REVIEW ARTICLE

Hypoglycemia unawareness and autonomic

dysfunction in diabetes: Lessons learned and
roles of diabetes technologies
Yu Kuei Lin1, Simon J Fisher2, Rodica Pop-Busui1,*
1
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA, and 2Division of
Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

Keywords ABSTRACT
Cardiovascular autonomic neuropathy, Impaired awareness of hypoglycemia (IAH) is a reduction in the ability to recognize low
Impaired awareness of hypoglycemia, blood glucose levels that would otherwise prompt an appropriate corrective therapy. Identi-
Type 1 diabetes fied in approximately 25% of patients with type 1 diabetes, IAH has complex pathophysiol-
ogy, and might lead to serious and potentially lethal consequences in patients with diabetes,
*Correspondence particularly in those with more advanced disease and comorbidities. Continuous glucose
Rodica Pop-Busui monitoring systems can provide real-time glucose information and generate timely alerts on
Tel: +1-734-615-9497
rapidly falling or low blood glucose levels. Given their improvements in accuracy, affordability
Fax: +1-734-232-8162
and integration with insulin pump technology, continuous glucose monitoring systems are
E-mail address:
rpbusui@med.umich.edu emerging as critical tools to help prevent serious hypoglycemia and mitigate its conse-
quences in patients with diabetes. This review discusses the current knowledge on IAH and
J Diabetes Investig 2020; 11: effective diagnostic methods, the relationship between hypoglycemia and cardiovascular
1388–1402 autonomic neuropathy, a practical approach to evaluating cardiovascular autonomic neu-
ropathy for clinicians, and recent evidence from clinical trials assessing the effects of the use
doi: 10.1111/jdi.13290 of CGM technologies in patients with type 1 diabetes with IAH.

INTRODUCTION of hypoglycemia definitions also include glucose levels <54 mg/

For almost 100 years, insulin has been the fundamental therapy dL (i.e., level 2 hypoglycemia16) for its associations with major
for type 1 diabetes1. By suppressing ketogenesis, insulin miti- comorbidities, such as increased mortality, cognitive dysfunction
gates the risk for the development of diabetic ketoacidosis, a and the development of impaired awareness of hypoglycemia
life-threatening acute complication of diabetes. The Diabetes (IAH)18, a condition in which patients have diminished or lost
Control and Complications Trial2 and Epidemiology of Dia- ability to perceive the onset of hypoglycemia19. The Diabetes
betes Interventions and Complications study3 further estab- Control and Complications Trial study defined severe hypo-
lished the use of intensive insulin therapy to prevent or delay glycemia as hypoglycemic episodes requiring assistance of
the development of chronic microvascular and macrovascular another person for recovery9. This definition was subsequently
complications. Based on recent updates, the impacts of this rel- adopted as the universal definition of severe (or level 3) hypo-
atively short-term glucose control appear to confer durable glycemia11,15,16.
metabolic benefits for at least 30 years4–8. However, intensive Iatrogenic hypoglycemia is not restricted to type 1 diabetes
insulin therapy comes at a price. Intensive insulin treatment patients. Both sulfonylurea use and insulin therapy in patients
almost invariably increases the incidence of severe hypo- with type 2 diabetes result in increased risks for hypo-
glycemia9,10, which is associated with altered mental state, sei- glycemia20,21. Interestingly, there has been intensive debate as
zures, cardiac arrhythmias and even death11–14. to whether severe hypoglycemic events in type 2 diabetes
Hypoglycemia has traditionally been defined by blood glu- patients is merely a marker of, or indeed causal of, the well-
cose levels of <70 mg/dL (recently termed level 1 hypo- documented increased risk of cardiovascular events and mor-
glycemia15,16), as these levels trigger the normal physiology of tality after hypoglycemia22–25.
counterregulatory responses to hypoglycemia17. Recent revisions Continuous glucose monitoring systems (CGMs, or real-time
CGMs) are devices that measure subcutaneous interstitial glu-
cose to estimate blood glucose levels, and report the glucose
Received 2 April 2020; revised 1 May 2020; accepted 7 May 2020

1388 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi Does CGM improve hypoglycemia awareness?

levels and trends to patients in real time26. CGMs can also gen- A major cause of IAH and impaired adrenomedullary
erate audible or vibrating alarms for low/high glucose levels, responses to hypoglycemia is recurrent episodes of hypo-
based on the settings customized by patients or healthcare pro- glycemia, which (as part of a vicious cycle) perpetuate these
viders, to alert the patients to hypo/hyperglycemic events. Based conditions52–54. There is also evidence that IAH can be induced
on their capability to (i) improve hemoglobin A1C (HbA1c) by sleep55,56, psychological stress57 and alcohol58, yet there are
and average glucose levels; (ii) reduce the risk for serious hypo- still controversies as to whether exercise59,60 and beta-adrenergic
glycemic complications27–29; and (iii) reduce the burden of blockers61,62 have detrimental or beneficial effects on hypo-
repetitive fingerstick glucose monitoring30, CGMs are now con- glycemia awareness status.
sidered the standard of care for type 1 diabetes patients31–33. The mechanisms for the development of IAH remain to be
CGM use has also been further established with improvements elucidated63. Earlier studies evaluated the relationships between
in accuracy34, feasibility for patients of various ages35,36 and dia- this condition and adrenal medulla destruction64, cortisol (as a
betes duration37, and the standardization of metrics for quanti- systemic mediator)65 or CAN66. Some studies focused on the
fying hypoglycemia18,38. The interest and availability of CGMs glucose sensing in the brain and how it is altered with antece-
that are integrated to sensor-augmented insulin pumps is also dent hypoglycemia. Consistent with this central nervous sys-
rapidly expanding39. For patients with type 2 diabetes, data tem-impaired glucose sensing, recent studies have implicated
showing the beneficial roles of CGM technology for glucose the use of alternative fuels (e.g., lactate67 or monocarboxylic
control40, weight control and lifestyle adherence41 are also acids68) and changes in the neurotransmitter signaling in the
emerging. brain (e.g., GABAergic69, glutaminergic and opioidergic70 sig-
The current review gives a brief overview of the current naling) as likely causes for IAH and the impaired sympathoad-
knowledge of the IAH, and its assessment methods, the rela- renal response to hypoglycemia.
tionships between hypoglycemia and cardiovascular autonomic As these impaired responses are purported to be caused by
neuropathy (CAN), a practical approach on CAN evaluations recurrent antecedent hypoglycemia, it is logical that a reduction
in clinical care, and the recent clinical trial evidence on the role in the incidence of hypoglycemia would be expected to improve
of CGMs use in the IAH population. hypoglycemia awareness and adrenomedullary responses. In
support of this notion, studies have shown that strict hypo-
IMPAIRED AWARENESS OF HYPOGLYCEMIA AS A glycemia avoidance with rigorous monitoring and behavioral
BARRIER FOR GLUCOSE CONTROL modifications can help improve hypoglycemia awareness in as
Patients with IAH develop unrecognized hypoglycemic events little as 2 weeks71–74. Additionally, blood glucose awareness
and thereby can often miss the opportunity to treat their hypo- training75, education to optimize insulin dosing76 and hypo-
glycemia in a timely manner19. Commonly co-existing with glycemia avoidance motivational programs77 have also been
IAH is the attenuation or loss of sympathoadrenal mechanisms, shown to improve hypoglycemia awareness.
which limits the endogenous glucoregulatory recovery from
hypoglycemia (specifically, catecholaminergic stimulation of HYPOGLYCEMIA AND CARDIOVASCULAR AUTONOMIC
hepatic glucose output and restraint of muscle glucose NEUROPATHY
uptake)42. Thus, for people with type 1 diabetes, who have Diabetic CAN, defined as the impairment of autonomic control
already lost the ability to decrease endogenous insulin secretion of the cardiovascular system in the setting of diabetes after
and increase glucagon production as counterregulatory mecha- exclusion of other causes78, is a major diabetic comorbidity that
nisms, IAH and impaired adrenomedullary responses result in has been associated with a significant increase in mortality in
a further significant loss of defense mechanisms to avoid severe both patients with type 1 diabetes79–81 and type 2 diabetes82–84.
hypoglycemia (Figure 1)19. Indeed, IAH is associated with an Despite the association between CAN and increased mortality,
approximately sixfold increased risk of developing severe hypo- currently there is no effective therapy to prevent or reverse this
glycemia43,44. Clinically, because of the risk of developing dan- condition beyond glycemic control6,85,86 and symptomatic man-
gerously low glucose levels, patients and healthcare providers agement87. The role of autonomic dysfunction as a risk factor
alike are often reluctant to practise/advocate tight glucose con- for IAH had been studied quite extensively. Particularly as a
trol to achieve proposed glycemic targets45. hallmark of IAH is the loss of sympathetic symptoms (e.g., pal-
Approximately 25–40% of type 1 diabetes patients were pitation, tremor and anxiety) and the epinephrine responses to
found to have IAH, with a stable prevalence over the past two hypoglycemia, it was postulated that autonomic dysfunction
decades43,44,46,47. This value is most certainly an underestima- including CAN might directly contribute to the development of
tion, as even patients who report having intact hypoglycemia IAH88. However, more recent evidence showed that in some
awareness are indeed unaware of CGM-confirmed hypo- patients IAH can be induced by a single episode of hypo-
glycemia48. In the type 2 diabetes population, the IAH preva- glycemia53. This suggests that although autonomic dysfunction
lence ranges from approximately 6 to 17% in those using and CAN might further impact IAH risk and consequences89,90,
insulin injection programs, and the IAH status is associated it is unlikely to be the main mechanism involving its develop-
with 9–17-fold increased risk for severe hypoglycemia49–51. ment66,91,92. Furthermore, it appears that self-reported IAH does

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 6 November 2020 1389
REVIEW ARTICLE
Lin et al. http://wileyonlinelibrary.com/journal/jdi

Loss of
Hypoglycemia counterregulatory
Recurrent mechanism
hypoglycemia

T1D1

Decrease in Increase in Increase in

Hypoglycemic
insulin glucagon catecholamine
symptoms
secretion secretion release

Hepatic Treatment
gluconeogenesis administration

Hormonal Behavioral
counterregulatory counterregulatory
mechanism mechanism

Figure 1 | Hypoglycemia counterregulatory mechanisms and the impacts of type 1 diabetes (T1D) and recurrent hypoglycemia on these
mechanisms. 1Or advanced type 2 diabetes.

not predict CAN93. Yet, the associations between hypoglycemia sensory and autonomic neuropathy, often with a dramatic
and CAN in particular are quite complex, and remain to be onset and course109,110.
further elucidated. There is ample evidence that CAN is inde-
pendently associated with hypoglycemia in patients with dia- ASSESSMENT OF IMPAIRED AWARENESS OF
betes25,94,95. Several studies have also shown that hypoglycemia HYPOGLYCEMIA AND IMPAIRED ADRENOMEDULLARY
can promote reductions in heart rate variability and the barore- RESPONSES TO HYPOGLYCEMIA
flex sensitivity in both patients with diabetes96,97 and healthy The hyperinsulinemic hypoglycemic clamp technique is the
controls98 that might last for many hours after euglycemia is gold standard of assessing hypoglycemia awareness and hor-
restored97. In addition, our group has reported that increased monal responses to hypoglycemia17,111. This validated tool
glucose variability, particularly with a predominance of hypo- assesses the hypoglycemia awareness status by collecting hypo-
glycemic stress measures, was associated with blunting in mea- glycemic symptoms during the clamp procedure at specified
sures of heart rate variability in type 1 diabetes patients94. intervals to determine at what level of glucose hypoglycemic
These data lend support to a potential role of hypoglycemia in symptoms are experienced112,113. Information is captured on
the development of CAN and the loss of the protective cardio- several domains that include: difficulty thinking/confused,
vagal mechanisms, which might directly impact cardiac electri- warm, shaky/tremulous, nausea, tired/drowsy, hungry, weak,
cal activities and thus eventually increase the risk of cardiac sweaty, headache, heart-pounding, difficulty speaking, nervous/
arrhythmias in these patients94,97,99–101. Experimental evidence anxious, dizzy, faint, tingling and blurred vision112. In general,
reported that hypoglycemia might lead to peripheral nerve axo- it is accepted that individuals who do not develop significant
nal degeneration, possibly through alterations in the glucose hypoglycemic symptoms around glucose levels of 50–54 mg/dL
uptake, depletion of energy substrates and changes in Schwann are considered to have IAH114. Additional methods include the
cell metabolism affecting particularly the large myelinated assessment of epinephrine levels and other counterregulatory
fibers102,103, although the exact mechanisms and whether these hormones (norepinephrine, glucagon, cortisol, growth hormone,
hypoglycemia-associated changes are functional104,105, reversi- pancreatic polypeptide) during the various stages of hypo-
ble106 or permanent are still unclear107,108. An additional exam- glycemia17. Techniques in measuring the endogenous glucose
ple of the complex interactions between hypoglycemia, CAN production for the assessment of hepatic glucose output can
and neuropathy is treatment-induced neuropathy. Treatment- also be incorporated into hypoglycemic clamps115. Both single-
induced neuropathy is a condition described in patients who step116 (from baseline to one single hypoglycemia glucose level
have experienced a rapid decline in blood glucose levels after target) or step-wise117 (from baseline to sequentially lower
the use of insulin, oral hypoglycemic medications, or even diet hypoglycemic level targets) clamps are commonly used. Some
only to control hyperglycemia, and often manifests as a painful studies also carry out additional hyperinsulinemic-euglycemic

1390 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi Does CGM improve hypoglycemia awareness?

clamps117, in randomized orders with the hypoglycemic clamps, awake/sleep, and the hypoglycemia frequency, severity and
to blind the participants, so that the participants’ hypoglycemic impacts on patients. This questionnaire was validated with
symptoms and hormonal measures would not be confounded strong correlations with the Gold and Clarke questionnaires,
by the knowledge of an anticipated hypoglycemic event or insu- together with weak correlations with diabetes-related distress
lin administration. Although the hypoglycemic clamp is a well- and HbA1c. Other than wide usability with their non-invasive-
established method to objectively measure the status of counter- ness and no/minimal cost, self-reported hypoglycemia aware-
regulatory mechanisms, the pitfalls of clamp studies are the ness assessments might also benefit from the direct reporting of
invasiveness, expense and the significant time commitment patients’ experiences in real life120, rather than in highly con-
from the patients, and thus these studies are often restricted to trolled inpatients settings of hypoglycemic clamps. In contrast,
a small patient cohort. The interlaboratory variabilities in epi- the subjectivity of the experience (e.g., possibly influenced more
nephrine assays also prohibit the comparison among studies by the recent events) or lack of a controlled environment might
(Table 1)118. generate biases for the awareness reporting.
In the outpatient setting, methods to assess hypoglycemia
awareness based on questionnaires (i.e., “self-reported hypo- DIAGNOSIS OF DIABETIC CARDIOVASCULAR
glycemia awareness”) have also been developed and widely uti- AUTONOMIC NEUROPATHY IN CLINICAL CARE
lized, particularly for studies requiring larger sample sizes. The The American Diabetes Association recommends that screening
Gold questionnaire43 contains a single question (besides two for CAN should be carried out for patients with evidence of
questionnaire-validation questions) asking individuals to report other chronic complications, such as nephropathy, peripheral
their experience in detecting hypoglycemic events with scores neuropathy, retinopathy and cardiovascular disease, as well as
ranging from 1 (always aware) to 7 (never aware) on a Likert- for patients with IAH121, with high glucose variability, before
type scale. In contrast, the Clarke questionnaire44 is comprised insulin dose adjustments and/or perioperatively79. The symp-
of eight questions evaluating participants’ prior hypoglycemia toms of CAN are less prevalent in contemporary cohorts of
experiences, such as the history of severe hypoglycemia devel- patients with diabetes, and most patients with CAN are com-
opments and the glucose levels at which patients start to detect pletely asymptomatic101,121. Weakness, lightheadedness, palpita-
hypoglycemic symptoms, and generates a score (0–7) based on tions, syncope with standing or exercise intolerance are usually
the responses. Scores ≥4 are indicative of IAH, and ≤2 indicates associated with advanced CAN6,85,122.
normal awareness for both the Gold and Clark questionnaires. Clinical signs, such as resting tachycardia (>100 b.p.m.) and
The Pedersen-Bjergaard questionnaire46 asks individuals to orthostatic hypotension (a fall in systolic or diastolic blood
report whether they recognize symptoms during hypoglycemic pressure by >20 mmHg or >10 mmHg, respectively, on stand-
events and, based on the answer, the hypoglycemia awareness ing without an appropriate increase in heart rate) are both easy
status is categorized as “normal,” “impaired awareness,” to document in an office78,123, but in general present in later
“unawareness” and :undetermined.” All of these questionnaires stages of CAN121,124. A decrease in heart rate variability is the
have been previously validated based on their associations with earliest sign of CAN78,125,126, and can be assessed in an office
severe hypoglycemia. The Clarke questionnaire has also been by obtaining an electrocardiogram during 1–2 min of deep
validated with hypoglycemic clamps114. HypoA-Q119 is a 33- breathing and calculating indices of heart rate variability127,128.
item questionnaire assessing hypoglycemia awareness when However, given that both the symptoms and signs described

Table 1 | Current measures for assessing hypoglycemia awareness

Measurements Advantages Disadvantages

Outpatient Questionnaires: • Non-invasive • Subjectivity bias

• Gold4344 • No/minimal cost • Recall bias
• Clark • Reporting of experience from • Uncontrolled environment
• Pedersen-Bjergaard46
real-life hypoglycemic episodes • Lack of sensitivity to detect/quantify
• HypoA-Q 119
• Amenable to use in large patient cohorts changes in awareness with short-term
• Feasible for clinical use interventions

Inpatient Edinburgh Hypoglycemia Scores112 • Controlled environment, including • Invasiveness

determined during the reproducible hypoglycemic levels • Expense
hyperinsulinemic • Patient time commitment
hypoglycemic clamp. • Small patient cohorts

