Medicine Section - Continuous Monitoring of Glucose in the Interstitial Fluid

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Measurements of glucose in the interstitial fluid have been developed as a technique of automatically measuring glucose values throughout the day, producing data which shows the trends in glucose measurements, in contrast to the isolated glucose measurements of the traditional blood glucose monitors.  A sensor is placed subcutaneously and continuously measures glucose levels in the interstitial fluid.  The devices are also designed to be used with an insulin pump.  Through a transmitter, the glucose monitor sends glucose readings every five minutes to the insulin pump.  Fingerstick confirmations of the readings are still recommended.

FDA Approval

The following devices have received FDA approval:

• Continuous Glucose Monitoring System (CGMS) (MiniMed) (Medtronic, Inc)
• Guardian CGMS (upgraded version)
• GlucoWatch G2 Biographer with Autosensor (no longer available after July 31, 2008)
• DexCom STS™ (DexCom)
• Guardian® RT (Real-Time) System (Medtronic, Inc)
• FreeStyle Navigator CGM System (Abbott)
• Paradigm REAL-Time System (Medtronic, Inc) – pediatric version
• Guardian REAL-Time System (pediatric version) (Medtronic, Inc) – pediatric version

While continuous interstitial glucose monitoring devices potentially eliminate or decrease the number of required daily fingersticks, it should be noted that, according to the FDA labeling, none of the devices are intended to be an alternative to traditional self monitoring of blood glucose with a home glucose monitor, but rather serve as an adjunct, supplying additional information on glucose trends that are not available from self monitoring. It is hoped that this information on glucose trends will lead to improved antidiabetic regimens and ultimately normalization of hemoglobin A1c (HbA1c) levels with a decreased risk of hypoglycemia.  The optimal control level is an HbA1c of less that 7%. Patients are generally considered near that range when HbA1c is in the range of about 7 to 8%.

Note: This policy only addresses continuous monitoring of glucose in the interstitial fluid. Intermittent monitoring of glucose in the interstitial fluid for up to 72 hours may be considered medically necessary.

Policy/Criteria

1. Continuous monitoring of glucose levels in interstitial fluid as a technique of diabetic monitoring, including real-time monitoring, may be considered medically necessary when the following criteria (A, B, and C) are met:
1. The patient has diabetes requiring treatment with insulin; and
2. The patient uses best practices, including compliance with a regimen including four or more fingersticks per day and adjustment of insulin; and
3. One of the following two criteria is met:
   1. The patient is pregnant, or
   2. The patient has documented recurrent unexplained severe symptomatic hypoglycemia that puts the patient or others at risk.  Severe symptomatic hypoglycemia is generally associated with blood glucose levels less than 50 mg/dl.
2. Other uses in diabetics of continuous monitoring of glucose levels in interstitial fluid, including real-time monitoring, are considered not medically necessary. Uses in conditions other than diabetes are considered investigational.

Scientific Background

Data presented to the FDA advisory committee meeting consisted of studies validating the correlation between the measurements of glucose in interstitial fluid with the blood glucose measurements made with home monitoring devices. (2-4) While the individual values between the two may vary, in general the panel found that the overall trends in glucose levels detected by frequent measurements produced potentially clinically important information. There is some clinical data that the MiniMed CGMS with the implanted sensor improves hemoglobin A1c measurements and decreases the incidence of hypoglycemic episodes in those whose antidiabetic medications and diet were managed based on results of three day continuous monitoring of interstitial fluid glucose. Prior studies have shown that hemoglobin A1c levels are lowest among patients who have the highest frequency of daily blood glucose measurements. (5) The use of trends of daily glucose levels implies a different type of diabetic management compared to traditional methods of serial fingerstick glucose methods. The following clinical applications were suggested by the FDA advisory panels:

• Hypoglycemic episodes can be identified more readily by the use of an alarm in the Glucowatch device. This may be particularly helpful in patients with hypoglycemic unawareness or overnight hypoglycemia. In addition, patients with adequate glucose control as measured by HbA1c may undergo monitoring to ensure that this control does not come at the expense of unrecognized hypoglycemia.
• Unsuspected postprandial hyperglycemia may be detected, which contributes to elevated HbA1c concentrations in patients whose blood glucose readings are considered adequate. Postprandial hyperglycemia has been related to increased cardiovascular risks. Both fast acting insulin (insulin lispro) and fast acting oral hypoglycemics (i.e. repaglinide) may be particularly effective in treating postprandial hyperglycemia.
• The devices may be used periodically to confirm the status of current antidiabetic therapy. Currently some patients may perform 7-9 fingersticks a day on a periodic basis to confirm the success of the diabetic management.
• Patients may use the devices in specific circumstances when the normal routine is upset, i.e. changes in work shifts or while traveling.
• The devices may be used to monitor changes in insulin therapy; i.e. the initiation

