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.

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.

Inclusion Criteria:

• Age ≧40 and ≦80
• Age of diabetes diagnosis ≧35
• T2DM on no treatment, or metformin monotherapy
• White British
• HbA1c ≦8% (64mmol/mol) in last 6 months
• eGFR ≧50ml/min-1
• ALT ≦2.5*ULN
• Able to consent

Exclusion Criteria:

• Does not meet inclusion criteria
• Pregnancy, lactation or a female planning to conceive within the study period
• Previous acute pancreatitis
• 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
• Inability or unwillingness to comply with protocol