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 6 November 2020 1391
REVIEW ARTICLE
Lin et al. http://wileyonlinelibrary.com/journal/jdi

are non-specific, a careful differential diagnosis is required to 180 mg/dL), and 41% and 55% reduction of the time in hypo-
exclude other common medical causes (e.g., hyperthyroidism, glycemia and the number of patients who developed severe
anemia, dehydration, adrenal insufficiency, arrhythmic disor- hypoglycemia, respectively. The Gold scores at the end of the
ders), prescription medications effects (e.g., antihypertensive CGM phase were lower, and tended to be lower compared with
agents, antimuscarinic agents, diuretics), over-the-counter sup- the end of the SMBG phase and to the baseline, respectively.
plements and recreational agents121. Similar findings, however, were not observed in the Clarke
The cardiovascular reflex tests that assess changes in heart scores. Although the cross-over design allows more “individual-
rate and blood pressure in response to several simple physiolog- ized” comparisons to evaluate CGMs’ impact, it was unclear if
ical maneuvers, such as deep breathing, standing or Valsalva, a 16-week CGM intervention was long enough to significantly
remain the gold standard diagnostic for autonomic testing in improve self-reported hypoglycemia awareness, and whether
both clinical care and research settings, although these are more the 12-week washout period could sufficiently “reset” the hypo-
expensive and add burden for both clinicians and patients121. glycemia awareness to the baseline.
In 2018, Rickels et al.134 carried out a small cohort, 18-month
CLINICAL TRIALS TESTING THE USE OF CONTINUOUS pre-post trial evaluating the changes in the endogenous glucose
GLUCOSE MONITORING SYSTEMS IN TYPE 1 DIABETES production and epinephrine responses with CGM interventions.
PATIENTS WITH IMPAIRED AWARENESS OF In this IAH population with severely problematic hypoglycemia,
HYPOGLYCEMIA the incidence of severe hypoglycemia decreased nearly 60% dur-
Early CGM clinical trials primarily focused on the CGMs’ ing the intervention. The hypoglycemic clamps also showed a
impact on glucose control, hypoglycemia reduction and quality doubled endogenous glucose production at 18 months, with no
of life129. Additional questions were raised regarding the poten- statistically significant improvements in epinephrine responses.
tial benefits of the CGM technology in improving the hypo- Improvements in autonomic symptom scores and self-reported
glycemia awareness and epinephrine responses in patients with hypoglycemia awareness were also observed.
IAH. Below we summarize some of the most relevant trials that The HypoDE (or "Hypoglycemia in Deutschland") study135 is
have addressed these questions. the largest randomized trial (CGM vs SMBG) to date testing
In 2011, Ly et al.130 carried out a small group randomized CGMs’ effects in patients with IAH or severe hypoglycemia his-
clinical trial study to evaluate whether the use of CGMs versus tory. The CGM group showed 72% fewer hypoglycemic epi-
self-monitoring of blood glucose (SMBG) might improve epi- sodes with glucose ≤54 mg/dL, along with 64% fewer severe
nephrine responses during hypoglycemic clamps in adolescents hypoglycemic episodes. The entire cohort also had a 40%
with type 1 diabetes and IAH (Table 2). The target glucose improvement in hypoglycemia awareness scores, although no
levels were 108–180 mg/dL in both groups, and the CGM group difference was found between the CGM and SMBG groups.
had the hypoglycemia alarm thresholds set at 108 mg/dL. Flash glucose monitoring systems (e.g., FreeStyle LibreTM), like
Although after 4 weeks the CGM group had greater epinephrine CGMs, can provide glucose levels and trends, but without the fea-
responses during the hypoglycemic clamps (Table 3), suggesting ture of automated low/high glucose alarms136. Flash glucose mon-
a potential benefit of CGMs in improving hypoglycemia aware- itoring systems have been documented to reduce the time in
ness, these findings were limited by the small sample size and to hypoglycemia137 and severe hypoglycemia138 for type 1 diabetes
a group with relatively short diabetes duration. patients, and reduce hypoglycemia139 and improve HbA1c140 in
Subsequently, the comparison of optimised MDI versus pumps the type 2 diabetes population. Reddy et al. compared the efficacy
with or without sensors in severe hypoglycaemia group131 carried of CGMs versus Flash glucose monitoring systems in reducing
out a 2 9 2 factorial (SMBG vs CGM; multiple daily injections, hypoglycemia in type 1 diabetes patients with IAH or severe
MDI vs continuous subcutaneous insulin infusion) randomized hypoglycemia history141. The CGM group showed greater hypo-
trial to assess whether hypoglycemia avoidance with intensive glycemia reduction, particularly at night, attributed to the low glu-
education could improve hypoglycemia awareness regardless of cose alarm systems. However, the improvements in hypoglycemia
the glucose monitoring and insulin delivery models. At the study awareness in these two groups were statistically indistinguishable.
end, the incidence of hypoglycemia was reduced in all study Potential confounders include flash glucose monitoring systems’
arms, and the degree of hypoglycemia awareness improvements lower glucose accuracy in the low glucose range136,142,143 that
was similar between the CGM and SMBG groups, including the might have falsely reported more hypoglycemia.
hypoglycemia symptoms scores during the hypoglycemic clamps Although CGMs have clearly shown the benefit of hypo-
in a subcohort study132. However, the low CGM use time (<50%) glycemia reduction without compromising the overall glycemic
in approximately 40% of the participants could have significantly control, the extent to which CGMs can help improve hypo-
confounded the results. glycemia awareness and epinephrine responses remains unclear.
The effects of RT-CGM on glycemia and QoL in patients Although meticulous avoidance of hypoglycemia has been
with T1DM and IHA study group133 evaluated glucose control shown to improve hypoglycemia awareness within 2–16
(CGM vs SMBG) in IAH patients with a cross-over trial. The weeks71–74, none of the aforementioned studies showed an
CGM phase was related to 15% more time-in-range (72– absolute avoidance of hypoglycemia, which could explain this

1392 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 Table 2 | Clinical trials evaluating continuous glucose monitoring use in type 1 diabetes patients with impaired awareness of hypoglycemia

Authors (year) Main objective Trial design and targeted Primary outcome(s) Baseline population CGM models (active
population characteristics usage time)

Ly et al. (2011)130 Assess if the use of CGMs with Randomized, controlled. Epinephrine response to CGM n = 6; SMBG n = 5 Medtronic Minimed
preset hypo alarms (at Two arms (CGM vs SMBG). hypoglycemia measured Female: Not reported paradigm real-time
glucose 108 mg/dL) Duration: 4 weeks. during hypoglycemia clamp Age: system (not reported)
improves counterregulatory Adolescents (aged 12– study. CGM:13.7 – 0.7 years
response to hypoglycemia. 18 years) with IAH defined Standard:
per modified Clarke (n = 11). 15 – 0.8 yearsDoD:
CGM: 5.2 – 1.4 years
http://wileyonlinelibrary.com/journal/jdi

Standard:
6.5 – 1.2 yearsHbA1c:
CGM: 7.7 – 0.2%
Standard: 7.9 – 0.3%
MDI: Not reported
Little et al. Determine if rigorous Randomized, controlled. Difference in hypoglycemia 83 patients completed Medtronic (median
(HypoCOMPaSS; hypoglycemia prevention 2 9 2 factorial (CGM vs SMBG, awareness (assessed with study; CGM n = 42 and 57%)
2014)131; improves hypoglycemia CSII vs MDI). Gold) between the CGM and SMBG n = 41

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
Leelarathna et al. awareness and prevents SH Duration: 24 weeks. SMBG groups, and between Female: 64%
(HypoCOMPaSS clamp development in patients with Patients with IAH defined per the MDI and CSII groups. Age: 48.6 – 12.2 years
sub-cohort study; IAH, independent of insulin Gold. (n = 96) Clamp subcohort study: the DoD: 28.9 – 12.3 years
2013)132 delivery and glucose glucose concentration at HbA1c: 8.2 – 1.2%
monitoring modalities. which participants felt MDI: 97%
hypoglycemic during Clamp Subcohort
progressive hypoglycemia. n = 18 (CGM n = 11,
SMBG n = 7)
Female: 66.7%
Age: 50 – 9 years
DoD: 35 – 10 years
HbA1c: 8.1 – 1%
MDI: 50%
van Beers et al. Assess whether CGM use Randomized, cross-over. Mean difference in the CGM n = 26, SMBG n = 26 Medtronic Enlite
(IN CONTROL; 2016)133 improves glycemia control Two arms (CGM vs SMBG). percentages of time in Female: 46% glucose sensor
and prevents severe Duration: 16-week intervention normoglycemia. Age: 48.6 – 11.6 years (median 89.4; IQR 80.8
hypoglycemia in patients with 12-week washout. DoD: 30.5 – 40.8 years –95.5);
with IAH. Patients with IAH defined per HbA1c: 7.5 – 0.8%
Gold, either on CSII or MDI. MDI: 56%
(n = 52)
Rickels et al. (2018)134 Assess if hypoglycemia Single arm (CGM). Difference in the endogenous Female: 55% Dexcom seven plus/G4

J Diabetes Investig Vol. 11 No. 6 November 2020

avoidance with CGMs Duration: 18 months. glucose production response Age: 44 – 4 years or Medtronic Sof-
improves glucose during stepped- DoD: 31 – 4 years Sensor (n = 7/4)
counterregulation in patients HbA1c: 7.2 – 0.2%

