全球胆固醇治疗试验协作组Robert Byington团队研究了他汀类药物对肌肉症状的影响。2022年8月29日，《柳叶刀》杂志发表了这一成果。

他汀类药物治疗可有效预防动脉粥样硬化性心血管疾病，并被广泛使用，但持续存在的担忧是他汀类治疗可能经常导致肌肉疼痛或无力。该研究旨在通过对他汀类药物治疗的大型、长期、随机、双盲试验中所有记录的不良肌肉事件的个体参与者数据进行荟萃分析来解决这些问题。

研究组筛选出他汀类药物治疗的随机试验，招募至少1000名参与者，计划治疗持续时间至少为2年，并涉及他汀类与安慰剂或更高强度与较低强度他汀类治疗方案的双盲比较。研究组分析了19项他汀类药物与安慰剂的双盲试验（123940例）和4项强化与非强化他汀类治疗方案双盲实验（30724）的个体参与者数据。根据预先指定的方案，对肌肉结果的影响进行了标准逆方差加权荟萃分析。

在19项安慰剂对照试验中（平均年龄63岁，34533名[27.9%]为女性，59610名[48.1%]既往有血管疾病，22925名[18.5%]为糖尿病患者），加权平均中位随访4.3年，服用他汀类药物的患者中有16835名（27.1%）报告肌肉疼痛或无力，服用安慰剂的患者中有16446名（26.6%），比率比（RR）为1.03。

在第1年，他汀类药物治疗导致肌肉疼痛或无力相对增加7%（1.07），相当于每1000人-年11个事件的绝对过量率，这表明接受他汀类治疗参与者的这些肌肉相关报告中，只有1/15实际上是由于他汀类。第1年后，首次报告的肌肉疼痛或无力没有明显增加（0.99）。

在所有年份中，与安慰剂相比，强度更高的他汀类方案（即40-80 mg阿托伐他汀或20-40 mg瑞舒伐他汀，每天一次）产生的RR高于强度较低或中等强度方案（分别为1.08与1.03），1年后，强度更大的方案出现少量过量（1.05）。没有明确证据表明不同他汀类药物或不同临床情况下的RR不同。他汀类药物治疗使肌酸激酶中值小幅增加，临床意义不显著，约为正常上限的0.02倍。

研究结果表明，他汀类药物治疗引起轻微肌肉疼痛。参与他汀类药物治疗受试者的所有肌肉症状报告中，大多数（>90%）不是由于他汀类。肌肉症状的小风险远低于已知的心血管益处。需要回顾服用他汀类药物患者肌肉症状的临床管理。

附：英文原文

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

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

Issue&Volume: 2022-08-29

Abstract:

Background

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.

Methods

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=123940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol.

Findings

Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34533 [27·9%] women, 59610 [48·1%] participants with previous vascular disease, and 22925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16835 (27·1%) allocated statin versus 16446 (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 of normal.

Interpretation

Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin.

DOI: 10.1016/S0140-6736(22)01545-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01545-8/fulltext