Incidence of COVID-19 and Risk of Diabetic Ketoacidosis in New-Onset Type 1 Diabetes
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Incidence of COVID-19 and Risk of
Diabetic Ketoacidosis in New-Onset
Type 1 Diabetes
Clemens Kamrath, MD,a,* Joachim Rosenbauer, MD,b,c,* Alexander J. Eckert, MSc,c,d Angeliki Pappa, MD,e
Felix Reschke, MD,f Tilman R. Rohrer, MD, PhD,g Kirsten M€onkem€oller, MD,h Michael Wurm, MD,i Kathrin Hake, MD,j
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Klemens Raile, MD, PhD,k Reinhard W. Holl, MD, PhDc,d
With this study, our aim was to quantify the relative risk (RR) of diabetic
OBJECTIVES: abstract
ketoacidosis at diagnosis of type 1 diabetes during the year 2020 and to assess whether it was
associated with the regional incidence of coronavirus disease 2019 (COVID-19) cases and
deaths.
METHODS: Multicenter cohort study based on data from the German Diabetes Prospective
Follow-up Registry. The monthly RR for ketoacidosis in 2020 was estimated from observed
and expected rates in 3238 children with new-onset type 1 diabetes. Expected rates were
derived from data from 2000 to 2019 by using a multivariable logistic trend regression model.
The association between the regional incidence of COVID-19 and the rate of ketoacidosis was
investigated by applying a log-binomial mixed-effects model to weekly data with Germany
divided into 5 regions.
RESULTS: The observed versus expected frequency of diabetic ketoacidosis was significantly
higher from April to September and in December (mean adjusted RRs, 1.48–1.96). During the
first half of 2020, each increase in the regional weekly incidence of COVID-19 by 50 cases or 1
death per 100 000 population was associated with an increase in the RR of diabetic
ketoacidosis of 1.40 (95% confidence interval, 1.10–1.77; P 5 .006) and 1.23 (1.14–1.32;
P < .001), respectively. This association was no longer evident during the second half of 2020.
CONCLUSIONS:These findings suggest that the local severity of the pandemic rather than health
policy measures appear to be the main reason for the increase in diabetic ketoacidosis and
thus the delayed use of health care during the pandemic.
a
Division of Pediatric Endocrinology and Diabetology, Centre of Child and Adolescent Medicine, Justus Liebig
WHAT’S KNOWN ON THIS SUBJECT: Significant delays in
University, Giessen, Germany; bInstitute for Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre diagnosis and treatment were reported during the coronavirus
for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany; cGerman Centre for Diabetes disease 2019 pandemic, leading to increased rates of diabetic
Research, Munich-Neuherberg, Germany; dInstitute of Epidemiology and Medical Biometry, Ulm University, Ulm, ketoacidosis in children. Temporal associations between
Germany; eDepartment of Pediatrics, University Hospital Rheinisch-Westfaelische Technische Hochschule Aachen, delayed hospital presentations or treatment initiations and
Aachen, Germany; fDiabetes Centre for Children and Adolescents, Children's Hospital Auf der Bult, Hannover,
pandemic containment measures have been reported.
Germany; gDepartment of Pediatrics, Saarland University, Homburg, Saarland, Germany; hDepartment of
Pediatrics, Kinderkrankenhaus Amsterdamer Strasse, Cologne, Germany; iDepartment of Pediatrics, Klinik St. WHAT THIS STUDY ADDS: With this study, we found that the
Hedwig, University Hospital Regensburg, Krankenhaus Barmherzige Br€ uder, Regensburg, Germany; jDepartment of regional 7-day incidence of coronavirus disease 2019 cases and
k
Pediatrics, M€uritz Klinikum, Waren, Germany; and Department of Pediatric Endocrinology and Diabetology, Charite,
deaths, rather than nationwide pandemic containment
University Medicine Berlin, Germany
measures such as social distancing, were associated with risk
*Contributed equally as co-first authors. of ketoacidosis and in children with new-onset type 1 diabetes.
