Development of a treatment selection algorithm for SGLT2 and DPP-4 inhibitor therapies in people with type 2 diabetes: a retrospective cohort study

John M. Dennis (Lead / Corresponding author), Katherine G. Young, Andrew P. McGovern, Bilal A. Mateen, Sebastian J. Vollmer, Michael D. Simpson, William E. Henley, Rury R. Holman, Naveed Sattar, Ewan R. Pearson, Andrew T. Hattersley, Angus G. Jones, Beverley M. Shields, MASTERMIND consortium

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Abstract

Background: Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies. Methods: In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 m 2, or did not have a valid baseline glycated haemoglobin (HbA 1c) measure (<53 or ≥120 mmol/mol). The primary efficacy outcome was the HbA 1c value reached 6 months after drug initiation, adjusted for baseline HbA 1c. Clinical features associated with differential HbA 1c outcome on the two therapies were identified in CPRD (n=26 877), and replicated in reanalysis of 14 clinical trials (n=10 414). An algorithm to predict individual-level differential HbA 1c outcome on the two therapies was developed in CPRD (derivation; n=14 069) and validated in head-to-head trials (n=2499) and CPRD (independent validation; n=9376). In CPRD, we further explored heterogeneity in 6-month weight change and treatment discontinuation. Findings: Among 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbA 1c, age, BMI, eGFR, and alanine aminotransferase were associated with differential HbA 1c outcome with SGLT2 inhibitor and DPP-4 inhibitor therapies. The median age of participants was 62·0 years (IQR 55·0–70·0). 10 016 (37·3%) were women and 16 861 (62·7%) were men. An algorithm based on these five features identified a subgroup, representing around four in ten CPRD patients, with a 5 mmol/mol or greater observed benefit with SGLT2 inhibitors in all validation cohorts (CPRD 8·8 mmol/mol [95% CI 7·8–9·8]; CANTATA-D and CANTATA-D2 trials 5·8 mmol/mol [3·9–7·7]; BI1245.20 trial 6·6 mmol/mol [2·2–11·0]). In CPRD, predicted differential HbA 1c response with SGLT2 inhibitor and DPP-4 inhibitor therapies was not associated with weight change. Overall treatment discontinuation within 6 months was similar in patients predicted to have an HbA 1c benefit with SGLT2 inhibitors over DPP-4 inhibitors (median 15·2% [13·2–20·3] vs 14·4% [12·9–16·7]). A smaller subgroup predicted to have greater HbA 1c reduction with DPP-4 inhibitors were twice as likely to discontinue SGLT2 inhibitors than DPP-4 inhibitors (median 26·8% [23·4–31·0] vs 14·8% [12·9–16·8]). Interpretation: A validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes. Funding: BHF-Turing Cardiovascular Data Science Award and the UK Medical Research Council.

Original languageEnglish
Pages (from-to)E873-E883
Number of pages11
JournalThe Lancet Digital Health
Volume4
Issue number12
Early online date22 Nov 2022
DOIs
Publication statusPublished - Dec 2022

ASJC Scopus subject areas

  • Decision Sciences (miscellaneous)
  • Health Information Management
  • Health Informatics
  • Medicine (miscellaneous)

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