{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:23:43Z","timestamp":1760149423844,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"INFARMED\u2014National Authority of Medicines and Health Products","award":["UIDB\/00709\/2020","UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020","UIDP\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology\/MCTES","award":["UIDB\/00709\/2020","UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020","UIDP\/00709\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Healthcare"],"abstract":"<jats:p>The first line medication for the treatment of type 2 diabetes is metformin. This study aims to investigate the safety profile of metformin and metformin combination medications in older adults using pharmacovigilance data. A literature search was used to identify published clinical studies reporting safety of metformin in older patients (age \u2265 65 years old), which were then thoroughly evaluated. Additionally, a deep analysis was performed, taking into account suspected adverse drug reaction (ADR) reports submitted to the Portuguese Pharmacovigilance System involving patients with 65 years old or older, with metformin or metformin combination as the suspected drug. The results suggest that metformin is safer when used in combination with other antidiabetics than when used in monotherapy. Metformin prolonged-release tablets have a lower incidence of adverse effects compared to treatment with immediate-release metformin tablets. The analysis of the reports showed that \u201cgastrointestinal disorders\u201d was one of the most common classes reported, and metformin alone was the drug most commonly associated with serious gastrointestinal reactions that resulted in hospitalization. In addition, it was the drug most commonly associated with the lactic acidosis ADR. Even though most ADRs in the reports were serious, the majority progressed to cure. According to the analysis performed, the results suggest that the patient\u2019s renal function should be considered in order to prevent ADRs associated with metformin, such as lactic acidosis. Therefore, monitoring the safety profile of metformin remains essential to prevent serious ADRs.<\/jats:p>","DOI":"10.3390\/healthcare11152197","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T11:13:06Z","timestamp":1691061186000},"page":"2197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of Reports Sent to the Portuguese Pharmacovigilance System and Published Literature Regarding the Safety of Metformin in the Elderly"],"prefix":"10.3390","volume":"11","author":[{"given":"Beatriz","family":"Esteves","sequence":"first","affiliation":[{"name":"Health Science Faculty, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5225-6222","authenticated-orcid":false,"given":"Cristina","family":"Monteiro","sequence":"additional","affiliation":[{"name":"UFBI-Pharmacovigilance Unit of Beira Interior, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"},{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-5977","authenticated-orcid":false,"given":"Ana Paula Coelho","family":"Duarte","sequence":"additional","affiliation":[{"name":"UFBI-Pharmacovigilance Unit of Beira Interior, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"},{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-019-1911-y","article-title":"GDF15 mediates the effects of metformin on body weight and energy balance","volume":"578","author":"Coll","year":"2020","journal-title":"Nature"},{"unstructured":"American Diabetes Association (2022). Standards of Medical Care in Diabetes-2022, Diabetes Care.","key":"ref_2"},{"key":"ref_3","first-page":"127","article-title":"Practical Aspects in Metformin Therapeutics","volume":"9","author":"Nunes","year":"2014","journal-title":"Port. J. Diabetes"},{"unstructured":"(2022, August 03). Metformin: Summary of Product Characteristics. Available online: https:\/\/extranet.infarmed.pt\/INFOMED-fo\/pesquisa-avancada.xhtml.","key":"ref_4"},{"unstructured":"FDA Drug Safety Communication (2023, April 08). FDA Revises Warnings Regarding Use of the Diabetes Medicine Metformin in Certain Patients with Reduced Kidney Function. 