D I A B E T E S
`
`Current Application of Continuous
`Glucose Monitoring in the Treatment
`of Diabetes
`Pros and cons
`
`1
`JEROEN HERMANIDES, MD
`2
`MOSHE PHILLIP, MD, PHD
`J. HANS DEVRIES, MD, PHD
`
`1
`
`T he ultimate goal of diabetes technol-
`
`ogy is to create an artificial pancreas,
`or closed-loop system. In the early
`1970s, the first prototypes became avail-
`able (1). Although recent advances are
`promising, the closed-loop system is cur-
`rently confined to the clinical research
`center (2). The continuous subcutaneous
`insulin infusion (CSII) pump became
`commercially available in the 1980s, and
`it is now a common and accepted way of
`providing insulin (3,4). The emergence of
`continuous glucose monitoring (CGM)
`followed in the 1990s, with the first re-
`ports on CGM by microdialysis in 1992
`(5,6). Retrospective needle-type CGM
`systems were introduced just before the
`turn of the century (7–10). Currently,
`there are four subcutaneous CGM sys-
`tems on the market that have real-time
`glucose values on display every 1–5 min
`and feature an alarm function for hypo-
`and hyperglycemia: the Freestyle Navi-
`gator (Abbot Diabetes Care, Alameda,
`CA), the Guardian Real-Time (Medtronic
`MiniMed, Northridge, CA), the Dexcom
`SEVEN (Dexcom, San Diego, CA), and
`the GlucoDay (Menarini Diagnostics).
`The first three are needle-type CGMs
`and the latter is a microdialysis-type sen-
`sor. All of these measure glucose via the
`glucose-oxidase reaction. In this article,
`
`we will discuss the pros and cons of the
`current application of CGM in the treat-
`ment of diabetes.
`
`PROS OF CGM—From the Diabetes
`Control and Complications Trial and the
`UK Prospective Diabetes Study, we
`learned that lowering HbA1c reduces
`morbidity and mortality (11,12) and
`that tight glycemic control is associated
`with an increased rate of severe hypogly-
`cemic episodes. We therefore should
`judge the pros of CGM by its HbA1c-
`lowering potency and its influence on
`severe hypoglycemia rates. Table 1 sum-
`marizes all intervention trials that have
`been performed with real-time CGM re-
`garding HbA1c and the incidence of severe
`hypoglycemia.
`The Juvenile Diabetes Research Foun-
`dation (JDRF) landmark study random-
`ized 322 adults, adolescents, and children
`with type 1 diabetes at a baseline HbA1c of
`7.0–10.0% to CGM or self-monitoring of
`blood glucose (SMBG). CGM use for 26
`weeks significantly reduced HbA1c by
`0.5% in adult patients (13). Although
`the intention-to-treat analyses did not
`show a significant HbA1c reduction in
`children and adolescents, it was demon-
`strated among all age groups that there
`was a significant HbA1c reduction in
`
`c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
`
`From the 1Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam,
`the Netherlands; and the 2Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of
`Israel and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
`Corresponding author: Jeroen Hermanides, j.hermanides@amc.uva.nl.
`This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in
`Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were
`made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol-
`Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La
`Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pfizer.
`DOI: 10.2337/dc11-s219
`© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
`cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/
`licenses/by-nc-nd/3.0/ for details.
`
`patients who used CGM for $6 days/
`week (14). The adolescents were the
`most infrequent users of CGM devices.
