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Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes: a joint modeling approach

Authors Dennis JM, Shields BM, Jones AG, Pearson ER, Hattersley AT, Henley WE

Received 16 July 2018

Accepted for publication 24 October 2018

Published 14 December 2018 Volume 2018:10 Pages 1869—1877

DOI https://doi.org/10.2147/CLEP.S179555

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Professor Henrik Toft Sørensen


John M Dennis,1 Beverley M Shields,2 Angus G Jones,2 Ewan R Pearson,3 Andrew T Hattersley,2
William E Henley1

On behalf of the MASTERMIND consortium

1Health Statistics Group, University of Exeter Medical School, Exeter, UK; 2National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK; 3Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

Objective: Precision medicine drug therapy seeks to maximize efficacy and minimize harm for individual patients. This will be difficult if drug response and side effects are positively associated, meaning that patients likely to respond best are at increased risk of side effects. We applied joint longitudinal–survival models to evaluate associations between drug response (longitudinal outcome) and the risk of side effects (survival outcome) for patients initiating type 2 diabetes therapy.
Study design and setting: Participants were randomized to metformin (MFN), sulfonylurea (SU), or thiazolidinedione (TZD) therapy in the A Diabetes Outcome Progression Trial (ADOPT) drug efficacy trial (n=4,351). Joint models were parameterized for 1) current HbA1c response (change from baseline in HbA1c) and 2) cumulative HbA1c response (total HbA1c change).
Results: With MFN, greater HbA1c response did not increase the risk of gastrointestinal events (HR per 1% absolute greater current response 0.82 [95% CI 0.67, 1.01]; HR per 1% higher cumulative response 0.90 [95% CI 0.81, 1.00]). With SU, greater current response was associated with an increased risk of hypoglycemia (HR 1.41 [95% CI 1.04, 1.91]). With TZD, greater response was associated with an increased risk of edema (current HR 1.45 [95% CI 1.05, 2.01]; cumulative 1.22 [95% CI 1.07, 1.38]) but not fracture.
Conclusion: Joint modeling provides a useful framework to evaluate the association between response to a drug and the risk of developing side effects. There may be great potential for widespread application of joint modeling to evaluate the risks and benefits of both new and established medications.

Keywords: diabetes mellitus, type 2, drug-related side effects, HbA1c, hypoglycemia, joint model, precision medicine, thiazolidinediones, metformin, sulfonylurea compounds, ADOPT, edema

Creative Commons License This work is published by Dove Medical Press Limited, and licensed under a Creative Commons Attribution License. The full terms of the License are available at http://creativecommons.org/licenses/by/4.0/. The license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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