Effect of Dipeptidyl Peptidase 4 Inhibitors Used in Combination with Insulin Treatment in Patients with Type 2 Diabetes: A Systematic Review and Meta-analysis.

Introduction: To evaluate the efficacy and safety of dipeptidyl peptidase 4 inhibitors (DPP4i) used in combination with insulin in patients with type 2 diabetes mellitus (T2DM).

Methods: We searched the MEDLINE, Embase, and Cochrane library databases for randomized controlled trials (RCTs) published through June 2018. Studies with at least a 12-week treatment period were included to compare the addition of DPP4i to insulin with insulin control therapy. Meanwhile, groups on a stable insulin dosage (insulin-stable subgroup) or titrating insulin dosage (insulin-flexible subgroup) were analyzed separately.

Results: Twenty-one RCTs with 3697 patients randomized to a DPP4i/insulin treatment arm and 3538 to an insulin control arm were included. DPP4i, when added to insulin therapy, led to a significantly greater reduction in HbA1c (- 0.57%, 95% CI - 0.66, - 0.48) and provided significantly greater odds of achieving the HbA1c target < 7% (OR 3.45; 95% CI 2.58, 4.63). These effects were achieved in the context of a decrease in the daily insulin requirement, without increases in hypoglycemia risk and body weight, compared with the control treatment. Subgroup analysis showed control-adjusted reductions in HbA1c from baseline in the insulin-stable subgroup (-  0.64%; 95% CI - 0.74, - 0.53) and the insulin-flexible subgroup (- 0.43%; 95% CI - 0.56, - 0.30). Other results occurred similarly in both subgroups.

Conclusions: The addition of DPP4i to insulin is associated with a statistically significant reduction in glycemic control as measured by HbA1c, fasting plasma glucose, and 2-h postprandial glucose, without increasing the risk of hypoglycemia and weight gain. These conclusions were also observed in both stable-dose and flexible-dose insulin subgroups.