Where does combination therapy with an SGLT2 inhibitor plus a DPP-4 inhibitor fit in the management of type 2 diabetes?

Hyperglycemia is the critical risk factor for diabetic microvascular complications. Several landmark studies, e.g., UK Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT), have demonstrated that lowering the HbA1c by 1% decreases microvascular complications by approximately 35% (1,2). Despite the unequivocal evidence for the importance of achieving good glycemic control in patients with type 2 diabetes mellitus (T2DM), approximately half of individuals with T2DM fail to achieve the American Diabetes Association (ADA) goal of glycemic control (HbA1c ,7.0%) (3). Thus, novel therapeutic agents and strategies are required to improve glycemic control in T2DM patients. Two novel classes of antihyperglycemic drugs have been developed during the last decade for the treatmentof T2DM: dipeptidyl peptidase-4 inhibitors (DPP-4i) (4) and sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) (5). DPP-4i have been in clinical use for the treatment of T2DM for more than a decade. DPP-4i inhibit the enzyme that degrades the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and result in elevated plasma GLP-1 and GIP concentrations. The increase in plasma GLP-1 and GIP concentrations stimulates insulin secretion from the b-cell and inhibits glucagon secretion from the a-cell, leading to inhibition of endogenous glucose production (EGP) and reduction in plasma glucose concentration (6). SGLT2i are a novel class of antidiabetes drugs that recently have been approved for the treatment of T2DM. Members of this class reduce the plasma glucose concentration by inhibiting renal glucose reabsorption and producing glucosuria. Urinary glucose loss results in negative energy balance and because SGLT2i also block sodium absorption in the proximal tubule, they causeweight loss (;2–3 kg) and decrease in blood pressure (4–6/1–2 mmHg systolic/diastolic) (5). Because the pathogenesis of T2DM is complex and involves multiple metabolic defects (7), the use of combination therapy with antidiabetes drugs with different mechanisms of action has the advantage of preventing compensatory mechanisms and has the potential of producing an additive reduction in HbA1c. Thus, the combination of SGLT2i plus DPP-4i has the potential to produce a robust reduction in HbA1c. This combination is particularly appealing in light of recent findings that glucosuria produced by SGLT2i is associated with an increase in the rate of EGP (8,9), which offsets the glucose-lowering effect by approximately 50% (8). As DPP-4i inhibit glucagon secretion and reduce EGP, one can speculate that the combination of DPP-4i plus SGLT2i would prevent the increase in EGP following SGLT2 inhibition and produce an additive, even synergistic, effect to reduce HbA1c. In this issueofDiabetesCare, Rosenstock et al. (10) examine this hypothesis. They randomized 534 poorly controlled, metformin-treated T2DM patients to receive dapagliflozin (10 mg) alone, saxagliptin (5 mg) alone, or a combination of saxagliptin plus dapagliflozin for 24 weeks. While saxagliptin alone lowered the HbA1c by 0.88% and dapagliflozin alone lowered the HbA1c by 1.2%, the combination of dapagliflozin plus saxagliptin lowered the HbA1c by only 1.47%, which is significantly lower than expected from this combination. Similarly, the effect of saxagliptin plus dapagliflozin on both the fasting and postprandial plasma glucose concentrations was far less than additive. As expected, dapagliflozin alone or in combination with saxagliptin caused a modest weight loss (2–3 kg) and a small decrease in systolic blood pressure (2–4 mmHg), while saxagliptin alone had no effect on blood pressure or body weight. This well-designed double-blind randomized clinical trial provides a definitive answer to the question of the efficacy of combination therapy with SGLT2i plus DPP-4i in poorly controlled T2DM patients. The only limitation of