Dr Kamrath had the idea of this study, conceptualized the study, interpreted the analyses,
drafted the initial manuscript, and reviewed and revised the manuscript; Dr Rosenbauer To cite: Kamrath C, Rosenbauer J, Eckert AJ, et al. Incidence
conceptualized the study, analyzed the data, supervised the statistical analysis, and critically of COVID-19 and Risk of Diabetic Ketoacidosis in New-Onset
reviewed and revised the manuscript; Mr Eckert conducted the initial analyses and reviewed Type 1 Diabetes. Pediatrics. 2021;148(3):e2021050856
and revised the manuscript; Prof Holl conceptualized the study, coordinated and supervised
PEDIATRICS Volume 148, number 3, September 2021:e2021050856 ARTICLE
The pandemic of coronavirus diabetes and could serve as a measure was obtained from patients or their
disease 2019 (COVID-19) caused by of delayed access to health care.11–14 guardians. The ethics committee of
severe acute respiratory syndrome Ulm University approved the
coronavirus 2 (SARS-CoV-2) spread Our aim of this study was to quantify analysis of anonymized data from
quickly across Europe and America the relative risk (RR) of diabetic the DPV registry. This study
during March and April 2020.1 ketoacidosis at diagnosis of type 1 followed the Strengthening the
Within Germany, however, there diabetes during the year of 2020 and Reporting of Observational Studies
were large regional differences in to assess whether the increased risk in Epidemiology reporting guideline
the number of COVID-19 cases and was associated with the regional for cohort studies.16
deaths; the south, namely, the incidence of COVID-19 cases and
The data of the pandemic were taken
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federal states of Bavaria and Baden- COVID-19–related deaths. Knowledge
of factors leading to a decrease in from the official statistics from the
W€urttemberg, and the west, namely,
health care use and to a delay in Robert Koch Institute, Berlin,
North Rhine-Westphalia, of Germany
diagnosis could help to prevent future Germany.2 In accordance with the
were particularly affected at the
health risks from non–COVID-19 international standards of the World
beginning of the pandemic.2 In Health Organization, all laboratory
diseases by taking countermeasures
response to the pandemic, confirmations of SARS-CoV-2,
and by improving the resilience of
nationwide health policy measures irrespective of the presence and
outpatient and inpatient care to
to contain the spread of SARS-CoV-2 severity of clinical symptoms, were
sudden massive challenges.
were swiftly implemented in considered as COVID-19 cases.1
Germany to achieve social
METHODS Variables
distancing, such as restrictions on
social contacts, school closures, and Data Source and Study Population Demographic data included year,
the general recommendation to stay month (additionally week for 2020
For this study, we used data from
at home. Although the rates of new data) and age at diabetes onset, sex,
the German Diabetes Prospective
cases of COVID-19 increased and immigrant background (patient
Follow-up Registry DPV (Diabetes-
remarkably during March and Patienten-Verlaufsdokumentation) of or at least 1 parent born outside of
peaked in early April, and deaths Germany).
children and adolescents aged
related to COVID-19 peaked in mid- between 6 months and 18 years
April in Germany, the rates declined For regional analysis, Germany was
living in Germany with the diagnosis
thereafter and stabilized at lower divided into 5 geographical regions:
of new-onset type 1 diabetes during
levels in May and June.1,2 In early the north, consisting of the federal
the year 2020. The control group
October, however, COVID-19 cases states of Schleswig-Holstein,
consisted of 42 417 children and
showed another sharp increase in a Mecklenburg-Western Pomerania,
adolescents living in Germany with
Hamburg, Bremen, and Lower
second COVID-19 wave, with a peak new-onset type 1 diabetes Saxony; the middle, consisting of
in late December.1,2 diagnosed during the years Saarland, Rhineland-Palatinate, and
2000–2019. The DPV registry has a Hesse; the west, consisting of North
The pandemic has also resulted in nationwide coverage of >90% of
harm to patients who were not Rhine-Westphalia; the east,
pediatric patients with type 1 consisting of Thuringia, Saxony,
affected by COVID-19. Admissions for diabetes in Germany and comprises Saxony-Anhalt, Berlin, and
health care during the pandemic have 257 pediatric diabetes centers Brandenburg; and the south,
markedly declined.3–6 As a result, (hospitals and practices) as of consisting of Bavaria and Baden-
diagnoses were delayed, and diseases March 2021.15 Twice a year, locally W€urttemberg (Fig 1A). Patients
were identified at an advanced collected longitudinal data are were assigned to regions on the
stage.6–9 This delay has been pseudonymized and transmitted for basis of their residence at diabetes
quantified for instance by an increase central plausibility checks and onset if the information was
in the frequency of diabetic analyses to Ulm University, Ulm, available, and if this was not the
ketoacidosis at onset of type 1 Germany. Inconsistent data are case, they were assigned via the
diabetes in children and adolescents reported back to participating postal code of the first-care clinic.
