Diabetes Interventional Assessment of Slimming or Training to Lessen Inconspicuous Cardiovascular Dysfunction

This is a single centre study, which will comprise of a cross-sectional analysis of the baseline data of a 3-arm 12 week Prospective, Randomised, Open label, Blinded End point (PROBE) trial of TDR and an exercise programme compared with standard care. Clinical follow-up will take place at 6-12 months.

The trial has two primary objectives:

1\) Identify the determinants of diastolic dysfunction, assessed by MRI, in younger adults with T2DM through multivariate analysis of baseline dataset (cross-sectional study analysis) 2) Determine if diastolic dysfunction (classified by diastolic strain rate) can be reversed by either TDR or an exercise programme (PROBE trial)

Secondary objectives include:

1. Determine the reference range for diastolic strain rate in healthy adults 2. Determine the optimum field strength for the assessment of PEDSR

* Sample size:

Cross-sectional Analysis: A sample size of 100 T2DM participants will have approximately 80% power to test up to 10 variables in a multivariate regression analysis, with an estimated combined R2 of 15%, for the identification of determinants of diastolic stain rate.

\- PROBE Trial:

All participants from Phase I who agree to take part in Phase II will be randomized. The Investigators expect, based on experience from previous studies, an attrition rate of up to 10% following the first data collection session. Therefore, approximately 90 participants are expected to be randomized to the three arms (approximately 30/group). The power calculation is based on the Investigators pilot MRC study. The T2DM patients had diastolic strain rate of 1.5s-1 with standard deviation of 0.2 s-1. Based on this, 30 patients per group will have 80% power to detect a between group difference in peak early diastolic strain rate (PEDSR) of 0.2s-1 assuming alpha=0.025 (to allow for two primary comparisons, i.e. TDR vs standard care and exercise vs standard care) and a maximum 30% drop-out. Such an improvement would result in a strain rate (1.7 s-1) similar to that seen in the obese controls (1.8 s-1) but still lower than the lean controls (2.0 s-1). * Randomization:

Randomization will be stratified by sex, given different left ventricular remodeling processes in males and females, and by baseline glucose lowering therapy (any GLP-1, DPP-IV or SGLT-2 vs none of these). The statistician undertaking the final analysis will be blinded to the treatment groups.

\- Healthy controls:

Twenty healthy controls will be recruited and undertake all baseline measures only. This population will serve to confirm normal ranges on the relevant scanners and will inform the cross-sectional analysis of baseline data and provide a comparator group for the study endpoints i.e. determine if the interventions have caused reversion to normal diastolic function in the T2DM population.

\- Test Re-Test MRI sub-study:

An optional sub-study examining test-retest reproducibility of MRS at 1.5 and 3T will be performed on selected participants willing to undergo a second scan. Details of this sub-study are provided below. As outlined above our preferred field strength for the assessment of PEDSR is 1.5T. However, due to higher signal to noise of 3T imaging, MRS for myocardial triglyceride may be better at 3T but there have been no direct comparisons.

Participants enrolled for the main study will be asked if they would be willing to take part in the reproducibility sub-study, until ten participants have been recruited. These participants will then undertake an additional 20 minute scan on the same on the 3T platform to assess myocardial triglyceride and PEDSR. The 3T scan will consist of localisers, cine long axis 4 chamber, 3 chamber and short axis at mid for calculation of myocardial strain rates as previously described, followed by single voxel H+ MRS of the interventricular septum to allow calculation of myocardial triglyceride content. No contrast will be administered during this examination.

\- Statistical Analysis:

Cross-sectional Analysis:

The aim of these analyses is to identify determinants of diastolic dysfunction in individuals with T2DM. Outcome and potential explanatory variables will be summarized using mean (standard deviation) for normally distributed continuous variables, median (interquartile range) for non-normally distributed continuous variables, and count (percentage) for categorical variables. We anticipate including the following potential explanatory variables: duration of diabetes, age, sex, myocardial and liver triglyceride content, myocardial perfusion reserve, blood pressure, HBA1c, blood pressure and myocardial extracellular volume. Univariate linear regression models will then be fitted with diastolic strain rate as the outcome, and each of the explanatory variables under consideration as the covariate in turn to identify factors associated with diastolic strain rate. Variables that have a significant univariate association with diastolic strain rate will be entered into a multivariate regression analysis to determine independent associations with diastolic strain rate. Redundant variables will be removed in a stepwise manner, based on a significance level of 0.05.

\- PROBE trial/Phase II:

The aim of these analyses is to compare the primary outcome (diastolic strain rate) at 12 weeks between the TDR and standard care arms, and between the exercise and standard care arms. The primary analysis will be a per protocol analysis as this is a proof of principle study where we are primarily interested in the size of the treatment effect, rather than the practicability of the intervention. A CONSORT diagram will be produced. At baseline and each follow-up, outcome and descriptive variables will be summarized by arm using mean (standard deviation) for normally distributed continuous variables, median (interquartile range) for non-normally distributed continuous variables, and count (percentage) for categorical variables. Each intervention will be compared with the control group (i.e. TDR v standard care and Exercise v standard care) using linear regression to allow missing outcome data to be imputed using multiple imputation methods. If necessary, the outcome variable will be appropriately transformed so that the assumptions of the linear regression model are held.

\- Healthy controls:

The aim of these analyses is to quantify the diastolic strain rate of healthy individuals as this is currently unknown. These analyses will provide context in which to interpret the results of the PROBE trial, and are not powered for a formal comparison between the T2DM patients and healthy controls as they are considered to be exploratory. A baseline summary of the outcome and descriptive variables used in the PROBE trial will be produced using mean (standard deviation) for normally distributed continuous variables, median (interquartile range) for non-normally distributed continuous variables, and count (percentage) for categorical variables.

Should any unexpected and significant findings occur as a result of these tests, they will be communicated to the patients GP. This will be stated in the consent form for the healthy controls.

\- Test re-test:

The aim of these analyses is determine whether diastolic strain rate measured on a 3T scanner (gold standard) is comparable with that measured on a 1.5T scanner. Descriptive characteristics of those participating in the test-retest sub-study will be summarized. Diastolic strain rate will be summarized using mean (standard deviation) or median (interquartile range), as appropriate, by scanner. Bland-Altman Limits of Agreement will be produced.

The formal end of the study will occur following the final 12 week assessment of the final patient recruited

We will conduct two further follow-up visits to assess maintenance at 6 and 12 months (or at study end). We will collect data for weight, blood pressure, lipid profile and glycaemic control. Patients will be asked to consent to the investigators accessing long-term follow-up (10 years) through review of clinical records and Hospital Episode statistics through flagging with the Health and Social Care Information Centre. * Study interventions:

Recruited participants will be randomised to one of three groups for the PROBE study; 1. Standard of care as per NICE guidance plus lifestyle advice or 2. Total Dietary Replacement (TDR) or 3. Supervised exercise training. * Participant Compliance:

TDR Group Participant Compliance:

Previous studies with LED/VLED with TDR have indicated that compliance is between 70-80%. The patients in both the TDR and exercise groups will have regular contact with investigators to encourage compliance and offer support. The standard care group will also receive weekly telephone calls to encourage compliance to suggested lifestyle changes. Participants will be offered £50 compensation for completing each of the three assessments, which will take approximately 3-4 hours. However, those patients in the TDR arm that do not achieve a loss of \>4% body weight at week 1 and 10% at week four will be considered non-compliant and excluded from the study.

Exercise Group Participant Compliance:

Compliance will be assessed by attendance at the supervised sessions. Participants in the exercise arm who attend less than two thirds of the supervised sessions in the first 4 weeks will be excluded (PI discretion will be applied to this determination where necessary).

\- Alterations to medication regime:

Due to the potential risk of hypoglycaemia and symptomatic hypotension; medication at enrolment will need to be adjusted initially and throughout the study for both the TDR and the exercise training groups.

Participants randomised to the TDR group:Will be asked to discontinue with all glucose lowering therapies before the baseline study, as previously advised for a recently published study with similar intervention (of 8 weeks). Metformin and Sulphonylureas are to be discontinued 72hours prior to initiation of TDR. DPP IV inhibitors 2, GLP-1 therapies and SGLT2s will be discontinued 2 weeks prior to the initiation of the TDR. Antihypertensive drugs will be stopped on the day the TDR is commenced. This is a safety measure because blood pressure is likely to fall substantially (mean drop in SBP \~ 20mmHG) on the diet. Medication will be adjusted DiRECT study protocol (see supplementary material) however, individual clinical decisions may be necessary for a patient's best interest and therefore any alterations to medication are ultimately made at the discretion of the study clinician(s). Blood pressure will be monitored throughout the study at the clinical review sessions as per the DiRECT protocol. Treatments for other conditions and primary prevention of cardiovascular disease (e.g. statins) will be continued. This will be discussed in detail and decided upon at the level of the individual, at the initial consultation. Furthermore, their medical history will be taken and any participant with a history of constipation other bowl related problems will be prescribed a fibre supplement i.e. fybogel to help to prevent its occurrence. We will ask participants to continue with their habitual levels of physical activity throughout the course of the study.

Participants who achieve a 50% reduction in excess body mass before completion of the 12-week programme will revert to a maintenance diet and will complete the assessments at 12 weeks.

Participants randomised to exercise training: Will have their medication reviewed by the study clinician. Those with a HbA1c ≤ 8% who are currently taking a sulphonylurea will initially have the dose reduced by 50% 72hours prior to the first exercise session. Their regimes will be continued to be down titrated starting with the sulphonylurea and then moving, where applicable, onto their current SGLT or DPP-IV or GLP-1 therapies ac

• Left ventricular mass [Срок оценки: Baseline, 4 and 12 weeks]
• End diastolic volume [Срок оценки: Baseline, 4 and 12 weeks]
• End systolic volume [Срок оценки: Baseline, 4 and 12 weeks]
• Ejection Fraction [Срок оценки: Baseline, 4 and 12 weeks]
• LA Volumes [Срок оценки: Baseline, 4 and 12 weeks]
• Myocardial Systolic strain (Circumferential & Longitudinal) [Срок оценки: Baseline, 4 and 12 weeks]
• Systolic Strain Rates [Срок оценки: Baseline, 4 and 12 weeks]
• Mean Ascending & Descending Aortic Distensibility [Срок оценки: Baseline, 4 and 12 weeks]
• Pulse-wave velocity [Срок оценки: Baseline, 4 and 12 weeks]
• Global Myocardial Perfusion Reserve [Срок оценки: Baseline, 4 and 12 weeks]
• Myocardial triglyceride content [Срок оценки: Baseline, 4 and 12 weeks]
• Liver triglyceride content [Срок оценки: Baseline, 4 and 12 weeks]