1393
Does CGM improve hypoglycemia awareness?
REVIEW ARTICLE
 Table 2 (Continued)

1394
Lin et al.

Authors (year) Main objective Trial design and targeted Primary outcome(s) Baseline population CGM models (active
population characteristics usage time)

with long-standing diabetes Patients with IAH defined per hypoglycemic and MDI: 27%
and IAH. Clarke and other criteria†. euglycemic clamps. (median 100%)
REVIEW ARTICLE

(n = 11)
Heinemann et al. Ascertain whether the Randomized, controlled. The mean difference in the 141 patients in final Dexcom G5 (mean
(HypoDE; 2018)135 incidence and severity of Two arms (CGM vs SMBG). number of hypoglycemic analysis; CGM n = 75, 90.7%)
hypoglycemia can be Duration: 22-week intervention events (defined as CGM SMBG n = 66
reduced through CGM use in and 4-week follow up. glucose ≤54 mg/dL for Female:
patients on MDI and with Patients on MDI with SH ≥20 min) between baseline CGM: 47%
high risk for developing SH. within the last year or IAH and the follow up phase. Control: 34%Age:
defined per Clarke. (n = 149)
CGM: 45.8 – 12.0 years
Control:

J Diabetes Investig Vol. 11 No. 6 November 2020

47.3 – 11.7 yearsDoD:
CGM: 21.6 – 13.9 years
Control:
20.9 – 14.0 yearsHbA1c:
CGM: 7.6 – 1.0%
Control: 7.3 – 1.0%MDI:
100%
Reddy et al. (I-HART; Assess the impacts of CGMs Randomized. The median difference CGM n = 20, SMBG n = 20 Dexcom G5 (not
2018)141 and FGMs on hypoglycemia Two arms (CGM vs FGM). between the change of time Female: 40% reported)
reduction in patients on MDI Duration: 8 weeks. in hypoglycemia (<59 mg/ Age: 49.5 years (37.5–63.5)
with high risk for developing Patients on MDI with SH dL) from baseline to end- DoD: 30.0 years (21.0–36.5)
SH. within the last year or IAH point. HbA1c: 7.3% (6.5–7.8)
defined per Gold (n = 40) MDI: Not reported‡

Data presented in mean – standard deviation or median (interquartile range [IQR]). AUC, area under the curve; CSII, continuous subcutaneous insulin infusion; DoD, duration of diabetes;
HbA1c, hemoglobin A1C; IAH, impaired awareness of hypoglycemia; SH, severe hypoglycemia; SMBG, self-monitoring of blood glucose; T1D, type 1 diabetes. †Severely problematic hypo-
glycemia (hypoglycemia [hypo] score ≥1,047), marked glycemic lability (glycemic lability index ≥433 mmol/L2/h/week or a composite of HYPO score ≥423 and glycemic liability index
≥329 mmol/L2/h/week, and either at least one episode of severe hypoglycemia in the past 12 months or the presence of >5% of time spent at <60 mg/dL by 72-h blinded continuous
glucose monitoring (CGM). ‡The study aimed to assess the CGM effects on multiple daily injection (MDI)-using population; actual percentage not reported.
http://wileyonlinelibrary.com/journal/jdi

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi Does CGM improve hypoglycemia awareness?

Table 3 | Reported time in hypoglycemia, hypoglycemia awareness and autonomic response outcomes in clinical trials evaluating continuous
glucose monitoring use in type 1 diabetes patients with impaired awareness of hypoglycemia

Author Time in hypoglycemia at Hypoglycemia Endogenous Glucoregulatory

study end† (%) awareness outcomes Response Outcomes

Ly et al. (2011)130 NA NA Changes in epinephrine levels during

hypoglycemic clamps compared with
euglycemic clamps (%)
Baseline:
CGM: 214 – 72%
Standard: 288 – 151% (P = 0.688)
Study end (4 weeks):
CGM: 604 – 234%
Standard: 114 – 83% (P = 0.048)‡
Changes in epinephrine levels during
hypoglycemic clamps at baseline vs
study end:
CGM: P = 0.031
Standard: P = 0.375
Little et al. Glucose <72 mg/dL Gold scores Clamp Study Subcohort –AUC of
(HypoCOMPaSS; CGM: 6.3 – 9.1% Baseline: 5.1 – 1.1 incremental metanephrine levels
2014)131; SMBG: 5.2 – 4.2% Study end: 4.1 – 1.4 (P < 0.001)‡ Baseline: 2,412 (-3,026 to 7,279)
Leelarathna, et al. (P = 0.47) Clarke scores Study end: 5,180 (-771 to 11,513)
(HypoCOMPaSS Glucose ≤54 mg/dL (P = 0.02)
Baseline: 4.1 – 1.6
clamp subcohort Glucose thresholds for metanephrine
CGM: 2.1 – 5.1% Study end: 3.2 – 1.7 (P < 0.001)
study; 2013)132 response
SMBG: 1.3 – 2.1% HypoA-Q scores
(P = 0.36) Baseline: 43 (41–45) mg/dL
Baseline: 13.4 – 3.4
Clamp Study Subcohort Study end: 49 (41–58) mg/dL
Study end: 9.1 – 4.2 (P < 0.001)
– AUC of the % of time (P = 0.03)
No differences in hypoglycemia awareness
spent with glucose No differences in the above measures
scores between the CGM vs SMBG and CSII
<54 mg/dL (mean – s- between the CGM vs SMBG and CSII
vs MDI models.
tandard error): vs MDI models.
Clamp Study Subcohort
CGM: 658 – 223
Plasma glucose level of first felt hypoglycemia
SMBG: 797 – 193
Baseline: 47 – 2 mg/dL
(P = 0.64)
Study end: 56 – 4 mg/dL (P = 0.02)‡
Symptom score AUC
Baseline: 500 (364–685)
Study end: 650 (365–1,285) (P = 0.02)
No differences in the above measures between
CGM vs SMBG and CSII vs MDI models.
van Beers et al. (IN Glucose ≤70 mg/dL Gold scores NA
CONTROL; 2016)133 CGM: 6.8% [5.2–8.3] End of CGM phase: 4.6 [4.3–5.0]
SMBG: 11.4% [9.9–13.0] End of SMBG phase: 5.0 [4.6–5.4] (P = 0.035)
(P < 0.0001) Change in Gold scores from baseline
End of CGM phase: -0.5 [-0.8 to -0.1]
End of SMBG phase: -0.1 [-0.4–0.2]
(P = 0.076)Clarke scores
End of CGM phase: 4.4 [3.9–4.8]
End of SMBG phase: 4.4 [3.9–4.8] (P = 0.953)
Change in Clarke scores from baseline
End of CGM phase: -0.1 [-0.5–0.3]
End of SMBG phase: -0.4 [-0.8–0.0]
(P = 0.216)

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 6 November 2020 1395
REVIEW ARTICLE
Lin et al. http://wileyonlinelibrary.com/journal/jdi

Table 3 (Continued)

Author Time in hypoglycemia at Hypoglycemia Endogenous Glucoregulatory

study end† (%) awareness outcomes Response Outcomes

Rickels et al. Glucose <60 mg/dL Clark scores Epinephrine levels during hypoglycemia
(2018)134 Run-in: 6.5 – 1.6% Baseline: 6 (6–7) Baseline: 152 – 37 pg/mL
Study end (18-months): 6 months: 4 (4–5) 6 months: 204 – 37 pg/mL (P = NS)
4.0 – 0.7% (P = NS) 12 months: 3 (2–5) 18 months: 152 – 36 pg/mL (P = NS)
18 months: 3 (2–5) Norepinephrine levels during hypo-
(P < 0.01)Clamp Study glycemia
Autonomic symptoms during hypoglycemic vs Baseline: 378 – 44 pg/mL
euglycemic clamps: 6 months: 317 – 38 pg/mL (P = NS)
Baseline: 3.7 – 0.9 vs 2.5 – 0.3 (P = NS) 18 months: 362 – 60 pg/mL (P = NS)
6 months: 5.1 – 1.0 vs 1.5 – 0.7) (P < 0.05) Endogenous glucose production
18 months: 5.6 – 1.2 vs 2.2 – 0.6 (P < 0.05) (compared to baseline):‡
No statistical significance when comparing
Baseline: 0.42 – 0.08 mg/kg/min
the symptom scores at 6 and 18 months to
6 months: 0.54 – 0.07 mg/kg/min
baseline.
(P = NS)
18 months: 0.84 – 0.15 mg/kg/min
(P < 0.05)
Heinemann et al. Glucose ≤70 mg/dL Clark scores NA
(HypoDE; 2018)135 CGM: 1.6% (0.9–3.7) Baseline
Control: 6.4% (3.7–12.0) CGM: 5.0 (4.0–6.0)
Adjusted between- Control: 5.0 (4.0–6.0)Follow up
group differences:
CGM: 3.0 (1.0–4.0)
P < 0.0001Glucose
Control: 3.0 (1.0–5.0)Adjusted between-group
≤54 mg/dL
differences: P = 0.7662
CGM: 0.3% (0.1–0.9)
Control: 2.5% (1.0–6.1)
Adjusted between-
group differences:
P < 0.0001
Reddy et al. (I-HART; Glucose <70 mg/dL Gold scores NA
2018)141 CGM: 6.2% (3.1–10.2) Baseline:
FGM: 11.0% (8.2–17.0) CGM: 5 (5–6)
Median change from FGM: 5 (4–5)Study end (8 weeks):
baseline: P < 0.01Glu-
CGM: 4.5 (3.0–5.0)
cose <50 mg/dL
FGM: 5.0 (3.5–6.0)Median change from base-
CGM: 0.9% (0.2–1.8) line:
FGM: 3.8% (3.0–6.4)
CGM: 0.0 [-1.0 to 0.0] (P = NS)
Median change from
FGM: 0.0 [-0.8 to 0.0] (P = NS)Differences in
baseline: P < 0.003
median changes from baseline to study end:
P = 0.23

