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Response to Comments: GlycoMark Testing for Glycemic Control

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Response to Comments: GlycoMark Testing for Glycemic Control
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Response to Comments
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03/06/2017
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The following are comments received by CGS Administrators during the open comment period, 11/16/2016 to 01/03/2017,  for DL36906 GlycoMark Testing for Glycemic Control.

Response To Comments

Number Comment Response
1 We appreciate CGS’ willingness to consider coverage of the GlycoMark® Test for Glycemic Control. Reported studies supporting its use are few, have small numbers of patients, and have only rarely been correlated with other markers of recent glycemic control such as frequent self-monitoring or continuous monitoring of plasma glucose levels. Therefore, given the lack of evidence at this time, we support the non-coverage decision Thank you.
2 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” Comment: In order to control hyperglycemia, especially PPG, one needs to identify PPG. The physiological basis for relationship between abnormally low 1,5-AG levels and hyperglycemic excursions about the renal threshold uniquely positions 1,5-AG as a marker of recent hyperglycemia, over the prior 1-2 weeks (Buse et al, Diabetes Technol Ther 2003; Yamanouchi and Akanuma, Diabetes Res Clin Pract 1994). Measurements of glycated proteins such as A1C and fructosamine or glycated albumin are indicators of average glucose levels over the prior 2-3 months or 2-4 weeks, respectively. While measurements of average glucose levels are useful in the management of diabetes, they are not able to distinguish between an average glucose level with low glycemic variability, and an average glucose level with high variability (Derr et al, Diabetes Care 2003). Glycemic variability is characterized by hyperglycemic excursions offset by lower glucose levels, which may or may not be associated with hypoglycemia. Considering these limitations of markers related to average glucose levels, 1,5-AG is an ideal marker to help physicians identify hyperglycemia associated with glycemic variability. An added advantage of 1,5-AG in this context is that it overcomes the limitations of self-monitored blood glucose (SMBG) measurements, which must be perfectly timed to capture hyperglycemia associated with PPG and glycemic variability, yet does not carry the significant cost associated with continuous glucose monitoring (CGM), another useful tool for identification of PPG and glycemic variability. Another important point raised by the authors is that A1C is related to hemoglobin glycation over the erythrocyte lifespan. Accordingly, hundreds of hemoglobinopathies and other factors affecting erythrocyte lifespan can affect the ability of A1C to accurately reflect glycemic control (Smaldone, Diabetes Spectrum 2008; Hirsch et al Diabetes Techol Ther 2012). The incidence of factors known to influence A1C is thought to affect more than 9% of potential A1C measurements, and one condition known to affect the ability of A1C to reflect glycemic control, iron deficiency, has a prevalence in women of nearly 14% (Wright and Hirsch, Diab Spectrum 2012; Hirsch et al, Diabetes Techol Ther 2012). Further, glycated albumin and fructosamine measurements are influenced by protein levels, protein metabolism, and the method for analysis. There is currently no consensus for the standardization of glycated albumin and fructosamine measurements. Because 1,5-AG does not have these limitations associated with measurements of glycated protein, its measurement in association with other measures of glycemic control may be valuable to physicians seeking to obtain a more complete assessment of their patient’s overall glycemic control. The LCD does not disagree that 1,5-AG has potential to be a specific marker to help physicians identify hyperglycemia associated with glycemic variability. The ability of the test to identify glycemic variability is not the issue. To address the Medicare reasonable and necessary requirement, it is incumbent for the test developer to demonstrate how the physician is to use the test to improve patient outcomes, or change management of patients based on the test results. The developer has to show through published data how 1,5-AGs “measurement in association with other measures of glycemic control may be valuable to physicians seeking to obtain a more complete assessment of their patient’s overall glycemic control.” A randomized, prospective controlled trial would demonstrate that the therapeutic intervention (end points that are widely considered to be clinical appropriate by the medical community) based on the 1,5-AG test results leads to statistically and clinically significant improvement in patient outcomes compared to a currently accepted standard of care, with the trial adequately powered to address the outcome of the intervention based on the test.
