Efficacy and safety of combination therapy with SGLT2 and DPP4 inhibitors in the treatment of type 2 diabetes: A systematic review and meta-analysis

Background: This review evaluated the efficacy and safety of a combination therapy comprising a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in type 2 diabetes. Methods: A literature search through to May 2017 was carried out of PubMed, Embase and the Cochrane Central Register of Controlled Trials. Studies were eligible if they were randomized controlled trials (RCTs) comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) against DPP4i ± placebo or SGLT2i ± placebo and published in English. The primary outcome was change in HbA _1c from baseline. Results: Eight RCTs comparing SGLT2i/DPP4i and DPP4i, and five RCTs comparing SGLT2i/DPP4i and SGLT2i, with three RCTs involving both comparisons, were included in the present review. SGLT2i/DPP4i resulted in a greater mean HbA _1c reduction [weighted mean difference (WMD]): −0.62%] than did DPP4i alone, which was a much less marked reduction (WMD: −0.35%) than with SGLT2i alone. Also, significant differences in body weight loss from baseline were observed only with SGLT2i/DPP4i vs. DPP4i, but not vs. SGLT2i. The risk of hypoglycaemic events was low and similar between treatment groups. When subjects were stratified based on baseline HbA _1c , any reduction by SGLT2i/DPP4i in relation to DPP4i was proportional to baseline HbA _1c levels. However, compared with SGLT2i, HbA _1c reductions with SGLT2i/DPP4i were modest regardless of baseline HbA _1c . Conclusion: Combination therapy with SGLT2i and DPP4i is both efficacious and safe. In particular, a marked additional glucose-lowering effect is evident when SGLT2i is combined with or added to DPP4i, and not vice versa. However, baseline HbA _1c determined the additional glucose-lowering effects of SGLT2i in combined treatment with DPP4i.