severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes
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Severe Hypoglycemia and Diabetic Ketoacidosis in Adults WithType 1 Diabetes: Results From the T1D Exchange Clinic Registry
Ruth S. Weinstock,Dongyuan Xing,David M. Maahs,Aaron Michels,Michael R.
Rickels,Anne L. Peters,Richard M. Bergenstal,Breanne Harris,Stephanie N.DuBose,Kellee M. Miller,Roy W. Beck,andfor the T1D Exchange Clinic Network
DOI:http://dx.doi.org/10.1210/jc.2013-1589 Received: March 07, 2013Accepted: June 04, 2013Published Online: June 12, 2013
Abstract
Context:
Few studies have assessed factors associated with severe hypoglycemia (SH) and diabetic ketoacidosis
(DKA) in adults with type 1 diabetes (T1D).
Objective:
Our objective was to determine frequency of and factors associated with the occurrence of SH and DKA
in adults with T1D.
Design and Setting:
We conducted a cross-sectional analysis from the T1D Exchange clinic registry at 70 U.S. endocrinology
centers.
Patients:
Analysis included 7012 participants in the T1D Exchange clinic registry aged 26 to 93 years old with T1D
for 2 years.
Results:
Higher frequencies of SH and DKA were associated with lower socioeconomic status (P< .001). SH was
strongly associated with diabetes duration (P< .001), with 18.6% of those with diabetes 40 years having
an event in the past 12 months. SH frequency was lowest in those with hemoglobin A1c (HbA1c) levels of
7.0% (53 mmol/mol) to 7.5% (58 mmol/mol), being higher in those with HbA1c levels 58 mmol/mol). DKA frequency increased with higher HbA1c levels (P< .001), with
21.0% of those with HbA1c 10.0% (86 mmol/mol) having an event in the past 12 months.
Conclusions:
SH and DKA are more common in those with lower socioeconomic status. DKA, most common in those
with HbA1c 10.0% (86 mmol/mol), should be largely preventable. In contrast, SH, most frequent withdiabetes 40 years duration, cannot be abolished given the limitation of current therapies. To reduce SH
in adults with longstanding diabetes, consideration should be given to modifying HbA1c goals, particularly
in patients with very low HbA1c levels.
Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) are major acute complications of type
1 diabetes (T1D). Many studies are available concerning the prevalence of these complications in
children and adolescents with T1D, but there is a paucity of data in adults. Although recent data are
available from European registries (1, 2), recent U.S. data are largely from clinical trials, which may not be
representative (3, 4). To provide current data in clinical practice settings in the United States, we used the
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large database of the T1D Exchange clinic registry to assess the frequencies of and identify factors
associated with SH and DKA in adults with T1D. We hypothesized that rates of DKA would be positively
associated with hemoglobin A1c (HbA1c) and that SH would be inversely associated with HbA1c.
Moreover, we hypothesized that rates of DKA and SH would be associated with factors such as
socioeconomic status, age, pump use, and diabetes duration.
Subject and methods
The T1D Exchange Clinic Network includes 70 U.S.-based pediatric and adult endocrinology practices. A
registry of individuals with T1D commenced enrollment in September 2010 (5). Each clinic received
approval from an institutional review board, and informed consent was obtained according to institutional
review board requirements. Data were collected for the registry's central database from the
participant's medical record and by having the participant complete a comprehensive questionnaire, as
previously described (5). This report includes data on 7012 participants enrolled at 44 of the sites through
August 1, 2012, who were at least 26 years old and had duration of T1D of at least 2 years.
