Vol. 17 • Issue 8 • Page 39
Since 1980, the crude prevalence of diagnosed diabetes in the United States has increased more than 132%.1This skyrocketing diabetes rate is associated with a 61% rise in obesity.1For the past decade, type 2 diabetes has been diagnosed more frequently in patients younger than 44.2This changing epidemiology creates clinical challenges because diagnosis of a younger generation leads to a need for lifelong medical management.
Caring for patients with diabetes requires close monitoring of glycemic control and knowledge of the increasing variety of medications used to treat the disease.3
The relationship between diabetes and microvascular and macrovascular complications is well documented, as is the importance of maintaining tight glycemic control to prevent these sequelae.3More obscure is the optimal approach to achieving and maintaining target glycemic levels.
Since publication of the Diabetes Control and Complications Trial results in 1995, hemoglobin A1cmeasurement has been considered the gold standard for assessing glycemic control. However, many patients who demonstrate control by a target A1calso have significant postprandial hyperglycemia, a precursor recently identified as a potential independent risk factor for the development of diabetes complications. A1creflects average glucose levels only, potentially missing important hyperglycemic excursions that may be balanced out by hypoglycemia.2
Biochemical Markers
In recent years, various biochemical markers have been approved by the Food and Drug Administration for the assessment of glycemia. These include self-monitored blood glucose methods and assays for A1cand fructosamine (FA). A key difference between these tests is the time period in which measured values reflect glycemia. Self-monitored blood glucose measurements provide a real-time assessment of ambient circulating glucose but say nothing about the consistency of glycemic control. In contrast, FA and A1cmeasurements reflect time-averaged glycemia from the previous 2 to 3 weeks and in the previous 2 to 3 months, respectively.
As stated, A1cmeasurement, not FA, has been identified in multiple studies as the most valid predictor of complication risk. But despite the widespread use of A1cmeasurements, its slower rate of response to change may contribute to delays in therapy modification.
Thus, a marker that responds rapidly and significantly to changes in glycemia, that demonstrates low biological variability, and that is metabolically stable and can be easily measured would prove more useful in managing patients with diabetes.4
1,5AG
Plasma 1,5-anhydroglucitol (1,5AG) has been proposed as a marker conforming to these criteria. 1,5AG is a naturally occurring dietary polyol that was discovered in the plant family Polygala senega in 1888. Its structure, which resembles glucose, was identified in 1943, and the presence of the compound in human blood and cerebrospinal fluid was established in the 1970s.
During normoglycemia, 1,5AG is filtered and then completely reabsorbed by the kidneys. But if glucose levels exceed 10 mmol/L (the average renal threshold for glucose), plasma 1,5AG levels fall in direct proportion to the severity of glycosuria due to competitive inhibition of glucose for renal tubular reabsorption.5Consequently, 1,5AG responds sensitively and rapidly to changes in serum glucose, reflecting even transient elevations of glucose within a few days.2
ith this in mind, Japanese research groups discovered reduced concentrations of 1,5AG in hyperglycemic patients compared with normoglycemic patients. A gradual normalization of 1,5AG values in patients who responded to antidiabetic therapies has also been demonstrated.
Additional studies have shown that 1,5AG measurements reflect glycemic status over the previous 48 hours to 2 weeks. Based on these early analytic and clinical findings, an automated assay using an enzymatic methodology has been commercially available in Japan since 1991. A U.S. version of this assay, GlycoMark, was cleared for marketing in 2008 as a tool for immediate-term monitoring of glycocemia.6
Evidence for Use
The first U.S. trial of the GlycoMark assay evaluated its ability to respond to and reflect changes in glycemia in a cohort of type 1 and type 2 diabetes patients with suboptimal glycemic control who were being managed aggressively with antihyperglycemic treatments. The researchers sought to determine whether the assay could reflect changes in accordance with A1c This longitudinal 8-week trial compared changes of serum 1,5AG with A1cmeasurements, FA and random serum glucose measurements. Each patient received combination therapy consisting of diabetes education, nutrition counseling and addition or dose adjustment of various insulins or oral antihyperglycemic medications. Therapy was targeted to reduce mean A1cby 1% or more over the monitoring period.4
To determine the degree of concordance between longitudinal changes in 1,5AG and A1c each of the 77 patients was scored based on the direction of change in measured values from baseline (an A1cof 7% or greater) and at 2, 4 and 8 weeks after initiation of therapy. 1,5AG was most closely associated with A1c indicating 100% accordance in these patients. Furthermore, 1,5AG responded rapidly and notably to population-based changes in glycemia, with the first significant change appearing 2 weeks after treatment. In contrast, A1cresponded more slowly. The researchers concluded that both A1cand FA displayed more modest changes than 1,5AG.4
Another study that explored the relationships between mean and fasting glucose demonstrated agreement with the previously summarized study. Researchers examined the role of 1,5AG as an assessment of patients who were in modest control as reflected by A1c to determine postprandial glycemic excursions. Thirty-four patients with type 1 or type 2 diabetes who had an A1cbetween 6.5% and 8% wore a continuous glucose monitoring system for two consecutive 72-hour periods. The researchers compared mean glucose, mean postprandial maximum glucose and area under the curve for glucose (glucose results in the established range for the study) above 180 mg/dL with 1,5AG, FA and A1cat baseline, day four and day seven. They concluded that 1,5AG reflects glycemic excursions, often in the postprandial state, more robustly than A1cor FA.2 Two more recently published studies that examined postprandial glucose values also support the use of 1,5AG.5,7One group of researchers compared the relationship between the glycemic index of 438 patients during a 75-gram oral glucose tolerance test and the insulinogenic index and 1,5AG according to overall glycemic state.5 hey concluded that decreased 1,5AG levels are closely correlated with postprandial hyperglycemia.
