1095573

research-article2022
DSTXXX10.1177/19322968221095573Journal of Diabetes Science and TechnologyPfützner et al

Original Article

Journal of Diabetes Science and Technology

Laboratory Protocol and Pilot Results

2024, Vol. 18(1) 59­–65
© 2022 Diabetes Technology Society

for Dynamic Interference Testing of Article reuse guidelines:

sagepub.com/journals-permissions
Continuous Glucose Monitoring Sensors https://doi.org/10.1177/19322968221095573
DOI: 10.1177/19322968221095573
journals.sagepub.com/home/dst

Andreas Pfützner, MD, PhD1,2,3 , Hendrick Jensch, BSc1,

Christopher Cardinal1, Geetham Srikanthamoorthy1,3,
Eric Riehn, PhD1, and Nicole Thomé, PhD1

Abstract
Background: Testing the potential influence of interfering substances on the measurement performance of needle sensors
for continuous glucose monitoring (CGM) is a challenging task. For proper function, the sensors need an almost stable fluidic
environment. Previously published in vitro interference experiments were measuring under static concentration conditons.
Our experimental setup allows for interference testing with dynamic changes of the interferent concentrations.
Methods: We designed a macrofluidic test stand that is fueled by several high-pressure liquid chromatography (HPLC)
pumps generating programmable glucose and/or interferent gradients in phosphate-buffered saline (PBS). After optimizing
experimental parameters (channel dimensions, temperature, flow rates, gradient slopes, buffer, pH etc.), we validated the
setup using Dexcom G6 (G6) and Freestyle Libre 2 (L2) sensors with/without interferents, and using YSI 2300 Stat plus as
the reference glucose device at room temperature.
Results: Both sensors tracked the programmed glucose changes. After calibration, G6 results closely matched glucose
reference readings, while L2 routinely showed ~50% to 60% lower readings, most likely because of the factory-based
calibration and temperature compensation. Gradients of maltose, acetaminophen, and xylose were employed to further
validate the setup. As expected, both sensors were not affected by maltose. We confirmed previous findings regarding
susceptibility of G6 readings to acetaminophen and L2 readings to xylose. Signals from both sensors are influenced by
temperature in a linear fashion.
Conclusions: Our experimental in vitro setup and protocol may provide a useful method to dynamically test CGM sensors
for interfering substances. This may help to improve the accuracy of future CGM sensor generations.

Keywords
continuous glucose monitoring, CGM, interference testing, in vitro test protocol, dynamic interference, cocktail interference

Introduction interfere with the glucose measurement technology of the

CGM
Sensors for continuous glucose monitoring (CGM) in the Similar to blood glucose, test strips using the same mea-
interstitial fluid have improved over the past decades CGM surement technology, sensors for CGM can be subject to
devices have reached a glucose reading quality leading to interference by other molecules. Well-known examples are
regulatory approval for the determination of insulin doses the impact of vitamin C and the influence of the frequently
based on their results. However, no CGM device fulfills the used pain drug acetaminophen (paracetamol) on some of the
ISO standards for blood glucose measurement yet.1,2 Still
clinically unexplainable deviations between sensor read-
ings and blood glucose concentrations have been observed
1
Pfützner Science & Health Institute, Mainz, Germany
on a regular basis, where both factory-calibrated and user- 2
University for Digital Technologies in Medicine and Dentistry, Wiltz,
calibrated sensor technologies show high and sometimes Luxembourg
clinically unacceptable differences to the blood glucose 3
Technical University, Bingen, Germany
concentrations, which cannot be explained by the well-
Corresponding Author:
characterized glucose dynamics between the interstitial Andreas Pfützner, MD, PhD, Pfützner Science & Health Institute, Haifa-
fluid and the blood.3-7 One explanation are concentration Allee 20, Mainz D-55128, Germany.
changes of substances in the interstitial fluid, which Email: [email protected]
60 Journal of Diabetes Science and Technology 18(1)

Figure 1. Sketch of the design of the laboratory test stand for dynamic interference testing of continuous glucose monitoring needle
sensors.

