Metabolic Responses of Dapagliflozin vs Sitagliptin in T2DM Patients Inadequately Controlled With Insulin Therapy

Sodium glucose co-transporter 2 (SGLT2) inhibitors introduce a novel approach of glycaemic control in type 2 diabetes (T2DM). Inhibition of SGLT2 causes glycosuria and lowers blood glucose levels regardless of insulin sensitivity and beta cell function. It has recently been shown that SGLT2 inhibition is efficacious and safe not only in diabetic patients with normal renal function but also in patients with chronic kidney disease stage 3a [estimated glomerular filtration rate (eGFR) 45-59 mL/min/1.73m2]. While the clinical efficacy has been well proven by various randomized controlled trials, the significance of increased serum ketone levels after SGLT2 inhibition, however, remains to be elucidated. Certainly, the risk of ketoacidosis, albeit small, has raised considerable concern among both patients and clinicians. On the other hand, although still controversial at this stage, an alternate fuel hypothesis has emerged that tries to explain the cardiovascular benefits observed with SGLT2 inhibitors.

Several mechanisms have been proposed to explain the increased serum ketone levels after SGLT2 inhibition. In patients who are on background insulin therapy, reduced insulin dose, hoping to minimize risk of hypoglycaemia during concomitant use of SGLT2 inhibitors, could increase lipolysis and hepatic ketogenesis. In addition, even among those who are insulin naïve, the use of SGLT2 inhibitors might decrease renal clearance of ketone bodies, or increase ketone production through augmented glucagon to insulin ratio. Recent studies had also demonstrated that SGLT2 inhibitors shifted substrate utilization from glucose to lipid oxidation, thereby contributing to increased ketones production. In a study involving 9 subjects with T2DM treated with dapagliflozin, plasma ketone levels increased significantly from 0.05 mmol/L to 0.19 mmol/L over 2 weeks. In another study of 66 subjects with T2DM treated with empagliflozin, plasma ketone levels did not rise after a single dose administration but increased statistically from 0.02 mmol/L to 0.06 mmol/L after 4 weeks. Importantly, both studies included subjects who were either insulin or even drug naïve with relatively short duration of diabetes. It is well known that insulin deficiency increases the risk of developing ketoacidosis with SGLT2 inhibitors. Moreover, since the glucose-lowering effect of SGLT2 inhibitors is at its maximum at 3 to 6 months after use, the extent of increase in serum ketone levels and its clinical relevance with chronic use of SGLT2 inhibitors, especially among insulin-treated patients that often have longer duration of diabetes and potentially more insulin deficient than those who are insulin naive, have not been clearly defined. Therefore, the investigators perform this randomised study to evaluate the effect of SGLT2 inhibitors on serum ketone levels among Chinese patients with T2DM inadequately controlled with insulin therapy.