Precision medicine in Type 2 diabetes: Clinical markers of insulin resistance are associated with altered short and long-term glycemic response to DPP4-inhibitor therapy
American Diabetes Association
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Currently under an indefinite embargo pending publication by American Diabetes Association . No embargo required on publication
Objective A ‘precision’ approach to type 2 diabetes therapy would aim to target treatment according to patient characteristics. We examined if measures of insulin resistance and secretion were associated with glycemic response to DPP4-inhibitor therapy. Research Design and Methods We evaluated whether markers of insulin resistance and insulin secretion were associated with 6 month glycemic response in a prospective study of non-insulin treated participants starting DPP4-inhibitor therapy (PRIBA, n=254), with replication for routinely available markers in UK electronic healthcare records (CPRD, n=23,001). In CPRD we evaluated associations between baseline markers and 3 year durability of response. To test the specificity of findings we repeated analyses for GLP-1 receptor agonists (PRIBA n=339, CPRD n=4,464). Results In PRIBA markers of higher insulin resistance (higher fasting C-peptide (p=0.03), HOMA2 insulin resistance (p=0.01) and triglycerides (p<0.01)) were associated with reduced 6 month HbA1c response to DPP4 inhibitors. In CPRD higher triglycerides and BMI were associated with reduced HbA1c response (both p<0.01). A subgroup defined by obesity (BMI≥30kg/m2) and high triglycerides (≥2.3mmol/L) had reduced 6 month response in both datasets (PRIBA HbA1c reduction 5.3[95%CI 1.8,8.6]mmol/mol (0.5%) (obese, high triglycerides) vs 11.3[8.4,14.1] mmol/mol (1.0%) (non-obese, normal triglycerides), p=0.01. In CPRD the obese, high triglycerides subgroup also had less durable response (hazard ratio 1.28[1.16,1.41], p<0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists. Conclusions Markers of higher insulin resistance are consistently associated with reduced glycemic response to DPP4-inhibitors. This finding provides a starting point for the application of a precision diabetes approach to DPP4-inhibitor therapy.
The PRIBA study was funded by A National Institute for Health Research (U.K.) Doctoral Research Fellowship (DRF-2010-03-72, Jones) and supported by the National Institute for Health Research Clinical Research Network. The MASTERMIND consortium is supported by the Medical Research Council (UK) (MR/N00633X/1). AGJ is supported by an NIHR Clinician Scientist award. TJM is a National Institute for Health Research CSO Clinical Senior Lecturer. ATH and RHH are NIHR Senior Investigators. ERP is Wellcome Trust New Investigator (102820/Z/13/Z), ATH is a Wellcome Trust Senior Investigator. ATH, AVH, BAK and BMS are supported by the NIHR Exeter Clinical Research Facility. NS acknowledges support by Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115372, the resources of which comprise financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in any part of the study or in any decision about publication.
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