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 Diabetes Technology & Therapeutics > Vol. 25, No. S3 >  Free Access Figures References Related Details

Advancements in Diabetes Technology Are

Outpacing the Evidence
Michael Rickson, Eugene E. Wright Jr.  , Anila Bindal, and Laith Ghonim

Published Online: 12 Jun 2023 https://doi.org/10.1089/dia.2023.0145

 Sections PDF/EPUB  Permissions & Citations  Share Information

Copyright 2023, Mary Ann Liebert, Inc., publishers

Abstract To cite this article:

Michael Rickson, Eugene E. Wright Jr., Anila Bindal, and Laith Ghonim.
Diabetes technologies such as continuous glucose monitoring (CGM) continue to evolve at an increasingly rapid pace.
Advancements in Diabetes Technology Are Outpacing the Evidence.
Seventeen new CGM devices have been introduced to the market during the past decade. The introduction of each new Diabetes Technology & Therapeutics. Jun 2023. S-35-S-41.
system is supported by well-designed randomized controlled trials and real-world retrospective and prospective studies. http://doi.org/10.1089/dia.2023.0145

However, translation of the evidence into clinical guidelines and coverage policies often lags. This article reviews the major Published in Volume: 25 Issue S3: June 12, 2023
limitations of the current approach to clinical evidence assessment and presents a more appropriate method for evaluating
rapidly evolving technologies such as CGM.
Topics

Introduction Continuous glucose monitoring

On January 9, 2007, Apple CEO Steve Jobs unveiled the brst iPhone®. Eighteen months later, Apple introduced its successor,
the iPhone 3G. In the subsequent years, Apple continued to innovate with a new version every 12–24 months, iPhone 4
(June 4, 2010), iPhone 6 (March 31, 2016), iPhone 11 (September 20, 2019), and so on, each version offering new
capabilities. Most recently, Apple introduced the iPhone 14, which features a sophisticated camera, crash detection, and
“Emergency SOS” service via satellite. The point here is that innovations in technology occur swiftly.

The same holds true with the evolution of diabetes technologies. Unlike pharmaceutical products, which often take several
years to make their way through the various phases of safety and ehcacy trials required by regulatory agencies, the time
between innovation and market launch is signibcantly shorter. For example, during the past 10 years, the 3 major continuous
glucose monitoring (CGM) manufacturers, combined, have introduced 15 new generations of CGM devices (Fig. 1).

FIG. 1. Evolution of CGM over the past decade (FDA Approval).

Although there is always published evidence to support the most current generation of CGM technology, it is sometimes
dihcult for clinicians who are unfamiliar with CGM to separate the old from the new, which can injuence their prescribing
decisions. Moreover, because payers strongly consider recommendations from published practice guidelines when
determining coverage policies, it is important that medical associations place greater emphasis on the outcome studies
assessing the newest generation CGM systems. Otherwise, the improved outcomes provided by these new devices could be
diluted by less robust bndings from earlier studies of older generation technologies that do not offer the same capabilities.

In this article, we review the major limitations of our current approach to clinical evidence assessment and present a more
appropriate method for evaluating rapidly evolving technologies such as CGM.

Strengths and Limitations of Current Methods for Assessing Evidence

Systematic reviews/meta-analyses
Most medical organizations recognize systematic reviews and meta-analyses (SRMAs) of well-designed randomized
controlled trials (RCTs) as the highest level of scientibc evidence when developing practice guidelines.1 Although RCT
designs are well suited for assessing the ehcacy and safety of a given medication, they may not accurately reject the
effects of a given technology on clinical outcomes.

For example, pharmaceutical RCTs are designed to measure the physiological response(s) to a given medication within a
prespecibed population under tightly controlled clinical selection and conditions. The goal is to determine whether the
medication works as intended, how well it works, and any adverse effects that would outweigh its benebts. Participants are
only required to administer the medication as prescribed; the mechanism of action is purely physiologic.

Although RCTs involving CGM pursue the same fundamental goal as pharmaceutical studies, the mechanism of action is
primarily external. Although the performance of the CGM device (e.g., accuracy, reliability) plays a role in these assessments,
the outcomes are heavily dependent on a number of external and potentially confounding factors such as participants'
competencies, attitudes, and behaviors (Table 1). Therefore, a number of limitations should be considered when evaluating
the results from these studies and assessing their relevance in clinical practice.

