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Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study

Abstract

Patient preference is very important for medication selection in chronic medical conditions, like type 2 diabetes, where there are many different drugs available. Patient preference balances potential efficacy with potential side effects. As both aspects of drug response can vary markedly between individuals, this decision could be informed by the patient personally experiencing the alternative medications, as occurs in a crossover trial. In the TriMaster (NCT02653209, ISRCTN12039221), randomized double-blind, three-way crossover trial patients received three different second- or third-line once-daily type 2 diabetes glucose-lowering drugs (pioglitazone 30 mg, sitagliptin 100 mg and canagliflozin 100 mg). As part of a prespecified secondary endpoint, we examined patients’ drug preference after they had tried all three drugs. In total, 448 participants were treated with all three drugs which overall showed similar glycemic control (HbA1c on pioglitazone 59.5 sitagliptin 59.9, canagliflozin 60.5 mmol mol−1, P = 0.19). In total, 115 patients (25%) preferred pioglitazone, 158 patients (35%) sitagliptin and 175 patients (38%) canagliflozin. The drug preferred by individual patients was associated with a lower HbA1c (mean: 4.6; 95% CI: 3.9, 5.3) mmol mol−1 lower versus nonpreferred) and fewer side effects (mean: 0.50; 95% CI: 0.35, 0.64) fewer side effects versus nonpreferred). Allocating therapy based on the individually preferred drugs, rather than allocating all patients the overall most preferred drug (canagliflozin), would result in more patients achieving the lowest HbA1c for them (70% versus 30%) and the fewest side effects (67% versus 50%). When precision approaches do not predict a clear optimal therapy for an individual, allowing patients to try potential suitable medications before they choose long-term therapy could be a practical alternative to optimizing treatment for type 2 diabetes.

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Fig. 1: Study design for the TriMaster three-treatment, three-period crossover trial of pioglitazone, sitagliptin and canagliflozin.
Fig. 2: Flow diagram showing participant flow through the study, with full breakdown of numbers on each drug at each stage and exclusions.
Fig. 3: On treatment outcomes by preferred drug.

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Data availability

To minimize the risk of patient re-identification, de-identified individual patient-level clinical data are available under restricted access. Requests for access to anonymized individual participant data (IPD) and study documents should be made to the corresponding author and will be reviewed by the Peninsula Research Bank Steering Committee. Access to data through the Peninsula Research Bank will be granted for requests with scientifically valid questions by academic teams with the necessary skills appropriate for the research. Data that can be shared will be released with the relevant transfer agreement.

Code availability

Requests for access to code should be made to the corresponding author and will be reviewed by the Peninsula Research Bank Steering Committee. Access to code through the Peninsula Research Bank will be granted for requests with scientifically valid questions by academic teams with the necessary skills appropriate for the research. Code will be released by the lead statistician.

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Acknowledgements

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. In particular, we thank S. Senn for his invaluable guidance on the analysis of this trial. In addition, we thank the Exeter NIHR Clinical Research Facility and the Exeter Clinical Trials Unit (CTU), particularly L. Quinn and S. Creanor for their support with the study, and the CTU Data Team. We thank A. Kerridge and S. Todd of the R&D and Pharmacy Departments at the Royal Devon and Exeter NHS Foundation Trust for support and sponsorship. Full acknowledgements of all members of the trial study group and committees are listed in the primary paper15. 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 under study grant MR/N00633X/1. 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 and 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) license to any author-accepted manuscript version arising.

Author information

Authors and Affiliations

Authors

Contributions

B.S. helped design the study, wrote the statistical analysis plan, performed analysis and drafted the manuscript. C.A. was the trial manager, helped design the study, performed analysis in parallel and drafted the manuscript. M.S. helped design the patient preference questionnaires and edited the manuscript, N.B. advised on design of the patient preference questionnaires and edited the manuscript. A.J. advised on study design and edited the manuscript. N.S. advised on study design and edited the manuscript. R.H. advised on study design and edited the manuscript. E.P. helped design the study and edited the manuscript. A.H. was chief investigator on the study, led the study design, advised on analysis and edited the manuscript.

Corresponding author

Correspondence to Andrew T. Hattersley.

Ethics declarations

Competing interests

N.S. is supported by a British Heart Foundation Centre of Excellence Award (RE/18/6/34217). R.H. is an Emeritus National Institute for Health Research Senior Investigator. A.H. was a Wellcome Senior Investigator (098395/Z/12/Z) and is an Emeritus Senior Investigator at the NIHR. A.H., B.S., M.S., A.G. and C.A. are supported by the NIHR Exeter Clinical Research Facility and National Institute for Health and Care Research Exeter Biomedical Research Centre. E.P. has received Honoraria from Lilly, Sanofi and Illumina. N.S. has consulted for and/or received speaker honoraria from Abbott Laboratories, Afimmune, Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novo Nordisk, Novartis, Sanofi and Pfizer and received grant funding paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. R.R.H. reports research support from AstraZeneca, Bayer and Merck Sharp & Dohme, and personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis and Novo Nordisk. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks V. Volovici, N. Maruthur and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editor: J. Sargent, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1

Bar chart showing, at baseline, how patients ranked the importance of 5 particular attributes when considering a glucose lowering treatment. Data presented as proportions of patients choosing each level of importance for each of the 5 attributes.

Extended Data Fig. 2

Distribution of side effects experienced on each of the three study drugs for the 457 participants who provided information on drug preference (pioglitazone represented by blue bars, sitagliptin by yellow bars, and canagliflozin by red bars) with proportions experiencing the side effects at baseline shown by black bars.

Extended Data Fig. 3

3a) HbA1cs and b) Side effects on the three drugs, split by preferred therapy on 1st ranking before being fed back HbA1c and weight information. Bars represent the mean and error bars represent the 95% confidence intervals.

Extended Data Table 1 Baseline characteristics of 457 participants who provided information on their drug preference in the TriMaster trial
Extended Data Table 2 Reason for choosing preferred drug for 430 participants when ranking order of drugs on first ranking before being fed back HbA1c and weight information for all three therapies
Extended Data Table 3 Number changing preference by drug and reasons given for the 125 participants that changed their preference on second ranking after being fed back HbA1c and weight information for all three therapies
Extended Data Table 4 List of side effects patients asked to report at baseline and follow-up study visits

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Shields, B.M., Angwin, C.D., Shepherd, M.H. et al. Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study. Nat Med 29, 384–391 (2023). https://doi.org/10.1038/s41591-022-02121-6

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