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

• ClinicalTrials.gov Identifier: NCT02201602
• Recruitment Status: Completed
• First Posted: July 28, 2014
• Last Update Posted: September 1, 2016
• Sponsor: Khoo Teck Puat Hospital
• Information provided by (Responsible Party): Su Chi Lim, Khoo Teck Puat Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetes	Drug: Gliclazide; Drug: Glibenclamide	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study
• Study Start Date: August 2014
• Actual Primary Completion Date: June 2016
• Actual Study Completion Date: July 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Mean blood glucose level [ Time Frame: 6 days ]

Secondary Outcome Measures :

1. Glycemic variability [ Time Frame: 6 days ]
   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).

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Singapore

Khoo Teck Puat Hospital

Singapore, Singapore, 768828

Sponsors and Collaborators

Khoo Teck Puat Hospital

Investigators

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

More Information

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.

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.

• Responsible Party: Su Chi Lim, Senior Consultant, Khoo Teck Puat Hospital
• ClinicalTrials.gov Identifier: NCT02201602
• Other Study ID Numbers: Gliclazide
• First Posted: July 28, 2014
• Last Update Posted: September 1, 2016
• Last Verified: August 2016

Keywords provided by Su Chi Lim, Khoo Teck Puat Hospital:

sulphonylureas; gliclazide; glibenclamide

Additional relevant MeSH terms:

Gliclazide; Glyburide; Hypoglycemic Agents; Physiological Effects of Drugs