SGLT-2 inhibitors and their potential in the treatment of diabetes

Abstract

Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2) inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol - an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA) and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c), body weight, and blood pressure of -0.34% to -1.03%, -2.0 to -3.4 kg, and -1.7 to -6.4 mmHg/-0.3 to -2.6 mmHg (systolic blood pressure/diastolic blood pressure), respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3%) occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated and likely ascribed to the presence of preexisting cancer. As these agents emerge, clinicians should embrace the addition to the formulary for treating type 2 diabetes, but must also weight the risk-benefit of this new class in deciding which patient types are most likely to benefit from their novel mechanism of action.

Keywords: canagliflozin; dapagliflozin; diabetes; empagliflozin; sodium–glucose transporter 2.

Figure 1

The kidneys’ role in glucose reabsorption. Abbreviations: GLUT, glucose transporter; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; S1, segment 1; S2, segment 2; S3, segment 3.

Figure 2

SGLT2 inhibitors in development. Notes: ^aDapagliflozin: FDA declined approval January 19, 2012 and issued a complete response letter requesting additional clinical data on the benefit–risk profile due to the concern of a cancer signal; ^bcanagliflozin: FDA approved March 29, 2013. Johnson & Johnson (New Brunswick, NJ, USA); Bristol-Myers Squibb (New York, NY, USA); AstraZeneca (London, UK); Boehringer Ingelheim Pharmaceuticals, Inc (Ingelheim, Germany); Eli Lilly and Company (Indianapolis, IN, USA); Astellas Pharma US, Inc. (Northbrook, IL, USA); Kotobuki Pharmaceutical Co., Ltd. (Hanishina, Japan); Taisho Pharmaceutical Co., Ltd. (Tokyo, Japan); Kowa Company, Ltd. (Nagoya, Japan); Sanofi SA (Paris, France); Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan); Kissei Pharmaceutical Co., Ltd. (Matsumoto City, Japan); BHV Pharma, Inc. (Research Triangle Park, NC, USA); Pfizer, Inc. (New York, NY, USA); Lexicon Pharmaceuticals, Inc. (The Woodlands, TX, USA); Theracos, Inc. (Marlborough, MA, USA); GlaxoSmithKline (London, UK); ISIS Pharmaceuticals, Inc. (Carlsbad, CA, USA); and Mitsubishi Tanabe Pharma Corporation (Osaka, Japan). Abbreviations: FDA, Food and Drug Administration; SGLT2, sodium glucose co-transporter 2.