There are numerous possible reasons why it could be speculated that HbA1c variability may affect complication risk. Of interest are the concepts that both laboratory and clinic evidence suggests that periods of sustained hyperglycemia are 'remembered' (metabolic memory), this in turn is recognized to place patients at greater long-term risk of complications. As such it can be speculated that the detrimental effect of variability in HbA1c may be mediated via the same mechanism as 'metabolic memory' phenomenon.

Aims: To determine whether treatment to one of 2 threshold levels will result in one group of type 2 diabetes patients having the same mean HbA1c but with differing HbA1c variability to that of another and related to markers of oxidative stress, inflammation and microvascular complications. To determine whether a difference in HbA1c variability between the 2 groups will reflect in changes in small nerve fibers assessed with the sensitive method of corneal confocal microscopy and cardiac autonomic function testing. To assess the reproducibility of HbA1c measurement from a whole blood samples initially analyzed and then stored at -80C until the end of the study (2-3 years), as well as storing an aliquot of haemolysate, for reanalysis at the end of the study.

In one arm the investigators will intensify treatment in those with FPG>140mg/dl until their FPG is <90mg/dl, using whatever treatment is clinically appropriate for them, and only intensify it further if their FPG rises to >140mg/dl again. In the other group the investigators will intensify if their FPG is >115 mg/dl until it is <=115 mg/dl and intensify further if >115 mg/dl again. A total of 20 visits within a time frame of 2 and half years will be performed. Visits procedures will include routine biochemistry, eGFR, lipids, fasting glucose, insulin and full blood count, HbA1c, SHBG, hsCRP. EPIC and G-PAQ questionnaires will be collected. Autonomic function testing using deep breathing heart rate variability, and a sensitive measure of small fiber neuropathy using corneal confocal microscopy and a 24 hour urine collection for urinary isoprostanes to measure oxidative stress will be performed, at baseline, 12 and 24 months.

One of the last unanswered question in relation to the influence of glycemic control on diabetes complications is whether increased month-to-month changes in blood glucose (as measured by variability in glycated hemoglobin (HbA1c)) compounds the complication rate and if this can be altered with intervention. Qatar has a high prevalence of diabetes, affecting approximately 23% of the adult population (International Diabetes Federation 2014) that is going to lead to the development of both microvascular and macrovascular complications resulting in the increased morbidity and mortality associated with the disease. The fact that improved glucose control in type 2 as well as type 1 diabetes reduces the risk of microvascular complications is well established. However, more recently it has been demonstrated that the month-to-month variability (the 'rises and falls') in glucose control are also associated with an increased risk of developing these diabetes-associated problems. An individual's long term measure of blood glucose control is represented by the amount of HbA1c measured in the blood. The HbA1c level changes slowly over a much longer period than the constantly fluctuating glucose levels, giving a good indication of overall glucose control in the preceding 2-3 months. What is not known is whether interventions to reduce variability in HbA1c could, in turn, lead to a reduction in diabetes complications. For example even when HbA1c mean is the optimal 7%, there can be high variability in the HbA1c measures (large standard deviation) that may still lead to complications.

This study proposes to gather data to determine whether different treatment thresholds for diabetes in Qatar people have inherently different effects on the variability of HbA1c on a month-to-month basis. By establishing an understanding of how different treatment regimens for hyperglycemia may affect HbA1c variability, this study would then inform on a long term study designed to determine whether interventions to reduce HbA1c variability can reduce micro- or macrovascular complication risk independently of mean HbA1c. If proven, this concept would allow patients to help avoid glycaemia-related vascular complications without having the high potential risk of hypoglycemia that is associated with the current gold standard of diabetes care.

The investigators plan to recruit 150 patients on any glucose lowering medication (HbA1c 7.5-9%), randomize them into one of two treatment threshold groups and test their HbA1c every 6 weeks for 20 visits (visit 1 baseline; therefore 114 weeks) to assess the HbA1c variability of each group. Self-monitored fasting plasma glucose (FPG) measurement will be undertaken 3 times weekly and reported back to the medical team as part of the safety monitoring. Patients will be randomly divided into 2 treatment thresholds. In one the investigators will intensify treatment in those with FPG>140mg/dl until their FPG is <90mg/dl, using whatever treatment is clinically appropriate for them, and only intensify it further if their FPG rises to >140mg/dl again. In the other group Investigators will intensify if their FPG is >115 mg/dl until it is <=115 mg/dl and intensify further if >115 mg/dl again. As such the study will be treatment threshold dependent and therapy independent. This will help circumvent any concern that the drug regimen could complicate the analysis or present a confounder. In practical terms it means the investigators give both groups of patients the same therapy that is intensified according to the treatment threshold with the addition of the same hypoglycemic agents as used in routine clinical practice. Intensifying treatment dose would be undertaken if three consecutive FPG were above the target of 140 or 115 mg/dl. This will be advised by the patient ringing the study coordinator and/or the study coordinator ringing the patient weekly and advising the consultant what the FPG values are for action. It is anticipated that the mean HbA1c will be comparable but the variability of the HbA1c will differ between the 2 populations.

Whole blood samples taken from the recruited patients will be freshly analyzed in a biochemical and HbA1c analyzer. Following this the samples and an aliquot of haemolysate will be stored at -80C for 2-3 years (the duration of the study), when they will be reanalyzed at the completion of the study and the results will be compared with the measurements prior to storage.

All patients entering the study will be assessed by a dietician at Hamad hospital and advised how to complete the food frequency questionnaire that was devised for an Arab population and based on EPIC. It will be completed every six weeks at the time that the HbA1c is taken. Patients will also be asked to fill in the WHO Global Physical Activity Questionnaire (G-PAQ) that has been translated into Arabic and will be collected on a six weekly basis.