The key clinical outcomes regarding the clinical utility of interstitial measurements of glucose, relates to their ability to provide either additional information on glucose levels leading to improved glucose control, or to improve the morbidity/mortality associated with clinically significant severe and acute hypoglycemia or hyperglycemic events.  Because diabetic control encompasses numerous variables including diabetic regimen and patient self-management, randomized controlled trials are important to isolate the contribution of interstitial glucose measurements to the overall diabetic management.

Continuous Glucose Monitoring System (CGMS)

A 2003 TEC Assessment reviewed the published controlled clinical trials and offered the following discussion. (6) At the time four randomized trials had been reported.  The largest of them, enrolling 128 adult patients with type 1 diabetes is available in abstract only. (7) Among the 109 patients completing the three-month trial (there was a 15% dropout rate), there was no statistically significant difference in HbA1c levels.  Mean HbA1c levels in both the control and study groups declined from 9% at baseline to 8.3% at three months.  Similarly, in another randomized study of 75 patients, there was no statistical difference in HbA1c levels after the three-month intervention. (7) The other randomized studies included only 11 and 27 patients, respectively. (8,9)

Tanenberg and colleagues reported on a study of 128 patients randomized to insulin therapy adjustments using data from either the CGMS or self-monitoring of blood glucose (SMBG) using a home glucose monitor over a twelve week period. (10)  At twelve weeks, HbA1c levels and hyperglycemic event frequency and duration did not differ with any statistical significance in the treatment groups.  However, at twelve weeks, events of hypoglycemia (glucose equal to or less than 60 mg/dL) were found to be significantly shorter in the CGMS group than the SMBG group (49.4 +/- 40.8 vs. 81.0 +/- 61.1 minutes per event, p=0.009).  The authors concluded durations of hypoglycemia can be further reduced by adjusting insulin therapy with data from the CGMS rather than using SMBG data alone.  Nevertheless, the biochemically-defined measurements of hypoglycemia (without accompanying evidence of symptoms and/or a clinically significant hypoglycemic event) are not compelling outcomes.  The clinical significance of these test results have not been established, i.e., there is insufficient evidence showing the link between increased duration of asymptomatic hypoglycemia and subsequent clinical outcomes.

Additional studies continue to evaluate continuous glucose monitoring systems. In two separate studies, Lagarde and colleagues and Yates and colleagues found a slight improvement in HbA1c levels using CGMS compared to controls in children with type 1 diabetes. (19, 20) However, the differences did not reach statistical significance (p = 0.13 and p=0.87, respectively). In a European study using a cross-over design, Deiss and colleagues reported that CGMS did not decisively influence glycemic control of the total study cohort of children and adolescents with type 1 diabetes. (21) They suggested that more frequent use of CGMS at shorter intervals may be of greater value. A recent review raised questions about the accuracy of these systems. (22)

The results of the Minimally Invasive Technology Role and Evaluation (MITRE) study were presented at the 2007 ADA 67th Scientific Sessions. (24) This randomized controlled study compared the efficacy of two continuous glucose monitoring devices in patients with insulin-dependent diabetes.  The patients were randomized to the Minimed CGMS (n=102), the Animas Biographer (n=100). Standard control (n=102) or attention control (n=100).  The attention control group was created in an effort to control for the increase in attention from healthcare professionals in the device groups. All of the groups experienced a reduction in mean HbA1c but over time the benefit waned.  At 18 months, the researchers reported that the Biographer had a 1% mean relative decline while the other three groups were 3.9% to 4.6%.  The authors reported the percentage of each group that showed a 12.5% reduction in HbA1c at set times during the 18 months.  The Minimed device had the largest number with that reduction at three months (29%) and the Biographer had the smallest number at 18 months (15%).  The control groups had similar numbers ending at 24% (standard) and 27% (attention) at 18-months. The researchers concluded that CGMS has a small benefit but it does not last and the Biographer had a smaller effect on HbA1c than the CGMS or standard treatments.

A recent systematic review of randomized studies identified 7 studies with 335 patients that fulfilled their inclusion criteria. (25) Study duration varied from 12 to 24 weeks. This review concluded that compared with self-monitoring, CGMS was associated with a non-significant reduction in HbA1c levels and that evidence is insufficient to support the notion that CGMS provides a superior benefit over self-monitoring for HbA1c reduction. There was some indication from this review of improved detection of asymptomatic nocturnal hypoglycemia in the CGMS group.

Murphy and colleagues reported outcomes from  an open-label randomized controlled trial comparing a small patient population of pregnant women with diabetes who received standard antenatal care or antenatal care plus continuous glucose monitoring (CBGM). (29)  No significant differences between the groups were noted in first or second trimester.  However, in the third trimester, HbA1c levels were significantly better in the CBGM group.

Real Time Continuous Glucose Monitoring Systems (Guardian® RT System and DexCom STS™ Continuous Glucose Monitoring System)

One of the cornerstones of long term diabetes management has been monitoring of HbA1c levels, which reflect the mean glucose levels over the previous three months.  However, the availability of continuous glucose monitoring creates the opportunity of studying the relationship between HbA1c levels and patterns of glucose throughout the day, specifically to identify the extreme fluctuations in glucose that may be missed with periodic fingersticks. (11) For example, there ahs been ongoing interest in postprandial glucose levels and their relationship to HbA1c and the vascular complications of diabetes.  These hyperglycemic episodes may be missed using the typical schedule of fingersticks (i.e., fasting, pre-prandial and bedtime).  If it can be shown that postprandial hyperglycemia is an independent risk factor for vascular complications, then further strategies to better manage postprandial glucose levels may be appropriate.  However, the postprandial period is difficult to study with fingersticks due to the prolonged and variable length, but may by better studied with continuous glucose monitoring. (12-15)

Other research has suggested that the complications of diabetes may be mediated through hyperglycemic-induced oxidative stress. (16) Using continuous glucose monitoring, Monnier and colleagues found a linear correlation between oxidative stress and acute fluctuations in glucose levels, including but not limited to the postprandial period.  There was no correlation between oxidative stress and chronic sustained glucose levels.  These avenues of research suggest that managing glucose fluctuations may be a way of reducing the risk of diabetic complications without further lowering HbA1c.  In the accompanying editorial, the author agrees that this is an appealing concept, since lowering of HbA1c levels must be balanced with an increased risk of hypoglycemic events. (17) The editorial concludes by stating that the timing and frequency of self-monitoring necessary to minimize glycemic variability needs to be determined by future investigations.  Additional work is needed to determine the best pharmacologic strategies for minimizing glycemic variability and the increased free radical production it causes.

At the time there were no published randomized trials reporting the long term outcomes comparing continuous glucose monitoring with real time feedback to standard finger stick blood glucose monitoring.  There was one randomized trial of the DexCom STS™ System in 91 insulin dependent patients. (18) Patients were randomized to a control group or display group to gather information on the clinical effectiveness of continuous glucose data and high and low level alarms when compared to a control group where continuous glucose readings were not provided to the patients.  Patients wore the sensors and monitors for three consecutive three day periods (total nine days of monitoring).  The control group was blinded to the glucose data for the nine days and the display group was blinded to the data for the first three day period and unblinded to the data for the last two periods.  Patients took finger stick measurements of blood glucose for calibration and comparative means.  When unblinded the display group was only required to take finger stick measurements to calibrate the system and to confirm hypoglycemia and hyperglycemia alerts.  Outcomes included validation of the STS System glucose readings compared to laboratory measurements, accuracy of the high and low alarm alerts compared to blood glucose measurements, comparison of the number of hypoglycemic and hyperglycemic events, including nocturnal hypoglycemic events in the two study groups.  Real-time sensor values coincided with blood glucose values 95.4% of the time.  When compared with the control subjects, the display group spent 21% less time as hypoglycemic, 23% less time as hyperglycemic, and 26% more time in the target glucose range of 80 to 140 mg/dL. (p=0.001 for each comparison).  Nocturnal hypoglycemia, as assessed at 10:00 PM and 6:00 AM, was also reduced by 38% and 33% respectively (p=0.001) in the display group compared with controls. The study did not document impact on HbA1c levels or overall long term diabetic complications of the patients in the study.

Deiss reported on a 3-month study of 81 children and 81 adults with stable type 1 diabetes who had HbA1c levels of 8.1% or greater. (23) Patients were randomized to continuous real-time monitoring, continuous monitoring for 3 days every 2 weeks, or self-monitoring of blood glucose. At 3 months, 50% of patients with continuous real-time monitoring had a decrease in HbA1c of at least 1% compared to 37% of those with intermittent continuous monitoring, and 15% of controls. These results suggest that continuous glucose monitoring may have potential for improving control in patients with diabetes; however, as the authors note, additional work is needed to determine long-term efficacy, clinical feasibility in patients with varying levels of glycemic control, and effect on rates of hypoglycemia.

In December 2007 the Juvenile Diabetes Research Foundation (JDRF) completed recruitment for a 6-month trial at 10 centers of real-time CGMS in patients with type 1 diabetes. (27) Results of this study, that randomly assigned 322 adults and children with type I diabetes to continuous glucose monitoring or self (home) monitoring, were released in 2008. (28) With HbA1c as the primary outcome measure, there was a significant difference among patients 25 years of age or older that favored continuous monitoring (mean HbA1c difference 0.53%), while the difference between groups was not statistically significant for those age 15 to 24 years or 8 to 14 years. Unlike many prior studies, this study was sufficiently large to detect a meaningful change in HbA1c levels between groups. The population in this study had relatively well controlled diabetes in that entry criterion was glycated Hb of 7 to 10% but about 70% had levels between 7 and 8%; in addition, over 70% of patients were using an insulin pump. No significant differences were noted in rates of hypoglycemic events, but the study was likely not sufficiently large to detect potential differences. The authors also reported that monitor use was greatest in those patients age 25 or older where 83% of patients used the monitor 6 or more days per week.

Combination Real Time Continuous Glucose Monitors and Insulin Pumps (Paradigm®)

Several randomized studies are nearing completion or currently underway.  For example, the STAR I study, sponsored by Medtronic, has randomized a total of 1437 diabetic patients with insulin pumps to receive continuous glucose monitoring devices or standard monitoring for a period of six months.  Outcomes measures include reduction in HbA1c, frequency of hypoglycemia and quality of life.  The STAR 3 study is a similarly designed randomized study focusing on diabetic patients not on insulin pumps.   To date, these studies have not been published.

Guidelines

The 2007 Standards of Medical Care by the American Diabetes Association (ADA) does not mention this technology in the section on assessment of glycemic control. (25) Recommendations in this section are for self-monitoring of blood glucose three or more times daily for patients using multiple insulin injections. The 2008 Standards of Care from the ADA include a recommendation that “CGMS may be a supplemental tool to SMBG for selected patients with type 1 diabetes, especially those with hypoglycemia unawareness.” (26) This recommendation is level E, based on expert consensus or clinical experience. According to the American Association of Clinical Endocrinologists, their guidelines closely reflect the above ADA guidelines. (30)

Summary

In summary, the available studies demonstrate that intermittent glucose monitoring provides a different type of data than results from fingerstick glucose levels. In addition to providing more data points, it also provides information about trends in glucose levels. This additional information is most likely to benefit those patients with type I diabetes who do not have adequate control despite use of current best practices, including multiple (four or more) daily checks of blood glucose.

Continuous monitoring may be considered medically necessary, to provide additional data for management of those who have recurrent unexplained symptomatic hypoglycemia, despite use of current best practices, that puts the patient or others at risk and for pregnant type I diabetics.

Data that demonstrate improved outcomes for devices that allow wireless connectivity between a continuous monitoring device and insulin pump are still lacking.

References

1. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy No. 1.01.20
2. CGMS: FDA Summary of Safety and Effectiveness: www.fda.gov/cdrh/pdf/p980022b.pdf (Verified 03/24/09)
3. GlucoWatch G2 Biographer: FDA Summary of Safety and Effectiveness: www.fda.gov/cdrh/pdf/p990026S008b.pdf (Verified 03/24/09)
4. Tamada JA, Garg S, Jovanovic L et al. Noninvasive glucose monitoring: comprehensive clinical results. J Amer Med Assoc 1999;282:1839-44
5. Evans JM, Newton RW, Ruta DA et al. Frequency of blood glucose monitoring in relation to glycaemic control: Observational study with diabetes database. BMJ 1999;319:83-86
6. BlueCross and BlueShield Association Technology Evaluation Center (TEC) Assessment, Use of Intermittent or Continuous Interstitial Fluid Glucose Monitoring In Patients with Diabetes Mellitus, 2003; Vol 18, Tab 16
7. Bode B, Lane C, Levetan J et al. Therapy adjustments based on CGMS data lower HbA1c with less hypoglycemia than blood glucose meter data alone. Abstracts from the American Diabetes Association’s 63rd Scientific Sessions. 2003, #386-P
8. Chico A, Vidal-Rios P, Subira M et al. The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes Care 2003;26(4):1153-7
9. Ludvigsson J, Hanas R. Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study. Pediatrics 2003;111(5 pt 1):933-8
10. Tanenberg R, Bode B, Lane W et al. Use of Continuous Glucose Monitoring System to guide therapy in patients with insulin-treated diabetes: a randomized controlled trial. Mayo Clin Proc 2004;79(12):1521-6
11. Bode BW, Schwartz S, Stubbs HA et al. Glycemic characteristics in continuously monitored patients with type 1 and type 2 diabetes. Diabetes Care 2005;28(10):2361-6
12. Landgraf R. The relationship of postprandial glucose to HbA1c. Diabetes Metab Res Rev 2004;20(suppl 2):S9-S12
13. Manuel-y-Keenoy B, Vertommen J, Abrams P et al. Postprandial glucose monitoring in type 1 diabetic mellitus: use of a continuous subcutaneous monitoring device. Diabetes Metab Res Rev 2004;20(suppl 2):S24-S31
14. Heine RJ, Balkau B, Ceriello A et al. What does postprandial hyperglycemia mean? Diabet Med 2004;21(3):208-13
15. Ceriello A. Postprandial hyperglycemia and diabetes complications: Is it time to treat? Diabetes 2005;54(1):1-7
16. Monnier L, Mas E, Ginet C et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006;295(14):1681-7
17. Brownlee M, Hirsch IB. Glycemic variability: A hemoglobin A1c-independent risk factor for diabetic complications. JAMA 2006;295(14):1707-8
18. Garg S, Zisser H, Schwartz S et al. Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor. A randomized trial. Diabetes Care 2006;29:44-50
19. Lagarde WH, Barrows FP, Davenport ML et al. Continuous subcutaneous glucose monitoring in children with type I diabetes mellitus: a single-blind, randomized, controlled trial. Pediatr Diabetes 2006;7(3):159-64
20. Yates K, Milton AH,  Dear K et al. Continuos Glucose Monitoring-Guided Insulin Adjustment in children and adolescents on near-physiological insulin regimens. A randomized controlled trial. Diabetes Care 2006;29(7):1512-17
21. Deiss D, Hartmann R, Schmidt J et al. Results of a randomized controlled cross-over trial on the effect of continuous subcutaneous glucose monitoring (CGMS) on glycemic control in children and adolescents with type 1 diabetes. Exp Clin Endocrinol Diabetes 2006;114(2):63-7
22. Continuous glucose monitoring. Med Lett Drugs Ther 2007;49(1254):13-5
23. Deiss D, Bolinder J, Riveline JP et al. Improved glycemic control in poorly controlled patients with type-1 diabetes using real-time continuous glucose monitoring. Diabetes Care 2006;29(12):2730-2
24. Newman SP, Hurel SJ, Cooke D et al. A randomized control trial of continuous glucose monitoring devices on HbA1c – the MITRE study. Presented at the American Diabetes Association’s 67th Scientific Sessions.   http://professional.diabetes.org/Abstracts_Display.aspx?TYP=1&CID=54094 (Verified 03/24/09)
25. Chetty VT, Almulla A, Odueyungbo A et al. The effect of continuous subcutaneous glucose monitoring (CGMS) versus intermittent whole blood finger-stick glucose monitoring (SBGM) on hemoglobin A1c (HBA1c) levels in Type I diabetic patients: a systematic review. Diabetes Res Clin Pract 2008; 81(1):79-87
26. American Diabetes Association. Standard of medical care in diabetes – 2007. Diabetes Care 2007; 30 (suppl 1):S4-41
27. American Diabetes Association. Standard of medical care in diabetes – 2008. Diabetes Care 2008; 31(suppl 1):S12-54
28. Tamborlane W, Ruedy K, Wysocki T et al.; JDRF CGM Study Group. JDRF randomized clinical trial to assess the efficacy of real-time continuous glucose monitoring in the management of type 1 diabetes: research design and methods. Diabetes Technol Ther 2008; 10(4):308-19
29. The Juvenile Diabetes Research Foundation CGM Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 2008 Sept 8; 359 [Epub ahead of print]
30. Murphy HR; Rayman G et al. Effectiveness of Continuous Glucose Monitoring in Pregnant Women with Diabetes: Randomised Clinical Trial. BMJ 2008; 337:a1680
31. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice For The Management of Diabetes Mellitus. Endocrine Practice 2007; 13(suppl 1)

Cross References

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