CONTINUOUS GLUCOSE MONITORING

CONTINUOUS GLUCOSE MONITORING — Real-time, continuous glucose monitoring (CGM) has the potential to improve glycemic control while decreasing the incidence of hypoglycemia [24,25]. However, the improvement in glycemic control compared with self-monitoring of blood glucose (SMBG) is variable, CGM is relatively expensive, and, because of reliability issues and the need to calibrate most CGM devices, CGM does not eliminate the need for at least occasional fingersticks. (See 'CGM systems' below and 'Efficacy' below and 'Cost' below.)

Patient selection — Patient selection is a key factor for the successful use of CGM [1]. For maximum benefit of CGM, patients must understand the technology and use CGM on a near daily basis. Patients with type 1 diabetes most likely to benefit from CGM include those who [25]:

●Understand and are highly motivated to use intensive insulin therapy

●Continue frequent home glucose monitoring, using fingersticks as indicated

●Use CGM consistently

●Use the trending information from CGM to make insulin adjustments (eg, a mealtime insulin dose could be reduced if the trend on the CGM device shows a brisk downward trend)

In a study of 20 adults with type 1 diabetes evaluating patients who did and did not have an improvement in A1C or a reduction in hypoglycemia with CGM, good coping skills, the ability to retrospectively analyze data, and adequate spousal or significant other involvement were important factors for the effective use of CGM [26].

These patient selection criteria are largely consistent with guidelines from the American Diabetes Association (ADA) and the Endocrine Society [1,27]. In particular, the Endocrine Society Guidelines recommend CGM in adults with type 1 diabetes with A1C levels ≤7 percent and who have demonstrated that they can use these devices on a nearly daily basis [27]. CGM is not recommended for the inpatient or critical care setting.

CGM has the greatest potential value in patients with hypoglycemic unawareness who are at risk for or have severe hypoglycemia [28], including pregnant women. Intermittent use of CGM can be particularly useful for improving safety in patients with nocturnal hypoglycemia, hypoglycemia unawareness, and/or frequent episodes of hypoglycemia.

In addition to its use in type 1 diabetes, CGM also may be appropriate for selected patients with type 2 diabetes treated with multiple daily insulin injections, particularly in patients with frequent hypoglycemia or hypoglycemic unawareness [1,29]. (See 'Efficacy' below.)

CGM systems — A variety of continuous glucose monitoring (CGM) systems are available. They measure the glucose content of interstitial fluid (which correlates well with plasma glucose) using an electrochemical enzymatic sensor. Interstitial fluid is accessed by a needle sensor inserted subcutaneously [30,31]. Because of reliability issues and the need to calibrate the devices, CGM does not eliminate the need for at least occasional fingersticks.

In 2018, the US Food and Drug Administration (FDA) approved the Dexcom G6 device, which can be integrated with an automated insulin dosing system, such that a rise in blood glucose would trigger release of insulin from an insulin pump without the need for confirmatory fingerstick glucose testing [32]. Fingerstick glucose determinations are also not needed for calibration. In a study using an older version of the Dexcom device, use of CGM without confirmatory SMBG was as safe and effective as using CGM with SMBG [33,34]. Older Dexcom CGMs and the Enlite CGM do not have a non-adjunctive claim, so fingerstick glucose readings are required both for calibration and as confirmation of glucose levels before making decisions on insulin dosing.

Another CGM device, the Libre, received a non-adjunctive indication from the FDA in 2017. Fingerstick glucose determinations are not needed for calibration or confirmation of routine blood glucose values. However, fingerstick glucose levels are required to confirm hypoglycemia or impending hypoglycemia [35,36]. With this device, which uses flash technology, glucose data are obtained by swiping a reader next to a transmitter worn on the arm. The system does not alarm for hypoglycemia or hyperglycemia like other CGM systems.

With some devices (sometimes referred to as "professional CGM"), the patient receives no information while wearing the device. Results can be determined in a clinician's office and graphed, providing useful information about the frequency of unrecognized hypoglycemia and the extent of within-day and between-day variations in blood glucose (figure 2).

Most devices (often referred to as "personal CGM") now provide the patient with real-time results of glucose values on a continuous basis, which can be automatically and securely shared with a clinician via a mobile medical glucose-monitoring application downloaded on to a mobile device, such as a cell phone [37].

Efficacy

●Type 1 diabetes – In meta-analyses of trials comparing CGM with SMBG in patients with type 1 diabetes, consistent and reliable use of a CGM system can modestly improve glycemic control (weighted mean difference [WMD] in A1C -0.2 to -0.5 percent) [38-42]. In general, consistent use of CGM (rather than intermittent use) is necessary to obtain glycemic benefits.

Studies to date have demonstrated variable outcomes with regard to improving hypoglycemia. Although there was a small reduction in the incidence of hypoglycemia with CGM in one analysis, the interpretation of the data was limited by the overall low frequency of hypoglycemia and significant heterogeneity among the trials [38].

CGM devices can be used with multiple injections or insulin pump therapy. In multicenter trials published subsequent to the above-noted meta-analyses, CGM compared with conventional monitoring improved A1C and reduced some measures of hypoglycemia in adults with type 1 diabetes treated with multiple daily injections [28,43,44]:

•In one of the trials, 158 adults with type 1 diabetes (mean A1C 8.6 percent), were randomly assigned to CGM or usual care (SMBG at least four times daily) [43]. Patients in the CGM group verified the CGM glucose value with the blood glucose meter prior to injecting insulin. Patients in the CGM group performed a mean of 3.6 fingersticks daily, compared with 4.6 per day in the control group.

