Study of Sulphonylurea Synergy With DPP4 Inhibitors
Condition: Type 2 Diabetes
Study type: Interventional

Summary: 
      The Study of Sulphonylurea Synergy with DPP4 Inhibitors (SSS Study) will establish whether a
      very low dose of sulphonylurea will have a synergistic role on augmentation of insulin
      secretion when given in combination with a DPP4 inhibitor as a primary outcome. The study
      will recruit 30 patients with type 2 diabetes mellitus controlled with no treatment or
      metformin monotherapy with an HbA1c <64mmol/mol (<8%). In this unblinded, randomised
      physiological study, participants will receive four 14-day intervention blocks: low dose
      sulphonylurea alone, DPP4 inhibitor alone, low dose sulphonylurea + DPP4 inhibitor or no
      treatment change. The primary outcome will be assessed through evaulation of insulin
      secretion and sensitivity at mixed meal test at the end of each treatment block. Glycaemic
      variability on continuous glucose monitoring for each intervention block will be evaluated as
      a secondary outcome. In addition, the primary outcome will be evaulated for KCNJ11 genotype
      as an additional secondary outcome.
    

Detailed description: 
      The Study of Sulphonylurea Synergy with DPP4 Inhibitors (SSS Study) aims to establish whether
      a very low dose of SU will have a synergistic role to increase insulin secretion when given
      in combination with DPP4 inhibitors (DPP4i). This physiological study will assess glucose
      variability and insulin secretion through mixed meal tests and continuous glucose monitoring.

      The SSS Study is a follow-on study from The Study of Sulphonylurea Synergy with Incretins
      (LOGIC Study 2018DM01, 18/ES/0064, ClinicalTrials.gov NCT03705195) which established that the
      use of low dose sulphonylurea as a physiological stimulus augments insulin secretion through
      synergistic action with incretin hormones.

      In this study, low dose sulphonylurea will again be used as a physiological stimulus. A DPP4i
      will be given to increase levels of incretin hormones. The investigator's hypothesis is that
      a combination of low-dose sulphonylurea with a DPP4i will further augment insulin secretion
      than with low-dose SU alone. In addition, utilising results from LOGIC Study, the low-dose SU
      has been shown to promote insulin secretion in a glucose-dependent mechanism via synergy with
      incretin hormones, therefore glycaemic variability should be minimised.

      The SSS study will take place at The Clinical Research Centre in Dundee over 6 visits. It
      will evaluate 30 patients with T2DM on no diabetes therapy or metformin monotherapy. All
      participants will continue their existing diabetes treatment for the duration of the study.

      SSS Study clinical stage will be 8 weeks. A screening visit will obtain Informed Written
      Consent for Study, along with baseline medical information and screening bloods to ensure the
      participant is safe to take part.

      There are four, 2-week blocks during the clinical phase of the study:

        -  Block 1: No change to treatment

        -  Block 2: Low Dose Sulphonylurea Once Daily

        -  Block 3: DPP4i Once Daily

        -  Block 4: Low Dose Sulphonylurea + DPP4i Once Daily

      The SSS Study is randomised to intervention order. Participants will crossover to receive
      each intervention during the study period. They will be randomised using a computer
      randomisation software.

      At the four intensive visits, participants will undergo a two-hour MMT to assess
      post-prandial glucose variance. In addition, participants will wear CGM (Freestyle Libre Pro
      Flash Continuous Glucose Monitoring System, Abbot) for the duration of study to assess
      overall physiological glucose variability. The CGM sensor will be replaced at each study
      visit. The CGM has a dedicated software, meters will be downloaded to a secure University
      computer. The software produces an analysis of blood sugar readings for the last 14 days.

      Comparison of glycaemic variability and post-prandial insulin secretion after each of the
      treatment periods will investigate whether low-dose SU and DPP4i further augment insulin
      secretion compared with low-dose SU alone.
    

Intervention name(s): Sulfonylurea; DPP4 Inhibitor
Intervention type(s): Drug; Drug
Intervention description(s): Given at very low dose as a physiological stimulus on the beta cell not as medical treatment. 20mg gliclazide is being used in this study.; Given as a physiological stimulus to augment endogenous incretin hormone levels, not as a medical treatment. 100mg sitagliptin is being used in this study.
Other intervention name(s): Diamicron; Nordialex; Gliclazide; Sitagliptin; Januvia; Janumet; Ristaben; Tesavel; Velmetia; Xelevia
Intervention MeSH terms: Sitagliptin Phosphate; Gliclazide; Dipeptidyl-Peptidase IV Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Physiological Study
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Metformin; Sulphonylurea; Gliclazide; DPP4 Inhibitor; Sitagliptin; Continuous Glucose Monitoring; KCNJ11; Incretin Effect