Sodium-glucose cotransporter-2 inhibitors in combination with other glucose-lowering agents for the treatment of type 2 diabetes mellitus

Abstract

Involvement of multiple physiological pathways and complex pathogenesis is responsible for the onset and progression of type 2 diabetes mellitus (T2DM). Since it is difficult to manage multiple pathophysiological defects by monotherapy, a combination therapy with two or more oral antidiabetic agents (OADs) may help achieve euglycemia in T2DM patients. Choice of OADs is difficult with growing armamentarium of antidiabetic therapy. Ideally, drug combination should aim at reversal of known pathogenic abnormalities and demonstrate improvement in the overall metabolic health rather than simply reduce glycosylated hemoglobin (HbA1c) levels. Increased glucose reabsorption, a faulty pathological mechanism, is targeted by a novel class of drugs, namely, the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Combination of SGLT2 inhibitors and other OADs complement each other due to their unique mechanism of action. In addition, the glucose-lowering effect of SGLT2 inhibitors remains independent of β-cell function and insulin sensitivity which reduces the chances of severe hypoglycemia in patients receiving these agents. Clinical studies from the past favor the use of SGLT2 inhibitors in combination with other agents to achieve better HbA1c levels, weight loss, and blood pressure control. In this review, we have made an attempt to explore the recommended guidelines for combination therapy, its advantages as either combination therapy or fixed-dose combinations therapy, and the role of SGLT2 inhibitors as a choice of drug as a combination with other OADs.