Combination therapy of sodium–glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: rationale and evidences

ABSTRACT

No single antidiabetic agent can correct all the pathophysiologic defects manifested in type 2 diabetes mellitus (T2DM) and, therefore, multiple agents are often required to achieve optimal glycemic control. Combination therapies, having different mechanisms of action, not only have the potential to complement their action, but may possess the properties to counter the undesired compensatory response. Recent finding suggests that sodium–glucose co-transporter-2 inhibitors (SGLT2i) increase endogenous glucose production (EGP) from liver, due to the increase in glucagon which may offset its glucose-lowering potential. In contrast, dipeptidyl peptidase-4 inhibitors (DPP4i) decrease glucagon and EGP. Especially in the light of this finding, combination therapies with SGLT2i and DPP4i are particularly appealing, and are expected to produce an additive effect. Indeed, studies find no drug–drug interaction between SGLT2i and DPP4i. Moreover, significant reduction in glycated hemoglobin has also been observed. This article aims to review the efficacy and safety of combination therapy of SGLT2i and DPP4i in T2DM.

KEYWORDS:

• Sodium–glucose co-transporter-2 inhibitors
• dipeptidyl peptidase-4 inhibitors
• type 2 diabetes
• combination therapies
• genitourinary infections

Acknowledgment

The authors would like to thank Dr Kaushik Mondal for collecting the data while writing the manuscript.

Financial & competing interest disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• SGLT2 inhibitors are newly approved class of drugs proven to be associated with moderate and durable glucose lowering with associated weight loss and blood pressure reduction. Moreover, reduction in CV death and all-cause mortality seen with empagliflozin is noteworthy. This outcome will obviously tempt clinicians to use this drug or its class more frequently. Nonetheless, empagliflozin or any SGLT2 inhibitors with or without background metformin therapy cannot bring down HbA1c to target in large number of diabetic patients, which is essential to prevent microvascular complication. This demands a similarly effective antidiabetic agent which is cardiac-safe, does not potentiate hypoglycemia and can be combined easily with these agents. DPP4 inhibitors fit to be an exciting companion in this regard.

• Increase in glucagon, decrease in insulin and associated increase in EGP is a clear disadvantage with SGLT2 inhibitors, which can offset its glycemic potential. Interestingly, DPP4 inhibitors decrease glucagon and increase insulin and thus combination of these agents appears rational and expected to be synergistic.

• Several studies have clearly demonstrated that combination of these agents effectively reduce HbA1c without inducing further hypoglycemia. Reduction in body weight has also been observed with combination therapy compared to DPP4 inhibitors; however, no superiority observed over SGLT2 inhibitors alone.

• Lesser genitourinary infection has been observed with combinations therapy compared to SGLT2 inhibitors monotherapy in few studies; however, this needs to be substantiated conclusively from many more studies.