Table 1. Examples of Potential Confounding Factors Relative to CGM Use

Competencies Correct sensor placement

Sensor connection with App or reader
Appropriate response to the data
Ability to perform other self-management tasks as prescribed

Attitudes Trust in their data

Con<dence in responding to their data
Trust in the clinical staff conducting the study

Behaviors Persistence in wearing the sensor

Persistence in appropriately responding to the data
Persistence in performing other self-management tasks as prescribed

One limitation is that RCTs often exclude populations that would benebt most from CGM use due to age, comorbidities,
and/or extremely poor glycemic control at baseline. For example, many of the large landmark RCTs investigating the ehcacy
of CGM excluded individuals with a history of severe hypoglycemia or impaired hypoglycemia awareness.2–5 Although CGM
devices have been around for more than 20 years, the brst RCT to study patients with these conditions was not conducted
until 2016,6 with results published in 2018.7

Another limitation of SRMAs is the potential challenge of assessing the most up-to-date performance of CGM technologies
as they become available. For example, in a 2020 meta-analysis of RCTs by Maiorino et al., 12 of the 18 studies examined
were published before 2018.8 Since then, seven new CGM devices were developed and made commercially available (Fig.
1). This is an important consideration when assessing the value and utility of CGM technology in toto based on SRMAs
because of the ongoing improvements in accuracy, safety, and convenience features offered in each new generation of CGM
devices.

It is also important to consider the time required to design, recruit participants, and conduct large RCTs. One example is the
DIAMOND type 2 diabetes (T2D) trial, which initiated in September 2014 and assessed a CGM sensor that was available at
that time.3 However, 1 year after the study was initiated, the company introduced a newer CGM device and although the
results were published 2 years later in August 2017, the RCT was not able to assess the updated CGM. Although the
accuracy was similar to the initial sensor, an important difference was the change from adjunctive (requiring conbrmatory
blood glucose for therapeutic decisions) to nonadjunctive use, which signibcantly changed the way patients were able to
use their devices. Patients were able to avoid painful bngersticks and follow the guidance provided by their CGM data, using
the current glucose value and trend arrows.

Unlike the initial sensor, patients had the option to view their data in either the handheld reader or the smartphone app.
Although not formally evaluated, it is reasonable to assume that both of these changes positively impacted patient
convenience and persistence in CGM use, which have been demonstrated to be important factors in achieving optimal
glycemic control.9–20

Because SRMAs often aggregate results from diverse clinical trials, they may not be able to differentiate between the
strengths and limitations of specibc CGM devices. Since the technology features can change as newer devices are
introduced, there needs to be discussion about which factors are responsible for the results described. For example, in a
2020 study that investigated glycemic control (time in range and time in hypoglycemia), Visser et al. compared a version of
the jash CGM without alarms (introduced in 2018) with a real-time CGM (rtCGM) with alarms.21 Use of the rtCGM sensor in
that study was associated with less hypoglycemia. As such, the American Association of Clinical Endocrinology (AACE)
recommended rtCGM over jash CGM for people with problematic hypoglycemia who require predictive alerts in its 2021
guidelines.22

However, the newer jash CGM with alarms was Conformite Europeenne (CE) marked in 2018 and cleared by the FDA in
2020. Although the AACE guidelines used this evidence to recommend rtCGM over jash CGM, published studies were
needed to see if rtCGM was superior to the newer generation jash CGM with alarms.

Findings from SRMAs can become even less reliable when the included studies overrepresent a specibc CGM device. In a
report that is heavily weighted with studies of a specibc CGM device that is less accurate than the other devices studied, the
aggregated outcomes will, by default, conclude less favorable assessment of CGM as a category.

It is also important to consider the heterogeneity of population studies. For example, while the IMPACT study by Bolinder et
al.,5 which used jash CGM, showed no change in a secondary endpoint of HbA1c, a similar study (DIAMOND type 1 diabetes
[T1D] trial) reported a signibcant reduction in the primary endpoint of HbA1c.2 Both the primary endpoints (change in
hypoglycemia vs. change in HbA1c, respectively) and baseline HbA1c levels (6.7% vs. 8.6%, respectively) between the two
studies were signibcantly different; this heterogeneity of the population likely played a major role in the outcomes.

These limitations call into question the veracity of recommendations for CGM use based solely on bndings from SRMAs of
RCTs. Results from other types of studies should also be considered.

Real-world evidence
There has been growing interest in use of real-world evidence (RWE) to complement RCTs in elucidating the impact of both
medications and technologies. Common sources of real-world data have traditionally included medical records, patient
registries, claims databases, and health surveys.

While RCTs yield important insights about the degree to which a given intervention produces more positive than negative
effects under controlled conditions, RWE assesses the extent to which the intervention achieves the necessary risk:reward
ratio when applied under the usual conditions of daily clinical practice. As reported in a meta-analysis that included both
RCTs and either cohort or case-control studies that assessed the same interventions and endpoints, Concato et al.
concluded that the results of well-designed observational studies do not overestimate the magnitude of treatment effects
when compared to those reported in RCTs.23

Given that diabetes management is primarily patient driven, it is important that bndings from RCTs be conbrmed in real-
world settings. For example, in a 2010 post hoc analysis by Zoungas et al. of the ADVANCE study, a large RCT of 11,140 T2D
patients, investigators demonstrated an association between severe hypoglycemia, the risk of macrovascular and/or
microvascular events, and patients.24 Five years later, Khunti et al. conducted a large retrospective cohort study of 265,868
T1D and T2D patients, with similar outcome measures.25 Investigators not only conbrmed the bndings reported in the earlier
study but also demonstrated that there was no difference in risk between the T1D and T2D cohorts. They also found that
individuals in both groups with established cardiovascular disease (CVD) had signibcantly greater risk than those without
CVD, which was not reported in the Zoungas study.

A key advantage of real-world studies is that they can provide meaningful information that is fundamental to diabetes
management but cannot be assessed through RCTs. For example, before 2004,26 the American Diabetes Association (ADA)
did not provide a glycemic target for postprandial glucose due to ethics (safety) considerations. Although it was suspected
that excessive postprandial glucose excursions may be linked to the development of microvascular and macrovascular
disease,27 investigators were unable to conduct a randomized trial because of potential harm to patients. Instead,
organizations began to focus on the numerous prospective and retrospective studies that clearly showed the relationship
between postprandial glucose and the chronic complications of diabetes.28–34 These studies and others were foundational
for the International Diabetes Foundation (IDF) Postmeal Glucose guidelines, published in 2007.35

Ongoing digitization of health care data has led to the development of massive databases that can be easily queried to
assess demographic information, medical records, pharmacy prescriptions, outpatient care, hospitalizations, and
emergency department utilization for large groups of patients. However, real-world studies utilizing such data have notable
limitations.

Although these databases present clinical and demographic information, they often provide little or no information about
education level or socioeconomic status. Nor do they capture information about patient behavior, which is extremely
relevant in CGM studies. For example, information about patient-specibc factors that can impact outcomes is seldom
available. Why did they select one CGM device over another? How often did they wear the device? Are they accurately
interpreting their data? Are they using their data to make daily self-management decisions—why or why not? Are they
satisbed with their device? Has their quality of life improved? Even how patients received their data and handheld reader or
app can impact glucose control. As reported in a recent retrospective study by Kao et al., app users spent less time in
hyperglycemia and more time in range, with lower average glucose and glycemic variability.36 This information has never
been reported in RCTs.

Therefore, while large database analyses can demonstrate associations between acquisition of a CGM device and clinical
outcomes, the underlying reasons for success or failure with device use cannot be determined. While many regulatory
agencies are now requiring manufacturers to submit RWE in conjunction with bndings from their RCTs when reporting the
safety, effectiveness, and cost-benebt parameters of new medications and medical devices,37–40 they are also demanding
data that provide a more holistic understanding of individuals' competencies, attitudes, and behaviors relevant to use of
each new technology.41

Person-Reported Outcomes
While physical metrics (e.g., HbA1c, time in range) provide an indication of patients' glycemic status and risk of diabetes-
related complications, these measures do not elucidate patients' perceptions of how diabetes is affecting their health and
quality of life, which can affect their self-management behaviors. Because psychological and socioeconomic factors can
impact patient adherence and quality of life, it is important that studies utilize the standardized instruments to fully
understand the effects and feasibility of CGM use within various diabetes populations. Primary domains of interest in
diabetes studies include treatment satisfaction, diabetes-related distress, depression/anxiety, sexual health, impact of
therapies/technologies on quality of life, hypoglycemia awareness and fear, and sleep quality. Each of these domains can
signibcantly injuence patients' ability to achieve optimal diabetes control. The underlying questions here are: How is the
burden of the management of the chronic disease impacted by the device? Is the burden reduced or increased?