Data presented in mean – standard deviation or median (interquartile range) or mean/median [95% confidence interval], unless noted otherwise.
AUC, area under the curve; CSII, continuous subcutaneous insulin infusion; FGM, flash glucose monitoring; HypoCOMPaSS, comparison of optimised
MDI versus pumps with or without sensors in severe hypoglycaemia; HypoDE, hypoglycemia in Deutschland; IAH, impaired awareness of hypo-
glycemia; I-HART, impact on hypoglycaemia awareness of real time CGM and intermittent continuous glucose data; IN CONTROL, effects of RT-
CGM on glycemia and QoL in patients with T1DM and IHA; MDI, multiple daily injections; NA, not available; NS, not significant; T1D, type 1 dia-
betes. † Variable definitions for hypoglycemia were used. These trials were performed prior to the current continuous glucose monitoring (CGM)/hy-
poglycemia guidelines. For self-monitoring of blood glucose level (SMBG) groups or run-in phase, time in hypoglycemia were assessed with
blinded CGMs. ‡ Primary outcomes of the trials.

1396 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi Does CGM improve hypoglycemia awareness?

finding. Recent observational data144–146 show that IAH is still epidemiology of diabetes interventions and complications
common and problematic in type 1 diabetes patients, despite study. Diabetes Care 2014; 37: 31–38.
CGM use, and thus IAH might unfortunately remain an 7. deBoer IH. Kidney disease and related findings in the
important clinical obstacle in diabetes management for CGM diabetes control and complications trial/epidemiology of
users. diabetes interventions and complications study. Diabetes
To definitively determine whether CGMs/diabetes technolo- Care 2014; 37: 24–30.
gies could improve hypoglycemia awareness, more optimal trial 8. Aiello LP. Diabetic retinopathy and other ocular findings in
design that eliminates confounders and provides sufficient the diabetes control and complications trial/epidemiology
intervention duration is important131. This includes matching of diabetes interventions and complications study. Diabetes
individuals for age, duration of diabetes, HbA1c, hypoglycemia Care 2014; 37: 17–23.
awareness scores and hypoglycemia cognition145 to reduce some 9. The Diabetes Control and Complications Trial Research
effects from the individual variabilities. It would also be of Group. Hypoglycemia in the diabetes control and
interest whether a treat-to-target approach (e.g., time in hypo- complications trial. The Diabetes Control and Complications
glycemia targets of <4%147 or even <1%148), with techniques Trial Research Group. Diabetes1997; 46: 271–286.
such as more rigorous strategies to engage patients to CGMs149 10. Gubitosi-Klug RA, Braffett BH, White NH, et al. Risk of
or CGM alarm setting adjustments150,151, could improve hypo- severe hypoglycemia in type 1 diabetes over 30 years of
glycemia awareness or epinephrine responses to hypoglycemia. follow-up in the DCCT/EDIC Study. Diabetes Care 2017; 40:
1010–1016.
CONCLUSION 11. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and
CGM is an effective tool to help reduce hypoglycemia and sev- diabetes: a report of a workgroup of the American
ere hypoglycemic episodes in type 1 diabetes patients, including Diabetes Association and the Endocrine Society. Diabetes
those with IAH. Whether CGMs could help improve hypo- Care 2013; 36: 1384–1395.
glycemia awareness, and how CAN and IAH are interrelated, 12. Amiel SA, Aschner P, Childs B. Minimizing hypoglycemia in
remain to be determined or further elucidated. diabetes. Diabetes Care 2015; 38: 1583–1591.
13. McCoy RG, Van Houten HK, Ziegenfuss JY, et al. Increased
ACKNOWLEDGMENTS mortality of patients with diabetes reporting severe
SJF is supported by the NIH R01DK118082. RPB is supported hypoglycemia. Diabetes Care 2012; 35: 1897–1901.
by NIH 1R01DK107956-01 and U01DK119083, and the JDRF 14. Lung TW, Petrie D, Herman WH, et al. Severe
Center of Excellence at the University of Michigan. hypoglycemia and mortality after cardiovascular events for
type 1 diabetic patients in Sweden. Diabetes Care 2014; 37:
DISCLOSURE 2974–2981.
The authors declare no conflict of interest. 15. Agiostratidou G, Anhalt H, Ball D, et al. Standardizing
Clinically Meaningful Outcome Measures Beyond HbA1c
REFERENCES for Type 1 Diabetes: A Consensus Report of the American
1. Katsarou A, Gudbjo €rnsdottir S, Rawshani A, et al. Type 1 Association of Clinical Endocrinologists, the American
diabetes mellitus. Nat Rev Dis Primers 2017; 3: 17016. Association of Diabetes Educators, the American Diabetes
2. Nathan DM, Genuth S, Lachin J et al. The effect of intensive Association, the Endocrine Society, JDRF International, The
treatment of diabetes on the development and progression Leona M. and Harry B. Helmsley Charitable Trust, the
of long-term complications in insulin-dependent diabetes Pediatric Endocrine Society, and the T1D Exchange.
mellitus. N Engl J Med 1993; 329: 977–986. Diabetes Care 2017; 40: 1622–1630.
3. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes 16. 6. Glycemic Targets. Standards of medical care in diabetes—
treatment and cardiovascular disease in patients with type 2020. Diabetes Care 2020; 43(Supplement 1): S66–S76.
1 diabetes. N Engl J Med 2005; 353: 2643–2653. 17. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of
4. Nathan DM. The diabetes control and complications trial/ glycemic thresholds for counterregulatory hormone
epidemiology of diabetes interventions and complications secretion, symptoms, and cerebral dysfunction. Am J
study at 30 years: overview. Diabetes Care 2014; 37: 9–16. Physiol 1991; 260(1 Pt 1): E67–E74.
5. Diabetes Control and Complications Trial (DCCT)/ 18. International Hypoglycaemia Study Group. Glucose
Epidemiology of Diabetes Interventions and Complications concentrations of less than 3.0 mmol/L (54 mg/dL) should
(EDIC) Study Research GroupIntensive diabetes treatment be reported in clinical trials: a joint Position statement of
and cardiovascular outcomes in type 1 diabetes: the DCCT/ the American Diabetes Association and the European
EDIC study 30-year follow-up. Diabetes Care 2016; 39: 686– Association for the Study of Diabetes. Diabetes Care 2017;
693. 40: 155–157.
6. Martin CL, Albers JW, Pop-Busui R. Neuropathy and related 19. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes
findings in the diabetes control and complications trial/ 2008; 57: 3169–3176.

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 6 November 2020 1397
REVIEW ARTICLE
Lin et al. http://wileyonlinelibrary.com/journal/jdi

20. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: 33. 7. Diabetes technology: Standards of Medical Care in
pathophysiology, frequency, and effects of different Diabetes—2020. Diabetes Care 2020; 43(Supplement 1):
treatment modalities. Diabetes Care 2005; 28: 2948–2961. S77–S88.
21. UK Prospective Diabetes Study (UKPDS) Group. Intensive 34. Reiterer F, Polterauer P, Schoemaker M, et al. Significance
blood-glucose control with sulphonylureas or insulin and reliability of MARD for the accuracy of CGM systems. J
compared with conventional treatment and risk of Diabetes Sci Technol 2017; 11: 59–67.
complications in patients with type 2 diabetes (UKPDS 33). 35. Lal RA, Maahs DM. Clinical use of continuous glucose
Lancet1998; 352: 837–853. monitoring in pediatrics. Diabetes Technol Ther 2017; 19(S2):
22. Bonds DE, Miller ME, Bergenstal RM, et al. The association S37–S43.
between symptomatic, severe hypoglycaemia and 36. Volcansek S, Lunder M, Janez A. Acceptability of
mortality in type 2 diabetes: retrospective epidemiological continuous glucose monitoring in elderly diabetes patients
analysis of the ACCORD study. BMJ 2010; 340: b4909. using multiple daily insulin injections. Diabetes Technol Ther
23. Lee AK, Warren B, Lee CJ, et al. The association of severe 2019; 21: 566–574.
hypoglycemia with incident cardiovascular events and 37. Prahalad P, Addala A, Scheinker D, et al. CGM initiation
mortality in adults with type 2 diabetes. Diabetes Care soon after type 1 diabetes diagnosis results in sustained
2018; 41: 104–111. CGM Use And Wear Time. Diabetes Care 2020; 43:
24. Zinman B, Marso SP, Christiansen E, et al. Hypoglycemia, e3–e4.
cardiovascular outcomes, and death: the LEADER 38. Danne T, Nimri R, Battelino T, et al. International consensus
experience. Diabetes Care 2018; 41: 1783–1971. on use of continuous glucose monitoring. Diabetes Care
25. Davis SN, Duckworth W, Emanuele N, et al. Effects of 2017; 40: 1631–1640.
severe hypoglycemia on cardiovascular outcomes and 39. Kravarusic J, Aleppo G. Diabetes technology use in adults
death in the veterans affairs diabetes trial. Diabetes Care with type 1 and type 2 diabetes. Endocrinol Metab Clin
2019; 42: 157–163. North Am 2020; 49: 37–55.
26. Rodbard D. Continuous glucose monitoring: a review of 40. Beck RW, Riddlesworth TD, Ruedy K, et al. Continuous
recent studies demonstrating improved glycemic glucose monitoring versus usual care in patients with type
outcomes. Diabetes Technol Ther 2017; 19(S3): S25–s37. 2 diabetes receiving multiple daily insulin injections: a
27. Tamborlane WV, Beck RW, Bode BW, et al. Continuous randomized trial. Ann Intern Med 2017; 167: 365–374.
glucose monitoring and intensive treatment of type 1 41. Taylor PJ, Thompson CH, Brinkworth GD. Effectiveness and
diabetes. N Engl J Med 2008; 359: 1464–1476. acceptability of continuous glucose monitoring for type 2
28. Beck RW, Riddlesworth T, Ruedy K, et al. Effect of diabetes management: a narrative review. J Diabetes
continuous glucose monitoring on glycemic control in Investig 2018; 9: 713–725.
adults with type 1 diabetes using insulin injections: the 42. Cryer PE. Mechanisms of hypoglycemia-associated
DIAMOND randomized clinical trial. JAMA 2017; 317: 371– autonomic failure in diabetes. N Engl J Med 2013; 369:
378. 362–372.
29. Lind M, Polonsky W, Hirsch IB, et al. Continuous glucose 43. Gold AE, Macleod KM, Frier BM. Frequency of severe
monitoring vs conventional therapy for glycemic control in hypoglycemia in patients with type i diabetes with
adults with type 1 diabetes treated with multiple daily impaired awareness of hypoglycemia. Diabetes Care 1994;
insulin injections: The GOLD randomized clinical trial. JAMA 17: 697–703.
2017; 317: 379–387. 44. Clarke WL, Cox DJ, Gonder-Frederick LA, et al. Reduced
30. Aleppo G, Ruedy KJ, Riddlesworth TD, et al. REPLACE-BG: A awareness of hypoglycemia in adults with IDDM. A
randomized trial comparing continuous glucose prospective study of hypoglycemic frequency and
monitoring with and without routine blood glucose associated symptoms. Diabetes Care 1995; 18: 517–522.
monitoring in adults with well-controlled type 1 diabetes. 45. Smith CB, Choudhary P, Pernet A, et al. Hypoglycemia
Diabetes Care 2017; 40: 538–545. unawareness is associated with reduced adherence to
31. Peters AL, Ahmann AJ, Battelino T, et al. Diabetes therapeutic decisions in patients with type 1 diabetes.
technology—continuous subcutaneous insulin infusion Evidence from a clinical audit. Diabetes Care 2009; 32:
therapy and continuous glucose monitoring in adults: an 1196–1198.
endocrine society clinical practice guideline. J Clin 46. Pedersen-Bjergaard U, Pramming S, Thorsteinsson B. Recall
Endocrinol Metab 2016; 101: 3922–3937. of severe hypoglycaemia and self-estimated state of
32. Fonseca VA, Grunberger G, Anhalt H, et al. Continuous awareness in type 1 diabetes. Diabetes Metab Res Rev 2003;
glucose monitoring: a consensus conference of the 19: 232–240.
american association of clinical endocrinologists and 47. Geddes J, Schopman JE, Zammitt NN, et al. Prevalence of
american college of endocrinology. Endocr Pract 2016; 22: impaired awareness of hypoglycaemia in adults with type
1008–1021. 1 diabetes. Diabet Med 2008; 25: 501–504.

1398 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi Does CGM improve hypoglycemia awareness?

48. Kubiak T, Hermanns N, Schreckling HJ, et al. Assessment of awareness in non-diabetic recurrently hypoglycaemic rats.
hypoglycaemia awareness using continuous glucose Diabetologia 2019; 62: 676–686.
monitoring. Diabet Med 2004; 21: 487–490. 63. Cryer PE. Mechanisms of sympathoadrenal failure and
49. Henderson JN, Allen KV, Deary IJ, et al. Hypoglycaemia in hypoglycemia in diabetes. J Clin Invest 2006; 116: 1470–
insulin-treated Type 2 diabetes: frequency, symptoms and 1473.
impaired awareness. Diabet Med 2003; 20: 1016–1021. 64. Cryer PE Hypoglycemia. Pathophysiology, Diagnosis and
50. Schopman JE, Geddes J, Frier BM. Prevalence of impaired Treatment. New York: Oxford University Press, 1997.
awareness of hypoglycaemia and frequency of 65. Goldberg PA, Weiss R, McCrimmon RJ, et al. Antecedent
hypoglycaemia in insulin-treated type 2 diabetes. Diabetes hypercortisolemia is not primarily responsible for
Res Clin Pract 2010; 87: 64–68. generating hypoglycemia-associated autonomic failure.
51. Alkhatatbeh MJ, Abdalqader NA, Alqudah MAY. Impaired Diabetes 2006; 55: 1121–1126.
awareness of hypoglycaemia in insulin-treated type 2 66. Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated
diabetes mellitus. Curr Diabetes Rev 2019; 15: 407–413. autonomic failure in insulin-dependent diabetes mellitus.
52. Heller SR, Cryer PE. Reduced neuroendocrine and Recent antecedent hypoglycemia reduces autonomic
symptomatic responses to subsequent hypoglycemia after responses to, symptoms of, and defense against
1 episode of hypoglycemia in nondiabetic humans. subsequent hypoglycemia. J Clin Invest 1993; 91: 819–828.
Diabetes 1991; 40: 223–226. 67. Chan O, Sherwin R. Influence of VMH fuel sensing on
53. Davis SN, Mann S, Galassetti P, et al. Effects of differing hypoglycemic responses. Trends Endocrinol Metab 2013; 24:
durations of antecedent hypoglycemia on 616–624.
counterregulatory responses to subsequent hypoglycemia 68. Mason GF, Petersen KF, Lebon V, et al. Increased brain
in normal humans. Diabetes 2000; 49: 1897–1903. monocarboxylic acid transport and utilization in type 1
54. Davis SN, Shavers C, Mosqueda-Garcia R, et al. Effects of diabetes. Diabetes 2006; 55: 929–934.
differing antecedent hypoglycemia on subsequent 69. Hedrington MS, Tate DB, Younk LM, et al. Effects of
counterregulation in normal humans. Diabetes 1997; 46: antecedent GABA A receptor activation on
1328–1335. counterregulatory responses to exercise in healthy man.
55. Jones TW, Porter P, Sherwin RS, et al. Decreased Diabetes 2015; 64: 3253–3261.
epinephrine responses to hypoglycemia during sleep. N 70. Vele S, Milman S, Shamoon H, et al. Opioid receptor
Engl J Med 1998; 338: 1657–1662. blockade improves hypoglycemia-associated autonomic
56. Banarer S, Cryer PE. Sleep-related hypoglycemia-associated failure in type 1 diabetes mellitus. J Clin Endocrinol Metab
autonomic failure in type 1 diabetes: reduced awakening 2011; 96: 3424–3431.
from sleep during hypoglycemia. Diabetes 2003; 52: 1195– 71. Cranston I, Lomas J, Maran A, et al. Restoration of
1203. hypoglycaemia awareness in patients with long-duration
57. Pohl J, Frenzel G, Kerner W, et al. Acute stress modulates insulin-dependent diabetes. Lancet 1994; 344: 283–287.
symptom awareness and hormonal counterregulation 72. Fanelli C, Pampanelli S, Epifano L, et al. Long-term recovery
during insulin-induced hypoglycemia in healthy individuals. from unawareness, deficient counterregulation and lack of
Int J Behav Med 1998; 5: 89–105. cognitive dysfunction during hypoglycaemia, following
58. Kerr D, Macdonald IA, Heller SR, et al. Alcohol causes institution of rational, intensive insulin therapy in IDDM.
hypoglycaemic unawareness in healthy volunteers and Diabetologia 1994; 37: 1265–1276.
patients with type 1 (insulin-dependent) diabetes. 73. Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of
Diabetologia 1990; 33: 216–221. hypoglycemia unawareness, but not defective glucose
59. Galassetti P, Mann S, Tate D, et al. Effects of antecedent counterregulation, in IDDM. Diabetes 1994; 43: 1426–1434.
prolonged exercise on subsequent counterregulatory 74. Fritsche A, Stefan N, Haring H, et al. Avoidance of
responses to hypoglycemia. Am J Physiol Endocrinol Metab hypoglycemia restores hypoglycemia awareness by
2001; 280: E908–E9017. increasing beta-adrenergic sensitivity in type 1 diabetes.
60. Potashner D, Brown RE, Li A, et al. Paradoxical rise in Ann Intern Med 2001; 134(9 Pt 1): 729–736.
hypoglycemia symptoms with development of 75. Cox D, Gonder-Frederick L, Polonsky W, et al. A multicenter
hyperglycemia during high-intensity interval training in evaluation of blood glucose awareness training-II. Diabetes
type 1 diabetes. Diabetes Care 2019; 42: 2011–2014. Care 1995; 18: 523–528.
61. Ramanathan R, Cryer PE. Adrenergic mediation of 76. Hopkins D, Lawrence I, Mansell P, et al. Improved
hypoglycemia-associated autonomic failure. Diabetes 2011; biomedical and psychological outcomes 1 year after
60: 602–606. Structured Education In Flexible insulin therapy for people
62. Farhat R, Su G, Sejling AS, et al. Carvedilol prevents with type 1 diabetes: The U.K. DAFNE experience. Diabetes
counterregulatory failure and impaired hypoglycaemia Care 2012; 35: 1638–1642.

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 6 November 2020 1399
REVIEW ARTICLE
Lin et al. http://wileyonlinelibrary.com/journal/jdi

77. deZoysa N, Rogers H, Stadler M, et al. A Psychoeducational 90. Bottini P, Boschetti E, Pampanelli S, et al. Contribution of
program to restore hypoglycemia awareness: The DAFNE- autonomic neuropathy to reduced plasma adrenaline
HART Pilot Study. Diabetes Care 2014; 37: 863–866. responses to hypoglycemia in IDDM: evidence for a
78. Spallone V, Ziegler D, Freeman R, et al. Cardiovascular nonselective defect. Diabetes 1997; 46: 814–823.
autonomic neuropathy in diabetes: clinical impact, 91. Hepburn DA, Patrick AW, Eadington DW, et al.
assessment, diagnosis, and management. Diabetes Metab Unawareness of hypoglycaemia in insulin-treated diabetic
Res Rev 2011; 27: 639–653. patients: prevalence and relationship to autonomic
79. Pop-Busui R, Braffett BH, Zinman B, et al. Cardiovascular neuropathy. Diabet Med 1990; 7: 711–717.
autonomic neuropathy and cardiovascular outcomes in the 92. Ryder RE, Owens DR, Hayes TM, et al. Unawareness of
diabetes control and complications trial/epidemiology of hypoglycaemia and inadequate hypoglycaemic
diabetes interventions and complications (DCCT/EDIC) counterregulation: no causal relation with diabetic
study. Diabetes Care 2017; 40: 94–100. autonomic neuropathy. BMJ 1990; 301: 783–787.
80. O’Brien IA, McFadden JP, Corrall RJ. The influence of 93. Olsen SE, Bjorgaas MR, Asvold BO, et al. Impaired
autonomic neuropathy on mortality in insulin-dependent awareness of hypoglycemia in adults with type 1 diabetes
diabetes. Q J Med 1991; 79: 495–502. is not associated with autonomic dysfunction or peripheral
81. Soedamah-Muthu SS, Chaturvedi N, Witte DR, et al. neuropathy. Diabetes Care 2016; 39: 426–433.
Relationship between risk factors and mortality in type 1 94. Jaiswal M, McKeon K, Comment N, et al. Association
diabetic patients in Europe: the EURODIAB Prospective between impaired cardiovascular autonomic function and
Complications Study (PCS). Diabetes Care 2008; 31: 1360– hypoglycemia in patients with type 1 diabetes. Diabetes
1366. Care 2014; 37: 2616–2621.
82. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of 95. Kennedy FP, Go VL, Cryer PE, et al. Subnormal pancreatic
cardiac autonomic dysfunction on mortality risk in the polypeptide and epinephrine responses to insulin-induced
Action to Control Cardiovascular Risk in Diabetes hypoglycemia identify patients with insulin-dependent
(ACCORD) trial. Diabetes Care 2010; 33: 1578–1584. diabetes mellitus predisposed to develop overt autonomic
83. Maser RE, Mitchell BD, Vinik AI, et al. The association neuropathy. Ann Intern Med 1988; 108: 54–58.
between cardiovascular autonomic neuropathy and 96. Koivikko ML, Salmela PI, Airaksinen KE, et al. Effects of
mortality in individuals with diabetes: a meta-analysis. sustained insulin-induced hypoglycemia on cardiovascular
Diabetes Care 2003; 26: 1895–1901. autonomic regulation in type 1 diabetes. Diabetes 2005; 54:
84. Beijers HJ, Ferreira I, Bravenboer B, et al. Microalbuminuria 744–750.
and cardiovascular autonomic dysfunction are 97. Rao AD, Bonyhay I, Dankwa J, et al. Baroreflex sensitivity
independently associated with cardiovascular mortality: impairment during hypoglycemia: implications for
evidence for distinct pathways: the Hoorn Study. Diabetes cardiovascular control. Diabetes 2016; 65: 209–215.
Care 2009; 32: 1698–1703. 98. Adler GK, Bonyhay I, Failing H, et al. Antecedent
85. Pop-Busui R, Low PA, Waberski BH, et al. Effects of prior hypoglycemia impairs autonomic cardiovascular function:
intensive insulin therapy on cardiac autonomic nervous implications for rigorous glycemic control. Diabetes 2009;
system function in type 1 diabetes mellitus: the Diabetes 58: 360–366.
Control and Complications Trial/Epidemiology of Diabetes 99. Lee SP, Yeoh L, Harris ND, et al. Influence of autonomic
Interventions and Complications study (DCCT/EDIC). neuropathy on QTc interval lengthening during
Circulation 2009; 119: 2886–2893. hypoglycemia in type 1 diabetes. Diabetes 2004; 53: 1535–
86. Nathan DM, Genuth S, Lachin J, et al. The effect of 1542.
intensive treatment of diabetes on the development and 100. Limberg JK, Farni KE, Taylor JL, et al. Autonomic control
progression of long-term complications in insulin- during acute hypoglycemia in type 1 diabetes mellitus.
dependent diabetes mellitus. N Engl J Med 1993; 329: 977– Clin Auton Res 2014; 24: 275–283.
986. 101. Ang L, Dillon B, Mizokami-Stout K, et al. Cardiovascular
87. Pop-Busui R. What do we know and we do not know autonomic neuropathy: A silent killer with long reach.
about cardiovascular autonomic neuropathy in diabetes. J Auton Neurosci 2020; 225: 102646.
Cardiovasc Transl Res 2012; 5: 463–478. 102. Mohseni S, Hildebrand C. Hypoglycaemic neuropathy in BB/
88. Hoeldtke RD, Boden G. Epinephrine secretion, Wor rats treated with insulin implants: electron microscopic
hypoglycemia unawareness, and diabetic autonomic observations. Acta Neuropathol 1998; 96: 151–156.
neuropathy. Ann Intern Med 1994; 120: 512–517. 103. Potter CG, Sharma AK, Farber MO, et al. Hypoglycemic
89. Meyer C, Grossmann R, Mitrakou A, et al. Effects of neuropathy in experimental diabetes. J Neurol Sci 1988; 88
autonomic neuropathy on counterregulation and (1–3): 293–301.
awareness of hypoglycemia in type 1 diabetic patients. 104. Bernardi L, Rosengard-Barlund M, Sandelin A, et al. Short-
Diabetes Care 1998; 21: 1960–1966. term oxygen administration restores blunted baroreflex

1400 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi Does CGM improve hypoglycemia awareness?

