Version October 2024
INTRODUCTION — Lipid-altering agents encompass several classes of drugs that include hydroxymethylglutaryl (HMG) CoA reductase inhibitors or statins, fibric acid derivatives, bile acid sequestrants, cholesterol absorption inhibitors, and nicotinic acid. These drugs differ with respect to mechanism of action and to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Conventional dosing regimens and common adverse reactions are described in a table (table 1) and the range of expected changes in the lipid profile are listed in a separate table (table 2).
Lipid lowering, at least with statins, is beneficial for primary and secondary prevention of coronary heart disease in patients with dyslipidemias. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
The mechanisms of benefit seen with lipid lowering are incompletely understood. Regression of atherosclerosis occurs in only a minority of patients; furthermore, clinical benefits of lipid lowering are seen in as little as six months, before significant regression could occur. Thus, other factors must contribute; these include plaque stabilization, reversal of endothelial dysfunction, and decreased thrombogenicity. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
The characteristics and efficacy of the statins will be reviewed here (table 3). The efficacy of fibrates, lipid-lowering drugs other than statins and fibrates, and diet and dietary supplements are also discussed separately. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "Lipid management with diet or dietary supplements" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates'.)
The major adverse reaction limiting statin use is the development of muscle symptoms, a condition known as statin-associated muscle symptoms (SAMS). This problem, including predisposing drug interactions, is discussed in detail separately. (See "Statin muscle-related adverse events".)
Therapeutic decision-making in patients with elevated lipid levels, including indications for and dosing of statins, is also discussed in detail separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
MECHANISM OF ACTION — Available statins include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin (table 3). These agents are competitive inhibitors of hydroxymethylglutaryl (HMG) CoA reductase, the rate-limiting step in cholesterol biosynthesis (figure 1). They occupy a portion of the binding site of HMG CoA, blocking access of this substrate to the active site on the enzyme [1].
A reduction in intrahepatic cholesterol leads to an increase in low-density lipoprotein (LDL) receptor turnover that results from an enhanced rate of hepatic LDL receptor cycling [2]. Statins also reduce very low-density lipoprotein (VLDL) production via an effect mediated by hepatic apolipoprotein B secretion [3,4], which is associated with a diminished rate of recovery of HMG CoA reductase activity after drug treatment [5].
Most of the statins have modest high-density lipoprotein (HDL) cholesterol raising properties (approximately 5 percent), although rosuvastatin has a larger effect (see 'Effect on HDL' below). Triglyceride concentrations fall by an average of 20 to 40 percent depending upon the statin and dose used (see 'Effect on triglycerides' below). The clinical relevance of these differences is uncertain. The reduction in plasma triglycerides is due to a decrease in VLDL synthesis and to clearance of VLDL remnant particles by apolipoprotein B/E (LDL) receptors.
The mechanisms by which statins may affect cardiovascular disease are discussed separately. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
EFFICACY — The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia.
Effect on LDL cholesterol
Potency — Aside from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, statins are the most powerful drugs for lowering low-density lipoprotein (LDL) cholesterol, with reductions in the range of 30 to 63 percent (table 3) [6-10]. When switching between statin drugs, equipotent doses with regard to LDL cholesterol reduction can be found in the figure (figure 2).
Rosuvastatin is somewhat more potent than atorvastatin [10,11], and both these agents are significantly more potent than simvastatin, lovastatin, pravastatin, and fluvastatin [11,12]. At maximal prescribed doses, LDL cholesterol reduction is greater with rosuvastatin and atorvastatin than with the other available statins (figure 2).
At doses of up to 40 mg/day, fluvastatin is the least potent statin (figure 2). However, at doses of 80 mg/day, fluvastatin is as effective on lowering LDL cholesterol as most statins other than rosuvastatin and atorvastatin [13]. Fluvastatin, pitavastatin, and pravastatin are less likely to have drug interactions or produce muscle toxicity than some other statins. (See 'Side effects' below.)
Although simvastatin 80 mg/day is a high-intensity dose of statin, given high rates of adverse muscle symptoms including rhabdomyolysis [14] and the availability of generic rosuvastatin and atorvastatin, we suggest not treating patients with doses of simvastatin above 40 mg/day. Additionally, clinicians should strongly consider switching even patients who are currently tolerating simvastatin 80 mg/day to one of these other statin options since future medication therapy or illness could increase the risk for development of myopathy on high-dose simvastatin. High-dose simvastatin may be appropriate for a small number of patients who have tolerated it well for many years or who are intolerant of other high-potency statin options.
There is an additive hypolipidemic effect when any of the statins is used in combination with a bile acid sequestrant (figure 3) [15-17], or the cholesterol absorption inhibitor ezetimibe. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)
LDL subfractions — Statins are the most effective oral agents for lowering total LDL particle concentration; however, they are nonselective for reducing LDL subclasses; they reduce the predominant subclass [18]. Among patients with the atherogenic dyslipidemia profile, the reduction in the predominant subclass of small, dense LDL particles results in a shift of the LDL subfractions to more buoyant, and potentially less atherogenic, LDL [19-21]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Small dense LDL (LDL phenotype B)' and "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Intermediate-density lipoprotein (remnant lipoproteins)' and "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Low-density lipoprotein'.)
Effect on HDL — Statin therapy alters high-density lipoprotein (HDL) cholesterol levels, typically raising them, but these effects vary by statin and by dose of statin and do not correlate with the effects on LDL cholesterol levels. As examples, simvastatin and rosuvastatin appear to raise HDL cholesterol more as the dose is increased, while the increase in HDL cholesterol seen with atorvastatin is attenuated at higher doses [22]. In some patients, HDL cholesterol may decline on statin therapy. The variable effects of statins on HDL cholesterol levels and HDL function may be due to their effects on hepatic microRNA33 (miR33); inhibitory mRNA 33 interferes with macrophage ABCA1-mediated efflux [23-25]. Whether the changes seen in HDL cholesterol with statin therapy are clinically important is uncertain. (See "HDL cholesterol: Clinical aspects of abnormal values".)
