Study of Sulphonylurea Synergy With Incretins

NCT03705195 | Completed

• 1 other identifier: 2018DM01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K)

  Through four study visits completed over 4 weeks

Study Arms (2)

No Intervention

NO INTERVENTION

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

Low Dose Gliclazide

EXPERIMENTAL

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

Interventions

Gliclazide DRUG

Low dose liquid gliclazide will be used with the second matched clamp (OGTT/IGII) in visits 4 \& 5.

Also known as: Diamicron, Zicron

Low Dose Gliclazide

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Dundee: lead
• NHS Tayside: collaborator

Study Sites (1)

Ninewells Hospital and Medical School

Dundee, DD1 9SY, United Kingdom

Location

Related Publications (6)

• Aaboe K, Knop FK, Vilsboll T, Volund A, Simonsen U, Deacon CF, Madsbad S, Holst JJ, Krarup T. KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. J Clin Endocrinol Metab. 2009 Feb;94(2):603-8. doi: 10.1210/jc.2008-1731. Epub 2008 Dec 2.

  PMID: 19050053 BACKGROUND

• Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004 Apr 29;350(18):1838-49. doi: 10.1056/NEJMoa032922.

  PMID: 15115830 BACKGROUND

• Fritsche A, Stefan N, Hardt E, Schutzenauer S, Haring H, Stumvoll M. A novel hyperglycaemic clamp for characterization of islet function in humans: assessment of three different secretagogues, maximal insulin response and reproducibility. Eur J Clin Invest. 2000 May;30(5):411-8. doi: 10.1046/j.1365-2362.2000.00649.x.

  PMID: 10809901 BACKGROUND

• Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):127-36. doi: 10.1016/j.mce.2008.08.012. Epub 2008 Aug 20.

  PMID: 18786605 BACKGROUND

• Henquin JC. Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia. 2009 May;52(5):739-51. doi: 10.1007/s00125-009-1314-y. Epub 2009 Mar 14.

  PMID: 19288076 BACKGROUND

• Cordiner RLM, Mari A, Tura A, Pearson ER. The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function. J Clin Endocrinol Metab. 2021 Jun 16;106(7):2036-2046. doi: 10.1210/clinem/dgab151.

  PMID: 33693776 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Gliclazide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Study Officials

• Ewan R Pearson

  University of Dundee

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Research Fellow, Specialty Registrar Diabetes and Endocrinology

Model Details: Proof-of-Concept Physiological Study

Study Record Dates

• First Submitted: July 3, 2018
• First Posted: October 15, 2018
• Study Start: August 3, 2018
• Primary Completion: June 26, 2019
• Study Completion: June 26, 2019
• Last Updated: February 24, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)