existing and commercially available glucose oxidase-based cocktail composition. This would be extremely time and
needle sensors.8-15 resource consuming. Having this as a regulatory requirement
At this stage, the only effective way to investigate the rel- would even prevent companies to pursue or enter into future
evance of such interference on a CGM sensor are clinical stud- continuous glucose sensor developments. At the same time,
ies in animals or humans, where a potentially interfering long-lasting and economically affordable CGM systems still
substance is ingested in clinically approved amounts or doses. represent a major unmet medical need for people with
Consecutive comparison of blood glucose and sensor glucose diabetes.
readings under consideration of the pharmacokinetic profile of In this project, we have tried to design and realize an in-
the ingested substance are required to understand the nature vitro test setup and suitable protocol to be able to address the
and size of the interference. However, only few clinical studies interference issues raised above under consideration of the
about CGM interference have been reported in the literature so specific conditions required for dynamic interference testing
far.8-11 At the same time, the manufacturers and the users need of CGM needle sensors in the laboratory. Our plan was to
to understand the relevance of a potential interferent to draw realize a test bench setup, where (1) several CGM sensors
correct conclusions about clinical or regulatory consequences can be tested in parallel, (2) different glucose concentrations
(eg, warnings in the instructions for use).16 and gradients can be investigated, (3) dynamic concentration
In addition, there is no information existing in the litera- changes of individual substances can be superimposed on a
ture at all about a potential interaction of dynamic changes of selected glucose concentration, and (4) different substances
several potentially interfering substances when taken in par- can be combined for dynamic “cocktail” testing.
allel on CGM performance. However, this is clinical reality,
for example, when patients take multiple drugs in the morn-
ing prior to breakfast and sometimes in conjunction with Materials and Methods
multiple nutritional supplements. In Germany, the Freestyle
Libre sensor is very popular and frequently prescribed for Setup of the In Vitro Bench Test
patients with type-2 diabetes suffering also from coronary After multiple experimental attempts, we managed to design
artery disease, atrial fibrillation, hypertension, dyslipidemia, a sensor test bench, consisting of a 3D-printed solid PPE
heart failure, and many other diseases in parallel. A signifi- block (15 cm × 15 cm × 4 cm) as the sensor housing com-
cant proportion of these patients take up to 10 and more ponent. On one side, a macrofluidic channel was left out
drugs, for example, prior to breakfast. According to our from the solid material as shown in Figure 1 (2 mm × 10 mm
knowledge, nothing is known about potential potentiating, × 500 mm). The CGM sensors were located on top of the
additive, or subtractive effects of individual components of channel and the inner spaces between the sensor needles
such drug and nutritional supplement “cocktails” on the were carefully filled with chemically inert cotton wool to
measurement performance of CGM sensors. block any fluidic turbulences around the sensor tips during
It is clearly impossible to run clinical trials in people with the measurements. Tubing connections were also 3D-printed
diabetes to test for each and every possible interferent and on both sides of the channel to allow for fixation of
Pfützner et al 61

high-pressure liquid chromatography (HPLC) pump tube signal strength). We superimposed an acetaminophen gradi-
connectors on one side, and tubing leading to a waste con- ent from 0 to 20 mg/dL within 30 min, and maintained this
tainer on the other side. High-pressure liquid chromatogra- level for 30 min. Thereafter, the levels were reduced back to
phy pumps were used to supply the test bench channel with 0 mg/dL over the next 30 min and were finally maintained at
buffer, variable glucose concentrations and different concen- 0 mg/dL for final 30 min. Similar experiments were run with
trations of candidate substances for interference (Waters xylose (up to 200 mg/dL) and maltose (up to 600 mg/dL).
2695, Waters, Eschborn, Germany). A design schematic is The supraphysiological interferent concentrations were cho-
provided in Figure 1. sen in these proof-of-concept experiments to surely induce
signal interference if it existed.
General Test Protocol
Temperature Interference Test Protocol
We tested several buffers and finally decided to use a phos-
phate-buffered saline (PBS) buffer (Carl Roth, Karlsruhe, For this experiment, a glucose concentration of 200 mg/dL
Germany) in our general experimental protocol (18 g NaCl, was programmed, and the system ran for 1 h at room tem-
0.20 g KCl, 0.20 g KH2PO4, 1.15 g Na2HPO4×2 H2O in perature (20°C). The test platform was placed into a warm-
1000 ml H2O, pH 7.2). The sensors proved to be sensitive to ing chamber and the temperature was increased to 30°C
the overall speed of the pumping operations and also to the within 30 min, kept stable at 30°C for 30 min, increased to
slope of the glucose or interferent gradients. Finally, we 37°C within 30 min, kept stable at 37°C for 30 min, increased
identified an overall pumping speed of maximally 1 ml/min to 40°C within 30 min and kept stable for 30 min at 40°C.
and substance increases of less than 4%/min of the planned Thereafter, temperature was dropped again to room tempera-
maximal concentration as suitable flow conditions. Glucose, ture within 30 min and kept there for another 60 min.
xylose and maltose were obtained from Carl Roth Sigma
Aldrich (Hamburg, Germany) and acetaminophen from
Sigma Aldrich, Darmstadt, Germany).
Statistical Analysis
In this setup, we tested the Dexcom G6 CGM sensor (G6; A proper calibration of G6 allows to define substance-spe-
Dexcom, Mainz, Germany) and the Freestyle Libre 2 sensor cific interference, if differences of >20% occur between the
(L2; Abbott, Wiesbaden, Germany). Three sensors from each reference glucose readings and the sensor readings at the
CGM system were placed on the test bench as shown in maximal interferent concentration. The same is not possible
Figure 1 and were tested in parallel. Initiation of device oper- for the factory.calibrated L2 sensor as the signal deviates
ation was performed in-line with manufacturer’s instruc- from the reference readings most likely due to the in vitro
tions, and each was connected to an individual read-out nature of our experiments. We therefore determined the mean
device. The G6 sensors were calibrated as provided in the absolute relative deviation from the glucose signal measured
instructions for use at an initially stable glucose level of 120 at baseline with no present interferent at the timepoint of
mg/dL against the reference method Yellow Springs maximal interferent concentration as a benchmark parameter
Instruments (YSI Stat 2300 plus, Yellow Springs Inc., Silver (BOB = bias over baseline). Interference was asumed if
Springs City, US), while the results from the factory-cali- BOB was >20%.
brated L2 sensors were recorded as displayed on the Libre
readers, and G6 on the respective Dexcom readers. Each
experiment was done with 3 sensors per device type in paral-
Results
lel. During all experiments, samples were taken at the out- The results of testing dynamic glucose gradients with our
flow tube of the channel at least every 10 min for a YSI bench test are provided in Figure 2. The flow rate of 1 mL/
reference reading. min was determined to be a suitable experimental flowrate.
Faster flow results in frequent signal errors from the sensors.
Slower flow leads to unpractical signal delays between sen-
Substance Interference Test Protocol sors sitting at the later positions in the test channel and makes
Each individual experiment was conducted at least twice and comparisons more difficult.
the final individual experimental settings are shown together It can be seen that the calibrated G6 sensors closely fol-
with the results in the result section. We first ran a glucose lowed the programmed glucose gradients and the reference
gradient experiment, starting with a glucose level of 100 mg/ glucose readings. The factory calibrated L2 sensors had a
dL for 30 min, increasing to 300 mg/dL over 100 min (2 mg/ corresponding and parallel signal pattern, but the displayed
dL/min), maintained at 300 mg/dL for 30 min, prior to return- results were consistently about 50% to 60% lower than the
ing to 100 mg over 100 min (−2 mg/dL/min), then maintain- reference readings. This difference could not be resolved, for
ing at 100 mg/dL for another 30 min. In a second experiment, example, by an individual sensor calibration of the L2 sen-
we chose a stable glucose value of 200 mg/dL (to ensure suit- sors, and it was hence observed throughout all performed
able L2 signals in case an interferent would lead to a reduced experiments.
62 Journal of Diabetes Science and Technology 18(1)

