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Comparative Muscle Tolerability of Different Types and Intensities of Statins: A Network Meta-Analysis of Double-Blind Randomized Controlled Trials

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Abstract

Purpose

The benefits of statins for ischemic cardio-cerebrovascular diseases are well known. However, concerns around muscle adverse events still exist. We therefore aimed to compare the muscle safety of individual statins in adults.

Methods

PubMed, Embase, Cochrane Central Register of Controlled Trials and Web of Science were searched to include double-blind randomized controlled trials (RCTs) comparing one statin with another or with control treatment. Pairwise meta-analyses and network meta-analyses were undertaken with Stata 14.0 software. Relative risk (RR) with 95% confidence intervals (CIs) was adopted for each outcome.

Results

A total of 83 RCTs were included. In the pairwise meta-analysis, statins were significantly associated with only a slight increase in muscle symptoms compared with control (RR=1.05; 95% CI=1.01–1.09). In the drug-level network meta-analyses, no statistically significant difference was found between individual statins in the incidence of muscle symptoms, myalgia, myopathy, rhabdomyolysis, creatine kinase (CK) >10 times the upper limit of normal (ULN) or discontinuation due to muscle adverse events. In the dose-level network meta-analyses, there were no statistically significant dose-dependent effects on any outcomes except that moderate-intensity statins had a higher incidence of muscle symptoms than control (RR=1.13; 95% CI=1.01–1.27). Moderate simvastatin (RR=6.57; 95% CI=1.26–34.41) and moderate pravastatin (RR=5.96; 95% CI=1.00–35.44) had a statistically significantly higher incidence of CK >10×ULN compared with moderate atorvastatin. Lipophilic statins and statins metabolized by liver cytochrome P450 3A4 were not associated with an increased risk of muscle adverse events.

Conclusion

Statins may be generally safe on muscle. Moderate atorvastatin may be superior to equivalent simvastatin and pravastatin in muscle tolerability.

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Data Availability

All the data supporting our findings are presented in this published article and its Supplementary Information files.

Abbreviations

CI :

Confidence interval

CK :

Creatine kinase

ULN :

Upper limit of normal

CYP3A4 :

Cytochrome P450 3A4

CENTRAL :

Cochrane Central Register of Controlled Trials

IF :

Inconsistency factor

MeSH :

Medical Subject Headings

NFP :

Network forest plot

RCT :

Randomized controlled trial

RR :

Relative risk

SUCRA :

Surface under the cumulative ranking curve

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81901425).

Funding

This work was supported by grants from the National Natural Science Foundation of China (81901425).

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Authors and Affiliations

  1. Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, 1# Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China

    Qingtao Hou & Yingxiao Zhang

  2. Neuroscience Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Yuqin Chen

  3. Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Caishuang Pang

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  1. Qingtao Hou
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Contributions

All authors contributed to the study conception and design. Data extraction and analysis were performed by Qingtao Hou, Yuqin Chen and Yingxiao Zhang. Methodological supervision of the manuscript was provided by Caishuang Pang. The first draft of the manuscript was written by Qingtao Hou and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qingtao Hou.

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Fig. S1

Online Source 3. Pairwise meta-analyses between statins as a class and control treatment: (a) muscle symptoms, (b) myalgia, (c) myopathy, (d) rhabdomyolysis, (e) CK >10×ULN, (f) discontinuation due to muscle adverse events. CK, creatine kinase; CI, confidence interval; RR, relative risk; ULN, upper limit of normal (PNG 2035 kb)

High-resolution image (TIF 3205 kb)

Fig. S2

Online Source 4. Ranking of different-intensity statins based on probability of CK >10×ULN according to the cumulative ranking area (SUCRA): larger probability, lower incidence of CK >10×ULN. CK, creatine kinase; ULN, upper limit of normal; AH, high-intensity atorvastatin; AM, moderate-intensity atorvastatin; FL, low-intensity fluvastatin; FM, moderate-intensity fluvastatin; PiM, moderate-intensity pitavastatin; PrL, low-intensity pravastatin; PrM, moderate-intensity pravastatin; RH, high-intensity rosuvastatin; RM, moderate-intensity rosuvastatin; SM, moderate-intensity simvastatin (PNG 176 kb)

Fig. S3

Risk-of-bias graph of included trials (PNG 7 kb)

Fig. S4

Risk-of-bias summary of included trials (PNG 67 kb)

Fig. S5

The comparison-adjusted funnel plots for the network of muscle adverse events: (a) muscle symptoms, (b) myalgia, (c) myopathy, (d) rhabdomyolysis, (e) CK >10×ULN, (f) discontinuation due to muscle adverse events. CK, creatine kinase; ULN, upper limit of normal (PNG 1445 kb)

Fig. S6

Loop-specific inconsistency approach for muscle adverse events: (a) muscle symptoms, (b) myalgia, (c) myopathy, (d) rhabdomyolysis, (e) CK >10×ULN, (f) discontinuation due to muscle adverse events. CK, creatine kinase; CI, confidence interval; IF, inconsistency factors; ULN, upper limit of normal (PNG 1197 kb)

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Hou, Q., Chen, Y., Zhang, Y. et al. Comparative Muscle Tolerability of Different Types and Intensities of Statins: A Network Meta-Analysis of Double-Blind Randomized Controlled Trials. Cardiovasc Drugs Ther (2022). https://doi.org/10.1007/s10557-022-07405-0

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