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MASTERMIND: Stratification of glycaemic response the ADOPT and RECORD studies

MASTERMIND: Stratification of glycaemic response the ADOPT and RECORD studies

Professor Andrew Hattersley, M.D. FRS

University of Exeter Medical SchoolExeter, UK

This pilot study work will be incorporated and funded by the MRC as part of the MRC APBI Stratification and Extreme Response Mechanism IN Diabetes (MASTERMIND) consortium which has been awarded to the University of Exeter to establish a platform for a stratified medicines approach in type 2 diabetes. The pilot award of £2.9 million runs February 2013 to September 2015, grant reference MR/K005707/1.


16 Apr 2014

Multiple therapies are used for lowering high blood sugar in patients with Type 2 diabetes. The individual response to these varies; the same treatment may reduce glucose significantly in one person but have little effect in another. There are major advantages in identifying patients who are more or less likely to respond to a treatment or experience side effects, so patients could be treated with therapies most likely to benefit them. There are known differences in how patients respond to different diabetes drugs but currently there is no way of identifying which patients will be good responders.

This project aims to identify predictors of response to 3 types of glucose lowering therapy, thiazolidinediones, sulphonylureas & metformin, all of which have different mechanisms of action. We will determine if clinical characteristics or simple blood measurements associated with insulin secretion or resistance to insulin secretion may be used to identify individuals likely to benefit from a specific therapy.

Specific aims are to identify:

If markers of insulin secretion and insulin resistance are associated with glycaemic (glucose lowering) response to thiazolidinediones, and if the same relationship exists for sulphonylurea and metformin therapy
If characteristics associated with good treatment response are also associated with an increase in side effects
To determine if characteristics associated with treatment response are true predictors of response or simply predictors of different rates of diabetes progression
This research is part of an MRC study (MASTERMIND: MRC APBI STratification and Extreme Response Mechanism IN Diabetes) examining response to diabetes medications.

We will combine data for those treated with a thiazolidinediones, sulphonylureas and metformin in the ADOPT and RECORD studies. We will define initial response to treatment based on the change from the first HbA1c (measure of 3 monthly average blood sugar) prior to starting treatment to the closest HbA1c to 6 months after treatment. We will look at characteristics of the patients at study baseline to see associations between them and initial treatment response. This includes both clinical characteristics such as duration of diabetes, or weight & the results of blood tests measuring insulin secretion or resistance, & the presence of antibodies to the cells making insulin. We will see if factors associated with treatment response are also associated with progression of diabetes or with the development of medication side effects. We will assess if these are influenced by other factors such as the number of tablets or changes in weight.

Dissemination to academic will be via national & international meetings & publications in journals. Results will be communicated to clinicians & patients through media. The group has excellent connections with the patient organisation Diabetes UK and will collaborate with them to communicate results to the wider diabetes community.

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Statistical Analysis Plan

John M. Dennis, William E. Henley, Michael N. Weedon, Mike Lonergan, Lauren R. Rodgers, Angus G. Jones, William T. Hamilton, Naveed Sattar, Salim Janmohamed, Rury R. Holman, Ewan R. Pearson, Beverley M. Shields, Andrew T. Hattersley
Diabetes Care Sep 2018, 41 (9) 1844-1853; DOI: 10.2337/dc18-0344

Rodgers LR, Dennis JM, Shields BM, et al. Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study. J Clin Epidemiol. 2020;122:78-86. doi:10.1016/j.jclinepi.2020.03.007

Dennis JM, Shields BM, Henley WE, Jones AG, Hattersley AT. Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: an analysis using clinical trial data. Lancet Diabetes Endocrinol. 2019;7(6):442-451.

Donnelly LA, Dennis JM, Coleman RL, et al. Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study [published online ahead of print, 2020 Aug 14]. Diabetes Care. 2020;dc201104. doi:10.2337/dc20-1104