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HgbA1c and glucose control: We cannot play it straight with patients

      The article from the Endocrinology group at the VA in Minneapolis has made an attempt to address a very thorny problem and one that periodically confronts clinicians that treat diabetic patients.
      • Hassan Y.
      • Johnson B.
      • Nader N.
      • Gannon M.C.
      • Nuttall F.Q.
      The relationship between 24-hour integrated glucose concentrations and % glycohemoglobin.
      Self-reported fingerstick glucose levels and HgbA1c determinations are both used to adjust glucose lowering therapy. When values for these measures are generally concordant, decisions about treatment are easier than when there is an apparent disparity between fingerstick (capillary) glucose values and the expected glycohemoglobin value obtained at the corresponding visit. Furthermore, fingerstick glucose values may seem to improve or deteriorate without a corresponding change in the glycohemoglobin value.
      Figure thumbnail gr1
      Fig 1Figure 2B modified to show glucose variability for 3 different HgbA1c concentrations.
      Although this study was performed in 4 different patient populations (nondiabetic and diabetic) with different glucose measures (interstitial and plasma glucose) and somewhat different glucose sampling frequencies, it gives some insight into these clinical observations. Perhaps the 2 most striking observations from these data are the variability in mean glucose values versus HgbA1c and the curvilinear relationship between integrated measures of glucose and the corresponding HgbA1c. This is in sharp contrast to the prevalent concept that a tight linear relationship exists between HgbA1c and mean glucose concentrations, in which a HgbA1c of 7% represents a mean glucose of 150 mg/dL and every 1% increase in HgbA1c corresponds to a 30-mg/dL increase in mean glucose. Figure 2B from the article is instructive to illustrate the clinical observations (horizontal lines for 3 HgbA1c values and vertical lines for the mean glucose range have been added for illustrative purposes). Mean glucose values for a typical “normal” HgbA1c of 5% (horizontal solid line) range from 80 to 120 mg/dL, a typical “target” HgbA1c of 7% (hatched line) range from 120 to 180 mg/dL, and a generally typical “elevated” HgbA1c value of 9% (dotted line) range from 180 to 230 mg/dL. Although there are fewer data points for HgbA1c greater than 11%, the scatter for mean glucose values seems to become proportionately greater.
      There are several reasons for variability. Obvious contributors to variability include a concept in which even “continuous” glucose sampling in this study was not truly continuous for the intervals studied or continuous across the full life span of the red blood cell (RBC). Assay variation for HgbA1c determinations also contributes to variability. Rates of protein glycation may not be constant across either the range of glucose concentrations or the RBC life span. In fact, wide glucose excursion versus narrow glucose excursion around the same mean glucose may not result in the same HgbA1c. Tahara and Shima
      • Tahara Y.
      • Shima K.
      Kinetics of hgbA1c, glycated albumin, and fructosamine and analysis of their weight functions against preceding plasma glucose level.
      analyzed glycation kinetics for hemoglobin, albumin, and fructosamine in 9 carefully studied diabetic subjects and reported that glycation rates of hgb are variable among persons. Furthermore, with mathematical modeling, they reported that a weighted mean BG was a better predictor of HgbA1c than the actual integrated mean. Recent BG concentrations had the greatest influence on HgbA1c values with 50% of the effect coming from the most recent month, 25% in the month just prior, and 25% from the 2 months earlier. Similar analyses were not performed in the current study; however, many subjects had BG values that were immediately proximate to the HgbA1c determinations. Other mechanisms may also contribute to the variability (some noted by the authors) including RBC survival, RBC permeability, intracellular glucose transport, osmotic effects, exposure of specific amino acids available for glycation, and perhaps less obvious variables such as nephropathy
      • Cohen R.M.
      • Holmes Y.R.
      • Chenier T.C.
      • Joiner C.H.
      Discordance between HbA1c and fructosamine evidence for a glycosylation gap and its relation to diabetic nephropathy.
      and body mass index.
      • Couturier M.
      • Amman H.
      • Des Rosiers C.
      • Comtois R.
      Variable glycation of serum proteins in patients with diabetes mellitus.
      What are the implications for patients who present with elevated fingerstick values and a near-normal HgbA1c? These data support the concept that treating such patients based on fingerstick glucose values is justified. Conversely, patients who report near-physiologic fingerstick glucose values in the face of an elevated HgbA1c values do not always need to be viewed with suspicion simply because of the apparent lack of correlation in the measures of glucose control.
      The information presented in this article helps us understand the limitations of HgbA1c as a commonly used measure of glycemic control. This article should provide additional impetus for studies that critically analyze alternative measures of integrated glycemic control for patient management. Finally the data suggest that glycation of other proteins may have wide variability and nonlinear relationships when related to the risk for complications of diabetes mellitus.

      References

        • Hassan Y.
        • Johnson B.
        • Nader N.
        • Gannon M.C.
        • Nuttall F.Q.
        The relationship between 24-hour integrated glucose concentrations and % glycohemoglobin.
        J Lab Clin Med. 2006; 147: 21-26
        • Tahara Y.
        • Shima K.
        Kinetics of hgbA1c, glycated albumin, and fructosamine and analysis of their weight functions against preceding plasma glucose level.
        Diabetes Care. 1995; 18: 440-447
        • Cohen R.M.
        • Holmes Y.R.
        • Chenier T.C.
        • Joiner C.H.
        Discordance between HbA1c and fructosamine.
        Diabetes Care. 2003; 26: 163-167
        • Couturier M.
        • Amman H.
        • Des Rosiers C.
        • Comtois R.
        Variable glycation of serum proteins in patients with diabetes mellitus.
        Clin Invest Med. 1997; 20: 103-109

      Linked Article

      • The relationship between 24-hour integrated glucose concentrations and % glycohemoglobin
        The Journal of Laboratory and Clinical MedicineVol. 147Issue 1
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          Objective: Since glycohemoglobin values are widely used clinically as a surrogate for average glucose concentration over an extended period of time, we decided to determine the actual relationship between 24-hour integrated glucose values and percent total glycohemoglobin (%tGHb) in cohorts of people with and without diabetes. Research Design and Methods: In 48 people without known diabetes with known stability of fasting glucose over a 1-year period of time, the calculated 24-hour integrated glucose concentration was compared with their %tGHb.
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