The Use of Continuous Glucose Monitoring in Patients with Type 2 Diabetes

Abstract

Since the late 1970s, self-monitoring of blood glucose has been the standard for assessing daily glycemic control. The first continuous glucose monitor became available in 1999. Numerous clinical trials have documented the benefits of continuous glucose monitoring (CGM) in patients with type 1 diabetes mellitus (DM). However, the data supporting the use of CGM in type 2 DM patients are less substantial. This review article examines the clinical evidence for using CGM in patients with type 2 DM. An extensive literature search was performed to identify relevant studies for this review. Articles published in English from 2000 to May 2010 were identified through searches of PubMed and International Pharmaceutical Abstracts databases using the search terms type 2 DM and continuous glucose monitoring. Relevant references were examined for additional articles. The literature search revealed 27 original articles and reviews, 12 of which were included in this review. Five out of the 12 studies reviewed showed a decrease in glycosylated hemoglobin using CGM in patients with type 2 DM. The use of CGM in patients with type 2 DM can improve glycemic control, but other benefits include modification of diet and exercise, detection of unrecognized hypoglycemia, and identification of hyperglycemia excursions.

Introduction

W hen self-monitoring of blood glucose (SMBG) became available to patients in the late 1970s, it offered more accuracy than urine testing, but the effectiveness of SMBG in patients with type 2 diabetes mellitus (DM) who are not on insulin is controversial.¹ Poolsup et al.² concluded a reduction in glycosylated hemoglobin (A1C) was seen when treatment decisions were based on SMBG results. SMBG provides a value for a single point in time but cannot detect glycemic fluctuations during the day. Continuous glucose monitoring (CGM) is the latest technology to offer a detailed look at glycemic control. A tiny, subcutaneous sensor filament measures the glucose concentration of the interstitial fluid. The first CGM system was approved in 1999, but more recent products have increased accuracy and ease of use and offer retrospective or real-time information.

The benefits of intensive glycemic control on microvascular and neuropathic complications are well documented in both type 1 and type 2 DM.^3,4 Current data support the use of CGM in patients with type 1 DM. The Juvenile Diabetes Research Foundation trial published in October 2008 showed that A1C improved in the oldest and youngest patients with type 1 DM when the continuous glucose monitor was used an average 6 or more days per week.⁵ Other clinical data showed improved metabolic control (A1C decrease) in type 1 patients on insulin or pump therapy and using CGM.^6
–8 The aim of this review was to provide a summary of data supporting the use of CGM in patients with type 2 DM.

Methods

An extensive literature search was performed to identify relevant studies for this review. PubMed and International Pharmaceutical Abstracts databases were searched using the terms “type 2 diabetes” and “continuous glucose monitoring.” The search was limited to articles published in English from 2000 to May 2010. Relevant references were examined for additional articles. Studies that evaluated the effect of CGM on clinical outcomes (A1C, hypoglycemia, and glycemic variability) were included. This review focused on adult patients with type 2 DM. Fifteen studies were excluded from this review when CGM was used to review efficacy of medication regimens, confirm accuracy of oral glucose tolerance test, or assess exercise or for specific patient populations (peritoneal dialysis, obstructive sleep apnea).

Results

The literature search revealed 27 original articles and reviews, 12 of which were included in this review. In general, studies evaluating the use of CGM in type 2 DM tend to enroll fewer patients and are of shorter duration than those for type 1 DM, and some do not use the latest glucose sensor technology. A summary of trials included in this review is provided in Table 1.

Table 1.

Summary of Continuous Glucose Monitoring Trial Results

Reference (year)	Patients (n)	Type of diabetes	Treatment	Duration	Device	Results ^a
Yoo et al.⁹	65	2	Insulin+oral agents	12 weeks (3 days once a month for 3 months)	Real-time	↓A1C, BMI, weight, total calories, and time blood glucose>250 mg/dL ↑exercise time
Bailey et al.¹⁰	140	1 and 2 (109/31)	Insulin or oral agents	12 weeks	Real-time	↓A1C
Allen et al.¹¹	52	2	Oral agents only	72 hrs	Blinded	↓A1C, BMI, and SBP ↑activity
Zick et al.¹²	367	2	Insulin+oral agents	8 weeks (72 h pretreatment and then 8 weeks later)	Blinded	↓A1C
						Episodes of hypoglycemia underreported when CGM compared with SMBG
Weber et al.¹³	31	2	Insulin or oral agents	8 weeks (72 h pretreatment and then 8 weeks later)	Blinded	High number of unrecognized hypoglycemia episodes; therapy modification after CGM decreased episodes of hypoglycemia
Chico et al.¹⁴	105	1 and 2 (75/30), type 1 control group (35)	Insulin or oral agents	Baseline for 3 days, then followed up for 2–3 months	Blinded	Higher incidence of asymptomatic nocturnal hypoglycemia in T2DM treated with oral agents
Tanenberg et al.¹⁵	109	1 and 2 (97/12)	Insulin only	12 weeks (3–72-h periods)	Blinded	↓A1C for both CGM and SMBG↓duration of hypoglycemia for CGM
Bode et al.¹⁸	101	1 and 2 (60/41)	Insulin	21 days	Blinded	Despite frequent fingersticks patients were only able to maintain the ADA optimal range less than 30% of the time.
Praet et al.¹⁹	22	2 and without diabetes (11/11)	Oral agents only	24 h	Blinded	Breakfast hyperglycemia ↑total amount of hyperglycemia. Standard measures underestimate the amount of hyperglycemia.
Hay et al.²⁰	25	2 elderly (>65 years)	Oral agents only	Two consecutive 72-h periods 1 month apart	Blinded	Hypoglycemia and postprandial excursions are common in well-controlled (A1C<7.5%) patients treated with SFU.
Garg et al.²¹	91	1 and 2 (75/16)	Insulin only	9 days (3 consecutive 72-h periods)	Blinded and real-time	Real-time↓hypoglycemia and hyperglycemia, ↑time spent in target, and ↓nocturnal hypoglycemia
Garg and Jovanovic²²	86	1 and 2 (69/17)	Insulin only	21 days (3-consecutive 7-day periods)	Blinded and real-time	Real-time↓hypoglycemia and hyperglycemia and ↑time spent in target
						Glycemic improvement across all A1C values

↓=significant decrease;↑= significant increase.

A1C, glycosylated hemoglobin; ADA, American Diabetes Association; BMI, body mass index; CGM, continuous glucose monitor; SBP, systolic blood pressure; SFU, sulfonylurea; SMBG, self-monitoring of blood glucose.

Lifestyle interventions and A1C reduction were the focus of a Korean study using CGM in type 2 DM patients. This was a prospective, open-label, randomized trial of 65 patients with poorly controlled type 2 DM (A1C 8–10%).⁹ Diabetes therapy included oral hypoglycemic agents or insulin or a combination of the two. Patients used real-time CGM for 3 days every month for 3 months or SMBG at least four times a week. Both groups received monthly lifestyle counseling, but the patients in the real-time group were instructed to increase exercise and eat less in response to alarms for hyperglycemia. Medication adjustment was allowed only in response to hypoglycemia. The CGM group had a significant reduction in A1C after 12 weeks (from 9.1±1% to 8±1.2%, P<0.001) compared with the SMBG group. In addition to lower A1C the real-time CGM group had a decrease in postprandial levels, total calorie intake, body mass index, and body weight. Patients in the real-time group also experienced a decrease in the time spent above 250 mg/dL (17.8% when first used to 8.98% when used in the third month, P=0.01). There was also an increase in the time spent in the well-controlled range (80–250 mg/dL), but this was not statistically significant. The authors concluded that real-time CGM was superior to SMBG, but also that the continuous glucose monitor was a useful tool to decrease caloric intake and increase exercise time. These results are opposite to those from studies performed in patients with type 1 DM that documented continuous wear (at least 6 days) was needed to improve glycemic control.

