SGLT-2 Inhibitor Empagliflozin Effects on Appetite and Weight Regulation: A Randomised Double-blind Placebo-controlled Trial (The SEESAW Study)

Out of a family of six sodium glucose co-transporters, two have been extensively studied for therapeutic indications involving glucose reabsorption from the glomerular filtrate. Sodium glucose co-transporter-1 (SGLT-1), which is mainly found in both the renal tubule and enterocytes lining intestinal villi, transfers glucose across a concentration gradient resulting in glucose absorption from the gut and accounting for 10% of the glucose reabsorption from the renal tubules. Sodium glucose co-transporter-2 (SGLT-2), which is mostly found in the kidneys, is responsible for reabsorbing 90% of the glucose that is filtered by the renal tubules. Compared with healthy individuals, SGLT-2 is over-expressed and over-activated in those with type 2 diabetes.

SGLT-2 inhibitors are a new class of glucose-lowering drugs for the management of type 2 diabetes which reduce plasma glucose levels by increasing urinary glucose excretion (UGE) by up to 60-80g (240-320 kilo Calories) per day. SGLT-1 inhibitors and combined SGLT-1 and -2 inhibitors are currently in development.

Several SGLT-2 inhibitors are commercially available and licensed for use in the UK including dapagliflozin, canagliflozin and Empagliflozin (Jardiance™). They all lower glycated haemoglobin (HbA1c) effectively compared with placebo (mean difference vs. placebo -0.66% (95% Confidence Interval, -0.73% to -0.58%). They also result in weight loss of approximately 1.8kg compared with placebo and in combination with other oral hypoglycaemic medications. Some of this weight loss can be attributed to fluid loss due to osmotic diuresis from UGE. Weight is lost from both subcutaneous and visceral stores of adipose tissue.

Phase II studies have shown that the highly selective and potent SGLT-2 inhibitor Empagliflozin (Jardiance™) results in significant reductions in HbA1c level after 12 weeks of therapy compared with placebo (HbA1c 0.4-0.6% reduction with 5-25mg daily dose, p<0.0001) and reduction was similar to that seen with metformin. Weight loss of between 1.81-2.33kg was also achieved depending on Empagliflozin (Jardiance™) dose along with reduction in fasting plasma glucose (FPG). Similar improvements in HbA1c, weight and FPG have been seen in phase III trials with Empagliflozin (Jardiance™) both as monotherapy and in combination with metformin, sulphonylureas or insulin.

Empagliflozin (Jardiance™) is licensed in the UK for use in type 2 diabetes management. In this study, we will be using Empagliflozin (Jardiance™) according to its licensed indications and dosage. The commonest known side-effects include urinary tract and genital mycotic infections which are more frequent in women than men and generally mild in severity. Dehydration and postural hypotension may occur due to volume depletion and modest lowering of blood pressure. Increased urinary frequency may also occur. Increased risk of hypoglycaemia is observed when Empagliflozin (Jardiance™) is combined with sulphonylureas or insulin.