After 24 weeks, the reduction in A1C was greater with CGM (1.0 versus 0.4 percentage points, respectively). Median duration of hypoglycemia (<70 mg/dL) was lower in the CGM group (43 versus 80 minutes). The incidence of severe hypoglycemia was low and did not differ between the two groups.

•Another trial was a crossover trial in which 161 adults with type 1 diabetes (mean A1C 8.6 percent) were randomly assigned to CGM or conventional monitoring with a washout period of 17 weeks [44]. Mean A1C was lower during CGM (7.92 versus 8.35 percent). The mean percentage of time spent in a hypoglycemic range (<70 mg/dL) was lower in the CGM group (2.79 versus 4.79 percent). There were one and five severe hypoglycemic events during CGM and conventional monitoring, respectively. Patients in the CGM group performed a mean of 2.75 fingersticks daily, compared with 3.66 per day in the control group.

•In the third trial, patients with type 1 diabetes and a history of impaired hypoglycemic awareness or severe hypoglycemia during the previous year wore a masked CGM system for 28 days and then were randomly assigned to unmasked CGM versus SMBG [28]. The primary outcome, hypoglycemic events per 28 days, was defined as glucose values of ≤54 mg/dL (3 mmol/L) for at least 20 minutes, preceded by a minimum of 30 minutes with glucose values >54 mg/dL. There was a greater reduction in the primary outcome in the CGM group (10.8 to 3.5 versus 14.4 to 13.7 events, respectively). There was also a significant reduction in the number of nocturnal hypoglycemic events in the CGM but not the control group. A1C values remained similar in both groups.

In all three trials, satisfaction with CGM use was high.

Studies are evaluating the efficacy of a fully automated, closed-loop system of insulin delivery based upon continuous glucose sensing. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Continuous subcutaneous insulin infusion (insulin pump)'.)

●Type 2 diabetes – There are fewer trials evaluating CGM in patients with type 2 diabetes. In one meta-analysis, there was a significant reduction in A1C with use of CGM versus SMBG in adults with type 2 diabetes (WMD -0.7 percent) [39]. In a subsequent trial, 158 adults treated with multiple daily injections of insulin (mean A1C 8.5 percent), were randomly assigned to CGM or usual care (SMBG at least four times daily) [45]. After 24 weeks, the reduction in A1C was greater with CGM (0.8 versus 0.5 percentage points, respectively; adjusted mean difference -0.3, 95% CI -0.5 to 0.0 percent). Patients in the CGM group performed a mean of 2.9 fingersticks daily, compared with 3.8 per day in the control group. There was no difference in hypoglycemia, which was infrequent in both groups, or in quality-of-life measures.

Reliability — The interstitial fluid glucose sensor yields lower glucose values compared with venous plasma glucose when blood glucose concentrations are rapidly rising, owing to delayed equilibration between the different physiologic compartments (figure 2) [31]. The accuracy of CGM is improving. In an evaluation of over 60,000 paired sensor and glucose meter values from 72 patients with type 1 diabetes, the overall percentage of sensor readings within ±20 and ±30 percent agreement with reference glucose readings was 75.6 and 86.6 percent, respectively [46]. The highest rate of agreement occurred in the 240 to 400 mg/dL (13.3 to 22.2 mmol/L) range. In another study evaluating paired sensor and venous blood glucose values from subjects with type 1 diabetes, the overall percentage of sensor readings with large errors (≥25 percent above or below the reference values) was 17.5 percent [47]. Very large errors (≥50 percent from reference glucose) occurred in 2.6 percent.

CGM tends to be less accurate in the lower glucose range (<70 mg/dL or 3.9 mmol/L) [48,49]. In one study comparing two CGM devices (Dexcom G4 and MiniMed Medtronic Enlite) with capillary glucose levels collected approximately every 15 minutes, the mean absolute relative difference of the sensor glucose compared with the capillary value for levels <72 mg/dL (4 mmol/L) was 20 and 34.7 percent for Dexcom G4 and Enlite, respectively [50]. In the normoglycemic range (72 to 180 mg/dL [4 to 10 mmol/L]), the mean absolute relative difference was 14.1 and 17.3 percent, respectively. Thus, the Dexcom G4 sensor showed greater accuracy than the Enlite sensor in both the normoglycemic and hypoglycemic range. Overall, the accuracy of either sensor was better in the normoglycemic than hypoglycemic range.

Patients taking medications containing acetaminophen may experience falsely elevated CGM glucose values. This is a dose-dependent effect (depending on acetaminophen tissue levels), which results from oxidation of acetaminophen by CGM electrodes [51].

Cost — Currently available CGM instruments are relatively expensive. Initial costs are approximately USD $1000 to 2000 for devices that directly sample subcutaneous fluid, with additional costs for supplies ranging between USD $350 to 450 per month. The Libre will cost approximately USD $120 per month, and the reader will cost approximately USD $80 and will last three years. Insurance companies have improved reimbursement over the past five years. Medicare now pays for both the Dexcom Gen 5 and Libre for both type 1 and type 2 diabetes as long as patients are receiving multiple injections (or pump therapy) and are testing fingerstick blood glucose levels at least four times daily.