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Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the Europian Association for the Study of Diabetes

Authors:
POSITION STATEMENT
Glucose concentrations of less than 3.0 mmol/l (54 mg/dl)
should be reported in clinical trials: a joint position statement
of the American Diabetes Association and the Europian
Association for the Study of Diabetes
The International Hypoglycaemia Study Group
Published online: 21 November 2016
#The Author(s) 2016. This article is published with open access at Springerlink.com
The International Hypoglycaemia Study Group recom-
mends that the frequency of detection of a glucose con-
centration<3.0mmol/l(<54mg/dl),whichitconsiders
to be clinically significant biochemical hypoglycaemia,
be included in reports of clinical trials of glucose-
lowering drugs evaluated for the treatment of diabetes
mellitus.
The glycaemic thresholds for symptoms of hypoglycaemia
and for glucose counterregulatory (including sympathoadrenal)
responses to hypoglycaemia, as plasma glucose concentrations
fall, are not fixed in patients with insulin-, sulfonylurea- or
meglitinide- (glinide)-treated diabetes. They are at higher glu-
cose concentrations in those with poor glycaemic control and at
lower glucose concentrations in those with tight glycaemic con-
trol [15]. The shifts in glycaemic threshold to lower glucose
concentrations are largely the result of more frequent episodes
of iatrogenic hypoglycaemia during intensive glycaemic thera-
py. Glycaemic thresholds for responses to hypoglycaemia vary,
not only among individuals with diabetes but also in the same
individual with diabetes as a function of their HbA
1c
levels and
hypoglycaemic experience; it is therefore not appropriate to cite
a specific glucose concentration that defines hypoglycaemia in
diabetes. As a consequence, the American Diabetes
Association has defined hypoglycaemia in diabetes non-
numerically as all episodes of an abnormally low plasma glu-
cose concentration that expose the individual to potential harm
[6,7].
Nonetheless, the International Hypoglycaemia Study
Group believes that it is important to identify and re-
cord a level of hypoglycaemia that needs to be avoided
because of its immediate and long-term danger to the
individual. A single glucose level should be agreed to
that has serious clinical and health-economic conse-
quences. This would enable the diabetes and regulatory
communities to compare the effectiveness of interven-
tions in reducing hypoglycaemia, be they pharmacolog-
ical, technological or educational. It would also permit
the use of meta-analysis as a statistical tool to increase
power when comparing interventions.
In its discussion, the International Hypoglycaemia
Study Group considered glucose concentration levels
of <3.0 mmol/l (<54 mg/dl) and <2.8 mmol/l
(<50 mg/dl) detected by self-monitoring of plasma glu-
cose, continuous glucose monitoring (for at least
20 min) or a laboratory measurement of plasma glucose.
Both of these levels are distinctly low glucose concen-
trations that do not occur under physiological conditions
in non-diabetic individuals [8]. Thus, they are unequiv-
ocally hypoglycaemic values. They approximate the up-
per and lower limits, respectively, of the non-diabetic
Members of the International Hypoglycaemia Study Group are listed in
the Appendix.
Simultaneous publication: This article is being simultaneously published
in Diabetes Care and Diabetologia by the American Diabetes
Association and the European Association for the Study of Diabetes.
*The International Hypoglycaemia Study Group
s.heller@sheffield.ac.uk
c/o Simon R. Heller, Department of Oncology and Metabolism,
University of Sheffield, Medical School, Beech Hill Road, S10
2RX Sheffield, UK
Diabetologia (2017) 60:36
DOI 10.1007/s00125-016-4146-6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
glycaemic threshold for symptoms of insulin-induced
hypoglycaemia [810]. The generic non-diabetic
glycaemic threshold for impairment of cognitive func-
tion is <2.8 mmol/l [810], but higher glucose levels
have been reported for some tests [1114]. Glucose con-
centrations of both <3.0 mmol/l and <2.8 mmol/l cause
defective glucose counterregulation and impaired aware-
ness of hypoglycaemia, the core components of
hypoglycaemia-associated autonomic failure in diabetes
[5]. Avoiding these glucose levels could reverse im-
paired awareness of hypoglycaemia [1518]andsome
aspects of defective glucose counterregulation [1517]
in many affected patients. In type 1 diabetes, failure to
recognise ones own hypoglycaemia at a glucose con-
centration <3.0 mmol/l increased the risk of severe
hypoglycaemia (defined as needing the help of another
person for recovery) fourfold [17]. In type 2 diabetes,
both glucose concentrations were associated with cardi-
ac arrhythmias [19,20]. Finally, a glucose concentration
<2.8 mmol/l was associated with mortality in patients
with type 2 diabetes in the Action to Control
Cardiovascular Risk in Diabetes (ACCORD) trial
(NCT00000620) [21], and possibly in the Outcomes
Reduction with an Initial Glargine Intervention
(ORIGIN) trial (NCT00069784) [22] and among pa-
tients treated in intensive care units in the
Normoglycemia in Intensive Care EvaluationSurvival
Using Glucose Algorithm Regulation (NICE-SUGAR)
trial (NCT00220987) [23]. A glucose concentration
<3.0 mmol/l was associated with mortality in the
NICE-SUGAR trial [23] and, possibly, in the ORIGIN
trial [22].