Effect on triglycerides — Atorvastatin and rosuvastatin are more effective at lowering triglycerides (14 to 33 percent) than other statins in patients with hypercholesterolemia [11,26-28]. The magnitude of triglyceride lowering with statins may be as high as 40 to 44 percent in patients with hypertriglyceridemia.
The effects of atorvastatin and rosuvastatin on serum triglycerides are dose-dependent [11,26]. As an example, in a series of 56 patients with primary hypertriglyceridemia in whom the average triglyceride concentration was 600 mg/dL and LDL cholesterol concentration was 120 mg/dL (3.1 mmol/L), the administration of atorvastatin at doses of 5, 20, or 80 mg/day produced reductions in triglycerides of 27, 32, and 46 percent, respectively, and in LDL cholesterol of 17, 33, and 41 percent, respectively [26].
Genetic/race effects — Part of the variability in the response to and side effects with statins may be related to genetic differences in the rate of drug metabolism. As an example, CYP2D6 is a member of the cytochrome P450 superfamily of drug oxidizing enzymes. CYP2D6 is functionally absent in 7 percent of White and African American individuals, while deficiency is rare among Asian persons.
The CYP2D6 phenotype appears to be important in patients treated with simvastatin, as it can affect both the degree of lipid lowering and tolerability [29]. Polymorphisms in the gene coding for hydroxymethylglutaryl (HMG) CoA reductase also appear to affect the LDL cholesterol response to statins, but not the HDL cholesterol response [30].
Concerns have been raised that persons from Asia (mostly China, Japan and Korea) may have greater responses to low doses of statins than European American individuals [31]. Prescribing information for rosuvastatin recommends starting therapy at a lower initial dose in Asian individuals than in other groups, given observed differences in pharmacokinetics [32]. There is no strong evidence supporting such an approach with other statins.
Prevention of cardiovascular disease — The major use of statins is in the primary and secondary prevention of cardiovascular disease. This use is discussed extensively elsewhere:
●(See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".)
●(See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
Noncardiovascular disease outcomes — A pooled analysis of meta-analyses of observational studies and randomized trials examining outcomes of statin found no convincing evidence of an association between statins and most noncardiovascular disease outcomes [33]. A possible exception may be a beneficial effect on all-cause mortality among patients with kidney disease. (See 'Kidney dysfunction' below.)
SIDE EFFECTS
Frequency — Adverse reactions occur less frequently with the statins than with most other classes of lipid-lowering agents. Adverse muscle events remain important side effects [34,35] (see "Statin muscle-related adverse events"). Hepatic dysfunction has been a source of concern; however, the actual risk appears to be very small.
In randomized trials, statin therapy appears to cause only a slight increased risk of side effects compared with placebo, and no increased risk of discontinuation of therapy compared with placebo [36,37]. In a 2017 meta-analysis of 22 placebo-controlled trials on statin use involving nearly 130,000 participants, 13.3 percent of subjects receiving a statin discontinued the drug compared with 13.9 percent of subjects on placebo (odds ratio [OR] 0.99, 95% CI 0.93-1.06) over a mean follow-up of 4.1 years [38]. In clinical practice, side effects with statins are common, which could be related in part to a heightened awareness of adverse reactions traditionally attributed to the drug and treatment in patients with comorbidities that were often excluded from clinical trials. In a randomized double-blind, placebo-controlled trial involving over 10,000 patients, atorvastatin therapy was not associated with an increased rate of muscle-related adverse events [39]. By contrast, in a subsequent nonrandomized, nonblinded extension of the study, muscle-related adverse events were reported more often in patients taking atorvastatin compared with placebo (1.26 versus 1.00 percent per annum). These results suggest that some muscle-related adverse events attributed to atorvastatin are not causally linked to the drug.
There have been concerns that the more lipophilic statins (simvastatin, lovastatin, atorvastatin, and fluvastatin) may be associated with more adverse events than the more hydrophilic statins (pravastatin and rosuvastatin) [40,41]; however, fluvastatin (a lipophilic statin) appears to have a low rate of muscle side effects [42]. Differences in adverse events may derive from heterogeneity in drug elimination pathways [34,35].
Management considerations — As discussed above, while data from clinical trials suggest low rates of statin side effects leading to discontinuation, in clinical experience, it is relatively common to find patients who are intolerant of one or more statins because of myalgias or other muscular symptoms. Less commonly, aminotransferase elevations require making changes in the statin, the statin dose, or changes to another class of cholesterol-lowering therapy.
The approach to managing statin-induced muscle adverse events is shown in the algorithm and is discussed in detail separately (algorithm 1). (See "Statin muscle-related adverse events", section on 'Management'.)
Options in patients with aminotransferase elevations (more than three times the upper limit of normal; confirmed on repeat testing) are similar, and include (see 'Hepatic dysfunction' below):
●Use of a different statin
●Dose reduction
●Alternate day therapy (see 'Alternative dosing regimens' below)
Observational data suggest that, while discontinuation of statin therapy for side effects is relatively common, many patients tolerate the same drug or another statin when rechallenged [43,44]. In addition, there may be risk associated with discontinuing statin therapy. In a retrospective cohort study of 28,266 patients on statins who reported an adverse reaction, over 70 percent were able to remain on therapy [44]. Of note, four years later, the cumulative incidence of a cardiovascular event (myocardial infarction or stroke) or death was lower in patients who continued on statin therapy compared with those who had stopped it (12.2 versus 13.9 percent [hazard ratio [HR] 0.87, 95% CI 0.81-0.93]). In another study of 105,329 Medicare beneficiaries following hospitalization for myocardial infarction, statin down-titration or discontinuation compared with adherence to high-intensity statin therapy over a median of 1.9 to 2.3 years of follow-up was associated with an increased risk of recurrent myocardial infarction (HR 1.50, 95% CI 1.30-1.73) [45].
