Role of continuous glucose monitoring for type 2 in diabetes management and research

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Summary

The advent of continuous glucose monitoring (CGM) is a significant stride forward in our ability to better understand the glycemic status of our patients. Current clinical practice employs two forms of CGM: professional (retrospective or ā€œmaskedā€) and personal (real-time) to evaluate and/or monitor glycemic control. Most studies using professional and personal CGM have been done in those with type 1 diabetes (T1D). However, this technology is agnostic to the type of diabetes and can also be used in those with type 2 diabetes (T2D). The value of professional CGM in T2D for physicians, patients, and researchers is derived from its ability to: (1) to discover previously unknown hyper- and hypoglycemia (silent and symptomatic); (2) measure glycemic control directly rather than through the surrogate metric of hemoglobin A1C (HbA1C) permitting the observation of a wide variety of metrics that include glycemic variability, the percent of time within, below and above target glucose levels, the severity of hypo- and hyperglycemia throughout the day and night; (3) provide actionable information for healthcare providers derived by the CGM report; (4) better manage patients on hemodialysis; and (5) effectively and efficiently analyze glycemic effects of new interventions whether they be pharmaceuticals (duration of action, pharmacodynamics, safety, and efficacy), devices, or psycho-educational. Personal CGM has also been successfully used in a small number of studies as a behavior modification tool in those with T2D. This comprehensive review describes the differences between professional and personal CGM and the evidence for the use of each form of CGM in T2D. Finally, the opinions of key professional societies on the use of CGM in T2D are presented.

Introduction

Among the major advances in the field of diabetes has been the development of accurate methods of self-monitoring of blood glucose (BG). The Diabetes Control and Complications Trial which began recruiting in 1983 was the first large clinical trial to use self-monitoring of blood glucose (SMBG) with either a reflectance meter or visual observation of the color changes of a glucose-oxidase embedded strip (Diabetes Control and Complications Trial Research Group, 1993). Although primitive by today's standards, these BG measurements permitted intensive insulin administration. The next advance in glucose measurement technology occurred in 1987 when a biosensor system was developed employing artificial electron acceptors (i.e., electron mediators or redox dyes) instead of oxygen (Clarke & Foster, 2012). The resultant current was read amperometrically, permitting the development of smaller and more accurate BG meters. Subsequent improvements in this technology afforded faster results in devices that require less blood.

Essentially the same glucose-oxidase methodology developed for BG meters has been adapted for use in most continuous glucose monitoring (CGM) systems. The first of these CGM systems using a glucose-oxidase sensor for venous blood was contained in an artificial pancreas system over 40Ā years ago (Albisser et al., 1974). Devices using other methodologies such as microdialysis (Dehennis et al., 2015, Schierenbeck et al., 2013, Valgimigli et al., 2010) and fluorescence (Dehennis et al., 2015) have been developed for both subcutaneous and intravenous use but neither is currently commercially available. The advantage of CGM over SMBG by fingerstick is that CGM displays interstitial glucose readings every 5Ā min. As a result, CGM can show the effects of diet, exercise, medications, sleep, and stress on glucose levels and makes a ā€œvital sign.ā€ With 288 glucose measurements a day, CGM has enabled investigators to develop new metrics of glycemic control that were not feasible with BG monitoring alone. This enhanced our understanding of how diabetes interventions affect glycemic control beyond the surrogate metric for mean glucose, hemoglobin A1C (HbA1C). These include the percent time-in-range, in hypo- and hyperglycemic ranges, the intensity of the hypo- and hyperglycemic excursion (area-under-the-curve), and glycemic variability (e.g., standard deviation [SD], Mean Amplitude of Glucose Excursion [MAGE], continuous overlapping net glycemic action [CONGA], and mean of daily differences [MODD]) within and between days. The value of these glucose measurements was demonstrated by the FDA accepting for labeling purposes the area-under-the-curve of nocturnal low sensor glucose values as the primary outcome metric in the in-home trial evaluating the threshold suspend insulin pump (Bergenstal et al., 2013).

Section snippets

Use cases of CGM

The two major use cases for CGM are professional (retrospective or diagnostic) CGM in which the patient does not see the display in real-time and personal (real-time) in which the patient can observe the changes and also be alerted to values that cross a preset or predicted high or low glucose threshold (Table 1). These use cases apply to patients with both type 1 diabetes (T1D) and type 2 diabetes (T2D) with or without insulin therapy in those with T2D. A new approach to glucose monitoring

Evidence for use of professional CGM in patients with type 2 diabetes

Professional and real-time CGM has been used primarily in patients with T1D and most of the evidence for its benefit is in that group (Floyd, Liebl). However, there has been growing evidence that those with T2D may benefit from the use of this technology by CGM's ability to uncover previously unknown hypoglycemia particularly in those with hypoglycemic unawareness and/or during sleep as well as unrecognized hyperglycemia particularly post-prandially. The evidence for use of professional and

Randomized controlled trials

Several studies (Table 2) have been performed to determine whether or not professional CGM can reduce HbA1C (Allen et al., 2008, Blackberry et al., 2014, Cosson et al., 2001, Leinung et al., 2013, Mohan et al., 2016, Murphy et al., 2008, Pepper et al., 2012, Young et al., 2015). Five randomized controlled trials showed that 3ā€“7Ā days of professional CGM results in improvement in HbA1C (0.6%ā€“2.3%). Two of these involve patients who were not taking insulin. Allen et al. (2008) used the CGM report

Evidence for use of personal (real-time) CGM in patients with type 2 diabetes

There have been a limited number of trials using personal CGM in patients with T2D. In a short-term trial, Garg et al. (2006) studied 91 patients with diabetes which included 15 insulin-requiring type 2 diabetic patients in a randomized controlled trial of 9Ā days of CGM. All patients wore the CGM in professional (retrospective) mode for the first 3Ā days and then were randomly assigned to either personal (real-time) or professional mode for the next 6Ā days. Those who had access to real-time days

Use of CGM in drug research

HbA1C is considered a gold standard for diabetes control as it is a proxy for glycation of proteins in the body and is used as a measurable link between glucose levels potential complications (Diabetes Control and Complications Trial Research Group, 1993). Since it is metric reflecting long-term glycemic control, it is inadequate for measurement of short-term drug response nor does it capture hypoglycemic exposure or the pharmacodynamic and pharmacokinetic responses to agents which are often a

Professional societies' statements on the use of CGM in type 2 diabetes

Four major professional societies have developed positions related to the use of CGM in those with T2D (Table 3). The Endocrine Society recently updated its Clinical Practice Guideline on diabetes technology (Peters et al., 2016). They use the GRADE method for developing recommendations (Andrews et al., 2013, Brozek et al., 2013). This method is used by more than 80 entities including professional societies (Endocrine Society. American College of Physicians), governmental agencies (Agency for

Conclusion

The development of continuous glucose monitoring technology has created an opportunity to improve glycemic control and thereby reduce the complications of diabetes due to its ability to provide robust data not available through SMBG. While initially applied to those with T1D, recent studies have demonstrated that there is a role for its use in both the professional and personal forms in the management of those with T2D. While there is considerable debate among diabetologists about what are the

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    Conflict of interest: Both authors are full time employees of Medtronic Diabetes.

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