Precision medicine in type 2 diabetes: clinical markers of insulin resistance are associated with altered short- and long-term glycemic response to DPP-4 inhibitor therapy

Dennis, J. M. et al. (2018) Precision medicine in type 2 diabetes: clinical markers of insulin resistance are associated with altered short- and long-term glycemic response to DPP-4 inhibitor therapy. Diabetes Care, 41(4), pp. 705-712. (doi: 10.2337/dc17-1827) (PMID:29386249)

Abstract

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 dipeptidyl peptidase 4 (DPP-4) 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 noninsulin-treated participants starting DPP-4 inhibitor therapy (Predicting Response to Incretin Based Agents [PRIBA] study; n = 254), with replication for routinely available markers in U.K. electronic health care records (Clinical Practice Research Datalink [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 glucagon-like peptide 1 (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 DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA1c response (both P < 0.01). A subgroup defined by obesity (BMI ≥30 kg/m2) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA1c reduction, 5.3 [95% CI 1.8, 8.6] mmol/mol [0.5%] [obese and high triglycerides] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [nonobese and 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 DPP-4 inhibitors. This finding provides a starting point for the application of a precision diabetes approach to DPP-4 inhibitor therapy.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed
• Authors: Dennis, J. M., Shields, B. M., Hill, A. V., Knight, B. A., McDonald, T. J., Rodgers, L. R., Weedon, M. N., Henley, W. E., Sattar, N., Holman, R. R., Pearson, E. R., Hattersley, A. T., and Jones, A. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Diabetes Care
• Publisher: American Diabetes Association
• ISSN: 0149-5992
• ISSN (Online): 1935-5548
• Published Online: 31 January 2018
• Copyright Holders: Copyright © 2018 The American Diabetes Association
• First Published: First published in Diabetes Care 2018
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher