Clinical and Health Affairs
An Overview of Continuous Glucose Monitoring and the Ambulatory Glucose Profile
By Roger Mazze, Ph.D., Bryan Akkerman, and Jeanne Mettner, M.A., B.E.L.S.
■ Managing diabetes is essentially a balancing act, as patients and physicians work together to control blood glucose levels to avoid the symptoms of and long-term organ damage caused by glucose variability—the often unpredictable fluctuations between levels that are too high (hyperglycemia) and too low (hypoglycemia). For years, self-monitoring of blood glucose levels has been the treatment standard. With newer technology, however, continuous blood glucose monitoring (CGM) is now possible. This article describes CGM, presents evidence about its efficacy, and outlines how visual displays of CGM data can improve clinicians’ decisions about therapies.
The goal of treating patients with diabetes is helping them achieve good glycemic control. Landmark trials such as the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study have demonstrated that achieving good glycemic control reduces the risk of comorbidities of diabetes, particularly organ-related complications (eg, heart disease).1,2 The definition of “good glycemic control,” however, is still being debated. Also, research has shown that efforts to maintain an optimal level of control can result in increases in the rate and severity of glucose variability and hypoglycemia.1 Recent evidence suggests that using such summary measures as hemoglobin A1c (HbA1c) and mean blood glucose may be insufficient for characterizing “good” glycemic control, as they do not take into account glucose variability, which many consider to be an important contributor to the development and progression of vascular diseases in people with diabetes.3,4
The association between glucose variability and microvascular/macrovascular disease appears to be that variability leads to overproduction of reactive oxygen species, which damage mitochondria and genomic DNA.2 Furthermore, when hyperglycemia is characterized by oscillations (rapid changes in glucose level), especially during exercise, after meals, and when under stress, oxidative stress and endothelial dysfunction worsen.4-6 Concern that abnormal glucose metabolism increases the risk of irreparable cellular damage that can lead to vascular complications has led some to suggest that glucose variability needs to be a focus of treatment.
Despite the best efforts of both patients and clinicians, glucose variability and hypoglycemia are still frequent complications of diabetes therapy. For decades, clinicians have relied on self-monitoring of blood glucose (SMBG) in order to help prevent hypoglycemic episodes. Research has demonstrated, however, that SMBG has significant flaws. In several studies, investigators compared data from blood glucose monitors that had onboard memory capability with patients’ self-reported data and found underreporting (omission of undesirable values), overreporting (addition of values within target), and imprecise reporting (errors in reporting) in patients’ reports.7-10 In addition, overnight glucose values are generally not measured and thus not represented in an overall glucose profile. Moreover, the fact that each individual chooses when to measure his or her glucose level throughout the day could mean that a measurement may not always include the most useful information.
Technological innovations that have taken place during the last decade now allow for continuous glucose monitoring (CGM), which offers clinicians and patients a more comprehensive view of an individual’s glucose levels. With CGM, an electrochemical sensor smaller than 5 mm in diameter is inserted into interstitial tissue, usually in the abdomen. (In most cases, the sensor can remain in place for three to seven days.11,12)
Readings from the sensor are transmitted wirelessly to a pager-sized receiver worn by the patient. That data, when transferred to a computer for analysis, can show an individual’s glucose patterns throughout the day, including at night and after meals, thereby providing information that is unbiased, complete, and verifiable.
Most CGM systems require that patients disconnect from the monitor and upload results before they can be analyzed. Newer ones allow real-time downloading of data, thus enabling clinicians to immediately intervene in response to the readings.
Advantages
The primary advantage of CGM is that it allows many patients to reduce their HbA1c level without significantly increasing the frequency or severity of hypoglycemic episodes.13 Of the trials14-24 that have been conducted comparing the efficacy of CGM with that of SMBG, all but one24 demonstrated reductions in average HbA1c levels with CGM (ranging from -1.2% to -0.2%). Highlights of these studies include the following:
- In the Juvenile Diabetes Research Foundation CGM study completed in 2008,14 which randomized 322 adults, adolescents, and children with type 1 diabetes to CGM or SMBG, CGM use reduced HbA1c levels 0.5 percentage points in the adult group. Children 8 to 14 years of age in the CGM group were more likely to lower their HbA1c level by at least 10% and achieve an HbA1c level below 7% compared with the control group. Participants in the 15- to 24-year-old CGM group experienced no significant improvements; however, only 30% of patients in this group used CGM at least six days per week, compared with 83% of the patients age 25 and older and 30% of those 8 to 14 years of age.
- Deiss and colleagues15 randomized patients with type 1 diabetes to three months of continuous CGM, biweekly CGM, or intensive insulin treatment with SMBG. The group using CGM for three months experienced a 0.6 percentage point reduction in their average HbA1c levels compared with those doing SMBG; the group doing biweekly CGM experienced no significant improvement in their HbA1c levels.
- In the Sensor-Augmented Pump Therapy for A1c Reduction 3 (STAR-3) trial, Bergenstal and colleagues16 randomized 156 children and 329 adults with type 1 diabetes to either initiate use of a continuous subcutaneous insulin infusion (CSII) pump with CGM or to maintain insulin injections with SMBG. After one year, the adults and children using the pump and CGM decreased their average HbA1c levels by 0.6 percentage points and 0.5 percentage points, respectively, compared with the group doing SMBG and insulin injections.
- In a study of 132 adults and children with type 1 diabetes, Raccah and team found combined use of CSII and CGM to be superior to CSII alone in reducing average HbA1c levels.17
Patients who use CGM have reported improved quality of life. In the late 2000s, Peyrot and colleagues18 published results of a survey administered to 162 patients who used CGM with CSII and to 149 patients who used CSII alone. The group using CGM and CSII responded more positively than the other group to questions about convenience, acceptability of blood glucose monitoring requirements, control efficacy, diabetes worries, and overall satisfaction.18
Disadvantages
Despite studies that show the benefits of CGM, a number of concerns remain:
Questionable accuracy. When compared with actual glucose values measured in plasma, CGM devices can be inaccurate up to 21% of the time,13 particularly during hypoglycemic episodes and during rapid rise and fall of plasma glucose.25 This might be because CGM units measure glucose in the interstitial fluid, not the plasma, and glucose levels in interstitial fluid fluctuate more slowly than those in plasma. The fact that the electrochemical sensor records the glucose level at set time intervals (three minutes to five minutes) may exacerbate the difference. Keenan and team26 reviewed commercially available, minimally invasive CGM units and found that the time lag between blood and plasma glucose levels ranged from three minutes to 12 minutes, while the processing lag with the electrochemical sensor was one minute to two minutes.
Questionable effect on severe hypoglycemia. Although recently published data have shown that CGM is associated with reduced time spent in hypoglycemia,23 the majority of studies have failed to demonstrate that CGM is protective against hypoglycemia.14-22 Specifically—and contrary to what was initially hypothesized—CGM does not seem to prevent severe hypoglycemic episodes; at this point, most studies have not demonstrated that hypoglycemia rates decrease significantly enough with CGM for it to be regarded as superior in lowering hypoglycemia. The inaccuracy of the devices may account for this.
Restricted use. Currently, CGM is used primarily in people with type 1 diabetes. Its application is limited in patients with type 2 diabetes, who account for 90 percent of all individuals with the disease. Research has demonstrated that use of CGM can lead to reductions in HbA1c levels among patients with type 2 diabetes,27,28 but additional trials are needed to establish reliability and validity of CGM in this population.