Some patients do not tolerate statin therapy even after changing to a different statin, reducing the dose, and/or using alternate-day dosing. The clinical management of patients unable to take statin therapy for secondary prevention is discussed in detail separately. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome", section on 'Statin intolerance' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
Hepatic dysfunction — Clinical studies of statins have demonstrated a 0.5 to 3.0 percent occurrence of persistent elevations in aminotransferases in patients receiving statins. This has primarily occurred during the first three months of therapy and is dose dependent.
Rare episodes of more severe liver injury have also been seen, and one study suggested that these predominantly occur three to four months after initiation of statin therapy [46], with a range in one study of one month to 10 years [47]. However, these are sufficiently uncommon that the overall incidence of hepatic failure in patients taking statins appears to be no different from the incidence in the general population [48]. The pattern of more severe hepatotoxicity attributed to statins has included hepatocellular, cholestatic, and autoimmune injury [47].
Several randomized trials have reported no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo therapy [49-51]. A similar finding was noted in a review of three pravastatin trials with over 112,000 patient-years of exposure [52]. There was no difference in the incidence or severity of serum aminotransferase elevations with pravastatin or placebo, including patients with aminotransferase elevations at study entry. A meta-analysis of 35 randomized trials found an excess risk of aminotransferase elevation with statin therapy versus placebo of 4.2 cases per 1000 patients [36].
A large cohort study from England and Wales found similar risks of hepatic dysfunction with different statins, with the exception of a higher risk with fluvastatin [53].
A review of one year of records for 1014 patients taking statins in a primary care practice found that 1 percent of patients had transaminase elevations more than three times normal and 0.5 percent had transaminase elevations two to three times normal [54]. None of these elevations appeared to be related to statin use. Similarly, a review of five years of a health maintenance organization's computerized records on 23,000 patients who were receiving statins found that 17 (0.1 percent) had an alanine aminotransferase (ALT) level more than 10 times the upper limit of normal that appeared to be attributable to statin therapy [55]. Of these, all but four were associated with drug interactions.
In 2012, the US Food and Drug Administration (FDA) revised its labeling information on statins to only recommend liver function testing prior to initiation of statin therapy and to only repeat such testing for clinical indications [56]. We and others agree that routine monitoring of liver function tests in patients receiving statin therapy is not necessary [51,55,57,58].
We recommend changing medications or lowering the statin dose in patients who are found to have an ALT level more than three times the upper limit of normal that is confirmed on a second occasion.
Muscle injury — Development of muscle toxicity is a concern with the use of statins. This problem, including predisposing drug interactions and an approach to management, is discussed in detail separately. (See "Statin muscle-related adverse events".)
Hypothyroidism is a potential cause of dyslipidemia (see "Lipid abnormalities in thyroid disease"), and hypothyroidism may predispose patients to statin-induced myopathy [59,60] (see "Statin muscle-related adverse events", section on 'Hypothyroidism, hypovitaminosis D, and other disorders'). As such, we suggest checking a thyroid-stimulating hormone level prior to initiating statin therapy.
Kidney dysfunction — Statin use does not appear to increase the risk of acute kidney injury (AKI); however, some data suggest that rosuvastatin may increase the risk of adverse kidney outcomes. A retrospective analysis of large, population-based cohorts found an association between high potency statins and hospital admission for AKI, particularly in the first 120 days after initiation of statin therapy [61]. However, subsequent meta-analyses of randomized trials did not find evidence of an increase in AKI or serious adverse kidney events [33,62].
However, a large cohort study raised the possibility that rosuvastatin, specifically, may be associated with an increase in adverse kidney outcomes, particularly at high doses. In this cohort study of 947,900 new statin users who were followed for eight years, rosuvastatin was associated with increased risk of hematuria (HR 1.08, 95% CI 1.04-1.11), proteinuria (HR 1.17, 95% CI 1.10-1.25), and kidney failure requiring replacement therapy (HR 1.15, 95% CI 1.02-1.30), compared with atorvastatin [63]. Rates were dose dependent and may be partially explained by the fact that 44 percent of participants with an estimated glomerular filtration rate <30 mL/min per 1.73 m2 were prescribed a rosuvastatin dose that exceeded the recommended daily dose of 10 mg. Although earlier studies comparing rosuvastatin with other statins found comparable rates of adverse kidney events, results from those studies were imprecise and consistent with either potential benefit or harm [64-66].
Statins may cause proteinuria through tubular inhibition of active transport of small molecular weight proteins [67,68]; however, the clinical significance of this finding is unclear [32,69].
Statin use reduces all-cause and cardiovascular mortality and cardiovascular events in individuals with nondialysis chronic kidney disease. Statin therapy in these patients is discussed separately. (See "Lipid management in patients with nondialysis chronic kidney disease".)
Behavioral and cognitive — Although concerns have been raised about increased suicide in patients treated with some lipid-lowering therapies, statins do not appear to be associated with an increased risk of suicide or depression [70]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
There have been case reports of patients developing severe irritability and aggression associated with the use of statins [71]. It is not known whether the statin use caused these symptoms, but very rare idiosyncratic reactions of this sort could be missed in controlled trials.
A retrospective cohort study in older adult patients found an association between perioperative statin use and postoperative delirium [72]; however, it is difficult to tell whether this association was causal [73]. Perioperative administration of statins may have important cardiovascular benefits. (See "Perioperative medication management", section on 'Statins'.)
Concerns have been raised in the media and popular press about cognitive dysfunction and memory loss associated with statin use [74]. A review of adverse events reported to the FDA between November 1997 and February 2002 found 60 reports of patients who had memory loss associated with statins [75]. Fourteen of 25 patients had improvement when the statin was discontinued, and four had recurrence of memory loss on rechallenge. The statins involved were simvastatin (36 patients), atorvastatin (23 patients), and pravastatin (1 patient).
