1 REVIEW

2 Safitri et al

3 A Narrative Review of Statin-Induced

4 Rhabdomyolysis: Molecular Mechanism, Risk
5 Factors, and Management
6 Nisa Safitri1

7 Maya F. Alaina1

8 Dian Ayu Eka Pitaloka1,2

9 Rizky Abdulah1,2
1
10 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas

11 Padjadjaran, Sumedang 45363, Indonesia

2
12 Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas

13 Padjadjaran, Sumedang 45363, Indonesia

14

15 Correspondence: Dian Ayu Eka Pitaloka

16 Tel +62-22-84288812

17 Email : dian.pitaloka@unpad.ac.id

18
19 Abstract: Despite the effective use of statins in hypercholesterolemia, they can have various side

20 effects, including rhabdomyolysis, which can be fatal. This review evaluated the incidence of

21 rhabdomyolysis due to statin therapy, molecular mechanism statin-induced rhabdomyolysis,

22 analyzed the risk factors, and how to prevent and manage it. We focused on clinical and

23 randomized clinical trials, both on monotherapy and combinations of statins with other drugs. The

24 primary mechanism of statin-induced rhabdomyolysis therapy is believed due to a decrease in

25 ubiquinone (coenzyme Q), produced by the HMG-CoA pathway. Different types of lipophilic and

26 hydrophilic statins also play a role in the occurrence of rhabdomyolysis. Although statin-induced

27 rhabdomyolysis still has a low incidence, there is no guarantee that patients will be free from this

28 side effect. Prevention by reducing the risk factors for rhabdomyolysis, such as avoiding using

1
29 CYP3A4 inhibitors, not initiating high-dose statins, and minimizing strenuous physical activity,

30 hopefully, can help manage the incidence of rhabdomyolysis.

31 Keywords: Statin, hypercholesterolemia, adverse effect, rhabdomyolysis, risk factor

32 Introduction

33 Cholesterol is a fatty substance necessary for the proper functioning of the body by the

34 synthesis of hormones, and vitamin D. Cholesterol is transported through the blood by a specific

35 class of particles called lipoproteins. Low-density lipoprotein (LDL) carries liver cholesterol to the

36 cells, and high-density lipoprotein (HDL) removes excess cholesterol from different tissues and

37 transports it back to the liver for elimination.1 LDL is known as bad cholesterol and is the most

38 important factor in cardiovascular disease development. LDL can lead to atherosclerosis

39 (formation of plaque on the artery walls), which reduces blood flow and can even cause a heart

40 attack.2 The maximum tolerated cholesterol limit is 200 mg/dL for total cholesterol, 100 mg/dL for

41 LDL cholesterol (LDL-C), and not less than 50 mg/dL for HDL cholesterol (HDL-C). When plasma

42 cholesterol levels exceed these levels, the condition is called hypercholesterolemia.3

43 Statins are well-known lipid-lowering agents and one of the world's most prescribed drugs.

44 Statins lower cholesterol levels through three linked mechanisms. The first mechanism is

45 selective and competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)

46 reductase. This mechanism limits the conversion speed of HMG-CoA to mevalonic acid, a

47 precursor of sterols, including cholesterol in the mevalonate pathway, causing the substrate to

48 bind to the active site and reducing cholesterol synthesis.4 The second indirect mechanism is

49 increasing the receptor-mediated absorption of LDL, reducing plasma LDL. The third mechanism

50 is correlated with lowering very-low-density lipoprotein and intermediate-density lipoprotein, which

51 are LDL precursors, further reducing plasma LDL-C.5

52 Statins have been reported to have side effects on muscles, which the most common are

53 muscle pain, stiffness, myalgia, myopathy, and rhabdomyolysis.6 Rhabdomyolysis occurs due to

54 damage of the skeletal muscle, which disrupts muscle integrity and releases muscle components

55 such as CK, myoglobin, lactate dehydrogenase, aldolase, and electrolytes into the bloodstream.7,8

2 2
56 Clinical presentations of rhabdomyolysis include muscle pain, swelling, weakness, and red urine

57 due to increased myoglobin levels.9 Several reports have shown that the use of statins causes

58 rhabdomyolysis.10–13 It rarely happens, but it becomes a concern because of its clinically severe

59 effects.

