INTRODUCTION

Statins have dramatically transformed the treatment of dyslipidemia and remain the first-line therapy for the prevention of atherosclerotic cardiovascular disease, as supported by numerous clinical trials [1,2]. They have demonstrated clear benefits in improving clinical outcomes across various stages of the cardiovascular continuum [3,4]. Furthermore, statins exert additional effects beyond lipid lowering, including anti-inflammatory properties, stabilization of atherosclerotic plaques, improvement of vascular endothelial function, and enhancement of left ventricular contractility [5]. However, concerns persist regarding statin-associated adverse effects, most notably muscle-related symptoms, hepatotoxicity, and incident diabetes mellitus (Fig. 1) [6]. These concerns represent major barriers to achieving optimal lipid-lowering strategies with statins, as they may lead patients to question treatment effectiveness and reduce adherence. As a consequence, the anticipated cardiovascular protective benefits may not be fully realized.

Are these concerns merely the result of patient misconceptions, or are they supported by objective evidence? In this review, we sought to analyze the extensive literature on statin-related adverse effects and to propose strategies aimed at optimizing patient adherence to statin therapy while maximizing cardiovascular protection.

MUSCLE-RELATED SYMPTOMS

Clinical prevalence and risk factors

Statin-related muscle symptoms, for which many consensus groups have unified the terminology as “statin-associated muscle symptoms” (SAMS) [7], represent the most common statin-related complication and account for nearly two-thirds of all statin-associated adverse effects [8]. These manifestations include myalgia (muscle aches, stiffness, or cramping), myopathy (muscle weakness), myositis (elevated creatine kinase above the normal range), and rhabdomyolysis (creatine kinase levels more than 10 times the upper limit of normal) [6]. SAMS are also the leading reason for statin discontinuation, regardless of symptom severity [9].

However, the reported prevalence of SAMS varies considerably across the literature, and these discrepancies are closely related to the absence of definitive diagnostic criteria for this clinical entity [10]. A prior study by Cohen et al. [11] investigated statin use in the United States using an internet-based survey of 10,138 patients. The authors reported an adherence rate exceeding 70%, along with a marked reduction in low-density lipoprotein cholesterol (LDL-C) levels following treatment. Nevertheless, approximately 25% of participants experienced muscle-related symptoms, and nearly one-third reported discontinuing statin therapy without consulting a physician. The relatively high frequency of muscle-related symptoms observed in this study is likely attributable to the self-reported nature of the data, the lack of investigator verification for individual events, and the absence of clear causal attribution between reported symptoms and statin use. In contrast, randomized controlled trials consistently report a much lower prevalence of pharmacologic SAMS. A meta-analysis of 23 randomized double-blind statin trials, including more than 150,000 patients, specifically examined whether statins truly cause muscle symptoms [12]. The results demonstrated that statins were associated with less than 3% of reported muscle-related symptoms. Notably, this effect largely disappeared after the first year of statin therapy, and the analysis suggested that more than 90% of reported SAMS were not pharmacologic in origin.

Several risk factors for SAMS have been reported. Advanced age, female sex, physical frailty, and low body mass index are considered potential contributors to symptom development [13]. Hypothyroidism may increase systemic statin exposure by reducing metabolic clearance. Low muscle mass has also been proposed as a contributing risk factor for SAMS.

Approaches to SAMS

Immediate discontinuation of statin therapy without confirmation by objective diagnostic evidence when muscle symptoms occur is not necessarily the optimal approach, as statin discontinuation is closely associated with adverse clinical outcomes [14]. Therefore, a thoughtful and systematic strategy is required to address SAMS. Evidence suggests that many muscle-related symptoms reported in clinical practice do not reflect true pharmacologic adverse effects but instead arise from patient misconceptions or the nocebo effect [15]. Excessive concern regarding statin therapy may lead patients to anticipate or perceive symptoms, thereby creating a substantial barrier to continued treatment [16]. Accordingly, clinicians should reassure patients that statins are generally safe and effective, and that any adverse effects are typically reversible upon discontinuation. Clinical decision-making should rely on objective diagnostic evaluation rather than subjective symptom reporting alone. In fact, more than 90% of patients diagnosed with SAMS at specialized centers were ultimately able to tolerate statin therapy successfully [17].

For patients who report muscle pain, initial measurement of creatine kinase is essential, as it facilitates accurate identification of true SAMS and distinguishes affected individuals from those with nonpharmacologic complaints [18]. If true SAMS is confirmed, temporary statin discontinuation may be appropriate, with the expectation that symptoms will resolve. Many patients can subsequently tolerate statins when reintroduced at lower doses or in combination regimens. The addition of ezetimibe can effectively reduce adverse symptom burden associated with statin monotherapy [19,20]. Furthermore, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent effective alternative therapies. These agents are approved as adjunctive treatment to maximally tolerated statin therapy in patients with heterozygous familial hypercholesterolemia or those at high cardiovascular risk, and their potent LDL-C–lowering effects are well established [21]. PCSK9 inhibitors may therefore be used in patients with severe statin intolerance attributable to SAMS.

