Relationship Between Improvement in Insulin Secretion and Decrease in HbA1c in GLP-1 RA Therapy in T2DM Patients
Trial Snapshot
- Phase
- Phase 4
- Sponsor
- Dasman Diabetes Institute
- Enrollment
- 315
- Locations
- 1
- Primary Endpoint
- HbA1c
Study Overview
Brief Summary
GLP-1 receptor agonists (GLP-1 RA) is group of antidiabetic agents very effective in lowering the plasma glucose concentration in T2DM patients . Currently there are several agents approved for the treatment of T2DM which are classified into two groups: (1) short acting GLP-1 RA and include exenatide BID and lexisenatide, and (2) long acting agents which are given once daily or weekly injection and include liraglutide, semaglutide, dulaglutide and budyreon . Clinical studies have demonstrated that long acting GLP-1 RA (e.g. liraglutide, bydureon and dulaglutide) produce ~1.5% reduction in the HbA1c , which was significantly greater than that caused by other classes of antidiabetic agents (e.g. DPP4 inhibitors, and SGLT2 inhibitors). Members of this class of drugs exert multiple metabolic actions in T2DM. They potentiate insulin-stimulated insulin secretion from the beta cell , inhibit glucagon secretion from the alpha cells and inhibit appetite and promote weight loss. Together, these metabolic actions of GLP-1 RA contribute to the improvement in glucose metabolism and decrease in HbA1c.
Although GLP-1 RA produce a robust mean decrease in HbA1c (~1.5%), the magnitude of decrease in HbA1c in the individual patient vary considerably. Clinical studies showed that approximately one third of T2DM patients receiving GLP-1 RA experience very modest to no decrease in the HbA1c while another third of patients experience a robust decrease in the HbA1c. the reason for this large variability in the individual response to GLP-1 RA is unknown. Studies which attempted to identify possible clinical predictors that distinguish between "good responders" and "poor responders" have failed to identify clinical parameter that can predict the magnitude of decrease in HbA1c by GLP-1 RA in T2DM patients.
Because of the central role of beta cell function in the regulation of plasma glucose concentration, the study investigators hypothesis that varying degree of beta cell response to GLP-1 RA action is the principal factor responsible for the large variability in the decrease in HbA1c by GLP-1 RA. The aim of the present study is to test this hypothesis.
Detailed Description
Study Design: Eligible subjects will receive the following: (1) medical history and physical examination, (2) Measurement of general chemistry, CBC, HbA1c, TSH, and (3) 75 grams OGTT.
After completing the OGTT, subjects will be randomized to receive for 6 months, in an open label fashion: (1) weekly exenatide (bydureon) 2 mg per week (n=105); (2) liraglutide 1.8 mg per day (n=105); or (3) dulaglutide 1.5 mg per week (n=105).
Liraglutide will be started on 0.6 mg/day and dulaglutide will be started at 0.75 mg/week and the dose will be increased to the maximal tolerated dose according to the patient response.
During the treatment period, subjects will be seen monthly for follow-up visits. Each visit, medical history, physical examination will be performed. Body weight, blood pressure, FPG, Insulin, C-Peptide, glucagon, and HbA1c will be measured. At the end of 6-month treatment period, the OGTT will be repeated.
Patient will be asked to bring the injection device at each monthly follow-up visit, and patient's compliance will be examined. Subjects with compliance rate <80% will be dropped off the study by the PI and other patient will be recruited to replace him
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 21 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •age 21-75 years
- •BMI=18-45 kg/m2
- •HbA1c >7.% and <14.0%
- •Subjects must be on stable antihyperglycemic therapy during the 3 months prior to enrolment.
- •Good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, lipid profile.
- •Stable body weight (± 3 lbs) over the preceding three months
- •Not participate in an excessively heavy exercise program.
Exclusion Criteria
- •Subjects receiving therapy with GLP-1 RA or received in the past 3 months. Subjects who received GLP-1 therapy > 3 months prior to the study are eligible to participate if their body weight has returned to the pretreatment level.
- •Subjects receiving DPP4 inhibitors or who received DPP4 inhibitor in the 3 month preceding the study. Subjects on DPP4 inhibitors who are interested in switching therapy to GLP-1 RA must have 3 months washout period.
- •Haematocrit < 32.0
- •history of thyroid cancer or pancreatitis,
- •Creatinine > 1.5 mg/dl,
- •history of malignant disease,
- •Congestive heart failure
Arms & Interventions
Arm 1
Treatment with GLP-1 RA
Intervention: GLP-1 receptor agonist (Drug)
Outcomes
Primary Outcomes
HbA1c
Time Frame: 6 months
Change in HbA1c from baseline to 6 months
Secondary Outcomes
- Weight loss(6 months)
- Fasting Plasma Glucagon(6 months)
- Beta cell function(6 months)
Investigators
Dr. Ebaa Al Ozairi
Chief Medical Officer
Dasman Diabetes Institute