Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study

Gliclazide has greater glucose lowering efficacy than glibenclamide among type 2 diabetes mellitus patients with minor haplotype (K23/A1369) at the KCNJ11/ABCC gene locations.

Study Overview

• Status: Completed
• Conditions: Diabetes
• Intervention / Treatment: Drug: Gliclazide; Drug: Glibenclamide

Detailed Description

Sulphonylurea (SU) is a glucose-lowering agent used widely to treat type 2 diabetes mellitus (T2DM). SU promotes insulin secretion from the pancreatic islet beta cell via binding and inhibition of the ATP-sensitive potassium (KATP) channel. The KATP channel is made up of two subcomponents, an inner Kir6.2 K+ channel (coded by the KCNJ11 gene) and an outer SU receptor 1 (SUR1) (coded by the ABCC8 gene). Although all SUs are mechanistically similar in terms of increasing insulin secretion, they bind to distinct regions of Kir 6.2 and SUR1 to exert their function. Different types of SU (e.g. tolbutamide, glibenclamide, glipizide, glimepiride and gliclazide) can therefore be grouped by their binding sites (A/B/A+B site) on the KATP channel [3]. Interestingly, the KCNJ11 E23K (rs5219) variant was shown to confer susceptibility to T2DM and the ABCC8 S1369A (rs757110) variant was found to be in complete linkage disequilibrium with it i.e. inherited together as a genetic block (haplotype). A recent in vitro molecular study suggested that the minor haplotype (K23/A1369) of KATP channel is sensitive to inhibition by gliclazide (binds to A-site) but not glibenclamide (binds to A+B site), and that the increased responsiveness to gliclazide was largely due to the A1369 allele. Understanding how the response to these two SUs may vary with the presence of the minor haplotype (K23/A1369) would therefore be beneficial for customization of patient treatment to achieve better clinical outcomes.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 4

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 768828
    • Khoo Teck Puat Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes
• Age 21-65
• HbA1c >8.0% on two consecutive visits

Exclusion Criteria:

• Currently taking insulin at a regime more complex than basal insulin
• Not willing to perform self-blood glucose monitoring (SBGM)
• Renal impairment i.e. eGFR<50mls/min
• Pregnancy or unwilling to practice adequate contraception
• Taking other medications that may affect blood glucose e.g. systemic glucocorticoids.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gliclazide; Gliclazide, 80 mg tablet, half to maximal dose, 3 weeks	Drug: Gliclazide; Other Names: Sun-Glizide; SIN09350P
Active Comparator: Glibenclamide; Glibenclamide, 5 mg tablet, half to maximal dose, 3 weeks	Drug: Glibenclamide; Other Names: Benil; SIN07284P

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean blood glucose level	6 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycemic variability	Glycemic variability will be assessed using the EasyGV software (http://www.phc.ox.ac.uk/research/diabetes/software/easygv/) which is capable of calculating 10 different measures of glycemic variability from continuous glucose monitoring data, such as Standard Deviation (SD) and M-value, mean amplitude of glycemic excursions (MAGE).	6 days

Collaborators and Investigators

• Sponsor: Khoo Teck Puat Hospital
• Investigators: Principal Investigator: Su Chi Lim, MBBS, PhD, Khoo Teck Puat Hospital

Publications and helpful links

General Publications

• Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003 Feb;52(2):568-72. doi: 10.2337/diabetes.52.2.568.
• Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, Light PE. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes. 2009 Oct;58(10):2419-24. doi: 10.2337/db09-0143. Epub 2009 Jul 8.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: July 22, 2014
• First Submitted That Met QC Criteria: July 25, 2014
• First Posted (Estimate): July 28, 2014

Study Record Updates

• Last Update Posted (Estimate): September 1, 2016
• Last Update Submitted That Met QC Criteria: August 31, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: glibenclamide; sulphonylureas; gliclazide
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Gliclazide; Glyburide
• Other Study ID Numbers: Gliclazide