Cochrane Library

1. [mh "Diabetic Ketoacidosis"]
2. [mh "Diabetic Coma"]
3. (("hyperglycaemic" or "hyperglycemic" or diabet*) next emergenc*):ti,ab,kw
4. (diabet* and (keto* or acidos* or "coma")):ti,ab,kw
5. "DKA":ti,ab,kw
6. {or #1‐#5}
7. [mh "Insulin Lispro"]
8. [mh "Insulin Aspart"]
9. [mh "Insulin, Short‐Acting"]
10. ("glulisine" or "apidra"):ti,ab,kw
11. ("humulin" or "novolin"):ti,ab,kw
12. ("lispro" or "aspart"):ti,ab,kw
13. ("novolog" or "novorapid"):ti,ab,kw
14. (insulin* near/4 analogue*):ti,ab,kw
15. (acting next insulin*):ti,ab,kw
16. {or #7‐#15}
17. #6 and #16

MEDLINE (Ovid SP)

1. Diabetic Ketoacidosis/
2. Diabetic Coma/
3. ((hyperglyc?emic or diabet*) adj emergenc*).tw.
4. (diabet* and (keto* or acidos* or coma)).tw.
5. DKA.tw.
6. or/1‐5
7. Insulin Lispro/
8. Insulin Aspart/
9. Insulin, Short‐Acting/
10. (glulisine or apidra).tw.
11. (humulin or novolin).tw.
12. (lispro or aspart).tw.
13. (novolog or novorapid).tw.
14. (insulin* adj3 analogue*).tw.
15. acting insulin*.tw.
16. or/7‐15
17. 6 and 16
18. exp animals/ not humans/
19. 17 not 18

PubMed

#1 (hyperglycemic emergenc*[tw] OR hyperglycaemic emergenc*[tw] OR diabetic emergenc*[tw] OR (diabet*[tw] AND (ketoac*[tw] OR acidos*[tw] OR coma[tw])) OR DKA[tw])

#2 (glulisine[tw] OR apidra[tw] OR humulin[tw] OR novolin[tw] OR lispro[tw] OR aspart[tw] OR novolog[tw] OR novorapid[tw] OR (insulin[tw] AND analog*[tw]) OR acting insulin*[tw])

#3 #1 AND #2

#4 #3 NOT medline[sb] NOT pmcbook

EMBASE (Ovid SP)

1. diabetic ketoacidosis/
2. diabetic coma/
3. ((hyperglyc?emic or diabet*) adj emergenc*).tw.
4. (diabet* and (keto* or acidos* or coma)).tw.
5. DKA.tw.
6. or/1‐5
7. insulin lispro/
8. insulin aspart/
9. insulin glulisine/
10. short acting insulin/
11. (glulisine or apidra).tw.
12. (humulin or novolin).tw.
13. (lispro or aspart).tw.
14. (novolog or novorapid).tw.
15. (insulin* adj3 analogue*).tw.
16. acting insulin*.tw.
17. or/7‐16
18. 6 and 17
[19: Wong et al. 2006 "sound treatment studies" filter – BS version]
19. random*.tw. or clinical trial*.mp. or exp health care quality/
20. 18 and 19
21. limit 20 to embase

LILACS (IAHx)

(MH: "Diabetic Ketoacidosis" OR MH: "Diabetic Coma" OR (diabet$ AND (keto$ OR acidos$ OR "coma"))) AND (MH: "Insulin Lispro" OR MH: "Insulin Aspart" OR MH: "Insulin, Short‐Acting" OR ("glulisine" OR "apidra") OR ("humulin" OR "novolin") OR ("lispro" OR "aspart") OR ("novolog" OR "novorapid") OR (insulin$ AND analogue$) OR (acting AND insulin$))
+ Filter "Controlled Clinical Trial"

CINAHL (Ebsco)