3 “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.3,4,5 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 Therole 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” Comment: We agree with the author’s assessment of the link between improving glycemic control and improved outcomes. Accordingly, it has been well established that poor glycemic control is associated with an increased incidence of diabetes-related complications. In their assessment of published evidence supporting the benefit of 1,5-AG measurements in clinical practice, the authors failed to mention two landmark publications demonstrating the association between 1,5-AG and both microvascular as well as cardiovascular outcomes (Selvin et al Clin Chem 2014; Selvin et al Diabetes 2016). Both studies demonstrated a dose-response, where lower 1,5-AG levels were associated with increased occurrence of adverse outcomes, as well as an independent association between 1,5-AG and outcomes. This association is important in light of the association between 1,5-AG and hyperglycemic excursions, which is more specific than the association between A1C and hyperglycemic excursions, and offer a partial explanation to why A1C explained only about 11% of the variation in microvascular complication (retinopathy) risk in the DCCT trial, leaving the remaining 89% attributable to other factors (Hirsch and Brownlee, JAMA 2010). As described earlier, as well as in the following comment, 1,5-AG testing may be useful to help physicians identify and manage hyperglycemic excursions, e.g. PPG, that may not be evident through A1C measurements. The Selvin, et. al. articles suggests an strong association between 1,5-AG and diabetic microvascular and cardiovascular outcomes, and “suggests that 1,5-AG has prognostic value in persons with diabetes and particularly those with Hb A1c =7%”. We note that the authors of this study conclude with this statement - “additional studies are needed to fully evaluate the clinical utility of 1,5-AG in the setting of diabetes management”.
4 “Considerable data indicates that elevated PPG levels, even in the absence of fasting hyperglycemia, increases the risk for CV disease9,10,11 Numerous epidemiological studies have demonstrated a correlation between risk for CVD and both fasting and postprandial plasma glucose levels or A1C values.11 TheUnited Kingdom Prospective Diabetes Study (UKPDS)3,the Diabetes Control and Complications Trial (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 werelandmark 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 essentialto optimize blood glucose levels has been confirmed by randomized controlled trials where therapeutic agents primarily target postprandial hyperglycemia.15,16,17” Comment We emphatically agree with the statements above, about the need to control post-prandial hyperglycemia, especially with the objective of achieving A1C targets <7%. In addition to the evidence described, this also is consistent with Monnier et al (Diabetes Care, 2003), which report that PPG has a greater influence on A1C levels as A1C levels decrease, with a substantially greater effect as A1C levels approach treatment goals of 7%. The fundamental goal of all treatment programs for diabetes, regardless of whether the treatment includes medical management, is to avoid hyperglycemia without causing hypoglycemia. Hyperglycemia is associated with glucose levels above the renal threshold, generally considered to be an average of 180 mg/dL. When glucose levels exceed the renal threshold, excess glucose is eliminated through urine, and urinary glucose (glycosuria) is a classical indicator of diabetes. As described later, 1,5-anhydroglucitol (1,5-AG) levels are directly related to hyperglycemia above the renal threshold in a dose-dependent manner, because glucose eliminated through urine competitively blocks re-absorption of 1,5-AG into the bloodstream. Again, to control PPG, one must be able to identify PPG. Currently, the most reliable methods for identifying PPG are SMBG and CGM. However, there is between-individual and betweenmean variability in the timing of peak glucose levels after meals, which makes it very difficult to time SMBG measurements accurately enough such that the peak glucose level is captured. CGM is an effective but extremely costly method for measuring PPG. 1,5-AG measurements are useful for the identification of PPG when used in combination with A1C. As A1C levels fall below 8%, the contribution of PPG to the A1C level becomes substantially greater than the contribution of basal glucose levels. Therefore, an abnormal 1,5-AG level (below the reference range), combined with an A1C result at or near goal suggests the presence of recent PPG within the prior 1-2 weeks. 1,5-AG levels have been shown to change more rapidly than A1C in response to changes in glycemic control (McGill et al, Diab Care 2004; Yamanouchi et al, Lancet 1996). The ability to rapidly detect changes in glycemic control is valuable when physicians are concerned about patient non-adherence to treatment programs, as well as when physicians want to determinethe effect of a treatment modification without having to wait months to observe a change in A1C. In addition, 1,5-AG correlates better than A1C with CGM indices of hyperglycemia (Dungan et al Diab Care 2006; Wang et al Diab Metab Res Rev. 2012). 1,5-AG may be a useful low-cost tool to identify and manage hyperglycemic excursions (e.g. PPG) without the need for perfectly timed SMBG measurements or more expensive options such as CGM, and to help identify patients with hyperglycemic excursions that may benefit from use of CGM to better understand glucose patterns. The commenter states that “an abnormal 1,5-AG level (below the reference range), combined with an A1C result at or near goal suggests the presence of recent PPG within the prior 1-2 weeks”. An assay has little value if it “suggests” the presence of something or other. Does it or doesn’t it prove/demonstrate PPG? Unless it provides clear evidence, there is no value to testing. Thus, the necessity of clinical utility best demonstrated through a prospective randomized clinical trial.