Figure 2. Glucose gradient experiment (YSI: Yellow Springs

Figure 3. Sensor response to a maltose gradient (0-480 mg/
Instruments Stat 2300 plus, glucose reference method, n = 3 for
dL) at stable glucose concentrations of 200 mg/dL at room
each sensor type).
temperature. The Dexcom G6 sensor was calibrated to the
baseline glucose level prior to the experiment, while the factory
When running interference experiments at stable glucose calibrated Libre 2 sensor does not provide this option and
levels and at room temperature, the L2 sensor signals showed displayed 50% to 60% lower results (BOB = bias over baseline, n
= 3 for each sensor type).
minor signal variations when substance concentrations
dynamically increased and decreased. This repetitive signal
pattern was observed for all substances irrespective of their
chemical nature and was interpreted as an experimental
setup-related sensor-specific measurement artifact. These
signal variations were considered to be either a temperature
artifact, or induced by local fluidic disturbances at the sensor
tip or a result of corrective actions of the sensor software
algorithm to compensate for local signal disturbances at the
sensor tip, or as a combined effect of all of the above.

Testing Interefering Substances

The results of the maltose interference experiment with malt-
ose concentrations between 0 mg/dL and 480 mg/dL are
shown in Figure 3. Figure 4. Sensor response to a xylose gradient (0-600 mg/dL) at
It can be seen that with exception of minor L2 signal dif- stable glucose concentrations of 200 mg/dL at room temperature.
ferences induced by increasing interferent concentrations The Dexcom G6 sensor was calibrated to the baseline glucose
level prior to the experiment, while the factory calibrated Libre
both sensors showed a stable signal, which was not affected
2 sensor does not provide this option and displayed 50% to 60 %
by the maltose gradient. lower results (BOB = bias over baseline, n = 3 for each sensor
The results of the interference experiments with xylose (0 type).
mg/dL to 600 mg/dL) are provided in Figure 4. There was no
impact of increasing or decreasing xylose concentrations up
to 600 mg/dL on the G6 sensor signals (BOB: 13%). The L2 this molecule, and there was no measurable difference at
sensor was substantially impacted by increasing xylose con- peak acetaminophen level (BOB: 0%). The reference read-
centrations in an additive manner. Bias over baseline at peak ings with the YSI 2300 Stat plus device closely followed the
xylose concentrations was 308%. programmed glucose concentrations in all experiments
The results of the interference experiments with acet- (BOB: 1%).
aminophen (0 mg/dL to 20 mg/dL) are provided in Figure 5. The temperature experiment revealed a major influence of
While L2 showed no interference (BOB: 0%), G6 showed the ambient temperature as shown in Figure 6. From the
significant interference starting directly with increasing acet- results, it was calculated that the mean signal increase per
aminophen concentrations. Bias over baseline at peak acet- 1°C was similar for both devices (2.3%/°C for L 2 and 2.4
aminophen concentration was 104%. %/°C for G6).
Except for the observed minor variations with increasing In additional experiments conducted with acetaminophen,
and decreasing acetaminophen levels, L2 was unaffected by maltose, and xylose at 37°C, it was observed that the
Pfützner et al 63

