Does Glycated Hemoglobin Variability in Type 2 Diabetes Differ Depending on the Diabetes Treatment Threshold Used in the Qatari Population: Implication on Diabetes Complication Risk?
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Determination of the variability of HbA1c (by measurement of standard deviation of HbA1c) between the 2 diabetes treatment thresholds
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
盲法说明
This is an randomized open label clinical trial.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Qatari subjects only with type 2 diabetes taking any medication.
- •HbA1c 7.5-9.0%.
- •Body mass index 26-
- •Age 18 - 65 years of age.
- •Recruitment of a gender balance reflecting the local eligible diabetes patients until 150 are recruited.
排除标准
- •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
研究组 & 干预措施
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: Metformin (Drug)
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: Gliclazide (Drug)
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: Sitagliptin (Drug)
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: Liraglutide (Drug)
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: Pioglitazone (Drug)
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: Dapagliflozin (Drug)
Treatment arm 1
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >140mg/dl
Intervention: intensify treatment until their FBG is <90mg/dl, using whatever treatment is clinically appropriate for them using different interventions (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin), and only intensify it further if their FPG rises to >140mg/dl again.
干预措施: human insulin (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: Metformin (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: Gliclazide (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: Sitagliptin (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: Liraglutide (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: Pioglitazone (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: Dapagliflozin (Drug)
Treatment arm 2
75 Type 2 diabetic patients with a gender balance who will have the intervention if/when their FBG >115mg/dl
Intervention: intensify treatment until FBG is <=115 mg/dl and intensify further if >115 mg/dl again, using what ever clinical treatment is necessary (Metformin, Gliclazide, Sitagliptin, Dapagliflozin, Liraglutide, Pioglitazone, human insulin).
干预措施: human insulin (Drug)
结局指标
主要结局
Determination of the variability of HbA1c (by measurement of standard deviation of HbA1c) between the 2 diabetes treatment thresholds
时间窗: 24-30 months
The primary objective of this study is 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.
次要结局
- Association of the variability of HbA1c (by measurement of standard deviation of HbA1c) to microvascular changes in heart rate variability, corneal nerve fiber density, albumin/creatinine ratio and estimated glomerular filtration rate.(24-30 months)
- Association of the variability of HbA1c (by measurement of standard deviation of HbA1c) to oxidative stress markers measured by urinary isoprostanes and inflammation measured by highly sensitive C-reactive protein.(24-30 months)
- Comparison of HbA1c (percent) for each subject at baseline and following sample storage of 2 years to assess HbA1c measurement stability.(2-3 years.)