Glycaemic Markers in Persons With Type 2 Diabetes on Haemodialysis
Condition: Diabetic Nephropathy Type 2; Type2 Diabetes
MeSH terms: Diabetic Nephropathies; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Observational

Summary: 
      To investigate the correlation between the mean glucose concentration measured by continuous
      glucose monitoring (CGM) and the estimated mean blood glucose from glycated haemoglobin A1c
      (HbA1c) in persons with type 2 diabetes and on chronic haemodialysis. Furthermore, the aim is
      to compare CGM and HbA1c with glycated albumin and fructosamine.
    

Detailed description: 
      Background:

      In persons with diabetes, glycated haemoglobin A1c (HbA1c) is used as a retrospective
      measurement of the patient's estimated mean blood glucose over the past 3 months. HbA1c forms
      in a non-enzymatic pathway when haemoglobin is exposed to blood glucose. The normal range of
      HbA1c and the correlation to the estimated mean blood glucose is determined from studies in
      persons with normal erythrocyte turnover of approximately 120 days and without severe chronic
      kidney disease (CKD). Several smaller studies have shown that HbA1c in persons with type 2
      diabetes and CKD, especially on chronic haemodialysis, is an uncertain marker of the mean
      blood glucose. Generally, studies show that HbA1c underestimate the actual mean blood
      glucose. The reason for a false low HbA1c in persons with type 2 diabetes and with CKD has
      yet to be established. However, it is known that erythropoietin treatment and iron infusion
      increases the erythropoiesis, which results in new non-glycated erythrocytes, and this is
      likely to lower HbA1c. The erythrocyte life span is found to be reduced in persons on
      dialysis, which in combination with blood loss from the dialysis also contributes to a
      reduction in HbA1c. The shorter erythrocyte life span is thought to be due to the toxic
      uraemic environment as well as mechanical damage caused by haemodialysis.

      Objective:

      To investigate the correlation between the mean glucose concentration measured by CGM and the
      estimated mean blood glucose from HbA1c in persons with type 2 diabetes and on chronic
      haemodialysis compared to a control groups of persons with type 2 diabetes and normal renal
      function.

      Method:

      Prospective case-control study over 17 weeks with 40 persons in each group. The case group
      consist of 40 persons with type 2 diabetes and on chronic haemodialysis. The control group
      consists of persons with type 2 diabetes and normal renal function (defined as and estimated
      glomerular filtration rate (eGFR) above 60 ml/min). CGM is performed for a maximum of seven
      days on week 0, 4, 8, 12 and 16 of the study period with simultaneous analysis of glycaemic
      markers (HbA1c, glycated albumine and fructosamine). Each of the first five visit was
      conducted with 3 to 5 weeks interval and the final visit not more than two weeks after the
      final visit. The erythrocyte life span will be measured with an isotope (Crom-51) method in
      both the dialysis group and the control group, to establish if diminished erythrocyte life
      span and falsely low HbA1c is correlated.

      Statistical methods:

      The null hypothesis is that there is no difference between the ratio of total mean glucose
      from CGM and estimated mean blood glucose from HbA1c at week 17 when measured in type 2
      diabetic persons on chronic haemodialysis compared to type 2 diabetic persons with normal
      renal function.

      The alternative hypothesis is that there is a difference in the ratio between the groups
      which in a pilot study of persons with diabetes on chronic haemodialysis was found to be 0.16
      (mean glucose from CGM/mean blood glucose from HbA1c) when compared to persons with diabetes
      with out nephropathy.

      From one of the pilot arms ώ = 0.148 and σ = 0.128 were extracted. The following scenarios
      were considered; β(0) = 0 and β (1) = 0, 0.01, ..., 0.2 and n = 40. For each scenario, 5000
      data sets were simulated in accordance with the above specifications. Each data set was
      analyzed by a mixed linear model with treatment arm as fixed effect and person as random
      effect. The hypothesis β(0) = β(1) was tested at a significance of 5%. The simulated effect
      in each scenario was calculated as the fraction of rejections in the 5000 tests. Datasets
      were simulated in the statistical programming language R (www.r-project.org). The smallest
      difference in the ratio of mean glucose from CGM and mean blood glucose from HbA1c that could
      be detected with a power of 80% based on the likelihood ratio test described above and using
      a 5% significance level was 0.1 for n=40 per arm.
    

Intervention name(s): Continuous glucose monitoring; Glycaemic markers; Erythrocyte life span; Carbon monoxide (CO)-rebreathing method
Intervention type(s): Device; Diagnostic Test; Radiation; Device
Intervention description(s): Continuous glucose monitoring five times over 17 weeks; Measurement of HbA1c by immunoassay (Roche) and chromatography (TOSOH), including glycated albumin and fructosamine.; Erythrocyte life span measured by Crom-51 labelling over 4 weeks; Measurement of total blood volume, plasma volume and erythrocyte volume
Intervention MeSH terms: Carbon Monoxide
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Total of 80 participants with 40 patients in each group.

        Case group: 40 patients on chronic haemodialysis with type 2 diabetes.

        Control group: 40 patients with type 2 diabetes and normal renal function (defined as eGFR
        >60 ml/min and with urinary protein excretion below 0.3g/day (24 hour urine collection) or
        300mg/g (Urinary Albumin-to-Creatinine Ratio).

        The patients are recruited from the department of Endocrinology or Nephrology at
        Rigshospitalet, from Herlev Hospital department of Nephrology, Gentofte Hospital and Steno
        Diabetes Center Copenhagen, Hillerød Hospital department of Endocrinology or Nephrology and
        Roskilde Hospital department of Nephrology.
      
Biospecimen description: 
      Blood samples will be collected for both immediately analyses (basic lab data) and later
      analyses (glycated albumin, fructosamine, HbA1c for immunoassay) and stored for 10 years
      whereafter they will be destroyed.
    
Keywords: HbA1c; Glycated albumin; Fructosamine; Continuous glucose monitoring