`In a follow-up study of the JDRF trial,
`patients initially randomized to the con-
`trol group were put on CGM after the
`trial. Again, HbA1c decrease was signifi-
`cantly associated with CGM use among
`all age groups (15). Previously, Deiss
`et al. (16) randomized type 1 diabetic pa-
`tients with baseline HbA1c of $8.1% to
`3 months of continuous CGM use, bi-
`weekly CGM use, or intensive insulin
`treatment with SMBG. Continuous CGM
`use resulted in a significant HbA1c reduc-
`tion of 0.6% compared with conventional
`treatment, whereas biweekly use did not
`improve HbA1c compared with conven-
`tional treatment. Thus, it seems that the
`frequency of CGM use is important. This
`is also evident from the Sensor-Augmented
`Pump Therapy for A1C Reduction 1
`(STAR-1) trial and the RealTrend study
`(Table 1), in which the efficacy of CGM
`with CSII was investigated in CSII users
`and insulin pump–naive type 1 diabetic
`patients, respectively (17,18). Although
`there was no significant between-group
`difference in HbA1c decrease in both stud-
`ies, subanalyses showed that sensor use of
`at least 60–70% of the time did result in a
`significant HbA1c decrease. The impor-
`tance of frequency of CGM use is further
`substantiated by results from O’Connell
`et al. (19), who randomized 62 patients
`with well-controlled type 1 diabetes using
`CSII to intervention with CGM or con-
`ventional SMBG for 3 months. HbA1c
`improved by 0.4% in favor of the interven-
`tion group, but within the intervention
`group, HbA1c was 0.5% lower in patients
`using CGM $70% of the time compared
`with ,70% use. Thus, CGM is effective in
`lowering HbA1c in patients who actually use
`it. In daily practice, patients who are non-
`compliant are easy to identify by accessing
`downloaded data, and (dis)continuation of
`CGM treatment can be openly discussed.
`In addition, initiating CGM treatment
`might even be more effective when com-
`bined with the initiation of CSII. This
`
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`result is relevant, since most type 1 di-
`abetic patients use multiple daily in-
`jection (MDI) therapy with SMBG as
`standard care, especially in Europe (3).
`In a multicenter randomized controlled
`trial (RCT) (the Eurythmics trial), adult
`type 1 diabetic patients (HbA1c at entry
`$8.2%) on intensive treatment were allo-
`cated to CGM, augmented with CSII or
`continuation of their multiple daily in-
`jections and SMBG regimen (20). After
`26 weeks, this regimen resulted in an
`HbA1c decrease in the CGM-augmented
`CSII group of 1.2%. Recently, the STAR-
`3 trial was published with a design similar
`to the Eurythmics trial. HbA1c decreased
`after 1 year in the CSII augmented with
`CGM group compared with continuation
`of injection treatment and SMBG in both
`children and adults (Table 1) (21). In the
`previously mentioned RealTrend study,
`initiating CGM-augmented CSII treat-
`ment was also superior to starting CSII
`treatment alone in the per-protocol anal-
`ysis, indicated by an HbA1c improvement
`of 0.4% in favor of the CGM-augmented
`CSII group (18).
`It is important to emphasize that
`these reductions in HbA1c with CGM
`was not associated with an increase in
`the number or severity of hypoglycemic
`episodes.
`Next to its effects on HbA1c, CGM
`seems to have a positive impact on
`patient-reported outcomes. Despite being
`confronted throughout the day with dia-
`betes through CGM alarms and the dis-
`comfort of the device itself, results from
`an Internet survey administered to 162
`patients using CGM-augmented CSII
`and 149 patients using CSII alone dem-
`onstrated that patients using CGM were
`more satisfied with their treatment and
`had better quality of life (22). In the Eu-
`rythmics trial, patients randomized to
`CGM-augmented CSII experienced sig-
`nificantly less problems with their diabe-
`tes and increased treatment satisfaction
`as measured by the Problem Area In Di-
`abetes questionnaire and the Diabetes
`Treatment Satisfaction questionnaire
`(20,23,24).
`Two other patient groups in which
`CGM might be of importance are preg-
`nant women with diabetes and hospital-
`ized patients (25,26). In an Australian
`RCT, 71 women with type 1 diabetes
`were randomized to antenatal care with
`CGM at 4- to- 6-week intervals during
`pregnancy or to standard antenatal care
`(27). Patients who were allocated to
`CGM had lower HbA1c levels at the end
`
`CGM in type 1 diabetes
`
`2)27
`1)32;
`2)1
`1)4;
`
`2)0
`1)1†;
`2)10
`1)9;
`2)0
`1)0;
`
`2)11
`1)14;
`2)18
`1)21*;
`3)0
`2)1;
`1)1;
`
`Children1)vs.2):20.5%,
`
`P,0.001
`
`Adults1)vs.2):20.6%,
`
`P,0.001;
`
`1)vs.2):21.2%,P,0.001
`1)vs.2):20.4%,P=0.004
`Perprotocolanalyses:
`1)vs.2):20.2%,P=0.09;
`
`1)vs.2):20.3%,P,0.001
`
`1)vs.2):20.4%,P=0.009
`
`P=0.29
`
`Children1)vs.2):20.1%,
`
`P=0.52;
`
`Adolescents1)vs.2):0.08%,
`
`Adults1)vs.2):20.5%,
`
`P,0.001;
`
`1)vs.2):20.11,P=0.37
`1)vs.2):NR,P=NS
`2)vs.3):NR,P=NS;
`1)vs.3):20.6%,P=0.003;
`
`*P,0.05.†Numberoftotalseverehypoglycemicepisodespergroupnotgiven,onlyepisodewithseizure/coma.NR,notreported.NS,notsignificant.