4 August 2016, Available online: https:\/\/www.fda.gov\/files\/drugs\/published\/Drug-Safety-Communication-FDA-revises-warnings-regarding-use-of-the-diabetes-medicine-metformin-in-certain-patients-with-reduced-kidney-function-%28PDF%29.pdf.","key":"ref_5"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0140-6736(07)61091-5","article-title":"Appropriate prescribing in elderly people: How well can it be measured and optimised?","volume":"370","author":"Spinewine","year":"2007","journal-title":"Lancet"},{"unstructured":"World Health Organization (2002). The Importance of Pharmacovigilance, World Health Organization.","key":"ref_7"},{"unstructured":"(2022, August 24). Introductory Guide MedDRA Version 22.1. September 2019. Available online: https:\/\/admin.meddra.org\/sites\/default\/files\/guidance\/file\/000354_intguide_22.1.pdf.","key":"ref_8"},{"unstructured":"The Uppsala Monitoring Centre (2013). The Use of the WHO-UMC System for Standardised Case Causality Assessment, The Uppsala Monitoring Centre.","key":"ref_9"},{"unstructured":"Medicines Agency, E. (2023, April 08). Guideline on Good Pharmacovigilance Practices (GVP)\u2014Module VI\u2014Collection, Management and Submission of Reports of Suspected Adverse Reactions to Medicinal Products (Rev 2). Available online: ema.europa.eu\/en\/documents\/regulatory-procedural-guideline\/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports_en.pdf.","key":"ref_10"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"712200","DOI":"10.3389\/fendo.2021.712200","article-title":"Comparison of Clinical Efficacy and Safety of Metformin Sustained-Release Tablet (II) (Dulening) and Metformin Tablet (Glucophage) in Treatment of Type 2 Diabetes Mellitus","volume":"12","author":"Guo","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4093\/dmj.2018.0051","article-title":"Efficacy and Safety of Voglibose Plus Metformin in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial","volume":"43","author":"Oh","year":"2019","journal-title":"Diabetes Metab. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e227102","DOI":"10.1136\/bcr-2018-227102","article-title":"Metformin-associated lactic acidosis precipitated by liraglutide use: Adverse effects of aggressive antihyperglycaemic therapy","volume":"11","author":"Hooda","year":"2018","journal-title":"BMJ Case Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/dom.12787","article-title":"Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: A double-blind randomized controlled trial (INICOM study)","volume":"19","author":"Lim","year":"2017","journal-title":"Diabetes Obes. Metab."},{"doi-asserted-by":"crossref","unstructured":"Schlender, L., Martinez, Y.V., Adeniji, C., Reeves, D., Faller, B., Sommerauer, C., Qur\u2019an, A., Woodham, A., Kunnamo, I., and S\u00f6nnichsen, A. (2017). Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: A systematic review for the development of recommendations to reduce potentially inappropriate prescribing. BMC Geriatr., 17.","key":"ref_15","DOI":"10.1186\/s12877-017-0574-5"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/bcpt.12526","article-title":"Cardiovascular Drugs and Metformin Drug Dosage According to Renal Function in Non-Institutionalized Elderly Patients","volume":"118","author":"Becquemont","year":"2016","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1186\/1752-1947-8-449","article-title":"Metformin-associated lactic acidosis and temporary ileostomy: A case report","volume":"8","author":"Margiani","year":"2014","journal-title":"J. Med. Case Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/dmrr.2444","article-title":"Oral hypoglycaemic agents and the development of non-fatal cardiovascular events in patients with type 2 diabetes mellitus","volume":"29","author":"Hung","year":"2013","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"601","DOI":"10.7326\/0003-4819-157-9-201211060-00003","article-title":"Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: A cohort study","volume":"157","author":"Roumie","year":"2012","journal-title":"Ann. Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.2337\/dc13-0229","article-title":"Increased Risk of Cognitive Impairment in Patients with Diabetes Is Associated with Metformin","volume":"36","author":"Moore","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1001\/archinternmed.2010.409","article-title":"Metformin Use and Mortality Among Patients With Diabetes and Atherothrombosis","volume":"170","author":"Roussel","year":"2010","journal-title":"Arch. Intern. Med."