Although this analysis of adverse event reports does not show that statins cause memory loss, the apparently high rate of reports with lipophilic statins (simvastatin and atorvastatin) compared with hydrophilic statins (pravastatin) does suggest a possible biologic effect. Randomized trials of lovastatin and simvastatin have shown some evidence of minor decrements in cognitive function as measured by neuropsychologic testing [76,77]. A systematic review of randomized trials and observational studies found that published data do not suggest that statins harm cognition; however, the quality of the evidence was felt to be only low to moderate, particularly with regard to high-intensity statin therapy [78]. A 2015 systematic review of randomized trials similarly concluded that statin therapy was not associated with harming cognitive function in either cognitively normal patients or those with Alzheimer disease [79]. However, randomized trials can fail to detect rare medication side effects. A large database observational study found an association between first exposure to statin therapy and acute memory loss (within 30 days); however, the same association was found for other lipid-lowering agents and the authors thought it more likely that the result reflected detection bias rather than a true causal effect of multiple lipid-lowering therapies [80]. In our experience, we have encountered rare patients who appear to experience cognitive side effects on a statin that resolve with discontinuation and recur with reinstitution; some of these patients appear to tolerate an alternative statin.
In the absence of more definitive data, it may be appropriate for clinicians to determine whether statin therapy was recently initiated in patients who develop new memory loss. If an individual patient appears to have memory loss associated with lipophilic statin therapy (simvastatin, lovastatin, atorvastatin, or fluvastatin) and has a strong indication for lipid-lowering therapy, it would be reasonable to attempt treatment with a more hydrophilic statin (pravastatin or rosuvastatin) [81].
In contrast to the above observations suggesting that statins may produce cognitive impairment, other studies have suggested that statins may have a role in the prevention of dementia. (See "Prevention of dementia", section on 'Statins'.)
Diabetes mellitus — It appears likely that statin therapy confers a small increased risk of developing diabetes and that the risk is slightly greater with intensive statin therapy than moderate statin therapy. As would be expected, given the evidence from clinical trials that statins reduce cardiovascular events in patient with diabetes (see "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease"), both randomized trials and observational studies suggest that the beneficial effects of statins on cardiovascular events and mortality outweigh any increased risk conferred by promoting the development of diabetes [82,83].
Statins could have effects on glucose metabolism that might influence the development of diabetes mellitus in nondiabetics or affect glycemic control in patients with existing diabetes. Experimental evidence has been conflicting about whether statins as a group improve glucose metabolism or whether some statins show beneficial effects while others show harmful effects [84-89].
Some clinical trials of statins had reported conflicting results on the issue of glucose metabolism [90-93]. However, a 2010 meta-analysis of 13 trials (n = 91,140) found little evidence of heterogeneity among large-scale chronic treatment trials [94]. For inclusion, trials were required to have more than 1000 patients and a duration of follow-up of more than one year. This meta-analysis found an overall small increased risk for diabetes in patients treated with statins (OR for incident diabetes 1.09, 95% CI 1.02-1.17). Subgroup analyses found very similar diabetes risks in trials of hydrophilic or lipophilic statins, and no clear differences among individual statins. The results were also similar after the exclusion of the JUPITER trial. Since JUPITER had raised much of the concern about diabetes and statins [91], the stability of the result without JUPITER lowers the likelihood that the glucose findings in the meta-analysis were due to chance.
A 2011 meta-analysis of five randomized trials (n = 32,752) also found an increased risk of incident diabetes with intensive statin therapy compared with moderate statin therapy (OR 1.12, CI 1.04-1.22) with little or no heterogeneity across trials [95]. This translates into approximately one additional case of diabetes for every 500 patients treated with intensive rather than moderate statin therapy. Similarly, a large observational study using administrative data found a higher risk of diabetes with high-potency statins, an intermediate risk with moderate-potency statins, and a lower risk with low-potency statins [96].
A 2015 meta-analysis confirmed these results both for the risk of diabetes with statins versus placebo (OR 1.11, CI 1.03-1.20) and for intensive versus moderate-intensity statin therapy (OR 1.12, 1.04-1.22) [97]. This study also included a Mendelian randomization study (see "Mendelian randomization") that found that decreased genetic hydroxymethylglutaryl (HMG) CoA reductase activity is associated with a higher risk of type 2 diabetes, such that at least some of the risk seen with statin therapy appears to be due to its on-target effect of inhibiting HMG CoA reductase. This is important because it means that this side effect of statins cannot likely be eliminated while maintaining the primary efficacy of statin therapy [98].
A 2016 analysis estimated that high-dose statin therapy (eg, atorvastatin 40 mg/day) would lead to 50 to 100 new cases of diabetes in 10,000 treated individuals [99].
Other possible associations
●Cancer – There is no convincing evidence from meta-analyses of randomized trial that statins increase or decrease the risk of cancer [33,100-106].
Statin eligibility for primary prevention using American College of Cardiology/American Heart Association (ACC/AHA) criteria may predict cancer risk and mortality. In a Framingham Heart Study analysis, the incident cancer rate was 15 percent in the statin-eligible group compared with 8.8 percent in those who were ineligible (HR 1.8, 95% CI 1.4-2.3) [107]. Cancer-related deaths occurred in 4.2 percent of the statin-eligible group compared with 0.4 percent in those who were ineligible (HR 12.1, 95% CI 4.7-31). In a stratified analysis, these findings were independent of known cancer risk factors such as increased body mass index, increased age, and smoking history. While the explanation for this observation is unclear, these results suggest that factors contributing to statin eligibility may also be predictive of an increased risk of cancer.
●Cataract – Most large case-control and cohort studies [108-110], as well as a small randomized trial [111], have not found an increased risk of cataract, although large cohort studies from England, Wales, and the United States military health system have found that statin use was associated with an increased risk of cataract [53,112].
In a subset analysis, one cohort study reported an association between statins and a decreased risk of one type of cataract (nuclear cataract) [110]. An analysis of safety results from a randomized trial also found an apparent protective effect of lipid-lowering therapy with simvastatin plus ezetimibe [113]; however, there were very few cataract events, the types of cataracts were not reported, the result was of borderline statistical significance, and reporting bias is a concern with these sorts of results from safety data. Additional study is clearly needed before it can be concluded that statins actually have any such protective effect.