`
`2)n=13
`1)n=19;
`2)n=4
`1)n=1;
`
`2)n=6
`1)n=14;
`2)n=1
`1)n=1;
`2)n=2
`1)n=5;
`
`2)SMBG
`1)CGMandCSII;
`2)SMBG
`1)CGMandCSII;
`
`2)SMBGandCSII
`1)CGMandCSII;
`2)SMBG
`1)CGM;
`2)SMBG
`1)CGM;
`
`1year
`
`6months
`
`6months
`
`6months
`
`3months
`
`MDI(385)
`CSII(0);
`MDI(83)
`CSII(0);
`
`MDI(132)
`CSII(0);
`MDI(18)
`CSII(111);
`MDI(0)
`CSII(62);
`
`7.4–9.5%
`
`156children;329adults;
`
`type1diabetes
`
`(STAR-3trial)
`
`Bergenstaletal.(21)
`(Eurythmicstrial)
`
`$8.2%
`
`$8.0%
`
`,7.0%
`
`#8.5%
`
`83adults;type1diabetes
`
`Hermanidesetal.(20)
`
`type1diabetes
`
`(RealTrendstudy)
`
`51children;81adults;
`
`Raccahetal.(18)
`
`67adults;type1diabetes
`29children;33adolescents;
`
`type1diabetes
`
`JDRFstudygroup(34)
`
`62childrenandadults;
`
`O’Connelletal.(19)
`
`hypoglycemia(n)
`
`OutcomeHbA1c
`
`Dropout
`
`Comparison
`
`treatment(n)Duration
`
`Severe
`
`Prestudy
`
`Inclusion
`
`Table1—CGMtrialsintype1diabetes
`
`2)n=2
`1)n=3;
`2)n=2
`1)n=6;
`3)n=0
`2)n=1;
`1)n=4;
`
`2)SMBG
`1)CGM;
`2)SMBG
`1)CGM;
`3)SMBG
`2)CGMbiweekly;
`1)CGMcontinuously;
`
`6months
`
`6months
`
`3months
`
`MDI(66)
`CSII(256);
`MDI(0)
`CSII(146);
`
`MDI(84)
`CSII(78);
`
`98adults;type1diabetes
`
`(JDRF-CGMtrial)
`
`7.0–10%
`
`114children;110adolescents;
`
`JDRFstudygroup(13)
`
`$7.5%
`
`$8.1%
`HbA1c
`
`type1diabetes
`
`(STAR-1)
`
`146adultsandchildren;
`
`Hirschetal.(17)
`
`type1diabetes
`
`81children;81adults;
`
`Deissetal.(16)
`
`Population
`
`Study
`
`S198
`
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`

`of pregnancy and an odds ratio for macro-
`somia of 0.36 (95% CI 0.13–0.98).
`For hospitalized patients, the ap-
`plication of CGM is being investigated,
`especially with regard to tight glycemic
`control in the intensive care unit (28).
`Although concerns exist about the accu-
`racy of sensors in this setting, a recent
`trial showed that CGMs may prevent hy-
`poglycemia in the intensive care unit
`(29).
`Finally, CGM is an essential part in
`the development of the closed-loop or
`artificial pancreas. In the last years, much
`research has been performed to develop
`and improve closed-loop systems (30–
`32). In particular, algorithms are being
`developed that use the continuous stream
`of data to control insulin titration (33,34).
`In a recent publication by Hovorka et al.
