Meta-Analysis of 11 Heterogeneous Studies regarding Dipeptidyl Peptidase 4 Inhibitor Add-On Therapy for Type 2 Diabetes Mellitus Patients Treated with Insulin

Abstract

Background. Several clinical trials have addressed the therapeutic strategy of adding dipeptidyl peptidase 4 (DPP-4) inhibitors to the treatment of type 2 diabetes mellitus (DM) inadequately controlled by insulin therapy. However, there is a high degree of heterogeneity in these studies, and the cause of which has not been identified. Methods. We conducted a meta-analysis of randomized controlled trials, which compared the efficacy and safety of adding DPP-4 inhibitors or placebo to insulin therapy; the level of hemoglobin A1c (HbA1c) in the patients was >7.0%, and the duration of treatment was ≥8 weeks. We focused on the mean changes in HbA1c from the baseline (ΔHbA1c) and the incidence of hypoglycemia. We assumed that five baseline parameters (HbA1c, fasting blood glucose, body mass index (BMI), duration of type 2 DM, and duration of treatment) could affect ΔHbA1c. Regarding the incidence of hypoglycemia, we suspected that the heterogeneity was caused by differences in the definition of hypoglycemia among the studies. Results. Data obtained from 11 studies ( $n=4654$ patients) were included in the analysis. The mean ΔHbA1c between the DPP-4 inhibitor and placebo groups was -0.61% (95% confidence interval (CI): -0.74 to -0.48, $I^2=73.4\%$ ). There was substantial heterogeneity among the 11 studies, but 74.1% of this variability was explained by the difference in BMI. The odds ratio for the incidence of hypoglycemia was 1.02 (95% CI: 0.74 to 1.42, $I^2=63.8\%$ ), with substantial heterogeneity due to differences in the definition of hypoglycemia among the studies. There was no apparent effect of publication bias. Conclusions. The addition of DPP-4 inhibitors to insulin therapy for adult patients with type 2 DM can significantly reduce HbA1c levels without increasing the occurrence of hypoglycemia. BMI and hypoglycemia definition could explain the heterogeneity in the clinical trials. This trial is registered with PROSPERO #CRD42016035994.