Cost. The cost of treatment with CGM has been estimated at $4,380 per person per year compared with $550 to $2,740 when using SMBG (depending on frequency of monitoring),29 and it is not typically covered by insurance. In the United States, the only likelihood for reimbursement is in cases where a patient with type 1 diabetes is experiencing severe, frequent hypoglycemia and is not achieving desired HbA1c values with SMBG. Some data, however, indicate the technology can be cost-effective over the long term. In an analysis of people who significantly lowered their HbA1c level through CGM, researchers found that those patients’ quality of life improved both immediately and over the long run, which translated into an “incremental cost-effectiveness ratio” of $98,679 per quality-adjusted life year in those whose HbA1c level remained at 7% or greater and $78,943 per quality-adjusted life year in those whose HbA1c level was less than 7%.30
The Ambulatory Glucose Profile
Although CGM technology may have flaws, it is an improvement over SMBG in that it reveals glucose variability and provides a more accurate view of glucose patterns during a given time period. Recent advances make it even easier to detect underlying glycemic patterns. The International Diabetes Center (IDC) in Minneapolis is conducting multiple ongoing clinical trials of CGM devices using newer data-analysis software. After collecting the data on glucose levels using CGM, IDC researchers connect the CGM device to a computer, download the data, and use software developed by the IDC team that can read data from any device regardless of the manufacturer to perform a statistical analysis of the data and generate a visual report for the clinician, called an ambulatory glucose profile (AGP). Rather than capturing a few isolated glucose readings, the AGP provides a comprehensive view of the patient’s changing glucose levels over the period during which the device was worn, thus allowing the clinician to see patterns and adjust therapy accordingly.
Currently, the AGP software is being used to evaluate the effect of new medications and new combinations of medications and whether achieving normalized glucose patterns can lead to improved health outcomes (primarily the prevention of complications associated with diabetes). The IDC is licensing the use of its AGP software for research purposes. The hope is that by using CGM with the analysis software, researchers can more accurately observe the effects of diabetes medications on HbA1c levels and on the frequency and severity of hypoglycemia.
Figure 1 shows the AGP of a male with type 2 diabetes who wore a CGM device for 30 days. Using the AGP, we can easily interpret that this patient has poor glycemic control both throughout the day and overnight despite his use of medications. The diurnal glucose patterns show that both basal and bolus insulin require adjustments. Interestingly, the patient does have periodic episodes of hypoglycemia lasting up to 100 minutes. Additionally, the AGP shows significant variability especially in the mid-morning hours. A clinician using this report could more accurately determine the proper course of treatment for this patient.
Figure 2 shows the AGP of a woman without diabetes who did CGM for 30 days. The lines are smooth compared with those of the patient with type 2 diabetes, indicating relatively greater stability throughout the day. Interestingly, with CGM we see that even patients without diabetes can have higher and lower glucose levels. The AGP of the person without diabetes provides a good illustration of postprandial rises and overnight dips in blood glucose. The AGP can even be used by providers caring for patients without diabetes so that they can offer advice about diet based on the data gathered.
Conclusion
Treatment decisions are best made using accurate and comprehensive data. Many researchers now believe that CGM can provide such data on patients with diabetes, as CGM provides a more comprehensive view of glucose levels than does self-monitoring. Research has demonstrated that use of the technology can help reduce HbA1c levels without increasing the severity or frequency of hypoglycemic episodes. However, at this point, CGM has not yet consistently been shown to mitigate severe hypoglycemia. Innovations such as the AGP software and computerized treatment algorithms show promise for advancing the therapeutic benefits of CGM while protecting patients from unpredictable, severe hypoglycemia. MM
Roger Mazze is head of the World Health Organization Collaborating Center at the International Diabetes Center and Mayo Clinic and chief academic officer at the International Diabetes Center in St. Louis Park. Bryan Akkerman is a health informatics specialist at the International Diabetes Center’s World Health Organization Technology Lab. Jeanne Mettner is a medical writer and the principal of Minneapolis-based Planetary Ink Editorial Consulting.
References
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86.
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
3. Zaccardi F, Pitocco D, Ghirlanda G. Glycemic risk factors of diabetic vascular complications: the role of glycemic variability. Diabetes Metab Res Rev. 2009;25(3):199-207.
4. Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA. 2006;295(14):1681-7.
5. Humpert PM. Oxidative stress and glucose metabolism—is there a need to revisit effects of insulin treatment? Diabetologia. 2010;53(3):403-5.
6. Ceriello A, Esposito K, Piconi L, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57(5):1349-54.
7. Shamoon H, Mazze R, Pasmantier R, Lucido D, Murphy JA. Assessment of long-term glycemia in type 1 diabetes using multiple blood glucose values stored in a memory-containing reflectometer. Am J Med. 1986;80(6):1086-92.