Figure 5. Sensor response to an acetaminophen gradient (0-20 Figure 6. Impact of ambient temperature on the sensor signals
mg/dL) at stable glucose concentrations of 200 mg/dL at room in our in vitro test setup (n = 3 for each sensor type).
temperature. The Dexcom G6 sensor was calibrated to the
baseline glucose level prior to the experiment, while the factory In a follow-up report, the same group used a similar pro-
calibrated Libre 2 sensor does not provide this option and
displayed 50-60 % lower results (BOB = bias over baseline, n =
tocol with 19 healthy drug-naïve subjects without diabetes to
3 for each sensor type). compare CGM glucose patterns to actual plasma glucose
concentrations after uptake of several drugs. They showed
that lisinopril, albuterol, and acetaminophen, and also red
influence of temperature on the sensor signals is linear. A G6 wine appear to interfere with commonly used CGM devices.10
sensor properly calibrated at 37°C showed the same curves At the same time, the manufacturers tried to solve known
as compared to calibration and running the experiments at interference issues and in 2018, Calhoun and coworkers
23°C. As a result, BOB was similar for the same substances reported a next generation CGM device (G6), where acet-
at the different temperature levels (data not shown). aminophen interference appeared to be solved by use of a
novel permselective membrane coating for the needle sensor.
In their study with 66 subjects with type 1 or type 2 diabetes,
Discussion
the observed mean difference of glucose levels induced by a
The susceptibility of CGM devices to erroneous readings in single dose of 1 g of acetaminophen was found to be only 3.1
the presence of interferences by common pharmaceuticals or ± 4.8 mg/dL (with an impact of 10 mg/dL defined as clini-
nutritional supplements is an open and at least partially cally relevant interference).17
unclear issue in diabetes technology.16 Only few reports exist In a complex experimental in vitro approach, 7 sugars, 7
in the current literature about such issues. We believe that it sugar alcohols, and 3 artificial sweeteners were in vitro
is fair to state that there is a general lack of experimental screened for interference with amperometric glucose oxidase
know-how and understanding in the scientific community (GOx) sensors at concentrations greater than physiologic con-
about the required testing conditions, which as of today pre- centrations, by Boehm and coworkers in 2019.18 Fourteen of
vents comprehensive standardized testing and data genera- the 17 tested substances did not exhibit any interference.
tion to fully explore the CGM interference situation. Galactose, xylose and mannose, affected sensor signals with
The most valid but also most resource-consuming MARDs > 20% but in concentrations significantly higher
approach is to assess CGM error to pharmacologic interfer- than normal physiologic concentrations. Galactose exhibited a
ences by means of clinical trials with oral administration of concentration-dependent MARD of 47-72% and was sub-
the candidate interference substance. Basu et al reported a jected to further testing. In this setup, the highest recorded
clinical trial protocol in 2017, with the aim to examine the mean relative difference (MRD) was 6.9 ± 1.3% when testing
responses of several different Food and Drug Administration– physiologically relevant galactose concentrations (0.1-10 mg/
approved and commercially available CGM systems dL). Enzyme kinetic analysis conducted with galactose sup-
(Dexcom Seven Plus, Medtronic Guardian, Dexcom G4 ported the notion that the reactivity of glucose-oxidase toward
Platinum) to oral acetaminophen administration in healthy nonglucose sugars and the presence of enzymatic impurities
volunteers without diabetes.9 Blood and microdialysate ISF (such as galactose oxidase) are 2 potential sources for sugar
samples were collected periodically and analyzed for glu- interference with glucose oxidase-based CGM- sensors.
cose and acetaminophen concentrations before and after oral The laboratory in vitro setup chosen by Boehm et al
ingestion of 1g of acetaminophen. They observed interfer- required a static stable interferent concentration prior to
ence with glucose measurements in the tested CGM devices obtaining a read-out from the investigated needle sensors.
that coincided temporally with appearance of acetaminophen Unfortunately, the authors did not disclose the names of the
in the ISF. commercially available sensors investigated in their study. In
64 Journal of Diabetes Science and Technology 18(1)