sensitivity in patients with type 1 diabetes. Diabetologia 119. Speight J, Barendse SM, Singh H, et al. Characterizing
2011; 54: 2164–2173. problematic hypoglycaemia: iterative design and
105. Esposito P, Mereu R, De Barbieri G, et al. Trained preliminary psychometric validation of the Hypoglycaemia
breathing-induced oxygenation acutely reverses Awareness Questionnaire (HypoA-Q). Diabet Med 2016; 33:
cardiovascular autonomic dysfunction in patients with type 376–385.
2 diabetes and renal disease. Acta Diabetol 2016; 53: 217– 120. Graveling AJ, Frier BM. Impaired awareness of
226. hypoglycaemia: a review. Diabetes Metab 2010; 36(Suppl 3):
106. Burger AJ, Weinrauch LA, D’Elia JA, et al. Effect of glycemic S64–S74.
control on heart rate variability in type I diabetic patients 121. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic
with cardiac autonomic neuropathy. Am J Cardiol 1999; 84: neuropathy: a position statement by the American
687–691. Diabetes Association. Diabetes Care 2017; 40: 136–154.
107. Mohseni S. Hypoglycemic neuropathy. Acta Neuropathol 122. Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic
2001; 102: 413–421. symptoms and diabetic neuropathy: a population-based
108. Jensen VF, Molck AM, Bogh IB, et al. Effect of insulin- study. Diabetes Care 2004; 27: 2942–2947.
induced hypoglycaemia on the peripheral nervous system: 123. The Consensus Committee of the American Autonomic
focus on adaptive mechanisms, pathogenesis and Society and the American Academy of Neurology.
histopathological changes. J Neuroendocrinol 2014; 26: Consensus statement on the definition of orthostatic
482–496. hypotension, pure autonomic failure, and multiple system
109. Gibbons CH, Freeman R. Treatment-induced neuropathy of atrophy. Neurology 1996; 46:1470.
diabetes: an acute, iatrogenic complication of diabetes. 124. Ang L, Cowdin N, Mizokami-Stout K, et al. Update on the
Brain 2014; 138: 43–52. management of diabetic neuropathy. Diabetes Spectr 2018;
110. Gibbons CH, Freeman R. Treatment-induced diabetic 31: 224–233.
neuropathy: a reversible painful autonomic neuropathy. 125. Task Force of the European Society of Cardiology and the
Ann Neurol 2010; 67: 534–541. North American Society of Pacing and Electrophysiology.
111. Bolli GB, De Feo P, De Cosmo S, et al. A reliable and Heart rate variability: standards of measurement,
reproducible test for adequate glucose counterregulation physiological interpretation and clinical use.
in type I diabetes mellitus. Diabetes 1984; 33: 732–737. Circulation1996; 93: 1043–1065.
112. Deary IJ, Hepburn DA, MacLeod KM, et al. Partitioning the 126. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a
symptoms of hypoglycaemia using multi-sample clinical perspective. Diabetes Care 2010; 33: 434–441.
confirmatory factor analysis. Diabetologia 1993; 36: 771– 127. Bernardi L, Spallone V, Stevens M, et al. Methods of
777. investigation for cardiac autonomic dysfunction in human
113. Towler DA, Havlin CE, Craft S, et al. Mechanism of research studies. Diabetes Metab Res Rev 2011; 27: 654–664.
awareness of hypoglycemia: perception of neurogenic 128. Ziegler D, Keller J, Maier C, et al. Diabetic neuropathy. Exp
(predominantly cholinergic) rather than neuroglycopenic Clin Endocrinol Diabetes 2014; 122: 406–415.
symptoms. Diabetes 1993; 42: 1791–1798. 129. McGill JB, Ahmann A. Continuous glucose monitoring with
114. Janssen MM, Snoek FJ, Heine RJ. Assessing impaired multiple daily insulin treatment: outcome studies. Diabetes
hypoglycemia awareness in type 1 diabetes: agreement of Technol Ther 2017; 19(S3): S3–S12.
self-report but not of field study data with the autonomic 130. Ly TT, Hewitt J, Davey RJ, et al. Improving epinephrine
symptom threshold during experimental hypoglycemia. responses in hypoglycemia unawareness with real-time
Diabetes Care 2000; 23: 529–532. continuous glucose monitoring in adolescents with type 1
115. Zenz S, Mader JK, Regittnig W, et al. Impact of C-Peptide diabetes. Diabetes Care 2011; 34: 50–52.
Status on the Response of Glucagon and Endogenous 131. Little SA, Leelarathna L, Walkinshaw E, et al. Recovery of
Glucose Production to Induced Hypoglycemia in T1DM. J hypoglycemia awareness in long-standing type 1 diabetes:
Clin Endocrinol Metab 2018; 103: 1408–1417. a multicenter 2 x 2 factorial randomized controlled trial
116. Hwang JJ, Parikh L, Lacadie C, et al. Hypoglycemia comparing insulin pump with multiple daily injections and
unawareness in type 1 diabetes suppresses brain continuous with conventional glucose self-monitoring
responses to hypoglycemia. J Clin Invest 2018; 128: 1485– (HypoCOMPaSS). Diabetes Care 2014; 37: 2114–2122.
1495. 132. Leelarathna L, Little SA, Walkinshaw E, et al. Restoration of
117. Hirsch IB, Boyle PJ, Craft S, et al. Higher glycemic self-awareness of hypoglycemia in adults with long-
thresholds for symptoms during beta-adrenergic blockade standing type 1 diabetes: hyperinsulinemic-hypoglycemic
in IDDM. Diabetes 1991; 40: 1177–1186. clamp substudy results from the HypoCOMPaSS trial.
118. Hjemdahl P. Inter-laboratory comparison of plasma Diabetes Care 2013; 36: 4063–4070.
catecholamine determinations using several different 133. vanBeers CA, DeVries JH, Kleijer SJ, et al. Continuous
assays. Acta Physiol Scand Suppl 1984; 527: 43–54. glucose monitoring for patients with type 1 diabetes and

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 6 November 2020 1401
REVIEW ARTICLE
Lin et al. http://wileyonlinelibrary.com/journal/jdi

impaired awareness of hypoglycaemia (IN CONTROL): a 142. Fokkert MJ, van Dijk PR, Edens MA, et al. Performance of
randomised, open-label, crossover trial. Lancet Diabetes the FreeStyle Libre Flash glucose monitoring system in
Endocrinol 2016; 4: 893–902. patients with type 1 and 2 diabetes mellitus. BMJ Open
134. Rickels MR, Peleckis AJ, Dalton-Bakes C, et al. Continuous Diabetes Res Care 2017; 5: e000320.
glucose monitoring for hypoglycemia avoidance and 143. Sato T, Oshima H, Nakata K, et al. Accuracy of flash
glucose counterregulation in long-standing type 1 glucose monitoring in insulin-treated patients with type 2
diabetes. J Clin Endocrinol Metab 2018; 103: 105–114. diabetes. J Diabetes Investig 2019; 10: 846–850.
135. Heinemann L, Freckmann G, Ehrmann D, et al. Real-time 144. Lin YK, Hung M, Sharma A, et al. Impaired awareness of
continuous glucose monitoring in adults with type 1 hypoglycemia continues to be a risk factor for severe
diabetes and impaired hypoglycaemia awareness or severe hypoglycemia despite the use of continuous glucose
hypoglycaemia treated with multiple daily insulin monitoring system in type 1 diabetes. Endocr Pract 2019;
injections (HypoDE): a multicentre, randomised controlled 25: 517–525.
trial. Lancet 2018; 391(10128): 1367–1377. 145. Cook AJ, DuBose SN, Foster N, et al. Cognitions associated
136. Mancini G, Berioli MG, Santi E, et al. Glucose monitoring: a with hypoglycemia awareness status and severe
review of the literature with a special focus on type 1 hypoglycemia experience in adults with type 1 diabetes.
diabetes. Nutrients 2018; 10: 992 Diabetes Care 2019; 42: 1854–1864.
137. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, et al. Novel 146. Lin YK, Groat D, Chan O, et al. Associations between the
glucose-sensing technology and hypoglycaemia in type 1 time in hypoglycemia and hypoglycemia awareness status
diabetes: a multicentre, non-masked, randomised in type 1 diabetes patients using continuous glucose
controlled trial. Lancet 2016; 388(10057): 2254–2263. monitoring systems. Diabetes Technol Ther 2020. https://doi.
138. Charleer S, De Block C, Van Huffel L, et al. Quality of life org/10.1089/dia.2020.0016
and glucose control after 1 year of nationwide 147. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets
reimbursement of intermittently scanned continuous for continuous glucose monitoring data interpretation:
glucose monitoring in adults living with type 1 diabetes recommendations from the international consensus on
(FUTURE): a prospective observational real-world cohort time in range. Diabetes Care 2019; 42: 1593–1603.
study. Diabetes Care 2020; 43: 389–397. 148. Shah VN, DuBose SN, Li Z, et al. Continuous glucose
139. Haak T, Hanaire H, Ajjan R, et al. Flash glucose-sensing monitoring profiles in healthy nondiabetic participants: a
technology as a replacement for blood glucose multicenter prospective study. J Clin Endocrinol Metab
monitoring for the management of insulin-treated type 2 2019; 104: 4356–4364.
diabetes: a multicenter. Open-Label Randomized 149. Barnard-Kelly KD, Polonsky WH. Development of a novel
Controlled Trial. Diabetes Ther 2017; 8: 55–73. tool to support engagement with continuous glucose
140. Kroeger J, Fasching P, Hanaire H. 99-LB: Meta-analysis of monitoring systems and optimize outcomes. J Diabetes Sci
three real-world, chart review studies to determine the Technol 2020; 14: 151–154.
effectiveness of FreeStyle Libre Flash Glucose Monitoring 150. Lin YK, Groat D, Chan O, et al. Alarm settings of
System on HbA1c in adults with type 2 diabetes. Diabetes continuous glucose monitoring systems and associations
2019; 68(Supplement 1): 99-LB. to glucose outcomes in type 1 diabetes. J Endocr Soc
141. Reddy M, Jugnee N, El Laboudi A, et al. A randomized 2020; 4: bvz005.
controlled pilot study of continuous glucose monitoring 151. Puhr S, Derdzinski M, Parker AS, et al. Real-world
and flash glucose monitoring in people with Type 1 hypoglycemia avoidance with a predictive low glucose
diabetes and impaired awareness of hypoglycaemia. alert does not depend on frequent screen views. J
Diabet Med 2018; 35: 483–490. Diabetes Sci Technol 2020; 14: 83–86.

1402 J Diabetes Investig Vol. 11 No. 6 November 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd