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

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.

Trial registration: ClinicalTrials.gov NCT01503112.

Conflict of interest statement

Conflict of Interest statement

WEH declares a grant from Quintiles, ERP declares personal fees from Lily, Novo Nordisk, and Astra Zeneca. NS declares personal fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Janssen and a grant from Astra Zeneca. RHH declares research funding from Bayer, Astra Zeneca, MSD and honoraria from Amgen, Bayer, Elcelyx, Jannsen, Intarcia, MSD, Novartis, Novo Nordisk and Servier. For all other authors there are no other potential conflicts of interest relevant to this article.

© 2018 by the American Diabetes Association.

Figures

Figure 1. DPP4 inhibitors - associations between markers of insulin resistance and HbA1c response at 6 months.

Circles (black = PRIBA, white = CPRD) denote the mean HbA1c change (mmol/mol) at 6 months per 1 standard deviation (SD) higher baseline value of each marker. Error bars denote 95% confidence intervals.

Figure 2. DPP4 inhibitors - predicted mean absolute HbA1c change from baseline at 6 months in a) PRIBA b) CPRD across subgroups defined by the presence or absence of obesity (BMI>=30 kg/m2) and high triglycerides (TRGs >=2.3mmol/L) - Subgroup A: non-obese and normal triglycerides, Subgroup B: non-obese OR normal triglycerides, Subgroup C: obese and high triglycerides.

Baseline HbA1c is standardised to the mean PRIBA baseline level of 74mmol/mol (8.9%) for all subgroups. Error bars denote 95% confidence intervals.

Figure 3. GLP-1 receptor agonists - associations between markers of insulin resistance and HbA1c response at 6 months.

Circles (black = PRIBA, white = CPRD) denote the mean HbA1c change (mmol/mol) at 6 months per 1 standard deviation (SD) higher baseline value of each marker. Error bars denote 95% confidence intervals.