Measurement of the serum lipids (total cholesterol, HDL), inflammatory marker (hsCRP) will be undertaken every 6 weeks when the HbA1c is measured. Twenty four hour urinary oxidative stress (urinary isoprostanes by LC/MS) will be measured at baseline, 12 and 24 months. These measures may provide some insight on the mechanism by which HbA1c variability may alter microvascular and macrovascular risk.

Measures for microvascular complications have been included and these include albumin/creatinine ratio and eGFR that will be undertaken every 4 months as a measure for nephropathy. For neuropathy, autonomic function testing using deep breathing heart rate variability, corneal nerve fiber density (CNFD), a sensitive measure of small fiber neuropathy will be performed at baseline, 12 and 24 months under the expertise of Professor Malik who has established the techniques here in Doha.

Recruitment of the patients:

Only Qatari patients will be recruited and the investigators will aim to recruit a gender balance that reflects that of the local eligible diabetes patients until 150 are recruited aged 18-65 years of age. Patients can be on any treatment including insulin as the study is aiming to look at treatment thresholds, rather than actual treatments. This would mean that patients might have additional medication added or substituted in order to reach the necessary threshold of the study. Patients who may be suitable will be given an information sheet detailing the study and asked to contact the designated coordinator within 2 days. After informed consent that will follow"HRP-803 and HRP-802 INVESTIGATOR GUIDANCE - Documentation of Informed Consent", taken by the study coordinator, subjects will be screened against the inclusion and exclusion criteria for eligibility. Should the patient be suitable for inclusion in the study then blood will be withdrawn for HbA1c, routine biochemistry including creatinine, insulin, fasting glucose, fasting lipids, blood for hsCRP and a full blood count at that visit. Urinary albumin/creatinine will also be assessed. Patients would be randomized at that point. Patients will either attend the clinic or have the study coordinator visit their home every 6 weeks to take blood for HbA1c, routine biochemistry including eGFR, lipids, and hsCRP. Urine for urinary isoprostanes will be taken as a measure of oxidative stress. Urinary albumin/creatinine will also be assessed. This will be undertaken for the 20 study visits to assess their HbA1c variability on their two treatment thresholds. A fasting insulin and glucose will be taken at the beginning, at week 60 and at the end of the study as a measure of insulin resistance (HOMA) to determine if there has been a change in insulin resistance over the course of the study. Sex hormone binding globulin (SHBG) as an indirect measure of insulin resistance will also be taken in the event that the fasting bloods cannot be obtained. Assessment of retinopathy by an ophthalmologist and neuropathy will be undertaken at the beginning, mid point and end of the study that fits with current clinical practice. Renal function will be determined every 6 weeks throughout the study by monitoring GFR and measuring urinary albumin/creatinine. Urinary isoprostanes will be measured using LC/MS in a validated assay that is currently in use.

Autonomic function testing using deep breathing heart rate variability, and a sensitive measure of small fiber neuropathy using corneal confocal microscopy to quantify corneal nerve fiber density (CNFD) will be performed at baseline, 12 months and at 24 months (a total of 3 times over the 2 year study period).

Study Visit Schedule

Visit 1:

• Consent, inclusion and exclusion criteria
• Anthropometric measurement
• Baseline bloods: routine biochemistry including eGFR, lipids, fasting glucose, insulin and full blood count, HbA1c, SHBG, hsCRP.
• Urinary measurements. Urinary albumin/creatinine ratio and isoprostane measurement.
• Randomization into one of the two treatment threshold regimes.
• Autonomic function testing using deep breathing heart rate variability and small fiber nerve measurement using corneal confocal microscopy.

Visits 2-10:

Bloods: HbA1c, lipids. Each specimen will be identified and coded as part of the trial. Urinary isoprostanes will be measured in a validated assay that is currently in use.

Visit 11:

Midpoint of the study Anthropometric measurement: Height, Weight, Waist circumference, blood pressure Baseline bloods: routine biochemistry including sGFR, lipids, fasting glucose, insulin and full blood count, HbA1c, SHBG, hsCRP Urinary measurements: urinary albumin/creatinine ratio 24 hour isoprostane measurement, corneal confocal microscopy and autonomic function assessment performed

Visits 12-20:

Bloods: HbA1c, lipids, eGFR, hsCRP. Each specimen will be identified and coded. 24 hour isoprostane measurement, corneal confocal microscopy and autonomic function assessment performed at visit 20.

Autonomic function testing using deep breathing heart rate variability, and a sensitive measure of small fiber neuropathy using corneal confocal microscopy and a 24 hour urine collection for urinary isoprostanes to measure oxidative stress will be performed, these measurements will be performed at baseline, 12 and 24 months.

Inclusion Criteria:

• Qatari subjects only with type 2 diabetes taking any medication.
• HbA1c 7.5-9.0%.
• Body mass index 26-36.
• Age 18 - 65 years of age.
• Recruitment of a gender balance reflecting the local eligible diabetes patients until 150 are recruited.

Exclusion Criteria:

• Patients with anemia or other conditions known to affect the validity of HbA1c measurement e.g. a haemoglobinopathy known to affect the Hamad HbA1c method or renal failure (CKD Stage 5)
• Patients with concurrent illness
• Patients on medication leading to insulin resistance e.g. corticosteroids
• Pregnancy
• Active retinopathy
• Any clinical exclusion for optimal diabetes control
• Hypoglycemic unawareness

This is an randomized open label clinical trial.