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

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. 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; = 254), with replication for routinely available markers in U.K. electronic health care records (Clinical Practice Research Datalink [CPRD]; = 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, = 339; CPRD, = 4,464). In PRIBA, markers of higher insulin resistance (higher fasting C-peptide [ = 0.03], HOMA2 insulin resistance [ = 0.01], and triglycerides [ < 0.01]) were associated with reduced 6-month HbA response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA response (both < 0.01). A subgroup defined by obesity (BMI ≥30 kg/m ) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA 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]; = 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 [1.16, 1.41]; < 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists. 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.