Remission Evaluation of a Metabolic Intervention in Type 2 Diabetes With Forxiga

The purpose of the study is to determine whether in patients with early type 2 diabetes, a short-term intensive metabolic intervention comprising Forxiga, metformin, basal insulin glargine and lifestyle approaches will be superior to standard diabetes therapy in achieving sustained diabetes remission.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Behavioral: Lifestyle therapy; Drug: insulin glargine; Drug: metformin; Drug: Forxiga

Detailed Description

This is a multicentre, open-label, randomized controlled trial in 152 patients with recently-diagnosed T2DM. Participants will be randomized to 2 treatment groups: (a) a 12-week course of treatment with Forxiga, metformin, insulin glargine and lifestyle therapy, and (b) standard diabetes therapy, and followed for a total of 64 weeks (1 year and 3 months). In all participants with HbA1C<7.3% at the 12 week visit, glucose-lowering medications will be discontinued and participants will be encouraged to continue with lifestyle modifications and regular glucose monitoring. Participants with HbA1C ≥ 7.3% at this visit or who experience hyperglycemia relapse after stopping drugs will receive standard glycemic management as informed by the current Canadian Diabetes Association clinical practice guidelines.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2T 5C7
      • University Of Calgary
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Health Science Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Hospital
    • London, Ontario, Canada, N6G 2M1
      • Western University
    • Toronto, Ontario, Canada, M4G 3E8
      • LMC
    • Toronto, Ontario, Canada, M5C 2T2
      • St. Michaels's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. men and women 30-80 years of age inclusive;
2. type 2 diabetes mellitus diagnosed by a physician within 8 years prior to patient enrollment;
3. anti-diabetic drug regimen (either drug or dose of drug) unchanged during 8 weeks prior to screening and randomization;
4. HbA1C 6.5-9.5% inclusive on no hypoglycemic agents or HbA1C ≤ 8.0% on up to 2 glucose-lowering agents;
5. body mass index ≥ 23 kg/m2;
6. ability and willingness to perform self-monitoring of capillary blood glucose (SMBG);
7. ability and willingness to self-inject insulin;
8. provision of informed consent.

Exclusion Criteria:

1. current use of insulin therapy;
2. history of hypoglycemia unawareness, or severe hypoglycemia requiring assistance;
3. history of end-stage renal disease or renal dysfunction as evidenced by eGFR<60 mL/min/1.73 m2 by MDRD formula;
4. history of lactic acidosis or diabetic ketoacidosis;
5. active liver disease or elevated alanine transferase (ALT) levels ≥ 2.5 times upper limit of normal at the time of enrollment;
6. history of bladder cancer or undiagnosed hematuria;
7. history of breast cancer;
8. history of polycythemia;
9. evidence of volume depletion or hypotension (systolic blood pressure < 90 mmHg);
10. systolic blood pressure > 180 mmHg or diastolic blood pressure > 105 mmHg;

11. diagnosed cardiovascular disease (unless cleared for a moderate intensity exercise program by a specialist) including:

