Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials

Blazing, Michael A.; Braunwald, Eugene; Lemos, James A. de; Murphy, Sabina A.; Pedersen, Terje R.; Pfeffer, Marc A.; White, Harvey D.; Wiviott, Stephen D.; Clearfield, Michael; Downs, John R.; Gotto, Antonio M.; Weis, Stephen E.; Fellström, Bengt; Holdaas, Hallvard; Jardine, Alan G.; Gordon, David; Davis, Barry R.; Furberg, Curt D.; Grimm, Richard H.; Pressel, Sara L.; Probstfield, Jeffrey L.; Rahman, Mahboob; Simpson, Lara M.; Koren, Michael; Dahlöf, Björn; Gupta, Ajay; Poulter, Neil; Sever, Peter; Wedel, Hans; Knopp, Robert H.; Cobbe, Stuart M.; Schmieder, Roland E.; Zannad, Faı̈ez; Betteridge, D. J.; Colhoun, Helen M.; Durrington, Paul N.; Fuller, John A.; Hitman, G. A.; Neil, Andrew; Hawkins, C. Morton; Moyé, Lemuel A.; Sacks, Frank M.; Kjekshus, John; Wikstrand, John; Wanner, Christoph; Krane, Vera; Franzosi, Maria Grazia; Latini, Roberto; Lucci, Donata; Maggioni, Aldo P.; Marchioli, Roberto; Nicolis, Enrico; Tavazzi, Luigi; Tognoni, Gianni; Bosch, Jackie; Lonn, Eva; Yusuf, Salim; Armitage, Jane; Bowman, Louise; Collins, Rory; Keech, Anthony; Landray, Martin J; Parish, Sarah; Pető, Richárd; Sleight, Peter; Kastelein, John J.P.; Glynn, Robert J.; Köenig, Wolfgang; MacFadyen, Jean; Ridker, Paul M.; MacMahon, Stephen; Marschner, Ian C.; Tonkin, Andrew; Shaw, John H.; Simes, John; Serruys, Patrick W.; Knatterud, Genell L.; Ford, Ian; Macfarlane, Peter W.; Packard, Chris J.; Sattar, Naveed; Shepherd, James; Trompet, Stella; Cannon, Christopher P.; Amarenco, Pierre; Welch, K. M. A.; Wilhelmsen, Lars; Barter, Philip J.; LaRosa, John C.; Kean, Sharon; Robertson, Michele; Young, Robin; Arashi, Hiroyuki; Clarke, Robert; Flather, Marcus; Goto, Shinichi; Goldbourt, Uri; Hopewell, Jemma C.; Hovingh, Kees; Kitas, George D.; Newman, Connie B.; Sabatine, Marc S.; Schwartz, Greg; Smeeth, Liam; Tobert, Jonathan A.; Varigos, John; Yamaguchi, Junichi; Kearney, Patricia; Jukema, J Wouter; Byington, Robert P.

doi:10.1016/s0140-6736(22)01545-8

Cited by 144 publications

(57 citation statements)

References 59 publications

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“…On the other hand, our ndings align with those of a recent individual participant data (IPD) metaanalysis of RCTs investigating the impact of statins on muscle symptoms [3]. IPD from 19 RCTs (N ~ 124,000) showed that statin therapy only causes a negligible increase in the risk of muscle pain or weakness compared to placebo (a 7% relative increase after the rst year and a 3% after 4 years) [3]. Additionally, evidence from randomized N-of-1 studies suggests that the observed muscle symptoms following statin initiation are largely due to a nocebo effect (up to 90%) and that most patients can successfully restart treatment with statins [14][15].…”

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

“…Statins can also impact the musculoskeletal system, causing rare cases of muscle necrosis or more common symptoms such as localized muscle pain and reduced strength [2]. However, evidence linking statins to muscle problems is inconsistent, with observational studies indicating elevated risk, which is not supported by randomized clinical trial (RCT) ndings [3]. This difference may be due to lower bias control in non-randomized studies or to RCTs underestimating musculoskeletal adverse events by excluding individuals with a personal or family history of muscle problems, and by lacking proper assessment of milder complaints [4].…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the Relationship between Statins and Muscle Problems in the ELSA-Brasil MSK Cohort

