Comparison of dipeptidyl peptidase-4 inhibitors and pioglitazone combination therapy versus pioglitazone monotherapy in type 2 diabetes A system review and meta-analysis

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitor and pioglitazone combination therapy have been widely used for patients with inadequate glycemic control on monotherapy. This meta-analysis assessed the efficacy and safety of this combination therapy in patients with type 2 diabetes mellitus (T2DM). Methods: We searched the MEDLINE, Embase, and Cochrane databases. Studies were eligible if they were randomized controlled trials (RCTs) on DPP-4 inhibitor and pioglitazone combination therapy in patients with T2DM through the end of February 2016, using the keywords "alogliptin," "dutogliptin, " "linagliptin," "saxagliptin," "sitagliptin," "vildagliptin," "gliptins," "DPP-4 inhibitor," and "pioglitazone." RCTs were selected if they compared DPP-4 inhibitors and pioglitazone as combination therapy; treatment duration was >= 12 weeks; and the reported data included hemoglobin A1c (HbA1c) or fasting plasma glucose (FPG) change, total or any other system Adverse Events (AEs). We estimated effect size with random-effects or fixed-effects meta-analysis, I-2 statistic was used to estimate heterogeneity of results. Results: Seven RCTs were included. Compared with pioglitazone monotherapy, combination DPP-4 inhibitor and pioglitazone therapy were associated with increased reduction in HbA1c ([MD] -0.64%; -0.73 to -0.55) and FPG ([MD] -0.94; -1.12 to -0.76) levels, more patients in the combination therapy groups versus pioglitazone monotherapy groups had an A1c of < 7% ([OR] 2.52; 2.18, 3.17) at the end of the studies, but was not associated with further reduction in higher risk of hypoglycaemia, edema, or any other system AEs. We also noticed that DPP-4 inhibitor and pioglitazone combination therapy were associated with better improvement of pancreatic beta-cell function. Conclusions: DPP-4 inhibitor and pioglitazone combination therapy provided better glycemic control, both according to HbA1c and FPG levels, than pioglitazone monotherapy. Safety analysis showed well tolerance of combination therapy, even in hypoglycemic and edema AEs. However, additional large-scale, high quality, long-term follow-up clinical trials are necessary to confirm its long-term effectiveness.