during the first 2 months of the centers for validation and/or
COVID-19 pandemic in Germany.10 correction. Data are then completely Diabetic ketoacidosis was defined as
Ketoacidosis is an acute life- anonymized for analysis. Verbal or a pH levelcontinuous variables, and frequencies
and percentages are provided for the
description of categorical variables.
Continuous or categorical variables
were compared among different
groups via the Kruskal-Wallis test or
the x2 test, respectively, adjusted for
multiple testing by using the
Bonferroni-Holm method.
For the selection of possibly
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confounding variables, we controlled
for covariates for which there is
evidence for association with the
outcome. Immigrant status, younger
age, and female sex are known to
increase the risk of ketoacidosis at
diabetes onset.17
Applying a multivariable logistic
trend regression model that
included the year at diabetes onset
(as a continuous term), the month
of diabetes onset, and an
interaction term of both, age group
at diabetes onset (6 months toTABLE 1 Description of the Study Population
All No Diabetic Ketoacidosis Diabetic Ketoacidosis (All) Severe Ketoacidosis
All patients, No. (%) 3238 (100) 2144 (66.2) 1094 (33.8) 401 (12.4)
Age, median (IQR), y 9.8 (6.0–12.9) 9.9 (6.1–13.0) 9.8 (5.8–12.9) 9.4 (4.8–12.5)a
Male sex, No. (%) 1799 (55.6) 1207 (56.3) 592 (54.1) 209 (52.1)
Immigrant background, No. (%) 808 (25.0) 486 (22.7) 322 (29.4)b 134 (33.4)b
Geographical regions, No. (%c)
North 657 (20.3) 441 (67.1) 216 (32.9) 90 (13.7)
Middle 436 (13.5) 305 (70.0) 131 (30.0) 47 (10.8)
West 807 (24.9) 524 (64.9) 283 (35.0) 98 (12.1)
East 503 (15.5) 330 (65.6) 173 (34.4) 60 (11.9)
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South 835 (25.8) 544 (65.1) 291 (34.9) 106 (12.7)
a
P 5 .01 versus no diabetic ketoacidosis (Kruskal-Wallis test adjusted for multiple testing by using the Bonferroni-Holm method).
b
P < .001 versus no diabetic ketoacidosis (x2 test adjusted for multiple testing by using the Bonferroni-Holm method).
c
The first column shows the percentage of patients in this region out of all patients; the following columns show the respective percentage based on the No. patients in the
respective region.
with the standardized expected the course of the pandemic, we (12.4%) were severe. Table 1
monthly rates of ketoacidosis and conducted the described analysis provides a descriptive overview of
severe ketoacidosis; the results are separately for the first and second the study population.
presented as adjusted RR with 95% half of the year 2020 (calendar
confidence intervals (CIs) and weeks 1–26 and 27–52, According to the applied
corresponding P values of Wald tests. respectively), corresponding to multivariable logistic trend model,
the first and second wave of the the standardized expected monthly
To evaluate the association of the pandemic. The results are proportions of ketoacidosis for the
regional severity of the COVID-19 presented as adjusted RRs with year 2020 ranged from 20.1%
pandemic with the regional rate of 95% CIs and corresponding P (95% CI, 16.1%–25.0%) in January
ketoacidosis in children and values of Wald tests. In to 25.3% (95% CI, 20.6%–31.0%)
adolescents with new-onset type 1 addition, the probability of a in October (Table 2). In contrast,
diabetes in the year 2020, we ketoacidosis at type 1 diabetes the standardized observed monthly
applied a multivariable log- rates of ketoacidosis during the
onset estimated from the log-
binomial mixed-effects model with year 2020 ranged from 22.6%
binomial model is plotted
ketoacidosis as the dependent (95% CI, 18.4%–27.8%) in January
dependent on the incidence of
variable and the regional to 43.3% (95% CI, 37.5%–50.1%)
COVID-19 cases or COVID-
incidence rate of the COVID-19 in August (Table 2). Compared
19–related deaths.
pandemic as the exposure with the expected monthly
variable, adjusting for sex, age A 2-sided P valueTABLE 2 Observed Versus Expected Rates of Diabetic Ketoacidosis, Severe Ketoacidosis, and Impaired Consciousness at Diagnosis of Type 1 Diabetes
During the COVID-19 Pandemic in Germany From January 1 to June 30, 2020
Expected Rate for 2020 Based
Observed Rate in 2020 on Data From 2000 to 2019 Observed Versus Expected
Month (N 5 3238), % (95% CI)a (N 5 42 417), % (95% CI)b Rate, Adjusted RR (95% CI)c P
Diabetic ketoacidosis
January 22.6 (18.4–27.8) 20.1 (16.1–25.0) 1.13 (0.83–1.52) .44
February 30.5 (25.5–36.4) 22.9 (18.5–28.4) 1.33 (1.01–1.76) .05
March 28.1 (23.0–34.3) 24.8 (20.0–30.8) 1.13 (0.84–1.52) .41
April 41.1 (35.5–47.6) 20.9 (16.5–26.5) 1.96 (1.49–2.59)Downloaded from http://publications.aap.org/pediatrics/article-pdf/148/3/e2021050856/1194501/peds_2021050856.pdf by guest on 13 December 2021 FIGURE 2 RRs of diabetic ketoacidosis at diagnosis of type 1 diabetes during the COVID-19 pandemic year 2020 in Germany and in 5 regions of Germany. Adjusted RR for ketoacidosis in 2020 was estimated from observed and expected rates. Expected rates were derived from data of 2000–2019 by using a multivariable logistic trend regression model. The dark line describes the mean RR, and the vertical lines represent the corresponding 95% CI. ketoacidosis was 0.92 (95% CI, of the year 2020 (RR, 0.98 [95% pandemic in Germany. Our finding 0.87–0.98; P 5 .007) per increase CI, 0.93–1.03]; P 5 .42) (Fig 3D). of an increased risk of ketoacidosis in the 7-day incidence of COVID- during the COVID-19 pandemic is 19 cases by 50 U/100 000 potentially indicative of a delayed population (Fig 3C). In addition, DISCUSSION admission to health care and is the association between the 7-day With this study, we found a consistent with reports from incidence of COVID-19–related significant increase in the risks of different parts of the world.10,18,19 deaths and the corresponding diabetic ketoacidosis and severe rates of ketoacidosis at diagnosis diabetic ketoacidosis in children and At the time of the highest RR of of type 1 diabetes was not adolescents with new-onset type 1 ketoacidosis, the severity of the significant during the second half diabetes during the coronavirus pandemic also reached its peak with PEDIATRICS Volume 148, number 3, September 2021 213
Downloaded from http://publications.aap.org/pediatrics/article-pdf/148/3/e2021050856/1194501/peds_2021050856.pdf by guest on 13 December 2021 FIGURE 3 Predicted rate of diabetic ketoacidosis dependent on weekly incidence of COVID-19 cases and deaths. The predicted rate of diabetic ketoacidosis dependent on the weekly incidence of new COVID-19 cases (A, C) and COVID-19–related deaths (B, D) for the first half (A, B) and the second half (C, D) of the year 2020 are shown, based on a multivariable log-binomial mixed-effects model. The dark line describes the predicted rate of diabetic ketoacidosis, and the light area around it represents the corresponding 95% CI. the highest incidence of new COVID- health care and diagnosis during the study revealed that these 2 regions 19 cases and deaths.1,2 During COVID-19 pandemic because this showed the most pronounced March, however, nationwide would have implications for further increases in the rates of diabetic measures were also taken to contain measures during this pandemic, as ketoacidosis in the following the pandemic, such as restrictions well as for future pandemics or months. on social contacts, school closures, similar disasters. Although general and the general advice on staying at measures to contain the pandemic Our analysis could demonstrate that home (Supplemental Table 4). affected the whole country in a the regional COVID-19 incidences of Because of the temporal parallelism similar way, both the severity of the new cases and deaths during the of both, namely, the increase of the pandemic and its development over first wave of the pandemic were incidence of COVID-19 and time varied considerably between associated with the risk of pandemic containment measures, it different regions within Germany; ketoacidosis in children and is important to determine which the south and the west of Germany adolescents at diagnosis of type 1 factors could have affected the were particularly affected during diabetes. During the rapid spread of increase in diabetic ketoacidosis at March and April (Supplemental SARS-CoV-2, there was a significant diagnosis of diabetes type 1 and Information, Fig 2).2,20,21 It is decrease in the number of children thus the delay in admission to therefore not surprising that our presenting in the emergency 214 KAMRATH et al
department, resulting in a diagnostic Because of the low incidence of One strength of our study is that
delay.22 Because the development of COVID-19 cases and deaths during the we analyzed data across the entire
ketoacidosis is commonly caused by summer months but the persistently first year of the pandemic. Another
a delay in diagnosis in patients with high rates of ketoacidosis, the strength of the current study
type 1 diabetes,11–14 our study paradoxical result of an inverse includes the large sample size of a
suggests that the incidence level of association between COVID-19 population-based cohort.
the pandemic may be associated incidence and risk of ketoacidosis in Furthermore, for comparisons with
with a delayed use of health the second half of the year emerged. observed frequencies, the
services. We assume that a rapidly This indicates that the behavior of the estimates of the expected
increasing number of COVID-19 population adapts to the changing frequencies of diabetic
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cases and deaths could cause environmental parameters such as the ketoacidosis in 2020 were derived
anxiety and insecurity among the dynamic or severity of the pandemic from appropriate statistical
population.23–24 As a result, contact after a certain delay. After the methods, considering the observed
with the health care system would summer, the incidence of COVID-19 slight but significant increase in
be avoided as far as possible for fear increased again from October onward. the frequency of diabetic
of possible infection. It has been In contrast to the first wave, when ketoacidosis in children with new-
reported that the obvious concern there was a prompt increase in the onset type 1 diabetes over the past
about COVID-19 led to a decline in rate of ketoacidosis, this increase was 2 decades.29 Limitations of our
the use of life-saving evidence-based clearly delayed in the second wave. study include that the
treatments.25,26 Therefore, our study During the second wave of the multivariable logistic regression
suggests that an early onset and a pandemic, when a significantly higher models included only some
rapid increase in COVID-19 cases incidence of COVID-19 has been potential confounders of the
and especially in COVID-19–related documented by the authorities, there association between COVID-19
deaths might have led to a high level was a smaller increase in the observed incidence and diabetic
of uncertainty and fear among the to predicted rate of ketoacidosis ketoacidosis. Thus, residual
population, which could explain the compared with the first wave. Beside confounding due to both individual
increase in diabetic ketoacidosis. differences in COVID-19 test capacities patient-level and population-level
between the first and the second confounders cannot be excluded.
This study shows that the increased wave, this may indicate that the Potentially confounding factors
risk of ketoacidosis outlasted the behavior of the population in relation include socioeconomic status,
first pandemic wave and also the to health care use changed during the distance to health facility, family
first lockdown by several months. It pandemic in the form of a habituation members with COVID-19, or
can therefore be assumed that effect. regional differences in health
neither the lockdown nor an policy measures. In addition, we
overload of the health care system In a French registry study, researchers calculated associations without
was responsible for the increase in found a decrease in hospital admissions evidence of causality. Because we
the rate of ketoacidosis observed in for myocardial infarction after the have not assessed the individual
our study. From the findings that lockdown that was irrespective of the behavior of the patients’ families,
the higher observed versus expected regional prevalence of COVID-19.27 We we cannot prove whether our
rate of ketoacidosis continued have previously reported that the presumption that uncertainty and
through the summer, when COVID- number of children and adolescents concern caused by the pandemic
19 infection rates were stable at a with new-onset type 1 diabetes did not led to avoidance of health care and
low level, it can be hypothesized change during the lockdown from mid- thus an increase in observed
that public concern and fear had March to mid-May in Germany.28 In compared to expected rates of
persisted for a considerable time. It contrast to the association between the diabetic ketoacidosis is true.
was not until September and decrease in hospital admission and the Further research is needed to
October that there was a marked regional prevalence of COVID-19 in the understand the reasons for the
decrease in the observed compared French study, we investigated the increased rates of diabetic
with the expected rates of association between the frequency of ketoacidosis during the COVID-19
ketoacidosis. Thereafter, the risk of advanced disease as a measure of a pandemic.
ketoacidosis then rose again while delay in admission to health care and
the incidence of COVID-19 cases and the weekly regional incidence of COVID- CONCLUSIONS
deaths increased during the second 19, which better reflects the dynamics With this study, we found a
wave of the pandemic. of the pandemic. significant increase in the frequency
PEDIATRICS Volume 148, number 3, September 2021 215of ketoacidosis associated with the hospitals and medical care. Germany) for statistical advice. We
regional severity of the pandemic Information and education thank the Robert Koch Institute for
(ie, the incidence of COVID-19 cases campaigns must communicate that the public provision of the COVID-
and deaths). The increased risk of avoiding the use of health care can 19 statistics. We thank all centers
ketoacidosis has outlasted the first lead to significant harm that is participating in the DPV project (a
wave of the COVID-19 pandemic by disproportionately higher than the list is available in the Supplemental
several months. The measures taken negligible risk of contracting Information).
to contain the spread of the virus COVID-19.
were implemented nationwide, were
limited in time, and do not explain ACKNOWLEDGMENTS ABBREVIATIONS
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the regional differences and the
Special thanks are due to A. Hungele CI: confidence interval
prolonged time in the risk of
and R. Ranz for support and the COVID-19: coronavirus disease
ketoacidosis seen in our study.
development of the DPV documenta- 2019
Therefore, these nationwide health
tion software, K. Fink and E. Bollow DPV: Diabetes-Patienten-
policy measures do not appear to be
for the DPV data management (all Verlaufsdokumentation
the main reason for the significant
clinical data managers, Institute of IQR: interquartile range
increase in diabetic ketoacidosis at
Epidemiology and Medical Biometry, RR: relative risk
presentation nor for the delayed use
Ulm University, Ulm, Germany), and SARS-CoV-2: severe acute
of health care. Instead, it could be
respiratory
that concern caused by the Prof O. Kuss (Institute for Biomet-
syndrome
pandemic itself may have been a rics and Epidemiology, German Dia-
coronavirus 2
reason for avoiding contact with betes Centre, Leibniz Centre for
health care. It is therefore important Diabetes Research at Heinrich Heine
that people regain confidence in University Dusseldorf, Dusseldorf,
data collection, acquired funding for the study, and critically reviewed the manuscript for important intellectual content; Drs Pappa and Reschke, Prof
Rohrer, Drs M€onkem€oller, Wurm, and Hake, and Prof Raile collected data and critically reviewed the manuscript for important intellectual content; and all
authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.
A.J.E. and R.W.H. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Access to the data is possible by remote data processing after reasonable request.
DOI: https://doi.org/10.1542/peds.2021-050856
Accepted for publication May 13, 2021
Address correspondence to Clemens Kamrath, MD, Division of Pediatric Endocrinology and Diabetology, Centre of Child and Adolescent Medicine, Justus Liebig
University, Feulgenstrasse 12, 35385 Giessen, Germany. E-mail: clemens.kamrath@paediat.med.uni-giessen.de
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2021 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: The Diabetes-Patienten-Verlaufsdokumentation is supported through the German Federal Ministry for Education and Research within the German
Centre for Diabetes Research (grant 82DZD14A02). Further financial support was received by the German Robert Koch Institute and the German Diabetes
Association. This study was partly funded by the Deutsche Diabetes Stiftung (FP-0433-2020). The funding organization had no role in the design and conduct
of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; or decision to submit the
article for publication.
POTENTIAL CONFLICT OF INTEREST: Prof Raile is an advisory board member of Lilly Diabetes and Abbott Diabetes Care and reports paid talks for Sanofi,
Dexcom Continuous Glucose Monitoring, Novo Nordisk, and Springer Healthcare outside the submitted work. Dr M€onkem€oller received educational fees from
Medtronic outside the submitted work; the other authors have indicated they have no potential conflicts of interest to disclose.
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