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This paper\u2019s aim is to compare the effects on HbA<jats:sub>1c<\/jats:sub> of sulfonylureas (SU), dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium\u2013glucose cotransporter-2 inhibitors (SGLT2i) added to metformin as second-line oral glucose-lowering treatments according to an individual\u2019s age, baseline HbA<jats:sub>1c<\/jats:sub> and presence of multiple long-term conditions (MLTCs).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We accessed primary care-hospital linked data for 41,790 individuals from the Clinical Practice Research Datalink (CPRD) in England who initiated second-line treatment after metformin between 2015 and 2021. We combined target trial emulation with instrumental variable analysis to reduce the risk of confounding. The outcome was change in HbA<jats:sub>1c<\/jats:sub> between baseline and 1 year follow-up. We reported results stratified by age (18\u201349 years, 50\u201369 years and \u226570 years), baseline HbA<jats:sub>1c<\/jats:sub> (&lt;67 mmol\/mol [&lt;8.3%], 67\u201377 mmol\/mol [8.3\u20139.2%] and &gt;77 mmol\/mol [&gt;9.2%]) and presence of MLTCs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The mean (95% CI) difference in HbA<jats:sub>1c<\/jats:sub> change for SGLT2i vs SU was larger for people aged 18\u201349 years (\u22125.74 mmol\/mol [\u22127.47, \u22124.01]) (\u22120.5% [\u22120.7, \u22120.4]) than for those aged 50\u201369 years (\u22124.03 mmol\/mol [\u22125.61, \u22122.44]) (\u22120.4% [\u22120.5, \u22120.2]) and for those aged 70 years or over (\u22122.68 mmol\/mol [\u22124.50, \u22120.86]) (\u22120.3% [\u22120.4, \u22120.07]). The mean (95% CI) difference in HbA<jats:sub>1c<\/jats:sub> change for SGLT2i vs DPP4i was \u22125.80 mmol\/mol (\u22127.60, \u22124.00) (\u22120.5% [\u22120.7, \u22120.4]) for those aged 18\u201349 years, \u22124.13 mmol\/mol (\u22125.82, \u22122.45) (\u22120.4% [\u22120.5, \u22120.2]) for those aged 50\u201369 years and \u22123.13 mmol\/mol (\u22125.01, \u22121.24) (\u22120.3% [\u22120.4, \u22120.1]) for those aged \u226570 years. The mean difference (improvement) in HbA<jats:sub>1c<\/jats:sub> was similar across subgroups defined by baseline HbA<jats:sub>1c<\/jats:sub> or presence of MLTCs. For SGLT2i vs SU, the mean (95% CI) difference was \u22125.37 mmol\/mol (\u22127.13, \u22123.62) (\u22120.5% [\u22120.6, \u22120.3]) for people without MLTC and \u22123.72 mmol\/mol (\u22125.34, \u22122.10]) (\u22120.3% [\u22120.5, \u22120.2]) for people with MLTC. For SGLT2i vs DPP4i the corresponding estimated differences (95% CI) were \u22125.44 mmol\/mol (\u22127.27, \u22123.61) (\u22120.5% [\u22120.7, \u22120.3]) for those without MLTC and \u22123.93 mmol\/mol (\u22125.64, \u22122.21) (\u22120.3% [\u22120.5, \u22120.2]) for those with MLTC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>Second-line treatment with SGLT2i is more effective than SU or DPP4i in reducing HbA<jats:sub>1c<\/jats:sub> across subgroups of people defined by age, baseline HbA<jats:sub>1c<\/jats:sub> and presence of MLTCs. Our evidence complements RCTs in using routinely available information on demographic characteristics, biomarkers and comorbidities to inform an individualised approach.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06447-x","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T14:06:50Z","timestamp":1748700410000},"page":"1908-1923","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparative effectiveness of alternative second-line oral glucose-lowering therapies for type 2 diabetes: a precision medicine approach applied to routine data"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-0090","authenticated-orcid":false,"given":"Stephen","family":"O\u2019Neill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7644-2030","authenticated-orcid":false,"given":"Patrick","family":"Bidulka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2621-5627","authenticated-orcid":false,"given":"David G.","family":"Lugo-Palacios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2449-790X","authenticated-orcid":false,"given":"Orlagh","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9788-0118","authenticated-orcid":false,"given":"Ignacio","family":"Leiva-Escobar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2744-1194","authenticated-orcid":false,"given":"Richard","family":"Silverwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0777-1997","authenticated-orcid":false,"given":"Andrew","family":"Briggs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2797-3385","authenticated-orcid":false,"given":"Amanda I.","family":"Adler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2343-7099","authenticated-orcid":false,"given":"Kamlesh","family":"Khunti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8899-1301","authenticated-orcid":false,"given":"Richard","family":"Grieve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"issue":"7","key":"6447_CR1","doi-asserted-by":"publisher","first-page":"e022768","DOI":"10.1136\/bmjopen-2018-022768","volume":"8","author":"S Wilkinson","year":"2018","unstructured":"Wilkinson S, Douglas I, Stirnadel-Farrant H et al (2018) Changing use of antidiabetic drugs in the UK: trends in prescribing 2000\u20132017. 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Basu (University of Washington, Seattle), P. Charlton (public contributor), I. Douglas (LSHTM) and L. Smeeth (LSHTM) for their helpful advice. We acknowledge and appreciate the support of the PERMIT study advisory team (K. Paterson, J. Lewsey (University of Glasgow), E. Pearson (University of Dundee), S. Finer (Queen Mary\u2019s University of London), S. Evans (LSHTM), B. Huston (public contributor) and R. Mohan) and the management and administrative support provided by E. Silver (Women and Children First), A. Carnegie (King\u2019s College London), P. Fry (LSHTM) and D. Mongiardi (LSHTM). This study is based in part on data from the Clinical Practice Research Datalink obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and entered by primary care practitioners as part of their care and support. The interpretation and conclusions contained in this study are those of the author\/s alone. The study was approved by the Independent Scientific Advisory Committee (approval no. 20_064).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"CPRD data of the form used in this paper are available by application to the CPRD Independent Scientific Advisory Committee ().","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This work was funded by the National Institute for Health and Care Research (NIHR) grant number NIHR128490. KK is supported by the NIHR Applied Research Collaboration East Midlands (ARC EM), NIHR Global Research Centre for Multiple Long Term Conditions, Multiple Long-Term Conditions Cross-NIHR Collaboration and the NIHR Leicester Biomedical Research Centre (BRC). AIA is supported by the NIHR Oxford BRC. The funder had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report or decision to submit the article for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"KK has acted as a consultant for, has been a speaker for, or has received grants for investigator-initiated studies from Astra Zeneca, Bayer, Novo Nordisk, Sanofi-Aventis, Servier, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Pfizer, Roche, Daiichi-Sankyo, Applied Therapeutics, Embecta and Nestle Health Science. AIA has received research income from Novo Nordisk. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"PB, SON, OC, DGLP, KK, AIA and RG were responsible for the conception and design of the study. All authors critically appraised and contributed to the study design and analysis plan. PB requested and extracted the data. PB, SON, DGLP and OC performed the data management and analysis. PB and ILE developed code lists for the identification of morbidities for the cohort with type 2 diabetes mellitus. SON, PB and RG wrote the manuscript with contributions from all authors. All authors critically revised and approved the manuscript. SON, PB and RG are guarantors and as such had full access to the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. SON and PB share first authorship. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}