Aims: Glycated Hemoglobin A1c (HbA1c) is widely used for the diagnosis and management of type 2 diabetes mellitus (T2D), with regular testing in primary care recommended every three to six months. We aimed to identify distinct, long-term HbA1c trajectories following a T2D diagnosis and investigate how these glycaemic control trajectories were associated with health-related traits and T2D complications. Methods: A cohort of 12,435 unrelated individuals of European ancestry with T2D was extracted from the UK Biobank data linked to primary care records. Latent class growth mixture modelling was applied to identify classes with similar HbA1c trajectories over the 10-years following T2D diagnosis. We tested for associations of HbA1c class membership with sociodemographic factors, biomarkers, polygenic scores, and T2D-related outcomes, using logistic regression and Cox proportional hazards models. Results: Six HbA1c trajectory classes were identified. The largest class (76.8%) maintained low and stable HbA1c levels over time. The other five classes demonstrated higher and more variable trajectories and included: two with parabolic shapes (starting low and distinguished by the height of their peaks), two with high initial HbA1c levels that declined over time (one rapidly, one slowly), and one class with a rapid increase in HbA1c five years after diagnosis. Younger age at T2D diagnosis, higher fasting glucose levels, higher random glucose levels, and higher body mass index polygenic score were associated with membership of these five classes. These classes were also more likely to be prescribed glucose-lowering medication at diagnosis and had fewer primary care visits in the month and year prior to diagnosis. Relative to the low and stable class, these five showed increased risks of T2D complications, including stroke (HR=1.55 [1.31-1.84]), kidney disease (HR=1.39 [1.27-1.53]), all-cause mortality (HR=1.36 [1.23-1.51]), and progression to combination therapy (HR=3.22 [3.04-3.41]) or insulin (HR=3.21 [2.89-3.55]). Conclusion: Individuals with T2D who show higher and more variable HbA1c trajectories are at increased risk of developing T2D-related complications. Early identification of patients at risk, based on factors such as age at diagnosis and previous healthcare utilisation could improve patient outcomes.

The authors have declared no competing interest.

This paper represents independent research part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The authors acknowledge use of the research computing facility at King's College London, CREATE. This research as supported by the Medical Research Council (MR/S0151132; MR/N015746). JT is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK [SBF004\1079].

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was granted by the NHS North West Research Ethics Committee (REC reference 11/NW/0382). Written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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Data used in this project is available via application to the UK Biobank.