A Systematic Review and Meta-Analysis on the Efficacy and Safety of Combination Therapy with Sodium-Glucose Cotransporter Type 2 Inhibitor (SGLT2i) and Dipeptidase-4 Inhibitor (DPP4i) in Treatment of Type 2 Diabetes

Background: The management and treatment of type 2 diabetes (T2D) remain difficult and complex, despite the wide range of pharmacotherapies available for glycemic control. As a result, researchers continue to look for new therapeutic molecules with modes of action that might fill in the gaps left by currently existing medications.The aim of this study was to assess the efficacy and safety of sodium-glucose cotransporter type2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in combination for treatment and management of type 2 diabetes (T2D). Methods: EMBASE, MEDLINE, PUBMED and Cochrane Central Register of Controlled Trials were subjected to literature search. RCTs comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) to DPP4iplacebo or SGLT2iplacebo were eligible if they were published in English and compared SGLT2i plus DPP4i (SGLT2i/DPP4i) to DPP4iplacebo or SGLT2iplacebo. The change in HbA1c from baseline was the primary endpoint. Results: The study comprised of eight RCTs comparing SGLT2i/DPP4i and DPP4ionly, five RCTs comparing SGLT2i/DPP4i and SGLT2ionly, and three RCTs involving both comparisons. The combination of both inhibitors resulted in a greater average HbA1c reduction [WMD: 0.62 percent] than DPP4i alone, which resulted in a much lesser reduction (WMD: -0.35 percent) than SGLT2i alone. Furthermore, only SGLT2i/DPP4i vs. DPP4i revealed notable differences in body weight loss from baseline, but not SGLT2i.The risk of hypoglycemia was modest and consistent across treatment groups. Any reduction by SGLT2i/DPP4i in relation to DPP4i was proportionate to baseline HbA1c levels when patients were stratified based on baseline HbA1c levels. However, despite of baseline HbA1c, HbA1c reductions with combination were minor when compared to SGLT2i alone. Conclusion: Combination of these two inhibitors is found to be safe and effective. A significant extra glucose-lowering impact is observed when SGLT2i is used with or added to DPP4i, but not the other way around. The extra hypoglycemic effects of SGLT2i in combination with DPP4i were assessed by baseline HbA1c. Keywords: Efficacy, safety, DPP4i, SGLT2i, Treatment, Type 2 Diabetes