    1. any history of acute coronary syndrome, hospitalization for unstable angina, myocardial infarction, or revascularization with coronary artery bypass grafting or percutaneous coronary intervention;
    2. other evidence of coronary artery disease;
    3. peripheral vascular disease, valvular heart disease, cardiomyopathy, aortic dissection, tachyarrhythmias, bradyarrhythmias, prior stroke or TIA;
    4. prior hospitalization for heart failure; or
    5. ECG findings concerning for ischemic heart disease (i.e. pathological Q-waves, ST-segment-T-wave abnormalities in contiguous leads, left anterior hemiblock, left bundle branch block, second or third degree atrioventricular block).
12. dependence on oxygen;
13. history of any disease requiring frequent intermittent or continuous systemic glucocorticoid treatment;
14. history of bariatric surgery, or planned bariatric surgery in the next 1.5 years;
15. history of any major illness with a life expectancy of < 3 years;
16. history of injury or any other condition that significantly limits participant's ability to achieve moderate levels of physical activity;
17. any history of excessive alcohol intake, acute or chronic;
18. currently pregnant, or breastfeeding, or not using a reliable method of birth control for the duration of the trial in all females with childbearing potential; reliable methods of birth control include oral contraceptive (birth control pill), hormonal injection, implant, patch, or vaginal ring, intrauterine device, barrier method (condom and spermicide), tubal ligation, partner vasectomy or abstinence;
19. known hypersensitivity to metformin, Forxiga, or insulin glargine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard Care; Standard glycemic care as informed by the current clinical practice guidelines
Experimental: Intervention; Drug: insulin glargine - sc injection; Drug: metformin, oral administration; Drug: forxiga, oral administration; Behavioral: lifestyle therapy, diet and exercise	Behavioral: Lifestyle therapy; Lifestyle intervention includes individualized dietary and exercise advice and frequent visits for goal reinforcement, behavior modification and problem-solving; Other Names: diet and exercise; Drug: insulin glargine; Dose is titrated to achieve fasting normoglycemia; Other Names: Lantus; Drug: metformin; Dose is titrated to 1 g bid or maximal tolerated dose; Drug: Forxiga; Dose is titrated to 10 mg po daily or maximal tolerated dose; Other Names: dapagliflozin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Achieving Drug-free Diabetes Remission in the Experimental Group Compared to the Control Group	Drug-free diabetes remission is defined as HbA1C < 6.5 % off glucose-lowering agents for at least 12 weeks.	24 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Achieving Drug-free Diabetes Remission	Drug-free diabetes remission is defined as HbA1C < 6.5 % off glucose-lowering agents for at least 12 weeks.	64 weeks after randomization
Number of Participants Achieving Drug-free HbA1C < 6.0%	Drug-free complete diabetes remission is defined as HbA1C < 6.0 % off glucose-lowering agents for at least 12 weeks.	24 weeks after randomization
Number of Participants Achieving Diabetes Relapse Without Overt Hyperglycemia Off Diabetes Drugs	Diabetes relapse without overt hyperglycemia is defined as HbA1C 6.5-6.9% off glucose-lowering agents for at least 12 weeks.	24 weeks
Glycated Hemoglobin (HbA1C)	Expressed in Diabetes Control and Complications Trial (DCCT) units	12 weeks after randomization
Number of Participants With Non-severe Symptomatic Hypoglycemic Episodes	Symptomatic hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia.	During 64 weeks of follow-up
Percentage of Weight Loss From Baseline	(Weight at randomization - weight at 12 weeks)/(weight at randomization)	12 weeks after randomization
Change in Waist Circumference From Baseline	(Waist circumference at 12 weeks - waist circumference at randomization)	12 weeks after randomization
Number of Participants With Severe Hypoglycemic Episodes	Severe hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following: (i) the event was associated with a documented self-measured or laboratory plasma glucose level </= 2.0 mmol/L or (ii) the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.	During 64 weeks of follow-up

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Natalia McInnes, MD, McMaster University; Study Chair: Hertzel C Gerstein, MD, Hamilton Health Sciences Corporation

Publications and helpful links

General Publications

• McInnes N, Hall S, Sultan F, Aronson R, Hramiak I, Harris S, Sigal RJ, Woo V, Liu YY, Gerstein HC. Remission of Type 2 Diabetes Following a Short-term Intervention With Insulin Glargine, Metformin, and Dapagliflozin. J Clin Endocrinol Metab. 2020 Aug 1;105(8):dgaa248. doi: 10.1210/clinem/dgaa248.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: September 16, 2015
• First Submitted That Met QC Criteria: September 24, 2015
• First Posted (Estimate): September 25, 2015

Study Record Updates

• Last Update Posted (Actual): November 24, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Diabetes; Insulin; Exercise; Metformin; Diet; Lifestyle; Glargine; Forxiga
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin; Metformin; Insulin Glargine
• Other Study ID Numbers: REMIT-Dapa