●Neuropathy – A number of studies have suggested that statin use may be associated with the development of peripheral neuropathy. However, a 2020 systematic review of 13 studies concluded that there was insufficient evidence that statin use was a risk factor for polyneuropathy, and that the available studies had methodologic flaws [114]. A small case-control study, conducted by the same authors, did not find an association between patients with polyneuropathy and prior statin use [114]. As such, a causal association between statin use and neuropathy remains possible but has not been proven.
●Lupus – There have been case reports of drug-induced lupus in patients receiving statins. (See "Drug-induced lupus".)
●Androgen synthesis – Some [115,116], but not all [117], studies suggest that statins may lower androgen levels in men, although it appears unlikely that this effect is clinically significant [118]. Statins may also reduce androgen levels in women, including in women with androgen excess [89].
●Immune response – Some observational studies have suggested that the immune response to influenza immunization, and the efficacy of that immunization in preventing clinical influenza, may be reduced in older adult patients receiving statin therapy. The possible implications of these results for patient management are discussed separately. (See "Seasonal influenza vaccination in adults".)
Risks in pregnancy and breastfeeding — In the United States, the FDA has recommended that statins be discontinued in most pregnant patients [119]. However, clinicians may consider their use in patients at very high risk of cardiovascular events during pregnancy, such as those with homozygous familial hypercholesterolemia or established cardiovascular disease. Breastfeeding is still not recommended in patients taking a statin, and clinicians are advised to determine whether it is better to temporarily stop statin therapy while breastfeeding or to continue statin therapy and not have the patient breastfeed. We strongly advise a patient-clinician dialogue to discuss the risks and benefits of continued statin therapy versus alternative treatments (eg, apheresis) to lower low-density lipoprotein (LDL) cholesterol during pregnancy and breastfeeding. Documentation of these discussions should be entered into the medical record.
If a statin is to be discontinued during pregnancy, we recommend, based on the drug half-life, withdrawal a minimum of 6 weeks and preferably 12 weeks before planned conception.
ADMINISTRATION
Timing of administration — The majority of cholesterol synthesis appears to occur at night [120], presumably reflecting the effects of a fasting state. For this reason, it is typically recommended that the statins with shorter half-lives be administered in the evening or at bedtime (table 3 and table 1).
In support of this, trials have found greater reductions in total and low-density lipoprotein (LDL) cholesterol when simvastatin, which has a relatively short half-life, is administered in the evening rather than in the morning [121,122]. A small study of atorvastatin, which has a long half-life, found no significant differences whether it was administered in the morning or the evening [123].
While it is unknown whether the timing of statin administration is important for clinical outcomes, we typically administer statins at the time recommended by the manufacturer (table 3). Lovastatin absorption is increased by food, and it should be administered with the morning and evening meals.
Alternative dosing regimens — Every-other-day statin therapy has been suggested as a strategy to improve utilization and decrease cost. Small studies have compared daily statin use with alternate-day dosing, and measured effects on lipid parameters and, in some cases, attainment of cholesterol goals over 6 to 12 weeks [124-128]. Every-other-day regimens, and even once-weekly regimens, have also been evaluated as strategies for improving tolerability [129-131].
Results with atorvastatin, fluvastatin, and rosuvastatin suggest that to yield similar LDL cholesterol lowering, the every-other-day dose needs to be on average nearly twice that of the daily dose [124,125,127,131]. There are few data on alternate-day regimens using a dose greater than 40 mg or on how patient adherence is impacted.
Major outcomes trials of statins have used daily statin therapy. In the absence of data from large, randomized trials demonstrating equivalent effects on clinical outcomes with alternative dosing regimens, we suggest daily dosing in patients who are treated with statins. We prefer other measures for cost control, such as price comparison among generic statins [132]. Clinical experience suggests that alternate-day dosing may improve the tolerability of statins in patients experiencing myalgias, and this strategy can reasonably be tried in patients unable to tolerate daily statin therapy. (See "Statin muscle-related adverse events", section on 'Alternate-day dosing'.)
Interchange — When switching between statin drugs, equipotent doses with regard to LDL cholesterol reduction can be found in the figure (figure 2). (See 'Potency' above.)
Simvastatin and atorvastatin may be associated with more adverse events than pravastatin or fluvastatin [42]. (See 'Side effects' above.)
Drug interactions — The uptake, metabolism, and clearance of each statin differs, and therefore each statin is subject to different types of drug interactions (table 3). Simvastatin, lovastatin, and to a lesser extent atorvastatin are metabolized by cytochrome P450 3A4 (CYP3A4). Fluvastatin clearance is partly dependent upon CYP2C9 metabolism, whereas rosuvastatin, pitavastatin, and pravastatin are cleared primarily by non-CYP450 transformations [133,134].
The most common concern regarding a potential harmful drug interaction between a statin and another drug is induced muscle injury potentially leading to acute kidney injury. This risk is substantially greater in patients receiving concurrent therapy with a number of drugs, particularly those that inhibit statin metabolism (eg, by CYP3A4) (table 4) or transmembrane transporters (eg, organic anion transporting polypeptides [OATPs] or breast cancer resistance proteins [BCRP]) [133]. Additionally, concurrent use of a drug or drug class that is independently considered a risk factor for myopathy (ie, glucocorticoids, fibrates daptomycin, zidovudine) may further increase risk of statin-related myopathy. This issue is discussed in greater detail separately. (See "Statin muscle-related adverse events".)
Certain drug interactions are discussed below. Additional detail about specific statin interactions and management suggestions is available from the drug interactions program included within UpToDate.
●CYP3A4 drugs – Drugs and substances that inhibit CYP3A4 (table 4) can increase the risk of statin myopathy when administered with statins extensively metabolized by CYP3A4 (eg, lovastatin, simvastatin, and to a lesser extent atorvastatin) (table 3) [134]. Select examples are discussed below; however, this list is not exhaustive.
●Calcium channel blockers – The non-dihydropyridine calcium channel blockers diltiazem and verapamil are moderate inhibitors of CYP3A4 metabolism and can increase exposure to statins that are extensively metabolized by CYP3A4. Manufacturer data indicate that, at a simvastatin dose of 20 to 80 mg/day, there is a 0.6 percent incidence of myopathy in patients also treated with verapamil (a value 10 times higher than seen in patients taking simvastatin without a calcium channel blocker) [135]. The risk is also increased when simvastatin is taken with the dihydropyridine calcium channel blocker, amlodipine, which is metabolized by and also weakly inhibits CYP3A4 [136].
●Human immunodeficiency virus (HIV) protease inhibitors – HIV protease inhibitors and pharmacologic boosters (eg, ritonavir, cobicistat) are potent inhibitors of CYP3A4. Thus, statins that are highly dependent upon CYP3A4 for clearance (eg, simvastatin, lovastatin) are contraindicated for use by patients receiving HIV protease inhibitors and boosting agents [136-138]. In general, other statins may be used with HIV protease inhibitors and boosting agents, but interactions should be checked before initiating statin therapy by using a drug interactions program as dose limitations may be required for some statins (eg, atorvastatin, rosuvastatin) and complete avoidance for other statins (eg, simvastatin, lovastatin). A detailed discussion of statin therapy in patients with HIV is available elsewhere. (See "Management of cardiovascular risk (including dyslipidemia) in patients with HIV", section on 'Statin use'.)
●Amiodarone – Amiodarone and its metabolites weakly inhibit CYP3A4 metabolism [133]. A pharmacokinetic study found a significant increase in simvastatin exposure with amiodarone, and pharmacovigilance data suggest that there is an increased risk of myopathy and rhabdomyolysis, particularly with simvastatin doses greater than 20 mg/day [136,139-142]. The risk of rhabdomyolysis in patients treated concurrently with amiodarone appears to be higher with simvastatin than with other statins [133].
●Grapefruit juice – Grapefruit juice inhibits intestinal CYP3A4; however, daily consumption of 8 oz (240 mL) or less of grapefruit juice, or one-half of a grapefruit or less, is unlikely to increase the risk of an adverse interaction or muscle injury with most statins [143]. However, in a crossover study with simvastatin, daily grapefruit juice consumption (200 mL) increased simvastatin exposure to 3.6 times the baseline [144]. For patients who consume large amounts of grapefruit or grapefruit juice, we recommend a hydrophilic statin (eg, rosuvastatin, pravastatin, pitavastatin).
●OATP inhibitors – OATPs are transport proteins that facilitate hepatic uptake of many drugs, including statins (properties of statins table). Though the role of OATPs in drug metabolism is not yet fully understood, OATP-mediated transport of statins from the systemic circulation into hepatocytes appears to be an important step preceding oxidative metabolism (eg, by CYP3A4) and/or biliary excretion (eg, by BCRP) [145]. OATP inhibition may increase statin serum concentrations and thereby increase adverse events including myopathy [133]. This may be additive with other pharmacokinetic effects such as CYP3A4 inhibition (as with cyclosporine and clarithromycin) or BCRP inhibition (as with some hepatitis C virus [HCV] protease inhibitor combinations). Manufacturer's labeling for certain statins (eg, rosuvastatin, atorvastatin, pitavastatin) include specific dose limits for interactions with OATP inhibitors [146-148].
●Cyclosporine – Cyclosporine is an inhibitor and substrate of CYP3A4 and an inhibitor of CYP2C9, various OATPs (eg, OATP1B1, OATP1B3), and BCRP [133,145]. Cyclosporine coadministration can increase serum concentrations of all statins via complex pharmacokinetic interactions, thus contributing to increased risk for adverse effects [133]. For example, regular-dose lovastatin (40 to 80 mg/day) and simvastatin (20 mg/day) are associated with an appreciable risk of myositis (as high as 13 to 30 percent) in cyclosporine-treated patients [149-151]. This is thought to be the result of cyclosporine inhibition of OATP1B1-mediated hepatic uptake of simvastatin and lovastatin and inhibition of CYP3A4 metabolism.
Although pitavastatin, pravastatin, and rosuvastatin are not significantly metabolized by CYP3A4, they interact with cyclosporine by non-CYP mechanisms (eg, by OATP1B1 and BCRP inhibition) [146,148,152]. Recommendations for statin therapy in patients with kidney and heart transplants is discussed in greater detail separately. (See "Lipid abnormalities after kidney transplantation", section on 'Patients without established ASCVD (primary prevention)'.)
●HCV direct-acting antivirals (DAAs) – Many HCV DAAs increase statin exposure and toxicity. Though the mechanisms are not well-established, inhibition of transporters such as OATPs and BCRP appear to play an important role in statin interactions with DAAs (eg, simeprevir, sofosbuvir-velpatasvir, glecaprevir-pibrentasvir) [146,153]. CYP interactions may also occur, though this seems less common [154]. Interactions should be checked using a drug interactions program before coadministration of statins with DAA-containing regimens.
●Fibrates – Fibrates are independently associated with muscle toxicity, and their concomitant use with statins can increase the risk of muscle injury, including rhabdomyolysis [155]. The effect is due in part to an increase in statin levels and varies according to the fibrate and statin. Toxicity can be minimized by the choice of fibrate and by using statins at relatively low doses [156-158].
Fenofibrate is the preferred fibrate in patients who require combined therapy with a statin due to minimal risk of increase in statin levels [40]. It appears to be safer than gemfibrozil due to a differential effect on statin excretion [159,160]. The relative safety of fenofibrate has been demonstrated in meta-analyses and individual trials, in which there has been no increase in muscle-related adverse events in patients taking fenofibrate plus a statin compared with a statin alone [161-163].
