Diabetic ketoacidosis (DKA) is a diabetes emergency associated with high morbidity in patients with diabetes (1). In patients with type 1 diabetes, DKA can occur at new onset of diabetes but can also recur due to lack of insulin use and precipitating causes such as infection. DKA is a hallmark of type 1 diabetes; however, DKA is increasingly recognized in patients with type 2 diabetes (2). In contrast to patients with type 1 diabetes who require life-long insulin therapy, most patients with type 2 diabetes who present with DKA can recover insulin secretion and maintain glycemic control with oral antidiabetes medications (3). While inpatient mortality rates for DKA are generally very low, <1% in the U.K. (4) and in the U.S. (5), DKA is the leading cause of mortality among children and young adults with type 1 diabetes, accounting for ∼50% of all deaths in this population (1). In addition, rates vary substantially based on health care setting; a recent analysis conducted in India reported that up to 30% of hospitalized DKA cases result in inpatient death (6).

The article by Zhong et al. (7) in this issue of Diabetes Care examines temporal trends of DKA according to the diagnosis of type 1 and type 2 diabetes between the years 1998 and 2013 in the U.K. This report used the Clinical Practice Research Datalink and the Hospital Episode Statistics databases. Overall, the authors found that hospitalizations for DKA increased in the U.K. for patients with both type 1 and type 2 diabetes. Most cases of DKA were associated with type 1 diabetes, but one in five cases of DKA were associated with a patient history of type 2 diabetes. For patients with type 1 diabetes, DKA admissions increased from 1998 to 2007 and then the rate stabilized from 2007 to 2013. The incidence in 2013 was 1.5 times higher (1.53) than in 1998 and higher than that for patients with type 2 diabetes. The incidence was highest for patients between the ages of 18 and 24 years with short duration of diabetes (<1 year). Incidence of DKA increased in men, patients with diabetes duration of <1 year or >20 years, and patients >35 years of age. Length of stay decreased over time without a change in 30-day readmission. In patients with type 2 diabetes, the incidence of hospitalization was lower than that in patients with type 1 diabetes but with an annual increase of 4.2% between 1998 and 2013. The incidence was highest in patients using insulin with <1 year or ≥10 years of diabetes and in young adults. Despite the increased hospitalizations, there were no changes in mortality or differences in mortality between patients with type 1 diabetes and those with type 2 diabetes.

The rise in hospitalization for DKA in the U.K. is similar to the trends observed in the U.S. and other countries. The Centers for Disease Control and Prevention reported that age-adjusted hospitalizations for DKA decreased 1.1% per year from 2000 to 2009 but increased 6.3% per year from 2009 to 2014 (8). A long-term observational cohort study in patients with type 1 diabetes in the U.S. (T1D Exchange) reported an incidence rate of DKA of ∼20 cases/1,000 patient-years at the 12-year follow-up (9). Several epidemiological studies have reported that hospitalizations for DKA have increased worldwide (10,11) (Table 1). A recent systematic review (12) reported worldwide incidence rates in patients with type 1 diabetes ranging between 8 and 51.3 cases/1,000 patient-years. In a Chinese study (13), a much higher incidence rate was reported (263/1,000 patient-years), which the investigators attributed, at least in part, to differences in national health care systems with limited access to routine health care for patients with type 1 diabetes as well as infrequent self-monitoring of blood glucose by patients (12). In some countries, such as Taiwan and Italy, hospitalization for DKA has been decreasing (10,14).