addition, their experimental setup did not work with dynamic We were able to show a direct linear influence of ambient
interferent concentration changes. Hence their results are of temperature on sensor signals. We had initially conducted
limited value for a real-life dynamic in-vivo situation. Still, it our presented proof-of-concept dynamic interference experi-
provides valuable information about a potential interference ments at room temperature, and repetition of the experiments
impact of galactose on glucose oxidase-based CGM at 37°C resulted in similar signal patterns (and even similar
devices.18 curves for G6 after calibration at 37°C). While we consider it
Dynamic measurement of interferences provides an addi- feasible to investigate substance interference at both tem-
tional degree of interference information in comparison to peratures, we have decided to choose 37°C for our standard
static measurements. A single static measurement only pro- protocol for future work to stay closer to the physiological
vides qualitative interference information and only for the operational sensor conditions in the body.
interferent concentration tested. Dynamic testing allows for By adding more HPLC infusion pumps to our setup, we
determination of the necessary interferent concentration to expect to be able to simulate the physiologic situation of par-
meet a predefined interference criteria (eg, a 20% difference) allel increases of multiple substances with interference
independent from the highest interferent concentration tested. potential, as can be frequently observed in daily practice in
In addition, in future experiments, we will be able to deter- multimorbid patients, for example, at breakfast and dinner.
mine if (and to what extent) prior presence of an interfering No information exists in the literature regarding additive,
substance may continue to influence sensor performance even subtractive, or potentiating effects of several interferents
when the interferent has disappeared from the testing site. occuring in the ISF at the same time as it may occur after
In our in vitro setup, the maximal acetaminophen concen- uptake of several drugs and nutritional supplements in the
tration tested was 10 to 20 times higher than the maximal ISF context of food uptake. Such “cocktail” assessment options
concentration measured by Basu et al after application of 1 g represent a new opportunity for understanding interference
of the drug.9 This may explain the difference between our of CGM sensors (and also for disposable single-use blood
findings and the work of Calhoun et al.17 Still, Denham D glucose test strips), which has not been explored so far.
reported increasing MARD values for the G6 sensors with At this stage, our experimental in vitro setup for interfer-
multiple consecutive uptakes of doses of 1 g of acetamino- ence testing of CGM sensors was able to confirm the known
phen every 4 hours.11 At this initial protocol development impact of acetaminophen at higher concentrations on the
stage, our approach was to explore the overall suitability of Dexcom G6 sensor signal and of xylose on the Libre 2 sensor
the designed in vitro setup to provide valid interference signal. We also confirmed that maltose does not exhibit inter-
results rather than simulating daily clinical circumstances. ference on the signals of both sensors. We therefore believe
This will be the topic of future studies. that our experimental protocol may be a suitable and low
One limitation of our methodology is a lack of valid infor- resource-consuming method to further investigate the impact
mation regarding the normal ranges and expected concentra- of potentially interfering substances on CGM sensor device
tions of potential interferents in the ISF after oral, performance in an in vitro setup. It may provide an option for
subcutaneous or intravenous administration. Further basic large scale in vitro substance screening to identify potential
research work will be necessary to close this information gap clinically relevant interfering substances (single or cocktails)
and to allow for determination of realistic maximal testing and in particular also to rule out non-interfering molecules.
concentrations for interference assessment of CGM sensors. This will allow focus on suspect interference candidates, when
Until this information becomes available, we suggest to assessing the clinical relevance of observed in vitro interfer-
employing the corresponding plasma concentrations or inter- ents in subsequent resource-consuming clinical trials.
ferent levels suggested by the FDA guidance to industry for
blood glucose meters for patient self-testing.19 Whenever Abbreviations
possible, the physiological and transfer factors that may arise BOB, %bias over baseline; CGM, continuous glucose monitoring;
due to differences between the blood and ISF compartments FDA, Food and Drug Agency; GOx, glucose oxidase; HPLC, high pres-
should be considered. sure liquid chromatography; ISF, interstitial fluid; ISO, International
Another—experimental—limitation of our test bench is Standardization Organization; MARD, mean absolute relative differ-
the fact that the sensors are connected in series. This results ence; MRD, mean relative difference; PBS, phosphate buffered saline,
in a time offset in the change of the concentrations, which PPE, Polyphenylene Ether; YSI, Yellow Springs Instruments.
can be seen very clearly in the figures. In the chosen series,
the 3 G6 sensors react first, followed by the 3 L2 sensors, and Declaration of Conflicting Interests
the reference measurement at the very end. The time delay The author(s) declared the following potential conflicts of interest
depends on the volume of the flow channel and the flow rate. with respect to the research, authorship, and/or publication of this
This limitation can be easily overcome in future experiments, article: In the context of this manuscript, APF declares that he is a
if the sensors were arranged in parallel or in randomized consultant or has receive travel support and/or speaker fees from
order. However, this limitation does not affect the suitability Sanofi/Germany, Lifescan/USA, Lifecare/Norway, and Abbott/
of the system to detect interferences. Wiesbaden. The other authors have no conflict of interest to report.
Pfützner et al 65

