Delayed-Onset Rhabdomyolysis of Bilateral Lower Extremities Following Statin Therapy in a 63-Year-Old Woman: A Case Report

Abstract

Patient: Female, 63-year-old

Final Diagnosis: Delayed-onset statin induced rhabdomyolysis

Symptoms: Muscle pain and weakness in both legs

Clinical Procedure: —

Specialty: Rheumatology

Objective: Rare disease

Background

Statins are widely prescribed for managing hypercholesterolemia and reducing cardiovascular risk but can cause myotoxicity ranging from mild myalgia to severe rhabdomyolysis. While statin-induced rhabdomyolysis typically manifests early, delayed-onset presentation is rare and poses diagnostic challenges. We report a rare case of delayed-onset rhabdomyolysis associated with rosuvastatin in a 63-year-old woman.

Case Report

A 63-year-old woman with coronary artery disease, hyperlipidemia, and hypertension, which had been well-controlled on rosuvastatin (40 mg/day) for 1 year without adverse effects, developed progressive bilateral lower-limb swelling, pain, and weakness. One week after a fall attributed to sudden leg weakness, she presented to the emergency department with bilateral lower-extremity edema and moderate-to-severe pain on palpation. Laboratory findings showed markedly elevated creatine kinase (CK, 26 000 U/L), mildly elevated creatinine (1.3 mg/dL), and abnormal liver function. Rosuvastatin was discontinued on admission, and intravenous hydration was initiated. Magnetic resonance imaging confirmed diffuse muscle edema. A muscle biopsy revealed myofiber degeneration consistent with rhabdomyolysis, excluding autoimmune myopathies. CK peaked at 31 080 U/L on day 3, then declined with treatment. By day 10, CK and creatinine had returned to normal levels, muscle strength had improved, and the patient’s edema had resolved. She was discharged after 2 weeks without restarting statins.

Conclusions

This case highlights the rare occurrence of delayed-onset statin-induced rhabdomyolysis, emphasizing the need for vigilant monitoring, prompt recognition, and cessation of statins to prevent severe complications, including acute kidney injury. Clinicians must remain alert to the potential of statin-induced myopathy, even in previously unaffected patients.

Introduction

According to the United States Centers for Disease Control and Prevention (the CDC), nearly 25 million adults in the United States have hypercholesteremia [1]. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the mainstay therapy for hypercholesterolemia due to their effectiveness and favorable safety profile [2,3]. Statins currently approved by the United States Food and Drug Administration (FDA) include atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, and pitavastatin [4]. Although statins are well-tolerated by most patients, up to 25% of patients being treated with statins may have muscle symptoms, and some develop severe myotoxicity [5,6]. The most serious risk of these conditions is myositis with rhabdomyolysis [5]. A patient’s risk of developing statin-induced rhabdomyolysis is influenced by the type of statin administered, statin dosage, medications taken concurrently, comorbidities, and the patient’s sex and genetic predisposition to myopathy [7,8]. The withdrawal of cerivastatin from the world market in 2001, after the drug was associated with at least 100 deaths due to rhabdomyolysis, serves as a reminder that our current knowledge is limited regarding the mechanisms by which these drugs can cause muscle toxicity [9]. These deaths also highlighted the necessity of surveillance in patients taking statins [10].

Symptoms of statin myopathy can range from asymptomatic CK elevations to muscle weakness, exercise intolerance, or full-blown rhabdomyolysis with significant CK elevation and life-threatening myoglobinuria with the risk of renal failure [11,12]. A complex of symptoms that includes cramps, myalgia, and proximal weakness should lead to a suspicion of statin myopathy, especially when statins are being combined with other medications, but myopathy caused by trauma, extreme physical exertion, and metabolic or electrolyte disorders must also be considered [11,13]. Failure to recognize and promptly intervene can lead to rhabdomyolysis, while discontinuation of statins leads to recovery in most patients [11]. A review of case reports detailing statin-induced rhabdomyolysis found that the mean time between statin initiation and rhabdomyolysis symptoms was 9 days in 112 patients identified in the literature [14]. A case of rhabdomyolysis 8 months after initiation of rosuvastatin has also been reported [15].

We present a rare case of late-onset rhabdomyolysis in a 63-year-old patient who developed rhabdomyolysis after more than 1 year of well-tolerated rosuvastatin therapy.