},{"key":"ref_22","first-page":"1218","article-title":"Treatment of Type 2 Diabetes and Outcomes in Patients with Heart Failure: A Nested Case\u2013Control Study from the U.K","volume":"33","author":"MacDonald","year":"2010","journal-title":"Gen. Pract. Res. Database Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.amjcard.2010.05.031","article-title":"Effect of metformin on mortality in patients with heart failure and type 2 diabetes mellitus","volume":"106","author":"Evans","year":"2010","journal-title":"Am. J. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s00125-015-3844-9","article-title":"Metformin and the gastrointestinal tract","volume":"59","author":"McCreight","year":"2016","journal-title":"Diabetologia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000471917","article-title":"Metformin-Associated Lactic Acidosis Undergoing Renal Replacement Therapy in Intensive Care Units: A Five-Million Population-Based Study in the North-West of Italy","volume":"44","author":"Mariano","year":"2017","journal-title":"Blood Purif."},{"unstructured":"INFARMED (2022, September 25). How Many Notifications Are Made Annually?. Available online: https:\/\/www.infarmed.pt\/web\/infarmed\/perguntas-frequentes-area-transversal\/medicamentos_uso_humano\/notificacao-de-reacoes-adversas\/efeitos-indesejaveis-de-medicamentos-ram.","key":"ref_26"},{"unstructured":"INFARMED (2022, September 25). Evolution of ADR Reports Received in SNF, 1992\u20132021. Available online: https:\/\/www.infarmed.pt\/documents\/15786\/2297404\/Notifica%C3%A7%C3%B5es+RAM+1992-2020\/db879ca4-1cf8-f21f-672c-43d1296d8841.","key":"ref_27"},{"unstructured":"Comiss\u00e3o Europeia (2022, September 25). Chronic Disease 27 July 2017. Available online: https:\/\/op.europa.eu\/pt\/publication-detail\/-\/publication\/ed838bf9-a5e7-4e04-b8f7-3706eed3a354.","key":"ref_28"},{"unstructured":"Hajjar, E.R., Gray, S.L., Slattum, P.W., Hersh, L.R., Naples, J.G., and Hanlon, J.T. (2017). Geriatrics|Pharmacotherapy: A Pathophysiologic Approach 10e, McGraw Hill.","key":"ref_29"},{"unstructured":"PORDATA, Funda\u00e7\u00e3o Francisco Manuel Santos (2023, April 09). Popula\u00e7\u00e3o Residente: Total e Por Grupo Et\u00e1rio. Available online: https:\/\/www.pordata.pt\/portugal\/populacao+residente+total+e+por+grupo+etario-10.","key":"ref_30"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"187103","DOI":"10.1155\/2011\/187103","article-title":"Sex differences in drug disposition","volume":"2011","author":"Soldin","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1002\/jcph.1284","article-title":"Developmental Changes in Pharmacokinetics and Pharmacodynamics","volume":"58","author":"Reed","year":"2018","journal-title":"J. Clin. Pharmacol."},{"key":"ref_33","first-page":"222","article-title":"Pharmacovigilance in Portugal: Activity of the Central Pharmacovigilance Unit","volume":"28","author":"Mendes","year":"2015","journal-title":"Acta Med. Port."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.therap.2017.04.004","article-title":"Comparative relevance of declaration of side effects by patients and health professionals","volume":"72","author":"Lagneau","year":"2017","journal-title":"Therapie"},{"doi-asserted-by":"crossref","unstructured":"Salvador, M.R., Monteiro, C., Pereira, L., and Duarte, A.P. (2022). Quality of Spontaneous Reports of Adverse Drug Reactions Sent to a Regional Pharmacovigilance Unit. Int. J. Environ. Res. Public Health, 19.","key":"ref_35","DOI":"10.3390\/ijerph19073754"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s00228-017-2225-3","article-title":"Hospital admissions due to adverse drug reactions in the elderly. A meta-analysis","volume":"73","author":"Oscanoa","year":"2017","journal-title":"Eur. J. Clin. Pharmacol."},{"doi-asserted-by":"crossref","unstructured":"Sandberg, A., Salminen, V., Heinonen, S., and Siv\u00e9n, M. (2022). Under-Reporting of Adverse Drug Reactions in Finland and Healthcare Professionals\u2019 Perspectives on How to Improve Reporting. Healthcare, 10.","key":"ref_37","DOI":"10.3390\/healthcare10061015"}],"container-title":["Healthcare"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9032\/11\/15\/2197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:25:30Z","timestamp":1760127930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9032\/11\/15\/2197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,3]]},"references-count":37,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["healthcare11152197"],"URL":"https:\/\/doi.org\/10.3390\/healthcare11152197","relation":{},"ISSN":["2227-9032"],"issn-type":[{"type":"electronic","value":"2227-9032"}],"subject":[],"published":{"date-parts":[[2023,8,3]]}}}