5 “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)20,21,22 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.” Comment We would like to clarify that 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 under euglycemic conditions, i.e. in the absence of hyperglycemia above the renal threshold, regardless of whether the individual has been diagnosed with diabetes. We would also like to clarify that 1,5-AG levels are related to the magnitude and duration of plasma glucose above the renal threshold (integrated area under the curve) over the prior 1-2 weeks. Accordingly, 1,5-AG levels below the reference range are indicative of glycemic excursions above the renal threshold over the prior 1-2 weeks, which may occur in the fasting state, the post-meal state, or both. Information noted. In other words, the 1,5-AG is cumulative over 1-2 weeks and is not likely to be abnormal with a single glycemic excursion. What does the assay validation show?
6 ”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 withinday 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.23,24,25,26,27,28 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.” Comment Consistent with the author’s assessment, an American Diabetes Association publication, Medical Management of Type 2 Diabetes, describes 1,5-AG measurements as follows: “A relatively new marker, 1,5-anhydroglucitrol (1,5-AG) reflects glycemic excursions, often in the postprandial state, more robustly than A1C and may be useful as a complementary marker to A1C to assess glycemic control in moderately controlled patients with diabetes (A1C<8%).” This is also consistent with a description of 1,5-AG measurements in another American Diabetes Association publication, Medical Management of Type 1 Diabetes: “The GlycoMark bood glucose test measures monosaccharide 1,5-anyhydroglycitol in the blood, which is a specific index of elevated postmeal glucose levels and short-term glycemic control. This test has proven useful in pharmaceutical research, as well as in patient care, when methods are being employed that specifically target glucose instability after meals.” We would like to clarify that 1,5-AG measurements are not only recommended for patients with A1C < 8%. Rather, 1,5-AG measurements provide useful information to the treating physician, regardless of A1C level. The American Diabetes Association publication, Medical Management of Type 2 Diabetes said that 1,5-AG may be useful. It does not say “recommended” or “should be used”. “Putative threshold of 10 µg/mL” is disconcerting when values above this level are within the reference range of women and near the lower limit of reference range for men.
7 “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.” Comment We respectfully disagree with the conclusion that the data supporting use of 1,5-AG measurements is based on correlations with other glycemic markers but not specific to the intended use population. The publications supporting use of 1,5-AG measurements is from the intended use population – patients with diabetes. The published evidence proves that 1,5-AG levels are specifically related to hyperglycemia above the renal threshold (as evidenced by 1,5-AG physiology and correlations with CGM parameters), and that the information provided by 1,5-AG measurements is independently associated with complications of diabetes. The authors are correct that correlations have been established between 1,5-AG and other markers of glycemic control. These correlations are statistically significant, but are not high enough such that one marker can be a perfect replacement for another. Because all validated biomarkers of glycemic control are inherently related to glucose levels, one would expect to observe a statistically significant correlation among them. However, each biomarker provides unique information that, when used together, can provide a more complete picture of the patient’s overall glycemic control. For example, A1C is an indicator of average glucose levels over the prior 2-3 months. Glycated albumin and fructosamine indicate average glucose levels over the prior 2-4 weeks. 1,5-AG indicates hyperglycemic excursions above the renal threshold over the prior 1-2 weeks. The 2-hour post prandial blood glucose measurement is also not an absolute indicator of the degree of post-prandial hyperglycemia, as there is variability in the time to peak glucose from meal-to-meal and individual-to-individual. According to Standards of Medical Care in Diabetes – 2016, “postprandial glucose measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes” (Table 5.2, page S43). This provides further evidence that the interval between the meal and peak plasma glucose is not constant among diabetic patients. Such variability will undoubtedly affect the correlation between 1,5-AG levels and a 2-hour post prandial glucose measurement. Finally, the 2-hour post prandial glucose measurement does not account for inter-individual variation in the renal threshold, which may be an advantage of 1,5-AG measurements due to its inherent relationship with the glucose renal threshold. We agree with the authors that there are no definitive guideline recommendations about the use of alternative glycemic control markers. However, this limitation exists not only for 1,5-AG, but also other measurements of glycated protein such as fructosamine and glycated albumin, which still enjoy Medicare reimbursement despite their limitations, evolving evidence, and lack of definitive guideline recommendations. We believe that reimbursement for low-cost evolving measures of glycemic control should be maintained, facilitating their access to progressive physicians that choose to treat their patients through a more complete assessment of glycemic control. Access to other markers of glycemic control are needed to provide more complete GlycoMark comment: Draft LCD DL36906 15 December 2016 information for optimization of treatment and assessment of efficacy (Kohnert et al, World J Diabetes 2015). The link between improved glycemic control and improved outcomes in patients with diabetes is clear. The prevention of diabetes-related complications is directly related to controlling glucose levels, specifically hyperglycemia. All diabetes treatment is focused on eliminating hyperglycemia without producing hypoglycemia. 1,5-AG is a clinically useful complement to estimates of average glucose levels obtained through A1C measurements because 1,5-AG is associated with hyperglycemia above the renal threshold. Importantly, the information provided by 1,5-AG measurements has been shown to be independently associated with diabetes-related complications, which represents a clinical validation that the information about glycemic control provided by 1,5-AG measurements is unique. Because the information provided by 1,5-AG measurements is directly linked to hyperglycemia - the physiological target of all diabetes treatment programs – and hyperglycemia as identified by 1,5-AG levels is independently associated with complications of diabetes, why is it necessary to prove, again, that management of hyperglycemia is important for improving outcomes of patients with diabetes? A DCCT-like large cohort study demonstrating that control of hyperglycemia, as identified by 1,5-AG measurements, improves clinical outcomes would be redundant, and add little to the existing evidence supporting the goal of diabetes treatment – the reduction and control of hyperglycemia. Such studies would also be prohibitively costly and extremely difficult, if not impossible to control due to the inherent individualized nature of effective diabetes management. A controlled study would require that physicians follow a pre-specified decision and treatment algorithm, which may not be appropriate for all patients with diabetes. 1,5-AG levels have already been shown to correlate with CGM hyperglycemia parameters better than other intermediate-term and long-term glycemic control markers. 1,5-AG levels have also been shown in long-term clinical outcome studies to be independently associated with diabetesrelated complications, in a dose-dependent manner (Selvin et al, Clin Chem 2014; Selvin et al, Diabetes Care 2016). 1,5-AG levels have been used as endpoint measures for assessing the effectiveness of diabetes treatments (Inagaki et al, Clin Ther 2012; Kadowaki et al, J Diab Invest 2013; Edelman et al, Diab Care 2014; Diamant et al, Lancet Diab Endocrinol 2014). 1,5-AG levels respond faster than other markers of glycemic control in response to changes in glycemic control (McGill et al, Diab Care 2004; Yamanouchi et al, The Lancet 1996). A1C is a standard measure of the overall quality of glycemic control, and changes in 1,5-AG levels have been shown to precede changes in A1C levels, both as glycemic control deteriorates as well as when it improves. The value in identifying possible deteriorations in glycemic control, such as those caused by patient non-adherence to treatment programs, cannot be excluded. Therefore, 1,5- AG measurements may be useful for physicians to maintain a “good” A1C level, as it would be possible to identify significant hyperglycemia before a deterioration in A1C is observed (Unger Am J Med 2008). Because A1C goals have been established due to the association with improved outcomes, tools that help physicians achieve and maintain an A1C level at goal should be inherently useful. The commenters have failed to identify any publication that demonstrates how 1,5-AG testing improves patient outcomes or improve physician management with defined clinical use pathways or treatment algorithms, and “acknowledges that a large cohort randomized trial conclusively demonstrating the value of 1,5-AG testing does not currently exist”. When such data becomes available in the literature, this policy is subject to reconsideration through the clearly defined process available on this contractor’s webpages. In summary, no changes will be made to the draft LCD. 1,5-AG remains non-covered by Medicare.
