Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03959501
Recruitment Status : Recruiting
First Posted : May 22, 2019
Last Update Posted : May 24, 2019
Sponsor:
Information provided by (Responsible Party):
The University of Hong Kong

Tracking Information
First Submitted Date  ICMJE May 20, 2019
First Posted Date  ICMJE May 22, 2019
Last Update Posted Date May 24, 2019
Actual Study Start Date  ICMJE August 16, 2017
Estimated Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
Change in serum ketone levels after treatment [ Time Frame: 24 weeks ]
Change in serum ketone levels before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03959501 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
  • Change in fasting glucose [ Time Frame: 24 weeks ]
    Change in fasting plasma glucose before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in glycated haemoglobin [ Time Frame: 24 weeks ]
    Change in glycated haemoglobin before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in body weight [ Time Frame: 24 weeks ]
    Change in body weight before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in blood pressure [ Time Frame: 24 weeks ]
    Change in systolic and diastolic blood pressure before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in fasting lipid [ Time Frame: 24 weeks ]
    Change in fasting lipid before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in free fatty acid levels [ Time Frame: 24 weeks ]
    Change in free fatty acid levels before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in fasting glucagon levels [ Time Frame: 24 weeks ]
    Change in fasting glucagon levels before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
  • Change in homeostasis model assessment 2 steady-state beta-cell function [ Time Frame: 24 weeks ]
    Change in homeostasis model assessment 2 steady-state beta-cell function before and after treatment with either dapagliflozin or sitagliptin for 24 weeks
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metabolic Responses of Dapagliflozin vs Sitagliptin in T2DM Patients Inadequately Controlled With Insulin Therapy
Official Title  ICMJE A Randomized Study to Evaluate the Metabolic Responses of Adding Dapagliflozin Versus Sitagliptin to Chinese Patients With Type 2 Diabetes Inadequately Controlled With Insulin Therapy (DISTINCTION Study)
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes
  • Ketonemia
Intervention  ICMJE
  • Drug: Dapagliflozin 10 mg
    Dapagliflozin 10mg daily for 24 weeks
    Other Name: Forxiga
  • Drug: Sitagliptin 100mg
    Sitagliptin 100mg daily for 24 weeks
    Other Name: Januvia
Study Arms  ICMJE
  • Experimental: Dapagliflozin
    Dapagliflozin 10mg daily PO for 24 weeks
    Intervention: Drug: Dapagliflozin 10 mg
  • Active Comparator: Sitagliptin
    Sitagliptin 100mg daily PO for 24 weeks
    Intervention: Drug: Sitagliptin 100mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 20, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2020
Estimated Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Chinese
  • Aged 21 to 75 both inclusive
  • Type 2 diabetes on single or two doses of insulin therapy with or without metformin, which include intermediate acting human insulin, premixed human insulin or insulin analogues
  • On stable insulin doses, as defined by less than 10% changes in total daily insulin dose within 3 months prior to randomization
  • Suboptimal glycaemic control with baseline HbA1c ≥8.0% and ≤10.5%, taken within 2 months prior to randomization
  • Body mass index between 21 and 40 kg/m2

Exclusion Criteria:

  • Type 1 diabetes mellitus
  • History of ketoacidosis
  • Concurrent use of sulphonylurea or glucagon like peptide-1 receptor (GLP1) agonists
  • Prior use of SGLT2 inhibitors, DPP4-inhibitors or GLP1 agonists within 3 months of randomization
  • History of intolerance to SGLT2 inhibitors or DPP4-inhibitors
  • Concurrent use of loop diuretics
  • eGFR <45 ml/min/1.73m2 within 3 months prior to randomization
  • History of acute or chronic pancreatitis
  • History of benign or malignant pancreatic tumours
  • History of bladder cancer
  • Alcohol or drug abuse
  • Pregnant or nursing women
  • Women at childbearing age not using and refused to start chemical or mechanical contraception after randomization
  • Severe liver disease with elevated plasma alanine aminotransferase (ALT) of more than five times the upper limit of normal, taken within 3 months prior to randomization
  • Active or history of malignancy within 5 years prior to randomization
  • Hospitalization for acute illness within 3 months prior to randomization
  • Severe mental disorder
  • Unable to understand written patient information and to give informed consent
  • Ongoing participation in other clinical intervention trials
  • Other unspecified concomitant conditions that deemed unsuitable for study participation upon professional judgments by principal investigators
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Chi Ho Lee, MBBS 22553711 pchlee@hku.hk
Listed Location Countries  ICMJE Hong Kong
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03959501
Other Study ID Numbers  ICMJE UW-17-166
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Individual participant data will be shared upon special request to principal investigator.
Responsible Party The University of Hong Kong
Study Sponsor  ICMJE The University of Hong Kong
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kathryn Tan, MD The University of Hong Kong
PRS Account The University of Hong Kong
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP