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

Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of a...

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Published in:The Lancet (British edition) 2022-09, Vol.400 (10355), p.832-845
Main Authors: Reith, Christina, Baigent, Colin, Blackwell, Lisa, Spata, Enti, Davies, Kelly, Wilson, Kate, Armitage, Jane, Preiss, David, Simes, John, Collins, Rory, Barnes, Elizabeth, Fulcher, Jordan, Herrington, William G, Kirby, Adrienne, Mihaylova, Borislava, O'Connell, Rachel, Amarenco, Pierre, Barter, Philip, Betteridge (deceased), D John, Blazing, Michael, Bosch, Jackie, Braunwald, Eugene, Clearfield, Michael, Cobbe, Stuart, Colhoun, Helen M, Dahlöf, Björn, de Lemos, James, Downs, John R, Durrington, Paul N, Fellström, Bengt, Franzosi, Maria Grazia, Fuller (deceased), John, Furberg, Curt, Glynn, Robert, Gordon, David, Gotto Jr, Antonio, Gupta, Ajay, Hawkins, C Morton, Hitman, Graham A, Holdaas (deceased), Hallvard, Jardine, Alan, Jukema, J Wouter, Kean, Sharon, Kjekshus, John, Knatterud (deceased), Genell, Knopp (deceased), Robert H, Koren, Michael, Krane, Vera, Latini, Roberto, Lonn, Eva, Lucci, Donata, Macfarlane, Peter, MacMahon, Stephen, Maggioni, Aldo, Marchioli, Roberto, Marschner, Ian, Moyé, Lemuel, Murphy, Sabina, Neil, Andrew, Nicolis, Enrico B, Packard, Chris, Parish, Sarah, Peto, Richard, Pfeffer, Marc, Pressel, Sara, Rahman, Mahboob, Ridker, Paul M, Robertson, Michele, Sacks, Frank, Schmieder, Roland, Serruys, Patrick W, Sever, Peter, Shaw (deceased), John, Shepherd (deceased), James, Simpson, Lara, Sleight (deceased), Peter, Tavazzi, Luigi, Tognoni, Gianni, Wanner, Christoph, Wedel, Hans, Weis, Stephen, Welch, K Michael, White, Harvey, Wilhelmsen, Lars, Young, Robin, Yusuf, Salim, Zannad, Faiez, Arashi, Hiroyuki, Clarke, Robert, Flather, Marcus, Goldbourt, Uri, Goto, Shinya, Hopewell, Jemma, Kearney, Patricia, Kitas, George, Newman, Connie, Schwartz, Greg, Smeeth, Liam, Tobert, Jonathan, Yamaguchi, Junichi
Format: Article
Language:English
Subjects:
Arteriosclerosis
Atherosclerosis
Atherosclerosis - drug therapy
Atorvastatin
Australia
Bias
Cardiovascular diseases
Cholesterol
Clinical trials
Creatine
Creatine kinase
Data analysis
Diabetes mellitus
Dictionaries
Double-blind studies
Female
Heart attacks
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects
Ischemia
Kinases
Low density lipoprotein
Male
Median (statistics)
Medical research
Meta-analysis
Middle Aged
Muscle pain
Muscles
Myalgia - chemically induced
Observational studies
Pain
Placebos
Randomized Controlled Trials as Topic
Signs and symptoms
Statins
Therapy
Variance analysis
Vascular diseases
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Summary:Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit
ISSN:0140-6736
1474-547X
1474-547X
DOI:10.1016/S0140-6736(22)01545-8