Combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor in type 2 diabetes: a systematic review with meta-analysis

Se Hee Min,Sun Joon Moon,Jeong-Hwa Yoon,Young Min Cho,Seokyung Hahn

doi:10.1038/s41598-018-22658-2

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors have complementary mode of action. For the meta-analysis comparing the efficacy and safety between SGLT2 inhibitor plus DPP4 inhibitor (SGLT2i/DPP4i) and placebo plus DPP4 inhibitor (PCB/DPP4i) in patients with type 2 diabetes mellitus (T2DM), we selected randomized controlled trials from electronic databases by predefined criteria. The primary outcome of interest was the change in glycated hemoglobin A1c (HbA1c) from baseline. Of 605 potentially relevant studies, 7 eligible RCTs comprising 2,082 patients were included.SGLT2i/DPP4i showed a greater reduction in HbA1c (weighted mean difference −0.6%, 95% CI −0.7 to −0.5%), fasting plasma glucose, 2 h postprandial plasma glucose, and body weight compared to PCB/DPP4i. The risk of hypoglycemia increased in SGLT2i/DPP4i compared to that in PCB/DPP4i only when insulin or sulfonylureas were included as a background therapy. The risk of urinary tract infection was not increased in SGLT2i/DPP4i; however, the risk of genital infection increased upon adding SGLT2 inhibitors to pre-existing DPP4 inhibitors. In conclusion, compared to PCB/DPP4i, SGLT2i/DPP4i achieved better glycemic control and greater weight reduction without increasing the risk of hypoglycemia and urinary tract infection in patients with inadequately controlled T2DM.

Highlights

The pathogenesis of type 2 diabetes is intertwined with multiple different mechanisms, which encompasses decreased insulin secretion, decreased insulin sensitivity, increased hepatic glucose production, decreased responses to incretin hormones, and increased renal reabsorption of glucose[1]
Three out of seven studies compared the simultaneous combination of an sodium glucose cotransporter 2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP4) inhibitor with the addition of a DPP4 inhibitor alone in drugnaïve or metformin failure patients, whereas the other four studies compared the addition of an SGLT2 inhibitor with a placebo as add-on therapy in patients inadequately controlled with a DPP4 inhibitor
The complementary mechanisms of action of SGLT2 inhibitors and DPP4 inhibitors may explain these beneficial effects of the combination

Summary

Introduction

The pathogenesis of type 2 diabetes is intertwined with multiple different mechanisms, which encompasses decreased insulin secretion, decreased insulin sensitivity, increased hepatic glucose production, decreased responses to incretin hormones, and increased renal reabsorption of glucose[1]. The combinatory use of different anti-diabetic agents with complementary mechanisms of action may enhance the glucose-lowering effect without compromising drug safety. SGLT2 inhibitors reduce hyperglycemia by increasing urinary glucose excretion independent of insulin secretion or action[2,3]. DPP4 inhibitors, which inhibit the breakdown of active incretin hormones, improve glucose homeostasis by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner[4,5]. In this regard, the combination of these two drugs could be effective and safe for the treatment of hyperglycemia in patients with suboptimally controlled type 2 diabetes. We performed a systematic review and meta-analysis to assess the efficacy and safety of a combination of an SGLT2 inhibitor and a DPP4 inhibitor in patients with suboptimally controlled type 2 diabetes

Methods

Results

Conclusion