Case Report

A 63-year-old woman presented to the emergency department with swelling in her lower extremities (LEs) and concern over sudden weakness. She had fallen to the floor while she was in the bathroom 1 week prior and described the reason for the fall as ‘sudden weakness’ of both LEs. She reported that she did not hit her head or pass out after the fall, and that she had not noticed any bruises from the fall. She did not seek medical attention afterward and reported that she spent the week mostly resting on the couch. She reported persistent generalized pain in her LEs and right shoulder. She did not remember if she hit these locations when she fell. This pain hindered her mobility, and she was unable to ambulate without assistance. She said that both her legs were swollen, from thigh to ankle, before the fall.

Her medical history was significant for coronary artery disease (CAD), hyperlipidemia, and hypertension. She had no history of any major injuries. Current daily medications included aspirin (81 mg), clonazepam (1 mg), clonidine (0.2 mg), dicyclomine (20 mg), prasugrel, rosuvastatin (40 mg), sertraline (100 mg), metoprolol (50 mg), tramadol (50 mg), and trazodone (100 mg). She had tolerated her high-dose statin (rosuvastatin 40 mg/day) for 1 year without any known adverse effects.

When she presented in the emergency department, both LEs were swollen from hip to ankle. She had moderate-to-severe pain on palpation of the LEs. Laboratory tests revealed significantly elevated creatine kinase (CK) levels (~26 000 U/L, reference range 30–135 U/L), which was indicative of muscle injury. She had a slightly elevated creatinine level of 1.3 mg/dL (reference range 0.5–1.4 mg/dL) and elevated liver function tests with an alanine aminotransferase (ALT) of 168 U/L (reference range 14–54 U/L) and an aspartate aminotransferase (AST) of 407 U/L (reference range 15–41 U/L). No signs of fracture were detected on hip or shoulder radiography. She did not have a history of liver disease or abdominal pain, and ultrasound of the right upper quadrant was normal. At this point, the etiology of her muscle symptoms remained elusive.

She was admitted to the hospital for further investigations and observation. Rosuvastatin was withheld starting on day 1, and intravenous fluid was initiated. On day 3, she reported that both LEs seemed to be more swollen (Figure 1). Magnetic resonance imaging (MRI) of the right thigh demonstrated diffuse muscle edema of the adductor muscle group and the posterior thigh (Figure 2). Rheumatology was consulted and ordered assessment of autoimmune markers to screen for diseases such as polymyositis and dermatomyositis. All the markers were within normal range (Table 1). Right posterior muscle biopsy demonstrated features consistent with rhabdomyolysis, including wide scattered myofiber degeneration in striated muscle. No active myositis, vasculitis, or inclusion bodies were noted in the pathology findings. She was diagnosed with rhabdomyolysis possibly due to statins.

Figure 1.

Legs of the patient on day 3 of admission. (A) Both thighs and legs demonstrated atypical swelling. Photographs were taken on day 3 of admission, which was when the patient’s creatine kinase levels were the highest during her hospitalization. (B) Close up of right thigh and leg. (C) Close up of left thigh and leg.

Figure 2.

Magnetic resonance imaging (MRI) of the right thigh without contrast. (A, B) Coronal plane with diffuse edema of the adductor muscle group (yellow arrows); (C, D) Axial plane with diffuse edema of the posterior muscle group of the thigh (yellow arrowheads).

Table 1.

Results of autoimmune marker screening.

Marker	Result*
Jo-1 Auto Ab	<0.2
Anti-Jp-1 Ab	<20
Anti-EJ Ab	Negative
Anti-Ku Ab	Negative
Anti-MDA-5 Ab	<20
Anti-Mi-2 Ab	Negative
Anti-NXP-2 Ab	<20
Anti-OJ Ab	Negative
Anti-PL-12 Ab	Negative
Anti-PL-7 Ab	Negative
Anti-PM/Scl-100 Ab	<20
Anti-SAE1 Ab	<20
Anti-SRP Ab	Negative
Anti-SS-A 52kD Ab	<20
Anti-TIF-1 gamma Ab	<20
Anti-U1 RNP Ab	<20
Anti-U2 RNP Ab	Negative
Anti-U3 RNP Ab	Negative

^*A negative test result is considered a normal reference value.

Ab – antibody; Jo-1 Auto Ab – anti-histidyl-tRNA synthetase antibody; Anti-PL-7 Ab – anti-threonyl-tRNA synthetase antibody; Anti-PL-12 Ab – anti-alanyl-tRNA synthetase antibody; Anti-OJ Ab – anti-isoleucyl-tRNA synthetase antibody; Anti-Jp-1 Ab – anti-asparaginyl-tRNA synthetase antibody; Anti-EJ Ab – anti-glycyl-tRNA synthetase antibody; Anti-MDA-5 Ab – anti-melanoma differentiation-associated gene 5 antibody; Anti-NXP-2 Ab – anti-nuclear matrix protein 2 antibody; Anti-SAE1 Ab – anti-small ubiquitin-like modifier activating enzyme 1 antibody; Anti-SRP Ab – anti-signal recognition particle antibody; Anti-TIF-1 gamma Ab –anti-transcription intermediary factor 1 gamma antibody; RNP – ribonucleoprotein.

CK levels and renal function were monitored daily. The patient’s CK level was highest on day 3 (31 080 U/L) and then trended downward (Figure 3). From day 3 onward, she showed good response to intravenous hydration and rosuvastatin withdrawal. Both CK and creatinine levels normalized within the following days. Her muscle strength in the LEs improved, and the swelling decreased. She was discharged after 2 weeks in the hospital. Statin therapy was not reinitiated after discharge.

Figure 3.

Creatine kinase and plasma creatinine levels during hospitalization. After discontinuation of rosuvastatin on day 1, creatine kinase (CK) levels had a downward overall trend and returned to normal levels ~10 days after admission.

Discussion

This case highlights the possibility of statin-induced rhabdomyolysis developing after an extended period of statin tolerance. Despite its rarity, delayed-onset myotoxicity can occur without typical risk factors, underscoring the necessity of ongoing monitoring in patients on chronic statin therapy. Prompt recognition, statin cessation, and supportive treatment are essential to avert severe outcomes, including acute kidney injury or long-term disability. Our patient had a history of statin usage for 1 year and presented with diffuse muscle weakness and edema, especially in the LEs. Her CK levels, which peaked on day 3 of admission, were suggestive of rhabdomyolysis. After rosuvastatin was discontinued and intravenous fluid was administered, her symptoms, CK levels, and renal function quickly improved. Common etiologies of rhabdomyolysis include trauma, extreme physical exertion, metabolic myopathies, and electrolyte disorders [13]. Statin-induced myopathy was the most likely diagnosis in this patient because CK normalization occurred after stopping rosuvastatin and trauma was determined to be an unlikely etiology because the patient reported that both of her LEs were swollen before the fall. Additionally, the fall reported by the patient occurred 1 week before admission, there were not any significant bruises or lesions on the legs on admission, and the possibility of an acute fracture was ultimately ruled out after normal results of hip and shoulder imaging.

Statin interactions with other drugs are common. Although there are several medications that can cause myotoxicity, cholesterol-lowering drugs, such as statins and fibric acid derivatives, are the most common cause of toxic myopathy [11,16]. Currently, little is known about the mechanisms by which statins cause myopathy [5,16]. However, other medications can affect the metabolism of statins, which can increase the risk of toxic myopathy [17]. Most of the currently available statins are lipid-soluble and metabolized via cytochrome p-450 3A4 (CYP-3A4), including lovastatin, simvastatin, and atorvastatin [11,18]. There are some exceptions, however. For example, fluvastatin is metabolized by cytochrome 2C9 isoenzyme (CYP-2C9), and pravastatin is metabolized by sulfation using an alternative pathway [18]. Most drugs that inhibit statin metabolism have an inhibitory effects on CYP-3A4 [11,18]. Thus, these medications tend to increase the serum levels of statins along and the risk of statin-associated myopathies [11,18]. In 2021, Osborn and colleagues [15] reported a case of rhabdomyolysis after 8 months of using rosuvastatin and amiodarone. In our case, the patient did not use amiodarone. However, she was taking several medications to alleviate pain and treat CAD, hyperlipidemia, hypertension, and depression. Sertraline has been reported to increase the risk of rhabdomyolysis [19,20], thus it is possible that the combination of sertraline and rosuvastatin may have contributed to the development of rhabdomyolysis in this patient.

Fatal rhabdomyolysis is a rare adverse effect of statins, with an overall incidence of 0.15 deaths per 1 million prescriptions [21]. In a meta-analysis of 74 102 patients from 35 trials from 1966 to 2005, Kashani and colleagues [22] reported that currently available statins, with the exception of cerivastatin, were not associated with a significant risk of rhabdomyolysis (P=0.13). Furthermore, the statins included in their meta-analysis were not associated with a significant increase in the risk of myalgias (95% confidence interval (CI) −3.2–8.7), CK elevation (95% CI −0.6–0.9), or discontinuation due to any adverse event (95% CI −4.3–3.3) [22]. Rhabdomyolysis is rarely caused by statins alone, however, and it is often precipitated by a combination therapy that includes a statin and a CYP-3A4 substrate or inhibitor [23]. Drug interactions associated with rhabdomyolysis also include fibrates, niacin, cyclosporine, warfarin, digoxin, macrolide antibiotics, and azole antifungals [11,24]. However, not all studies have found an association between the concomitant use of statins and fibrates and an increased risk of rhabdomyolysis [22], indicating a need for further research.

It is important to recognize populations with an increased risk of statin-associated myopathy [25]. In an observational study of 7924 hyperlipidemic patients who were receiving statin therapy in France (the Prediction of Muscular Risk in Observational conditions [PRIMO] study), Bruckert and colleagues [26] demonstrated that the strongest predictors of muscular symptoms included personal history of muscle pain during lipid-lowering therapy (odds ratio (OR), 10.12, 95% CI 8.23–12.45; P<0.0001), unexplained cramps (OR 4.14; 95% CI 3.46–4.95; P<0.0001) and a history of CK elevation (OR 2.04; 95% CI 1.55–2.68; P<0.0001). In a large cohort study that included 225 922 new users of statins and 1 778 770 non-users of statins, Hippisley-Cox and colleagues [27] reported a threefold-increased risk of moderate or severe myopathy in new female users of statins and a more than sixfold increased risk for new male users [27]. In both men and women, prescription of corticosteroids was associated with an increased risk of myopathy (hazard ratio (HR) 2.09, 95% CI 1.6–1.72 in men; HR 3.03, 95% CI 2.38–3.85 in women) [27]. In women, type 1 diabetes mellitus (T1DM), chronic liver disease, and hypothyroidism were also associated with an increased risk of moderate or severe myopathy (hazard ratio (HR) 4.78 (95% CI 2.1–10.86) for T1DM; HR 3.47 (95% CI 1.55–7.78) for chronic liver disease; HR 1.88 (95% CI 1.42–2.50) for hypothyroidism). Risk factors for statin-induced myotoxicity include female sex, low body mass index, combination therapy with cytochrome P450 inhibitors, and kidney or liver failure [28]. Our female patient had few additionally risk factors, however, highlighting the need for vigilant surveillance in all patients taking statins.

In a retrospective study examining 13 years of data from the University of Wisconsin Hospital, Hansen and colleagues [12] identified 45 patients diagnosed as having statin-associated myopathy among 437 patients with International Classification of Diseases, Ninth Revision (ICD-9) codes potentially representing cases of statin-associated myopathy. In these patients, the mean duration of statin therapy before symptom onset was 6.3 months (±9.8 months, range 0.25–48.0) [12]. Resolution of symptoms occurred 2.3 months after discontinuation of statins [12]. Approximately 4% of patients had reversible renal dysfunction, and one patient (2.2%) ended up requiring lifelong dialysis afterward [12]. Fortunately, our patient did not experience concomitant renal dysfunction. The most common symptom of statin myotoxicity was myalgia, which could occur diffusely (36%) or locally (58%), with the LEs being most commonly affected (27%) [12], as we observed in our patient.

Statin myopathy can occur without an elevation in CK enzymes [6]. Nonetheless, the presence of normal or mildly elevated CK levels is often used as an argument against statin-induced myopathy in patients with muscular symptoms during statin therapy [6,29], because there are other diseases that can affect the muscles, such as hypothyroidism and polymyalgia rheumatica [5]. This is likely misguided and could delay diagnosis. In 2002, Phillips and colleagues [6] identified 4 patients from an ongoing clinical trial with muscle symptoms, such as stiffness and tenderness, with normal CK levels. These patients were randomized into a double-blinded, crossover clinical trial to determine whether they could distinguish statin therapy from placebo. All 4 patients consistently recognized whether they were receiving statin therapy or placebo in this double-blind trial. Furthermore, muscle biopsies showed evidence of myopathy, including mitochondrial dysfunction [6]. These pathologic features were reversed after discontinuation of statins, and CK levels remained within a normal range in all the patients every time they became myopathic, both before and during the trial. The authors concluded that CK level is an insufficient diagnostic test for statin-associated myopathy [6]. Soininen and colleagues [29] reported a case series of 20 patients with statin-induced myopathy that limited their daily activities. Among the 18 patients with CK measurements, 5 patients (28%) did not have CK elevation, and 6 patients (33%) only had mild elevations of CK enzymes. Following statin discontinuation, there was resolution of both muscle symptoms and CK levels in 11 of the 13 patients with elevated CK [29]. The authors concluded that statins can cause muscle symptoms severe enough to limit daily activities without any CK elevation.

There have been 2 seemingly contradictory observations that make screening for statin-induced myopathy difficult: (1) Some asymptomatic patients taking statins have significantly increased levels of CK enzymes, and (2) some patients with significant muscle symptoms have normal CK levels [6,11,12,29]. For the former group, regular follow-up while continuing statins is reasonable [11], while earlier intervention is feasible for the latter group [6,29]. Interventions for symptomatic patients with a normal CK level include statin dose reduction, decreased statin dosing frequency, and the use of an alternate statin with more favorable pharmacokinetic properties [30].

Before starting statin therapy, CK baseline levels should be obtained and thyroid function should be assessed, because unnoticed hypothyroidism can predispose the patient to myopathy [11,27,31]. However, some physicians believe that high pretreatment CK levels, particularly 1–5 times the upper normal limit (UNL), should not discourage clinicians from starting or continuing statins to lower low-density lipoprotein cholesterol (LDL-C) [32]. Current recommendations suggest weekly measurements of CK levels in patients with muscle pain if CK is 3–10 times UNL without discontinuation of statins. For patients with CK levels exceeding 10 times UNL, statins and any other potentially adverse medications should be stopped [24]. Consideration of statin discontinuation can also be considered if serial CK measurements demonstrate an increasing trend [24]. Because our patient presented to our emergency department, we cannot speculate as to whether these assessments would have been helpful.

The discontinuation of the offending agents is often sufficient to reverse statin-induced myopathy. In patients with rhabdomyolysis, standard measures to prevent kidney damage are also utilized, including initiating intravenous fluids, as in our patient. Medical management of rhabdomyolysis focuses on intravenous hydration combined with diuresis [18]. Diuresis can help protect the kidneys by diluting myoglobin in the tubules, thus preventing toxic cast formation [18,33]. Hyperkalemia, which requires intervention with calcium gluconate or calcium chloride, can rapidly develop. However, these interventions should be used cautiously because rhabdomyolysis is associated with hyperphosphatemia, which can cause precipitation and calcium phosphate in damaged tissue [18]. Treatment with coenzyme Q10 (Co-Q10; 60 mg per day for 2 months) can be considered, because a decrease in Co-Q10 is hypothesized to be a mechanism underlying statin myotoxicity [11,34,35]. However, the American Heart Association (AHA) statement on statin safety concluded that Co-Q10 is not helpful in statin-associated myopathy [36].

Conclusions

Statins effectively lower LDL-C and reduce cardiovascular risk but can cause myotoxicity, ranging from mild myalgia to severe rhabdomyolysis. Delayed-onset rhabdomyolysis, as seen in our patient taking rosuvastatin, highlights the diagnostic challenges posed by an atypical presentation of a rare condition, particularly when comorbidities, such as T1DM, hypothyroidism, or impaired liver/kidney function, and drug interactions can increase the patient’s risk. Given the widespread use of statins, vigilant monitoring, even in previously unaffected patients, prompt recognition of rhabdomyolysis, and immediate cessation of statins are critical to prevent severe complications, including acute kidney injury.