Gemfibrozil has a greater potential to increase plasma levels of statins, especially when used with lovastatin, simvastatin, or atorvastatin [149,164-166]. This is in part related to potent inhibition of OATP1B1 by gemfibrozil, which is responsible for hepatic uptake of all statins. Pravastatin and fluvastatin are the safest statins in this situation [156,167-172] and can be considered for use with gemfibrozil if the benefit is likely to outweigh the risk.
●Colchicine – Myopathy is an infrequent adverse effect of colchicine treatment and several cases have been reported following its coadministration with a statin, particularly in the setting of kidney function impairment. Colchicine is metabolized to a substantial degree by CYP3A4 and concurrent use may increase serum concentrations of statins that compete for this metabolic pathway (eg, atorvastatin, lovastatin, simvastatin) [133,173]. However, multiple mechanisms seem to be involved as the interaction has been reported with a variety of statins, including pravastatin, which is not metabolized by CYP3A4 to a clinically significant extent [174-176].
●Fusidic acid – Several cases of rhabdomyolysis have been reported following coadministration of atorvastatin or simvastatin with fusidic acid, an antimicrobial available primarily outside the United States [177-183]. The interaction appears to cause significant elevation in levels of both the statin and fusidic acid and could be due to inhibition of OATP1B1-mediated hepatic uptake of statins or decreases in biliary efflux [184,185], but the exact mechanism is unknown.
●Niacin – Early reports suggested an increased risk of myopathy with combination niacin (nicotinic acid) and statin treatment [186], and this is reflected in longstanding warnings found in some of the statin drug labels [138,146,187]. This complication appears to be uncommon, and the risk of myopathy has seemed similar to that of either agent taken separately [188-190]. However, in a large randomized trial in patients receiving simvastatin, the combination of niacin and laropiprant increased the risk of definite myopathy (1.6 versus 0.4 events per 1000 patients per year; risk ratio 4.4, 95% CI 2.6-7.5) [191]. The risk was particularly increased in participants from China (see "Statin muscle-related adverse events", section on 'Patient characteristics'). It is uncertain whether niacin alone carries the same increased myopathy risk as niacin/laropiprant; however, this trial was much larger than prior studies and had the potential to have detected an interaction between niacin and statins that could have been missed in earlier smaller studies.
UpToDate contributors generally avoid administering niacin to most patients receiving statin therapy due to concerns about safety and lack of efficacy for clinical endpoints. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)
●Clopidogrel – The antiplatelet agent clopidogrel is a prodrug that is activated via metabolism by CYP450. Based on available evidence, clopidogrel therapy need not affect the choice of statin. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Interaction with other drugs'.)
●Dabigatran – Another potential harmful interaction is that of statin use in patients taking dabigatran. In a study of older patients (80 percent >75 years) taking dabigatran for atrial fibrillation, the use of lovastatin or simvastatin was found to be associated with an increased risk of major hemorrhage compared with other statins (odds ratio [OR] 1.46, 95% CI 1.17-1.82) [192]. This has not been observed with other direct oral anticoagulants (DOACs).
●Rifampin – Rifampin has been reported to both increase and decrease statin concentrations, presumably due to a combination of OATP1B1 inhibition and CYP3A4 induction, respectively [193-195]. Patients should be closely monitored for statin efficacy and adverse effects during concurrent rifampin use. Manufacturer labeling for pitavastatin recommends dose limitations for coadministration with rifampin [148]; manufacturer labeling for atorvastatin recommends simultaneous coadministration with rifampin to avoid reduced concentrations observed with delayed atorvastatin administration [147].
Dose limitations — Manufacturer labeling for all statins include contraindications or dose limitations for coadministration with a variety of other medications. For example, manufacturer recommendations for simvastatin and lovastatin, state that these statins are contraindicated in patients treated with most strong CYP3A4 inhibitors (table 3) and there are dose limitations or recommendations to avoid these statins when used in conjunction with a number of other medications, eg, limitation of simvastatin to 20 mg/day when taken with amlodipine [56,136].
Given high rates of myopathy with simvastatin 80 mg/day [196] and the availability of generic alternatives for high-intensity statin therapy (ie, rosuvastatin and atorvastatin), we do not treat patients with doses of simvastatin above 40 mg/day. Additionally, clinicians should strongly consider switching patients who are currently tolerating simvastatin 80 mg/day to atorvastatin or rosuvastatin. (See 'Potency' above.)
For more detailed information about dose limitations, refer to the relevant clinical treatment reviews in UpToDate and the individual drug monographs included with UpToDate.
Monitoring — Routine monitoring of serum creatine kinase (CK) levels is not recommended in patients on statins, but it is useful to obtain a baseline CK level for reference purposes prior to starting statin therapy. Patients treated with statins should be alerted to report the new onset of myalgias or weakness. (See "Statin muscle-related adverse events", section on 'Monitoring'.)
We check baseline aminotransferase levels prior to initiating statin therapy; we do not routinely monitor these levels in patients on statins. (See 'Hepatic dysfunction' above.)
Monitoring of the lipid response to statin therapy is discussed separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Monitoring therapy'.)
Specific populations
Older adults — A discussion of dosing in older patients is found elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Older patients'.)
Chronic kidney disease — Chronic kidney disease presents an additional challenge for the selection of a statin. Atorvastatin and fluvastatin do not require dose adjustment and are the statins of choice in patients with severe kidney function impairment [197,198].
Dose adjustment is warranted with other statins in patients with severe kidney disease (creatinine clearance [CrCl] less than 30 mL/min). If statins other than atorvastatin or fluvastatin are used, pravastatin may be safer than other statins. As an example, in a subset analysis of 1711 participants with chronic kidney disease (CrCl ≤75 mL/min) from the CARE trial, treatment with pravastatin for a median of 58.9 months significantly improved outcomes compared with placebo without an increase in side effects [199].
Chronic liver disease — Statins need to be used cautiously in patients at high cardiovascular risk with active or chronic liver disease. All statins are metabolized to a certain extent in the liver. However, there is little evidence which can be used to support the use of one agent over another [200,201].