Information on the occurrence of SH and DKA in the previous 12 months was obtained from the
participant. Initially, SH was defined as an episode in which the assistance of another individual was
needed or glucagon was given. However, it became apparent that the interpretation of needingassistance varied, and in some cases, glucagon was being given for mild hypoglycemia to avoid SH. As
a result, the questionnaire was modified to change the participant-reported SH definition to be an episode
in which hypoglycemia resulted in seizure or loss of consciousness (LOC); glucose data confirming an
event were not collected. Participant-reported DKA was defined as the occurrence of ketoacidosis that
resulted in overnight hospitalization. SH data were analyzed for the 4973 participants (71%) who
completed the modified questionnaire with the seizure/LOC definition, whereas DKA data were available
for 6796 participants (97%). In addition to participant reporting, information on the occurrence of DKA and
SH also was collected from the clinics' medical records. Clinic-documented DKA was defined as having
hyperglycemia and meeting all of the following criteria: 1) symptoms such as polyuria, polydipsia, nausea,
or vomiting; 2) serum ketones or large/moderate urine ketones; 3) arterial blood pH
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Results
The cohort included 7012 participants 26 to 93 years old; 54% were female, and 91% were non-Hispanic
white. Mean HbA1c (SD) was 7.7% (61 mmol/mol) 1.2% (13.1 mmol/mol). Median diabetes duration
was 24 years (interquartile range 15 to 34 years). Characteristics were similar in the cohort with available
DKA data (n = 6797) and those with available SH data (n = 4973) (Supplemental Table 1, published on
The Endocrine Society's Journals Online web site athttp://jcem.endojournals.org).Severe hypoglycemia
One or more SH events (seizure or LOC) within 12 months was reported by 11.8% of the 4973
participants with available data. SH frequency increased with longer diabetes duration, with the 12-month
frequency of 1 or more events being 18.6% in the 758 participants with diabetesfor 40 years (Figure 1A
andTable 1). Although the frequency of SH increased with older age (P< .001), as can be seen inFigure
1A, the age effect was largely explained by diabetesduration, and in the multivariate model, age was not
a significant factor (Table 1). With respect to HbA1c levels, SH frequency was lowest with HbA1c levels
7.0% (53 mmol/mol) to 7.5% (58 mmol/mol), with frequency being higher at levels above or below this
range (Figure 2A andTable 1). No evidence of a difference in SH frequency was found between adults
with HbA1c levels of 8.0% to 9.0%, 9.0% to 10.0%, and >10.0% (P> .05). There was a trend (P= .01) for
individuals with low (
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Figure 2.A, The 12-month frequency of severe hypoglycemia according to HbA1c level. * Mean HbA1c
averaged over 12 months before enrollment.Pvalue obtained by categorizing HbA1c with 3 levels:
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(tabel 2 ditaronya di bagian ini..)
Participant-reported versus clinic-reported events
The frequency of at least 1 DKA or SH event in the past 12 months was lower from clinic-reported data
from medical record review compared with participant-reported data (3.6% versus 11.8% for SH and 3.2%versus 4.8% for DKA). Logistic models using clinic-reported SH and DKA events to assess associated
factors produced results similar to the models using participant-reported events (Supplemental Tables 2
and 3).
Discussion
Using the T1D Exchange clinic registry data, we determined the frequencies of SH and DKA over the past
12 months in adults with T1D who were being treated at endocrinology practices in the United States.
Compared with the pediatric and young adult cohort in the T1D Exchange clinic registry, the 12-month
frequency of hypoglycemia-induced seizure/LOC in adults was higher (11.8% versus 6.1%) and DKA
frequency was lower (4.8% versus 9.6%) (5). Higher frequencies of both SH and DKA were associatedwith lower socioeconomic status, consistent with previous reports (610).
Our 12-month frequency of at least 1 SH episode with seizure/LOC (11.8%) is substantially higher than
the 2.2% 6-month frequency reported for control group participants with comparable characteristics in the
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF CGM) randomized
clinical trial (4)and the 4.8% 12-month frequency in the Sensor-Augmented Pump Therapy for A1c
Reduction (STAR3) trial (3)(R. Bergenstal, MD, personal communication, November 2012). This
suggests that clinical trial data may not be an appropriate source for estimating the real-world frequency
of SH. Most other registry and observational studies have reported SH frequency based on a definition of
an event in which the assistance of another person was needed. If it is assumed that about one-third of
SH events using this definition involved seizure/LOC, then the data on the 12-month SH frequency are
similar to our SH frequency: 31.5% in the Eurodiab Prospective Complications Study (2), 36.7% in a
Danish-English survey (7), 40.5% in a Dutch study (11), and 27% in a Swedish survey (12). The UKHypoglycemia Study Group reported an SH frequency of 22% over a 12-month period in adults with T1D
for 15 years (13). It is difficult to compare our SH frequency
with that of certain other studies such as the Diabetes Control and Complications Trial (DCCT) due to
differences in populations, SH definition, and reporting metrics (eg, frequency of 1 or more events versus
rate per 100 000 person-years).
Individuals with longstanding diabetes were at greatest risk for SH irrespective of age, with almost 1 in 5
of those with duration of 40 or more years reporting hypoglycemia-induced seizure/LOC within the
previous 12 months. Based on the work of Cryer (14)and others, it is likely that the increased risk with
longer duration is related to the loss of endogenous insulin secretion (C-peptide negative) removing any
autoregulatory capability to reduce excessive insulin, a greater prevalence of defective glucose
counterregulation with hypoglycemic unawareness including a reduced plasma glucagon response to
hypoglycemia, and loss of the epinephrine response to hypoglycemia (hypoglycemia-associated
autonomic failure). Impairments related to chronic diabetes-related complications and other comorbidities
also could be contributing factors. We did not find an association between SH and gender in contrast with
the JDRF CGM randomized trial and the Diabetes Control and Complications Trial (DCCT), which found a
higher SH rate in females (15).
