Medical Policy

Policy Num:       02.001.012
Policy Name:    Continuous  Glucose Monitoring 
Policy ID:          [02.001.012]  [Ac / B / M+ / P+]  [1.01.20]

Last Review:     August 05, 2024
Next Review:     August 20, 2025
 

Related Policies:

01.001.24 - Artificial Pancreas Device Systems

Continuous  Glucose Monitoring

SUMMARY

Description

Tight glucose control in patients with diabetes has been associated with improved health outcomes. Several devices are available to measure glucose levels automatically and frequently (e.g., every 5 to 10 minutes). The devices measure glucose in the interstitial fluid and are approved as adjuncts to or replacements for traditional self-monitoring of blood glucose levels. Devices can be used on a long-term (continuous) or short-term (often referred to as intermittent) basis.

Type 1 Diabetes

For individuals with type 1 diabetes who are willing and able to use the device, and have adequate medical supervision, who receive long-term continuous glucose monitoring (CGM), the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are symptoms, morbid events, quality of life (QOL), and treatment-related morbidity. Systematic reviews have generally found that at least in the short-term, long-term CGM resulted in significantly improved glycemic control for adults and children with type 1 diabetes, particularly highly compliant patients. A 2017 individual patient data analysis, pooling data from 11 RCTs, found that reductions in Hemoglobin A1c (HbA1c) levels were significantly greater with real-time CGM than with a control intervention. Two RCTs in patients who used multiple daily insulin injections and were highly compliant with CGM devices during run-in phases found that CGM was associated with a larger reduction in HbA1c levels than previous studies. One of the 2 RCTs prespecified hypoglycemia-related outcomes and reported that time spent in hypoglycemia was significantly less in the CGM group. One RCT in pregnant women with type 1 diabetes, which compared real-time CGM with self-monitoring of blood glucose, has also reported a difference in change in HbA1c levels, an increased percentage of time in the recommended glucose control target range, a smaller proportion of infants who were large for gestational age, a smaller proportion of infants who had neonatal intensive care admissions lasting more than 24 hours, a smaller proportion of infants who had neonatal hypoglycemia requiring treatment, and reduced total hospital length of stay all favoring CGM. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with type 1 diabetes who receive short-term continuous glucose monitoring, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity as well as intermediate outcomes related to measures of glucose control such as frequency and time in hypoglycemia and hyperglycemia. The evidence for short-term monitoring of glycemic control is mixed, and there was no consistency in HbA1c levels. Some trials have reported improvements in glucose control for the short-term monitoring group but limitations in this body of evidence preclude conclusions. The definitions of control with short-term CGM use, duration of use and the specific monitoring protocols varied. In some studies, short-term monitoring was part of a larger strategy aimed at optimizing glucose control, and the impact of monitoring cannot be separated from the impact of other interventions. Studies have not shown an advantage for intermittent glucose monitoring in reducing severe hypoglycemia events but the number of events reported is generally small and effect estimates imprecise. The limited duration of use may preclude an assessment of any therapeutic effect. Two RCTs of short-term CGM use for monitoring in pregnancy included women with both type 1 and 2 diabetes, with most having type 1 diabetes. One trial reported a difference in HbA1c levels at 36 weeks; the proportion of infants that were large for gestational age (>90th percentile) favored CGM while the second trial did not. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant in either study. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Continuous Glucose Monitoring with an Implantable Device (Eversense) Type 1 Diabetes

For individuals with type 1 diabetes who receive continuous glucose monitoring with an implantable device, the evidence includes an RCT and nonrandomized studies. The RCT compared implantable CGM with control (self-monitoring of blood glucose or intermittently scanned CGM). The RCT was conducted in France and enrolled participants in 2 cohorts; cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c >8.0% while cohort 2 (n=90) included participants with type 1 diabetes with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. In cohort 1, there was no difference in mean HbA1c, time in range, or patient-reported outcomes at day 180. In cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). There were no differences in patient reported outcomes. Nonrandomized prospective studies and post-marketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. In February 2022, the FDA expanded approval of the device for use up to 180 days. Approval was based on the PROMISE pivotal clinical trial, which assessed accuracy and safety but not glycemic outcomes. Limitations of the evidence base include limited comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Type 2 Diabetes

For individuals with type 2 diabetes who are treated with insulin therapy who receive long-term CGM, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity. RCTs have included individuals on intensive insulin therapy and individuals on basal insulin. Three RCTs have evaluated CGM compared to SMBG in individuals with type 2 diabetes on intensive insulin therapy; 1 using real-time CGM and 2 using an intermittently scanned device. One RCT evaluated CGM in patients treated with basal insulin. All found either improved glycemic outcomes or no difference between groups with no increase in hypoglycemic events. In the DIAMOND trial, the adjusted difference in mean change in HbA1c level from baseline to 24 weeks was -0.3% (95% CI, -0.5% to 0.0%; p=.022) favoring CGM. The adjusted difference in the proportion of patients with a relative reduction in HbA1c level of 10% or more was 22% (95% CI, 0% to 42%; p=.028) favoring CGM. There were no events of severe hypoglycemia or diabetic ketoacidosis in either group. Yaron et al (2019) reported higher treatment satisfaction with CGM compared to control (the primary outcome). At 12-month follow-up in one of the trials of the Freestyle Libre device, hypoglycemic events were reduced by 40.8% to 61.7% with a greater relative reduction in the most severe thresholds of hypoglycemia. In the Martens trial of individuals treated with basal insulin without prandial insulin, there was a statistically significantly greater decrease in mean HbA1c in the CGM group (adjusted difference, -0.4%; 95% CI -0.8% to -0.1%; p=.02), with 1 hypoglycemic event in each group. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with type 2 diabetes who are not treated with insulin therapy who receive long-term CGM, the evidence includes 4 RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity. Results were mixed regarding benefits of CGM with respect to glycemic control. Participant populations were heterogenous with regard to their diabetic treatment regimens, and participants might not have been receiving optimal therapy. In individuals on oral antidiabetic agents only, routine glucose monitoring may be of limited additional clinical benefit. Additional evidence would be needed to show what levels of improvement in blood glucose excursions and HbA1c levels over the short-term in this population would be linked to meaningful improvement in long-term health outcomes such as diabetes-related morbidity and complications. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with type 2 diabetes who receive short-term continuous glucose monitoring, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity as well as intermediate outcomes related to measures of glucose control such as frequency and time in hypoglycemia and hyperglycemia. The evidence for short-term monitoring of glycemic control is mixed, and there was no consistency in HbA1c levels. Some trials have reported improvements in glucose control for the short-term monitoring group but limitations in this body of evidence preclude conclusions. The definitions of control with short-term CGM use, duration of use and the specific monitoring protocols varied. In some studies, short-term monitoring was part of a larger strategy aimed at optimizing glucose control, and the impact of monitoring cannot be separated from the impact of other interventions. Studies have not shown an advantage for intermittent glucose monitoring in reducing severe hypoglycemia events but the number of events reported is generally small and effect estimates are imprecise. The limited duration of use may preclude an assessment of any therapeutic effect. Three RCTs of short-term CGM use for monitoring in pregnancy included women with both type 1 and 2 diabetes, with most having type 1 diabetes. One trial reported a difference in HbA1c levels at 36 weeks; the proportion of infants that were large for gestational age (>90th percentile) favored CGM while the other trials did not. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant in studies in which these outcomes were reported. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Continuous Glucose Monitoring with an Implantable Device (Eversense) Type 2 Diabetes

For individuals with type 2 diabetes who receive continuous glucose monitoring with an implantable device, the evidence includes an RCT and nonrandomized studies. The RCT compared implantable CGM with control (self-monitoring of blood glucose or intermittently scanned CGM). The RCT was conducted in France and enrolled participants in 2 cohorts; cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c >8.0% while cohort 2 (n=90) included participants with type 1 diabetes with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. In cohort 1, there was no difference in mean HbA1c, time in range, or patient-reported outcomes at day 180. In cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). There were no differences in patient reported outcomes. Nonrandomized prospective studies and post-marketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. In February 2022, the FDA expanded approval of the device for use up to 180 days. Approval was based on the PROMISE pivotal clinical trial, which assessed accuracy and safety but not glycemic outcomes. Limitations of the evidence base include limited comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Gestational Diabetes

For individuals who are pregnant with gestational diabetes who receive long-term CGM or short-term (intermittent) glucose monitoring, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity. In the RCT, the type of glucose monitoring was unclear. Trial reporting was incomplete; however, there was no difference between the groups for most reported outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

2019 Input

Clinical input was sought to help determine whether the use of continuous or intermittent monitoring of glucose in the interstitial fluid would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 3 respondents, including 3 physician-level responses identified through 1 specialty society, including 2 physicians with academic medical center affiliations.

Type 1 Diabetes

For individuals who have type 1 diabetes who receive short-term glucose monitoring, clinical input supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice when used in specific situations such as poor control of Type 1 diabetes despite the use of best practices and to help determine basal insulin levels prior to insulin pump initiation.

Type 2 Diabetes

For individuals who have type 2 diabetes who do not require insulin who receive long-term (continuous) CGM, clinical input does not support a clinically meaningful improvement in net health outcome and does not indicate this use is consistent with generally accepted medical practice.

For individuals with type 2 diabetes who are willing and able to use the device and have adequate medical supervision and who experience significant hypoglycemia on multiple daily doses of insulin or an insulin pump in the setting of insulin deficiency who receive long-term continuous glucose monitoring, clinical input supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice.

For individuals with type 2 diabetes who require multiple daily doses of insulin who receive short-term CGM, clinical input supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice when used in specific situations such as poor control of diabetes despite use of best practices and to help determine basal insulin levels prior to insulin pump initiation.

Further details from clinical input are included in the Appendix.

Objective

The objective of this evidence review is to determine whether continuous glucose monitoring improves the net health outcome in patients with type 1, type 2, or gestational diabetes.

Policy

Individuals with Type 1 Diabetes

Long-term continuous glucose monitoring (CGM) device monitoring of glucose levels in interstitial fluid, as a technique of diabetic monitoring, may be considered medically necessary in individuals with type 1 diabetes who have demonstrated an understanding of the technology, are motivated to use the device correctly and consistently, are expected to adhere to a comprehensive diabetes treatment plan supervised by a qualified provider, and are capable of using the device to recognize alerts and alarms

Short-term CGM monitoring of glucose levels in interstitial fluid may be considered medically necessary in individuals with type 1 diabetes whose diabetes is poorly controlled, despite current use of best practices (see Policy Guidelines section). Poorly controlled type 1 diabetes includes the following clinical situations: unexplained hypoglycemic episodes, hypoglycemic unawareness, suspected postprandial hyperglycemia, and recurrent diabetic ketoacidosis.

Short-term CGM monitoring of glucose levels in interstitial fluid may also be considered medically necessary in patients with type 1 diabetes prior to insulin pump initiation to determine basal insulin levels.

Individuals with Type 2 Diabetes

Long-term CGM monitoring of glucose levels in interstitial fluid may be considered medically necessary in individuals with type 2 diabetes who are willing and able to use the device and have adequate medical supervision and who experience significant hypoglycemia on multiple daily doses of insulin or an insulin pump in the setting of insulin deficiency.

Short-term and long-term CGM monitoring of glucose levels in interstitial fluid may be considered medically necessary in individuals with type 2 diabetes who require multiple daily doses of insulin and whose diabetes is poorly controlled, despite current use of best practices (see Policy Guidelines section) and are capable of using devices safely. Poorly controlled type 2 diabetes includes the following clinical situations: unexplained hypoglycemic episodes, hypoglycemic unawareness, persistent hyperglycemia, or hemoglobin A1c (HbA1c) levels above target.

Short-term CGM monitoring of glucose levels in interstitial fluid may be considered medically necessary in individuals with type 2 diabetes who require multiple daily doses of insulin to determine basal insulin levels prior to insulin pump initiation.

Short-term and long-term CGM monitoring of glucose levels in interstitial fluid in individuals with type 2 diabetes not on intensive insulin therapy (i.e., individuals on basal insulin or oral antidiabetic agents only) is considered investigational.

Gestational Diabetes

Other uses of long-term and short-term CGM monitoring of glucose levels in interstitial fluid as a technique of diabetic monitoring including use in gestational diabetes are considered investigational.

The use of implantable CGM devices for management of Type 1 and Type 2 diabetes mellitus is considered investigational.

Policy Guidelines

This policy only evaluates continuous (real time or intermittently scanned) interstitial glucose monitors and does not evaluate insulin pumps. Insulin pump systems with a built-in continuous glucose monitor and a low-glucose suspend feature are addressed in evidence review 1.01.30 (artificial pancreas device systems).