The use of real-time CGM reduced A1C (0.4±0.05%, P<0.0001) in 140 adults with type 1 (n=109) and type 2 (n=31) DM.¹⁰ Seventy-five patients were on continuous subcutaneous infusion, 58 were receiving multiple daily injections, and the remaining seven were treated with oral agents. In this observational study patients wore a CGM device for 12 weeks, and A1C was measured at baseline and weeks 6 and 12. Patients with baseline A1C>9% experienced more reduction in level of A1C (1.4±0.4%), and the episodes of hypoglycemia did not increase for any of the groups.

Allen et al.¹¹ utilized blinded CGM to identify multiple teaching opportunities regarding the effects of diet and exercise on glucose levels. The study randomized 52 sedentary, non–insulin-using individuals with type 2 DM to an intervention (n=27) or control (n=25) group. Both groups received diabetes education and wore the CGM device for 72 h. The intervention group received individual counseling based on their CGM graphs, compared with the control group, which received generic education. A dietary teaching event was defined as a change in glucose level of >20 mg/dL after a meal. An exercise teaching event reflected an increase in glucose levels following sedentary behavior. Participants in the intervention group showed moderate activity increased (P<0.05), systolic blood pressure decreased (P<0.05), and A1C and body mass index decreased (P<0.05). The intervention group participants reported more confidence in maintaining a program of physical activity.

Hypoglycemia

There is an increasing amount of evidence that shows unrecognized hypoglycemia in patients with type 2 DM.^12
–14 Hypoglycemia is an unwanted side effect as therapy is intensified. Severe hypoglycemia increased 3.3-fold during the Diabetes Control and Complications Trial.³

In a multicenter study, Zick et al.¹² demonstrated that episodes of hypoglycemia (glucose values ≤60 mg/dL) were underreported with SMBG in patients with type 2 DM receiving multiple daily injections. Blinded CGM was conducted over a 72-h period at pretreatment and 8 weeks later at post-treatment. The analysis of this multicenter study of 367 patients showed 56.9% experienced hypoglycemia as documented by CGM, but only 26.4% reported hypoglycemia by SMBG. The A1C did decrease over the course of the study from 6.9% to 6.67% at end point (P<0.001).

A study completed in Germany revealed unrecognized and/or nocturnal hypoglycemia in patients with type 2 DM using blinded CGM as opposed to SMBG.¹³ About 20 of the 31 patients were on insulin, and the remainder were taking oral agents. Patients wore the sensor initially and then again 8 weeks later to assess therapy adjustments. There was a significant decrease from 53 hypoglycemic events to 30 with the second monitoring (P=0.047). Other studies have also documented the benefit of CGM in type 2 DM patients to detect hypoglycemia.

Another study in 2003 found a higher incidence of asymptomatic nocturnal hypoglycemia in type 2 DM patients treated with oral agents.¹⁴ A total of 105 patients (40 type 1, 35 type 1 control group, and 30 type 2) were enrolled in the study. Participants with type 1 (n=40) and type 2 (n=30) wore a blinded CGM device for 3 days, and the data were used to modify treatment regimens. Three months after treatment modifications there was a significant reduction (P<0.01) in A1C levels for both the type 1 patients and the type 1 control group. Based on these data the investigators concluded CGM did not show superiority over frequent fingersticks (eight per day) to improve metabolic control in type 1 DM patients. However, the CGM detected unrecognized hypoglycemia in 62.5% of the patients with type 1 DM and 46.6% of the type 2 DM patients. In regard to patients with type 2 DM, asymptomatic hypoglycemia occurred at the same frequency (42.8%) during the day and night, but patients only detected 14.3% of the hypoglycemic episodes. Five of the patients who experienced unrecognized hypoglycemia were taking sulfonylurea in combination with metformin instead of insulin.

A randomized control trial of 109 patients compared CGM (n=51) and SMBG (n=58) in patients treated with insulin. Patients wore blinded CGM for 3 days or checked capillary blood glucose seven times a day (SMBG). In both groups therapy adjustments occurred at visits 3 and 5 after a review of data. The study population was predominantly patients with type 1 DM (n=97), but both CGM and SMBG showed a decrease in A1C after 12 weeks (P<0.001). However, the CGM group spent less time hypoglycemic compared with the SMBG group. The authors concluded that the use of CGM for therapy adjustments allows for improved A1C without increasing the risk of hypoglycemia when compared with SMBG.¹⁵

Glucose variability plays an important role in the development of diabetes complications. Studies suggest that postprandial and sustained hyperglycemia generates oxidative stress. The oxidative stress may cause microvascular and macrovascular complications of diabetes.¹⁶ In the past, clinicians have relied on fasting and premeal glucose values as an indicator of glycemic control and to make therapeutic adjustments. Current literature recommends that postprandial glucose should be included in the assessment for optimal control.¹⁷ CGM allows for the assessment of postprandial levels that are not always apparent with SMBG.

In a multicenter, prospective observational study with type 1 (n=60) and type 2 (n=41) DM patients, Bode et al.¹⁸ used blinded CGM to generate normative values. Patients were monitored for 21 days and blinded to the CGM data. This study revealed that despite frequent fingersticks (nine times per day), subjects were euglycemic (70–180 mg/dL) only 63% of the day. Both type 1 and type 2 DM patients spent less than 30% of the day within the American Diabetes Association optimal range. These data support the need for additional tools to monitor and assess therapy.

A study from the Netherlands compared 11 male patients with type 2 DM with the same number of subjects without diabetes.¹⁹ Results showed standard measurements underestimated the amount of hyperglycemia. The patients with diabetes were treated with oral glucose-lowering agents and experienced significant hyperglycemia (13±2 h over a 24-h period). This study also documented breakfast hyperglycemia as a major contributor to overall elevated glucose levels. Praet et al.¹⁹ concluded CGM was an excellent tool to evaluate glycemic control in patients with type 2 DM.

In 2003 Hay et al.²⁰ published a study that confirmed unrecognized hyperglycemia and hypoglycemia in well-controlled (A1C<7.5%) elderly patients with type 2 DM. A total of 25 patients wore a CGM device for 72 h and then again 1 month later. Twenty patients (80%) experienced hypoglycemic episodes (glucose values<50 mg/dL), and 24 patients (96%) experienced borderline hypoglycemia (50–65 mg/dL). Elevated postprandial levels were recorded after 57% of all meals. The investigators concluded that CGM was a useful tool to detect hypoglycemia and elevated postprandial readings in patients controlled on sulfonylurea with or without metformin.

Garg et al.²¹ demonstrated that insulin-requiring patients with type 1 (n=75) and type 2 (n=16) DM reduced hyperglycemia without increasing hypoglycemia. In this prospective, randomized, controlled trial patients wore the CGM device for 3 days, and this was repeated three consecutive times. During the first period patients did not have access to the data; however, during the second and third periods, patients had real-time information. The use of real-time data improved glycemic excursions with 21% less time as hypoglycemic (glucose values<55 mg/dL), 23% less time as hyperglycemic (≥240 mg/dL), and 26% more time in target (81–140 mg/dL) range (P<0.001 for each comparison).

In a similar study Garg and Jovanovic²² enrolled 86 patients (type 1, n=69; type 2, n=17) on either continuous subcutaneous insulin infusion or multiple daily injections. The patients wore a CGM device for 7 days over three consecutive periods. During the first period patients were blinded to the data and then unblinded during the second and third periods. Data from the blinded segment revealed patients with an A1C>10% had lower glucose levels in the middle of the day and higher levels at night and early morning. The fasting (midnight–7 a.m.) glucose levels improved when using real-time data. The study concluded all patients can benefit from CGM and that a well-controlled patient can improve glycemic control without increasing hypoglycemia. However, poorly controlled patients with a higher baseline A1C showed the most improvement.

