Diabetes Mellitus, Type 2Phase 4NCT04135287
Relationship Between Improvement in Insulin Secretion and Decrease in HbA1c in GLP-1 RA Therapy in T2DM Patients
A Phase 4 study testing GLP-1 receptor agonist in people with Diabetes Mellitus, Type 2, run by Dasman Diabetes Institute at 1 site in Kuwait.
Trial 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… Read more about this study
- Who is it for?
- Ages 21 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- GLP-1 receptor agonist
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 315 participants
- Where
- 1 siteKuwait
- Study dates
- 1 Mar 2020to 15 Jul 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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,
- Pregnancy.
- Congestive heart failure
Trial locations and contacts
1 site in 1 country.
Kuwait1 site, 1 recruiting
- Recruiting
Dasman Diabetes Institute
Kuwait City, 15462
About this study
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.
Read the 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
MATERIAL AND METHODS Screening: During this visit a complete medical history and physical exam will be performed. Blood will be drawn for general chemistries, lipid profile, complete blood count (CBC), and thyroid function tests (TSH and T3, T4). An additional 30 ml blood will be drawn and immediately frozen for the measurement of adipocytokines (adiponectin, TNF-alpha, IL6, resistin, leptin and hsCRP) and DNA extraction.
OGTT: All subjects will receive a 75 gram OGTT at 0800h after a 10-12 h overnight fast. Plasma glucose, insulin, C-peptide, GLP-1, GIP, glucagon, and FFA concentrations are measured at baseline (-15, -10 and 0 min) and every 30 min for 2 hours after glucose ingestion. Insulin sensitivity is calculated using the Matsuda Index (MI) of insulin sensitivity, which agrees closely with that measured with the euglycemic insulin clamp technique. The following indices of insulin secretion will be measured: early insulin response (ΔI0-30/ΔG0-30; ΔC-Pep0-30/ΔG0-30; ΔISR0-30/ΔG0-30) and total insulin response (ΔI0-120/ΔG0-120; ΔC-Pep0-120/ΔG0-120; ΔISR0-120/ΔG0-120), where ISR = insulin secretory rate calculated by plasma C-peptide deconvolution. Beta cell function is assessed using the insulin secretion/insulin resistance (disposition) index and is calculated as (ΔI/ΔG x Matsuda index; ΔISR/ΔG x Matsuda index).
Beta cell function during the OGTT also will be assessed using the Mari-Ferrannini model. This model expresses insulin secretion (in pmol min-1m-2) as the sum of two components: (i) beta cell glucose sensitivity which represents the dependence of insulin secretion on the plasma glucose concentration at any time point during the OGTT; (ii) rate sensitivity which represents the dependence of insulin secretion on the rate of change of plasma glucose. The ISR-plasma glucose dose-response curve is modulated by a potentiation factor that encompasses several potentiating mechanisms (prolonged exposure to hyperglycemia, non-glucose substrates, gastrointestinal hormones, neural modulation, time-dependent molecular/biochemical/enzymatic changes within the beta cell). In normal individuals, the potentiation factor typically increases from baseline to the end of the OGTT.
During the OGTT, 20 ml blood will be drawn to extract DNA and genome wide association analysis will be performed to identify genetic markers associated with beta cell function.
- Conditions
- Diabetes Mellitus, Type 2
- Being tested
- GLP-1 receptor agonist
- Keywords
- GLP-1 RA
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GLP-1 receptor agonistDrug
The main objective of the study is to determine the relationship between the increase in glucose-stimulated insulin secretion and decrease in HbA1c caused by GLP-1 RA therapy in poorly controlled T2DM patients. We also will identify a cut point of an increase in beta cell function which produces a clinically meaningful decrease in HbA1c.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | Treatment with GLP-1 RA Receives: Drug: GLP-1 receptor agonist |
What is being measured
The primary outcome is the main question the study is designed to answer.