The other research group checked self-measured postprandial blood glucose values in 55 patients for correlations with 1,5AG values over 3 days, 1 week and weekly for 12 weeks.5,7 The team concluded that 1,5AG best reflected the 2-hour postprandial glucose values of the 2 previous weeks.
Evidence Against Use
A 1999 study assessed the glucosuria-related urinary excretion of 1,5AG in relation to renal tubular function.8 he researchers aimed to prove or disprove that tubular function affects the urinary excretion of 1,5AG, which could modify its level in patients with diabetes. The team investigated the relationship between urinary excretion of 1,5AG and urinary β2-microglobulin in 21 patients who received an oral glucose load.
Results demonstrated that although urinary 1,5AG was positively correlated with glucosuria during an oral glucose tolerance test in each patient, the glucosuria-related urinary excretion of 1,5AG varied markedly among patients and was associated with renal tubular function.
The study authors proposed that levels may vary among diabetes patients with similar degrees of glucosuria because of individual variation in the urinary loss of 1,5AG per unit of glucosuria. They proposed that 1,5AG level is likely affected by several factors other than glycemic control, and they concluded that renal tubular function should be considered in the clinical application of 1,5AG level as a marker for glycemic control in diabetes patients.8
Putting It Into Practice
In clinical practice, A1cand 1,5AG may be used sequentially. The American Diabetes Association recommends measuring A1cat least twice per year in patients who have met their treatment goals and quarterly in those whose therapy has changed or who are not meeting their glycemic targets.
Thus, A1ccould first be used to identify patients whose glucose levels are moderately or well controlled (A1c6.5% to 8.0%). Then, apply the 1,5AG assay to determine the extent of postprandial glucose excursions. If the A1cis above target and the 1,5AG is normal, therapy targeting basal glucose may be most useful.
On the other hand, if the A1cis above target and the 1,5AG is low, targeting postprandial glucose elevations may be more productive. This hypothesis needs further testing in clinical trials. Future studies with larger sample sizes may show differences between subpopulations. Also, 1,5AG measurement may be less useful in patients with an altered renal threshold for glucose (e. g., intrinsic renal disease and pregnancy).2Although a home test for 1,5AG is in development, the GlycoMark assay is available for laboratory use only. Laboratory services for this assay are available at ARUP Laboratories, Doctors Laboratory, Esoterix Inc., LabCorp, Quest Diagnostics, and Specialty Laboratories. Fasting is not required, and results from off-site labs are usually reported within 1 or 2 days. The CPT code for this assay is 84378, and the average Medicare reimbursement is $16.6
he studies about 1,5AG measurement published so far conclude that this marker reflects postprandial state glycemic excursions more strongly than FA or A1c Therefore, 1,5AG may be useful in conjunction with A1c o assess glycemia in patients with moderate or good control.
With the increasing incidence of diabetes, earlier diagnoses and variations in treatment regimens, the addition of more ways to measure therapeutic effectiveness can only benefit us and our patients. NP
References
1. Centers for Disease Control and Prevention. Crude and age-adjusted percentage of civilian, noninstitutionalized population with diagnosed diabetes, United States, 1980-2006. Available at: http://www.cdc.gov/diabetes/statistics/prev/national/figage.htm. Accessed June 3, 2009.
2. Dungan KM, et al. 1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care. 2006;29(6):1214-1219.
3. Dailey G. Assessing glycemic control with self-monitoring of blood glucose and hemoglobin A1c measurements. Mayo Clin Proc. 2007;82(2):229-235.
4. McGill JB, et al. Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia: a US trial of the GlycoMark Assay. Diabetes Care. 2004;27(8):1859-1865.
5. Won J, et al. 1,5-anhydroglucitol reflects postprandial hyperglycemia and a decreased insulinogenic index, even in subjects with prediabetes and well-controlled type 2 diabetes. Diabetes Res Clin Pract. 2009;84:51-57.
6. GlycoMark. Available at http://www.glycomark.com/about/index.asp. Accessed Jun. 8, 2009.
7. Stettler C, et al. Association of 1,5-anhydroglucitol and 2-h postprandial blood glucose in type 2 diabetic patients. Diabetes Care. 2008;31(8):1534-1535.
8. Fujisawa T, et al. Renal tubular function affects glycosuria-related urinary excretion of 1,5-anhydroglucitol. Diabetes Care. 1999;22(5):863-864.
Jenea Smith is a family nurse practitioner who lives in Jacksonville, Fla. She recently graduated from a family nurse practitioner program.
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