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 treatment of 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 β-cell and inhibits glucagon secretion from the α-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 cause weight 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 …