Statin-induced Rhabdomyolysis Research Articles

Recurrent statin-induced rhabdomyolysis: Commonly overlooked drug

Statin-induced muscle pain and myopathy are common. However, statin-induced rhabdomyolysis causing severe nephropathy is somehow uncommon. Here, we present the case of a 68-year-old patient on statin therapy after percutaneous coronary intervention. We want to highlight the fact that physicians should differentiate muscle pain without biochemical derangement and with severe rhabdomyolysis leading to acute kidney injury and hyperkalemia. Patients should be made aware of this commonly overlooked drug causing severe complications.

Statins Ticagrelor and Rhabdomyolysis: A Coincidence or a Drug Interaction?

Statins play a key role in the management of atherosclerotic cardiovascular disease for both primary and secondary prevention. However, their increasing usage has correspondingly led to a higher incidence of adverse effects, with muscle symptoms being the most common. An intriguing drug interaction exists between ticagrelor and high-intensity statins, which may exacerbate the adverse effects of statin-induced rhabdomyolysis, leading to significant consequences. This study was conducted to examine the profile of patients who have experienced statin-induced rhabdomyolysis while undergoing percutaneous transluminal coronary angioplasty (PTCA). This was an observational study that included 1,862 patients who underwent PTCA at our institute over the course of 1 year. Over a 1-year period, we encountered four patients who were being treated with high-intensity statin therapy following acute coronary syndrome. These patients presented with muscle weakness and kidney injury. A notable commonality among all patients was the co-prescription of ticagrelor. Two patients died, while the other 2 were successfully managed through hydration, electrolyte balance, dialysis, and alternative lipid management drugs. The concomitant use of ticagrelor and high-intensity statins should be carefully considered due to the additional risk of rhabdomyolysis and kidney injury. Future pharmacokinetic studies are needed to establish a causal relationship and predict potential drug interactions, which, if not avoided, could be fatal.

S1506 Hepatic Decompensation & High-Intensity Statin Therapy Are Associated with Statin-Induced Rhabdomyolysis in Patients With Cirrhosis

S1506 Hepatic Decompensation & High-Intensity Statin Therapy Are Associated with Statin-Induced Rhabdomyolysis in Patients With Cirrhosis

Structure of human drug transporters OATP1B1 and OATP1B3

The organic anion transporting polypeptides OATP1B1 and OATP1B3 are membrane proteins that mediate uptake of drugs into the liver for subsequent conjugation and biliary excretion, a key step in drug elimination from the human body. Polymorphic variants of these transporters can cause reduced drug clearance and adverse drug effects such as statin-induced rhabdomyolysis, and co-administration of OATP substrates can lead to damaging drug-drug interaction. Despite their clinical relevance in drug disposition and pharmacokinetics, the structure and mechanism of OATPs are unknown. Here we present cryo-EM structures of human OATP1B1 and OATP1B3 bound to synthetic Fab fragments and in functionally distinct states. A single estrone-3-sulfate molecule is bound in a pocket located in the C-terminal half of OATP1B1. The shape and chemical nature of the pocket rationalize the preference for diverse organic anions and allow in silico docking of statins. The structure of OATP1B3 is determined in a drug-free state but reveals a bicarbonate molecule bound to the conserved signature motif and a histidine residue that is prevalent in OATPs exhibiting pH-dependent activity.

Abstract #1408127: A Case of Rhabdomyolysis Resulting in Fulminant Acute Kidney Injury in a Patient with Severe Hypothyroidism

