Practical considerations for the use of sodium–glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes

Abstract

Sodium–glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.

Keywords:

• Anti-diabetic agents
• Anti-hypertensive
• Insulin-independent
• Sodium–glucose co-transporter type 2 inhibitors
• Type 2 diabetes mellitus
• Weight loss

Declaration of funding

The development of this manuscript was supported by an unrestricted educational grant from AstraZeneca Hong Kong Ltd. All authors have read and approved the final manuscript and take full responsibility for the accuracy of its content.

Declaration of financial/other relationships

K.S.L.L. has disclosed that she has served as a consultant or advisor to Merck Sharp & Dohme, Eli Lilly, Johnson & Johnson, and AstraZeneca. C.C.C. has disclosed that he has received research funding from Boehringer Ingelheim and has served on the advisory board for AstraZeneca, Boehringer Ingelheim, and Eli Lilly. K.C.B.T. has disclosed that she has served on the advisory board for AstraZeneca. R.C.W.M. has disclosed that he has received research funding from AstraZeneca and Merck Sharp & Dohme and has served as a consultant or advisor to AstraZeneca and Johnson & Johnson. A.P.S.K. has disclosed that she has received honoraria from Abbott, AstraZeneca, Sanofi, Novo Nordisk, Eli Lilly, Merck Serono, Pfizer, and Nestle. The proceeds have been donated to the Chinese University of Hong Kong, American Diabetes Association, and other charity organizations to support diabetes research and education. P.C.Y.T. has disclosed that he has served on the advisory board for AstraZeneca, Johnson & Johnson, Boehringer Ingelheim, Novartis, and Eli Lilly. M.W.T. has disclosed that he has received sponsorship from AstraZeneca, Merck Sharp & Dohme, and Pfizer, has served as a consultant or advisor to AstraZeneca and Johnson & Johnson, and has been on the speaker bureau for Eli Lilly. T.M.C. has disclosed that he has served as an advisor to Astellas Pharma. K.K.L. has disclosed that he has served as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, and Roche and has been on speaker bureaus for Bayer and Sanofi. B.T. has disclosed that he has received sponsorship from AstraZeneca and research funding from Amgen, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. He has served as a consultant or advisor to Amgen, AstraZeneca, and Merck Serono and has been on speaker bureaus for Kowa, Merck Serono, and Servier. S.C.W.T. and W.Y.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewer 1 has disclosed that he is the recipient of research/grant funding from GlaxoSmithKline, Novartis, Novo Nordisk, Takeda, AstraZeneca, NIH, sanofi-aventis, Eli Lilly and Daiichi-Sankyo; is a consultant to, and lecturer for, GlaxoSmithKline, Novartis, Takeda, sanofi-aventis, Eli Lilly and Daiichi Sankyo; and is on the speakers bureau for Novo Nordisk and sanofi-aventis. CMRO peer reviewers 2 and 3 have no relevant financial or other relationships to disclose.

Acknowledgments

Technical editorial and manuscript drafting assistance was provided by Geraldine Toh of Research2Trials Clinical Solutions Pte Ltd, Singapore.

Notes

*Forxiga is a registered trade name of AstraZeneca

†Invokana is a registered trade name of Janssen Pharmaceuticals

‡Jardiance is a registered trade name of Boehringer Ingelheim and Eli Lilly