NEW-ONSET DIABETES MELLITUS

Net clinical benefit

The concern that statin therapy may lead to new-onset diabetes mellitus represents a significant barrier to maintaining consistent statin use. The JUPITER study randomized patients with LDL-C ≤130 mg/dL to rosuvastatin 20 mg/day (n=8,901) or placebo (n=8,901), and after 2 years, the incidence of new-onset diabetes was 0.6% higher in the rosuvastatin group (n=270 vs. n=216, P=0.01) [1]. However, statin therapy reduced major cardiovascular events by 44%, underscoring the drug’s overall net clinical benefit. Several meta-analyses have also examined the association between statin therapy and diabetes onset. In a meta-analysis comparing the incidence of new-onset diabetes according to statin intensity, high-intensity statin therapy was associated with a 4.4% incidence of new-onset diabetes, compared with 4.0% in the moderate-intensity group, a statistically significant but very small absolute difference [22]. Importantly, the reduction in cardiovascular events exceeded the number of new diabetes cases by more than threefold. Statins may impair insulin secretion and glucose metabolism by disrupting calcium channel function and mitochondrial activity in pancreatic beta cells [23]. They may also reduce glucose transporter type 4 (GLUT4) expression in adipocytes and alter forkhead box O (FOXO) gene family activity, thereby affecting carbohydrate metabolism [24]. As a result, the risk of new-onset diabetes increases slightly; however, this risk remains minimal when weighed against the substantial cardiovascular protective benefits. The underlying mechanism may be related to LDL-C reduction and could similarly occur with other potent lipid-lowering agents.

Approaches to new-onset diabetes mellitus

There is substantial evidence that statin therapy can induce diabetes mellitus. However, this association should not be a reason to discontinue statins, as their cardiovascular protective effects far outweigh the potential risk of diabetes. During statin therapy, it is important to monitor patients carefully and to assess any true increase in blood glucose levels through appropriate laboratory evaluation [25]. The importance of lifestyle modification should also be emphasized. As with the management of SAMS, combination therapy with agents such as ezetimibe, which may reduce statin dose–dependent diabetes risk, should be considered. In conclusion, for patients at high cardiovascular risk or with established atherosclerotic cardiovascular disease, high-intensity statin therapy should be prescribed without hesitation, as clinical outcomes in patients who develop diabetes during statin therapy are not significantly different from those in patients without diabetes [22].

HEPATOTOXICITY

Association to liver injury

Statins may occasionally cause elevations in liver enzymes, most commonly during the first 12 weeks of therapy [26]. Statin-related liver injury is typically defined as an elevation of alanine aminotransferase (ALT) greater than three times the upper limit of normal or an increase in conjugated bilirubin exceeding twice the upper limit of normal. Statin-related liver injury demonstrates a dose-dependent relationship with the severity of hepatotoxicity [27]. However, the use of more potent statins confers greater cardiovascular benefit, necessitating a balanced assessment of the degree to which this risk can be tolerated. In a study of 1,334 patients in Greece who were followed for more than 3 years while receiving statin therapy, the prevalence of liver enzyme elevation was 3.1%. In most cases, liver enzyme levels returned to normal following discontinuation of the medication [28]. Another large cohort study including more than 450,000 patients demonstrated that the risk of severe liver injury was not significantly higher in patients with elevated ALT levels compared with those with normal levels, suggesting that ALT elevation does not necessarily reflect clinically significant liver injury [29]. Additionally, a report from the US Drug-Induced Liver Injury Network found that over a 9-year period, only 22 of 1,188 cases (less than 2%) of drug-induced liver injury were attributable to statins, and fatal outcomes were rare, occurring in only one patient [30]. Therefore, it has been hypothesized that alterations in hepatocyte lipid membranes increase membrane permeability, leading to leakage of liver enzymes, which may explain the typically asymptomatic and transient nature of aminotransferase abnormalities [31].

Approaches to statin-related liver injury

Statin-related liver injury is extremely rare, and even when it occurs, it generally resolves spontaneously. Discontinuation of the offending agent typically leads to reversible improvement in laboratory abnormalities [32]. This underscores the importance of comprehensive evaluation, including medical history, laboratory testing, and imaging, when statin-induced liver injury is suspected [33]. However, current guidelines do not recommend routine monitoring of liver enzyme levels in the absence of clinical signs or symptoms of hepatotoxicity [34]. Statin therapy may be continued if aspartate transferase or ALT levels remain within three times the upper limit of normal. When levels exceed this threshold, statins should be discontinued, allowing liver enzyme levels to recover over time [35]. In most cases, no additional treatment is required beyond statin discontinuation [32].

CONCLUSIONS

Statins remain the cornerstone of dyslipidemia management and provide substantial cardiovascular protection across a broad spectrum of patients. Although concerns persist regarding adverse effects such as muscle-related symptoms, hepatotoxicity, and new-onset diabetes mellitus, the overall incidence of clinically significant complications is low. Most SAMS are reversible and can be effectively managed through appropriate strategies, including dose adjustment, temporary discontinuation, or the use of alternative lipid-lowering agents. Careful patient assessment, objective diagnostic evaluation, and patient education are essential for improving adherence and minimizing unnecessary treatment discontinuation. Clinicians should remain vigilant for adverse events while reassuring patients regarding the overall safety and efficacy of statin therapy. With evidence-based management, most patients can continue statin treatment safely, thereby achieving maximal cardiovascular protection while minimizing potential risks. Therefore, statin-related complications should not be viewed as a reason to avoid therapy but rather as challenges that must be addressed to ensure optimal cardiovascular outcomes.

ARTICLE INFORMATION

Conflicts of interest

The author has no conflicts of interest to declare.

Funding

The author received no financial support for this study.

Fig. 1.

Overview of statin-related side effects.

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Figure & Data

References

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