PEDROSO-CAMARGOS

Barreto

Telles

et al. 2023

Preprint

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Purpose. To investigate the association between statins and muscle problems in a highly diverse sample of Brazilian civil servants. Methods. We conducted a cross-sectional data analysis at baseline of the ELSA-Brasil MSK cohort. Pain was identified through self-reported symptoms in large muscle groups (lower back and/or hips/thighs). Muscle strength was assessed using the five-times-sit-to-stand (FTSTS) and handgrip tests, with weakness defined as the lowest and highest quintiles of age− and sex−stratified handgrip strength and FTSTS performance time, respectively. Multivariable logistic regression analyses were conducted to investigate the association between statin use and muscle pain and weakness. Secondary analyses explored the impact of different types of statins and their duration of use on the response variables. Results. A total of 2,156 participants (mean age 55.6 ± SD 8.9, 52.8% women) were included. We found no significant association between statin use and muscle problems. Secondary exploratory analysis on different types of statins revealed an association between atorvastatin and muscle weakness, as measured by the five-times-sit-to-stand test (OR 1.94 IC95% 1.12–3.37), but not by the handgrip test (OR 0.75 IC95% 0.29–1.42). No evidence was found to support a link between the duration of statin treatment and muscle problems. Conclusions. This study challenges previous claims of an efficacy-effectiveness gap between experimental and observational literature on statins, offering important insights into the widespread prescription of statins in diverse populations. The findings indicate that statin use does not contribute to muscular problems.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Uncovering the Relationship between Statins and Muscle Problems in the ELSA-Brasil MSK Cohort

PEDROSO-CAMARGOS

Barreto

Telles

et al. 2023

Preprint

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show abstract

“…The most common causes of statin intolerance have been shown to be statin-associated muscle symptoms; however, a meta-analysis of the results from randomized trials of statins revealed that more than 90% of muscle symptoms in patients receiving statin therapy were not due to the statins [ 69 ]. Typically, the average incidence of myopathy is approximately one case per 10,000 patients treated per year, and that of rhabdomyolysis is 2–3 cases per 100,000 patients [ 70 , 71 ].…”

Section: Challenges In Current Lipid-lowering Therapies and Perspecti...mentioning

confidence: 99%

Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease

Nishikido

2023

Cardiovasc Diabetol

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Elevated low-density lipoprotein cholesterol (LDL-C) level is associated with an increased risk of atherosclerotic cardiovascular disease. Although high-intensity lipid-lowering therapies with statins and ezetimibe are highly effective for reducing LDL-C levels, over half of high-risk patients do not achieve guideline-recommended LDL-C goals. Thus, there is a significant gap between treatment guidelines and their implementation in daily clinical practice. The major causes are individual variability in the response to lipid-lowering therapies and variation in treatment adherence. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies combined with statins provide marked and consistent reduction in LDL-C levels; however, poor adherence due to the need for subcutaneous injections every 2 or 4 weeks and high cost are major obstacles to their use in real-world clinical settings. Inclisiran, a recently approved novel small interfering ribonucleic acid (siRNA) molecule that inhibits PCSK9 synthesis, provides robust and long-term reduction in LDL-C levels with a low inter-individual variability in the LDL-C-lowering response. Moreover, its administration by biannual injection is expected to greatly improve treatment adherence. Clinical trials of this drug lasting for up to 4 years showed acceptable safety profiles, and ongoing studies accumulate evidence of its longer-term safety. This narrative review summarizes the available evidence on the efficacy and safety of inclisiran and analyzes its potential to overcome the gap between guideline recommendations and real-world clinical practice in current LDL-C-lowering therapies, with a focus on reduced LDL-C level variability and improved treatment adherence.

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“…These agents lower blood cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and, in addition, have beneficial immunomodulatory effects [ 38 ]. However, statins have also been linked to adverse effects of muscle damage and pain, and even rhabdomyolysis [ 39 ]. Although statin use is perceived as a probable risk for developing sarcopenia, the pros of cholesterol lowering drugs outbalance the possible risks.…”

Section: Disease-related Sarcopeniamentioning

confidence: 99%

The Cytokine Growth Differentiation Factor-15 and Skeletal Muscle Health: Portrait of an Emerging Widely Applicable Disease Biomarker

Paepe

2022

IJMS

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Growth differentiation factor 15 (GDF-15) is a stress-induced transforming growth factor-β superfamily cytokine with versatile functions in human health. Elevated GDF-15 blood levels associate with multiple pathological conditions, and are currently extensively explored for diagnosis, and as a means to monitor disease progression and evaluate therapeutic responses. This review analyzes GDF-15 in human conditions specifically focusing on its association with muscle manifestations of sarcopenia, mitochondrial myopathy, and autoimmune and viral myositis. The use of GDF-15 as a widely applicable health biomarker to monitor muscle disease is discussed, and its potential as a therapeutic target is explored.

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Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials

Cited by 144 publications

References 59 publications

Uncovering the Relationship between Statins and Muscle Problems in the ELSA-Brasil MSK Cohort

Uncovering the Relationship between Statins and Muscle Problems in the ELSA-Brasil MSK Cohort

Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease

The Cytokine Growth Differentiation Factor-15 and Skeletal Muscle Health: Portrait of an Emerging Widely Applicable Disease Biomarker

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