Ultimately, the International Hypoglycaemia Study
Group members agreed that a glucose concentration
<3.0 mmol/l (<54 mg/dl) is sufficiently low to indicate
serious, clinically important hypoglycaemia. Possible
terms used to describe this condition include
serious,clinically important,majoror clinically sig-
nificant. The group decided not to describe severe
hypoglycaemiain terms of glucose concentration since
there is currently widespread agreement that severe
hypoglycaemia, as defined by the American Diabetes
Association [6,7], denotes severe cognitive impairment
requiring external assistance for recovery. The group also
proposed that the frequency of detection of the glucose
alert value of 3.9 mmol/l (70 mg/dl) or less [24] need
not be reported routinely in clinical trials.
In conclusion we propose that the following glucose levels
be adopted by the diabetes community to address the issue of
hypoglycaemic risk (text box).
Funding The International Hypoglycaemia Study Group (IHSG) is
supported through an unrestricted educational grant from Novo Nordisk
awarded to Six Degrees Academy (SDA) of Toronto, ON, Canada. Along
with the IHSG chair, SDA has been solely responsible for membership
recruitment/selection and content/outcomes for the meetings. The ratio-
nale for the formation of IHSG is that hypoglycaemia is an under-
recognised problem that deserves increased awareness and focus across
the healthcare community. The groups ultimate goal is to improve the
lives of patients with diabetes.
Duality of Interest PA has served on scientific advisory boards
and/or as a lecturer for AstraZeneca, Boehringer Ingelheim/Lilly,
Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck Sharp &
Dohme, Novartis and Sanofi. BC has had research grant support
from Halozyme and Lilly to the former MidAmerica Diabetes
Associates. PEC has served on scientific advisory boards for
Novo Nordisk. BEdG has served on scientific advisory boards
for Novo Nordisk and Sanofi and received research grant support
from AstraZeneca. SRH has served on scientific advisory boards
and provided consultancy for which his institution has received
remuneration from Lilly, Novo Nordisk, Takeda, Merck Sharp &
Dohme and Becton Dickinson, has served as a speaker for which
he received remuneration from AstraZeneca, Lilly, Novo Nordisk,
Boehringer Ingelheim and Takeda and has received research sup-
port from Medtronic UK Ltd. BMF has served on scientific ad-
visory boards and as a speaker for Boehringer Ingelheim, Janssen,
Merck Sharp & Dohme, Novo Nordisk and Lilly. LG-F has
served as a consultant or speaker and/or has received research
grant support from Abbott Diabetes Care, AstraZeneca, Dexcom,
Johnson & Johnson and Merck Sharp & Dohme. TJ has served as
a speaker for Novo Nordisk, Lilly, Medtronic and Sanofi. KK has
Proposed glucose levels when reporting
hypoglycaemia in clinical trials
Level 1
A glucose alert value of 3.9 mmol/l (70 mg/dl)
or less. This need not be reported routinely in
clinical studies, although this would depend on
the purpose of the study
Level 2
A glucose level of <3.0 mmol/l (<54 mg/dl) is
sufficiently low to indicate serious, clinically
important hypoglycaemia
Level 3
Severe hypoglycaemia, as defined by the ADA
[6,7], denotes severe cognitive impairment
requiring external assistance for recovery
4 Diabetologia (2017) 60:36
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served as a consultant or speaker for AstraZeneca, Boehringer
Ingelheim, Janssen, Lilly, Merck Sharp & Dohme, Novartis,
Novo Nordisk and Sanofi and has received research grant support
from AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo
Nordisk, Roche and Sanofi. LAL has served as a consultant or
speaker for Abbott, AstraZeneca, Bristol-Myers Squibb,
Boehringer Ingelheim, Lilly, GlaxoSmithKline, Janssen, Merck
Sharp & Dohme, Novo Nordisk, Sanofi, Servier and Takeda.
