Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

**Covered Indications**

Continuous glucose monitors (CGMs) are class III medical devices that require
premarket approval by the United States Food and Drug Administration (FDA). In
order to be considered reasonable and necessary, the FDA approved indication
must include use as a therapeutic CGM.1 The FDA recently approved expanding
the indications of an implantable CGM (I-CGM) product to replace fingerstick
blood glucose measurements for diabetes treatment decisions.

Therapeutic I-CGMs are considered reasonable and necessary by Medicare when
all of the following coverage criteria (1-4) are met:

  1. The beneficiary has diabetes mellitus (DM) (Refer to the ICD-10 code list in the LCD-related Billing and Coding Article for applicable diagnoses); and,
  2. The beneficiary's treating practitioner has concluded that the beneficiary (or beneficiary's caregiver) has sufficient training using the I-CGM prescribed as evidenced by providing a prescription; and, 
  3. The I-CGM is prescribed in accordance with its FDA indications for use; and, 
  4. The beneficiary for whom an I-CGM is being prescribed, to improve glycemic control, meets at least 1 of the criteria below:
    1. The beneficiary is insulin-treated; or, 
    2. The beneficiary has a history of problematic hypoglycemia with documentation of at least 1 of the following:
      1. Recurrent (more than one) level 2 hypoglycemic events (glucose < 54 mg/dL (3.0 mmol/L)) that persist despite multiple (more than one) attempts to adjust medication(s) and/or modify the diabetes treatment plan; or,
      2. A history of one level 3 hypoglycemic event (glucose < 54 mg/dL (3.0 mmol/L)) characterized by altered mental and/or physical state requiring third-party assistance for treatment of hypoglycemia

**CGM Continued Coverage**

Every 6 months following the initial prescription of the CGM, the treating
practitioner conducts an in-person or Medicare-approved telehealth visit with
the beneficiary to document adherence to their CGM regimen and diabetes
treatment plan.

**Limitations**

I-CGM devices will not be considered reasonable and necessary for short-term
(72 hours to 1 week) diagnostic use.

**Exception:** For those beneficiaries who have previously met the coverage
criteria for a non-implantable therapeutic CGM through the Medicare durable
medical equipment (DME) benefit and subsequently choose to switch to the
implantable device, they may do so with a provider order. However, all other
coverage criteria above must be fulfilled in order for Medicare payment.

**Background**

DM is a chronic metabolic disease involving an underproduction or resistance
to insulin, resulting in elevated blood glucose levels. The 2 most common
types of diabetes are type 1 (T1DM) and type 2 (T2DM).2 T1DM comprises
approximately 5-10% of diabetes cases and describes an etiology in which an
autoimmune response damages the insulin-producing beta cells of the pancreas,
resulting in insufficient insulin production. Conversely, T2DM is
characterized by insulin resistance.2,3 In T2DM, an individual's insulin
production fails to offset the deficit that is created by the resistance.2
T2DM constitutes an estimated 90%-95% of diabetes cases.3

Approximately 11.3% of Americans have diagnosed diabetes, and an additional
3.4% of Americans are estimated to have undiagnosed diabetes. The prevalence
of diabetes is known to increase with age. In Medicare aged populations in the
United States (U.S.) ( 65 years of age), 22.4% of the population has
diagnosed diabetes, with an additional 4.7% estimated to have undiagnosed
diabetes.4 Economic evaluations have estimated that diabetes annually accounts
for $237 billion in direct U.S. medical expenditure, and an additional $90
billion in lost productivity.5

Acute complications of diabetes include hypoglycemia, hyperglycemia, diabetic
coma, and nonketotic hyperosmolar coma. Chronic hyperglycemia, resulting from
poorly controlled diabetes, may result in serious and life-threatening damage,
including dysfunction and failure of the eyes, kidneys, nervous system and
cardiovascular system. The complications of DM are far less common and less
severe in people who have well-controlled blood sugar levels.2

To prevent and/or delay the development of both short- and long-term
complications of diabetes, the American Diabetes Association (ADA) recommends
person-centered care aimed at timely treatment decisions following evidence-
based guidelines. Person-centered care goals include minimizing the
progression of hyperglycemia with more intensive approaches for individuals at
higher risk which include those with higher glucose levels (e.g., fasting
blood glucose 110-125 mg/dL, 2 hour post-challenge glucose 173-199 mg/dL, A1C
_>_ 6.0%).6

Diabetes treatment relies on diet, exercise, lifestyle modifications, and in
many, medications in order to keep their blood sugar under a stable and
controlled level. Close glucose monitoring either multiple times a day or
continuously may be warranted in those diabetics that are having difficulty
maintaining that level.2,7

CGM devices measure glucose via interstitial fluid instead of blood. CGM
systems traditionally rely on a multi-part system that often involves: 1.) a
sensor that is inserted into subcutaneous tissue; 2.) a receiver/mobile
application consisting of a display and interface; 3.) a transmitter component
that is attached to the sensor and worn externally.7,8 The sensors for these
subcutaneous CGM systems need to be removed and replaced every 6- to 14-days
depending upon the system.7

Despite the number of benefits that subcutaneous CGM offers in the DM
management paradigm, some CGM studies have reported relatively high attrition
rates that patients attributed to discomfort, contact dermatitis, issues
changing the sensors, and physical interference with activities of daily
living.9 The rationale for I-CGM seeks to circumvent these negative patient
experiences. Unlike with subcutaneous CGM, I-CGM involves a sensor that is
surgically implanted for longer spans of time between replacement, allowing
for skin barrier closure, and less frequent manipulation.

The primary aim of this summary of evidence is to determine if I-CGM performs
with equivalent clinical validity, efficacy, safety, and patient perceived
benefit when compared with subcutaneous CGM devices. The secondary aim of this
summary of evidence is to evaluate the expected magnitude of benefit across
the aforementioned outcomes resulting from the inclusion of I-CGM into the
diabetes management paradigm.

At the time of this review, the Eversense E3 is the only device that has
received clearance for use by the FDA. However, it is this Medicare
Administrative Contractor's expectation that additional devices are in the
development and/or FDA approval process and soon may be publicly available.
Hence, this LCD is written to reflect coverage criteria and accompanying
evidentiary review and analysis on I-CGM devices in an agnostic manner without
the endorsement of any specific product.

**FDA Approvals**

Eversense Continuous Glucose Monitoring System:
<https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160048A.pdf>

**Literature Analysis**

_Clinical Validity_

The accuracy of CGM devices is most commonly assessed by evaluating mean
absolute relative difference (MARD). The MARD value represents the average
percent difference between glucose readings that are concurrently obtained at
multiple timepoints via an index test (I-CGM in this instance) and via an
established reference standard test. MARD is then reported as a percentage,
with lower values signifying a higher degree of test accuracy.10 For
reference, 1 narrative review reported that the majority of CGM systems
achieve an average MARD of between 9% to 14%, and that a MARD of < 10% had
been discussed as a threshold for a CGM system that is accurate enough to
inform insulin dosage decisions.11 Thirteen of the studies (14 publications)
identified by the literature search evaluated the accuracy of I-CGM with
MARD.12-25

Four of these 13 studies performed comparative analyses analyzing the accuracy
of I-CGM compared with subcutaneous CGM systems.13,14,18,20

Fokkert and colleagues conducted a multi-test diagnostic cohort study among 23
athletes with T1DM. All 23 participants utilized an Eversense device, Free
Style Libre (FSL) Flash Glucose Monitoring (FGM) system (subcutaneous CGM),
and FSL Precision NeoPro strips (diagnostic standard). During normal activity
among this sample of patients, Eversense performed with a MARD of 13%  6%,
and the FSL FGM system had a MARD of 12%  5%; differences in these MARD
values were not statistically quantified.18

One study conducted a 3-way MARD analysis, comparing the accuracy of
Eversense, the FSL Pro system (subcutaneous CGM), and the Dexcom G5 system
(DG5) in a head-to-head fashion, with the StatStrip Xpress meter serving as
the diagnostic standard. In this trial, 23 adults with T1DM utilized all 4
glucose monitoring devices over a 6-week timespan. Over the course of this
trial, the authors reported that the MARD of Eversense was 14.8%  14.8%; FSL
Pro performed with a MARD of 16.3%  15.4%, and the MARD of Libre Pro was
18.0%  17.9%. Jafri, et al. then performed a pairwise comparison between
these 3 MARD values, and determined that in this study, DG5 was significantly
more accurate (P=0.004) than FSL Pro, and Eversense was significantly more
accurate than both DG5 (P=0.008) and FSL Pro (P<0.000).20

Boscari and colleagues performed 2 separate trials comparing the MARD of
Eversense with that of DG5. In the first trial, 11 adults with T1DM and HbA1c
> 10% at baseline were enrolled, and Yellow Spring Instruments (YSI) 2300 STAT
Plus was used as the reference standard. Over the 1-week follow-up, the MARD
of I-CGM (11.4% [interquartile range (IQR): 5.04% to 18.54%]) was
statistically significantly less accurate (signed-rank test _P_ <0.05)
compared with that of DG5 (7.91% [IQR: 4.14% to 14.30%]).13 The second trial
was designed as a crossover randomized controlled trial (RCT) study, in which
16 adults with T1DM and HbA1c < 10% underwent 12 weeks of DG5 and 12 weeks of
Eversense, with self-monitoring of blood glucose (SMBG) serving as the
reference test. Among this sample of 16 participants, the MARD of Eversense
(12.27%  11.55%) was significantly more accurate ( _P <_0.001) when compared
with the MARD of DG5 (13.14%  14.76%).14

Nine single-test diagnostic accuracy studies were also identified; these
publications assessed the MARD of I-CGM compared against a diagnostic
reference standard (YSI 2300 STAT Plus, SMBG, or venous blood laboratory
measurements). Among these 9 studies, the average MARD of I-CGM ranged between
8.8% to 12.3%.15-17,19,21-25

_Clinical Efficacy_

Glycated hemoglobin (HbA1c) is a key measure used to evaluate diabetes risk
and morbidity.2 Although the ADA recognizes that individual HbA1c normal
ranges may vary, they recognize 7% as the standard threshold which most adult
diabetics try to stay below.26 None of the 16 studies included in the
literature review performed a comparative analysis of HbA1c change between
I-CGM and subcutaneous CGM. However, 6 noncomparative studies meeting
inclusion did assess HbA1c among patients using Eversense, including 3 that
performed a pretest-posttest analysis. Among those 3 before-and-after trials,
all 3 determined that mean HbA1c levels statistically significantly decreased
between baseline (mean: 7.4% - 7.6%) and final study follow-up (mean: 6.9% -
7.19%).16,21,27 No statistical analyses were performed in the other 3 studies
evaluating HbA1c, but all 3 noted a trend of HbA1c reduction following
management with I-CGM.14,19,28

Time in range (TIR) is an often-utilized surrogate outcome, used to evaluate
the efficacy of diabetes management. TIR measures the percentage of time that
CGM readings fall within the target blood glucose range (commonly defined as
between 70 - 180 mg/dL).10,29 One study was identified that directly compared
TIR between patients using I-CGM systems and those utilizing subcutaneous CGM
systems.14 Boscari, et al. (2022) conducted a crossover RCT trial in which
patients underwent 12 weeks of management with Eversense I-CGM and 12 weeks
of management with the DG5 system. Results of this study showed that on
average, 71.14%  12.29% of the I-CGM group readings were in the target range,
which was statistically significantly favored ( _P_ <0.028) when compared with
the 66.99%  11.8% mean TIR exhibited by the DG5 group. Four additional
studies also evaluated TIR, but only among patients managing DM with
I-CGM.23,24,27,28 One of these 4 studies performed a pretest-posttest
statistical analysis among 100 adults with T1DM. Irace, et al. found that
diabetes management with Eversense was associated with a significant
improvement of TIR compared with baseline.27 For 3 of the 4 noncomparative
trials evaluating mean TIR during management with Eversense, the mean TIR was
between 62.3% - 69% 23,24,27; the fourth study had multiple different cohorts
based upon patient characteristics and could not be pooled.28

_Patient Reported Outcome Metrics (PROMs)_

Boscari, et al. (2022) was the only publication that comparatively analyzed
PROMs between I-CGM and subcutaneous CGM.14 In this crossover trial, all 16
patients underwent 12 weeks of management with the Eversense system and 12
weeks with the DG5. Patient quality of life (QOL) was measured with the
validated 17-item Diabetes Distress Scale (DDS), which asks respondents to
evaluate each item with a 6-point Likert Scale ranging from 1 (no problem) to
6 (serious problem). Eversense was statistically significantly favored
compared with DG5 for the total DDS score (I-CGM, 2.1  1.1; DG5, 2.6  1.4;
P=0.009) as well as for the emotional burden domain score (I-CGM, 2.1  1.0;
DG5, 2.7  1.4; P=0.01), regimen-related distress domain score (I-CGM, 2.1 
1.1; DG5, 2.7  1.3; P=0.007), and the interpersonal distress score (I-CGM,
2.0  1.1; DG5, 2.6  1.2; P=0.003). Only the physician-related distress
domain score was not significantly different (P=0.12) between DG5 and
Eversense groups. Patient satisfaction with CGM devices was measured with the
Diabetes Treatment Satisfaction Questionnaire (DTSQ), which is an 8-item
survey that patients are to score between 0 (not satisfied) and 6 (extremely
satisfied). The average total DTSQ score provided by respondents using
Eversense (31.2  4.3) was not significantly different ( _P_ =0.96) when
compared with the mean DTSQ respondent score for the DG5 system (31.3 
3.9).14

Two noncomparative studies (3 publications) evaluated patient perceived change
in QOL following diabetes management with I-CGM.12,21,28 Among the 3
publications, QOL was assessed with the 36-Item Short Form Health Survey
(SF-36), 28-Item DDS, and the Audit of Diabetes Dependent Quality of Life
(ADDQoL) questionnaire. Only 1 of these 2 trials performed a before-and-after
statistical analysis, and the authors concluded that no significant change in
QOL was observed over time.28 Three noncomparative studies evaluated patient
satisfaction with varying PROMs.12,16,28 One trial found that 84% of
respondents would choose to be re-inserted with Eversense for implantation
cycle if given the opportunity.12 Christiansen and colleagues examined patient
satisfaction with the validated CGM Satisfaction Scale Questionnaire, which
asks patients to rate items on a Likert Scale ranging from 1 (lowest
satisfaction/largest hassle) through 5 (most satisfaction/least hassle).16
This study found that among the 35 respondents, the mean overall satisfaction
score with I-CGM was 3.9  0.6. Among the respondents, only 20% of I-CGM users
indicated that they would be unwilling to use I-CGM again after the study
concluded. A third study found that the median DTSQ score over 180 days
changed between a median of 0-2 points, which was not statistically
quantified.28

_Safety_

None of the 16 primary studies meeting inclusion for the evidentiary review
performed a comparative safety analysis between I-CGM and subcutaneous CGM.

However, 10 noncomparative studies assessed the safety profile of I-CGM. Six
of the 10 studies considered the incidence of serious adverse events (SAEs),
with all 6 reporting that no SAEs occurred.15,17,19,21,27,30 Additionally, 2
studies stated that no adverse events (AEs) occurred at all during study
follow-up.13,14 For the remaining 8 studies assessing, the heterogeneity of
how AEs were grouped together and reported precluded the pooling of event
rates across studies. Generally, events were infrequent, and mostly consisted
of transient skin irritation at the patch site, site infection, pain, and
difficulty removing the sensor during first attempt.15,16,19,21,23,27,28,30

**Professional Society Recommendations**

While the American Diabetes Association (ADA), American Association of
Clinical Endocrinology (AACE), Diabetes Canada Clinical Practice Guidelines,
and National Institute for Health and Care Excellence (NICE) all have
position/guideline recommendations supporting CGM, none of these specifically
discuss if and when I-CGM should be considered in the treatment
paradigm.6,31-33 The following position statements directly invoke I-CGM, but
only discuss optimal patient selection criteria:

_American Diabetes Association (ADA)_ - In the safety subheading of a 2022
clinical practice guideline published by the ADA Professional Practice
Committee, the authors state that contact dermatitis has been associated with
all CGM devices, often linked to isobornyl acrylate. In some patients who have
sensitivities to the tape used with subcutaneous CGM patches, the authors
comment that I-CGM may provide an alternative that could preclude dermatitis
events.34

_European Association for the Study of Diabetes (EASD)_ __ - A consensus
report published jointly by the EASD and the ADA in 2021 states that I-CGM
could be a clinical alternative for patients who have sensitivities to the
adhesive that is required with subcutaneous CGM.35

_American Association of Clinical Endocrinology (AACE)_ __ - In 2021, the AACE
issued a Grade C recommendation that clinicians should ensure patients
undergoing treatment with CGM do not ingest any substances that could
interfere with reliable interstitial glucose readings.32 In the evidence
section that informs this recommendation, Grunberger, et al. cite other CGM
systems that are susceptible to inaccuracy when in the presence of
acetaminophen, ascorbic acid, xylose, bilirubin, or uric acid. Conversely,
this section reports that Eversense sensors are only vulnerable to inaccuracy
in the presence of mannitol or tetracycline, consistent with the
contraindications listed by the FDA packaging.36

**Other Expert Opinion**

Deiss, et al. (2019) present a collection of consensus best practice
recommendations by a panel of international clinicians who were involved with
early Eversense clinical trials.37 Among the best practices, the following
considerations are mentioned in relation to optimal patient selection
criteria:

  * The authors note that the adhesive for Eversense does not contain isobornyl acrylate. Additionally, they also discuss how the daily changing of adhesive allows for regular skin care at the site. They conclude that both of these characteristics make I-CGM a viable alternative for patients with a history of skin reactions to adhesives.
  * Deiss, et al. suggest that I-CGM is an ideal alternative to subcutaneous CGM for people who have an ongoing environmental risk to continued permanent breach of the skin, such as dust exposure.
  * Deiss and colleagues mention the need for mobile device compatibility with the app, as well as ability to navigate the app. They then comment that certain groups of patients may be unable to access or use this technology and would not be suitable candidates for I-CGM.

This updated evidentiary review is being conducted to evaluate whether the
published evidence base continues to support the equivalency of I-CGMs and
traditional subcutaneous CGMs in the management of adult DM. The evidence
suggests that for adult patients managing DM, I-CGM performs with little to no
difference in diagnostic accuracy, patient-reported efficacy outcomes,
objective efficacy measures, and device/procedure-related AE rate when
compared to subcutaneous CGM. Furthermore, the evidence suggests that the
optimal patient selection criteria for I-CGM and for subcutaneous CGM are
largely overlapping. Although limited in quality, this evidence base is
sufficient to determine noninferiority/equivalency between I-CGM and
subcutaneous CGM.

Additionally, although no direct evidence was identified that assessed I-CGM
utilization among non-insulin treated (NIT) patients with diabetes complicated
by hypoglycemia, there is still adequate evidence to infer equivalence with
subcutaneous CGM systems among this population based upon the totality of
evidence. Firstly, among the approved indications for I-CGM, the FDA has
cleared Eversense to "provide glucose trend information", and to "provide
alerts for the detection and prediction of episodes of low blood glucose
(hypoglycemia) and high blood glucose (hyperglycemia)".38 Also, although
outside of the scope of the main evidentiary review, 3 publications were
identified via bibliographic cross-referencing that evaluated subcutaneous CGM
benefit among this subgroup of patients. One of these 3 trials concluded that
among NIT patients with DM complicated by hypoglycemia, subcutaneous CGM
systems resulted in a significantly greater reduction in HbA1c than SMBG.33
The other 2 studies suggested CGM systems were able to detect hypoglycemic
events among NIT patients that were overwhelmingly undetectable by symptoms or
SMBG.39,40