`(2), the efficacy of a closed-loop format
`was investigated in a controlled trial.
`The closed-loop comprised different
`commercially available CGMs for data
`input, a control algorithm, and a nurse
`adjusting the insulin pump. Type 1 dia-
`betic patients using CSII were studied
`overnight, after a meal and after exercise.
`During the application of the closed-loop
`system, glucose was significantly more
`often in the target range and less in the
`hypoglycemic range compared with the
`standard CSII regimen. These results are
`promising, and future studies will have to
`work toward investigating the closed loop
`in outpatient settings, most preferably at
`home.
`
`CONS OF CGM—CGM is effective
`in specific patient groups with regard to
`HbA1c lowering. First, and most evi-
`dently, poorly controlled type 1 diabetic
`patients seem to benefit from CGM when
`they use it frequently enough. This result
`reveals the first problem, because espe-
`cially children and adolescents are non-
`compliant with CGM use, and its value
`in this patient group is therefore limited
`to only the most motivated patients
`(13,35). Second, there are many patients
`that do not tolerate the CGM devices. This
`scenario is illustrated by the higher drop-
`out rates in the CGM arms of the RCTs
`(Table 1). Also, in the JDRF trial and the
`Eurythmics trial, patients were already
`exposed to (blinded) CGMs before in-
`clusion or randomization to obtain a
`baseline CGM measurement for all pa-
`tients (13,20). This resulted in 23 of 345
`and 4 of 87 patients dropping out before
`randomization in the JDRF trial and
`Eurythmics trial, respectively—probably
`
`patients not tolerating the device. Clearly,
`CGM is not for everyone.
`Furthermore, in most trials summa-
`rized in Table 1, patients were either al-
`ready on CSII before randomization or
`were put on CSII during the trial. Conse-
`quently, we have to be cautious when ex-
`trapolating the RCT results to patients
`using CGM in combination with MDI
`therapy.
`Now that the first substantial ran-
`domized controlled trials on CGM have
`been performed, another conclusion is
`that CGM does not seem to prevent severe
`hypoglycemia. This is in contrast with
`early expectations and current beliefs.
`Table 1 shows the incidences of severe hy-
`poglycemia across several CGM trials that
`are mostly comparable in the intervention
`and control groups. In the STAR-1 trial,
`there were even significantly more severe
`hypoglycemic events in the CGM arm that
`in the control arm (17). There seem to be
`three possible explanations for the inabil-
`ity of CGM to prevent severe hypoglyce-
`mia. First, there is CGM inaccuracy.
`When compared with actual plasma glu-
`cose values, CGMs have an inaccuracy up
`to 21% (expressed as mean absolute dif-
`ference, |CGM glucose 2 plasma glucose|/
`plasma glucose). This number is even
`higher in the hypoglycemic range or during
`rapid rise and fall of the plasma glucose
`(36). Probably a physiologic and instru-
`mental delay, inherent to the current real-
`time CGMs, contribute to the inaccuracy of
`the devices (37).
`Second, during severe hypoglycemia,
`there is a decline of cognitive function and
`patients are less adequate in responding
`to acoustic or vibration alarms (38).
`Third, during intensive sport activities,
`which bring along an increased risk of hy-
`poglycemia, the CGM device is more
`likely to be put aside. However, we have
`to note that no trials so far were specifi-
`cally designed and powered to investigate
`CGM in relation to prevention of severe
`hypoglycemia. One multicenter trial is
`underway and the results are eagerly
`awaited (NCT00843609). In an observa-
`tional follow-up study from the JDRF-
`CGM study group, CGM use was associated
`with both HbA1c reduction and reduction
`in severe hypoglycemia rate (15). This as-
`sociation indicates the need for controlled
`trials, perhaps with a longer duration than
`6 months, to allow for the possibility that
`a longer user learning phase is needed to
`learn to avoid severe hypoglycemia. Such
`trials investigating the value of CGM in
`preventing severe hypoglycemia should
`
`Hermanides, Phillip, and DeVries
`
`be targeted to patients at high risk for
`severe hypoglycemia. This is also impor-
`tant for reimbursement of CGM in well-
`controlled type 1 diabetic patients. Because
`these patients have already achieved their
`HbA1c targets without CGM, the incre-
`mental CGM value has to come from pre-
`venting hypoglycemia and gaining quality
`of life.
