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. 2025 Nov 27:61:101547.
doi: 10.1016/j.lanepe.2025.101547. eCollection 2026 Feb.

Validation of an algorithm for selection of SGLT2 and DPP4 inhibitor therapies in people with type 2 diabetes across major UK ethnicity groups: a retrospective cohort study

Laura M Güdemann  1 , Katherine G Young  1 , Pedro Cardoso  1 , Bilal A Mateen  2 , Rury R Holman  3   4 , Naveed Sattar  5 , Ewan R Pearson  6 , Andrew T Hattersley  1 , Angus G Jones  1 , Beverley M Shields  1 , John M Dennis  1 ; MASTERMIND Consortium
Collaborators, Affiliations

Validation of an algorithm for selection of SGLT2 and DPP4 inhibitor therapies in people with type 2 diabetes across major UK ethnicity groups: a retrospective cohort study

Laura M Güdemann et al. Lancet Reg Health Eur. .

Abstract

Background: Routine clinical features of individual patients can potentially be used to guide selection of type 2 diabetes treatments. We aimed to evaluate a recently proposed treatment selection model predicting differences in glycaemic responses to SGLT2-inhibitors and DPP4-inhibitors across major UK ethnicity groups.

Methods: We externally validated the SGLT2i-DPP4i model in UK primary care cohort (CPRD Aurum, 2013-2020) independent of the original model development cohort. Non-insulin treated individuals with type 2 diabetes were identified and categorised by major UK self-reported ethnicity groups: White, Black, South Asian and Mixed/Other. For each ethnicity group, we applied a closed testing procedure to assess whether model recalibration was required. After model updates, we assessed the calibration accuracy of predicted differences in glycaemic response (6-month change in HbA1c) between SGLT2i and DPP4i for each ethnicity group.

Findings: SGLT2i (n = 57,749) and DPP4i (n = 87,807) initiations were identified amongst people of White (n = 114,287; 78.5%), Black (n = 6663; 4.6%), South Asian (n = 20,969; 14.4%) and Mixed/Other (n = 3637; 2.5%) ethnicities. Minor model adjustment was required to adjust for greater observed than predicted glycaemic responses to DPP4i (White-1.6 mmol/mol; Black-3.0 mmol/mol; South Asian-2.6 mmol/mol; Mixed/Other-2.6 mmol/mol). SGLT2i predictions did not require adjustment for non-White ethnicity groups. After model updates, average predicted HbA1c reduction was 3.7 mmol/mol (95% CI 3.5-3.9) greater with SGLT2i than DPP4i for those of White ethnicity; this was greater than for those of South Asian (2.1 mmol/mol (95% CI 1.6-2.6)), Black (0.6 mmol/mol (95% CI 0.5-1.7)) and Mixed/Other (2.6 mmol/mol (95% CI 1.4-3.8)) ethnicity groups. For all ethnicity groups, predicted differential glycaemic treatment effects were well calibrated.

Interpretation: Our model for selection of SGLT2-inhibitor and DPP4-inhibitor therapies was accurate for all major self-reported ethnicity groups in a UK primary care cohort. Simple recalibration is beneficial to optimise performance and this is recommended prior to deployment of the model in new populations and settings.

Funding: UK Medical Research Council, National Institute for Health and Care Research Exeter Biomedical Research Centre, and EFSD/Novo Nordisk.

Keywords: DPP4-inhibitors; Ethnicity; Heterogeneous treatment effects; Personalised medicine; Precision medicine; SGLT2-inhibitors; Type 2 diabetes.

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Conflict of interest statement

BAM holds an honorary professorial appointment at the University of Birmingham and is an employee of PATH. BAM declares grants from the UK Medical Research Council, Health Data Research UK, British Heart Foundation, the UK Engineering and Physical Sciences Research Council, the Gates Foundation, USAID, US CDC, GIZ, Wellcome Trust, Rockefeller Foundation, The Sall Family Foundation, and FCDO. RRH reports personal fees from Lilly, Merck KGaA, MitoRx, Novartis and Owen Mumford Ltd. NS declares personal fees from Abbott Diagnostics, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi; and grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. NS has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Menarini-Ricerche, Metsera, Novartis, Novo Nordisk, Pfizer, and Roche; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche outside the submitted work. ERP reports personal fees from Lilly and Novo Nordisk. AGJ was supported by an NIHR Clinician Scientist fellowship (CS-2015-15-018) and declares research funding from the UK Medical Research Council, Diabetes UK (charity), Juvenile Diabetes Research Foundation (charity), the European Foundation for the Study of Diabetes (charity) and the Novo Nordisk Foundation (Denmark), UK National Institute of Health and Care Research, and Breakthrough Type 1 diabetes. AGJ is also an advisory board member at Novo Nordisk Foundation UK. BMS declares research funding from the UK Medical Research Council, UK National Institute for Health Research, Diabetes UK (charity), Juvenile Diabetes Research Foundation (charity), and the European Foundation for the Study of Diabetes (charity). BMS is also a member of the Diabetes UK research grant committee. Representatives from GSK, Takeda, Janssen, Quintiles, AstraZeneca, and Sanofi have attended meetings as part of the industry group involved with the MASTERMIND consortium. All declarations are outside of this study. LMG, ATH, KGY, PC and JMD have nothing to declare.

Figures

Fig. 1
Fig. 1
SGLT2i-DPP4i treatment selection model performance in CPRD clinical data. Negative values reflect a predicted 6-month HbA1c benefit on SGLT2-inhibitor treatment, positive values reflect a predicted 6-month HbA1c on DPP4-inhibitor treatment. (a) Distribution of predicted individual-level differential treatment effects for 6-month HbA1c of SGLT2i-inhibitor treatment compared to DPP4-inhibitor treatment, by UK ethnicity group. (b) Calibration between observed and predicted 6-month HbA1c treatment effects by decile of predicted treatment effect, by UK ethnicity group. Red lines represent perfect calibration. Point estimates represent average HbA1c differences for subgroups defined by decile of predicted treatment benefit, with average HbA1c differences estimated as adjusted absolute mean differences in 6-month HbA1c outcome between individuals receiving each drug class. Bars represent 95% confidence intervals.
Fig. 2
Fig. 2
6-month HbA1c response, weight change and risk of treatment discontinuation across subgroups defined by clinical cutoffs of predicted treatment benefit, by UK ethnicity group, in CPRD clinical data. (a) HbA1c response (mmol/mol), estimated as unadjusted mean change from baseline in 6-month HbA1c. (b) Weight change (kg), defined as unadjusted mean change from baseline in 6-month weight. (c) Treatment discontinuation (%), defined as the unadjusted proportion of individuals discontinuing treatment within 6 months. Bars represent 95% confidence intervals. Supplementary Tables S4–S6 report the underlying results for HbA1c response, weight change, and treatment discontinuation.
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