This is a single centre, open-label, randomized, cross-over study. Participants will attend 4 visits in total over the course of approximately 40 weeks. Two cohorts of patients will be recruited: 28 lean-T2D patients and 28 obese-T2D patients.
Potential participants will be invited to the research centre for a screening/ baseline visit (Visit 1). At this visit, the participants will be given the Participant Information Sheet (PIS) to read through, and given the opportunity to ask questions. If they are interested in participating, their consent will be taken in written form. Each participant will then have a series of non-invasive tests. At this baseline visit, the following assessments will be done:
* Review of medical history and concomitant medications;
* Review of history of diabetes and complications;
* Review of inclusion/exclusion criteria;
* Collection of demographic data;
* Vital signs;
* Physical examination;
* Height and weight;
* Blood pressure;
* Urine pregnancy test in women of childbearing potential;
* Venepuncture (fasting sample): 20mls;
* Multiparametric MRI;
* EndoPAT testing;
* 6 minute walk test;
* 12-lead ECG;
* Randomization;
* Dispense study medication and issue patient diary; and
* Urine sample collection.
At this visit, participants will be randomized to receive either liraglutide or pioglitazone first. Participants that are already taking certain classes of glucose-lowering medications may be excluded from the study (see exclusion criteria for more detail). Participants will continue to take their previously prescribed medications throughout the study.
After 16 weeks of treatment (Visit 2), participants will return to the research centre and have the following assessments:
* Vital signs;
* Physical examination;
* Blood pressure;
* Weight;
* Venepuncture (fasting sample): 20mls;
* 12-lead ECG;
* Multiparametric MRI;
* EndoPAT testing;
* 6 minute walk test;
* Check current medication list and patient clinical status;
* Check study medication compliance (diary review); and
* Urine sample collection.
Participants will then have an 8 week washout period, in which they will take no study drug. After these 8 weeks, they will return to the research centre (Visit 3) and have the same assessments as listed above for Visit 2. They will start taking the second study drug for 16 weeks.
After 16 weeks, participants will attend the research centre for a final time (Visit 4) and have the same assessments as listed above for Visit 2.
Multiparametric MRI assessments will consists of 2 parts: Magnetic Resonance Spectroscopy (MRS): The relative concentration of phosphocreatine to ATP (PCr/ATP) by 31P-MRS and cardiac and hepatic triglyceride content by 1H-MRS.
Collected blood will be tested for triglycerides, alanine aminotransferase, haemoglobin, haematocrit, creatinine, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, insulin, free fatty acids, adiponectin, glucose and lipid profiles, glutamic acid decarboxylase antibodies, and Zinc transporter 8 antibodies. Urine will be spot-tested for albumin/ creatinine ratio.
Previous clinical studies have found an association between diabetes and impaired function of the endothelium of blood vessels. The EndoPAT 2000 is a machine that measures endothelium function via 2 thimble-sized sensors placed on the index fingers. This is a safe and non-invasive way of testing the condition of the participant's blood vessels, and testing takes about 5 minutes.
The 6 minute walk test is an exercise test that requires patients to walk along a long flat corridor for 6 minutes to see how far they can walk at their own pace.
Liraglutide will be administered at 0.6mg once daily to start, then titrated up to 1.2mg after 2 weeks if the participant's glucose levels permit. Participants will be trained how to administer the injection themselves. Glucose assessments will be done after 2 weeks of treatment with Liraglutide. Pioglitazone is taken orally. Participants will be started on 15mg once daily; this will be titrated up to 30mg after 2 weeks then to 45mg after another 2 weeks if glucose levels permit. Glucose assessments will be done 2 weeks after starting treatment, then 4 weeks after starting treatment. Participants will be told to continue their usual schedule of glucose monitoring at home while on the study drugs (no additional monitoring at home will be necessary).
Participants will be given diaries to complete while they are on both drugs.
