Metabolic Responses of Dapagliflozin vs Sitagliptin in T2DM Patients Inadequately Controlled With Insulin Therapy
Condition: Type 2 Diabetes; Ketonemia
MeSH terms: Diabetes Mellitus, Type 2; Ketosis
Study type: Interventional
Phase: Phase 4

Summary: 
      The use of sodium glucose co-transporter 2 inhibitors (SGLT2i) has been associated with
      increased serum ketone levels. However, most previous 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.
    

Detailed description: 
      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.
    

Intervention name(s): Dapagliflozin 10 mg; Sitagliptin 100mg
Intervention type(s): Drug; Drug
Intervention description(s): Dapagliflozin 10mg daily for 24 weeks; Sitagliptin 100mg daily for 24 weeks
Other intervention name(s): Forxiga; Januvia
Intervention MeSH terms: Sitagliptin Phosphate; Dapagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Type 2 diabetes; Sodium glucose co-transporter 2 inhibitors; Ketones