RJM has served on scientific advisory boards for Novo Nordisk
and Sanofi. ERS has undertaken consultancy for Sanofi, Novo
Nordisk, Lilly, Locemia and Medtronic and received grant support
from Lilly. RV is an employee and owns stock in Medtronic Inc.
SZ has served on scientific advisory boards for Amgen, Bristol-
Myers Squibb, AstraZeneca, Janssen, Merck Sharp & Dohme,
Novo Nordisk, Sanofi and Takeda, has served as a speaker for
Bristol-Myers Squibb, AstraZeneca, Janssen, Merck Sharp &
Dohme, Servier and Takeda, and has received research grant sup-
port from Bristol-Myers Squibb and AstraZeneca. No other poten-
tial conflicts of interest relevant to this article were reported.
Author Contributions The issues discussed here were developed
at meetings of the International Hypoglycaemia Study Group with
a final meeting taking place on 9 June 2016.
Appendix
Members of the International Hypoglycaemia Study
Group
Stephanie A. Amiel, RD Lawrence Professor of Diabetic
Medicine, Division of Diabetes and Nutritional Sciences,
Kings College London, London, UK
Pablo Aschner, Associate Professor of Endocrinology,
Javeriana University School of Medicine, Director of
Research, San Ignacio University Hospital and Scientific
Director of the Colombian Diabetes Association, Bogotá,
Colombia
Belinda Childs RN, Executive Director, Clinical
Nurse Specialist, Great Plains Diabetes, Wichita, KS,
USA
Philip E. Cryer, Professor of Medicine Emeritus,
Washington University in St Louis, St Louis, MO, USA
Bastiaan E. de Galan, Department of Internal Medicine,
Radboud University Nijmegen Medical Centre, Nijmegen,
the Netherlands
Simon R. Heller, Professor of Clinical Diabetes, University
of Sheffield, and Director of Research and Development and
Honorary Consultant Physician, Sheffield Teaching Hospitals
NHS Foundation Trust, Sheffield, UK
Brian M. Frier, Honorary Professor of Diabetes, The
Queens Medical Research Institute, University of
Edinburgh, Edinburgh, Scotland, UK
Linda Gonder-Frederick, Associate Professor, Department
of Psychiatry and Neurobehavioral Sciences, and Clinical
Director, Behavioral Medicine Center, University of Virginia
Health System, Charlottesville, VA, USA
Timothy Jones, Clinical Professor, School of
Paediatrics and Child Health, Telethon Institute for
Child Health Research, University of Western
Australia, and Head, Department of Endocrinology and
Diabetes, Princess Margaret Hospital for Children,
Perth, WA, Australia
Kamlesh Khunti, Professor of Primary Care Diabetes and
Vascular Medicine, University of Leicester, Leicester, UK
Lawrence A. Leiter, Division of Endocrinology and
Metabolism, St. Michaels Hospital and Professor of
Medicine and Nutritional Sciences, University of Toronto,
Toronto, ON, Canada
Rory J. McCrimmon, Professor of Experimental Diabetes
and Metabolism, Division of Molecular & Clinical Medicine,
School of Medicine, University of Dundee, Dundee, Scotland,
UK
Yingying Luo, Associate Professor, Endocrinology and
Metabolism Department, Peking University Peoples
Hospital, Beijing, China
Elizabeth R. Seaquist, Pennock Family Chair in Diabetes
Research, Professor of Medicine and Director, Division of
Endocrinology and Diabetes, Department of Medicine,
University of Minnesota, Minneapolis, MN, USA
Robert Vigersky, Medical Director, Medtronic Diabetes,
Washington DC, USA and Professor of Medicine,
Uniformed Services University of the Health Sciences,
Bethesda, MD, USA
Sophia Zoungas, Professor of Diabetes, Vascular
Health and Ageing, School of Public Health and
Preventive Medicine, Monash University, Melbourne,
VIC, Australia
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
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... 23 A newer definition of clinically significant hypoglycemia is a blood glucose level ≤3.0 mmol/L. 24 With regard to the issue of harm, it is not only the nadir glucose concentration that is dangerous but also the frequency and the duration of hypoglycemic events. Frequent hypoglycemic events interfere with daily living and lead to defective glucose counter-regulation and hypoglycemia unawareness. ...