8. Langer O, Mazze R. The relationship between glycosylated hemoglobin and verified self-monitored blood glucose among pregnant and non-pregnant women with diabetes. Pract Diabetes. 1987; 4(1):32-3.
9. Langer O, Mazze R. The relationship between large-for-gestational-age infants and glycemic control in women with gestational diabetes. Am J Obstet Gynecol. 1988;159(6):1478-83.
10. Zimmet P, Lang A, Mazze R, Endersbee R. Computer-based patient monitoring systems: use in research and clinical practice. Diabetes Care. 1988;11(Suppl 1):62-6.
11. Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, Cuddihy R. Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol Ther. 2008;10(3):149-59.
12. Goldstein DE, Little RR, Lorenz RA, et al. Tests of glycemia in diabetes. Diabetes Care. 2004;27(7):1761-73.
13. Hermanides J, Phillip M, DeVries JH. Current application of continuous glucose monitoring in the treatment of diabetes: pros and cons. Diabetes Care. 2011;34(Suppl 2):S197-201.
14. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Tamborlane WV, Beck RW, Bode BW, et al. Continous glucose monitoring and intensive treament of type 1 diabetes. N Engl J Med. 2008;359(14):1464-76.
15. 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.
16. Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363(4):311-20.
17. Raccah D, Sulmont V, Reznik Y, et al. Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: the RealTrend study. Diabetes Care. 2009;32(12):2245-50.
18. Peyrot M, Rubin RR. Patient-reported outcomes for an integrated real-time continous glucose monitoring/insulin pump system. Diabetes Technol Ther. 2009;11(1):57-62.
19. Hirsch IB, Abelseth J, Bode BW, et al. Sensor-augmented insulin pump therapy: results of the first randomized treat-to-target study. Diabetes Technol Ther. 2008;10(5):377-83.
20. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Effectiveness of continuous glucose monitoring in a clinical care environment: evidence from the Juvenile Diabetes Research Foundation continous glucose monitoring trial. Diabetes Care. 2010;33(1):17-22.
21. O’Connell MA, Donath S, O’Neal DN, et al. Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomized controlled trial. Diabetologia. 2009;52(7):1250-7.
22. Hermanides J, Norgaard K, Bruttomesso D, et al. Sensor-augmented pump therapy lowers HbA1c in suboptimally controlled Type 1 diabetes; a randomized controlled trial. Diabet Med. 4 February 2011. [Epub ahead of print]
23. Battelino T, Phillip M, Bratina N, et al. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care. 2011;34(4):795-800.
24. Cooke D, Hurel SJ, Casbard A, et al. Randomized controlled trial to assess the impact of continuous glucose monitoring of HbA(1c) in insulin-treated diabetes (MITRE Study). Diabet Med. 2009;26(5):540-7.
25. Wentholt IM, Hoekstra JB, DeVries JH. Continuous glucose monitors: the long-awaited watch dogs? Diabetes Technol Ther. 2007; 9(5):399-409.
26. Keenan DB, Mastrototaro JJ, Voskanyan G, Steil GM. Delays in minimally invasive continuous glucose monitoring devices: a review of current technology. J Diabetes Sci Technol. 2009;3(5):1207-14.
27. Yoo HJ, An HG, Park SY, et al. Use of a real time continuous glucose monitoring system as a motivational device for poorly controlled type 2 diabetes. Diabetes Res Clin Pract. 2008;82(1):73-9.
28. Cosson E, Hamo-Tchatchouang E, Dufaitre-Patouraux L, et al. Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients. Diabetes Metab. 2009;35(4):312-8.
29. Pham M. Medtronic. Diabetes: sizing the market for real-time, continuous blood glucose monitors from MDT, DXCM, and ABT. 2006. Available at www.research.hsbc.com/midas/Res/RDV?p=pdf&key=ate2b8rygn&name=127057.PDF. Accessed July 13, 2011.
30. Huang ES, O’Grady M, Basu A, et al. The cost-effectiveness of continuous glucose monitoring in type 1 diabetes. Diabetes Care. 2010;33(6):1269-74.