Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin: rationale and evidences

ABSTRACT

Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are recently approved class of anti-hyperglycaemic agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT-2I inhibits renal glucose reabsorption, thereby ensuing urinary glucose excretion in a dose-dependent manner. This caloric loss and osmotic diuresis, secondary to increased urinary glucose excretion, has a unique potential to counter insulin induced weight gain and fluid retention, with little potential of hypoglycemic exacerbation. Also, as these agents act independently of insulin secretion or action, they are effective even in long-standing diabetes with depleted β-cell reserve. Improvement in insulin sensitivity, as observed with SGLT-2I can also facilitate insulin action. Furthermore, significant reduction in total daily insulin dosage and reduction of body weight as observed during combination therapy renders SGLT-2I, a near-ideal partner to insulin. This review aims to evaluate the safety and efficacy of currently used SGLT-2I as an add-on to insulin therapy in the treatment of T2DM.

KEYWORDS:

• Sodium glucose co-transporter-2 inhibitors
• insulin
• hypoglycemia
• type 2 diabetes
• genito-urinary infection

Acknowledgments

Author would like to thank Dr. Jaydeep Mazumdar for data collection while writing the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key points

• SGLT-2Is have significant potential to further reduce plasma glucose (HbA1c and FPG), as add-on therapies to insulin. A significantly higher proportion of patients achieved the HbA1c target of <7% when SGLT-2Is were added to insulin.

• Addition of SGLT-2Is to insulin can counter the weight gain and fluid retention associated with high insulin dosage. Significant weight loss was also observed when SGLT-2Is were added to insulin.

• The daily dose of insulin requirement was significantly less with this combination therapy.

• Reduction in BP is an additional advantage and can be beneficial in the long run.

• However, use of SGLT-2I may be limited in the elderly population, and in patients with eGFR <45 ml/min, many of whom may be already receiving insulin therapy. Additionally, there also remains a risk of diabetic ketoacidosis precipitation, although very small, when the insulin dose is significantly reduced with SGLT-2I, as reported in various case series.