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Introduction Recurrent hypoglycemia due to postbariatric hypoglycemia (PBH) is a postoperative complication after Roux-en-Y gastric bypass (RYGBP). The historic term is late dumping syndrome or reactive hypoglycemia. The aim of this study was to assess clinically applicable tools, in order to diagnose these patients, for the purpose of preventing hypoglycemic complications. Research design and methods Ten patients with PBS and nine controls were recruited. Continuous glucose monitoring (CGM) and food intake were registered for 7 days, together with metabolic parameters at baseline. Results There was a significant difference (p<0.05) in Dumping Syndrome Rating Scale (DSRS) between the groups. There was no difference between p-glucose or HbA1c between the groups, but a highly significant difference in C peptide p<0.01 was observed. Using the Dexcom Studio system, the PBH group had significantly (p<0.05) more time during the day in very low blood sugar (5.9±4.2% vs 1.8%±2.3%) compared with the controls. Counting hyperglycemic and hypoglycemic episodes showed that the quantity of hypoglycemic episodes was significantly higher, p<0.01, in the PBH group compared with controls (16.6±11.0 vs 8.1±8.6 hypoglycemic events). C peptide was positively correlated with the late dumping group, p<0.01 (CI 95% 0.353 to 0.814) and very low blood sugar (<3.2 mmol/L) in all subjects with p<0.01 (CI 95% 0.194 to 0.763). Conclusions Finding patients with recurrent hypoglycemic episodes after bariatric surgery is important to prevent future health problems. To diagnose recurrent hypoglycemia (PBH) after RYGBP, we used blood sugar analyzing tools that are commonly available in clinical settings. Interestingly, patients with few or no symptoms of PHB still had recurrent hyperglycemic and hypoglycemic events. We recommend an active approach with dumping syndrome questionnaires, assessment of metabolic parameters and CGM with food registration. Assessment of PBH using this method can potentially lead to reduced blood glucose variability due to behavioral changes.
... Based on an observational study reporting reduced mortality in patients with a HbA1c ≥7% (53 mmol/mol) and mean blood glucose >180 mg/dL during ICU admission (7), a planned exploratory subgroup analysis was conducted for this group. A post-hoc analysis was conducted using the American Diabetes Association and the European Association for the Study of Diabetes position statement hypoglycemic threshold of <54 mg/dL (29). ...
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Rationale Blood glucose concentrations affect outcomes in critically ill patients but the optimal target blood glucose range in those with type 2 diabetes is unknown. Objective To evaluate the effects of a 'liberal' approach to targeted blood glucose range during intensive care unit (ICU) admission. Methods This mutlicenter, parallel-group, open-label, randomized clinical trial included 419 adult patients with type 2 diabetes expected to be in the ICU on at least three consecutive days. In the intervention group intravenous insulin was commenced at a blood glucose >252 mg/dL and titrated to a target range of 180 to 252 mg/dL. In the comparator group insulin was commenced at a blood glucose >180 mg/dL and titrated to a target range of 108 to 180 mg/dL. The primary outcome was incident hypoglycemia (<72 mg/dL). Secondary outcomes included glucose metrics and clinical outcomes. Main Results At least one episode of hypoglycemia occurred in 10 of 210 (5%) patients assigned the intervention and 38 of 209 (18%) patients assigned the comparator (incident rate ratio: 0.21 (95% CI, 0.09 to 0.49); P<0.001). Those assigned the intervention had greater blood glucose concentrations (daily mean, minimum, maximum), less glucose variability and less relative hypoglycaemia (P<0.001 for all comparisons). By day 90, 62 of 210 (29.5%) in the intervention and 52 of 209 (24.9%) in the comparator group had died (absolute difference 4.6 percentage points (95%CI, -3.9 to 13.2%); P=0.29). Conclusions A liberal approach to blood glucose targets reduced incident hypoglycemia but did not improve patient-centered outcomes. Clinical trial registration available at www.anzctr.org.au, ID: ACTRN12616001135404.
... The protocol of the study was written before the current International Hypoglycaemia Study Group recommendations concerning hypoglycaemia reporting were established. 17 Therefore, we report level 2 hypoglycaemia as 3.0 mmol/L or less, and not as less than 3.0 mmol/L. 12 Night time is defined conventionally in two ways: 12:00 AM-05:59 AM and 11:00 PM-06:59 AM. 12 Furthermore, we applied an exploratory 'real-life' definition from 4 hours after evening prandial or corrective bolus insulin administration until actual morning prandial insulin administration to exclude any influence of coincidental correction with rapid-acting insulin. ...
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Aims/hypothesis: Nocturnal hypoglycaemia remains a main limiting factor for achieving the recommended glycaemic target in type 1 diabetes (T1D). The long-acting insulin analogue degludec reduces the risk of nocturnal hypoglycaemia in patients with T1D at low risk of such events. This study investigates whether insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal and severe hypoglycaemia in patients prone to nocturnal severe hypoglycaemia. Methods: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last two years were included in a two-year prospective, randomised, open, multicentre, cross-over trial. A total of 149 patients were randomised 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period was one year long and consisted of three months of run-in or cross-over followed by nine months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. Results: Treatment with insulin degludec resulted in a 28% (95%CI: 9-43; p=0.02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95%CI: 16-53; p=0.002) RRR at level 2 (≤3.0 mmol/l), and a 35% (95%CI: 1-58; p=0.04) RRR in all-day severe hypoglycaemia compared to insulin glargine U100. Conclusions/interpretation: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec as compared with insulin glargine U100. This article is protected by copyright. All rights reserved.
... & Level 2 is for glucose values below 3.0 mmol/l (54 mg/dl) and considered clinically important hypoglycaemia. & Level 3 designates any hypoglycaemia characterised by altered mental state and/or physical status needing the intervention of a third party for recovery [100]. ...
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The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus statement on the management of type 1 diabetes in adults. The writing group has considered the rapid development of new treatments and technologies and addressed the following topics: diagnosis, aims of management, schedule of care, diabetes self-management education and support, glucose monitoring, insulin therapy, hypoglycaemia, behavioural considerations, psychosocial care, diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special populations, inpatient management and future perspectives. Although we discuss the schedule for follow-up examinations and testing, we have not included the evaluation and treatment of the chronic microvascular and macrovascular complications of diabetes as these are well-reviewed and discussed elsewhere. The writing group was aware of both national and international guidance on type 1 diabetes and did not seek to replicate this but rather aimed to highlight the major areas that healthcare professionals should consider when managing adults with type 1 diabetes. Though evidence-based where possible, the recommendations in the report represent the consensus opinion of the authors. Graphical abstract
Article
Introduction: Hypoglycaemia is a significant burden to people living with diabetes and an impediment to achieving optimal glycaemic outcomes. The use of continuous glucose monitoring CGM has improved capacity to assess duration and level of hypoglycaemia. The personal impact of sensor-detected hypoglycaemia SDH is unclear. Hypo-METRICS is an observational study designed to define the threshold and duration of sensor glucose that provides the optimal sensitivity and specificity for events that people living with diabetes experience as hypoglycaemia. Methods: We will recruit 600 participants: 350 with insulin-treated type 2 diabetes, 200 with type 1 diabetes and awareness of hypoglycaemia and 50 with type 1 diabetes and impaired awareness of hypoglycaemia who have recent experience of hypoglycaemia. Participants will wear a blinded CGM device and an actigraphy monitor to differentiate awake and sleep times for 10 weeks. Participants will be asked to complete three short surveys each day using a bespoke mobile phone app, a technique known as ecological momentary assessment. Participants will also record all episodes of self-detected hypoglycaemia on the mobile app. We will use particle Markov chain Monte Carlo optimization to identify the optimal threshold and duration of SDH that have optimum sensitivity and specificity for detecting patient reported hypoglycaemia. Key secondary objectives include measuring the impact of symptomatic and asymptomatic SDH on daily functioning and health economic outcomes. Ethics and dissemination: The protocol was approved by local ethical boards in all participating centres. Study results will be shared with participants, in peer-reviewed journal publications and conference presentations.
Article
Background and aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and methods: In the HypoDeg trial, 149 people with T1D were included in an open-label, randomized, cross-over trial. Sixty-seven participants accepted optional participation in the predefined sub-study of 4x6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; p<0.05) in nocturnal CGM-recorded hypoglycemia (≤ 3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events/person-week. In nocturnal CGM-recorded hypoglycemia (≤ 3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; p<0.001), corresponding to an ARR of 0.75 events/person-week. At the lower detection limit of the CGM (≤ 2.2 mmol/L) treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23% - 77%; p=0.005) The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared to insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia.