Short-term continuous glucose monitoring is generally conducted over 72-hour periods. It may be repeated subsequently depending on the individual's level of diabetes control.

Best practices in diabetes control include compliance with a self-monitoring blood glucose regimen of 4 or more fingersticks each day and use of an insulin pump or multiple daily injections of insulin. During pregnancy, 3 or more insulin injections daily could be considered best practice for individuals not on an insulin pump prior to the pregnancy. Prior short-term (72-hour) use of an intermittent glucose monitor would be considered a part of best practices for those considering long-term use of a continuous glucose monitor.

Significant hypoglycemia may include recurrent, unexplained, severe (generally blood glucose levels <50 mg/dL) hypoglycemia or impaired awareness of hypoglycemia that puts the individual or others at risk.

Individuals with type 1 diabetes taking insulin who are pregnant or about to become pregnant with poorly controlled diabetes are another subset of individuals to whom the policy statement on short-term continuous glucose monitoring may apply.

The strongest evidence exists for use of continuous glucose monitoring devices in individuals age 25 years and older. However, age may be a proxy for motivation and good control of disease, so it is also reasonable to select patients based on their ability to self-manage their disease, rather than their age. Multiple continuous glucose monitoring (CGM) devices have U.S. Food and Drug Administration labeling related to age.

Providers board-certified in endocrinology and/or providers with a focus on the practice of diabetes care may be considered qualified to evaluate and oversee individuals for continuous (i.e., long-term) monitoring.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

State mandates on coverage of diabetic supplies may apply; however, some state mandates may only apply to those supplies no longer considered investigational.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage. 

Background

Blood Glucose Control

The advent of blood glucose monitors for use by patients in the home revolutionized the management of diabetes. Using fingersticks, patients can monitor their blood glucose levels both to determine the adequacy of hyperglycemia control and to evaluate hypoglycemic episodes. Tight glucose control, defined as a strategy involving frequent glucose checks and a target hemoglobin A_1c (HbA_1c) level in the range of 7%, is now considered the standard of care for diabetic patients. Randomized controlled trials assessing tight control have demonstrated benefits for patients with type 1 diabetes in decreasing microvascular complications. The impact of tight control on type 1 diabetes and macrovascular complications such as stroke or myocardial infarction is less certain. The Diabetes Control and Complications Trial (2002) demonstrated that a relative HbA_1c level reduction of 10% is clinically meaningful and corresponds to approximately a 40% decrease in risk for progression of diabetic retinopathy and 25% decrease in risk for progression of renal disease.^1,

Due to an increase in turnover of red blood cells during pregnancy, HbA_1c levels are slightly lower in women with a normal pregnancy compared with nonpregnant women. The target A_1c in women with diabetes is also lower in pregnancy. The American Diabetes Association recommends that, if achievable without significant hypoglycemia, the A_1c levels should range between 6.0% to 6.5%; an A_1c  level less than 6% may be optimal as the pregnancy progresses.^2,

Tight glucose control requires multiple daily measurements of blood glucose (ie, before meals and at bedtime), a commitment that some patients may find difficult to meet.  The goal of tight glucose control has to be balanced with an associated risk of hypoglycemia. Hypoglycemia is known to be a risk in patients with type 1 diabetes. While patients with insulin-treated type 2 diabetes may also experience severe hypoglycemic episodes, there is a lower relative likelihood of severe hypoglycemia compared with patients who had type 1 diabetes.^3, An additional limitation of periodic self-measurements of blood glucose is that glucose levels are seen in isolation, and trends in glucose levels are undetected. For example, while a diabetic patient’s fasting blood glucose level might be within normal values, hyperglycemia might be undetected postprandially, leading to elevated HbA_1c levels.

Management

Measurements of glucose in the interstitial fluid have been developed as a technique to measure glucose values automatically throughout the day, producing data that show the trends in glucose levels. Although devices measure glucose in the interstitial fluid on a periodic rather than a continuous basis, this type of monitoring is referred to as continuous glucose monitoring (CGM).

Currently, CGM devices are of 2 designs; real-time CGM (rtCGM) provides real-time data on glucose level, glucose trends, direction, and rate of change and, intermittently viewed (iCGM) devices that show continuous glucose measurements retrospectively. These devices are also known as flash-glucose monitors.

Approved devices now include devices indicated for pediatric use and those with more advanced software, more frequent measurements of glucose levels, or more sophisticated alarm systems. Devices initially measured interstitial glucose every 5 to10 minutes and stored data for download and retrospective evaluation by a clinician. With currently available devices, the intervals at which interstitial glucose is measured range from every 1 to 2 minutes to 5 minutes, and most provide measurements in real-time directly to patients. While CGM potentially eliminates or decreases the number of required daily fingersticks, according to the U.S. Food and Drug Administration (FDA) labeling, some marketed monitors are not intended as an alternative to traditional self-monitoring of blood glucose levels but rather as adjuncts to monitoring, supplying additional information on glucose trends not available from self-monitoring while other devices are factory calibrated and do not require fingerstick blood glucose calibration.

Devices may be used intermittently (i.e., for periods of 72 hours) or continuously (i.e., on a long-term basis).

regulatory status

Multiple CGM systems have been approved or cleared by the FDA (see Table 1). FDA product codes: [PMA] QCD, MDS, PQF; [510(k)] QBJ, QLG, SAF.

CGM devices labeled as “Pro” for specific professional use with customized software and transmission to health care professionals are not enumerated in this list.

The Flash glucose monitors (eg FreeStyle Libre, Abbott) use intermittent scanning..The current version of the FreeStyle Libre device includes real-time alerts, in contrast to earlier versions without this feature.

Table 1. CGM Systems Approved by the U.S. Food and Drug Administration

CGM: continuous glucose monitoring.a As a supplement to the G4 premarketing approval.

RATIONALE

This evidence review was created in August 2000 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May16, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The evidence review focuses on the clinical utility of continuous glucose monitoring (CGM) systems. That is, their ability to provide additional information on glucose levels leads to improved glucose control, or to reduce the morbidity and mortality associated with clinically significant severe and acute hypoglycemic or hyperglycemic events. Because diabetic control encompasses numerous variables, including the diabetic regimen and patient self-management, RCTs are important to isolate the contribution of interstitial glucose measurements to overall diabetes management.

For the evaluation of the clinical utility of CGM, studies would need to use the test as either an adjunct or a replacement to current disease status measures to manage treatment decisions in patients with diabetes. Outcomes would include measures of glucose control, QOL and measures of disease progression. Hemoglobin A1c (HbA1c) has commonly been accepted as a marker of glucose control; more recent studies have also reported time in hyperglycemia, time in hypoglycemia, and time in range as intermediate outcome measures.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.”

Population Reference No. 1

Continuous Glucose Monitoring Devices for Long-Term Use in Type 1 Diabetes

In some parts of the analysis of type 1 diabetes, BCBSA combines discussion of real-time and intermittently scanned glucose monitoring because several systematic reviews provided information relevant to both types of devices.

Clinical Context and Therapy Purpose

The purpose of long-term CGM devices is to provide a testing option that is an alternative to or an improvement on existing testing used in the management of individuals with type 1 diabetes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with type 1 diabetes. All individuals with type 1 diabetes require engagement in a comprehensive self-management and clinical assessment program that includes assessment of blood glucose control.

Interventions

The test being considered is the use of a CGM device to assess blood glucose levels as part of optimal diabetes management. Long-term use is generally use for more than 72 hours.

Currently, CGM devices are of 2 designs; real-time CGM (rtCGM) provides real-time data on glucose level, glucose trends, direction, and rate of change, and intermittently scanned (iCGM) devices that show continuous glucose measurements retrospectively. These latter devices are also known as flash-glucose monitors.

Comparators

The following practice is currently being used to measure glucose levels: capillary blood sampling (finger stick) for self-monitoring of blood glucose (SMBG). Standard treatment for patients with type 1 diabetes includes injection of long-acting basal insulin plus multiple daily injections (MDI) of rapid-acting insulin boluses as required for meal intake. Activity level may require patients need to modify the timing and dose of insulin administration. Individuals with type 1 diabetes may also use an insulin pump either for initial treatment or convert to pump use after a period of MDI. Individuals are required to check their blood glucose before making preprandial insulin calculations, in response to symptoms of hypoglycemia or related to activity-related insulin adjustments.

Outcomes

The general outcomes of interest are change in HbA1c levels, time spent in hypoglycemia and hyperglycemia, time in range (generally glucose of 70 to 180 mg/dl), the incidence of hypoglycemic events, complications of hypoglycemia, and QOL. To assess short-term outcomes such as HbA1c levels, a minimum follow-up of 8 to 12 weeks is appropriate.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A number of systematic reviews and meta-analyses have assessed RCTs evaluating CGM for long-term, daily use in treating type 1 diabetes.^{5,6,7,8,9,10,} These systematic reviews have focused on slightly different populations, and some did not separate real-time CGM from intermittent glucose monitoring.^8,

The only analysis to use individual patient data was published by Benkhadra et al (2017).^11, The meta-analysis evaluated data from 11 RCTs that enrolled patients with type 1 diabetes and compared real-time CGM with a control intervention. Studies in which patients used insulin pumps or received multiple daily insulin injections were included. Reviewers contacted corresponding study authors requesting individual patient data; data were not obtained for 1 trial. Mean baseline HbA1c levels were 8.2% in adults and 8.3% in children and adolescents. The overall risk of bias in the studies was judged to be moderate. In pooled analyses, there was a statistically significantly greater decrease in HbA1c levels with real-time CGM versus control conditions. Overall, the degree of difference between groups was 0.26%. In subgroup analyses by age, there was a significantly greater change in HbA1c levels among individuals 15 years and older, but not among the younger age groups. There were no significant differences between groups in the time spent in hypoglycemia or the incidence of hypoglycemic events. Key findings are shown in Table 2.

Table 2. Individual Patient Data Meta-Analytic Outcomes for Real-Time CGM in Type 1 Diabetes

Adapted from Benkhadra et al (2017).11,CGM: continuous glucose monitoring: HbA1c: hemoglobin A1c.

Randomized Controlled Trials

Recent RCTs are described next and in Tables 3 and 4. HbA1c, blood glucose, event rates, and patient reported outcomes were assessed at 6 months. None of the studies were blinded. The studies had a large number of pre-specified secondary endpoints, and analyses took into consideration the statistical impact of multiple comparisons.

Two 2017 RCTs evaluated long-term, real-time CGM in patients with type 1 diabetes treated with multiple daily insulin injections. Both trials used the Dexcom G4 CGM device. Lind et al (2017) reported on a crossover study with 142 adults ages 18 and older who had baseline HbA1c levels of 7.5% or higher (mean baseline HbA1c level, >8.5%).^12, Enrolled patients underwent 26-week treatment periods with a CGM device and conventional therapy using SMBG, in random order. There was a 17-week washout period between intervention phases. The primary endpoint was the difference in HbA1c levels at the end of each treatment period. Mean HbA1c levels were 7.9% during CGM use and 8.4% during conventional therapy (MD, -0.4%; p<.01). Treatment satisfaction (measured by the Diabetes Treatment Satisfaction Questionnaire) was significantly higher in the CGM phase than in the conventional treatment phase (p<.001). There was 1 (0.7%) severe hypoglycemic event during the CGM phase and 5 (3.5%) events during conventional therapy. The percentage of time with hypoglycemia (<70 mmol/L) was 2.8% during CGM treatment and 4.8% during conventional therapy.

In the second study, Beck et al (2017) randomized 158 patients on a 2:1 basis to 24 weeks of CGM (n=105) or usual care (n=53).^13, The primary outcome (change in HbA1c levels at 24 weeks) was 1.0% in the CGM group and 0.4% in the usual care group (p<.001), with a between-group difference of 0.6%. Prespecified secondary outcomes on the proportion of patients below a glycemic threshold at 24 weeks also favored the CGM group. The proportion of patients with HbA1c levels less than 7.0% was 18 (18%) in the CGM group and 2 (4%) in the control group (p=.01). Prespecified secondary outcomes related to hypoglycemia also differed significantly between groups, favoring the CGM group. Comparable numbers for time spent at less than 50 mg/dL were 6 minutes per day in the CGM group and 20 minutes per day in the usual care group (p=.001). The median change in the rate per 24 hours of hypoglycemia events lasting at least 20 minutes at less than 3.0 mmol/L (54 mg/dL) fell by 30% from 0.23 at baseline to 0.16 during follow-up in the CGM group but was practically unchanged (0.31 at baseline and 0.30 at follow-up) in the usual care group (p=.03).^14,Quality of life measures assessing overall well-being (World Health Organization Well-Being Index), health status (EQ-5D-5L), diabetes distress (Diabetes Distress Scale), hypoglycemic fear (worry subscale of the Hypoglycemia Fear Survey), and hypoglycemic confidence (Hypoglycemic Confidence Scale) have also been reported.^15, There were no significant differences between CGM and usual care in changes in well-being, health status, or hypoglycemic fear. The CGM group demonstrated a greater increase in hypoglycemic confidence (p=.01) and a greater decrease in diabetes distress (p=.01) than the usual care group.

