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

TY - JOUR

T1 - Precision Medicine in Type 2 Diabetes

T2 - Clinical Markers of Insulin Resistance Are Associated With Altered Short- and Long-Term Glycemic Response to DPP-4 Inhibitor Therapy

AU - Dennis, John M.

AU - Shields, Beverley M.

AU - Hill, Anita V.

AU - Knight, Bridget A.

AU - McDonald, Timothy J.

AU - Rodgers, Lauren R.

AU - Weedon, Michael N.

AU - Henley, William E.

AU - Sattar, Naveed

AU - Holman, Rury R.

AU - Pearson, Ewan R.

AU - Hattersley, Andrew T.

AU - Jones, Angus G.

AU - MASTERMIND consortium

N1 - 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.

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - Journal article

KW - Precision Medicine/methods

KW - Predictive Value of Tests

KW - Prognosis

KW - Humans

KW - Middle Aged

KW - Insulin Resistance

KW - Male

KW - Treatment Outcome

KW - United Kingdom

KW - Biomarkers/metabolism

KW - Diabetes Mellitus, Type 2/diagnosis

KW - Blood Glucose/drug effects

KW - Female

KW - Hypoglycemic Agents/therapeutic use

KW - Aged

KW - Primary Health Care

KW - Retrospective Studies

KW - Dipeptidyl-Peptidase IV Inhibitors/therapeutic use

UR - https://www.scopus.com/pages/publications/85043583275

U2 - 10.2337/dc17-1827

DO - 10.2337/dc17-1827

M3 - Article

C2 - 29386249

SN - 0149-5992

VL - 41

SP - 705

EP - 712

JO - Diabetes Care

JF - Diabetes Care

IS - 4

ER -