Chapter
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Hypoglycemia, once detected in a timely manner, is commonly treated by administration of glucose or glucagon in accordance with HCP advice, however, identifying the hypoglycemic event or need to treat is of initial paramount importance. The definition of hypoglycemia is provided, together with the implications of such an event on clinical and economic outcomes. The current accuracy standards are discussed and how they are applied to the low blood glucose range and current technologies.
Article
Aim: The objective of the CRASH (Conversations and Reactions Around Severe Hypoglycemia) survey was to further our understanding of the characteristics, experience, behavior and conversations with healthcare professionals (HCPs) of persons with diabetes (PWD) receiving insulin, and of their caregivers (CGs), concerning hypoglycemia requiring external assistance (severe hypoglycemic events [SHEs]). Methods: CRASH was an online cross-sectional survey conducted across eight countries. The PWDs with self-reported type 1 (T1D) or insulin-treated type 2 (T2D) diabetes were aged ≥18 years and had experienced one or more SHEs in past the 3 years; CGs were non-medical professionals aged ≥18 years, caring for a PWD meeting all the above criteria except for PWD age (≥4 rather than ≥18 years). The present report is a descriptive analysis of data from France. Results: Among PWDs who had ever discussed SHEs with an HCP, 38.9% of T1D PWDs and 50.0% of T2D PWDs reported that SHEs were discussed at every consultation; 26.3% and 8.8% respectively had not discussed the most recent SHE with an HCP. 35.7% of T1D PWDs and 53.8% of T2D PWDs reported that glucagon was not available to them at the time of their most recent SHE. Only 16.9% of T1D PWDs and 6.5% of T2D PWDs who had discussed their most recent SHE with an HCP reported that the HCP recommended obtaining a glucagon kit or asked them to confirm that they already had one. High proportions of PWDs and CGs reported that the most recent SHE had made them feel unprepared, scared and helpless and had affected mood, emotional state and activities. Conclusion: CRASH survey data from France identify a need for greater discussion about SHEs between HCPs and PWDs and their CGs, and reveal gaps in the diabetes education of PWDs and CGs.
Article
The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus statement on the management of type 1 diabetes in adults. The writing group has considered the rapid development of new treatments and technologies and addressed the following topics: diagnosis, aims of management, schedule of care, diabetes self-management education and support, glucose monitoring, insulin therapy, hypoglycemia, behavioral considerations, psychosocial care, diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special populations, inpatient management, and future perspectives. Although we discuss the schedule for follow-up examinations and testing, we have not included the evaluation and treatment of the chronic microvascular and macrovascular complications of diabetes as these are well-reviewed and discussed elsewhere. The writing group was aware of both national and international guidance on type 1 diabetes and did not seek to replicate this but rather aimed to highlight the major areas that health care professionals should consider when managing adults with type 1 diabetes. Though evidence-based where possible, the recommendations in the report represent the consensus opinion of the authors.
Article
The presence of continuous glucose monitoring (CGM) systems has expanded diagnostic capabilities. The implementation of this technology into clinical practice allowed to determine the patterns and tendencies of excursions in glucose levels, to obtain reliable data concerning short-term glycemic control. Taking into consideration the large amount of obtained information using CGM systems, more than 30 different indicators characterizing glycemic variability were proposed. However, it is very difficult for a practitioner to interpret the data obtained due to the variety of indicators and the lack of their target values. The first step in the standardization of indices was the creation of the International Guidelines for CGM in 2017, where the Time in Range (TIR) (3,9–10,0 mmol/l, less often 3,9–7,8 mmol/l) was significant. To complement the agreed parameters and simplify the interpretation of obtained data using CGM, in 2019 the recommendations were prepared for the International Consensus on Time in Range, where TIR was validated as an additional component of the assessment of glycemic control along with HbA 1c . In the literature review the issues of the association of TIR with the development of micro- and macrovascular complications in type 1 and 2 diabetes are considered. The relationship with other indicators of the glycemic control assessment was also analyzed and the dependence of insulin therapy on TIR was shown. TIR is a simple and convenient indicator, it has a proven link with micro- and macrovascular complications of diabetes and can be recommended as a new tool for assessing the glycemic control. The main disadvantage of TIR usage is the insufficient apply of CGM technology by the majority of patients with diabetes.
Article
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OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.PARTICIPANTSFive members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.EVIDENCEThe writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.CONSENSUS PROCESSConsensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012.CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.
