Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study

TY - JOUR

T1 - Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes

T2 - the TriMaster study

AU - Shields, Beverley M.

AU - Dennis, John M.

AU - Angwin, Catherine D.

AU - Warren, Fiona

AU - Henley, William E.

AU - Farmer, Andrew J.

AU - Sattar, Naveed

AU - Holman, Rury R.

AU - Jones, Angus G.

AU - Pearson, Ewan R.

AU - Hattersley, Andrew T.

AU - TriMaster Study group

N1 - Funding Information: We thank all study participants. We gratefully acknowledge the TriMaster central coordinating team, all members of the TriMaster study group, MASTERMIND consortium, the Data Monitoring Committee, and the Trial Steering Committee (Supplementary Information). In particular, we thank Prof Stephen Senn for his invaluable guidance on the analysis for this trial. In addition, we thank the Exeter NIHR Clinical Research Facility and the Exeter Clinical Trials Unit (CTU), particularly Lynne Quinn and Siobhan Creanor for their support with the study, and the CTU Data Team. We thank Alison Kerridge and Shirley Todd of the R&D and Pharmacy Departments at the Royal Devon and Exeter NHS Foundation Trust for support and sponsorship. This trial is part of the MASTERMIND (MRC APBI Stratification and Extreme Response Mechanism IN Diabetes) consortium and is supported by the UK Medical Research Council study grant number MR/N00633X/1 (BM, JD, CA, WH, AF, NS, RH, AJ, EP, AH). The TriMaster trial was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre and National Institute for Health and Care Research Exeter Clinical Research Facility. The funder had no role in study design, data collection, data analysis, data interpretation, decision to publish or preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the MRC, the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising Copyright: © The Author(s) under exclusive license to Springer Nature America, Inc. 2022

PY - 2023/2

Y1 - 2023/2

N2 - Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. We tested two hypotheses: 1) individuals with BMI>30kg/m2, compared with BMI ≤30kg/m2, have greater glucose lowering with thiazolidinediones than DPP4-inhibitors, and 2) individuals with eGFR 60-90mls/min/1.73m2 compared with eGFR >90mls/min/1.73m2 have greater glucose lowering with DPP4-inhibitors than SGLT2-inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. 525 people with type 2 diabetes participated in a UK based randomised, double-blind, three-way crossover trial of 16 weeks treatment with each of sitagliptin 100mg/day, canagliflozin 100mg/day and pioglitazone 30mg/day added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs pioglitazone 59.6 mmol/mol , sitagliptin 60.0 mmol/mol, canagliflozin 60.6 mmol/mol (p=0.2). Participants with BMI>30kg/m2, compared with BMI≤30kg/m2, had a 2.88 mmol/mol (95% CI 0.98,4.79) lower HbA1c on pioglitazone than on sitagliptin (n=356, P=0.003). Participants with eGFR 60-90mls/min/1.73m2, compared with eGFR >90mls/min/1.73m2, had a 2.90 mmol/mol (95% CI 1.19,4.61) lower HbA1c on sitagliptin than on canagliflozin (n=342, P=0.001). There were 2201 adverse events reported, and 447/525 (85%) randomised participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple routinely available clinical measures to identify the drug class most likely to deliver the greatest glycaemic reduction for a given patient. ClinicalTrials.gov registration: NCT02653209; ISRCTN registration12039221.

AB - Precision medicine aims to treat an individual based on their clinical characteristics. A differential drug response, critical to using these features for therapy selection, has never been examined directly in type 2 diabetes. We tested two hypotheses: 1) individuals with BMI>30kg/m2, compared with BMI ≤30kg/m2, have greater glucose lowering with thiazolidinediones than DPP4-inhibitors, and 2) individuals with eGFR 60-90mls/min/1.73m2 compared with eGFR >90mls/min/1.73m2 have greater glucose lowering with DPP4-inhibitors than SGLT2-inhibitors. The primary endpoint for both hypotheses was the achieved HbA1c difference between strata for the two drugs. 525 people with type 2 diabetes participated in a UK based randomised, double-blind, three-way crossover trial of 16 weeks treatment with each of sitagliptin 100mg/day, canagliflozin 100mg/day and pioglitazone 30mg/day added to metformin alone or metformin plus sulfonylurea. Overall, the achieved HbA1c was similar for the three drugs pioglitazone 59.6 mmol/mol , sitagliptin 60.0 mmol/mol, canagliflozin 60.6 mmol/mol (p=0.2). Participants with BMI>30kg/m2, compared with BMI≤30kg/m2, had a 2.88 mmol/mol (95% CI 0.98,4.79) lower HbA1c on pioglitazone than on sitagliptin (n=356, P=0.003). Participants with eGFR 60-90mls/min/1.73m2, compared with eGFR >90mls/min/1.73m2, had a 2.90 mmol/mol (95% CI 1.19,4.61) lower HbA1c on sitagliptin than on canagliflozin (n=342, P=0.001). There were 2201 adverse events reported, and 447/525 (85%) randomised participants experienced an adverse event on at least one of the study drugs. In this precision medicine trial in type 2 diabetes, our findings support the use of simple routinely available clinical measures to identify the drug class most likely to deliver the greatest glycaemic reduction for a given patient. ClinicalTrials.gov registration: NCT02653209; ISRCTN registration12039221.

KW - Randomized controlled trials

KW - Type 2 diabetes

UR - https://www.scopus.com/pages/publications/85143532260

U2 - 10.1038/s41591-022-02120-7

DO - 10.1038/s41591-022-02120-7

M3 - Article

C2 - 36477733

SN - 1078-8956

VL - 29

SP - 376

EP - 383

JO - Nature Medicine

JF - Nature Medicine

ER -