Funding 8. Maahs DM, DeSalvo D, Pyle L, et al. Effect of acetamino-

phen on CGM glucose in an outpatient setting. Diabetes Care.
The author(s) disclosed receipt of the following financial support
2015;38:e158-e159.
for the research, authorship, and/or publication of this article: This
9. Basu A, Slama MQ, Nicholson WT, et al. Continuous glucose
project has received funding from the European Union’s Horizon
monitor interference with commonly prescribed medications: a
2020 research and innovation program under grant agreement No
pilot study. J Diabetes Technol Ther. 2017;11:936-941.
951933 (ForgetDiabetes) and also from Lifescan Global
10. Basu A, Veettil S, Dyer R, Peyser T, Basu R. Direct evidence of
Corporation, Malvern, PA, USA.
acetaminophen interference with subcutaneous glucose sensing
in humans: a pilot study. Diabetes Technol Ther. 2018;18(suppl
ORCID iD 2):S243-S247.
Andreas Pfützner https://orcid.org/0000-0003-2385-0887 11. Denham D. Effect of repeated doses of acetaminophen on a
continuous glucose monitoring system with permselective
membrane. J Diabetes Sci Technol. 2021;15:517-518.
References 12. Lorenz C, Sendowal W, Mortellaro M. Interference assessment
1. Juvenile Diabetes Research Foundation Continuous Glucose of various endogenous and exogenous substances on the perfor-
Monitoring Study Group . Continuous glucose monitoring mance of the eversense long-term implantable continuous glucose
and intensive treatment of type 1 diabetes. N Engl J Med. monitoring system. Diabetes Technol Ther. 2018;20:344-352.
2008;359:1464-1476. 13. Tellez S, Hornung L, Courter J, et al. Inaccurate glucose sen-
2. Hoeks L, Greven W, De Valk H. Real-time continuous glu- sor values after hydroxyurea administration. Diabetes Technol
cose monitoring system for treatment of diabetes: a systematic Ther. 2021;23:443-451.
review. Diabet Med. 2011;28:386-394. 14. Full Indications and Important Safety Information Freestyle
3. Joubert M, Reznik Y. Personal continuous glucose monitor- Libre 14 Day. https://www.freestyle.abbott/us-en/safety-infor-
ing (CGM) in diabetes management: review of the literature mation.html. Accessed Januray 17, 2022.
and implementation for practical use. Diabetes Res Clin Pract. 15. Interfering Substances and Risks. https://www.dexcom.com/
2012;96:294-305. interference. Accessed January 17, 2022.
4. Breton MD, Kovatchev BP. Impact of blood glucose self-mon- 16. Heinemann L. Interferences with CGM systems: practical rel-
itoring errors on glucose variability, risk for hypoglycemia, and evance? J Diabetes Sci Technol. 2022;16:271-274.
average glucose control in type 1 diabetes: an in silico study. J 17. Calhoun P, Johnson TK, Hughes J, Price D, Balo AK.
Diabetes Sci Technol. 2010;4:562-570. Resistance to acetaminophen interference in a novel con-
5. Lucarelli F, Ricci F, Caprio F, et al. GlucoMen Day continuous glu- tinuous glucose monitoring system. J Diabetes Sci Technol.
cose monitoring system: a screening for enzymatic and electro- 2018;12:393-396.
chemical interferents. J Diabetes Sci Technol. 2012;6:1172-1181. 18. Boehm R, Donovan J, Sheth D, Durfor A, Roberts J,
6. Shapiro AR. Nonadjunctive use of continuous glucose moni- Isayeva I. In vitro sugar interference testing with ampero-
tors for insulin dosing: is it safe? J Diabetes Sci Technol. metric glucose oxidase sensors. J. Diabetes Technol. Ther.
2017;11:833-838. 2019;13:82-95.
7. Shapiro AR. The safety of nonadjunctive use of continu- 19. FDA Guidance to industry Blood Glucose Monitoring Test
ous glucose monitors for insulin dosing: still not resolved. J Systems for Prescription Point-of-Care Use. https://www.fda
Diabetes Sci Technol. 2017;11:856-857. .gov/media/119829/download. Accessed March 16, 2022.