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

Abstract

IntroductionFor 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.Methods and analysisThe 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.Ethics and disseminationThis 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.

Ethnic and socioeconomic disparities in initiation of second‐line antidiabetic treatment for people with type 2 diabetes in England: A cross‐sectional study

“…We conducted a cross‐sectional study, nested within the Personalized Medicine for Intensification of Treatment in people with T2DM (PERMIT) cohort study, 25 to investigate disparities in second‐line antidiabetic treatment prescribed to people with T2DM by ethnicity and by deprivation status. Data sources included the Clinical Practice Research Datalink (CPRD) Gold and Aurum datasets (primary care), Hospital Episode Statistics (HES; secondary care), the Index of Multiple Deprivation (IMD), and the Office of National Statistics (ONS) death data.…”

“…The PERMIT study protocol describes PP contributions to the study design. 25 PP representatives will assist with drafting lay summaries, which we will share on the study website ( https://www.lshtm.ac.uk/research/centres-projects-groups/permit ) and at study workshops with a wider group of multi‐ethnic PP representatives. We will work with the Centre for Ethnic Health Research, led by co‐author K.K., to make culturally adapted lay summaries.…”

“…was involved in this study's design, provided feedback on this manuscript, and is a co‐author. The PERMIT study protocol describes PP contributions to the study design 25 . PP representatives will assist with drafting lay summaries, which we will share on the study website (https://www.lshtm.ac.uk/research/centres-projects-groups/permit) and at study workshops with a wider group of multi‐ethnic PP representatives.…”

“…We conducted a cross-sectional study, nested within the Personalized Medicine for Intensification of Treatment in people with T2DM (PERMIT) cohort study, 25 The CPRD is a large, population-based dataset covering approximately 20% of the UK population and is representative in terms of age, sex and ethnicity. 26,27 These data include clinical diagnoses, laboratory test results, and prescribing information recorded in primary care.…”

Triangulating Instrumental Variable, confounder adjustment and Difference-in-Difference methods for comparative effectiveness research in observational data

“…A similar approach of using clinical commissioning group prescribing history as an IV has been proposed to evaluate T2D treatment by Bidulka et al (2021). [36]…”