For this purpose, we define liver disease as unexplained aminotransferase values >3 times above upper normal range confirmed on repeat testing. In addition, statins are contraindicated in patients with decompensated cirrhosis or acute liver failure. The following should be considered when starting statin therapy:
●We ask the patient to completely abstain from alcohol.
●We start statin therapy cautiously with a low dose of an agent not extensively metabolized by the liver; pravastatin and rosuvastatin are examples. We then increase the dose based on changes in aminotransferase levels.
●Evaluate efficacy and impact on aminotransferases in 4 to 12 weeks; the statin dose may be increased if LDL-C remains elevated and aminotransferase levels have not increased further. For patients who do not reach LDL-C goals with this approach and in whom further LDL-C lowering is considered beneficial, we cautiously start a more potent statin and discuss with the patient the potential benefits and risks.
●Caution is needed in patients with biliary obstructive disease (eg, primary biliary cirrhosis) due to impaired hepatic metabolism of statins and case reports of rhabdomyolysis with lovastatin.
If the LDL cholesterol remains elevated, combined therapy with a bile acid sequestrant may allow such patients to achieve their LDL cholesterol target. Statins are contraindicated in patients with progressive liver disease.
Patients who simply have baseline elevations in aminotransferases do not appear to be at increased risk when prescribed a statin [48]. A study that looked at patients without evidence of alcohol abuse, hepatitis B, or hepatitis C compared a cohort of 342 patients (many of whom presumably had steatotic liver disease or metabolic dysfunction-associated steatohepatitis) with hyperlipidemia and baseline aminotransferase elevation (AST >40 international units/L [mean 55 international units/L] or alanine aminotransferase [ALT] >35 international units/L [mean 43 international units/L]) who were prescribed a statin with a cohort of 2245 patients with baseline aminotransferase elevation who were not prescribed a statin [202]. There was no significant difference between the cohorts in the incidence of mild to moderate aminotransferase elevations (4.7 versus 6.4 percent) or severe elevations (0.6 versus 0.4 percent). Rates of aminotransferase elevations were also similar in a cohort of hyperlipidemic patients with and without hepatitis C who were prescribed a statin [203].
A 36-week randomized trial comparing pravastatin 80 mg/day or placebo in 326 patients with well-compensated non-cholestatic chronic liver disease (64 percent with metabolic dysfunction-associated steatohepatitis; 23 percent with hepatitis C) found similar evidence of safety [204]. Over the course of the trial, rates of aminotransferase elevations were low in the group receiving pravastatin and no different from placebo, and none of the patients had an exacerbation of their underlying liver disease. Similarly, a post hoc analysis of a randomized trial of statin therapy (mainly atorvastatin, 24 mg/day) found no evidence of increased hepatic risk in patients with moderately abnormal liver function tests at baseline who were treated with a statin [205].
In a small study of patients with primary biliary cholangitis who were treated with atorvastatin, significant transaminase elevations were common [206]. Most statins are ultimately excreted in the bile, and toxic levels can develop in patients with cholestasis [207]. Additionally, the standard calculation of LDL cholesterol does not exclude lipoprotein X, which can accumulate in cholestasis but is not atherogenic and so not a target of therapy. While it may be possible to use statins safely in patients with mild cholestasis who have an appropriate indication for therapy [208], we avoid statin therapy in patients with significant cholestasis unless there are compelling indications such as established atherosclerotic vascular disease that is considered clinically important. (See "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)", section on 'Cholesterol metabolism in PBC' and "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)", section on 'Management'.)
The use of statins is believed to be safe in patients with Gilbert syndrome. (See "Gilbert syndrome".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: High cholesterol (The Basics)")
●Beyond the Basics topics (see "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: High cholesterol and lipid treatment options (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical use – Statins are powerful drugs for lowering low-density lipoprotein (LDL) cholesterol. They have proven benefit in primary and secondary prevention of coronary heart disease but do not improve noncardiovascular disease outcomes. (See 'Efficacy' above.)
●Choice of statin – The choice of statin depends upon a number of factors, including the degree of hyperlipidemia, pharmacokinetic properties, drug interactions, the presence of kidney function impairment, and cost.
•Potency – Rosuvastatin and atorvastatin are preferred in patients who require a potent statin because of high cardiovascular risk or who require >35 percent reduction in LDL cholesterol. (See 'Potency' above.)
•Kidney function impairment – In patients with severe kidney function impairment, we suggest treatment with atorvastatin or fluvastatin (Grade 2C). These medications do not require dose adjustment. (See 'Chronic kidney disease' above.)
•Chronic liver disease – In patients with chronic liver disease who require a statin because of high cardiovascular risk, we suggest complete abstinence from alcohol and the use of pravastatin at a low dose (Grade 2C). (See 'Chronic liver disease' above.)
•Drug interactions – Fewer pharmacokinetic drug interactions are likely to occur with pravastatin, fluvastatin, rosuvastatin, and pitavastatin because they are not metabolized through the CYP3A4 (table 4). (See 'Drug interactions' above.)
•Muscle-related adverse events – There are no clear data that the adverse event profile differs significantly among statins. However, pravastatin and fluvastatin appear less likely to cause muscle toxicity than other statins. This problem, including predisposing drug interactions and an approach to management, is discussed elsewhere. (algorithm 1) (See "Statin muscle-related adverse events".)
●Monitoring
•Creatine kinase – We suggest not routinely monitoring serum creatine kinase (CK), but it is useful to obtain a baseline CK level for reference purposes prior to starting statin therapy. Patients treated with statins should be alerted to report the new onset of myalgias or weakness. (See "Statin muscle-related adverse events", section on 'Monitoring'.)
•Aminotransferases – We suggest checking baseline aminotransferase levels prior to initiating statin therapy; routine monitoring of these levels is not necessary for patients on statins. (See 'Hepatic dysfunction' above.)
•Thyroid-stimulating hormone – We suggest checking a thyroid-stimulating hormone level prior to initiating statin therapy. (See 'Muscle injury' above.)
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