Protocol for an observational cohort study investigating personalised medicine for intensification of treatment in people with type 2 diabetes mellitus: the PERMIT study.

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. 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' 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. This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene & Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers.

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© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: PB, SO'N, AB, RJS, PC, LAT and LS have nothing to declare. SW is employed by Roche and holds stock in Roche. AB is an economic advisor on DiRECT trial with ongoing responsibility for economic analysis during long-term follow-up phase, and has also acted as consultant to GlaxoSmithKline, Merck, Novo Nordisk and Boehringer Ingelheim in relation to their diabetes products. AIA receives salary from the National Institute for Health Research (NIHR) via the University of Oxford and Addenbrooke’s Hospital, and also chairs an NICE technology appraisal committee, is a member of Diabetes UK, and manages people whose salaries are partially funded by completed trials involving sitagliptin and exenatide and an ongoing trial of empagliflozin. KK has acted as a consultant, speaker or received grants for investigator-initiated studies for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Berlin-Chemie AG/Menarini Group, Janssen, and Napp. IJD holds an unrestricted research grant from GSK and holds shares in GSK. RG sits on the NIHR commissioning committee.