Two RCTs were published in 2020 that assessed real-time CGM with a Dexcom G5 in adolescents and young adults (Laffel et al, 2020) ^16,, and in older adults (Pratley et al, 2020)^17, Both studies found modest but statistically significant differences in HbA1c between patients who used the CGM devices compared to the control arm at follow-up. Secondary measures of HbA1c and blood glucose were mostly better in the CGM arm. Patient-reported outcome measures were not significantly different between the groups, except that glucose monitoring satisfaction was higher in the adolescents and young adults who used CGM. With the newer technology, patients were able to use a smartphone app to monitor glucose levels.

Two RCTs have evaluated long-term use of intermittently-scanned CGM. Leelarathna et al (2022) reported results of the FLASH-UK (NCT03815006) multicenter RCT including individuals age 16 years and older in the United Kingdom with type 1 diabetes and HbA1c levels between 7.5% and 11.0% who were receiving either continuous subcutaneous insulin infusion or multiple daily injections of insulin.^18, The trial was conducted from 2019 to 2021 and compared intermittently-scanned CGM (FreeStyle Libre 2; n=78) worn on the arm for 14 days versus usual care with fingerstick testing (n=78). The primary outcome was the HbA1c at 24 weeks. The difference in decrease in HbA1c level at 24 weeks was −0.5% (95% CI, −0.7 to −0.3; p<.001) favoring CGM. The difference in time per day that the glucose level was in target range was 9.0% (95% CI, 4.7 to 13.3) higher or 130 minutes (95% CI, 68 to 192) longer in the CGM group compared to usual care. No participants in the CGM group versus 2 participants in the usual care group had an episode of severe hypoglycemia.

Yan et al (2023) reported results of a multicenter RCT (NCT03522870) conducted in China from 2019 to 2022 comparing intermittently-scanned CGM (FreeStyle Libre; n=54) to capillary blood glucose monitoring (n=50) in adults with sub-optimally controlled type 1 diabetes.^19, Participants had HbA1c between 7% and 10%. The primary outcome was change in HbA1c at 24 weeks. The mean reduction in the primary outcome in the CGM group was 0.7% versus 0.3% in the control group (difference, 0.3%; 95% CI, 0.0 to 0.6; p=.04). The mean time-in-range increased to 63% at 24 weeks in CGM versus 58% in control (difference, 6% [1.4 hours / day]; 95% CI, -11 to -1; p=.02). No participants in the CGM group versus 4 participants in the control group experienced an event of diabetic ketoacidosis. No participants in either group experienced severe hypoglycemia.

Table 3. Summary of Key RCT Characteristics in Patients with Type 1 Diabetes

BG: blood glucose; CGM: continuous glucose monitoring; HbA1c: hemoglobin A1C; RCT: randomized controlled trial; SMBG: self-monitored blood glucose; WISDM: Wireless Innovation for Seniors With Diabetes Mellitus.

Table 4. Summary of Key RCT Results in Patients with Type 1 Diabetes

 CGM: continuous glucose monitor; CI: confidence interval; HbA1c: hemoglobin A1c; NR: not reported; NS: not significant; PAD-PS; Problem Areas in Diabetes-Pediatric Survey; RCT: randomized controlled trial; SD: standard deviation; SMBG: self monitored blood glucose; WISDM: Wireless Innovation for Seniors With Diabetes Mellitus

Observational Studies

Because several RCTs exist, observational studies will be summarized briefly below only if they capture longer periods of follow-up- (>6 months), larger populations, or particular subgroups of interest.

Long-term follow-up

Observational studies with follow-up of more than 6 months including adults with type 1 diabetes have shown that reductions in acute diabetes events, including severe hypoglycemia and diabetic ketoacidosis are maintained for 1 to 2 years.^20,21,

Pregnant People

One trial of real-time CGM in pregnant women with type 1 diabetes has been reported. Study characteristics, results, and gaps are summarized here and in Tables 5 to 8. Feig et al (2017) reported results of 2 multicenter RCTs in women ages 18 to 40 with type 1 diabetes who were receiving intensive insulin therapy and who were either pregnant (≤13 weeks and 6 days of gestation) or planning a pregnancy.^22, The trial enrolling pregnant women is reviewed here. Women were eligible if they had a singleton pregnancy and HbA1c levels between 6.5% and 10.0%. The trial was conducted at 31 hospitals in North America and Europe. Women were randomized to CGM (Guardian REAL-Time or MiniMed Minilink system) plus capillary glucose monitoring or capillary glucose monitoring alone. Women in the CGM group were instructed to use the devices daily. Women in the control group continued their usual method of capillary glucose monitoring. The target glucose range was 3.5 to 7.8 mmol/L and target HbA1c levels were 6.5% or less in both groups. The primary outcome was the difference in change in HbA1c levels from randomization to 34 weeks of gestation. The proportion of completed scheduled study visits was high in both groups; however, participants using CGM had more unscheduled contacts, which were attributed both to sensor issues and to sensor-related diabetes management issues. The median frequency of CGM use was 6.1 days per week (interquartile range, 4.0 to 6.8 d/wk) and 70% of pregnant participants used CGM for more than 75% of the time. The between-group difference in the change in HbA1c levels from baseline to 34 weeks of gestation was statistically significant favoring CGM (MD, -0.19%; 95% CI, -0.34 to -0.03; p=.02). Women in the CGM group spent an increased percentage of time in the recommended glucose control target range at 34 weeks of gestation (68% vs. 61%; p=.003). There were no between-group differences in maternal hypoglycemia, gestational weight gain, or total daily insulin dose. A smaller proportion of infants of mothers in the CGM group were large-for-gestational-age (odds ratio [OR], 0.51; 95% CI, 0.28 to 0.90; p=.02). In addition, for infants of mothers in the CGM group, there were fewer neonatal intensive care admissions lasting more than 24 hours (OR, 0.48; 95% CI, 0.26 to 0.86; p=.02), fewer incidences of neonatal hypoglycemia requiring treatment with intravenous dextrose (OR, 0.45; 0.22 to 0.89; p=.025), and reduced total hospital length stay (3.1 days vs. 4.0 days; p=.0091). Skin reactions occurred in 49 (48%) of 103 CGM participants and 8 (8%) of 104 control participants.

Table 5. RCT Characteristics for Real-Time CGM in Pregnant People With Type 1 Diabetes

CGM: continuous glucose monitoring: HbA1c: hemoglobin A1c; NCT: national clinical trial; RCT: randomized controlled trial; SMBG: self-monitored blood glucose.

Table 6. RCT Outcomes for Real-Time CGM in Pregnant People With Type 1 Diabetes

Values are n or n (%) or as otherwise indicated. CGM: continuous glucose monitoring; CI: confidence interval; HbA1c: hemoglobin A1c; NR: not reported; OR: odds ratio; RCT: randomized controlled trial; TE: treatment effect.

The purpose of the limitations tables (see Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 7. Study Relevance Limitations of RCTs for Real-Time CGM in Pregnant People With Type 1 Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Enrolled study populations do not reflect relevant diversity.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 8. Study Design and Conduct Limitations of RCTs for Real-Time CGM in Pregnant People With Type 1 Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Continuous Glucose Monitoring Devices for Long-Term Use in Type 1 Diabetes

Numerous RCTs and several systematic reviews of RCTs have evaluated CGM in patients with type 1 diabetes. RCTs have evaluated both real-time and intermittently scanned CGM devices. Two recent RCTs in patients who used multiple daily insulin injections and were highly compliant with CGM devices during run-in phases found that CGM was associated with a larger reduction in HbA1c levels than previous studies. Reductions were 0.4% and 0.6%, respectively, compared with approximately 0.2% to 0.3% in previous analyses. One of the 2 RCTs prespecified hypoglycemia-related outcomes and time spent in hypoglycemia were significantly lower in the CGM group.

One RCT in pregnant women with type 1 diabetes (n=215) has compared CGM with SMBG. Adherence was high in the CGM group. The difference in the change in HbA1c levels from baseline to 34 weeks of gestation was statistically significant favoring CGM, and women in the CGM group spent an increased percentage of time in the recommended glucose control target range at 34 weeks of gestation. There were no between-group differences in maternal hypoglycemia, gestational weight gain, or total daily insulin dose. A smaller proportion of infants of mothers in the CGM group were large for gestational age, had neonatal intensive care admissions lasting more than 24 hours, and had neonatal hypoglycemia requiring treatment. The total hospital length of stay was shorter by almost 1 day in the CGM group.

For individuals with type 1 diabetes who are willing and able to use the device, and have adequate medical supervision, who receive long-term continuous glucose monitoring (CGM), the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are symptoms, morbid events, quality of life (QOL), and treatment-related morbidity. RCTs have evaluated both real-time and intermittently scanned CGMs.Long-term CGM resulted in significantly improved glycemic control for adults and children with type 1 diabetes, particularly highly compliant patients. Two RCTs in patients who used multiple daily insulin injections and were highly compliant with CGM devices during run-in phases found that CGM was associated with a larger reduction in hemoglobin HbA1c levels than previous studies. One of the 2 RCTs prespecified hypoglycemia-related outcomes and reported that time spent in hypoglycemia was significantly less in the CGM group. One RCT in pregnant women with type 1 diabetes, which compared real-time CGM with self-monitoring of blood glucose (SMBG), has also reported a difference in change in HbA1c levels, an increased percentage of time in the recommended glucose control target range, a smaller proportion of infants who were large for gestational age, a smaller proportion of infants who had neonatal intensive care admissions lasting more than 24 hours, a smaller proportion of infants who had neonatal hypoglycemia requiring treatment, and reduced total hospital length of stay all favoring CGM. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Continuous Glucose Monitoring Devices for Short-Term Use in Type 1 Diabetes

Clinical Context and Therapy Purpose

The purpose of the short-term use of CGM devices is to provide a testing option that is an alternative to or an improvement on existing testing used in the management of individuals with type 1 diabetes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with type 1 diabetes. All individuals with type 1 diabetes require engagement in a comprehensive self-management and clinical assessment program that includes assessment of blood glucose control. Individuals with type 1 diabetes may have poorly controlled diabetes, despite current use of best practices, including situations such as unexplained hypoglycemic episodes, hypoglycemic unawareness, suspected postprandial hyperglycemia, and recurrent diabetic ketoacidosis. In addition, individuals with type 1 diabetes may need to determine basal insulin levels prior to insulin pump initiation.

Interventions

The testing being considered is the short-term use of a CGM device to assess blood glucose levels as part of optimal diabetes management. Short-term use is generally for 72 hours. However, reports of use range from 3 to 30 days.

Comparators

The following practice is currently being used to measure glucose levels: capillary blood sampling (finger stick) for SMBG. Standard treatment for patients with type 1 diabetes includes injection of long-acting basal insulin plus MDI of rapid-acting insulin boluses as required for meal intake. Activity level may require patients need to modify the timing and dose of insulin administration. Individuals with type 1 diabetes may also use an insulin pump either for initial treatment or convert to pump use after a period of MDI. Individuals are required to check their blood glucose before making preprandial insulin calculations, in response to symptoms of hypoglycemia or related to activity-related insulin adjustments

Outcomes

For short-term use of CGM, the general outcomes of interest include time in range (generally glucose of 70 to 180 mg/dl), frequency and time spent in hypoglycemia and, frequency and time spent in hyperglycemia for the duration of the monitoring. Repeat CGM may be necessary to assess the impact of changes in management.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Meta-analyses of glucose monitoring devices for type 1 diabetes tend to combine studies of short-term glucose monitoring with studies of long-term CGM. For this body of evidence, there is variability in the definitions of short-term monitoring and the specific monitoring protocols used. Also, many of the trials of short-term monitoring have included additional interventions to optimize glucose control (e.g., education, lifestyle modifications).

Two meta-analyses were identified that reported separate subgroup analyses for short-term, intermittent monitoring. In a Cochrane review by Langendam et al (2012), 4 studies ( n=216 ) compared real-time short-term glucose monitoring systems with SMBG, and the pooled effect estimate for change in HbA1c levels at 3 months was not statistically significant (MD change, -0.18; 95% CI, -0.42 to 0.05).^7, The meta-analysis by Wojciechowski et al (2011), which assessed RCTs on CGM (described previously), also included a separate analysis of 8 RCTs of short-term intermittent monitoring.^9, On pooled analysis, there was a statistically significant reduction in HbA1c levels with short-term intermittent glucose monitoring compared with SMBG (WMD, -0.26; 95% CI, -0.45 to -0.06).

Randomized Controlled Trials

The largest RCT was the Management of Insulin-Treated Diabetes Mellitus (MITRE) trial, published by Newman et al (2009); it evaluated whether the use of the additional information provided by minimally invasive glucose monitors improved glucose control in patients with poorly controlled insulin-requiring diabetes. ^24,  This 4-arm RCT was conducted at secondary care diabetes clinics in 4 hospitals in England. This trial enrolled 404 people over the age of 18 years, with insulin-treated diabetes (types 1 or 2) for at least 6 months, who were receiving 2 or more injections of insulin daily. Most (57%) participants had type 1 diabetes (41% had type 2 diabetes, 2% were classified as “other”). Participants had to have 2 HbA1c values of at least 7.5% in the 15 months before trial entry and were randomized to 1 of 4 groups. Two groups received minimally invasive glucose monitoring devices (GlucoWatch Biographer or MiniMed Continuous Glucose Monitoring System [CGMS]). Short-term glucose monitoring was used (ie, monitoring was performed over several days at various points in the trial). These groups were compared with an attention control group (standard treatment with nurse feedback sessions at the same frequency as those in the device groups) and a standard control group (reflecting common practice in the clinical management of diabetes). Changes in HbA1c levels from baseline to 3, 6, 12, and 18 months were the primary indicator of short- to long-term efficacy. At 18 months, all groups demonstrated a decline in HbA1c levels from baseline. Mean percentage changes in HbA1c levels were -1.4% for the GlucoWatch group, -4.2% for the CGMS group, -5.1% for the attention control group, and -4.9% for the standard care control group. In the intention-to-treat analysis, no significant differences were found between any groups at any assessment times. There was no evidence that the additional information provided by the devices changed the number or nature of treatment recommendations offered by the nurses. Use and acceptability indicated a decline for both devices, which was most marked in the GlucoWatch group by 18 months (20% still using GlucoWatch vs 57% still using the CGMS). In this trial of unselected patients, glucose monitoring (CGMS on an intermittent basis) did not lead to improved clinical outcomes.

Pregnant People

Systematic Reviews

Voormolen et al (2013) published a systematic review of the literature on CGM during pregnancy ^25, They identified 11 relevant studies ( n=534 ). Two were RCTs, one of which was the largest of the studies (n=154). Seven studies used CGM devices that did not have data available in real-time; the remaining 4 studies used real-time CGM. Reviewers did not pool study findings; they concluded that the evidence was limited to the efficacy of CGM during pregnancy. The published RCTs are described next.

Randomized Controlled Trials

Three RCTs of short-term glucose monitoring in pregnant women with type 1 or type 2 diabetes are summarized in Tables 9 to 12 and the following paragraphs. While both trials included a mix of women with type 1 and type 2 diabetes, most women had type 1 diabetes in both trials, so the trials are reviewed in this section.

Voormolen et al (2018) reported results of the GlucoMOMS trial, a multicenter, open-label RCT conducted between 2011 and 2015 in the Netherlands including pregnant women age 18 years and over with either diabetes mellitus type 1 (n=109), type 2 (n=82), or gestational (n=109) diabetes requiring insulin therapy before 30 weeks of gestation. The trial compared blinded CGM (n=147) to standard treatment (n=153). ^26,  Glycemic control was measured by CGM for 5 tp 7 days every 6 weeks in the CGM group and SMBC was used in both groups. The primary outcome was macrosomia (birth weight above the 90th percentile). The incidence of large-for-gestational-age was 31% in the CGM group and 28% in the standard treatment group (RR=1.1; 95% CI, 0.8 to 1.4). HbA1c levels were similar between treatment groups.

Secher et al (2013) randomized 154 women with type 1 (n=123) and type 2 (n=31) diabetes to real-time CGM in addition to routine pregnancy care (n=79) or routine pregnancy care alone (n=75). .²⁷ Patients in the CGM group were instructed to use the CGM device for 6 days before each of 5 study visits and were encouraged to use the devices continuously; 64% of participants used the devices per-protocol. Participants in both groups were instructed to perform 8 daily self-monitored plasma glucose measurements for 6 days before each visit. Baseline mean HbA1c levels were 6.6% in the CGM group and 6.8% in the routine care group. The 154 pregnancies resulted in 149 live births and 5 miscarriages. The prevalence of large-for-gestational-age infants (at least 90th percentile), the primary study outcome, was 45% in the CGM group and 34% in the routine care group. The difference between groups was not statistically significant (p=.19). Also, no statistically significant differences were found between groups for secondary outcomes, including the prevalence of preterm delivery and the prevalence of severe neonatal hypoglycemia. Women in this trial had low baseline HbA1c levels, which might explain the lack of impact of CGM on outcomes. Other factors potentially contributing to the negative findings included the intensive SMBG routine in both groups and the relatively low compliance rate in the CGM group.

Murphy et al (2008) in the U.K. randomized 71 pregnant women with type 1 (n=46) and type 2 (n=25) diabetes to CGM or usual care.^27, The intervention consisted of up to 7 days of CGM at intervals of 4 to 6 weeks between 8 weeks and 32 weeks of gestation. Neither participants nor physicians had access to the measurements during sensor use; data were reviewed at study visits. In addition to CGM, the women were advised to measure blood glucose levels at least 7 times a day. Baseline HbA1c levels were 7.2% in the CGM group and 7.4% in the usual care group. The primary study outcome was maternal glycemic control during the second and third trimesters. Eighty percent of women in the CGM group wore the monitor at least once per trimester. Mean HbA1c levels were consistently lower in the intervention arm, but differences between groups were statistically significant only at week 36. For example, between 28 weeks and 32 weeks of gestation, mean HbA1c levels were 6.1% in the CGM group and 6.4% in the usual care group (p=.10). The prevalence of large-for-gestational-age infants (at least 90th percentile) was a secondary outcome. Thirteen (35%) of 37 infants in the CGM group were large-for-gestational age compared with 18 (60%) of 30 in the usual care group. The odds for reduced risk of a large-for-gestational-age infant with CGM was 0.36 (95% CI, 0.13 to 0.98; p=.05).

Table 9. RCT Characteristics for Short-Term CGM in Pregnant People With Type 1 Diabetes

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; NCT: national clinical trial; RCT: randomized controlled trial; SOC: standard of care.

Table 10. RCT Results for Short-Term CGM in Pregnant People With Type 1 Diabetes

Values are n or n (%) or as otherwise indicated.CGM: continuous glucose monitoring; CI: confidence interval; HbA1c: hemoglobin A1c; NR: not reported; OR: odds ratio; RCT: randomized controlled trial; TE: treatment effect.a N inconsistently reported for HbA1c outcome.

Tables 11 and 12 display notable limitations identified in each study.

Table 11. Study Relevance Limitations of RCTs of Intermittent CGM in Pregnant People With Type 1 Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; RCT: randomized controlled trial.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Enrolled study populations do not reflect relevant diversity.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 12. Study Design and Conduct Limitations of RCTs of Short-Term CGM Glucose Monitoring in Pregnant People With Type 1 Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Glucose Monitoring Devices for Short-Term Use in Type 1 Diabetes

For short-term monitoring of type 1 diabetes, there are few RCTs and systematic reviews. The evidence for short-term monitoring on glycemic control is mixed, and there was no consistency in HbA1c levels. Some trials have reported improvements in glucose control for the intermittent monitoring group but limitations in this body of evidence preclude conclusions. The definitions of control with short-term CGM use, duration of use and the specific monitoring protocols varied. In some studies, short-term monitoring was part of a larger strategy aimed at optimizing glucose control, and the impact of monitoring cannot be separated from the impact of other interventions. Studies have not shown an advantage for intermittent glucose monitoring in reducing severe hypoglycemia events but the number of events reported is generally small and effect estimates are imprecise. The limited duration of use may preclude an assessment of any therapeutic effect. RCTs of short-term CGM use for monitoring in pregnancy included women with both type 1 and 2 diabetes, with most having type 1 diabetes. One trial reported a difference in HbA1c levels at 36 weeks; the proportion of infants that were large for gestational age (>90th percentile) favored CGM while other trials did not. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant.

For individuals with type 1 diabetes who receive short-term continuous glucose monitoring, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity as well as intermediate outcomes related to measures of glucose control such as frequency and time in hypoglycemia and hyperglycemia. The evidence for short-term monitoring of glycemic control is mixed, and there was no consistency in HbA1c levels. Some trials have reported improvements in glucose control for the intermittent short-term monitoring group but limitations in this body of evidence preclude conclusions. The definitions of control with short-term CGM use, duration of use and the specific monitoring protocols varied. In some studies, short-term monitoring was part of a larger strategy aimed at optimizing glucose control, and the impact of monitoring cannot be separated from the impact of other interventions. Studies have not shown an advantage for intermittent glucose monitoring in reducing severe hypoglycemia events but the number of events reported is generally small and effect estimates imprecise. The limited duration of use may preclude an assessment of any therapeutic effect. Two RCTs of short-term CGM use for monitoring in pregnancy included women with both type 1 and 2 diabetes, with most having type 1 diabetes. One trial reported a difference in HbA1c levels at 36 weeks; the proportion of infants that were large for gestational age (>90th percentile) favored CGM while the second trial did not. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant in either study. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Medically Necessary by Clinical Input.

Population Reference No. 3

Continuous Glucose Monitoring Implanted Device

Clinical Context and Therapy Purpose

The purpose of an implantable CGM device is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with diabetes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with type 1  diabetes.

Interventions

One implantable CGM device (Eversense) is FDA cleared for use in the US. The Eversense Continuous Glucose Monitoring System is implanted in the subcutaneous skin layer and provides continuous glucose measurements over a 40 to 400 mg/dL range. The system provides real-time glucose values, glucose trends, and alerts for hypoglycemia and hyperglycemia and through a mobile application installed on a compatible mobile device platform. The Eversense CGM System is a prescription device indicated for use in adults (age 18 and older) with diabetes for up to 180 days. The device was initially approved as an adjunctive glucose monitoring device to complement information obtained from standard home blood glucose monitoring devices. Prescribing providers are required to participate in insertion and removal training certification.

Comparators

The following practice is currently being used to measure glucose levels: capillary blood sampling (finger stick) with blood glucose meters for self-monitoring.

Outcomes

The general outcomes of interest are a change in HbA1c levels, time spent in hypoglycemia, the incidence of hypoglycemic events, complications of hypoglycemia and QOL.

To assess short-term outcomes such as HbA1c levels, time spent in hypoglycemia, the incidence of hypoglycemic events, and complications of hypoglycemia, a minimum follow-up of 8 to 12 weeks is appropriate. To assess long-term outcomes such as QOL and maternal and infant outcomes, follow-up of 24 to 36 weeks would be appropriate.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Studies

One trial of implantable CGM in people with diabetes has been published. Trial characteristics, results, and limitations for the RCTs are shown in Tables 23 to 26 and briefly described below.

Renard et al (2022) reported results of the multicenter France Adoption Randomized Clinical Trial (NCT03445065) comparing implantable Eversense real-time CGM (n=159) versus self-monitoring of blood glucose or intermittently scanned CGM (n=80) in individuals with type 1 or type 2 diabetes.^45, Participants were adults, age 18 years and older, on multiple daily insulin injections or insulin pump. Participants were enrolled in 2 cohorts. Cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c levels >8%. Cohort 2 (n=90) included participants with type 1 with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. The primary outcomes were changes in HbA1c at day 180 in cohort 1 and change in time spent with glucose below 54 mg/dL between days 90 and 120 in cohort 2. In cohort 1, there was no difference in HbA1c at day 180 (difference=-0.1; 95% CI, -0.4 to 0.1; p=.34) or in time in range (difference=-0.9; 95% CI, -6.7 to 4.8; p=.75). For cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). Six out of 239 (3%) participants experienced skin irritation and/or redness from sensor insertion; 5 (2%) reported itching or pruritus and 5 (2%) reported at least one hematoma formation. Results for the patient-reported outcomes were not provided, but the text indicated that there were 'no significant changes'.

Table 23. Key RCT Characteristics for implantable CGM in People With Diabetes

Table 24. Summary of Key RCT Results for implantable CGM in People With Diabetes

Table 25. Study Relevance Limitations of RCTs for implantable CGM in People With Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Enrolled study populations do not reflect relevant diversity.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 26. Study Design and Conduct Limitations of RCTs for implantable CGM in People With Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Nonrandomized Studies

Data from 3 nonrandomized prospective studies (PRECISE, PRECISE II, AND PRECISION) were provided to the U.S. Food and Drug Administration (FDA) for the initial approval of Eversense as an adjunctive device.^50,51, Expanded approval was granted in June 2019 and Eversense is now approved as a device to replace fingerstick blood glucose measurements for diabetes treatment decisions.^52, Historical data from the system can be interpreted to aid in providing therapy adjustments. No new clinical studies were conducted to support the change in the indications for the device. The sponsor had previously performed clinical studies to establish the clinical measurement performance characteristics of the device, including accuracy across the claimed measuring range (40 to 400 mg/dL glucose), precision, claimed calibration frequency (every 12 hours), the wear period for the sensor (90 days), and performance of the alerts and notifications. This same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions.

In 2022, Eversense was FDA approved for use up to 180 days. Approval was based on the PROMISE pivotal study, which was designed to assess the safety and accuracy of the 180-day device.^53, PROMISE was a prospective, multicenter, unblinded, nonrandomized study of 181 adults with type 1 (69.6%) and type 2 (30.4%) diabetes conducted at 8 sites in the U.S. Participants had diabetes for at least 1 year. Participants were heterogenous with regard to diabetes treatment: 50.8% were using a continuous insulin infusion pump, 35.9% multiple daily injections of insulin, 8.8% oral diabetes medications only, and 4.4% basal insulin or only 1 injection per day (4.4%). Accuracy of the device was evaluated by comparing CGM to glucose analyzer values during 10 clinic visits. Sensors were removed after day 180. The safety endpoint was the rate of device-related or sensor insertion/removal procedure-related serious adverse events. For primary sensors, the percent CGM readings within 20% of glucose analyzer values was 92.9%; the overall mean absolute relative difference was 9.1%. There were no serious adverse events related to the device or insertion/removal procedures. There were no unanticipated adverse events and the most frequently reported adverse events were dermatological (e.g. skin irritation). All primary sensors were successfully removed on the first attempt.

Multiple post-marketing registry studies of the Eversense device have been published (Tables 27 and 28). Sanchez et al (2019) reported glucometric and safety data on the first 205 patients in the U.S. to use the Eversense device for at least 90 days.^54, Of the 205 patients, 62.9% reported having type 1 diabetes, 8.8% type 2 diabetes, and 28.3% were unreported; results were not reported separately by diabetes type. Diess et al (2019) reported safety outcomes for 3023 patients from 534 sites in Europe and South Africa who had used the device for 6 months or longer.^55, There were no serious adverse events, and the most commonly reported adverse events were sensor site infection and skin irritation. Tweden et al (2019) reported accuracy and safety data from 945 patients in Europe and South Africa who used either the 90-day or 180 day Eversense system for 4 insertion-removal cycles.^56, The percentage of patients using the 180-day system increased from cycle 1 to 4 as the device became more widely available (9%, 39%, 68% and 88% in cycles 1 to 4). There was no evidence of degradation of performance of the device over repeated insertion/removal cycles. Adverse events were not otherwise reported. Irace et al (2020) reported results of an uncontrolled study of 100 adults with type 1 diabetes at 7 centers in Italy who had the Eversense 180-day device inserted for the first time. Forty-five percent of participants were previous CGM users. Overall, HbA1c declined from a mean of 7.4% at baseline to 6.9% at 180 days (p<.0001). The greatest mean reduction was in the subgroup of participants who were CGM naive. No serious device-related adverse events occurred. There were 2 device-related adverse events: a mild incision site infection in one participant and inability to remove the device on the first attempt in a second participant.

Limitations of the evidence base include limited direct comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures. As a condition of approval, the Eversense sponsor is required to conduct a post-approval-study to evaluate the safety and effectiveness of the system compared to self-monitoring of blood glucose using a blood glucose meter in participants with either type 1 or type 2 diabetes (NCT04836546).^52, The study is expected to be completed in March 2026.

Table 27. Postmarketing Studies of the Eversense Device- Characteristics

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; SD: standard deviation; T1D: type 1 diabetes; T2D: type 2 diabetes.

Table 28. Postmarketing Studies of the Eversense Device- Results

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; IQR: interquartile range; MARD: mean absolute relative difference; NR: not reported; SD: standard deviation; SG: sensor glucose; TIR: time in range.

Section Summary: Continuous Glucose Monitoring Implanted Device for Long-Term Use

One RCT compared implantable CGM with control (self-monitoring of blood glucose or intermittently scanned CGM). The RCT was conducted in France and enrolled participants in 2 cohorts; cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c >8.0% while cohort 2 (n=90) included participants with type 1 diabetes with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. In cohort 1, there was no difference in mean HbA1c, time in range, or patient-reported outcomes at day 180. In cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). There were no differences in patient reported outcomes.

Nonrandomized prospective studies and postmarketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system that provides CGM for up to 4 insertion/removal cycles as an adjunct to home glucose monitoring devices. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. In February 2022, the FDA expanded approval of the device for use up to 180 days. Approval was based on the PROMISE pivotal clinical trial, which assessed accuracy and safety but not glycemic outcomes. Limitations of the evidence base include lack of direct comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures.

For individuals with type 1  diabetes who receive continuous glucose monitoring with an implantable device, the evidence includes an RCT and nonrandomized studies. The RCT compared implantable CGM with control (self-monitoring of blood glucose or intermittently scanned CGM). The RCT was conducted in France and enrolled participants in 2 cohorts; cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c >8.0% while cohort 2 (n=90) included participants with type 1 diabetes with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. In cohort 1, there was no difference in mean HbA1c, time in range, or patient-reported outcomes at day 180. In cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). There were no differences in patient reported outcomes. Nonrandomized prospective studies and post-marketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. In February 2022, the FDA expanded approval of the device for use up to 180 days. Approval was based on the PROMISE pivotal clinical trial, which assessed accuracy and safety but not glycemic outcomes. Limitations of the evidence base include limited comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Continuous Glucose Monitoring Devices for Use in Individuals with Type 2 Diabetes Who Are Treated with Insulin Therapy

There is limited ability to distinguish between long-term and short-term glucose monitoring in the analysis of the data for type 2 diabetes, consistent with the literature.

Clinical Context and Therapy Purpose

The purpose of long-term and short-term CGM devices is to provide a treatment option that is an alternative to or an improvement on existing therapies such as SBGM.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with type 2 diabetes who are treated with insulin therapy and who experience poor diabetes control despite current use of best practices. Poor control includes situations such as unexplained hypoglycemic episodes, hypoglycemic unawareness, and persistent hyperglycemia and A1C levels above target.

In addition, some individuals with type 2 diabetes may need to determine basal insulin levels prior to insulin pump initiation.

All individuals with type 2 diabetes require engagement in a comprehensive self-management and clinical assessment program that includes assessment of blood glucose control.

Interventions

The testing being considered is the use of long-term or short-term CGM devices to assess blood glucose levels as part of optimal diabetes management.

Comparators

Blood glucose monitoring is an essential component of type 2 diabetes management in order to monitor for and prevent hypoglycemia and hyperglycemia. For these individuals, guidelines recommend blood glucose monitoring prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when low blood glucose is suspected, after treating low blood glucose, and prior to and while performing critical tasks such as driving. The following practice is currently being used to measure glucose levels: SMBG (capillary blood sampling (finger stick) using blood glucose meters) and periodic measurement of HbA1c.

Outcomes

The general outcomes of interest are change in HbA1c levels, frequency of and time spent in hypoglycemia, frequency and time spent in hyperglycemia, complications of hypoglycemia and hyperglycemia, and QOL. To assess short-term outcomes such as HbA1c levels, a minimum follow-up of 8 to 12 weeks is appropriate. To assess long-term outcomes such as time spent in hypoglycemia, the incidence of hypoglycemic events, complications of hypoglycemia, and QOL, follow-up of 6 months to 1 year would be appropriate.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Kong et al (2024) published a systematic review and meta-analysis of CGM in type 2 diabetes.^29, The review included 17 RCTs (N=1619) of participants on insulin therapy (11 RCTs; n=1188) and not on insulin therapy (6 RCTs; n=431) published prior to May 2023 in Korean or English. All types of CGM were included. Ten of the 17 RCTs were published after 2015. Six of the RCTs were conducted in the United States, and 12 of the RCTs were multicenter. The meta-analytic effect size of CGM on HbA1c was -0.42 (95% CI, -0.79 to -0.05) for trials including participants on insulin therapy. The effect size was -0.25 (95% CI, -0.44 to -0.05) for trials including participants not receiving insulin therapy.

Randomized Controlled Trials

Several RCTs evaluated CGM in individuals on insulin therapy. Select trials are described below and in Tables 13 and 14.

Beck et al (2017) reported on the DIAMOND RCT.^30, DIAMOND compared CGM with the Dexcom device to SMBG in 158 participants at 25 endocrinology practices in North America (22 in the U.S., 3 in Canada). Participants who were adherent during a run-in period were eligible for randomization. Change in HbA1c level from baseline to 24 weeks was the primary outcome. Analyses were adjusted for baseline HbA1c levels and were performed using intention-to-treat analysis with missing data handling by multiple imputations. Week 24 follow-up was completed by 97% of the CGM group and 95% of the control group. Mean CGM use was greater than 6 days/week at 1 month, 3 months, and 6 months. The adjusted difference in mean change in HbA1c level from baseline to 24 weeks was -0.3% (95% CI, -0.5% to 0.0%; p=.022) favoring CGM. The adjusted difference in the proportion of patients with a relative reduction in HbA1c level of 10% or more was 22% (95% CI, 0% to 42%; p=.028) favoring CGM. There were no events of severe hypoglycemia or diabetic ketoacidosis in either group. The treatment groups did not differ in any of the QOL measures.

Haak et al (2017) compared intermittently scanned CGM with the Freestyle Libre device in 224 individuals at 26 European centers. ^31, At 6 months, there was no difference between groups in the primary outcome of change in HbA1c (p=.8222). However, results for secondary outcomes including time in hypoglycemia and treatment satisfaction favored the CGM group. No serious adverse events or severe hypoglycemic events were reported related to device use.

Yaron et al (2019) reported higher treatment satisfaction (the primary outcome) in 101 individuals using a flash glucose monitor compared to SMBG.^32, On secondary glycemic control measures, HbA1c was reduced by 0.82% compared to 0.33% in the control group (p=.005) without an increase in the frequency of hypoglycemic events.

Martens et al (2021) reported results of an RCT comparing real-time CGM with SMBG in 176 patients with poorly controlled type 2 diabetes (HbA1c levels 7.8% to 11.5%) treated with basal insulin without prandial insulin.^33, At 8 months, there was a statistically significantly greater decrease in mean HbA1c in the CGM group (adjusted difference, -0.4%; 95% CI -0.8% to -0.1%; p=.02), with 1 hypoglycemic event in each group. Aleppo et al (2021) reported a 6-month follow-up study of 163 patients who had been randomized in this same trial (93.1%).^34, Patients originally randomized to SMBG continued to use SMBG for another 6 months, and the CGM group was randomly reassigned either to continue CGM or discontinue CGM and resume SMBG. In the group that discontinued CGM, mean HbA1c increased from 7.9% at 8 months to 8.2% at 14 months, whereas in the group that continued CGM, mean HbA1c decreased from 8.2% to 8.1%.

Table 13. Key RCT Characteristics for CGM in Individuals with Type 2 Diabetes on Insulin

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; NCT: national clinical trial;NR: not reported; RCT: randomized controlled trial; SMBG: self-monitored blood glucose; T2D: type 2 diabetes.

Table 14. Key RCT Outcomes for CGM in Individuals with Type 2 Diabetes on Insulin

CGM: continuous glucose monitoring; CI: confidence interval; DTSQ: Diabetes Treatment Satisfaction; HbA1c: hemoglobin A1c; NCT: national clinical trial; NR: not reported; RCT: randomized controlled trial; SE: standard error; TE: treatment effect.

a serious hypoglycemic event defined as requiring third-party assistance.

Observational Studies

Because several RCTs exist, observational studies will be summarized briefly below only if they capture longer periods of follow-up (>6 months), larger populations, or particular subgroups of interest.

Long-term follow-up

Observational studies with follow-up of more than 6 months including adults with type 2 diabetes, the majority of whom were on insulin, have shown that reduction in mean HbA1c is maintained for 12 months,^36, and reductions in acute diabetes events, including severe hypoglycemia and diabetic ketoacidosis are maintained for 1 to 2 years.^21,37,22,

Individuals with Significant Hypoglycemia

Twelve-month open-access, follow-up results for long-term CGM with the Freestyle Libre device in 108 individuals from the Haak et al (2017) 6-month trial were reported in a second publication by Haak et al (2017).^38, Hypoglycemia was analyzed using 3 different glucose level thresholds (<70 mg/dl, <55 mg/dl, and <45 mg/dl). At 12-month follow-up, hypoglycemic events were reduced by 40.8% to 61.7% with a greater relative reduction in the most severe thresholds of hypoglycemia. At all 3 glucose level thresholds, there were statistically significant reductions in time in hypoglycemia, frequency of hypoglycemic events, time in nocturnal hypoglycemia, and frequency of nocturnal hypoglycemia. Change for hypoglycemic events per day at 12 months compared to baseline was also significant: -40.8% (glucose <70 mg/dl; p<.0001); -56.5% (glucose <55 mg/dl; p<.0001); -61.7% (glucose <45 mg/dl; p=.0001).

Pregnant People

Wilkie et al (2023) reported results of a systematic review of CGM in type 2 diabetes in pregnancy.^39, The review includes the same 3 RCTs described below. The meta-analytic treatment effect estimate of large-for-gestational-age infants (CGM, n=56 vs. control, n=53) was OR, 0.8 (95% CI, 0.3 to 1.8). There was no difference in development of preeclampsia (OR, 1.6, 95% CI, 0.3 to 7.2).

As discussed in the section on CGM in pregnant women with type 1 diabetes, 3 RCTs have evaluated short-term glucose monitoring in pregnant women with type 1 and type 2 diabetes. Most women had type 1 diabetes in both trials. There were 25 (35%) women with type 2 diabetes in Murphy et al (2008)^28, and 31 (20%) with type 2 diabetes in Secher et al (2013)^27, and 82 (27%) women with type 2 diabetes in Voormolen (2018).^26, Results for women with type 2 diabetes were not reported in Murphy et al (2008). Secher et al (2013) reported that 5 (17%) women with type 2 diabetes experienced 15 severe hypoglycemic events, with no difference between groups; other analyses were not stratified by diabetes type.

Section Summary: Continuous Glucose Monitoring Devices for Use in Individuals with Type 2 Diabetes Who Are Treated with Insulin

RCTs have evaluated CGM compared to SMBG in individuals with type 2 diabetes on intensive insulin therapy including both real-time CGM and intermittently scanned devices. One RCT evaluated CGM in patients treated with basal insulin using real-time CGM. All RCTs found either improved glycemic outcomes or no difference between groups with no increase in hypoglycemic events. In the DIAMOND trial, the adjusted difference in mean change in HbA1c level from baseline to 24 weeks was -0.3% (95% CI, -0.5% to 0.0%; p=.022) favoring CGM. The adjusted difference in the proportion of patients with a relative reduction in HbA1c level of 10% or more was 22% (95% CI, 0% to 42%; p=.028) favoring CGM. There were no events of severe hypoglycemia or diabetic ketoacidosis in either group. Yaron et al (2019) reported higher treatment satisfaction with CGM compared to control (the primary outcome). At 12-month follow-up in one of the trials of the Freestyle Libre device, hypoglycemic events were reduced by 40.8% to 61.7% with a greater relative reduction in the most severe thresholds of hypoglycemia. In the Martens trial of individuals treated with basal insulin without prandial insulin, there was a statistically significantly greater decrease in mean HbA1c in the CGM group (adjusted difference, -0.4%; 95% CI -0.8% to -0.1%; p=.02), with 1 hypoglycemic event in each group.

For individuals with type 2 diabetes who are treated with insulin therapy who receive long-term CGM, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity. RCTs have included individuals on intensive insulin therapy and individuals on basal insulin. Three RCTs have evaluated CGM compared to SMBG in individuals with type 2 diabetes on intensive insulin therapy; 1 using real-time CGM and 2 using an intermittently scanned device. One RCT evaluated CGM in patients treated with basal insulin. All found either improved glycemic outcomes or no difference between groups with no increase in hypoglycemic events. In the DIAMOND trial, the adjusted difference in mean change in HbA1c level from baseline to 24 weeks was -0.3% (95% CI, -0.5% to 0.0%; p=.022) favoring CGM. The adjusted difference in the proportion of patients with a relative reduction in HbA1c level of 10% or more was 22% (95% CI, 0% to 42%; p=.028) favoring CGM. There were no events of severe hypoglycemia or diabetic ketoacidosis in either group. Yaron et al (2019) reported higher treatment satisfaction with CGM compared to control (the primary outcome). At 12-month follow-up in one of the trials of the Freestyle Libre device, hypoglycemic events were reduced by 40.8% to 61.7% with a greater relative reduction in the most severe thresholds of hypoglycemia. In the Martens trial of individuals treated with basal insulin without prandial insulin, there was a statistically significantly greater decrease in mean HbA1c in the CGM group (adjusted difference, -0.4%; 95% CI -0.8% to -0.1%; p=.02), with 1 hypoglycemic event in each group. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Continuous Glucose Monitoring Devices for Use in Individuals with Type 2 Diabetes Who Are Not Treated with Insulin Therapy

Clinical Context and Therapy Purpose

The purpose of long-term and short-term CGM devices is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with type 2 diabetes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with type 2 diabetes who are not treated with insulin therapy.

All individuals with type 2 diabetes require engagement in a comprehensive self-management and clinical assessment program that includes assessment of blood glucose control.

Interventions

The testing being considered is the long-term or short-term use of CGM devices to assess blood glucose levels as part of optimal diabetes management.

Currently, CGM devices are of 2 designs; rtCGM provides real-time data on glucose level, glucose trends, direction, and rate of change, and iCGM devices that show continuous glucose measurements retrospectively. These devices are also known as flash-glucose monitors.

Comparators

SMBG (capillary blood sampling [finger stick]) using blood glucose meters and periodic measurement of HbA1c is used to measure glucose levels.

In contrast to recommendations in individuals on intensive insulin regimens, guidelines are less clear on when to prescribe blood glucose monitoring and how often monitoring is needed in individuals with type 2 diabetes who are not on insulin therapy. In individuals on oral antidiabetic agents only, routine glucose monitoring may be of limited additional clinical benefit. .^40,

Outcomes

The general outcomes of interest are change in HbA1c levels, frequency of and time spent in hypoglycemia, frequency and time spent in hyperglycemia, complications of hypoglycemia and hyperglycemia, and QOL. To assess short-term outcomes such as HbA1c levels, a minimum follow-up of 8 to 12 weeks is appropriate. To assess long-term outcomes such as time spent in hypoglycemia, the incidence of hypoglycemic events, complications of hypoglycemia, and QOL, follow-up of 6 months to 1 year would be appropriate.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

There is limited ability to distinguish between long-term and short-term glucose monitoring in the analysis of the data for type 2 diabetes, consistent with reporting in the literature. Therefore, this section includes both long-term and short-term uses.

Review of Evidence

Randomized Controlled Trials

Select RCTs that evaluated CGM in individuals with Type 2 diabetes who are not treated with insulin therapy are described below and in Tables 15 and 16.

Ehrhardt et al (2011) reported the results of a RCT evaluating the intermittent use of a CGM device over 12 weeks in adults with type 2 diabetes treated with diet/exercise and/or glycemia-lowering medications but not prandial insulin who had an initial HbA1c level of at least 7% but not more than 12%.^41, Twenty-nine of 100 participants (29.0%) were using basal insulin alone or in combination with oral agents. The trial compared real-time CGM with the Dexcom device used for 4 cycles (2 weeks on and 1 week off) with SMBG. Vigersky et al (2012) reported follow up data through 52 weeks.^42, The primary efficacy outcome was a mean change in HbA1c levels. Mean HbA1c levels in the CGM group were 8.4% at baseline, 7.4% at 12 weeks, 7.3% at 24 weeks, and 7.7% at 52 weeks. In the SMBG group, these values were 8.2% at baseline, 7.7% at 12 weeks, 7.6% at 24 weeks, and 7.9% at 52 weeks. During the trial, the reduction in HbA1c levels was significantly greater in the CGM group than in the SMBG group (p=.04). After adjusting for potential confounders (eg, age, sex, baseline therapy, whether the individual started taking insulin during the study), the difference between groups over time remained statistically significant (p<.001). The investigators also evaluated SMBG results for both groups. The mean proportions of SMBG tests less than 70 mg/dL were 3.6% in the CGM group and 2.5% in the SMBG group (p=.06).

Price et al (2021) reported results from the COntinuous Glucose Monitoring & Management In TypE 2 Diabetes (COMMITED; NCT03620357) RCT comparing rt-CGM (10 days a month for 3 months) to SMBG in adult patients with type 2 diabetes (HbA1c between 7.8% and 10.5%) who were receiving 2 or more oral antidiabetic drugs, but not insulin, in the U.S. and Canada between 2018 and 2020.^43, Participants were 47% female, 74% White, 14% Asian, 7% Black and 29% Hispanic. The mean age was 60 years. The change in HbA1c at week 12 was not statistically different (-0.5 (1.3)% vs -0.2 (1.1)% for the CGM and SMBG groups, respectively; p=.74). The reduction in HbA1c was not sustained at month 9 for either group (-0.2 (0.9)% vs 0.1 (1.3)%, respectively, for CGM versus SMBG groups (p=.79).

Wada et al (2020) reported results of an open-label, multicenter RCT in Japan including participants with non-insulin-treated type 2 diabetes with HbA1c ≥7.5% and <8.5%.^44, The trial compared flash glucose monitoring worn for 12 weeks (n=49) and conventional SMBG (n=51). The primary outcome was change in HbA1c level at 12 weeks. There was no significant between-group difference in the change from baseline in the 2 groups at 12 weeks (CMG, -0.43% vs. SMBG, -0.30%; difference=-0.13%; 95% CI, −0.35 to 0.09; p=.24) but there was a difference favoring CGM at 24 weeks (difference, −0.29%; 95% CI, −0.54 to −0.05; p=.02).

Aronson et al (2022) reported results of the IMMEDIATE multicenter RCT (NCT04562714) conducted in Canada including adults with type 2 diabetes and HbA1c of 7.5% or higher who were using at least 1 non-insulin antihyperglycemic therapy.^45, The 2 treatment groups were the flash glucose monitor CGM group (FreeStyle Libre Pro; n=58) worn 14 days at baseline and again at week 14 plus diabetes self-management education versus diabetes self-management education alone (DSME; n=58). DSME included instruction to self-monitor blood glucose at least 4 times daily. The primary outcome was the difference in percentage mean Time In Range (TIR; glucose 70-180 mg/dl) at 16 weeks. At 16 weeks, the CGM group had significantly greater mean TIR (difference=9.9%; 2.4 hours; 95% CI, 17.3% to 2.5%; p<.01).The mean HbA1c at 16 weeks was 7.6% in the CGM group compared to 8.1% in the DSME group (adjusted mean difference, 0.3%; 95% CI, 0% to 0.7%; p=.05). The Glucose monitoring satisfaction score was higher in the CGM group compared with the DSME group but there were no differences in the other patient-reported outcomes (Diabetes Distress Score, Adherence to Refills and Medications Scale for Diabetes and Skills, Confidence & Preparedness Index).

Tables 17 and 18 display notable limitations identified in the studies. These include a lack of blinding and heterogeneity in the participant populations, lack of data on diabetic events and percent of patients meeting target goals, and insufficient duration to determine effects on diabetic complications.

Table 15. Key RCT Characteristics for CGM in Individuals with Type 2 Diabetes not on Insulin Therapy

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c;  ; NR: not reported; RCT: randomized controlled trial; SMBG: self-monitored blood glucose; T2D: type 2 diabetes.

Table 16. Key RCT Outcomes for CGM in Individuals with Type 2 Diabetes not on Insulin Therapy

CGM: continuous glucose monitoring; CI: confidence interval; DDS: Diabetes Distress Scale; DTSQ: Diabetes Treatment Satisfaction; HbA1c: hemoglobin A1c; NCT: national clinical trial;NR: not reported; RCT: randomized controlled trial; TE: treatment effect.aSerious hypoglycemic event defined as requiring third-party assistance.

Table 17. Study Relevance Limitations of RCTs of CGM in Individuals with Type 2 Diabetes Not on Insulin Therapy for Glucose Monitoring in Type 2 Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; QOL: quality of life; RCT: randomized controlled trial.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Enrolled study populations do not reflect relevant diversity.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 18. Study Design and Conduct Limitations of RCTs of CGM in Individuals with Type 2 Diabetes Not on Insulin Therapy

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Continuous Glucose Monitoring Devices for Use in Individuals with Type 2 Diabetes Who Are Not Treated with Insulin Therapy

The trials reported mixed results with respect to benefits of CGM regarding glycemic control. However, participant populations were heterogenous with regard to their diabetic treatment regimens, and participants might not have been receiving optimal therapy. In individuals on oral antidiabetic agents only, routine glucose monitoring may be of limited additional clinical benefit. Additional evidence would be needed to show what levels of improvements in HbA1c over the short-term in this population would be linked to meaningful improvements over the long-term in health outcomes such as diabetes-related morbidity and complications.

For individuals with type 2 diabetes who are not treated with insulin therapy who receive long-term CGM, the evidence includes 4 RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity. Results were mixed regarding benefits of CGM with respect to glycemic control. Participant populations were heterogenous with regard to their diabetic treatment regimens, and participants might not have been receiving optimal therapy. In individuals on oral antidiabetic agents only, routine glucose monitoring may be of limited additional clinical benefit. Additional evidence would be needed to show what levels of improvement in blood glucose excursions and HbA1c levels over the short-term in this population would be linked to meaningful improvement in long-term health outcomes such as diabetes-related morbidity and complications. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 6

Short-term glucose monitoring for type 2 diabetes who require multiple daily doses of insulin and have poor control of diabetes 

For individuals with type 2 diabetes who receive short-term continuous glucose monitoring, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity as well as intermediate outcomes related to measures of glucose control such as frequency and time in hypoglycemia and hyperglycemia. The evidence for short-term monitoring of glycemic control is mixed, and there was no consistency in HbA1c levels. Some trials have reported improvements in glucose control for the short-term monitoring group but limitations in this body of evidence preclude conclusions. The definitions of control with short-term CGM use, duration of use and the specific monitoring protocols varied. In some studies, short-term monitoring was part of a larger strategy aimed at optimizing glucose control, and the impact of monitoring cannot be separated from the impact of other interventions. Studies have not shown an advantage for intermittent glucose monitoring in reducing severe hypoglycemia events but the number of events reported is generally small and effect estimates are imprecise. The limited duration of use may preclude an assessment of any therapeutic effect. Three RCTs of short-term CGM use for monitoring in pregnancy included women with both type 1 and 2 diabetes, with most having type 1 diabetes. One trial reported a difference in HbA1c levels at 36 weeks; the proportion of infants that were large for gestational age (>90th percentile) favored CGM while the other trials did not. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant in studies in which these outcomes were reported. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. .Medically Necessary by Clinical Input.

Population Reference No. 7

Continuous Glucose Monitoring Implanted Device

Clinical Context and Therapy Purpose

The purpose of an implantable CGM device is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with diabetes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with  2 diabetes.

Interventions

One implantable CGM device (Eversense) is FDA cleared for use in the US. The Eversense Continuous Glucose Monitoring System is implanted in the subcutaneous skin layer and provides continuous glucose measurements over a 40 to 400 mg/dL range. The system provides real-time glucose values, glucose trends, and alerts for hypoglycemia and hyperglycemia and through a mobile application installed on a compatible mobile device platform. The Eversense CGM System is a prescription device indicated for use in adults (age 18 and older) with diabetes for up to 180 days. The device was initially approved as an adjunctive glucose monitoring device to complement information obtained from standard home blood glucose monitoring devices. Prescribing providers are required to participate in insertion and removal training certification.

Comparators

The following practice is currently being used to measure glucose levels: capillary blood sampling (finger stick) with blood glucose meters for self-monitoring.

Outcomes

The general outcomes of interest are a change in HbA1c levels, time spent in hypoglycemia, the incidence of hypoglycemic events, complications of hypoglycemia and QOL.

To assess short-term outcomes such as HbA1c levels, time spent in hypoglycemia, the incidence of hypoglycemic events, and complications of hypoglycemia, a minimum follow-up of 8 to 12 weeks is appropriate. To assess long-term outcomes such as QOL and maternal and infant outcomes, follow-up of 24 to 36 weeks would be appropriate.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Studies

One trial of implantable CGM in people with diabetes has been published. Trial characteristics, results, and limitations for the RCTs are shown in Tables 23 to 26 and briefly described below.

Renard et al (2022) reported results of the multicenter France Adoption Randomized Clinical Trial (NCT03445065) comparing implantable Eversense real-time CGM (n=159) versus self-monitoring of blood glucose or intermittently scanned CGM (n=80) in individuals with type 1 or type 2 diabetes.^49, Participants were adults, age 18 years and older, on multiple daily insulin injections or insulin pump. Participants were enrolled in 2 cohorts. Cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c levels >8%. Cohort 2 (n=90) included participants with type 1 with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. The primary outcomes were changes in HbA1c at day 180 in cohort 1 and change in time spent with glucose below 54 mg/dL between days 90 and 120 in cohort 2. In cohort 1, there was no difference in HbA1c at day 180 (difference=-0.1; 95% CI, -0.4 to 0.1; p=.34) or in time in range (difference=-0.9; 95% CI, -6.7 to 4.8; p=.75). For cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). Six out of 239 (3%) participants experienced skin irritation and/or redness from sensor insertion; 5 (2%) reported itching or pruritus and 5 (2%) reported at least one hematoma formation. Results for the patient-reported outcomes were not provided, but the text indicated that there were 'no significant changes'.

Table 23. Key RCT Characteristics for implantable CGM in People With Diabetes

Table 24. Summary of Key RCT Results for implantable CGM in People With Diabetes

Table 25. Study Relevance Limitations of RCTs for implantable CGM in People With Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Enrolled study populations do not reflect relevant diversity.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 26. Study Design and Conduct Limitations of RCTs for implantable CGM in People With Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; RCT: randomized controlled trial.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Nonrandomized Studies

Data from 3 nonrandomized prospective studies (PRECISE, PRECISE II, AND PRECISION) were provided to the U.S. Food and Drug Administration (FDA) for the initial approval of Eversense as an adjunctive device.^50,51, Expanded approval was granted in June 2019 and Eversense is now approved as a device to replace fingerstick blood glucose measurements for diabetes treatment decisions.^52, Historical data from the system can be interpreted to aid in providing therapy adjustments. No new clinical studies were conducted to support the change in the indications for the device. The sponsor had previously performed clinical studies to establish the clinical measurement performance characteristics of the device, including accuracy across the claimed measuring range (40 to 400 mg/dL glucose), precision, claimed calibration frequency (every 12 hours), the wear period for the sensor (90 days), and performance of the alerts and notifications. This same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions.

In 2022, Eversense was FDA approved for use up to 180 days. Approval was based on the PROMISE pivotal study, which was designed to assess the safety and accuracy of the 180-day device.^53, PROMISE was a prospective, multicenter, unblinded, nonrandomized study of 181 adults with type 1 (69.6%) and type 2 (30.4%) diabetes conducted at 8 sites in the U.S. Participants had diabetes for at least 1 year. Participants were heterogenous with regard to diabetes treatment: 50.8% were using a continuous insulin infusion pump, 35.9% multiple daily injections of insulin, 8.8% oral diabetes medications only, and 4.4% basal insulin or only 1 injection per day (4.4%). Accuracy of the device was evaluated by comparing CGM to glucose analyzer values during 10 clinic visits. Sensors were removed after day 180. The safety endpoint was the rate of device-related or sensor insertion/removal procedure-related serious adverse events. For primary sensors, the percent CGM readings within 20% of glucose analyzer values was 92.9%; the overall mean absolute relative difference was 9.1%. There were no serious adverse events related to the device or insertion/removal procedures. There were no unanticipated adverse events and the most frequently reported adverse events were dermatological (e.g. skin irritation). All primary sensors were successfully removed on the first attempt.

Multiple post-marketing registry studies of the Eversense device have been published (Tables 27 and 28). Sanchez et al (2019) reported glucometric and safety data on the first 205 patients in the U.S. to use the Eversense device for at least 90 days.^54, Of the 205 patients, 62.9% reported having type 1 diabetes, 8.8% type 2 diabetes, and 28.3% were unreported; results were not reported separately by diabetes type. Diess et al (2019) reported safety outcomes for 3023 patients from 534 sites in Europe and South Africa who had used the device for 6 months or longer.^55, There were no serious adverse events, and the most commonly reported adverse events were sensor site infection and skin irritation. Tweden et al (2019) reported accuracy and safety data from 945 patients in Europe and South Africa who used either the 90-day or 180 day Eversense system for 4 insertion-removal cycles.^56, The percentage of patients using the 180-day system increased from cycle 1 to 4 as the device became more widely available (9%, 39%, 68% and 88% in cycles 1 to 4). There was no evidence of degradation of performance of the device over repeated insertion/removal cycles. Adverse events were not otherwise reported. Irace et al (2020) reported results of an uncontrolled study of 100 adults with type 1 diabetes at 7 centers in Italy who had the Eversense 180-day device inserted for the first time. Forty-five percent of participants were previous CGM users. Overall, HbA1c declined from a mean of 7.4% at baseline to 6.9% at 180 days (p<.0001). The greatest mean reduction was in the subgroup of participants who were CGM naive. No serious device-related adverse events occurred. There were 2 device-related adverse events: a mild incision site infection in one participant and inability to remove the device on the first attempt in a second participant.

Limitations of the evidence base include limited direct comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures. As a condition of approval, the Eversense sponsor is required to conduct a post-approval-study to evaluate the safety and effectiveness of the system compared to self-monitoring of blood glucose using a blood glucose meter in participants with either type 1 or type 2 diabetes (NCT04836546).^52, The study is expected to be completed in March 2026.

Table 27. Postmarketing Studies of the Eversense Device- Characteristics

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; SD: standard deviation; T1D: type 1 diabetes; T2D: type 2 diabetes.

Table 28. Postmarketing Studies of the Eversense Device- Results

CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; IQR: interquartile range; MARD: mean absolute relative difference; NR: not reported; SD: standard deviation; SG: sensor glucose; TIR: time in range.

Section Summary: Continuous Glucose Monitoring Implanted Device for Long-Term Use

One RCT compared implantable CGM with control (self-monitoring of blood glucose or intermittently scanned CGM). The RCT was conducted in France and enrolled participants in 2 cohorts; cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c >8.0% while cohort 2 (n=90) included participants with type 1 diabetes with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. In cohort 1, there was no difference in mean HbA1c, time in range, or patient-reported outcomes at day 180. In cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). There were no differences in patient reported outcomes.

Nonrandomized prospective studies and postmarketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system that provides CGM for up to 4 insertion/removal cycles as an adjunct to home glucose monitoring devices. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. In February 2022, the FDA expanded approval of the device for use up to 180 days. Approval was based on the PROMISE pivotal clinical trial, which assessed accuracy and safety but not glycemic outcomes. Limitations of the evidence base include lack of direct comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures.

For individuals with type 2 diabetes who receive continuous glucose monitoring with an implantable device, the evidence includes an RCT and nonrandomized studies. The RCT compared implantable CGM with control (self-monitoring of blood glucose or intermittently scanned CGM). The RCT was conducted in France and enrolled participants in 2 cohorts; cohort 1 (n=149) included participants with type 1 or type 2 diabetes with HbA1c >8.0% while cohort 2 (n=90) included participants with type 1 diabetes with time spent with glucose values below 70 mg/dL for more than 1.5 hours per day in the previous 28 days. In cohort 1, there was no difference in mean HbA1c, time in range, or patient-reported outcomes at day 180. In cohort 2, the mean difference in time spent below 54 mg/dL between days 90 and 120 was statistically significant favoring implantable CGM (difference=-1.6% [23 minutes]; 95% CI, -3.1 to -0.1; p=.04). There were no differences in patient reported outcomes. Nonrandomized prospective studies and post-marketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. In February 2022, the FDA expanded approval of the device for use up to 180 days. Approval was based on the PROMISE pivotal clinical trial, which assessed accuracy and safety but not glycemic outcomes. Limitations of the evidence base include limited comparisons to SMBG, lack of differentiation in outcomes for type 1 diabetes versus type 2 diabetes, and variability in reporting of trends in secondary glycemic measures. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. 

Population reference No. 8

Continuous Glucose Monitoring Use in Pregnant People With Gestational Diabetes

Clinical Context and Therapy Purpose

The purpose of long-term CGM and short-term (intermittent) glucose monitoring devices is to provide a treatment option that is an alternative to or an improvement on existing therapies in persons with gestational diabetes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are persons with gestational diabetes.

Interventions

The testing being considered are devices that provide continuous, long-term glucose levels to the patient to direct insulin regimens and intermittent (ie, 72 hours), short-term monitoring of glucose levels used by the provider to optimize management.

Comparators

The following practice is currently being used to measure glucose levels: capillary blood sampling (finger stick) for blood glucose meters for self-monitoring.

Outcomes

The general outcomes of interest are a change in HbA1c levels, time spent in hypoglycemia, the incidence of hypoglycemic events, complications of hypoglycemia, and QOL.

To assess short-term outcomes such as HbA1c levels, time spent in hypoglycemia, the incidence of hypoglycemic events, and complications of hypoglycemia, a minimum follow-up of 8 to 12 weeks is appropriate. To assess long-term outcomes such as QOL and maternal and infant outcomes, follow-up of 24 to 36 weeks would be appropriate.