Article
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Whether hypoglycemia leads to death in critically ill patients is unclear. We examined the associations between moderate and severe hypoglycemia (blood glucose, 41 to 70 mg per deciliter [2.3 to 3.9 mmol per liter] and ≤40 mg per deciliter [2.2 mmol per liter], respectively) and death among 6026 critically ill patients in intensive care units (ICUs). Patients were randomly assigned to intensive or conventional glucose control. We used Cox regression analysis with adjustment for treatment assignment and for baseline and postrandomization covariates. Follow-up data were available for 6026 patients: 2714 (45.0%) had moderate hypoglycemia, 2237 of whom (82.4%) were in the intensive-control group (i.e., 74.2% of the 3013 patients in the group), and 223 patients (3.7%) had severe hypoglycemia, 208 of whom (93.3%) were in the intensive-control group (i.e., 6.9% of the patients in this group). Of the 3089 patients who did not have hypoglycemia, 726 (23.5%) died, as compared with 774 of the 2714 with moderate hypoglycemia (28.5%) and 79 of the 223 with severe hypoglycemia (35.4%). The adjusted hazard ratios for death among patients with moderate or severe hypoglycemia, as compared with those without hypoglycemia, were 1.41 (95% confidence interval [CI], 1.21 to 1.62; P<0.001) and 2.10 (95% CI, 1.59 to 2.77; P<0.001), respectively. The association with death was increased among patients who had moderate hypoglycemia on more than 1 day (>1 day vs. 1 day, P=0.01), those who died from distributive (vasodilated) shock (P<0.001), and those who had severe hypoglycemia in the absence of insulin treatment (hazard ratio, 3.84; 95% CI, 2.37 to 6.23; P<0.001). In critically ill patients, intensive glucose control leads to moderate and severe hypoglycemia, both of which are associated with an increased risk of death. The association exhibits a dose-response relationship and is strongest for death from distributive shock. However, these data cannot prove a causal relationship. (Funded by the Australian National Health and Medical Research Council and others; NICE-SUGAR ClinicalTrials.gov number, NCT00220987.).
Article
Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on “conventional” insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n=16), or maintenance of the original “conventional” therapy (control group, CON, n=5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5±0.05 to 0.045±0.02 episodes/patient-day; HbA1C increased from 5.83±0.18 to 6.94±0.13% (range in non-diabetic subjects 3.8–5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p<0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.
Book
If you regularly see patients with diabetes who experience hypoglycaemia and need expert guidance, then this is the book for you. Hypoglycaemia in Clinical Diabetes, 3rd Edition once again provides health professionals involved in the management of people with diabetes with an expertly written, comprehensive guide to hypoglycaemia, the most common and feared side effect of insulin treatment for diabetes. With reference to ADA and EASD guidelines throughout, topics covered include the physiology of hypoglycaemia and the body's response to a low blood glucose, its presentation and clinical features, potential morbidity and optimal clinical management in order to achieve and maintain good glycaemic control. Particular attention is paid to the way hypoglycaemia is managed in different groups of patients, such as the elderly, in children, or during pregnancy. New chapters in this edition include: Psychological effects of hypoglycaemia. Technology for hypoglycaemia: CSII and CGM. Exercise management and hypoglycaemia in type 1 diabetes. Neurological sequelae of hypoglycaemia. Valuable for diabetologists, endocrinologists, non-specialist physicians and general practitioners, Hypoglycaemia in Clinical Diabetes, 3rd Edition provides expert clinical guidance to this extremely common and potentially serious complication associated with diabetic management.
Article
Hypoglycemia caused by treatment with a sulfonylurea, a glinide, or insulin coupled with compromised defenses against the resulting falling plasma glucose concentrations is a problem for many people with diabetes. It is often recurrent, causes significant morbidity and occasional mortality, limits maintenance of euglycemia, and impairs physiological and behavioral defenses against subsequent hypoglycemia. Minimizing hypoglycemia includes acknowledging the problem; considering each risk factor; and applying the principles of intensive glycemic therapy, including drug selection and selective application of diabetes treatment technologies. For diabetes health-care providers treating most people with diabetes who are at risk for or are suffering from iatrogenic hypoglycemia, these principles include selecting appropriate individualized glycemic goals and providing structured patient education to reduce the incidence of hypoglycemia. This is typically combined with short-term scrupulous avoidance of hypoglycemia, which often will reverse impaired awareness of hypoglycemia. Clearly, the risk of hypoglycemia is modifiable.
