Effects of sodium-glucose co-transporter 2 inhibitors on metabolism: unanswered questions and controversies

ABSTRACT

Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. These drugs also affect many anthropometric and metabolic parameters with various mechanisms of action.

Areas covered: We present the available evidence regarding these effects. SGLT2 inhibitors can decrease body weight mainly due to a reduction of total fat mass. SGLT2 inhibitors can decrease blood pressure levels and serum uric acid levels and may also reduce the degree of diabetes-related albuminuria. These effects may have contributed in the beneficial cardiovascular effects seen in the EMPA-REG OUTCOME trial. On the other hand, the SGLT2 inhibition-induced natriuresis and osmotic diuresis could lead to a decrease of extracellular volume. A small increase in serum low-density lipoprotein cholesterol has been observed with SGLT2 inhibitors. A small increase in serum phosphate concentration has been reported with these drugs due to increased phosphate reabsorption, which combined with an increase in serum parathormone may adversely affect bone homeostasis. In rare cases, SGLT2 inhibitors administration may be followed by euglycemic diabetic ketoacidosis.

Expert opinion: SGLT2 inhibitors improve many aspects of human metabolism and may be beneficial in diabetic patients if certain precautions are followed by clinicians during the administration of these drugs.

KEYWORDS:

• Sodium-glucose co-transporter 2
• body weight
• blood pressure
• uric acid
• albuminuria
• diabetic ketoacidosis
• electrolytes

Article highlights

• SGLT2 inhibitors represent important game changers in the field of diabetes mellitus therapeutics

• In addition to their inhibitory effect on proximal glucose and sodium reabsorption these drugs may also affect other important aspects of metabolism

• SGLT2 inhibitors decrease body weight mainly due to a reduction of total fat mass

• A decrease of serum uric acid levels has been commonly reported with these drugs. SGLT2 inhibitors can decrease blood pressure levels and may also reduce the degree of diabetes-related albuminuria

• A small increase in serum phosphate concentration has been reported with these drugs due to increased phosphate reabsorption, which combined with an increase in serum parathormone may adversely affect bone homeostasis

• Rarely, SGLT2 inhibitors administration may be followed by euglycemic diabetic ketoacidosis

This box summarizes key points contained in the article.

Declaration of interest

This review was written independently; no company or institution supported it financially. No competing financial interests exist. M Elisaf has received speaker honoraria, consulting fees, and research funding from AstraZeneca, Schering Plough, Merck, Pfizer, Solvay, Abbott, Boehringer Ingelheim and Fournier, and has participated in clinical trials with AstraZeneca, Merck, Sanofi-Synthelabo, Solvay, Glaxo, Novartis, Pfizer and Fournier. The authors have given talks and attended conferences sponsored by various pharmaceutical companies, including Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, Teva and MSD.

Additional information

Funding

This paper was not funded.