{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T03:42:02Z","timestamp":1780803722287,"version":"3.54.1"},"reference-count":48,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"unspecified","delay-in-days":26,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007602","name":"Programme Grants for Applied Research","doi-asserted-by":"publisher","award":["NIHR128490"],"award-info":[{"award-number":["NIHR128490"]}],"id":[{"id":"10.13039\/501100007602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,8,31]]},"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>For people with type 2 diabetes mellitus (T2DM) who require an antidiabetic drug as an add-on to metformin, there is controversy about whether newer drug classes such as dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce the risk of long-term complications compared with sulfonylureas (SU). There is widespread variation across National Health Service Clinical Commissioning Groups (CCGs) in drug choice for second-line treatment in part because National Institute for Health and Care Excellence guidelines do not specify a single preferred drug class, either overall or within specific patient subgroups. This study will evaluate the relative effectiveness of the three most common second-line treatments in the UK (SU, DPP4i and SGLT2i as add-ons to metformin) and help target treatments according to individual risk profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>The study includes people with T2DM prescribed one of the second-line treatments-of-interest between 2014 and 2020 within the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics and Office of National Statistics. We will use an instrumental variable (IV) method to estimate short-term and long-term relative effectiveness of second-line treatments according to individuals\u2019 risk profiles. This method minimises bias from unmeasured confounders by exploiting the natural variation in second-line prescribing across CCGs as an IV for the choice of prescribed treatment. The primary outcome to assess short-term effectiveness will be change in haemoglobin A1c (%) 12 months after treatment initiation. Outcome measures to assess longer-term effectiveness (maximum ~6 years) will include microvascular and macrovascular complications, all-cause mortality and hospital admissions during follow-up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene &amp; Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2020-046912","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T13:18:50Z","timestamp":1632748730000},"page":"e046912","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Protocol for an observational cohort study investigating personalised medicine for intensification of treatment in people with type 2 diabetes mellitus: the PERMIT study"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7644-2030","authenticated-orcid":false,"given":"Patrick","family":"Bidulka","sequence":"first","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirban","family":"Basu","sequence":"additional","affiliation":[{"name":"The Comparative Health Outcomes, Policy & Economics (CHOICE) Institute, University of Washington School of Pharmacy, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Personalized Healthcare Data Science, Roche Products Limited, Welwyn Garden City, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2744-1194","authenticated-orcid":false,"given":"Richard J","family":"Silverwood","sequence":"additional","affiliation":[{"name":"Centre for Longitudinal Studies, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Charlton","sequence":"additional","affiliation":[{"name":"Patient Research Champion Team, National Institute for Health Research, Twickenham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Briggs","sequence":"additional","affiliation":[{"name":"Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda I","family":"Adler","sequence":"additional","affiliation":[{"name":"Diabetes Trials Unit, The Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamlesh","family":"Khunti","sequence":"additional","affiliation":[{"name":"Diabetes Research Centre, University of Leicester, Leicester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie A","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Smeeth","sequence":"additional","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J","family":"Douglas","sequence":"additional","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Grieve","sequence":"additional","affiliation":[{"name":"Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"2025120600034636000_11.9.e046912.1","unstructured":"NICE . 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