Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus.

INTRODUCTION: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 - 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients. AREAS COVERED: A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA1c by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia. EXPERT OPINION: The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c < 8.5%.