S1. MH "Diabetic Ketoacidosis"
S2. MH "Diabetic Coma"
S3. TI (("hyperglycaemic" OR "hyperglycemic" OR diabet*) N1 emergenc*) OR AB (("hyperglycaemic" OR "hyperglycemic" OR diabet*) N1 emergenc*)
S4. TI (diabet* AND (keto* OR acidos* OR "coma")) OR AB (diabet* AND (keto* OR acidos* OR "coma"))
S5. TI ("DKA") OR AB ("DKA")
S6. S1 OR S2 OR S3 OR S4 OR S5
S7. MH "Insulin Lispro"
S8. MH "Insulin Aspart"
S9. MH "Insulin, Short‐Acting"
S10. TI ("glulisine" OR "apidra") OR AB ("glulisine" OR "apidra")
S11. TI ("humulin" OR "novolin") OR AB ("humulin" OR "novolin")
S12. TI ("lispro" OR "aspart") OR AB ("lispro" OR "aspart")
S13. TI ("novolog" OR "novorapid") OR AB ("novolog" OR "novorapid")
S14. TI (insulin* N3 analogue*) OR AB (insulin* N3 analogue*)
S15. TI (acting N1 insulin*) OR AB (acting N1 insulin*)
S16. S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15
S17. S6 AND S16

ICTRP Search Portal

Standard search:
diabet* AND keto* AND lispro OR
diabet* AND acidos* AND lispro OR
diabet* AND coma AND lispro OR
diabet* AND keto* AND aspart OR
diabet* AND acidos* AND aspart OR
diabet* AND coma AND aspart OR
diabet* AND keto* AND acting insulin OR
diabet* AND acidos* AND acting insulin OR
diabet* AND coma AND acting insulin OR
diabet* AND keto* AND analogue* OR
diabet* AND acidos* AND analogue* OR
diabet* AND coma AND analogue* OR
diabet* AND keto* AND glulisine OR
diabet* AND acidos* AND glulisine OR
diabet* AND coma AND glulisine

ClinicalTrials.gov

Advanced Search
Search terms: ((diabetic OR diabetes) AND (ketoacidosis OR ketoacidoses OR acidosis OR acidoses OR ketosis OR ketoses OR coma)) AND (lispro OR aspart OR glulisine OR acting insulin OR apidra OR humulin OR novolin OR novolog OR novorapid OR analogue OR analogues)

Intervention(s)

Adequate^a intervention

(Yes/No)

Comparator(s)

Adequate^a comparator

(Yes/No)

Umpierrez 2004a

Subcutaneous insulin lispro every hour: initial injection of 0.3 units/kg followed by 0.1 unit/kg/h until blood glucose levels reached 250 mg/dL; the insulin dose was then reduced to 0.05 units/kg/h, and the intravenous fluids were changed to dextrose 5% in 0.45% normal saline to keep blood glucose at a level of about 200 mg/dL until resolution of DKA

Yes

Intravenous regular insulin: initial bolus of 0.1 units/kg, followed by a continuous infusion of 0.1 units/kg/h until blood glucose levels decreased to approx. 250 mg/dL; at this time, intravenous fluids were changed to dextrose‐containing solutions, and the insulin infusion rate was decreased to 0.05 units/kg/h until resolution of DKA

Yes

Umpierrez 2004b

I1: initial injection of 0.3 units/kg, followed by 0.1 units/kg/h until blood glucose reached 250 mg/dL; the insulin dose was then reduced to 0.05 units/kg/h, and the intravenous fluids were changed to dextrose 5%, 0.45 saline to maintain blood glucose at 200 mg/dL until resolution of DKA

Yes

Intravenous regular insulin: initial bolus of 0.1 units/kg, followed by a continuous infusion of regular insulin calculated to deliver 0.1 units/kg/h until blood glucose levels were 250 mg/dL; the insulin dose was then reduced to 0.05 units/kg/h, and the intravenous fluids were changed to dextrose 5%, 0.45 saline to maintain blood glucose at 200 mg/dL until resolution of DKA