60 This review aims to study the evidence related to statin-induced rhabdomyolysis, identify

61 the risk factors for rhabdomyolysis, and describe possible prevention and management strategies

62 that can help reduce the risk of statin-induced rhabdomyolysis. We focus on evidence reported in

63 clinical trials and randomized controlled trials (RCTs) on monotherapy and multidrug therapy

64 related to statins.

65 Methods

66 Article selection was conducted using the PubMed database with the keywords "statins and

67 rhabdomyolysis," published in 2001–2021. The inclusion criteria were English articles in RCTs

68 and monotherapy or multidrug therapy in clinical trials associated with statins. A total of 1230

69 publications were found, of which 59 met the inclusion criteria. Through full-text screening, we

70 excluded articles that did not have an episode of rhabdomyolysis, articles that did not have

71 research results, and articles that were not related to the study. Of these 59 papers, only 12 were

72 on the incidence of rhabdomyolysis due to statins: 7 were RCTs, 4 were clinical trials, and 1 was

73 a clinical trial (phase 1) (Figure 1).

74

75 Current evidence of statin-induced rhabdomyolysis

76 Patient characteristics

77 The total number of patients reported in 12 studies was 1,129,477, of which 102 patients

78 (0.009%) had statin-induced rhabdomyolysis (Table 1). The mean age of the patients was 63.57

79 years, and most were males (57.4%). However, other characteristics, such as the body mass

80 index and comorbidities, were not mentioned in all 12 studies.

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 81 Drug treatment

82 The type of statin and doses used in the trial varied, but simvastatin was the most widely

83 used. Two studies reported using simvastatin as monotherapy.14,15 Abraldes et al. (2016)14

84 administered simvastatin (20 mg/day) for the first 15 days and continued with 40 mg/day of

85 simvastatin as standard therapy for increasing the survival rate in patients with cirrhosis.

86 Wierzbicki et al. (2001)15 compared the effects of 80 and 120 mg/day of simvastatin in patients

87 with hypercholesterolemia.15 Both of these studies show simvastatin monotherapy has a very

88 strong effect in inducing rhabdomyolysis seen from the percentage of the occurrence (Table 1).

89 Three studies performed simvastatin in combination with other drugs. The study from

90 HPS2-THRIVE (2013)13 reported a combination of simvastatin (40 mg/day) and niacin (1 g/day)

91 plus laropiprant (20 mg/day) administered for 4 weeks, followed by extended-release niacin (2

92 g/day) plus laropiprant (40 mg/day) for a further 3–6 weeks (ezetimibe 10 mg/day was given

93 when total cholesterol < 3.5 mmol/L). This combination therapy showed inducing rhabdomyolysis

94 with almost the same as the placebo group (simvastatin 40 mg/day), with the percentage of

95 0.109% and 0.114%, respectively. Another study used simvastatin monotherapy (40 mg/day) and

96 a combination with ezetimibe (10 mg/day) to analyze their efficacy in reducing LDL-C.11 Pose et

97 al. (2020)16 was also compared the efficacy of two doses of simvastatin (40 and 20 mg/day) in

98 combination with rifaximin (1200 mg/day), and it showed simvastatin of 40 mg/day induces

99 rhabdomyolysis higher than simvastatin of 20 mg/day.