Discussion

Current guidelines from the American Diabetes Association and the American Association of Clinical Endocrinologists recognize the benefits of CGM use in patients with type 1 DM. The American Diabetes Association acknowledges the use of CGM as a supplemental tool to SMBG in patients with hypoglycemia unawareness or frequent episodes of hypoglycemia.²³ Excluding patients with type 1 DM, American Association of Clinical Endocrinologists refers to those patients with an unacceptable A1C who may benefit from CGM.²⁴

In a review article, Monnier et al.²⁵ concluded that CGM should be extended to patients with type 2 DM to assist in identifying glucose fluctuations. Clinicians may experience difficulty in explaining postprandial excursions to patients, especially if meter blood glucose readings are all below 200 mg/dL. Hirsch et al.²⁶ advocated the use of intermittent CGM for patients with type 2 DM to understand the reason for changing or initiating therapy. Information obtained from CGM can motivate patients to start or continue lifestyle changes such as exercise and diet. Also, the data from CGM can be used to demonstrate to patients and/or providers the need for insulin therapy earlier in the disease process. In addition, as more patients are diagnosed with type 2 DM and as patients live longer, CGM may be a useful tool for monitoring and adjusting medication regimens. After any change in therapy follow-up CGM can show patients and providers how well their glycemic control has improved or the need for additional changes.

Study limitations

The majority of the studies evaluating CGM use in patients with type 2 DM were not designed to show a reduction in A1C. Only five of the studies reviewed documented a reduction in A1C, and of these five, only three focused exclusively on patients with type 2 DM. Studies of patients with type 2 DM had a smaller sample size than the studies reviewing CGM in patients with type 1 DM. The lack of a control group introduces the Hawthorne effect, where patients are more compliant when they are wearing the device. Of the 12 studies reviewed, only one did not have any type of a control group. Eight of the 12 studies reviewed compared CGM with SMBG, and two studies compared blinded CGM with real-time CGM.

The Hawthorne effect could be a factor for A1C reduction, but not in the documentation of hypoglycemia.

Limitations of this review

Only studies available through the databases listed above and references were taken into consideration. Also, only articles written in English were included. More research on the benefits of using CGM in patients with type 2 diabetes is needed.

Clinical practice

The question to use real-time or blinded professional CGM depends on what type of system or systems the medical office owns and the patients' medication regimen. One system currently available can be used as real-time or blinded, whereas another system only provides the option for blinded use. Patients on continuous subcutaneous insulin infusion or multiple daily injections have more flexibility dosing insulin, and therefore real-time may be preferred for this population. Real-time can also provide the opportunity for a patient to try real-time without personally investing in a system. On the other hand, patients taking oral hypoglycemic agents with or without insulin may benefit from blinded CGM because this group is less likely to adjust medications based on real-time information.

Education and implementation into clinical workflow are some of the barriers to utilization of professional CGM. Providers, office staff, and patients must be educated on how to use and interpret the data. Insurance coverage for CGM in type 2 DM patients continues to improve, but many carriers require preauthorization for the use of professional CGM and set limits on the number per year. Larger trials demonstrating cost-effectiveness and improved outcomes are needed to increase insurance coverage.

Conclusions

This review of studies using CGM in type 2 DM showed a decrease in A1C, modification of diet and exercise, and identification of hyperglycemia excursions. In addition, the literature reviewed clearly established the benefits of CGM in the detection of unrecognized or nocturnal hypoglycemia in patients with type 2 DM. This may be especially beneficial in patients who are fearful of hypoglycemia and allow their blood glucose levels to run high.

CGM has the potential to improve the quality of life for all patients with diabetes by decreasing the number of hypoglycemic events and improving glycemic control. Patients with suboptimal A1C levels, despite multiple medication changes, can now be evaluated with CGM. Because the number of patients with type 2 DM continues to increase, there is a need to improve glycemic control, especially when looking at the financial impact of long-term complications on the healthcare system. The ability to view glucose trends provides endless opportunities to improve glycemic control.

Footnotes

Author Disclosure Statement

L.T.M. was a Presenter for Medtronic Diabetes iPro Symposia in the fall of 2009 and is a certified product trainer for Dexcom and Medtronic.

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