Rhabdomyolysis is characterized by muscle necrosis and the release of intracellular muscle contents into circulation. Hypothyroidism is known to be associated with musculoskeletal problems, rarely rhabdomyolysis. We report a case of severe hypothyroidism due to a prior thyroidectomy with poor medication adherence, who presented with rhabdomyolysis resulting in severe acute kidney injury requiring urgent dialysis. A 65-year-old male with a past medical history of papillary thyroid cancer status post total thyroidectomy presented with lethargy, confusion, decreased oral intake and decreased urination. He recently ran out of levothyroxine. Notably, the patient had also been taking rosuvastatin. On examination, the patient was afebrile, with a pulse of 70 bpm and blood pressure of 111/70 mmHg. He was oriented to self and place but not to time. He demonstrated slow deep voice along with macroglossia and trace non-pitting lower extremity edema. There were no signs of proximal myopathy or neurological deficits. Workup was remarkable for TSH >90.00 mcU/mL, free T4 < 0.1 ng/dl, CPK 22,030 mcg/L, AST 233 U/L, ALT 205 U/L, creatinine 31.6 mg/dl, and BUN 124 mg/dl. The last known TSH was 4.5, free T4 was 1 ng/dL, and creatinine was 0.9 in January 2021. The urine specimen was positive for loaded red blood cells. Renal ultrasound showed no obstruction. Diagnosis of rhabdomyolysis with acute renal failure was made and he was promptly started on dialysis. Endocrinology was consulted and he was started on intravenous levothyroxine. A renal biopsy confirmed acute tubular necrosis due to rhabdomyolysis. After several days, his symptoms improved, and he was transitioned to oral levothyroxine however he remained on dialysis on discharge. Hypothyroid myopathy is most often limited to myalgia, cramps, and sometimes mildly elevated levels of muscle enzymes. Rhabdomyolysis can rarely develop due to severe hypothyroidism. Muscle breakdown in hypothyroidism is caused by poor contractility, low myosin ATPase activity, and low ATP turnover in the skeletal muscles. These metabolic abnormalities may sensitize patients with hypothyroidism to develop rhabdomyolysis. Acute renal failure, as a result of an accumulation of myoglobin in renal tubules, is the most life-threatening complication of rhabdomyolysis and can develop in up to 33% of patients. There have been very few case reports of hypothyroidism causing rhabdomyolysis, with a precipitating factor such as exercise, trauma, or drugs such as statin. Our patient presented with severe hypothyroidism complicated by rhabdomyolysis resulting in acute renal failure requiring dialysis. The patient was also on a statin which may cause statin-induced rhabdomyolysis due to hypothyroidism. This case emphasizes the importance of adherence to levothyroxine in hypothyroid patients as well as the importance of considering rhabdomyolysis in patients with severe hypothyroidism as a cause of acute renal failure. It also shows the importance of reviewing the patient's medication list and discontinuing all those medications which can escalate the process of rhabdomyolysis in a patient with hypothyroidism.

Detection of statin-induced rhabdomyolysis and muscular related adverse events through data mining technique

Background and objectiveRhabdomyolysis (RM) is a life-threatening adverse drug reaction in which statins are the one commonly related to RM. The study aimed to explore the association between statin used and RM or other muscular related adverse events. In addition, drug interaction with statins were also assessed.MethodsAll extracted prescriptions were grouped as lipophilic and hydrophilic statins. RM outcome was identified by electronically screening and later ascertaining by chart review. The study proposed 4 models, i.e., logistic regression (LR), Bayesian network (BN), random forests (RF), and extreme gradient boosting (XGBoost). Features were selected using multiple processes, i.e., bootstrapping, expert opinions, and univariate analysis.ResultsA total of 939 patients who used statins were identified consisting 15, 9, and 19 per 10,000 persons for overall outcome prevalence, using statin alone, and co-administrations, respectively. Common statins were simvastatin, atorvastatin, and rosuvastatin. The proposed models had high sensitivity, i.e., 0.85, 0.90, 0.95 and 0.95 for LR, BN, RF, and XGBoost, respectively. The area under the receiver operating characteristic was significantly higher in LR than BN, i.e., 0.80 (0.79, 0.81) and 0.73 (0.72, 0.74), but a little lower than the RF [0.817 (95% CI 0.811, 0.824)] and XGBoost [0.819 (95% CI 0.812, 0.825)]. The LR model indicated that a combination of high-dose lipophilic statin, clarithromycin, and antifungals was 16.22 (1.78, 148.23) times higher odds of RM than taking high-dose lipophilic statin alone.ConclusionsThe study suggested that statin uses may have drug interactions with others including clarithromycin and antifungal drugs in inducing RM. A prospective evaluation of the model should be further assessed with well planned data monitoring. Applying LR in hospital system might be useful in warning drug interaction during prescribing.