100 Pedersen et al. (2005)17 compared two types of statins in two different doses: simvastatin

101 (20 mg/day) and high-dose atorvastatin (40 mg/day). The study showed that simvastatin in a

102 lower dose had a greater effect on rhabdomyolysis by 0.07% than a higher dose. The

103 effectiveness of a loading dose of atorvastatin (80 mg/day) before and 24 h after percutaneous

104 coronary intervention followed by atorvastatin (40 mg/day) for 30 days was already performed in

105 the RCT study. Total three cases of rhabdomyolysis were reported in this study. 10 Clinical trials

106 were conducted to assess the safety of rosuvastatin (5-40 mg/day) in 16,874 patients 18
, and

107 assessed side effects on skeletal muscle after fluvastatin and rosuvastatin use (dose are not

4 4
108 available). One case of rhabdomyolysis occurred in a patient who received rosuvastatin in

109 combination with concomitant gemfibrozil treatment.19 Phase 1 clinical trial study was also

110 performed to evaluate the safety of rosuvastatin (1–8 mg/kg/day) and erlotinib (150 mg/day) to

111 treat advanced solid malignancies. One case of rhabdomyolysis was reported in this study.12

112 Other studies did not list the type of statin or doses used. Enger et al. (2010) 20 conducted

113 an RCT study that analyzed the side effects of lipid-lowering agents, such as statins and fibrates.

114 Based on the results, the percentage of statin-induced rhabdomyolysis increased when combined

115 with fibrates and showed a correlation between the use of fibrates and rhabdomyolysis. Another

116 RCT study reported the incidence of rhabdomyolysis in patients taking lipid-lowering agents,

117 including statins, but the dose of each drug was not clearly stated.21 Based on these findings, it

118 appeared that simvastatin is mostly induced rhabdomyolysis higher than other types of statins. It

119 follows the theory that lipophilic statins have a higher risk of side effects, and increasing the statin

120 dose causes a higher ratio of side effects. 22

121 Clinical signs and functional measurement

122 Most of the studies reported that patients experienced muscle weakness, myalgia, and

123 fatigue. Laboratory examinations showed CK levels above normal (>2000 U/L) or 10 times the

124 upper limit of normal (ULN).5,12,19 The urine also showed a color change to dark. 19 However, some

125 of the studies did not specifically list the symptoms experienced by patients and the laboratory

126 test results.

127 Goss et al. (2016)12 reported rhabdomyolysis-related death. Of 24 patients, 1 experienced

128 rhabdomyolysis after administration of rosuvastatin and erlotinib and died. On day 6 (erlotinib

129 only), this patient showed normal alanine transaminase (ALT), albumin, hepatic, renal, and

130 muscle function. However, on day 28 (rosuvastatin + erlotinib), the CK level increased to >2000

131 U/L. These findings showed that the percentage of rhabdomyolysis due to statin therapy is

132 relatively low. However, they did not mention the possibility of rhabdomyolysis in certain patients.

133

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134 Molecular mechanism of statin-induced rhabdomyolysis

135 The primary mechanism of rhabdomyolysis due to statin therapy (Figure 2) is still unknown,

136 but statins are believed to induce skeletal muscle necrosis, probably due to the decrease in

137 ubiquinone. In addition to cholesterol, the HMG-CoA pathway also produces other essential

138 molecules, such as ubiquinone (coenzyme Q). Ubiquinone is the component of the mitochondrial

139 respiratory chain and acts as a mitochondrial electron transport facilitator. Inhibiting the HMG-

140 CoA pathway may inhibit ubiquinone production and disrupt cellular energy production, which

141 causes muscular cell death.23

142 The proteasome ubiquitin pathway plays a vital role in maintaining skeletal muscle. This

143 pathway mediates protein turnover through several enzymes, and the presence of a catabolic

144 state can lead to muscle atrophy. One of the enzymes that play a role in this pathway is protein

145 ligase (atrogin-1), which increases after statin therapy and is associated with muscle loss.22

146 Different types of lipophilic and hydrophilic statins play a role in the occurrence of

147 rhabdomyolysis. In vitro studies have shown that lipophilic statins have a more significant

148 myopathic effect than hydrophilic statins. A rhabdomyolysis is a severe form of myopathy.

149 Lipophilic statins (atorvastatin, simvastatin, fluvastatin) increase cell disruption through apoptosis

150 and proteolysis. These statins can easily pass through the lipid layer membrane by passive

151 transport and have higher toxic effects.22 This theory is in line with the review findings. The

152 incidence of rhabdomyolysis is more common in patients taking atorvastatin and simvastatin.

153 These findings are also consistent with the research by Mendes et al. (2014)24. They examined

154 the incidence of rhabdomyolysis due to statin therapy in case reports published in 1990–2013

155 and found that simvastatin was the most widely reported statin associated with rhabdomyolysis

156 (55 of 112 cases).

157 The effect of statins on myofibers was observed from cultured rats and revealed that

158 statins could reduce intracellular adenosine triphosphate (ATP) and Ca 2+ levels in the

159 sarcoplasmic reticulum. It can inhibit muscle contraction and cause contractile dysfunction,

160 leading to cell damage, muscle cell death, and rhabdomyolysis.25,26

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161 In the body, statins also ionize as anions and are taken up by membrane transporters of

162 organic anions, one of them being an organic anion transporting polypeptide (OATP).27 Knauer et

163 al. (2010)28 reported that OATP2B1 (an isoform of OATP) facilitates the accumulation of statins in

164 human myotubes and increases their myotoxicity.28 A similar result was reported by Tanaka et al.

165 (2010)25. They investigated the mechanism of statin myotoxicity in rats and found that OATP

166 isoforms (OATP2b1 and OATP1a4) facilitate statin-induced myotoxicity and increase the risk of

167 rhabdomyolysis.

168

169 Risk factor associated with statin-induced

170 rhabdomyolysis

171 Statin-induced rhabdomyolysis may be due to monotherapy or combination therapy with

172 other drugs. However, certain drugs given concurrently with statins increase the risk of

173 rhabdomyolysis. Omar and Wilson (2002)29 examined the incidence of rhabdomyolysis due to

174 statin therapy using the Adverse Event Reporting System of the Food and Drug Administration

175 (FDA) and found that 50% of rhabdomyolysis cases due to statin therapy are caused by drug

176 interactions.

177 Combining statins with an inhibitor of cytochrome P450 3A4 (CYP3A4) enzyme such as

178 Verapamil, Diltiazem, Ritonavir, and Amiodarone potentially increases the risk of

179 rhabdomyolysis.30–32 Statins are oxidized by CYP3A4, which is produced by the liver. Inhibiting

180 CYP3A4 by certain drugs can reduce statin oxidation and inhibit statins metabolism; therefore,

181 statins remain longer in the body, leading to a high risk of side effects.24

182 Fibrates are also reported to be associated with rhabdomyolysis. Fibrates can decrease

183 LDL and increase HDL levels. However, Enger et al. (2010) 20 and another study have shown that

184 fibrates (mostly fenofibrate) induce rhabdomyolysis.33 The mechanism underlying fibrate-induced

185 rhabdomyolysis has not been precisely defined.34

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186 The incidence of rhabdomyolysis may also increase with increasing statin dose. The higher

187 the dose, the higher the plasma statin concentration and its active metabolite state.35 A meta-

188 analysis study conducted by LaRosa (2005)36 showed a comparison between 10 and 80 mg of

189 atorvastatin. The author reported five cases of rhabdomyolysis at the higher dose and three

190 cases at the lower dose.

191 Schech et al. (2007)37 identified the risk factors for rhabdomyolysis among statin users and

192 found that statin users aged 65 years and older have four times the risk of hospitalization for

193 rhabdomyolysis than those younger, which might be correlated with a decrease in organ function.

194 The authors also observed a more than two-fold increase in the risk of rhabdomyolysis among

195 females. Comorbidities, such as diabetes mellitus, were not related to the risk, but the renal

196 disease was statistically significant. Patients with pre-existing renal impairment who take

197 cerivastatin may be at increased risk of rhabdomyolysis since this drug is excreted through the

198 kidneys.37

199 Association between the incidence of rhabdomyolysis with other diseases was reported in

200 147 patients with rhabdomyolysis incidence. Two of them had a history of liver disease. Liver

201 disease is associated with decreased expression of SLCO1B, an anion transporter that regulates

202 statin absorption in the liver. If the nucleotide in SLCO1B loses its function, statin-induced

203 myopathy can be triggered.14

204 Patients who are prescribed statins but engage in strenuous exercise also have an

205 increased risk of rhabdomyolysis. One study showed an association between statin therapy and

206 strenuous exercise. Patients given lovastatin had 62%–77% higher CK levels after a workout than

207 patients receiving placebo.38 Another study using rodents also showed that taking cerivastatin

208 after using a treadmill could increase muscle damage. 39 The association between the type of

209 exercise and the severity of the risk of statin-induced rhabdomyolysis is unclear. However,

210 exercise could affect the absorption, distribution, metabolism, and excretion of statins, resulting in

211 pharmacokinetic changes that can cause specific side effects.40

212 Strenuous exercise also causes excessive heat production, resulting in intracellular Ca 2+

213 increase through ATP depletion. The loss of ATP disrupts the Ca2+-ATPase and Na+/K+-ATPase

8 8
214 pumps, resulting in high intracellular Ca2+. It activates proteases and reactive oxygen species and

215 leads to muscle damage.41 In the PubMed database, there were 17 individual cases of

216 heatstroke-associated rhabdomyolysis. It is recommended that individuals who work in hot

217 environments anticipate rhabdomyolysis and take reasonable precautions.42

218

219 Prevention and management of statin-induced

220 rhabdomyolysis

221 The best prevention strategy to prevent statin-induced rhabdomyolysis is to lower all risk

222 factors. In particular, individuals who take statins and perform strenuous exercise, such as

223 athletes or workers in certain occupations, should take frequent breaks to relax their muscles and

224 relieve stress to decrease the risk of rhabdomyolysis. 43 Clinicians who recommend using statins

225 can also prioritize hydrophilic-type statins (pravastatin and rosuvastatin) to reduce potential side

226 effects.

227 The FDA does not recommend prescribing high doses (80 mg) of simvastatin because of

228 the increased risk of developing statin-induced muscle injury.44 Simvastatin at a dose of 80 mg

229 can be prescribed if the patient has been receiving the same therapy for 12 months without any

230 side effects. The recommended dose of simvastatin is 5–40 mg once daily. 39 Therefore, it is

231 recommended that <80 mg of simvastatin or other types of statins be administered. Although

232 there is no guarantee that rhabdomyolysis or further muscle damage will not occur, this does

233 reduce the risk of muscle injury.

234 A combination of CYP3A4 inhibitors with statins can increase the risk of rhabdomyolysis.

235 Patients with hypercholesterolemia who have certain disease complications should avoid

236 CYP3A4 inhibitor drugs in combination with statins.45 Moreover, if a patient has rhabdomyolysis

237 due to a lipophilic statin (e.g., atorvastatin, simvastatin), it may be reasonable to switch to a

238 hydrophilic statin (e.g., pravastatin, rosuvastatin).

9 9
239 Patients suspected of having rhabdomyolysis should undergo renal examination, then

240 statin therapy should be discontinued. Rhabdomyolysis is typically treated with intravenous

241 rehydration or dialysis for patients with more severe symptoms. After assessing the patient's

242 condition, the statin can still be used then start with a lower dose.46 However, if the patient

243 experiences increasing CK levels up to five times the ULN, the statin should be immediately

244 discontinued47. The patient should be given another lipid-lowering drug instead of a statin.

245 The GAUSS-4 clinical trial examined the comparison of evolocumab and ezetimibe in

246 patients with statin intolerance due to rhabdomyolysis. Evolocumab was more effective than

247 ezetimibe with respect to lowering LDL-C levels. Evolocumab decreased LDL-C levels by 59.5%,

248 while ezetimibe reduced LDL-C levels by only 20.3% of baseline, both measured at 12 weeks of

249 drug administration.48 Thus, the use of evolocumab in a patient with statin intolerance should be

250 prioritized.

251

252 Limitation
253 While our selected data from the PubMed database support this concept, we have not

254 investigated the potential side effect of stain-induced rhabdomyolysis in another literature

255 database which is become our limitation in this review.

256 Conclusion

257 Despite their benefits in the management of hypercholesterolemia, statins may cause

258 rhabdomyolysis. The findings of this review suggest that although the incidence of statin-induced

259 rhabdomyolysis is low, the risk can still increase due to the presence of triggering factors, such as

260 the use of CYP3A4 inhibitors, initiation of high-dose statins, and strenuous physical

261 activity. Therefore, the use of statins should be closely monitored, especially CK levels that

262 indicate rhabdomyolysis.

10 10
263 Acknowledgments

264 Thank you to the Center of Excellence in Higher Education for Pharmaceutical Care Innovation

265 Universitas Padjadjaran for all the support and facilities given for this review.

266 Disclosure

267 The author reports no conflicts of interest in this work.

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391 0193-9

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410

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411 Table 1 Studies on statins and rhabdomyolysis included in this review (dibalik)

Study Number of
References Treatment Rhabdomyolysis
design patients

Simvastatin (20 mg/day) 0.07%

Pedersen et
RCT 8,888
al. (2005)17
Atorvastatin (80 mg/day) 0.05%

Statin** 0.003%
Enger et al.
RCT 584,784 Statin** + Fenofibrate* 0.015%
(2010)20
Statin** + Gemfibrozil* 0.207%

Simvastatin (40 mg/day) + ER niacin (2

HPS2- 0,109%
g/day) and laropiprant (40 mg/day)
THRIVE. RCT 25,673
(2013)13
Simvastatin (40 mg/day) 0.114%

Atorvastatin* 0.0057%

Pravastatin* 0.010%

Simvastatin* 0.0055%
Cziraky et al.
RCT 473,343 Lovastatin* 0.0038%
(2013)21
Fluvastatin* 0.016%

Rosuvastatin* 0.012%

Cerivastatin* 0.085%

Simvastatin (20 mg/day) (first 15 days)

Abraldes et
RCT 147 followed by simvastatin (40 mg/day) 2.9%
al. (2016)14
thereafter

Giugliano et Simvastatin (40 mg) + ezetimibe (10

RCT 15,281 0,137%
al. (2017)11 mg/day)

Berwanger Loading doses of atorvastatin (80

et al. RCT 4,191 mg/day), followed by atorvastatin (40 0.142%
(2018)10 mg/day)

Simvastatin (80 mg/day) 0%

Wierzbicki et Clinical
22
al. (2001)15 Trial
Simvastatin (120 mg/day) 4.5%

15 15
 Shepherd et Clinical
16,876 Rosuvastatin (5-40 mg/day) 0.047%
al. (2007)18 Trial

Rosuvastatin*
Drobny et al. Clinical
198 3.03%
(2014)19 Trial
Fluvastatin*

Clinical
Goss et al. Rosuvastatin (1-8 mg/kg/day) + erlotinib
Trial 24 4.167%
(2016)12 (150 mg/day)
phase 1

Simvastatin (40 mg/day) + rifaximin (1200

19%
Clinical mg/day)
Pose et al.
trial phase 50
(2020)16
2 Simvastatin (20 mg/day) + rifaximin (1200
0%
mg/day)
412

413 Abbreviations: RCT, Randomized controlled trial; * dose is not available; ** dose and type of

414 drug are not available

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

16 16
431 Figure 1 Flowchart of the literature search process

432
433

434

435

436

437

438

439

440

441

442

443

17 17
444 Figure 2 Potential mechanism underlying statin-induced rhabdomyolysis

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

18 18