HbA1c
Change in HbA1c from baseline to 6 months
Measured: 6 months
Secondary outcomes (3)
Beta cell function
Change in Beta cell function measured as ∆C-Pep/(∆G/IR) and glucose sensitivity during OGTT
Measured: 6 months
Weight loss
Change in body weight from baseline to 6 months
Measured: 6 months
Fasting Plasma Glucagon
Change in FPG from baseline to 6 months
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Oct 2019
- Study start1 Mar 2020
- Primary completion1 Mar 2023 (estimated)
- Study completion15 Jul 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Subjects will be randomized to receive for 6 months in an open label fashion GLP1RA
- Masking
- None (open label)
- Enrolment
- 315 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dasman Diabetes Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Ebaa Al Ozairi, Dasman Diabetes Institute
- Investigators
- Ebaa AlOzairi, MD, PhD, Principal investigator, Dasman Diabetes Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04135287
- Sponsor's protocol ID
- RA HM-2019-004
- Status last verified
- Jul 2020
- First submitted
- 20 Oct 2019
- Last updated
- 21 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Relationship Between Improvement in Insulin Secretion and Decrease in HbA1c in GLP-1 RA Therapy in T2DM Patients
- ClinicalTrials.gov ID
- NCT04135287
- Acronym / sponsor ID
- RA HM-2019-004
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- GLP-1 RA
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 315 participants (estimated)
- Lead sponsor
- Dasman Diabetes InstituteUniversity, hospital or other
- Study start
- 1 Mar 2020 (actual)
- Primary completion
- 1 Mar 2023 (estimated)
- Study completion
- 15 Jul 2023 (estimated)
- First posted
- 22 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
MATERIAL AND METHODS Screening: During this visit a complete medical history and physical exam will be performed. Blood will be drawn for general chemistries, lipid profile, complete blood count (CBC), and thyroid function tests (TSH and T3, T4). An additional 30 ml blood will be drawn and immediately frozen for the measurement of adipocytokines (adiponectin, TNF-alpha, IL6, resistin, leptin and hsCRP) and DNA extraction.
OGTT: All subjects will receive a 75 gram OGTT at 0800h after a 10-12 h overnight fast. Plasma glucose, insulin, C-peptide, GLP-1, GIP, glucagon, and FFA concentrations are measured at baseline (-15, -10 and 0 min) and every 30 min for 2 hours after glucose ingestion. Insulin sensitivity is calculated using the Matsuda Index (MI) of insulin sensitivity, which agrees closely with that measured with the euglycemic insulin clamp technique. The following indices of insulin secretion will be measured: early insulin response (ΔI0-30/ΔG0-30; ΔC-Pep0-30/ΔG0-30; ΔISR0-30/ΔG0-30) and total insulin response (ΔI0-120/ΔG0-120; ΔC-Pep0-120/ΔG0-120; ΔISR0-120/ΔG0-120), where ISR = insulin secretory rate calculated by plasma C-peptide deconvolution. Beta cell function is assessed using the insulin secretion/insulin resistance (disposition) index and is calculated as (ΔI/ΔG x Matsuda index; ΔISR/ΔG x Matsuda index).
Beta cell function during the OGTT also will be assessed using the Mari-Ferrannini model. This model expresses insulin secretion (in pmol min-1m-2) as the sum of two components: (i) beta cell glucose sensitivity which represents the dependence of insulin secretion on the plasma glucose concentration at any time point during the OGTT; (ii) rate sensitivity which represents the dependence of insulin secretion on the rate of change of plasma glucose. The ISR-plasma glucose dose-response curve is modulated by a potentiation factor that encompasses several potentiating mechanisms (prolonged exposure to hyperglycemia, non-glucose substrates, gastrointestinal hormones, neural modulation, time-dependent molecular/biochemical/enzymatic changes within the beta cell). In normal individuals, the potentiation factor typically increases from baseline to the end of the OGTT.
During the OGTT, 20 ml blood will be drawn to extract DNA and genome wide association analysis will be performed to identify genetic markers associated with beta cell function.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Subjects will be randomized to receive for 6 months in an open label fashion GLP1RA
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: GLP-1 receptor agonistTreatment with GLP-1 RA |
Who may qualify
- Ages
- 21 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (8 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GLP-1 receptor agonistThe main objective of the study is to determine the relationship between the increase in glucose-stimulated insulin secretion and decrease in HbA1c caused by GLP-1 RA therapy in poorly controlled T2DM patients. We also will identify a cut point of an increase in beta cell function which produces a clinically meaningful decrease in HbA1c. | Drug | Arm 1 |
Primary outcome
HbA1c
Time frame: 6 months
Change in HbA1c from baseline to 6 months
3 secondary outcomes
Beta cell function
Time frame: 6 months
Weight loss
Time frame: 6 months
Fasting Plasma Glucagon
Time frame: 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jul 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ebaa AlOzairi, MD, PhD principal investigator
Dasman Diabetes Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing GLP-1 receptor agonist in people with Diabetes Mellitus, Type 2, run by Dasman Diabetes Institute at 1 site in Kuwait.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Kuwait. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ebaa AlOzairi, Md, PhD (+965 22242999 ext. 3111, ebaa.alozairi@dasmaninstitute.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
HbA1c (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jul 2020; AzTrials last refreshed its copy on 30 Oct 2026.