The Study to Investigate the Contribution of Basal and Postprandial Glucose to Overall Hyperglycemia in T2DM
Condition: Diabetes, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Observational

Summary: 
      There was no any China mainland data showing the contribution of BBG and PBG to HbA1c in T2DM
      patients treated with OADs using the CGM method. Therefore this study is aimed to investigate
      the contribution of BBG and PBG to HbA1c in Chinese T2DM patients treated with OADs using
      CGMS. It's expected to generate evidence to support the concept of individualized therapy
      when patients are uncontrolled by OADs.
    

Detailed description: 
      Background The current evidence shows that hyperglycemia is one of the important cause of
      atherosclerosis。In the DCCT study[1], comparing with the conventional therapy group
      (HbA1c<9％), the risk of retinopathy, kidney disease and neuropathy was significantly reduced
      in the intensive therapy group (HbA1c<7％). The EDIC study[2] shows that there is a
      reduction(42% p=0.02) in the incidence of cardiovascular event in the intensive therapy group
      and the risk of nonfatal myocardial infarction, stroke, cardiovascular death reduced by 57%.
      (p=0.02). Based on those evidence, we could tell that a continued cardiovascular benefit
      after early intensive glucose control was evident among T1DM patients. Similarly, the UKPDS
      study[3,4] demonstrated that in the newly diagnosed T2DM patients, the incidence of the
      microvascular complication was 25% lower and the cardiovascular complication (include fatal
      and nonfatal MI) was 16% lower in the intensive glucose control group which is coincident
      with the conclusion from EDIC study. The blood glucose of the diabetes patients are consist
      of 3 parts：normal basal blood glucose ,basal hyperglycemia and postprandial hyperglycemia
      which is a further increase based on the basal hyperglycemia[5]. HbA1c is the standard
      indicator for glucose metabolism which is determined by Basal blood glucose (BBG) and post
      prandial glucose (PPG) levels. HbA1c is a risk factor for diabetes vascular lesions has
      become the consensus and UKPDS study shows that increasing HbA1c and fasting blood glucose
      levels maight be associated with the regression of beta cell function , basal hyperglycemia
      is a major cause of diabetic cardiovascular complications[6]. Most previous studies focused
      on HbA1c and FPG level to determine the control of blood glucose[7,8] .But now the
      relationship between PPG increasing and diabetes complications are gradually valued. Evidence
      shows PPG and HbA1c is main predictor of cardiovascular events and all-cause mortality in
      T2DM[9-11] . The contribution of basal and post-prandial blood glucose to overall glycaemia
      is one of point to investigate glucose metabolism impaired. Wenhui Li [12]et al found that
      the relationship between fasting, post-absorption blood glucose and HbA1c level is more
      closely than with PPG. Especially the blood glucose at 8:00 AM is closely related with HbA1c
      (r=0.84), The A1c-Derived Average Glucose study (ADAG) [13]also got the similar conclusion.
      However, some other study shows the relationship between PPG and HbA1c is much more closer
      [14]. The main reason that lead to this argument is the lack of an accepted accurate method
      to assess the contribution of basal and post-prandial blood glucose to overall glycaemia, and
      the contribution is associated with the choice of therapeutic strategy.

      Currently, few studies have been done to investigate the newly diagnosed or treatment-naive
      type 2 diabetes, Only Peter R, et al. found that the contribution of fasting hyperglycemia
      derived from a standardized meal test to excess hyperglycemia increase as glycaemia control
      deteriorates, becoming dominant with an HbA1c in excess of 7.0%. While in the T2DM patients
      treated by OAD, different researchers have concluded differences, such as Monnier et al[5,16]
      found that in the T2DM patients treated by OAD, if HbA1c ≤7%, the relative contribution of
      PPG was around 69.7%, but this proportion decreased gradually accompany with the increasing
      HbA1c. When HbA1c≥10.2%, the contribution of PPG was only 30.5%; Kikuchi et al[17] concluded
      the similar result with Monnier in the T2DM patients of Japan. Riddle et al[18] found that
      when HbA1c≤8%, PPG contributes more to HbA1c, with the deterioration of blood glucose, the
      relative contribution of FPG increased to 70%.

      However, blood glucose fluctuation is affected by many factors such as disease duration, sex,
      diet, food cooking methods and race[19]. Our previous study found compared with NGT, the
      intra-day blood glucose fluctuation was similar in IGR patients, but it had already occurred.
      In the newly diagnosed type 2 diabetic patients, the inter-day and intra-day blood glucose
      fluctuation was significantly increased, besides, the effect of different ratio of
      carbohydrate in the diet was different[20-24] For Asian yellow, there are less research and
      the conclusions are not consistent. Japanese scholars Kikuchi [17]obtained the similar
      conclusion with Monnier, but the study done by Taiwanese researchers [25] show that in the
      good blood glucose control patients, the relative contribution of PPG was up to 70% , but
      with the blood glucose control deterioration, FPG and PPG to its effect is similar, about 50%
      each.

      Until now, the research on the contribution of the BBG and PPG to HbA1c is less, and the
      results are different, May be different from the research methods and the study population.
      At present, all the research use 6.1mmol/L (WHO criteria)or 5.6mmol/L(ADA criteria) as normal
      FBG level (WHO criteria) to calculate the fasting or postprandial hyperglycemia, not
      according to the blood glucose fluctuation curve of NGT population, so that the BBG and PPG
      contribution of HbA1c might be underestimated or overestimated. In addition, Peter and
      Monnier used MTT method which would cause difference result from the T2DM patients in the
      real world .Peter, Monnier, Riddle and Kikuchi monitored the blood glucose by collecting pre
      or postprandial blood sample frequently or SMBG. The contribution of the postprandial glucose
      to HbA1c is underestimated. As the continuous glucose monitoring system (CGMS) is becoming
      more and more widely used, it is considered as a better method to evaluate the contribution
      of BBG and PPG to HbA1c because of the minimizing bias which is resulted of research
      methodology[25]. There was no any China mainland data showing the contribution of BBG and PBG
      to HbA1c in T2DM patients treated with OADs using the CGM method. Therefore this study is
      aimed to investigate the contribution of BBG and PBG to HbA1c in Chinese T2DM patients
      treated with OADs using CGMS. It's expected to generate evidence to support the concept of
      individualized therapy when patients are uncontrolled by OADs.

      Objectives Primary objective is to investigate the relative contribution of BBG and PBG to
      overall glycaemia in T2DM with OAD. The secondary is to investigate the absolute contribution
      of BBG and PBG to overall glycaemia in T2DM with OAD treatment, investigate the correlation
      between overall glycaemia exposure and HbA1c and regression equation of HbA1c to BBG and PBG.

      Sample size According to MONNIER' research, the contribution of PBG to whole day
      hyperglycemia use 6.1mmol/L as base line is： HbA1c<7.3%， 69.7%±4.18%(n=58)；
      HbA1c(7.3-8.4%)，51.34±4.18%(n=58)； HbA1c(8.5-9.2%)，44.18±3.58%(n=58)；
      HbA1c(9.3-10.2%)，40.60±4.78%(n=58)； HbA1c>10.2%，30.5%±3.58%(n=58)； If there are 5 groups, the
      mean CSS is 854.94, SD is 33.55,α=0.05.After enter the SAS 8.01 software, every group has 22
      sizes and totally 110 cases with 5 groups. So more than 132 cases will be enrolled ( rate of
      dropout and withdraw is 20%, the cases will need 110+110×0.2=132).

      One-Way ANOVA

      # Treatments = 5 CSS of Means = 854.94 Standard Deviation = 33.55 Alpha = 0.05

      N per Power Group

      0.800 17 0.850 19 0.900 22 （SAS 8.01 software）

      Because this is exploratory research, so we justified the sample:

      T2DM subjects: the primary endpoint is the relative contribution of FBG. The contribution
      will be calculated by individual subject. A sample size of 60 for each group produces a
      two-sided 95% confidence interval for relative contribution of FBG with a precision of
      approximately ±6.5% when the estimated standard deviation is 25% (refer to previous study),
      so the total subjects of five group is 300.

      Normal glycaemic subjects: a sample size of 100 normal glycaemic subjects produces a
      two-sided 95% confidence interval for AUC with a precision of approximately
      ±0.08d∙mmol∙L-1when the estimated standard deviation is 0.4d∙mmol∙L-1(refer to previous
      study).

      Number of subjects per treatment arm: N (normal glycaemic group)=100; N (T2DM with OADs)=300

      Cases with one of the following reasons should be removed

        -  Misdiagnos

        -  No medication or no regular medication

        -  Irregular diet

        -  No test recording

        -  Using any drug which might interfere the glucose metabolism and mislead the result.

      Study design This is a single center, two groups, cross sectional study.

        -  One group consists of normal glycaemic subjects, N=100.

        -  One group consists of T2DM subjects treated with OADs, N= 300, which will be divided
           into 5 sub-groups by HbA1c level and each sub-group will include 60 subjects
           (HbA1c<6.5%, 6.5-7.0%, 7.0-8.0%, 8.0-9.0%, >=9.0%) CGMS will be used to collect blood
           glucose data. The normal glycaemic subjects will not receive any treatment during this
           study. The T2DM subjects will maintain their previous OADs treatment and no other new
           treatment will be added during this study.

      Relative and absolute contribution will be calculated by two ways:

        -  Refer the methods of Monnier and Riddle to calculate the contribution with WHO normal
           FBG cut point of 6.1 mmol/L

             -  AUC 24h total high glycaemia=the area above the curve of FBG 6.1 mmol/L

             -  AUCPPG=(the area above pre-prandial glucose in a 4-h period after each meal)X3
                meals

             -  AUC BBG= AUC 24h total high glycaemia - AUCPPG

        -  Using the data of the group with normal glycaemic subjects as the basis to calculate the
           contribution (no need to select a normal FBG cut-off point, therefore avoid the
           overestimated or underestimated contribution of FBG due to the conflict of different FBG
           cut-off point in western guideline and China guideline with 5.6 mmol/L and 6.1 mmol/L
           respectively)

             -  AUC24h NGT total=the area above the curve of glucose 0 mmol/L

             -  AUC 24h T2DM total= the area above the curve of glucose 0 mmol/L

             -  Total high glycaemia= AUC 24h total high glycaemia = AUC 24hT2DM total -AUC 24h NGT
                total

             -  AUC PPG==(the area above post-prandial glucose in a 4-h period after each meal)X3
                meals in T2DM patients

             -  AUC BBG= AUC 24h total high glycaemia- AUCPPG

        -  Relative glucose contribution calculation:

             -  Relative contribution of BBG= AUC BBG/ AUC 24h total high glycaemia X100%

             -  Relative contribution of PPG= AUC PPG/ AUC 24h total high glycaemiaX100%

        -  Absolute glucose contribution calculation:

             -  Refer Monnier, et al: Absolute PBG contribution= HbA1c×(AUCPBG/AUCtotal)

             -  Refer Peter, at al: Absolute PBG contribution= [（mean HbA1c-T2DM - mean
                HbA1c-NGT）×AUCPBG/ AUCtotal]; Absolute BBG contribution= [（mean HbA1c-T2DM - mean
                HbA1c-NGT）×（AUCtotal-AUCPBG）/ AUCtotal]

      The contribution with ADA normal FBG cut point of 5.6mmol/L is the same as above.

      Adverse events record and report

        -  Definition: any adverse medical events which happened during the study regardless of the
           relationship with Investigational product

        -  Adverse events information obtain: observed by the physician, reported by subjects. In
           addition ,the physician should ask the adverse events information in every visit

        -  Recording：Time, severity, duration, treatment, and outcome of the adverse event

        -  Standard for determining the severity of adverse events:

             -  llight: does not affect the normal function of subjects.

             -  moderate: to a certain extent affect the normal function of subjects.

             -  severe: significantly affect the normal function of subjects. Timeline

        -  9/1/2015----11/1/2015 previous preparation，apply for ethical approval;

        -  11/18/2015---7/31/2017 Screen subjects in community , complete the subjects who were
           eligible for the trial and to wear 72h continuous glucose monitor systerm;

        -  8/1/2017---11/1/2016 Supplement experiment omission, organize data and data lock

        -  11/1/2017---1/30/2018 Statistical analysis, draw conclusions, the paper writing.
           Complete the report of the project finishing..
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        -  Age 18-75 years old, male or female

          -  Normal glycaemic and normal weight subjects:

               -  Normal results of routine blood and urine tests

               -  Normal kidney and liver function

               -  BMI >=18.5 and <=24.9 Kg/m2

               -  Normal blood lipid profile

               -  Normal blood pressure

               -  Normal OGTT (according WHO 1999 criteria)

          -  T2DM subjects:

               -  Diagnosed according WHO 1999 criteria

               -  Duration of T2DM diabetes>=6 months

               -  Treated with stable regimen of OADs >=3 months

          -  The subjects didn't receive any drug with potential impact on glycemic metabolism in
             the last one month

          -  Will sign the consent form
      
Keywords: post prandial glucose (PPG); basal blood glucose (BBG); overall glycaemia