Clinical implications and current perspectives of statin-induced rhabdomyolysis syndrome – case presentation

Abstract Though rare, statins can produce serious adverse effects with clinical implications that urge prompt intervention. However, in high-risk patients that require intense hypolipemiant treatment, such situations can be challenging and require complimentary therapies. We report the case of a 82-year-old hypertensive female patient admitted for diffuse myalgia, mainly in the lower limbs, fatigue and shortness of breath. The patient is known with a recent myocardial infarction (MI) treated by primary stent implantation. The electrocardiogram and transthoracic echocardiography confirmed the recent MI, with non-dilated left ventricle mildly reduced ejection fraction. Initial laboratory studies revealed elevated NT-proBNP, moderate renal impairment and increased serum levels of creatine kinase (CK), CK-MB fraction and transaminases. After stopping statin and receiving supportive treatment, the patient's paraclinical test results and symptoms improved: CK levels and transaminase dropped significantly and both myalgia and general fatigue resolved mostly within 4 days. PCSK9 inhibitor has been introduced with favourable results at follow-ups. Even though statins are effective and safe, they may still generate potential dangerous adverse effects in rare cases. Statin dose adjustment or replacement and adding other lipid lowering therapies represent current therapeutical options, especially in high-risk populations.

A Narrative Review of Statin-Induced Rhabdomyolysis: Molecular Mechanism, Risk Factors, and Management.

Although statins are effective for treating hypercholesterolemia, they can have various side effects, including rhabdomyolysis, a potentially fatal condition. This review evaluated the incidence and underlying molecular mechanism of statin-induced rhabdomyolysis and analyzed its risk factors, prevention, and management. We focused on the clinical and randomized clinical trials of statin monotherapies and combinations with other drugs. The primary mechanism of statin therapy-induced rhabdomyolysis is believed to be a decrease in ubiquinone (coenzyme Q) produced by the HMG-CoA pathway. Additionally, different types of lipophilic and hydrophilic statins play a role in causing rhabdomyolysis. Although statin-induced rhabdomyolysis has a low incidence, there is no guarantee that patients will be free of this side effect. Rhabdomyolysis can be prevented by reducing the risk factors, such as using CYP3A4 inhibitors, using high-dose statins, and strenuous physical activities.

A CASE REPORT ON A RARE COMPLICATION OF HMG-COA REDUCTASE INHIBITORS.

Rhabdomyolysis is the rare adverse effect of statin therapy. It is a condition characterized by the damage and breakdown of skeletal muscle. A 66 years old male patient was admitted to the hospital with the chief complaint of pain and weakness in both lower and upper limbs for ve days and was diagnosed with statin-induced rhabdomyolysis. The signicance of statin-induced rhabdomyolysis in a patient with recent Hepatitis B related Decompensated Chronic Liver Disease with portal Hypertension, and Severe Mitral Regurgitation is highlighted here. Based on this case report, we recommend that clinicians should inform regular follow-up to the patients when prescribing statins.

When Should Statins Be Stopped?

Mycobacterium chelonae is a non-tuberculous mycobacterium that can cause skin infections in immunocompetent individuals. We report a case of skin infection by this agent in a woman with dyslipidaemia, that culminated in statin-induced rhabdomyolysis due to the combination of clarithromycin, ciprofloxacin and simvastatin.LEARNING POINTSSkin infection with Mycobacterium chelonae is an increasing global problem among immunocompetent individuals.Statin-induced rhabdomyolysis is an important and avoidable end-result of drug–drug interaction.Inhibition of cytochrome P450 isoenzyme 3A4 and of organic anion transporting polypeptide 1B1 are two important examples of statin interference with metabolism, and clarithromycin can inhibit both.