Article
Aims: Hypoglycaemia caused by glucose-lowering therapy has been linked to cardiovascular (CV) events. The ORIGIN trial provides an opportunity to further assess this relationship. Methods and results: A total of 12 537 participants with dysglycaemia and high CV-risk were randomized to basal insulin glargine titrated to a fasting glucose of ≤ 5.3 mmol/L (95 mg/dL) or standard glycaemic care. Non-severe hypoglycaemia was defined as symptoms confirmed by glucose ≤ 54 mg/dL and severe hypoglycaemia as a requirement for assistance or glucose ≤ 36 mg/dL. Outcomes were: (i) the composite of CV death, non-fatal myocardial infarction or stroke; (ii) mortality; (iii) CV mortality; and (iv) arrhythmic death. Hazards were estimated before and after adjustment for a hypoglycaemia propensity score. During a median of 6.2 years (IQR: 5.8-6.7), non-severe hypoglycaemic episodes occurred in 41.7 and 14.4% glargine and standard group participants, respectively, while severe episodes occurred in 5.7 and 1.8%, respectively. Non-severe hypoglycaemia was not associated with any outcome following adjustment. Conversely, severe hypoglycaemia was associated with a greater risk for the primary outcome (HR: 1.58; 95% CI: 1.24-2.02, P < 0.001), mortality (HR: 1.74; 95% CI: 1.39-2.19, P < 0.001), CV death (HR: 1.71; 95% CI: 1.27-2.30, P < 0.001) and arrhythmic death (HR: 1.77; 95% CI: 1.17-2.67, P = 0.007). Similar findings were noted for severe nocturnal hypoglycaemia for the primary outcome and mortality. The severe hypoglycaemia hazard for all four outcomes was higher with standard care than with insulin glargine. Conclusion: Severe hypoglycaemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycaemia. Although allocation to insulin glargine vs. standard care was associated with an increased risk of severe and non-severe hypoglycaemia, the relative risk of CV outcomes with hypoglycaemia was lower with insulin glargine-based glucose-lowering therapy than with the standard glycaemic control. Trial Registration (ORIGIN ClinicalTrials.gov number NCT00069784).
Article
Severe hypoglycemia is one of the strongest predictors of adverse clinical outcomes in patients with type 2 diabetes. Our study addressed the question whether there is a relationship between hypoglycemic events (HE) and severe cardiac arrhythmias in type 2 diabetic patients with established clinical risk factors under real-world conditions. We included 94 patients with type 2 diabetes and documented cardiovascular disease, in which interstitial glucose values and Holter ECG were recorded for 5 days in parallel. Patients received a stable treatment with insulin and/or sulfonylurea and were instructed to record symptoms of hypoglycemia or arrhythmias. Continuous glucose monitoring revealed 54 HE (interstitial glucose <3.1 mmol/l) in a total of 26 patients. Patients perceived only 39 % of HE during the day and 11 % of HE during the night. Patients with HE had a significantly higher number of severe ventricular arrhythmias [ventricular tachycardia (VT) 32.8 ± 60 vs. 0.9 ± 4.2, p = 0.019], and multivariate regression analysis revealed the duration of severe HE and TSH level as independent predictors of the occurrence of a VT. In conclusion, our study suggests that hypoglycemia might be able to trigger at least under certain circumstances, such as low TSH, ventricular arrhythmias under real-world conditions. The large number of unrecognized HE and VT in vulnerable patients treated with insulin or sulfonylurea should encourage the practitioner to focus on stable glucose control and to search for silent HE.
Article
Recent trials of intensive glycemic control suggest a possible link between hypoglycemia and excess cardiovascular mortality in patients with type 2 diabetes. Hypoglycemia might cause arrhythmias through effects on cardiac repolarization and changes in cardiac autonomic activity. Our aim was to study the risk of arrhythmias during spontaneous hypoglycemia in type 2 diabetic patients with cardiovascular risk. Twenty-five insulin-treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability, and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for time of day. There were 134 h of recording at hypoglycemia, 65 h at hyperglycemia, and 1,258 h at euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after the counterregulatory phase may account for bradycardia and associated arrhythmias. QT intervals, corrected for heart rate, >500 ms and abnormal T-wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk. This is a plausible mechanism that could contribute to increased cardiovascular mortality during intensive glycemic therapy.
Article
Objective: To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. Participants: Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. Evidence: The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. Consensus process: Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012. Conclusions: The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.