8 “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.” Comment According to Pletcher and Pignone (Circulation 2011), there are three fundamental mechanisms where measuring a biomarker in the context of clinical care may improve health: 1) to help a patient understand his or her disease or risk of disease and thereby directly improve quality of life and/or mental health; (2) motivate the patient to make behavioral changes that improve health, such as eating a healthier diet, exercising more, or improving adherence to beneficial treatments prescribed by a clinician; or (3) help a clinician make a better clinical decision (e.g., about use of some treatment) that leads to improved health of the patient. 1,5-AG measurements satisfy all three mechanisms, because 1,5-AG levels have been conclusively demonstrated to be associated with the presence and degree of hyperglycemia above the renal threshold, and reduction of hyperglycemia has been conclusively shown to improve outcomes in patients with diabetes. Another critical consideration is that markers related to average glucose levels are not inherently specific for hyperglycemia. They are unable to differentiate between glucose profiles associated with low variability and those associated with significant variability, often characterized by otherwise hidden glycemic excursions above the renal threshold. The unique characteristics of 1,5-AG make it a useful complementary tool with standard measures of glycemic control, particularly A1C and SMBG. 1,5-AG measurements provide physicians with a low-cost indication of recent (1-2 week) hyperglycemia above the renal threshold, without the influence of measurement timing that affects the practicality of SMBG, and the various factors that affect the ability of A1C to accurately reflect average glucose levels. We understand that cost and cost-effectiveness alone is not an appropriate criterion for the determination of coverage. However, when comparing the National limit from the 2016 Medicare Clinical Laboratory Fee Schedule, a monthly $15.70 reimbursement for CPT 84378 compares favorably with 30x $4.32 = $129.60 for once-daily SMBG measurements (CPT 82948). This demonstrates that clinically relevant information obtained by 1,5-AG testing can be obtained at a cost below other common, covered markers of glycemic control. We are not suggesting that 1,5-AG testing should be a replacement for SMBG. Rather, the intent is to demonstrate that there is value in a minimum cost of $130 per month for measurements of current glucose levels on a daily basis, and an assessment of recent hyperglycemic excursions can be obtained for a fraction of this cost. Clinical necessity is typically evaluated on an individual basis by the treating physician. If the physician believes that the information provided by 1,5-AG measurements is clinically useful in helping them manage their patient’s diabetes, their access to the test should not be impeded through a denial in reimbursement. A blanket denial in reimbursement of 1,5-AG testing unnecessarily restricts the ability of the treating physician to use a marker that may allow them to overcome some of the limitations of existing tools for managing glycemic control, and it also unnecessarily limits the use of an adjunctive marker that provides unique and useful information for the individualized management of diabetes. Additionally, the draft non-coverage determination represented an incomplete evaluation of the published evidence supporting 1,5- AG measurements, as it did not appear to consider several publications describing the clinical validation and usefulness of 1,5-AG measurements (summary provided in Appendix 2), including the independent association with complications of diabetes. Therefore, we respectfully request that CGS Administrators, LLC reconsider its decision against Medicare coverage for 1,5-AG testing. GlycoMark welcomes the opportunity to work with CGS Administrators, LLC to evaluate all current evidence supporting 1,5-AG testing, to ensure that physicians and appropriate patients have reasonable access to beneficial, novel, and cost-effective tools for monitoring and management of diabetes. A test must first be proven to have analytical and clinical validity, and must, preferably proven prospectively, have clinical utility. Clinical utility means that testing improves patient outcomes and/or changes physician management that results in improved patient outcomes. To repeat the author’s draft LCD 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.
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