Response to Comments: GlycoMark Testing for Glycemic Control

The LCD author: a) Did not appear to consider evidence from several peer-reviewed publications demonstrating clinical validity of 1,5-AG information; b) Did not address the potential value of a low-cost test that is more specific than other available glycemic control markers; c) Did not address the potential value of 1,5-AG testing to overcome the limitations of other methods of evaluating glycemic control (e.g. hemoglobin A1C, fructosamine/glycated albumin, and self-monitored blood glucose), when used in addition to existing methods for evaluating glycemic control.

The evidence for clinical validity was evaluated. This LCD’s non-coverage determination is based on the absence of the evidence of clinical utility. The clinical utility questions, necessary to meet reasonable and necessary for Medicare coverage, that have not been addressed in the available 1,5-AG literature is: a) Does use of the assay improve patient outcomes? b) Does use of the assay improve the management of patients? c) Does use of the assay change physician recommendations in a way that benefits patients? d) Does the assay provide information for a management decision above and beyond what is available with established clinical and pathological characteristics?

The test developer acknowledges “that a large cohort randomized trial conclusively demonstrating the value of 1,5-AG testing does not currently exist, …, we also believe that supportive evidence for 1,5-AG testing is available, or could be reasonably generated, without requiring a DCCT-type of clinical evaluation.” The commenter requests that the draft policy be re-considered, and request the opportunity to partner with Palmetto GBA to ensure that an appropriate level of access to 1,5-AG testing is available for healthcare professionals and their patients with diabetes.

The contractor will reconsider coverage for 1,5-AG testing when there is published data/studies that address and answer the above clinical utility questions.

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.

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 A_1c ≥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”.

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 between- mean 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 determine the 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.

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?

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 blood 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. For example, physicians may use 1,5-AG measurements from patients with high A1C (> 8%) as a baseline value from which to rapidly judge progression toward improved glycemic control, without waiting months to observe a change in A1C level. This may be especially useful in patients with a history of non-adherence to their treatment program. For patients that are near goal, with A1C levels between 7-8%, the combination of 1,5-AG and A1C might help the physician to identify the presence of persistent hyperglycemia – possibly PPG – that could be further evaluated through structured SMBG or CGM. Additionally, an abnormal 1,5-AG level may prompt the physician to more closely evaluate the patient’s diet and exercise program. For patients with A1C levels that are at goal (< 7%), 1,5-AG measurements may be useful as an adjunct to A1C measurements for identifying deterioration in glycemic control that precedes an elevation in A1C. Within the time necessary for A1C to become elevated in response to a deterioration in glycemic control, significant hyperglycemia and its detrimental effects may have already occurred. Statistically significant associations between the various glycemic control markers are expected, since each is ultimately associated with plasma glucose levels. However, glycated protein and 1,5-AG are not correlated highly enough such that one is a replacement for the other, which is yet another indication that the markers are providing related but unique information. Measurements of glycated protein reflect average glucose levels over a period of time, but 1,5- AG levels are more specifically related to hyperglycemia above the renal threshold, and the goal of diabetes treatment is to manage hyperglycemia. The relationship between 1,5-AG and hyperglycemia is supported, as the authors identify, by several publications comparing 1,5-AG levels and CGM indices. The authors indicate that “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”. We agree that there is a high correlation among all indicators of glycemic control in patients with overtly elevated glucose, because overtly elevated glucose levels will produce abnormal values in all glycemic control markers. However, this clinical circumstance does not consider the unique information and strengths of each glycemic control marker. As with most biomarkers, the target of therapy is to achieve values within the reference range, which are generally consistent with the absence of disease. In the case of 1,5-AG measurements, the reference ranges have been well established for men and women without evidence of hyperglycemia. Additionally, a putative threshold of 10 µg/mL has been proposed in some publications, and 1,5-AG levels above 10 µg/mL have been associated with lower rates of complications of diabetes, with hazard ratios less than 1.0 (Selvin et al Clin Chem 2014; Selvin et al Diabetes 2016). Of note, values above 10 µg/mL are within the reference range for women and are near the lower limit of the reference range for men.

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.

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 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 diabetes- related 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.

Please consider removing CPT® 84999 from the policy.

Agree to remove as this test is to be billed with CPT® 84378

College of American Pathologists submitted a letter expressing their support for non-coverage at this time.

Noridian appreciates this feedback from CAP.