BACKGROUND: Apart from baseline glycated hemoglobin (HbA1c), little is known about clinical parameters that affect glycemic response to a dipeptidyl peptidase-4 (DPP4) inhibitor when used in routine clinical practice. We aimed to use a large primary care database to assess the variability in response to a DPP4 inhibitor when used as add-on therapy. MATERIALS AND METHODS: Data on 25,386 patients with type 2 diabetes, newly treated with a DPP4 inhibitor (2007-2013), were sourced from a United Kingdom general practice database via the Health Improvement Network database. Baseline clinical parameters of patients (n = 13,525) for whom a DPP4 inhibitor was added because of suboptimal glucose control (HbA1c >7%) were compared with 12-month follow-up data. An optimum response to the DPP4 inhibitor was defined as an HbA1c level of <7.0% at 12 months. Descriptive analyses and unadjusted comparisons using χ(2) and t tests were carried out to ascertain glycemic and body weight responses to treatment intensification with a DPP4 inhibitor. Predictor of response analyses were performed using multivariate logistic regression. RESULTS: Overall, 1,708 (13%) of our study population achieved an HbA1c level of <7%. Intensification with a DPP4 inhibitor was associated with significant reductions in HbA1c (-0.5%), body weight (-0.9 kg), and total cholesterol (-0.1 mmol/L) (P < 0.001). Independent predictors of achieving optimal HbA1c target of <7% included the use of metformin (adjusted odds ratio [OR] = 2.58; 95% confidence interval [CI], 2.18-3.04) and use of metformin plus sulfonylurea (1.42; 95% CI, 1.21-1.68) as opposed to no use. The independent predictors of suboptimal glucose control included a higher baseline HbA1c level (OR = 0.64; 95% CI, 0.61-0.68) (i.e., 1% increase in HbA1c was associated with a 36% reduced likelihood of response), longer diabetes duration (per every year increase) (OR = 0.85; 95% CI, 0.83-0.88), and intensification therapy below 9 months compared with 9-12 months. CONCLUSIONS: There is a significant variability in glycemic response to a DPP4 inhibitor in routine practice. The best effect is achieved as add-on to metformin and metformin plus sulfonylurea, but responses are significantly lower with increased diabetes duration and among patients with high HbA1c levels at baseline.