Yes

I2: initial dose of 0.3 units/kg followed by 0.2 units/kg 1 h later and every 2 h until blood glucose reached 250 mg/dL; the insulin dose was then reduced to 0.1 units/kg every 2 h, and the intravenous fluids were changed to dextrose 5%, 0.45 saline to keep blood glucose at 200 mg/dL until resolution of DKA

Yes

Della Manna 2005

0.15 units/kg of a insulin lispro was administered subcutaneously every 2 h; when capillary blood glucose levels neared 249 mg/dL, 0.15 units/kg were administered every 4 h for the next 24 h

After approx. 12 h of intensive insulin administration, intermediate human insulin was initiated at a dosage of 0.4 unit/kg every 12 h

Yes

Regular insulin was infused with a syringe pump at a rate of 0.1 unit/kg/h from an independent intravenous line through a second catheter inserted into a peripheral vein. This infusion was continued until capillary blood glucose levels decreased to ≤ 249 mg/dL; thereafter, 0.15 units/kg regular insulin were given subcutaneously 30 min before stopping the intravenous line and every 4 h for the next 24 h

After approx. 12 h of intensive insulin administration, intermediate human insulin was initiated at a dosage of 0.4 unit/kg every 12 h

Yes

Ersöz 2006

Following a bolus injection of 0.15 units/kg i.v. regular insulin, group L received half of this dose as hourly s.c. insulin lispro. Insulin dose was titrated according to serum glucose and pH levels; if serum glucose did not fall by 50‐70 mg/dL in the first hour, insulin dose was planned to be doubled hourly until glucose fell by 50‐70 mg/dL

Yes

Following a bolus injection of 0.15 units/kg i.v. regular insulin, group R was treated conventionally with standard i.v. regular insulin infusion. Insulin dose was titrated according to serum glucose and pH levels; if serum glucose did not fall by 50‐70 mg/dL in the first hour, insulin dose was planned to be doubled hourly until glucose fell by 50‐70 mg/dL

Yes

Karoli 2011

Initial bolus of 0.3 units/kg followed by 0.2 units/kg 1 h later and then 0.2 units/kg every 2 h until blood glucose reached 250 mg/dL; the insulin dose was then reduced to 0.1 units/kg/h to keep blood glucose at approx. 200 mg/dL

Yes

Initial bolus of regular insulin 0.1 unit/kg i.v. followed by continuous infusion of regular insulin calculated to deliver 0.1 unit/kg/h until blood glucose levels decreased to approx. 250 mg/dL; the insulin infusion rate was then decreased to 0.05 units/kg/h until resolution of DKA, and intravenous fluids were changed to dextrose‐containing solutions (5% dextrose) to keep blood glucose level at approx. 200 mg/dL

Yes

^aThe term 'adequate' refers to sufficient use of the intervention/comparator with regard to dose, dose escalation, dosing scheme, provision for contraindications, and other features necessary to establish a fair contrast between intervention and comparator.

DKA: diabetic ketoacidosis; I: intervention

Intervention(s) and comparator(s)

Duration of intervention
(duration of follow‐up)
[days, months, years ...]

Description of participants

Trial period
[year to year]

Country

Setting

Ethnic groups
[%]

Duration of diabetes [mean/range years (SD), or as reported]

Umpierrez 2004a

I: s.c. insulin lispro

Resolution of DKA: mean 10 h

(mean hospital stay: 4 d)

Adults with "uncomplicated" DKA (not stated if type 1 or 2 diabetes)

‐

USA

Regional medical centre

DKA established in the ED

Regular medicine ward, intermediate care unit (step‐down unit)

African American: 75

6.7 (5)

C: i.v. regular insulin

Resolution of DKA: mean 11 h

(mean hospital stay: 4 d)

Regional medical centre

DKA established in the ED

ICU

African American: 80

6.9 (4)

Umpierrez 2004b

I1: s.c. insulin aspart, every hour

Resolution of DKA: mean 10 h

(mean hospital stay: 3.4 d)

Adults with "uncomplicated" DKA (not stated if type 1 or 2 diabetes)