In 2016, the ADA published a position statement recommending that health care providers consider formal assessments of
symptoms of diabetes distress, depression, anxiety, disordered eating, and/or of cognitive capacities using patient-
appropriate standardized/validated tools at the initial visit, at periodic intervals, and when there is a change in disease,
treatment, or life circumstance.40 Input from caregivers and family members should be included in these assessments.
Unfortunately, the social and psychological conditions that can adversely affect patient self-management are not routinely
assessed in clinical care or research programs despite strong recommendations from national and global health
organizations.42,43

Impact of Evidence Assessments on Guideline Developers and Prescribers

A decision-making pathway
To understand whether technology such as CGM ultimately ends up in patients' hands, it is important to identify the various
steps involved in the decision-making pathway (Fig. 2). After a given technology product is created, the companies must
satisfy regulatory requirements by demonstrating its safety, ehcacy, and impact on psychosocial measures. While the
product is under regulatory review, companies often publish their premarket data to create awareness within the clinical care
community. Once the product is approved, it becomes a candidate for inclusion in clinical guidelines. As discussed earlier,
guideline developers often place greater weight on RCTs, with less emphasis on RWE or person-reported outcome (PRO)
data and evidence, depending on the medical organization.

FIG. 2. Simplibed schematic for technology decision pathway.

While regulatory approval is essential for payers in determining whether to provide coverage, payers also consider the
published evidence to further debne their coverage criteria (e.g., T1D only, intensive insulin therapy regardless of diabetes
type). While prescribers are strongly injuenced by guideline recommendations and coverage policies, many will also
consider published evidence when deciding whether and/or for whom they will prescribe use of the technology.

Potential unintended consequences

While this schematic presents a very logical approach to evidence-based decision-making, there is a strong potential for
misinterpretation of the safety and ehcacy of technology when used in real-world clinical settings if RWE and PRO
outcomes are not considered by all decision-makers. While an RCT may show clear glycemic benebts when the product is
used in selected patients (e.g., inclusion/exclusion criteria) under controlled conditions, issues with usability (e.g.,
complexity, inconvenience) may negatively impact patients' willingness to use it persistently (if at all). Also, the impact of the
Hawthorne Effect is often not apparent in RCTs. Sometimes using the product may cause additional anxiety or distress,
which will either impact adherence or exacerbate poor quality of life.

Misinterpretations can also occur when outdated evidence is used. Decision-makers who rely heavily on SRMAs or RCTs are
particularly susceptible. While compiling and publishing these reports is a lengthy process in and of itself, one must also
consider the time required to conduct each of the RCTs included in the reports. At best, even the most current SRMAs are at
least one generation behind the latest technology. There can also be confusion among prescribers who may not be able to
stay up to date with the most current literature.

Changing the paradigm

Shortening the delay between the introduction and adoption of new technologies will require fundamental changes in how
institutions and individuals assess all available evidence. Institutions must adopt new methodologies that place greater
emphasis on RWE and PRO evidence to establish guidelines that more accurately reject the potential benebts of these
technologies when used by various diabetes populations under real-world, real-life conditions. Moreover, it is important that
the individuals responsible for developing these guidelines are experienced in using these technologies and are deeply
immersed in the most current research bndings. Although the guidelines should certainly include historical data relative to
these technologies, the most recent evidence should be highlighted as such.

Summary
During the past two decades, the diabetes community has witnessed a continuous stream of innovative technologies for
glucose monitoring. The benebts of these new technologies have been rigorously assessed and proven effective in
improving diabetes management. Although adoption of CGM is steadily increasing, inclusion of the most current
technologies and subsequent insurance coverage is often delayed due to the rigid and often outdated methodologies used
by policymakers when assessing clinical evidence related to technology. Although SRMAs and RCTs remain the gold
standard when assessing the robustness of evidence, it is important to assess the totality of the available evidence,
including results from real-world studies and PRO evidence. Additional pragmatic trials, with greater representation of real-
world populations are needed to fully address specibc research questions and expedite access to technologies that have
been demonstrated effective in improving diabetes management and patient quality of life.

Acknowledgments
The authors thank Christopher G. Parkin, MS, for his insights, analysis, and editorial support in developing this article.

Authors' Contributions
All authors were involved in article conceptualization, writing/revisions, and approval for submission. M.R. is the guarantor
of this work and takes responsibility for the integrity of the data and the accuracy of the content.

Author Disclosure Statement

E.E.W. has received consulting fees from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Mannkind, Merck,
Sanob U.S., and Voluntis and has acted as a speaker for Abbott, Bayer, Boehringer Ingelheim and Eli Lilly. M.R., A.B., and L.G.
are Abbott Diabetes Care employees.

Funding Information
Funding for the development of this article was provided by Abbott Diabetes Care.

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