`In addition, CGM is always discussed
`in the context of type 1 diabetes, whereas
`the vast majority of the diabetes popula-
`tion consists of type 2 diabetic patients.
`Blood glucose monitoring with SMBG is
`the standard of care, but its effectiveness is
`debated (39). Having this in mind, the
`evidence on CGM in the type 2 diabetic
`population is surprisingly scarce. Yoo
`et al. (40) performed an RCT in 65 pa-
`tients with type 2 diabetes, comparing
`12 weeks of intermittent real-time CGM
`use (3 days per month) with standard care
`using SMBG. In both groups, HbA1c de-
`creased, but it decreased significantly
`more (20.5%, P = 0.004) in the CGM
`arm. To our knowledge, this is the only
`RCT that specifically assessed HbA1c de-
`crease by CGM in type 2 diabetes. Ade-
`quate powered trials with sufficient
`follow-up time are needed.
`Finally, the costs of the CGM devices
`are a major con. Treatment with CGM
`costs about $4,930–7,120 per person-
`year compared with $550–2,740 for
`SMBG (41). It can be assumed that
`CGM would be cost-effective in poorly
`controlled type 1 diabetic patients be-
`cause of the gain in long-term health ben-
`efits, as indicated by HbA1c lowering.
`However, the cost-effectiveness of CGM
`in other patient groups or in preventing
`hypoglycemia is hard to assess because of
`the existing lack of evidence. This result is
`reflected in the current reimbursement
`status of CGMs. In the U.S., federal Medi-
`care and most other health plans reim-
`burse real-time CGM only for type 1
`diabetic patients who are not meeting
`the ADA HbA1c targets or experience se-
`vere hypoglycemic events. In Europe,
`real-time CGM is only reimbursed in
`Sweden and Slovenia. CSII-using patients
`in Sweden with two or more severe hypo-
`glycemic episodes per year, patients with
`HbA1c .10% while receiving intensive
`insulin therapy, and children who require
`at least 10 plasma glucose tests per 24 h
`are eligible for reimbursement. If CGM
`does not have the desired effect after 3
`months, it should be discontinued. In
`Israel, real-time CGM is included in the
`National Health Basket and is reimbursed
`
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`CGM in type 1 diabetes
`
`by the Sickness Funds. Children (aged 6–
`18 years) with type 1 diabetes and severe
`hypoglycemia unawareness, experiencing
`two severe episodes of hypoglycemia in
`the past 12 months (requiring ambulance
`assistance or emergency ward treatment),
`can apply for reimbursement.
`
`CONCLUSIONS—According to cur-
`rently available evidence, CGM lowers
`HbA1c without increase in the incidence
`of severe hypoglycemic episodes in pa-
`tients with type 1 diabetes who use the
`device frequently. Furthermore, CGM
`seems to have a positive impact on quality
`of life in this patient group. Treating ado-
`lescents and children with CGM requires
`additional attention, since these patients
`tend to use CGM less frequently. So far,
`CGM is not indicated for preventing se-
`vere hypoglycemia or treating type 2 di-
`abetes because supporting evidence is
`pending. Results of the application of
`CGM in pregnant women with diabetes
`or in-hospital hyperglycemia are promis-
`ing but need further investigation. Future
`studies should address the patient groups
`that have been neglected so far and ana-
`lyze cost-effectiveness. Finally, CGM ac-
`curacy needs improvement, as does the
`user-friendliness of the devices. Predic-
`tions on the feasibility of the closed-loop
`system have proven too optimistic too of-
`ten; however, we do believe that major
`steps forward have been made in the last
`few years.
`
`Acknowledgments—M.P. received research
`grants from Abbott Diabetes Care and Med-
`tronic. J.H.D. received fees for speaking en-
`gagements and research support from Abbott
`Diabetes Care, Dexcom, and Medtronic. No
`other potential conflicts of interest relevant to
`this article were reported.
`
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`S201
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`ABBOTT Exhibit 2012
`Dexcom v. Abbott Diabetes Care, IPR2023-01409
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