Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone

Ertugliflozin, a sodium glucose cotransporter‐2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two‐period study design with 14C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin. Eight healthy adult men received 100‐μg i.v. 14C‐ertugliflozin (400 nCi) dose 1 h after a 15‐mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14C‐ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high‐performance liquid‐chromatography tandem mass spectrometry (HPLC‐MS/MS). 14C‐ertugliflozin plasma concentrations were determined using HPLC‐accelerator mass spectrometry (AMS) and 14C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o./14C‐AUCi.v.)*(14C‐Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C‐Dosei.v./14C‐Dosep.o.)) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and β-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients.

Worldwide, the incidence of diabetes mellitus, a chronic metabolic disease that results in four million deaths from it and associated complications annually, is increasing and its treatment is an enormous public health concern. Type 1 diabetes is treated by insulin, but a variety of drugs are used to treat the more prevalent type 2 diabetes. Inhibitors of sodium glucose cotransporters (SGLTs) are the newest drugs to reach the market to achieve the blood‐glucose control needed to treat type 2 diabetes. SGLT1 and 2 carry out renal reabsorption of more than 90% of glucose from urine against a concentration gradient using the electrochemical energy from the cotransport of sodium ions. Blocking SGLTs causes excess glucose to be excreted through the urine, reducing blood sugar. The first known SGLT inhibitor was the O ‐glycosylated flavonoid natural product phlorizin, which enabled the discovery of SGLTs and served as the initial lead compound for medicinal chemistry. O ‐ and C ‐Glycosylated flavonoid and dihydrochalcone natural products also inhibit SGLTs. The drugs on the market today, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, and others, are all aryl C ‐glycosides. They are selective for SGLT2 over SGLT1 to avoid adverse side effects associated with SGLT1 inhibition. Studies have suggested that SGLT inhibitors have a renal and cardiovascular protective effect that is advantageous, although their use increases the risk of urinary tract and genital infections and ketoacidosis. SGLT inhibitors are in trials as an adjuvant to insulin for the treatment of type 1 diabetes.