4-T Ancillary Studies
Glycated Albumin Study
Funder: Asahi Kasei Pharma Corporation
Background : The levels of HbA1c in patients with type 2 diabetes is a reliable clinical test to identify the average plasma glucose concentration over prolonged periods of time, although it does rely on an average turn-over of red blood cells. Recently, serum glycated albumin (GA) was hypothesized to be an alternative marker for glycaemic control, over the preceding 2 weeks, which is not affected by changes in the survival time of red blood cells.
Aim: The aim of this study was to compare postprandial glucose excursions as measured by both HbA1c and GA levels.
Methods: GA levels were assayed using a kit provided by Asahi Kasei Pharma corporation, in baseline and one-year fasting plasma samples from 625 patients enrolled in the 4-T study. A mixed effects linear regression model was derived to explore the relationship of postprandial glucose rise with GA and HbA1c having adjusted for fasting plasma glucose, treatment effect and possible centre effect.
Inclusion: All patients in the 4-T study with HbA1c levels 7-10%.
Results: GA and HbA1c measures of glycation reflect postprandial glucose rise to a similar extent.
Continuous Glucose Monitoring Study
Funder: Diabetes UK
Background: Good glycaemic control is essential in patients with type 2 diabetes to improve outcomes, but in routine clinical practice this is not often the case and initiation of insulin therapy may be delayed. Continuous glucose monitoring (CGM) systems are a relatively new advance which give complementary information to HbA1c and home blood glucose monitoring when assessing glycaemic control. Use of the CGM system within the 4-T study will allow detailed comparison of 24 hour glycaemic profiles for each treatment arm.
Aims: The primary objective is to ascertain the proportion of time over 24 hours that each treatment regimen maintains plasma glucose levels within clinically acceptable target levels, that is 4.0 to 5.5 mmol/L inclusive when fasting and between meals, and 4.0 to 7.0 mmol/L inclusive for the 3 hour period after each main meal.
Methods: This is a multi-centred, open-label, randomised, parallel-group design in a subset of patients across each of the three arms of the 4-T main study. Subjects will be blinded to the data. Investigators should not alter insulin treatment as a response to data except in cases of excessive periods of hypoglycaemia. CGM will be performed prior to the end of the first year, and at the end of the study. Subjects will undergo 72 hours of continuous glucose monitoring using a sensor inserted under the skin of the abdomen and connected to a monitor. During the monitoring period, the subjects will be asked to record, meal times, dose times and any symptoms of hypoglycaemia in their study diary.
Main inclusion: All Patients at a subset of 4-T centres were invited to take part. A total of 112 patients were recruited to the study from 17 clinical centres across the UK and Ireland.
Results: The first year results from the CGM study were presented at the 68th ADA.
HOMA Study
Funder: Novo Nordisk
Background: Beta cell function and insulin sensitivity can be measured using the Homeostasis Model Assessment (HOMA) to calculate beta cell function (%B) and insulin sensitivity (%S) from simultaneously measured fasting plasma glucose (FPG), fasting plasma insulin (FPI) and fasting plasma C-peptide (FCP) values. The 4-T study provides a good setting to study the decline of beta-cell function and change in insulin sensitivity with time.
Aim: To validate a modified version of the HOMA calculator which has been designed to determine %B and %S in patients with Type 2 Diabetes when treated with exogenous insulin, to determine if the rate of decline of beta cell function differs by when patients with Type 2 Diabetes are treated with different insulin regimens outlined in the 4-T main protocol, to evaluate the contribution of sulphonylurea therapy to glycaemic control after discontinuation and to examine the relationship of the baseline fasting proinsulin (FPR) to fasting insulin (FPI) ratio on future insulin requirements and changes in beta cell function.
Methods: Fasting plasma glucose, fasting plasma insulin and fasting plasma C-peptide measurements will be performed prior to insulin therapy, three times during, and at the end of the study. Fasting proinsulin will be measured one during the study.
Main inclusion: As this study was added to the main protocol as an amendment, recruitment from the 4-T took place after 10/01/05.
Qualitative Interviews Study
Funder: Diabetes UK
Background: Despite support provided during the 4-T trial, initial data indicate that the HbA1c study target of ≤6.5% was not achieved in the majority of patients and it is proposed that patients’ understanding and health professionals’ guidance of the 4-T trial may be a contributing factor.
Aims : To develop insights into why, across all 3 treatment groups, trial targets for glycaemic control have not been achieved, whether specific aspects of the different insulin therapies affect treatment adherence. Also, to enhance understanding and interpretations of the 4-T study, and to provide recommendations to patients with Type 2 Diabetes to increase compliance and thus good glycaemic control.
Methods: A retrospective design was used, comprising single in-depth interviews with patients and health professionals who have participated in the 4-T trial. Approximately 45 patients, and 15-20 health professionals spanning 11 study centres was interviewed by a designated research fellow.
The interviews covered aspects such as patients’ understanding and experience of the 4-T trial, diabetes self management, treatment adherence and perception of the patients’ role within the trial and quality of life. Health professionals were invited to discuss their involvement with the trial, patient care in the context of 4-T, insulin treatment, patient treatment preference and general difficulties encountered within the 4-T with possible resolutions.
Interviews were then transcribed for in-depth analysis by team members, to identify emerging themes.
Main inclusion criteria: Patients within the 4-T study, stratified to include equal numbers of patients from each treatment group. Health professional recruitment will take place in the same centres as those used for patient recruitment.
