Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials
- PMID: 41655587
- DOI: 10.1016/S0140-6736(25)01578-8
Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials
Abstract
Background: Statin product labels (eg, Summaries of Product Characteristics [SmPCs]) list certain adverse outcomes as potential treatment-related effects based mainly on non-randomised and non-blinded studies, which might be subject to bias. We aimed to assess the evidence for such undesirable effects more reliably through a meta-analysis of individual participant data from large double-blind trials of statin therapy.
Methods: In this meta-analysis of individual participant-level data from double-blind randomised controlled trials, we generated a list of all undesirable effect terms listed in statin SmPCs by searching an electronic medicines compendium for five statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin). Randomised trials were eligible for meta-analysis of these effects if they involved at least 1000 participants, had a scheduled treatment period 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. Event rate ratios (RRs) and 95% CIs were calculated with statistical significance assessed after controlling the false discovery rate (FDR) at 5%.
Findings: 19 trials compared statin versus placebo (123 940 participants, median follow-up 4·5 years [IQR 3·1-5·4]). In addition to previously reported effects on muscle outcomes and diabetes, only four of 66 further undesirable outcomes that had been attributed to statins were FDR significant: abnormal liver transaminases (783 participants [0·30% per annum] allocated statin vs 556 [0·22% per annum] allocated placebo, RR 1·41 [95% CI 1·26-1·57]) and other liver function test abnormalities (651 participants [0·25% per annum] allocated statin vs 518 [0·20% per annum] allocated placebo, RR 1·26 [1·12-1·41]; absolute annual excess of 0·13% for combined liver function test abnormality), urinary composition alteration (556 [0·21% per annum] allocated statin vs 472 [0·18% per annum] allocated placebo, RR 1·18 [1·04-1·33]), and oedema (3495 [1·38% per annum] allocated statin vs 3299 [1·31% per annum] allocated placebo, RR 1·07 [1·02-1·12]). Analysis of the four trials of more intensive versus less intensive statin regimens also found significant excesses for abnormal liver transaminases and other liver function test abnormalities (supporting a dose-dependent effect), but no significant excess was found for urinary composition alteration or oedema.
Interpretation: Adverse event data from blinded randomised trials do not support causal relationships between statin therapy and most of the conditions (including cognitive impairment, depression, sleep disturbance, and peripheral neuropathy) listed in product labels as potential undesirable effects. In light of these findings, such labelling and other official sources of health information should be revised so that patients and their doctors can make appropriately informed decisions regarding statin therapy.
Funding: British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.
Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of interests CR, LB, JRE, DP, KD, CH, HH, LH, KW, RH, AJR, MJL, BM, JA, RC, and CB are affiliated with the Nuffield Department of Population Health (NDPH) at the University of Oxford, which has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. NDPH only seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings (https://www.ndph.ox.ac.uk/about/independence-of-research). Project and departmental grants have been awarded to NDPH by the British Heart Foundation and the UK Medical Research Council which has helped support NDPH staff working on this project. CR reports previously receiving funding to the University of Oxford (but no personal funding) from Merck–Schering-Plough Pharmaceuticals for the SHARP trial of simvastatin–ezetimibe, the UK National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme (17/140/02) and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. JRE declares grant funding from Regeneron Pharmaceuticals and AstraZeneca to the University of Oxford (but no personal funding) to support the Mexico City Prospective Study, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial. DP reports receiving funding to the University of Oxford (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial, and being a committee member for National Institute for Health and Care Excellence Cardiovascular Disease: Risk Assessment and Reduction Including Lipid Modification guideline. ES reports now being an employee of AstraZeneca. CH reports receiving funding to the University of Oxford (but no personal funding) from Novo Nordisk for the ASCEND PLUS trial of semaglutide. AJR reports receiving funding to the University of Oxford (but no personal funding) from the NIHR Oxford Biomedical Research Centre, Boehringer Ingelheim, and Eli Lilly. CPC reports grants or contracts from Amgen, Better Therapeutics, Boehringer-Ingelheim, and Novo Nordisk; salary support from Colorado Prevention Center Clinical Research, which gets research grant support from Amgen, Bayer, Cleerly, Esperion, Lexicon and Silence; consulting fees from Amryt–Chiesi, Amgen, Ascendia, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Genomadix, Lilly, Janssen, Lexicon, Milestone, Novartis, Pfizer, and Rhoshan; and participation on a Data and Safety Monitoring Board (DSMB) or Advisory Board for Areteia, Novo Nordisk, ROMTherapy, and the Veterans Administration. SG reports grants or contracts to his institution from MEXT–JSPS KAKENHI 19H03661, AMED (grant number A368TS and A447TR), and the Nakatani Foundation, consulting fees from Jansen Pharma, Amgen, and Merck Sharp and Dohme, payment or honoraria from Sysmex, and roles as Vice President of The Japanese College of Angiology, Associate Editor for Circulation, and Council Member of the International Society of Thrombosis and Haemostasis. GAH reports funding from Pfizer, Diabetes UK, and NHS England for the CARDS trial. GKH reports being an employee of Novo Nordisk and having stock options in Novo Nordisk. WK reports grants and provision of reagents to their institution from Singulex, Dr Beckmann Pharma, Abbott, and Roche Diagnostics, consulting fees from AstraZeneca, Novartis, Amgen, Pfizer, The Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, OMEICOS, Daichii Sankyo, Novo Nordisk, New Amsterdam Pharma, TenSixteen Bio, Genentech, and Esperion, and payment or honoraria from Bristol Myers Squibb, Novartis, Amgen, Berlin-Chemie, Sanofi, and AstraZeneca. MJL reports funding to their institution for clinical trials from Novartis, Regeneron, and Boehringer Ingelheim, funding to their institution for trial methodology research from Regeneron, Moderna, GSK, and Sanofi, funding to their institution for consultancy from GSK, Verve, and Marea, and roles as Adviser, Regulatory Affairs Committee for the European Society of Cardiology and Lead for the Good Clinical Trials Collaborative (funded by Wellcome and the Gates Foundation). BM reports a research grant to the University of Oxford and Queen Mary University of London from UK NIHR HTA (17/140/02) and a research grant to Queen Mary University of London from UK NIHR Barts Biomedical Research Centre, and support for attending meetings or travel from the European Society of Cardiology for attending a round table addressing unmet medical needs in cardiology. CN reports royalties for a textbook from Elsevier of less than US$5000 in the past 3 years, support from the Endocrine Society for travel and registration for lecture and for membership on planning committee in relation to the 2024 and 2025 meetings, and an unpaid roles as Vice President of the Medical Women's International Association and a board member for the Women in Medicine Legacy Foundation. MSS reports research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Marea, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics, consulting fees from Amgen, AMPEL BioSolutions, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, CCRN, Dr Reddy's Laboratories, General Medicines, Merck, NATF, Novo Nordisk, and Precision BioSciences, and reports being a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abiomed, ARCA Biopharma, Cleerly, Janssen Research and Development, MedImmune, Regeneron Pharmaceuticals, Roche, Softcell Medical, The Medicines Company, and Zora Biosciences. NS reports grants or contracts paid to his institution from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche, consulting fees paid via his institution from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GSK, Hanmi Pharmaceuticals, Menarini-Ricerche, Metsera, Novo Nordisk, Pfizer, and Roche, personal consulting fees from Novartis, and payment or honoraria paid via his institution from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Roche. GGS reports research support to the University of Colorado from AstraZeneca, Sanofi, and Silence Therapeutics and support from The University of Oxford for travel to attend clinical trial steering committee meetings. AMT reports payments for chairing a steering committee related to a survey of the adequacy of lipid management in patients in Australian general practice from Novartis and membership of the Data Monitoring Committee of the ORION-4 study of inclisiran supported by Novartis. HDW reports grant support paid to his institution by Sanofi-Aventis, Regeneron Pharmaceuticals for the ODYSSEY OUTCOMES trial, by American Regent for the HEART–FID study, by DalCor Pharma UK for the GenE Study, by CSL Behring for the AEGIS-II trial, by US National Institutes of Health for the ISCHEMIA and MINT studies, by Esperion Therapeutics for the CLEAR Outcomes study, by Omthera Pharmaceuticals for the STRENGTH trial, by Sanofi Aventis Australia for the SOLIST-WHF and SCORED trials, by Janssen Research and Development for the Librexia AF study and Librexia ACS studies, by Merck Sharp & Dohme (New Zealand) for the MK0616 study; fees from DalCor Pharma UK for serving on the steering committee for the GenE Study, CSL Behring for serving on the steering committee for the AEGIS-II trial, Sanofi Aventis Australia for serving on the steering committee for the SOLIST-WHF and SCORED trials, Esperion Therapeutics for serving on the steering committee for the CLEAR Outcomes study, and Janssen Research and Development for serving on the steering committee for the Librexia AF study and Librexia ACS studies; support from the South Australian Health and Medical Research Institute for attendance at the clinical trial forum (2022 and 2023), the National Health and Medical Research Council (NHMRC) Clinical Trials Centre; being the University of Sydney Chair of the DSMB for the EVIDENCE Study; being on the CSL Behring Advisory Board; and receiving VERVE HF advisory board fees (2024). JA reports an unpaid Independent Data Monitoring Committee role for the WOMAN2 trial. AK reports funding from the NHMRC Australia with an NHMRC Programme grant and Senior Research Fellowship to support all research activities; research grant funding from the Australian Medical Research Future Fund; research grants from Amgen, Abbott, and Viatris; being a DSMB member for the Harvard University and Kowa Pharmaceuticals PROMINENT trial; and drug provisions for research from Viatris. JS reports research grant to his institution from NHMRC Australia, Bristol Myers Squibb, Roche, Bayer, Amgen, and MSD, advisory board fees to his institution from FivepHusion, and being an unpaid Chair of the STAREE DSMB. RC declares grants to the University of Oxford from Merck, Novartis, UK Medical Research Council, British Heart Foundation, Cancer Research UK, AstraZeneca, Wellcome Trust, and Regeneron Pharmaceuticals; a patent for a statin-related myopathy genetic test from Boston Heart Diagnostics for which RC waived any personal reward with any share in royalty and other payments waived in favour of the Nuffield Department of Population Health, University of Oxford; and being Deputy Chair of the not-for-profit clinical trial company PROTAS, Chief Executive of UK Biobank, and Chair of the steering committee of the ORION-4 trial of inclisiran. CB declares support from Boehringer Ingelheim through a grant to the University of Oxford for the EMPA-KIDNEY and EASi-KIDNEY trials, being the Medical Research Council Population Health Research Unit Director from 2019–24, being a co-applicant on a Health Data Research UK Substantive Site award from 2018–23, being an unpaid DSMB or Advisory Board Chair for Merck for a phase 2 trial of factor X1-inhibitor for dialysis patients and for the NIHR HTA to prepare for a kidney care trial, and having unpaid roles in the NIHR HTA as Chair of Aspirin To Target Arterial Events in Chronic Kidney Disease (ATTACK) and Desmopressin for Acute Stroke due to Haemorrhage (DASH). All other authors declare no competing interests.
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