The reasons for increasing hospitalizations for DKA are unknown. This finding may in part be explained by the number of adults and children presenting with DKA at initial diagnosis of diabetes. Worldwide, 12.8–80% of patients present with DKA as the initial presentation of diabetes (15). Although the exact number of patients with type 2 diabetes who present with DKA is unknown, it is possible that the number of patients with ketosis-prone diabetes has increased. Ethnic minorities usually present with ketosis-prone diabetes, and the incidence of diabetes has been rising in these populations. Although the report by Zhong et al. (7) did not specify which of the hospitalizations were DKA at diagnosis of diabetes, the rates of DKA increased even when data were analyzed only including the first DKA hospitalization. Further, hospitalizations for DKA have increased mostly in younger patients with a short duration of diabetes for both type 1 and type 2 diabetes, suggesting that more patients are presenting with DKA at the time of diagnosis. It is also possible that DKA is underrecognized in adults. According to the T1D Exchange registry, 78% of patients presenting with type 1 diabetes at age >18 years have a detectable C-peptide level (16). This can possibly lead to misdiagnosis of type 1 diabetes and lack of awareness of DKA symptoms until presentation with DKA.

In the report by Zhong et al. (7), recurrent DKA accounted for a significant portion of the hospitalizations; 65.72% for type 1 diabetes and 35.28% for type 2 diabetes. Recurrent DKA is associated with increased mortality in both the U.S. and the U.K. (4,17). A possible explanation for this increase could be admissions for mild DKA. In 2001, the American Diabetes Association expanded the definition of DKA to include mild DKA (18). The rise in DKA hospitalizations was observed starting in 2004. Although there is no biochemical data in the study by Zhong et al., it is possible that the rise in DKA could be due to presentation with mild DKA, especially since the length of stay has decreased without change in mortality. An important component in prevention of readmissions is appropriate education after the initial hospital discharge. A survey of U.K. hospitals in 2014 performed after the institution of new guidelines for treatment of DKA noted a shortage of staff needed for patient education (19). This could lead to improper insulin administration and poor recognition of symptoms of DKA with an increase in recurrent episodes.

The study by Zhong et al. (7) and previous reports (Table 1) highlight the need to have targeted programs to prevent DKA at new onset of diabetes and recurrent episodes of DKA in adults. Strategies such as early screening, close follow-up of high-risk children, and education of parents and communities have been successful in prevention of DKA at onset of diabetes. In The Environmental Determinants of Diabetes in the Young (TEDDY) study, there was a lower incidence of DKA at diagnosis when parents were made aware of the high risk of diabetes in their children (20). Similarly, in the Diabetes Autoimmunity Study in the Young (DAISY), close follow-up of high-risk children in the prediabetes stage reduced hospitalizations for DKA at diagnosis (21). In Italy, a prevention program aimed at education of parents, pediatricians, and personnel at primary and secondary schools to recognize symptoms of DKA significantly decreased the number of children presenting with DKA at initial diagnosis of diabetes (22).

Strategies for prevention of recurrent episodes of DKA include more intensive care coordination with patient and family engagement. The Novel Interventions in Children’s Healthcare is a comprehensive program that includes care coordination with family while incorporating telemedicine to engage youth with multiple hospitalizations for DKA (23). This program showed that daily communication through text messages and other forms of telecommunication decreased DKA readmissions in adolescents (23). Similar programs targeted toward adults need to be instituted to prevent recurrent episodes. Incorporating new technology such as real-time continuous glucose monitoring and insulin pumps could be useful for prevention of recurrent DKA episodes. Recent studies showed that use of real-time continuous glucose monitoring decreased DKA incidence in both children and adults (2426). Further, newer insulin analogs with long half-life such as insulin degludec or glargine U300, which facilitate management by allowing for variable timing of insulin dose, are currently being investigated for prevention of recurrent DKA in patients with type 1 diabetes (NCT03001323, ClinicalTrials.gov). Future studies should adapt successful strategies in the pediatric population to the adult population to prevent both DKA at diagnosis and recurrent episodes and to reduce the increasing rate of DKA hospitalizations.

See accompanying article, p. 1870.

Funding. P.V. is supported in part by National Institutes of Health grant K12HD085850. G.E.U. is supported in part by the National Institutes of Health National Center for Advancing Translational Sciences (grant UL1TR000454) and the National Institutes of Health and National Center for Research Resources (grant 1P30DK111024-01).

Duality of Interest. P.V. has received consultant fees from Boehringer Ingelheim. G.E.U. has received unrestricted research support for inpatient studies (to Emory University) from Merck, Novo Nordisk, AstraZeneca, and Sanofi. No other potential conflicts of interest relevant to this article were reported.

1.
Umpierrez
G
,
Korytkowski
M
.
Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia
.
Nat Rev Endocrinol
2016
;
12
:
222
232
[PubMed]
2.
Newton
CA
,
Raskin
P
.
Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences
.
Arch Intern Med
2004
;
164
:
1925
1931
[PubMed]
3.
Vellanki
P
,
Umpierrez
GE
.
Diabetic ketoacidosis: a common debut of diabetes among African Americans with type 2 diabetes
.
Endocr Pract
2017
;
23
:
971
978
4.
Gibb
FW
,
Teoh
WL
,
Graham
J
,
Lockman
KA
.
Risk of death following admission to a UK hospital with diabetic ketoacidosis
.
Diabetologia
2016
;
59
:
2082
2087
[PubMed]
5.
Kitabchi
AE
,
Umpierrez
GE
,
Miles
JM
,
Fisher
JN
.
Hyperglycemic crises in adult patients with diabetes
.
Diabetes Care
2009
;
32
:
1335
1343
[PubMed]
6.
Agarwal
A
,
Yadav
A
,
Gutch
M
, et al
.
Prognostic factors in patients hospitalized with diabetic ketoacidosis
.
Endocrinol Metab (Seoul)
2016
;
31
:
424
432
[PubMed]
7.
Zhong
VW
,
Juhaeri
J
,
Mayer-Davis
EJ
.
Trends in hospital admission for diabetic ketoacidosis in adults with type 1 and type 2 diabetes in England, 1998–2013: a retrospective cohort study
.
Diabetes Care
2018
;
41
:
1870
1877
[PubMed]
8.
Benoit
SR
,
Zhang
Y
,
Geiss
LS
,
Gregg
EW
,
Albright
A
.
Trends in diabetic ketoacidosis hospitalizations and in-hospital mortality - United States, 2000-2014
.
MMWR Morb Mortal Wkly Rep
2018
;
67
:
362
365
[PubMed]
9.
Weinstock
RS
,
Xing
D
,
Maahs
DM
, et al.;
T1D Exchange Clinic Network
.
Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange clinic registry
.
J Clin Endocrinol Metab
2013
;
98
:
3411
3419
10.
Liu
CC
,
Chen
KR
,
Chen
HF
,
Huang
HL
,
Ko
MC
,
Li
CY
.
Trends in hospitalization for diabetic ketoacidosis in diabetic patients in Taiwan: analysis of national claims data, 1997-2005
.
J Formos Med Assoc
2010
;
109
:
725
734
11.
Venkatesh
B
,
Pilcher
D
,
Prins
J
,
Bellomo
R
,
Morgan
TJ
,
Bailey
M
.
Incidence and outcome of adults with diabetic ketoacidosis admitted to ICUs in Australia and New Zealand
.
Crit Care
2015
;
19
:
451
[PubMed]
12.
Fazeli Farsani
S
,
Brodovicz
K
,
Soleymanlou
N
,
Marquard
J
,
Wissinger
E
,
Maiese
BA
.
Incidence and prevalence of diabetic ketoacidosis (DKA) among adults with type 1 diabetes mellitus (T1D): a systematic literature review
.
BMJ Open
2017
;
7
:
e016587
[PubMed]
13.
Li
J
,
Yang
D
,
Yan
J
,
Huang
B
,
Zhang
Y
,
Weng
J
;
Guangdong Type 1 Diabetes Translational Study Group
.
Secondary diabetic ketoacidosis and severe hypoglycaemia in patients with established type 1 diabetes mellitus in China: a multicentre registration study
.
Diabetes Metab Res Rev
2014
;
30
:
497
504
[PubMed]
14.
Lombardo
F
,
Maggini
M
,
Gruden
G
,
Bruno
G
.
Temporal trend in hospitalizations for acute diabetic complications: a nationwide study, Italy, 2001-2010
.
PLoS One
2013
;
8
:
e63675
[PubMed]
15.
Jefferies
CA
,
Nakhla
M
,
Derraik
JG
,
Gunn
AJ
,
Daneman
D
,
Cutfield
WS
.
Preventing diabetic ketoacidosis
.
Pediatr Clin North Am
2015
;
62
:
857
871
[PubMed]
16.
Davis
AK
,
DuBose
SN
,
Haller
MJ
, et al;
T1D Exchange Clinic Network
.
Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes
.
Diabetes Care
2015
;
38
:
476
481
[PubMed]
17.
Mays
JA
,
Jackson
KL
,
Derby
TA
, et al
.
An evaluation of recurrent diabetic ketoacidosis, fragmentation of care, and mortality across Chicago, Illinois
.
Diabetes Care
2016
;
39
:
1671
1676
[PubMed]
18.
American Diabetes Association
.
Hyperglycemic crises in patients with diabetes mellitus
.
Diabetes Care
2001
;
24
:
154
161
[PubMed]
19.
Dhatariya
KK
,
Nunney
I
,
Higgins
K
,
Sampson
MJ
,
Iceton
G
.
National survey of the management of diabetic ketoacidosis (DKA) in the UK in 2014
.
Diabet Med
2016
;
33
:
252
260
[PubMed]
20.
Elding Larsson
H
,
Vehik
K
,
Bell
R
, et al.;
TEDDY Study Group
;
SEARCH Study Group
;
Swediabkids Study Group
;
DPV Study Group
;
Finnish Diabetes Registry Study Group
.
Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up
.
Diabetes Care
2011
;
34
:
2347
2352
[PubMed]
21.
Barker
JM
,
Goehrig
SH
,
Barriga
K
, et al.;
DAISY study
.
Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up
.
Diabetes Care
2004
;
27
:
1399
1404
[PubMed]
22.
Vanelli
M
,
Chiari
G
,
Ghizzoni
L
,
Costi
G
,
Giacalone
T
,
Chiarelli
F
.
Effectiveness of a prevention program for diabetic ketoacidosis in children. An 8-year study in schools and private practices
.
Diabetes Care
1999
;
22
:
7
9
[PubMed]
23.
Wagner
DV
,
Barry
SA
,
Stoeckel
M
,
Teplitsky
L
,
Harris
MA
.
NICH at its best for diabetes at its worst: texting teens and their caregivers for better outcomes
.
J Diabetes Sci Technol
2017
;
11
:
468
475
[PubMed]
24.
Wong
JC
,
Foster
NC
,
Maahs
DM
, et al.;
T1D Exchange Clinic Network
.
Real-time continuous glucose monitoring among participants in the T1D Exchange clinic registry
.
Diabetes Care
2014
;
37
:
2702
2709
[PubMed]
25.
Charleer
S
,
Mathieu
C
,
Nobels
F
, et al
.
Effect of continuous glucose monitoring on glycemic control, acute admissions, and quality of life: a real-world study
.
J Clin Endocrinol Metab
2018
;
103
:
1224
1232
26.
Parkin
CG
,
Graham
C
,
Smolskis
J
.
Continuous glucose monitoring use in type 1 diabetes: longitudinal analysis demonstrates meaningful improvements in HbA1c and reductions in health care utilization
.
J Diabetes Sci Technol
2017
;
11
:
522
528
[PubMed]
27.
Abdulrahman
GO
,
Amphlett
B
,
Okosieme
OE
.
Trends in hospital admissions with diabetic ketoacidosis in Wales, 1999-2010
.
Diabetes Res Clin Pract
2013
;
100
:
e7
e10
[PubMed]
28.
Henriksen
OM
,
Røder
ME
,
Prahl
JB
,
Svendsen
OL
.
Diabetic ketoacidosis in Denmark: incidence and mortality estimated from public health registries
.
Diabetes Res Clin Pract
2007
;
76
:
51
56
[PubMed]
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