Study of Sulphonylurea Synergy With Incretins

Study Overview
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Brief Summary
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The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral glucose tolerance test followed by an isoglycaemic intravenous glucose infusion (IGII). The study will investigate whether there is synergy between a physiological sulphonylurea (SU) stimulus and the incretin effect, causing augmentation of insulin secretion in patients with type 2 diabetes mellitus (T2DM). The study will take place at The Clinical Research Centre at Ninewells Hospital in Dundee over five visits. It will evaluate 20 patients with T2DM on no diabetes therapy, or metformin monotherapy. All participants will undergo two matched clamps. The first matched clamp will be with no intervention. The second intervention matched clamp, low-dose liquid gliclazide will be administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in this this instance will be used as a physiological stimulus and will only be given on two occasions as part of the second matched clamp. The first eight participants will participate in the dose-ranging phase. They will receive either 10mg or 20mg gliclazide as a stimulus to augment the incretin effect. A further twelve participants will then be recruited to complete the study utilising the dose which caused the greatest increment in insulin secretion. LOGIC will also evaluate the cohort for effect of KCNJ11 genotype on physiological response.

Detailed Description
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The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral glucose bolus test followed by an isoglycaemic intravenous glucose infusion (IGII) the next day. The study will investigate whether there is synergy between a physiological sulphonylurea (SU) stimulus and the incretin effect, causing augmentation of insulin secretion in patients with type 2 diabetes mellitus (T2DM). The study will take place at The Clinical Research Centre at Ninewells Hospital in Dundee over five visits. It will evaluate 20 patients with T2DM on no diabetes therapy, or metformin monotherapy. The first visit is a screening visit to ensure the participant meets inclusion and exclusion criteria, and, if so, to obtain written informed consent for study. Visits 2-5 will all occur following an overnight 10-hour fast at home. The second and third visits will make up the first matched clamp. In visit 2, the participant will undergo a 75-gram oral glucose bolus with frequent blood sampling to assess the glucose variance, insulin secretion and incretin hormone response from an oral glucose stimulus. Blood glucose level (BGL) will be sampled every 5 minutes along with hormone biochemical analysis at regular defined time points. The third visit consists of an IGII to replicate the glucose curve from the OGTT to allow measurement of incretin effect. BGL will again be sampled every 5 minutes with regular biochemical analysis of hormones. The investigators aim to establish whether a low-dose of sulphonylurea will have a synergistic role on insulin secretion with endogenously secreted GLP-1 and GIP, therefore visits four and five will complete the same matched clamp, however, low-dose liquid gliclazide will be administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in this this instance will be used as a physiological stimulus and will only be given on two occasions as part of the second matched clamp. The first eight participants will receive either 10mg or 20mg gliclazide as a stimulus to augment the incretin effect. A further twelve patients will then be recruited to complete the study utilising the dose which caused the greatest increment in insulin secretion. The comparison of these tests will investigate the hypothesis that there is a synergistic effect between low-dose sulphonylurea and augmentation of the incretin effect on the beta cell. LOGIC will also evaluate the cohort for effect of KCNJ11 genotype on physiological response. Participants will be consented for genotyping as part of this study.

Official Title
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Study of Sulphonylurea Synergy With Incretins

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Gliclazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40 - 80, Age of Diabetes Diagnoses ≥ 35 T2DM on no treatment or metformin monotherapy White British HbA1c ≤ 8% (64mmol/mol) eGFR ≥ 50ml/min-1 ALT ≤ 2.5 x ULN Able to consent Exclusion Criteria: Type 1 Diabetes Mellitus HbA1c > 8.0% (> 64mmol/mol) eGFR <50ml/min-1 ALT >2.5 x ULN Anaemia (Haemoglobin <12.0 g/dL for women, <13.0 g/dL for men) Pregnancy, lactation or a female planning to conceive within the study period Established pancreatic disease Participating in clinical phase of another interventional trial/study or have done so within the last 30 days Any other significant medical reason for exclusion as determined by the investigator

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Proof-of-Concept Physiological Study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No Intervention<br>All participants in study will complete two matched clamp studies (OGTT + IGII). The first matched clamp without any intervention the second matched clamp with low dose gliclazide | |
| Experimental: Low Dose Gliclazide<br>The first 8 participants will complete the dose-ranging phase of LOGIC study. Low dose gliclazide is being used a physiological stimulus. In the dose-ranging phase, 4 participants will receive 10mg gliclazide, the remaining 4 will receive 20mg gliclazide. The allocation to 10mg or 20mg will be randomised and unblinded. The study will analyse after the first 8 participants to assess which dose produces the greatest augmentation of insulin secretion when acting synergistically with the incretin effect. The further 12 participants will complete the study with the identified best dose. | Drug: Gliclazide<br>* Low dose liquid gliclazide will be used with the second matched clamp (OGTT/IGII) in visits 4 & 5.<br>* Other names: Zicron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in insulin secretion and incretin effect between two matched clamps (presence and absence of low dose gliclazide) | Comparison of two matched clamps (oral glucose tolerance test + isoglycaemic intravenous glucose infusion). Matched clamp 1 - control. Matched clamp 2 - low dose gliclazide. Levels of insulin/c-peptide, incretin hormones and plasma glucose will be compared in the presence and absence of low dose gliclazide | Through four study visits completed over 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K) | Difference in insulin secretory response to low dose gliclazide calculated by insulin/cpeptide levels in matched clamp(gliclazide). Differences will then be compared by participants genotype e.g. insulin secretory response for E23K, E23E, K23K variants. | Through four study visits completed over 4 weeks |