OBJECTIVE: With the expanding armamentarium of noninsulin therapies for type 2 diabetes mellitus, the use of insulin with various oral agents is becoming more common. In this study, we assessed the efficacy and cardiovascular (CV) safety of the dipeptidyl peptidase-4 inhibitor linagliptin as add-on to insulin in patients with type 2 diabetes. METHODS: In this post hoc analysis, data for patients receiving basal or basal-bolus insulin were pooled from 4 randomized, double-blind, phase 3 clinical trials of linagliptin 5 mg once daily or placebo given as add-on to background glucose-lowering treatment. Changes in glycated hemoglobin (A1C) and CV risk factors were assessed from baseline to end of trial. The primary CV endpoint was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to unstable angina. RESULTS: The number of patients receiving basal or basal-bolus insulin as background therapy was 1613 (linagliptin: n=811; placebo: n=802). The placebo-adjusted mean (SE) change from baseline in A1C was -0.41 (0.05)% (95% CI -0.50, -0.32; p<0.0001). Treatment with linagliptin provided a relative weight benefit and reduced insulin requirements without affecting blood pressure, heart rate or lipids. The incidence of hypoglycemia with linagliptin was similar to that for placebo (38.7% vs. 39.4%, respectively). The hazard ratio (HR) for the primary endpoint showed that treatment with linagliptin was not associated with an increased CV risk (HR 1.07 [95% CI 0.62, 1.85]). CONCLUSIONS: Linagliptin, when added to ongoing insulin treatment in patients with type 2 diabetes, improves glycemic control and has a neutral impact on major adverse CV events.