This is a non-coverage policy for the GlycoMark assay (aka
1,5-anhydroglucitol [1,5-AG]; developed by Nippon Kayaku, Co., Ltd).

**Current Diabetes Testing**  
  
Hemoglobin A1C measurement, reflecting hemoglobin glycation over the
erythrocyte life span, is proportional to the mean glucose concentration over
the preceding 2-3 months. A1C testing is recommended by the American Diabetes
Association (ADA) and the European Association for the Study of Diabetes
(EASD) consensus guideline for pharmacotherapy to control hyperglycemia in
type 2 diabetes.1 In addition to A1C, fasting plasma glucose is used by
patients and physicians to monitor diabetes. However, recent evidence strongly
suggests that control of post-prandial hyperglycemia (PPG) may be necessary to
achieve A1C targets <7%.2  
  
Several landmark clinical trials have convincingly demonstrated that
individuals with diabetes are at increased risk of developing microvascular
complications including retinopathy, nephropathy, and neuropathy, as well as
cardiovascular (CV) disease.3-5 The importance of tight glycemic control for
protection against microvascular and CV disease in diabetes was established in
the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes
Interventions and Complications (EDIC) study.6 The role of glycemic control on
microvascular disease in type 2 diabetes was documented in the United Kingdom
Prospective Diabetes Study (UKPDS).7 In addition, improving glycemic control
improves microvascular outcomes, as illustrated by the findings of a meta-
analysis of randomized trials (34,912 participants).8  
  
Considerable data indicates that elevated PPG levels, even in the absence of
fasting hyperglycemia, increases the risk for CV disease.9-11 Numerous
epidemiological studies have demonstrated a correlation between risk for CVD
and both fasting and postprandial plasma glucose levels or A1C values.11 The
UKPDS,3 the DCCT,5 the Action to Control Cardiovascular Risk in Diabetes
(ACCORD),12 and the Action in Diabetes and Vascular Disease: Preterax and
Diamicron Modified Release Controlled Evaluation (ADVANCE)13 were landmark
controlled clinical trials that evaluated the benefits of intensive glucose
control on diabetes complications. Both the DCCT and UKPDS primary
intervention studies also demonstrated long-term macrovascular benefits
(>10-year follow-up).6,14 These studies illustrate that intensive glycemic
control early in the course of diabetes is important in achieving CV benefit
and provides guidance in terms of stratification of patients' target glycemic
control. The fact that postprandial glucose control is essential to optimize
blood glucose levels has been confirmed by randomized controlled trials where
therapeutic agents primarily target postprandial hyperglycemia.15-17  
  
 **1,5-AG Assay**  
  
Measurement of serum 1,5-anhydroglucitol (1,5-AG) is thought to be a useful
index of postprandial hyperglycemia, and is thought to be more robust than
hemoglobin A1C (A1C) or fructosamine (used to evaluate glycemic control over
10-14 days).18,19 There is evidence that glycemic excursions, an aspect of
diabetes control incompletely captured by A1C, may contribute to vascular
damage independently of mean glucose concentration (A1C).20-22 Testing for
1,5-AG has been proposed to be an additional glycemic biomarker to assist
clinicians in the management of glycemic control, particularly in patients
with moderate to near-normal glycemic control to complement frequent self-
monitoring or continuous monitoring of plasma glucose to confirm overall
glycemic control.  
  
The 1,5-AG test measures the blood level of 1,5-anhydroglucitol, a compound
that is ingested in food. Because the compound is not metabolized, a
relatively constant blood level is maintained in individuals with blood
glucose below 180 mg/dL via urinary excretion and reabsorption. In non-
diabetic individuals, the rate of intake of 1,5-AG is matched by the daily
excretion rate such that the serum levels and urinary excretion remain
constant. When a diabetic's blood glucose exceeds 180 mg/dL, 1,5-AG
reabsorption is competitively blocked by glucose and the serum level of 1,5-AG
falls. Serum 1,5-AG decreases until glucose level drops below 180 mg/dL when
1,5-AG reabsorption resumes a steady rate. In brief, 1,5-AG levels are
inversely proportional to the degree of hyperglycemia.  
  
Proponents of serum 1,5-AG claim that testing reflects hyperglycemia over the
past 2 weeks (inter-day excursions) and is recommended by the manufacturer for
use in persons with diabetes and A1C <8% to help identify patients with
frequent hyperglycemic excursions, and may be useful for estimating within-day
glycemic excursion. They specify that serum 1,5-AG correlates with
postprandial hyperglycemia in persons with diabetes and A1C <7% and is stated
to be more strongly correlated with glucose variability as compared to A1C,
fructosamine or glycated albumin over 2 to 3 days in persons with moderate
glycemic control (A1C <8%). Data suggests that 1,5-AG is strongly inversely
associated with A1C and fasting glucose in persons diagnosed with diabetes but
is poorly correlated with fasting glucose and A1C in persons without diabetes.
Multiple publications correlate various 1,5-AG end points with continuous
glucose monitoring and show potentially improved correlation with glucose
fluctuation and A1C in patients with diabetes and A1C <8% than other
biomarkers.23-28 However, the number of studies and the quality of study
correlations is poor. Appropriate clinical targets are unclear, as the
strongest correlations are observed at the highest glucose concentrations,
which suggests that the utility of 1,5-AG may primarily be limited to persons
with overtly elevated glucose.

Level of Evidence:

Quality:  Poor  
Strength:  Poor  
Weight: Minimal

In summary, the data to support the use of this test is based on showing
correlations over short periods with other early glycemic markers (A1C,
fructosamine, or glycated albumin) but is not specific to the intended use
population. Comparative studies do not show that 1,5-AG is as good as a 2-hour
post prandial blood glucose, or alternative biomarker. At the current time,
the relationship of 1,5-AG to long term diabetic complications in a patient
with A1C <8% is unknown. Furthermore, no prospective studies have shown that
managing 1,5-AG in patients with an A1C of 6.5-8% reduces micro- or
macrovascular complications. In addition, there are no definitive guidelines
for using alternative biomarkers as adjuncts to standard markers of glycemia,
such as A1C, fasting glucose, or self-monitoring blood glucose measures. Long-
term prospective studies are lacking, and large cohort studies are warranted
to determine whether alternative biomarkers have potential utility for early
diagnosis, management of diabetes, and prevention of diabetic complications.  
  
Due to the lack of clinical utility, 1,5-AG testing is not reasonable and
necessary for the management of diabetes or the prevention of diabetic
complications, and is not covered by Medicare.