The lowest SH frequency was seen in those with HbA1c levels in the range of 7.0% (53 mmol/mol) to
7.5% (58 mmol/mol), with the frequency being higher in those with HbA1c levels 58 mmol/mol). These data support the contention that hypoglycemia is an important barrier
for the achievement of near-normal glycemic control in T1D. There was a suggestion in the data that SH
frequency might be higher in those who are the most insulin sensitive (based upon lower insulin
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requirements), but there was not an association between SH and BMI. This suggests that the ability to
achieve glycemic targets varies in people with T1D. This may be related to differences in C-peptide
status, insulin sensitivity (independent of obesity), and/or varying capacities to secrete glucagon and
other factors. These data suggest that the avoidance of SH requires setting individualized flexible
glycemic targets, with caution in recommending a goal HbA1c of
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longstanding diabetes, given the limitation of current therapies, consideration should be given to
modifying HbA1c goals, particularly in patients with very low HbA1c levels and SH. In addition to
hypoglycemic risk, the decision to raise the target HbA1c should take into consideration age, self-care
capacities, presence of comorbidities including vascular complications, and life expectancy.
Abbreviations:BMI body mass index
DKA diabetic ketoacidosis
HbA1c hemoglobin A1c
JDRF CGM Juvenile Diabetes Research Foundation Continuous Glucose Monitoring
LOC loss of consciousness
SH severe hypoglycemia
T1D type 1 diabetes.
Acknowledgments
We acknowledge the patients who chose to participate in this registry and the T1D Exchange Clinic
Network investigators and coordinators for their hard work and dedication. A listing of clinical sites,investigators, and coordinators participating in the clinic registry is located in the Supplemental Appendix.
The T1D Exchange Clinic Network is funded through a grant provided by the Leona M. and Harry B.
Helmsley Charitable Trust. The Helmsley Trust had no role in the study design; collection, analysis, and
interpretation of data; writing of this report; or the decision to submit the report for publication.
R.S.W. initiated the idea for the manuscript, researched data, contributed to discussion, wrote the
manuscript, and reviewed/edited the manuscript. D.X. researched data, contributed to discussion, and
wrote the manuscript. A.M. contributed to discussion and reviewed/edited the manuscript. M.R.
contributed to discussion and reviewed/edited the manuscript. A.P. contributed to discussion and
reviewed/edited the manuscript. R.M.B. contributed to discussion and reviewed/edited the manuscript.
B.H. contributed to discussion and reviewed/edited the manuscript. S.D. researched data, contributed to
discussion, and wrote the manuscript. K.M. researched data, contributed to discussion, and
reviewed/edited the manuscript. R.W.B. contributed to discussion and reviewed/edited the manuscript.R.W.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes
responsibility for the integrity of the data and accuracy of the data analysis.
Disclosure Summary: D.X., B.H., S.D., and K.M. have no disclosures. R.S.W.'s nonprofit employer has
received grant money as the site for multicenter clinical trials sponsored by Eli Lilly, Medtronic, Astra-
Zeneca, GlaxoSmithKline, and Johnson & Johnson. D.M.'s nonprofit employer has received research
grants from Eli Lilly, Abbott, and Diabetes Care. A.M.'s nonprofit employer has received a research grant
from Novartis. M.R. has received consultancy fees from Longevity Biotech. A.P.'s nonprofit employer has
received research grants from Sanofi; consultancy fees from Eli Lilly, Roche, Janssen, Amylim, and
Sanofi; and payment for lectures from Amylin, Abbott, Eli Lilly, NovoNordisk, Takeda, and Dexcom.
R.M.B. has served on a scientific advisory board, consulted or performed clinical research with
Abbott Diabetes Care, Amylin, Bayer, Becton Dickinson, Boehringer Ingelheim, Intuity, Calibra, DexCom,
Eli Lilly, Halozyme, Helmsley Trust, Hygieia, Johnson & Johnson, Medtronic, Merck, National Institutes ofHealth, Novo Nordisk, ResMed, Roche, Sanofi, and Takeda. His employer, Park Nicollet, has contracts
with the listed companies for his services, and no personal income goes to R.M.B. He has inherited Merck
stock and has been a volunteer officer of the American Diabetes Association. R.W.B.'s nonprofit employer
has received consultant payments on his behalf from Sanofi and Animas and a research grant from
NovoNordisk with no personal compensation to R.W.B.
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