Sodium Glucose Cotransporter 2 and Dipeptidyl Peptidase-4 Inhibition

Promise of a Dynamic Duo

Ildiko Lingvay, MD, MPH, MSCS


Endocr Pract. 2017;23(7):831-840. 

In This Article

Abstract and Introduction


Objective: This article reviews evidence supporting sodium glucose cotransporter 2 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination therapy for management of type 2 diabetes mellitus (T2DM).

Methods: We conducted a nonsystematic review of the literature focusing on single-pill or fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors available in the United States.

Results: SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiologic abnormalities present in T2DM without overlapping toxicities. The combination of these 2 agents has several advantages including a low risk of hypoglycemia, the potential for weight loss, the ability to coformulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials reported to date support the safety of the DPP-4 class and suggest possible cardioprotective effects for SGLT2 inhibitors ??? at least based on the first reported study that used empagliflozin. Recent clinical evidence shows that SGLT2 inhibitor/DPP-4 inhibitor therapy is an effective combination for T2DM treatment, providing glycated hemoglobin (HbA1c) reductions of 1.1 to 1.5%, and weight reductions of approximately 2 kg when added to metformin, which is its primary place in therapy.

Conclusion: The combination of an SGLT2 inhibitor/DPP-4 inhibitor is a safe and effective treatment choice for patients with T2DM who are unable to obtain adequate glycemic control with metformin therapy, cannot use metformin, or have a higher baseline HbA1c.


Type 2 diabetes mellitus (T2DM) is a multifactorial condition with a complex etiology and a progressive disease course.[1] Because monotherapy fails to address multiple underlying pathophysiologic defects,[1] treatment with a single agent followed by sequential addition of glucose-lowering agents, as recommended in treatment algorithms, has been called a "treat-to-failure" approach.[2] Most individuals eventually will require additional pharmacotherapy to maintain glycemic control.[3,4] Thus, some experts advocate combining glucose-lowering agents with complementary mechanisms of action at the outset of treatment.[2]

Combination therapy offers several potential benefits over monotherapy. Early intensive glycemic control, which typically requires the use of ???1 glucose-lowering agent, may be associated with a legacy effect,[5] and some evidence suggests that this approach may preserve ??-cell function.[6] A meta-analysis found that initial combination therapy with a second glucose-lowering agent added to metformin provided greater overall glycated hemoglobin (HbA1c) lowering, increased attainment of HbA1c goals, and greater reductions in fasting plasma glucose than metformin alone, although the risk of hypoglycemia was slightly higher in studies using sulfonylureas or glinides.[7]

The American Diabetes Association (ADA) recommends metformin as initial pharmacotherapy for most patients, and dual combination therapy initially for patients with high baseline HbA1c levels (???9%).[8] Similarly, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests initiating monotherapy for patients with baseline HbA1C levels <7.5% and combination therapy for patients with baseline HbA1C levels ???7.5%.[9] In both algorithms, metformin is the preferred first-line agent for monotherapy; other agents may be selected when metformin is not tolerated or is contraindicated. Both algorithms recommend advancing to combination therapy after 3 months if adequate glycemic control is not achieved. Combination therapy may be administered as separate pills, or as a single-pill combination (i.e., a formulation that contains 2 medications in 1 tablet). Metformin or metformin extended release (XR) are available as single-pill combinations with older glucose-lowering agents such as the sulfonylureas and thiazolidinediones, and with newer agents such as the dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors. This article reviews the newest oral combination therapy available for treatment of T2DM???combination therapy with an SGLT2 inhibitor and a DPP-4 inhibitor???primarily focusing on efficacy, safety, and place in current algorithms.