Statin-induced rhabdomyolysis in a 60-year-old woman with decompensated type 2 diabetes: a case report

Rhabdomyolysis is a very rare and most severe form of statin-induced muscle adverse event characterized by muscle pain, muscle necrosis with myoglobinemia and/or myoglobinuria with a very high risk of acute kidney injury and death. The article presents a case report of developing rhabdomyolysis in a middleaged female patient with hypertension, decompensated type 2 diabetes and albuminuria. A 60-year-old woman was admitted to the hospital for emergency indications with complaints of severe muscle weakness that began in the neck, which spread over several days to the upper and lower extremities, with a symptoms progression up to paresis. According to the appointment of a primary care physician, three months before hospitalization, the patient was switched from therapy with European generic brand-name rosuvastatin 20 mg to the Russian generic unbranded atorvastatin in the same dose (20 mg), which is not comparable in lipid-lowering effect. In a laboratory study, an increase in creatine phosphokinase level by 348 times (50462 U/L) of upper normal limit in combination with severe hypokalemia 1б7 mmol/L in the absence of renal dysfunction was recorded. Cancellation of statin, metformin and empagliflozin, intensive infusion therapy and treating electrolyte imbalance made it possible to prevent the development of acute renal damage, life-threatening arrhythmias and completely stop muscle complaints within a few days. The patient was discharged from the hospital on the 23rd day with reference clinical and laboratory values, including creatine phosphokinase.This case emphasizes the importance of maintaining clinical suspicion regarding rhabdomyolysis in patients receiving statin therapy in the presence of risk factors (in this case, female sex, hyperglycemia, chronic kidney disease, concomitant therapy), as well as the relevance of timely diagnosis and treatment of this condition.

Abstract P147: Association Of Rosuvastatin Use With Risk Of Rhabdomyolysis Across Chronic Kidney Disease Status

Introduction: Statin-induced rhabdomyolysis is a rare, but potentially life-threatening condition. It is unknown whether specific statins carry a greater risk of rhabdomyolysis and whether the risk differs between patients with and without chronic kidney disease (CKD). The objective of this study was to investigate the association of rosuvastatin use vs. atorvastatin use with the risk of rhabdomyolysis across CKD status. Hypothesis: Rosuvastatin use is associated with a higher risk of rhabdomyolysis as compared to atorvastatin use and the risk is greater among those with CKD than those without CKD. Methods: We identified adult patients who initiated rosuvastatin or atorvastatin between January 1, 2004 and December 31, 2018 and were free of end-stage kidney disease at the time of prescription in the Geisinger Health System. The association between rosuvastatin use and rhabdomyolysis was assessed using Cox proportional hazards regression models with an interaction between rosuvastatin use and CKD (i.e., estimated glomerular filtration rate &lt;60 ml/min/1.73 m 2 ) in an inverse probability of treatment weighted (IPTW) sample. Results: Of 8,748 rosuvastatin users (mean [SD] age, 59.7 [12.6] years; 49.8% female; 11.8% CKD) and 31,770 atorvastatin users (mean [SD] age, 59.1 [12.6] years; 48.2% female; 11.9% CKD), 0.7% and 0.4% patients developed rhabdomyolysis, respectively, during a median follow-up of 5.1 years. Rosuvastatin use was associated with a higher risk of rhabdomyolysis in patients with CKD (hazard ratio [HR], 3.29; 95% CI, 1.53-7.09), but not in those without CKD (HR, 1.29; 95% CI, 0.82-2.03; p-interaction=0.04). A higher risk of rhabdomyolysis associated with rosuvastatin use in lower eGFR was also observed in the analysis with continuous eGFR ( Figure ). Conclusions: The findings suggest that rosuvastatin use in patients with CKD may be associated with excess risk of rhabdomyolysis as compared to atorvastatin.

Statin-induced toxic rhabdomyolysis with hepatocellular jaundice in the elderly

Adverse drug reactions (ADRs) are a common cause of hospitalization, increased morbidity and mortality in the elderly. ADRs are difficult to diagnose in the elderly as they often present with nonspecific symptoms such as fatigue, falls, cognitive decline, and constipation. Statins are generally well-tolerated drugs used in the secondary prevention of coronary artery disease. We report a 75-year-old lady who developed jaundice and became bedbound due to statin-induced hepatitis and acute rhabdomyolysis causing proximal myopathy following initiation of atorvastatin 40 mg for the management of coronary artery disease. She had rapid clinical improvement with discontinuation of statin therapy and supportive management. ADR must be considered a part of differential diagnosis in elderly patients during the evaluation of illnesses. In the elderly initiated on statins, it is essential to differentiate benign muscle pain from severe muscle injury with biochemical abnormalities. Prompt discontinuation of statins will lead to rapid improvement and prevent further worsening.

Statin-induced rhabdomyolysis: a cautionary tale for high-dose rosuvastatin

Statins are a widely prescribed lipid-lowering agent for preventing adverse cardiovascular events. However, a major side effect is rhabdomyolysis, a breakdown of muscle tissue, which can cause acute kidney injury and death. We present a case of a 77-year-old Chinese woman who was started on 40 mg rosuvastatin post-percutaneous coronary intervention and ultimately developed rhabdomyolysis and acute kidney injury one month later. This case highlights the need to consider patient risk factors for developing statin-induced rhabdomyolysis when choosing the right dose of statin to prescribe.

Blepharoptosis and Cholesterol-Lowering Medications: A Retrospective Study.

To investigate the prevalence and frequency of patients with blepharoptosis who take anticholesterol therapies. To our knowledge, this is the first large single-center series to evaluate this association. A retrospective chart review of adult patients presenting with ptosis on concomitant anticholesterol medications. Two hundred ninety-three adult patients with ptosis taking anticholesterol therapy were identified from October 2011 to October 2016. Forty-seven patients (16.0%) reported muscle weakness. Laboratory markers including creatine kinase (CK) and myoglobin levels were obtained. Of the 47 patients, 13 patients (4.4%) were identified to have ptosis and laboratory confirmed anticholesterol therapy-induced myopathy. Two additional patients with statin-induced myositis and rhabdomyolysis were identified from the period 2008-2011. All patients had measurably elevated CK and/or myoglobin levels. All patients experienced improvement in ptosis or systemic symptoms after discontinuation or changing medications. Nine patients (60%) demonstrated statistically significant improvement in the ptosis. Many patients with involutional ptosis also have both cardiovascular disease and hyperlipidemia and thus take cholesterol-lowering medication. Our study demonstrates a World Health Organization-defined probable association between ptosis and anticholesterol-induced myopathy. The frequency of anticholesterol-induced myopathy in adult ptosis was 4.4%, which is substantially higher than previously predicted. Anticholesterol-induced myositis can cause a reversible ptosis, and thus, a thorough evaluation of adult patients presenting with involutional ptosis includes inquiry into the use of anticholesterol drugs and associated muscle weakness.Anticholesterol medication may induce or exacerbate myogenic ptosis in some individuals.

Prediction of pharmacokinetic drug-drug interactions causing atorvastatin-induced rhabdomyolysis using physiologically based pharmacokinetic modelling

Atorvastatin and its lactone form metabolite are reported to be associated with statin-induced myopathy (SIM) such as myalgia and life-threatening rhabdomyolysis. Though the statin-induced rhabdomyolysis is not common during statin therapy, its incidence will significantly increase due to pharmacokinetic drug-drug interactions (DDIs) with inhibitor drugs which inhibit atorvastatin’s and its lactone’s metabolism and hepatic uptake. Thus, the quantitative analysis of DDIs of atorvastatin and its lactone with cytochrome P450 3A4 (CYP3A4) and organic anion-transporting polypeptide (OATP) inhibitors is of great importance. This study aimed to predict pharmacokinetic DDIs possibly causing atorvastatin-induced rhabdomyolysis using Physiologically Based Pharmacokinetic (PBPK) Modelling. Firstly, we refined the PBPK models of atorvastatin and atorvastatin lactone for predicting the DDIs with CYP3A4 and OATP inhibitors. Thereafter, we predicted the exposure changes of atorvastatin and atorvastatin lactone originating from the case reports of atorvastatin-induced rhabdomyolysis using the refined models. The simulation results show that pharmacokinetic DDIs of atorvastatin and its lactone with fluconazole, palbociclib diltiazem and cyclosporine are significant. Consequently, clinicians should be aware of necessary dose adjustment of atorvastatin being used with these four inhibitor drugs.

Can vitamin D supplementation decrease risk of statin-induced rhabdomyolysis in patients receiving statin therapy?

Can vitamin D supplementation decrease risk of statin-induced rhabdomyolysis in patients receiving statin therapy?

Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells.

Patients with end-stage kidney disease (ESKD) are at higher risk for rhabdomyolysis induced by statin than patients with normal kidney function. Previously, we showed that this increase in the severity of statin-induced rhabdomyolysis was partly due to uremic toxins. However, changes in the quantity of various trace elements in ESKD patients likely contribute as well. The purpose of this study is to determine the effect of trace elements on statin-induced toxicity in rhabdomyosarcoma cells exposed to uremic serum (US cells) for a long time. Cell viability, apoptosis, mRNA expression, and intracellular trace elements were assessed by viability assays, flow cytometry, real-time RT-PCR, and ICP-MS, respectively. US cells exhibited greater simvastatin-induced cytotoxicity than cells long-time exposed with normal serum (NS cells) (non-overlapping 95% confidence intervals). Intracellular levels of Mg, Mn, Cu, and Zn were significantly less in US cells compared to that in NS cells (p < 0.05 or 0.01). Pre-treatment with TPEN increased simvastatin-induced cytotoxicity and eliminated the distinction between both cells of simvastatin-induced cytotoxicity. These results suggest that Zn deficiencies may be involved in the increased risk for muscle complaints in ESKD patients. In conclusion, the increased severity of statin-induced rhabdomyolysis in ESKD patients may be partly due to trace elements deficiencies.

Case Report: Rehabilitation of a 65 Year-Old Female with Statin-Induced Rhabdomyolysis

Case Report: Rehabilitation of a 65 Year-Old Female with Statin-Induced Rhabdomyolysis Jonathan Swartz, DPT; Donna Cech, PT, DHS, PCS; Christian C Evans, PT, PhD; James Donahue, DPT Abstract Statin-induced rhabdomyolysis is a debilitating condition of muscle breakdown that can lead to severe functional limitations. Prior reports of physical therapy treatment have focused on athletes and military personal following acute exertional rhabdomyolysis, however there is minimal information for treatment of statin-induced rhabdomyolysis in the geriatric population. A 65 year-old female with a diagnosis of rhabdomyolysis due to the interaction of atorvastatin and clarithromycin was seen in an out-patient orthopedic clinic for weakness, fatigue, and difficulty completing daily tasks. The treatment approach was adapted from work based on previous military programs in managing acute exertional rhabdomyolysis by decreasing the pace and intensity of the exercises to accommodate an elderly patient, but still maintaining a focus on achieving active range of motion before progressing to isotonic exercises and functional activities. Primary outcome measures included the Timed Up and Go (TUG), 6 Minute Walk Test (6MWT), and 5 Time Sit to Stand (5xSTS). By discharge all outcome measures demonstrated improvement and the patient was able to return to work. Full Text: PDF DOI: 10.15640/ijhs.v5n1a1

Association of aspartate aminotransferase in statin-induced rhabdomyolysis.

INTRODUCTION The risk of rhabdomyolysis in the general population is elevated by the increased prevalence of statin use. As the presentation of rhabdomyolysis is varied, there is a risk of delayed diagnosis leading to patient complications and increased healthcare costs. Creatine kinase (CK) alone is not sufficiently predictive for risk stratification. Beyond serum CK, other biomarkers such as transaminases may be used as surrogates to evaluate rhabdomyolysis severity and predict complication risks. AIM To assess if other biomarkers are associated with peak CK and severity of rhabdomyolysis to aid in clinical diagnosis of rhabdomyolysis. METHODS A retrospective study was conducted at an acute care hospital from 2008 to 2011. Inclusion criteria were: (1) patients diagnosed with statin-induced rhabdomyolysis; and (2) peak CK levels of ≥1000 IU/L. Patients with post-operational rhabdomyolysis, acute myocardial infarction and who had suffered from road traffic accidents were excluded. A total of 24,332 patients were screened, and 78 patients fulfilled our inclusion criteria. RESULTS Aspartate aminotransferase (AST) was found to be positively associated with peak CK levels in the multivariable linear regression model after adjusting for alanine aminotransferase (ALT) levels (P = 0.002; β = 83.18). Aspartate aminotransferase was found to be associated with severity of rhabdomyolysis in the multivariable logistics regression model after adjusting for ALT levels (P = 0.015; OR = 1.01). DISCUSSION Aspartate transferase is associated with raised peak CK levels and severity of rhabdomyolysis. Clinicians may consider ordering AST to aid in the clinical diagnosis of rhabdomyolysis.