Study Selection

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Two trials of glucose monitoring in women with gestational diabetes have been published. Trial characteristics, results, and limitations for the RCTs limited to gestational diabetes are shown in Tables 19 to 22 and briefly described below. In addition, the GlucoMOMS trial described in the previous section on pregnant women with type 1 diabetes also included 109 women with gestational diabetes.^26,

Lai et al (2023) published results of an RCT comparing CGM plus SMGB (n=77) to SMGB (n=77) in pregnant people with gestational diabetes at 24 to 28 gestation with HbA1c <6% between 2019 and 2021 at a single center in China (NCT03955107).^47, Study visits occurred at 4 and 8 weeks. Participants in the CGM group were provided with a Medtronic CGM system that measured subcutaneous interstitial glucose for 3 consecutive days and were instructed to use CGM every 4 weeks (0, 4, and 8 weeks). The SMBG group was instructed to perform SMBG 4 times per day for 3 consecutive days every 4 weeks (0, 4 and 8 weeks). Participants in both groups continued their usual protocol of capillary glucose monitoring during their pregnancy and were asked to perform SMBG at least 7 times weekly. Most outcomes did not differ by treatment group with the exception of proportion of participants within recommended gestational weight gain (59.7% vs. 40.3%, p=.046).

In the RCT, Wei et al (2016) evaluated the use of CGM in 120 women with gestational diabetes at 24 to 28 weeks.^48, Patients were randomized to prenatal care plus CGM (n=58) or SMBG (n=62). The CGM sensors were reportedly inserted for 48 to 72 hours on weekdays; it is not clear whether the readings were available in real-time. The investigators assessed a number of endpoints and did not specify primary outcomes; a significance level of p<.05 was used for all outcomes. The groups did not differ significantly in a change in most outcomes, including a change in maternal HbA1c levels, rates of preterm delivery before the 35th gestational week, cesarean delivery rates, proportions of large-for-gestational-age infants, or rates of neonatal hypoglycemia. Women in the CGM group gained significantly less weight than those in the SMBG group.

Table 19. Key RCT Characteristics for CGM in Pregnant People With Gestational Diabetes

BMI: Body mass index; CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; RCT: randomized controlled trial; SMBG: self-monitored blood glucose.

Table 20. RCT Outcomes for CGM in Pregnant People With Gestational Diabetes

Values are n (%) or as otherwise indicated.

CGM: continuous glucose monitoring; CI: confidence interval; HbA1c: hemoglobin A1c; NR: not reported; RCT: randomized controlled trial; RR: relative risk; TE: treatment effect.a N inconsistently reported for HbA1c outcome.

Tables 21 and 22 display notable limitations identified in the studies.

Table 21. Study Relevance Limitations of RCTs for CGM in Pregnant People With Gestational Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; HbA1c: hemoglobin A1c; RCT: randomized controlled trial.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Enrolled study populations do not reflect relevant diversity.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 22. Study Design and Conduct Limitations of RCTs for CGM in Pregnant People With Gestational Diabetes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.CGM: continuous glucose monitoring; CI: confidence interval; RCT: randomized controlled trial.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Continuous Glucose Monitoring Use in Pregnant People With Gestational Diabetes

The 2 RCTs in women with gestational diabetes were conducted in China with the intervention starting in the second or third trimester and mean baseline HbA1c level less than 6.0%. The GlucoMOMS trial also included women with gestational diabetes. Trial reporting was incomplete; however, there were no differences between groups for most reported outcomes.

For individuals who are pregnant with gestational diabetes who receive long-term CGM or short-term (intermittent) glucose monitoring, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related morbidity. In the RCTs, trial reporting was incomplete; however, there was no difference between the groups for most reported outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2019 Input

Clinical input was sought to help determine whether the use of continuous or intermittent monitoring of glucose in the interstitial fluid would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 3 respondents, including 3 physician-level responses identified through 1 specialty society, including 2 physicians with academic medical center affiliations.

Type 1 Diabetes

For individuals who have type 1 diabetes who receive short-term glucose monitoring, clinical input supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice when used in specific situations such as poor control of Type 1 diabetes despite the use of best practices and to help determine basal insulin levels prior to insulin pump initiation.

Type 2 Diabetes

For individuals who have type 2 diabetes who do not require insulin who receive long-term continuous glucose monitoring (CGM), clinical input does not support a clinically meaningful improvement in net health outcome and does not indicate this use is consistent with generally accepted medical practice.

For individuals with type 2 diabetes who are willing and able to use the device and have adequate medical supervision and who experience significant hypoglycemia on multiple daily doses of insulin or an insulin pump in the setting of insulin deficiency who receive long-term continuous glucose monitoring, clinical input supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice.

For individuals with type 2 diabetes who require multiple daily doses of insulin who receive short-term CGM, clinical input supports that this use provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice when used in specific situations such as poor control of diabetes despite use of best practices and to help determine basal insulin levels prior to insulin pump initiation.

Further details from clinical input are included in the Appendix.

PRACTICE GUIDELINES AND POSITION STATEMENTS

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Association of Clinical Endocrinologists

In 2023, the American Association of Clinical Endocrinology (AACE) published an updated consensus statement on an algorithm for type 2 diabetes management. A subset of the statements regarding CGM are below.^58,

• "CGM is highly recommended to assist persons with diabetes in reaching goals safely. CGM has provided a major advance in the treatment of persons with all forms of DM."
• "The use of CGM is recommended for persons treated with insulin to optimize glycemic control while minimizing hypoglycemia."

In 2022, the American Association of Clinical Endocrinology (AACE) published clinical practice guideline for developing diabetes care plans and made the following recommendations (level of evidence) on CGM:^59,

• "All persons who use insulin should use continuous glucose monitoring (CGM) or perform blood glucose monitoring (BGM) a minimum of twice daily and ideally before any insulin injection." (Grade A; Best Evidence Level 1)

• "Real-time continuous glucose monitoring (rtCGM) or intermittently scanned continuous glucose monitoring (isCGM) is recommended for all persons with T1D [type 1 diabetes], regardless of insulin delivery system, to improve A1C levels and to reduce the risk for hypoglycemia and DKA." (Grade A; Best Evidence Level 1)

• "rtCGM or isCGM is recommended for persons with T2D [type 2 diabetes] who are treated with insulin therapy, or who have high risk for hypoglycemia and/or with hypoglycemia unawareness." (Grade A; Best Evidence Level 1)

In 2021, the American Association of Clinical Endocrinology (AACE) published recommendations on the use of advanced technology in the management of diabetes and made the following recommendations (level of evidence) on CGM:^60,

• CGM is strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as 3 or more injections of insulin per day or the use of an insulin pump. (Grade A; High Strength of Evidence)

• CGM is recommended for all individuals with problematic hypoglycemia (frequent/severe hypoglycemia, nocturnal hypoglycemia, hypoglycemia unawareness).(Grade A; Intermediate-High Strength of Evidence)

• CGM is recommended for children/adolescents with T1D. (Grade A; Intermediate-High Strength of Evidence)

• CGM is recommended for pregnant women with T1D and T2D treated with intensive insulin therapy. (Grade A; Intermediate-High Strength of Evidence)

• CGM is recommended for women with gestational diabetes mellitus (GDM) on insulin therapy. (Grade A; Intermediate Strength of Evidence)

• CGM may be recommended for women with GDM who are not on insulin therapy. (Grade B; Intermediate Strength of Evidence)

• CGM may be recommended for individuals with T2D who are treated with less intensive insulin therapy. (Grade B; Intermediate Strength of Evidence)

American Diabetes Association

The American Diabetes Association (2023) “Standards of Medical Care in Diabetes^61," made the following recommendations (level of evidence) on CGM devices:

• "Real-time CGM (A) or intermittently scanned continuous glucose monitoring (B) should be offered for diabetes management in adults with diabetes on multiple daily injections or continuous subcutaneous insulin infusion who are capable of using devices safely (either by themselves or with a caregiver). The choice of device should be made based on patient circumstances, desires, and needs."

• "Real-time CGM (A) or intermittently scanned continuous glucose monitoring (C) should be offered for diabetes management in adults with diabetes on basal insulin who are capable of using devices safely (either by themselves or with a caregiver). The choice of device should be made based on patient circumstances, desires, and needs."

• "Real-time CGM (B) or intermittently scanned continuous glucose monitoring (E) should be offered for diabetes management in youth with type 1 diabetes on multiple daily injections or continuous subcutaneous insulin infusion who are capable of using the device safely (either by themselves or with a caregiver). The choice of device should be made based on patient circumstances, desires, and needs."

• "Real-time continuous glucose monitoring or intermittently scanned continuous glucose monitoring should be offered for diabetes management in youth with type 2 diabetes on multiple daily injections or continuous subcutaneous insulin infusion who are capable of using the devices safely (either by themselves or with a caregiver). The choice of device should be made based on the individual’s circumstances, preferences, and needs." (E)

• When used as an adjunct to pre- and postprandial blood glucose monitoring, CGM can help to achieve A1c targets in diabetes and pregnancy (B).

• Periodic use of real-time or intermittently scanned cCGM or use of professional CGM can be helpful for diabetes management in circumstances where continuous use of CGM is not appropriate, desired, or available (C).

National Institute for Health and Care Excellence

In 2022, the National Institute for Health and Care Excellence (NICE) updated its guidance on management of type 1^62, and type 2^63, diabetes. The guidance included the following updated recommendations on CGM (refer to source documents for complete guidance):

Type 1 Diabetes

• "Offer adults with type 1 diabetes a choice of real-time continuous glucose monitoring (rtCGM) or intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash'), based on their individual preferences, needs, characteristics, and the functionality of the devices available. "

"When choosing a (CGM) device:

• use shared decision making to identify the person's needs and preferences, and offer them an appropriate device

• if multiple devices meet their needs and preferences, offer the device with the lowest cost"^62,

Type 2 Diabetes

"Offer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to adults with type 2 diabetes on multiple daily insulin injections if any of the following apply:

• they have recurrent hypoglycaemia or severe hypoglycaemia

• they have impaired hypoglycaemia awareness

• they have a condition or disability (including a learning disability or cognitive impairment) that means they cannot self-monitor their blood glucose by capillary blood glucose monitoring but could use an isCGM device (or have it scanned for them)

• they would otherwise be advised to self-measure at least 8 times a day."

"Offer isCGM to adults with insulin-treated type 2 diabetes who would otherwise need help from a care worker or healthcare professional to monitor their blood glucose."

"Consider real-time continuous glucose monitoring (rtCGM) as an alternative to isCGM for adults with insulin-treated type 2 diabetes if it is available for the same or lower cost."^63,

The guidance and accompanying evidence review do not specifically mention implantable CGM devices.

Endocrine Society

The Endocrine Society (2022) published clinical practice guidelines of management of individuals at high risk of hypoglycemia and included the following recommendations on CGM:^64,

• We recommend CGM rather than self-monitoring of blood glucose (SMBG) by fingerstick for patients with type 1 diabetes (T1D) receiving multiple daily injections (MDIs).

• We suggest real-time continuous glucose monitoring CGM be used rather than no CGM for outpatients with type 2 diabetes (T2D) who take insulin and/or sulfonylureas (SUs) and are at risk for hypoglycemia.

The Endocrine Society (2016) published clinical practice guidelines that included the following recommendations on CGM^65,:

6. "Real-time continuous glucose monitors in adult outpatients

6.1 We recommend real-time continuous glucose monitoring (RT-CGM) devices for adult patients with T1DM who have A1C levels above target and who are willing and able to use these devices on a nearly daily basis.

6.2 We recommend RT-CGM devices for adult patients with well-controlled T1DM who are willing and able to use these devices on a nearly daily basis.

Use of continuous glucose monitoring in adults with type 2 diabetes mellitus [T2DM]

6.3 We suggest short-term, intermittent RT-CGM use in adult patients with T2DM (not on prandial insulin) who have A1C levels ≥7% and are willing and able to use the device."

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVeRAGE

In January 2017, the Centers for Medicare & Medicaid Services (CMS) ruled that CGM devices (therapeutic CGMs) approved by the U.S. Food and Drug Administration (FDA) that can be used to make treatment decisions are considered durable medical equipment.^66, A CGM is considered a therapeutic CGM if it is approved by the FDA for use in place of a blood glucose monitor for making diabetes treatment decisions such as changes in diet and insulin dosage. Initially, CMS did not consider the smartphone application as a DME component and did allow payment for that part of the CGM system. Subsequently, in June 2018, CMS made an announcement that Medicare’s published coverage policy for CGMs will be modified to support the use of CGMs in conjunction with a smartphone, including the important data sharing function they provide for patients and their families.^67, Currently marketed therapeutic CGM systems are included in Table 1.

In 2020, Medicare assigned relative value units to the insertion, removal and removal/reinsertion codes uses for provision of the implantable glucose sensor device.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 29.

Table 29. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

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Codes

Applicable Modifiers

As per correct coding guidelines

Policy History