates across 5 years.⁵³ This is attributed to the intense attention that these patients receive while enrolled in the study, with the specific goal of maintaining adherence. Obviously, these intense interventions cannot be replicated in the real world, but they cast light on the types of interventions that are effective.

One particularly important element of clinical trials is reliable information and education regarding the risks and benefits of medications.⁶² Indeed 1 small study showed that extensive education about cardiovascular risk improved adherence compared to routine care.⁶⁵ Additionally, a report based on patient experience in the English National Health Care system reported that 21% of patients wanted more information regarding side effects of their medication.⁶⁶ Recommendations for improving medication adherence advocate for improved shared decision making, a critical aspect of which is delivery of risk and benefit information.⁶⁷ To demonstrate this, 1 study randomized 202 patients on statins for secondary prevention to comprehensive information (including side effects) or no additional information about their statin.⁵ As a result, they had better adherence (62.7% vs 46%) and were more likely to achieve cholesterol targets (64.7% vs 43%).

Using the 5 Ms represents a convenient and time-efficient way to inform the patient of the most well-known and publicized side effects of statins. By engaging the patient in a dialogue regarding these side effects, it is more likely that the patient will trust their physician to give them a balanced appraisal of the evidence and help them to make the best choice for their care. This circumstance is far preferable to the contradictory, and often unsubstantiated, information patients are likely to encounter outside their doctor’s office. Such a systematic and clear explanation is a key element of the newest cholesterol management guidelines and carries the promise to improve medication adherence and, ultimately, outcomes.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Addressing Statin Adverse Effects in the Clinic

Abstract

Keywords

Case History

Introduction

Metabolism

Background

Studies/RCTs/Systematic Reviews

Summary

Muscle

Background

Studies/RCTs/Systematic Reviews

Summary

Medication Interactions

Background

Studies/RCTs/Systematic Reviews

Summary

Memory

Background

Studies/RCTs/Systematic Reviews

Summary

Major Organ Effects

Background

Studies/RCTs/Systematic Reviews

Liver

Kidney

Summary

Medication Adherence: The Sixth M

Footnotes

Declaration of Conflicting Interests

Funding

References