‐

USA

Regional medical centre

DKA established in the ED

General medical ward or step‐down unit

‐

‐

I2: s.c. insulin aspart, every 2 h

Resolution of DKA: mean 10.7 h

(mean hospital stay: 3.9 d)

C: i.v. regular insulin

Resolution of DKA: mean 11 h

(mean hospital stay: 4.5 d)

Regional medical centre
DKA established in the ED

ICU

Della Manna 2005

I: s.c. insulin lispro

Resolution of metabolic acidosis/ketosis: "in the next 6 h interval" (later than after i.v. regular insulin)

Resolution of DKA: 12 h after capillary glucose < 250 mg/dL

(mean hospital stay 2‐3 d)

Children and adolescents with DKA

2001 to 2003

Brazil

University children's hospital, 57 DKA episodes treated in ED, 3 DKA episodes treated in ICU

‐

‐

C: i.v. regular insulin

Resolution of metabolic acidosis/ketosis: 6 h after capillary glucose ≤ 250 mg/dL

Resolution of DKA: 12 h after capillary glucose < 250 mg/dL

(mean hospital stay 2‐3 d)

Ersöz 2006

I: s.c. insulin lispro

Resolution of DKA: no data
(hospital stay: no data)

Adults with mild or moderate DKA (not stated if type 1 or 2 diabetes)

‐

Turkey

‐

‐

3.9 (4.5)

C: i.v. regular insulin

4.5 (4.3)

Karoli 2011

I: s.c. insulin lispro

Resolution of DKA: mean 12 h

(mean hospital stay 6 d)

Adults with mild to moderate DKA (> 50% of participants had type 2 diabetes)

2009 to 2010

India

Teaching hospital, ED

‐

6.4 (5)

C: i.v. regular insulin

Resolution of DKA: mean 11 h

(mean hospital stay 6.6 d)

Teaching hospital, ICU

6.8 (4)

‐ denotes not reported

C: comparator; d: days; DKA: diabetic ketoacidosis; ED: emergency department; h: hours; I: intervention; ICU: intensive care unit; i.v.: intravenous; s.c.: subcutaneous; SD: standard deviation

Intervention(s) and comparator(s)

Sex
[female %]

Glucose levels at admission
(mean mg/dL (SD))

Age
(mean years (SD))

HbA1c
(mean % (SD))

BMI
(mean kg/m² (SD))

Comedications / Cointerventions

Comorbidities

Umpierrez 2004a

I: s.c. insulin lispro

40

674 (154)

37 (12)

‐

26 (7)

‐

‐

C: i.v. regular insulin

35

611 (264)

39 (14)

‐

27 (9)

‐

‐

Umpierrez 2004b

I1: s.c. insulin aspart, every hour

27

787 (378)

36 (8)

11.5 (1.6)

27 (6)

‐

27% had an associated comorbid condition (leg abscess, pneumonia, urinary tract infection, pancreatitis)

I2: s.c. insulin aspart, every 2 h

33

758 (373)

38 (12)

11.4 (2)

29 (7)

‐

27% had an associated medical illness (cellulitis, urinary tract infection, olanzapine overdose, failure to take oral antidiabetic agent)

C: i.v. regular insulin

33

717 (239)

40 (13)

11.7 (2)

27 (7)

‐

27% had an associated medical illness (pneumonia, cellulitis, urinary tract infection, and tooth abscess)

Della Manna 2005

I: s.c. insulin lispro

68

434 (142)

11 (4)

‐

‐

‐

‐

C: i.v. regular insulin

76

434 (146)

12 (3)

‐

‐

‐

‐

Ersöz 2006

I: s.c. insulin lispro

50

512 (138)

39 (20)

13.9 (2.3)

‐

‐

Retinopathy/neuropathy/nephropathy/cardiovascular disease/cerebrovascular disease: 10%/10%/0%/10%/10%

C: i.v. regular insulin

60

556 (43)

49 (18)

11.6 (1.7)

‐

‐

Retinopathy/neuropathy/nephropathy/cardiovascular disease/cerebrovascular disease: 20%/20%/0%/30%/0%

Karoli 2011

I: s.c. insulin lispro

44

650 (113)

34 (13)

‐

25 (3)

‐

‐

C: i.v. regular insulin

36

679 (125)

35 (11)

‐

24 (2)

‐

‐

‐ denotes not reported

BMI: body mass index; C: comparator; HbA1c: glycosylated haemoglobin A1c; I: intervention; i.v.: intravenous; s.c.: subcutaneous; SD: standard deviation

Endpoints quoted in trial document(s)
(ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a

Study results posted in trial register, publications specified in trial register

Endpoints quoted in publication(s)^b,c

Endpoints quoted in abstract of publication(s)^b,c

Umpierrez 2004a

N/T

Primary outcome measure(s): response to medical therapy: the time required for resolution of hyperglycaemia and ketoacidosis, and the rate of hypoglycaemia during insulin infusion

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): levels of blood glucose, electrolytes, phosphorus, venous pH, beta‐hydroxybutyrate, free fatty acids, insulin; medical care data (site of admission and treatment in the hospital, amount of fluid and insulin administration, length of hospitalisation); deaths

Other outcome measure(s): duration of treatment until correction of hyperglycaemia and resolution of ketoacidosis, deaths, length of hospital stay, amount of insulin until resolution of diabetic ketoacidosis, rate of hypoglycaemia, hospitalisation charges

Umpierrez 2004b

N/T

Primary outcome measure(s): time to resolve ketoacidosis

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): levels of glucose, electrolytes, phosphorus, venous pH, beta‐hydroxybutyrate, free fatty acids, insulin; response to medical
therapy (time and amount of insulin required for resolution of hyperglycaemia and ketoacidosis and the number of hypoglycaemic events during therapy)

Other outcome measure(s): duration of treatment until resolution of hyperglycaemia and ketoacidosis, total length of hospitalisation, amount of insulin administration until resolution of hyperglycaemia and ketoacidosis, number of hypoglycaemic events

Della Manna 2005

N/T

Primary outcome measure(s): ‐

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): blood glucose, blood gas, beta‐hydroxybutyrate, electrolytes, phosphate, magnesium, urea nitrogen, creatinine, urine ketones; resolution of metabolic acidosis and ketosis, DKA recovery; (near) deaths, cerebral oedema; hypoglycaemic episodes

Other outcome measure(s): blood glucose, blood gas, beta‐hydroxybutyrate, electrolytes, metabolic acidosis and ketosis, DKA recovery

Ersöz 2006

N/T

Primary outcome measure(s): ‐

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): serum glucose, pH, beta‐hydroxybutyrate, electrolytes, urine ketone levels and urinary output, lipids; resolution of ketoacidosis, time elapsed until normalisation of the monitored parameters, total amount of insulin delivered until resolution of DKA; mortality, hypoglycaemic events

Other outcome measure(s): time needed for normalisation of serum glucose, beta‐hydroxybutyrate, blood pH and urine ketone levels; mortality, serious side effects

Karoli 2011

N/T

Primary outcome measure(s): ‐

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): blood glucose levels, resolution of DKA, response to therapy was assessed by time and amount of insulin required for resolution of hyperglycaemia and ketoacidosis, number of hypoglycaemic events; duration of hospital stay; deaths

Other outcome measure(s): response to therapy (duration of treatment and amount of insulin administered until resolution of hyperglycaemia and ketoacidosis, total length of hospital stay, and number of hypoglycaemic events); mortality

‐ denotes not reported

^aTrial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturers' websites, trial registers)
^bPublication(s) refers to trial information published in scientific journals (primary reference, duplicate publications, companion documents, or multiple reports of a primary study)
^cOther outcome measures refer to all outcomes not specified as primary or secondary outcome measures

DKA: diabetic ketoacidosis; EMA: European Medicines Agency; FDA: US Food and Drug Administration; N/T: no trial document available

Outcome

High risk of bias
(category A)^a

High risk of bias
(category D)^b

High risk of bias
(category E)^c

High risk of bias
(category G)^d

Umpierrez 2004a

N/A

N/A

N/A

N/A

N/A

Umpierrez 2004b

N/A

N/A

N/A

N/A

N/A

Della Manna 2005

Time to resolution of DKA

Yes

N/A

N/A

N/A

Ersöz 2006

Time to resolution of DKA

Yes

N/A

N/A

N/A

Karoli 2011

N/A

N/A

N/A

N/A

N/A

^aClear that outcome was measured and analysed; trial report states that outcome was analysed but reports only that result was not significant.
(Classification 'A', table 2, Kirkham 2010)
^bClear that outcome was measured and analysed; trial report states that outcome was analysed, but no results reported.
(Classification 'D', table 2, Kirkham 2010)
^cClear that outcome was measured but not necessarily analysed; judgement says likely to have been analysed but not reported because of non‐significant results.
(Classification 'E', table 2, Kirkham 2010)
^dUnclear whether the outcome was measured; not mentioned, but clinical judgement says likely to have been measured and analysed but not reported on the basis of non‐significant results.
(Classification 'G', table 2, Kirkham 2010)

DKA: diabetic ketoacidosis; N/A: not applicable; ORBIT: Outcome Reporting Bias In Trials

Resolution of diabetic ketoacidosis

All‐cause mortality

Morbidity

Patient satisfaction

HbA1c

Socioeconomic effects

Umpierrez 2004a

Serum bicarbonate level ≥ 18 mEq/L and venous pH > 7.30

N/D

N/I

N/I

N/I

Hospital stay in days and cost as data on hospital charges

Umpierrez 2004b

Serum bicarbonate level ≥ 18 mmol/L and venous pH > 7.30

N/D

N/I

N/I

N/I

Length of hospital stay in days

Della Manna 2005

Mentally alert and able to eat, serum bicarbonate > 15 mmol/L, venous pH > 7.30, anion gap < 16 mmol/L

N/D

Cerebral oedema

N/I

N/I

N/I

Ersöz 2006

Serum glucose < 200 mg/dL , serum bicarbonate level > 18 mmol/L, venous pH > 7.30, capillary hydroxybutyrate level < 0.6 mmol/L, and negative urine ketone

N/D

N/I

N/I

N/I

N/I

Karoli 2011

Serum bicarbonate level > 18 mmol/L and arterial pH > 7.30

N/D

Venous thrombosis, adult respiratory distress syndrome, hyperchloraemic acidosis

N/I

N/I

N/I

HbA1c: glycosylated haemoglobin A1c; N/D: not defined; N/I: not investigated

All hypoglycaemic events

Severe hypoglycaemia

Nocturnal hypoglycaemia

Severe/serious
adverse events

Umpierrez 2004a

≤ 60 mg/dL

N/I

N/I

N/I

Umpierrez 2004b

≤ 60 mg/dL

N/I

N/I

N/I

Della Manna 2005

< 60 mg/dL, described as "mild"

N/I

N/I

N/I

Ersöz 2006

N/D

N/I

N/I

N/D

Karoli 2011

< 60 mg/dL, described as "mild"

N/I

N/I

N/I

N/D: not defined; N/I: not investigated

Intervention(s) and comparator(s)

Participants included in analysis
[N]

Deaths
[N]

Deaths
[%]

Participants with at least one adverse event
[N]

Participants with at least one adverse event
[%]

Participants with at least one severe/serious adverse event
[N]

Participants with at least one severe/serious adverse event
[%]

Umpierrez 2004a

I: s.c. insulin lispro

20

0

0

‐

‐

‐

‐

C: i.v. regular insulin

20

0

0

‐

‐

‐

‐

Umpierrez 2004b

I1: s.c. insulin aspart, every hour

15

0

0

‐

‐

‐

‐

I2: s.c. insulin aspart, every 2 h

15

0

0

‐

‐

‐

‐

C: i.v. regular insulin

15

0

0

‐

‐

‐

‐

Della Manna 2005

I: s.c. insulin lispro

25

0

0

‐

‐

‐

‐

C: i.v. regular insulin

21

0

0

‐

‐

‐

‐

Ersöz 2006

I: s.c. insulin lispro

10

0

0

‐

‐

0

0

C: i.v. regular insulin

10

0

0

‐

‐

0

0

Karoli 2011

I: s.c. insulin lispro

25

0

0

‐

‐

‐

‐

C: i.v. regular insulin

25

0

0

‐

‐

‐

‐

‐ denotes not reported

C: comparator; I: intervention; i.v.: intravenous; s.c.: subcutaneous

Intervention(s) and comparator(s)

Participants included in analysis
[N]

Participants discontinuing trial due to an adverse event
[N]

Participants discontinuing trial due to an adverse event
[%]

Umpierrez 2004a

I: s.c. insulin lispro

20

0

0

C: i.v. regular insulin

20

0

0

Umpierrez 2004b

I1: s.c. insulin aspart, every hour

15

0

0

I2: s.c. insulin aspart, every 2 h

15

0

0

C: i.v. regular insulin

15

0

0

Della Manna 2005

I: s.c. insulin lispro

25

0

0

C: i.v. regular insulin

21

‐

‐

Ersöz 2006

I: s.c. insulin lispro

10

0

0

C: i.v. regular insulin

10

0

0

Karoli 2011

I: s.c. insulin lispro

25

0

0

C: i.v. regular insulin

25

0

0

‐ denotes not reported

C: comparator; I: intervention; i.v.: intravenous; s.c.: subcutaneous

Intervention(s) and comparator(s)

Participants included in analysis
[N]

Participants with hypoglycaemic episodes
[N]

Participants with hypoglycaemic episodes
[%]

Participants with nocturnal hypoglycaemic episodes
[N]

Participants with nocturnal hypoglycaemic episodes
[% participants]

Participants with severe/serious hypoglycaemic episodes
[N]

Participants with severe/serious hypoglycaemic episodes
[%]

Umpierrez 2004a

I: s.c. insulin lispro

20

1

5

‐

‐

‐

‐

C: i.v. regular insulin

20

1

5

‐

‐

‐

‐

Umpierrez 2004b

I1: s.c. insulin aspart, every hour

15

1

6.6

‐

‐

‐

‐

I2: s.c. insulin aspart, every 2 h

15

1

6.6

‐

‐

‐

‐

C: i.v. regular insulin

15

1

6.6

‐

‐

‐

‐

Della Manna 2005

I: s.c. insulin lispro

25

4

16

‐

‐

‐

‐

C: i.v. regular insulin

21

6

29

‐

‐

‐

‐

Ersöz 2006

I: s.c. insulin lispro

10

0

0

‐

‐

‐

‐

C: i.v. regular insulin

10

0

0

‐

‐

‐

‐

Karoli 2011

I: s.c. insulin lispro

25

1

4

‐

‐

‐

‐

C: i.v. regular insulin

25

2

8

‐

‐

‐

‐

‐ denotes not reported

C: comparator; I: intervention; i.v.: intravenous; s.c.: subcutaneous

'Summary of findings' tables outcome measures (for both insulin lispro and insulin aspart)

All‐cause mortality

Hypoglycaemic episodes

Morbidity

Adverse events other than hypoglycaemic episodes

Time to resolution of diabetic ketoacidosis

Patient satisfaction

Socioeconomic effects (length of hospital stay)

Trial limitations
(risk of bias)^a

Was random sequence generation used (i.e. no potential for selection bias)?

Unclear

Yes/unclear

N/A

N/I

Unclear

N/I

Yes/unclear

Was allocation concealment used (i.e. no potential for selection bias)?

Unclear

Unclear

Unclear

Unclear

Was there blinding of participants and personnel (i.e. no potential for performance bias)?

No

No (↓)

No (↓)

No (↓)

Was there blinding of outcome assessment (i.e. no potential for detection bias)?

Unclear

Unclear

Unclear

No (↓)

Was an objective outcome used?

Yes

Yes

Yes

Yes

Were more than 80% of participants enrolled in trials included in the analysis (i.e. no potential reporting bias)?^e

Yes

Yes

Yes

Yes

Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?

Yes

Yes

Unclear

Yes

No other biases reported (i.e. no potential for other bias)?

Yes

Yes

Yes

Yes

Did the trials end as scheduled (i.e. not stopped early)?

Yes

No

Yes

Yes

Inconsistency^b

Point estimates did not vary widely?

N/A

Yes^f

Yes^f

Yes^f

To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least 1 of the included studies' point estimate;
some: confidence intervals overlap, but not all overlap at least 1 point estimate; no: at least 1 outlier: where the confidence interval of some of the studies does not overlap with those of most included studies)?

N/A

Substantial^f

Substantial^f

Substantial^f

Was the direction of effect consistent?

Yes

Yes^f

No (↓)^f

Yes^f

What was the magnitude of statistical heterogeneity (as measured by I²): low (I² < 40%), moderate (I² 40% ‐ 60%), high (I² > 60%)?

N/A

Low^f

High (↓)^f

Low^f

Was the test for heterogeneity statistically significant (P < 0.1)?

N/A

Not statistically significant^f

Not statistically significant^f

Not statistically significant^f

Indirectness^a

Were the populations in the included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Were the interventions in the included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Was the included outcome not a surrogate outcome?

Yes

Yes

Yes

Yes

Was the outcome time frame sufficient?

Sufficient

Sufficient

Sufficient

Sufficient

Were the conclusions based on direct comparisons?

Yes

Yes

Yes

Yes

Imprecision^c

Was the confidence interval for the pooled estimate not consistent with benefit and harm?

N/A

No (↓)^f

No (↓)^f

No (↓)^f

What is the magnitude of the median sample size (high: 300 participants, intermediate: 100‐300 participants, low: < 100 participants)?^e

Intermediate^g

Intermediate^g

Low (↓)

Low (↓)

What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5‐10 studies, small: < 5 studies)?^e

Small (↓)

Small (↓)

Small (↓)

Small (↓)

Was the outcome a common event (e.g. occurs more than 1/100)?

N/A

Yes

N/A

N/A

Publication bias^d

Was a comprehensive search conducted?

Yes

Yes

Yes

Yes

Was grey literature searched?

No (↓)

No (↓)

No (↓)

No (↓)

Were no restrictions applied to study selection on the basis of language?

Yes

Yes

Yes

Yes

There was no industry influence on studies included in the review?

No (↓)

No (↓)

No (↓)

No (↓)

There was no evidence of funnel plot asymmetry?

N/A

Unclear

Unclear

Unclear

There was no discrepancy in findings between published and unpublished trials?

Unclear

Unclear

Unclear

Unclear

^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual trials
^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I²

^cWhen judging the width of the confidence interval, it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful
^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished trials
^eDepends on the context of the systematic review area

^fN/A for insulin aspart

^gLow for insulin aspart

(↓): key item for possible downgrading the quality of the evidence (GRADE) as shown in the footnotes of the 'Summary of findings' table(s)
GRADE: Grading of Recommendations Assessment, Development and Evaluation; N/A: not applicable; N/I: not investigated

Date trial author contacted

Date trial author replied

Trial author asked for additional information
[short summary]

Trial author provided data
[short summary]

Umpierrez 2004a

2 April 2015

No reply

N/A

N/A

Umpierrez 2004b

2 April 2015

No reply

N/A

N/A

Della Manna 2005

2 April 2015

No reply

N/A

N/A

Ersöz 2006

2 April 2015

No reply

N/A

N/A

Karoli 2011

2 April 2015

No reply

N/A

N/A

El Ebrashy 2010

2 April 2015

No reply

N/A

N/A

Baldwin 2009

2 April 2015

No reply

N/A

N/A

N/A: not applicable