First Author, Year (Reference No.) |
Duration of Study |
Total No. of Participants |
Mean Age, years |
% Female |
Mean Duration of Diabetes Mellitus, years |
SGLT-2 Inhibitor (Dose) or Exposure Group |
Comparator (Dose) |
Definition of DKA |
Randomized Controlled Trials |
Barnett, 2014 (12) |
104 weeks |
741 |
63.9 |
41.7 |
NR |
Empagliflozin (10 mg or 25 mg) |
Placebo |
Assessed through the reporting of adverse events up to 7 days after the last dose of the study drug; coded using MedDRA (https://www.meddra.org/) version 15.0 |
Bode, 2015 (13) |
52 weeks |
714 |
63.6 |
44.5 |
11.7 |
Canagliflozin (100 mg or 300 mg) |
Placebo |
Data on events were collected through nonsystematic assessment; coded using MedDRA versions 14.0 and 16.0 |
Roden, 2015 (14) |
76 weeks |
899 |
55.0 |
38.7 |
NR |
Empagliflozin (10 mg or 25 mg) |
Placebo/sitagliptin (100 mg) |
Assessed through the reporting of adverse events; coded using MedDRA version 16.0 |
Rosenstock, 2014 (15) |
52 weeks |
563 |
56.7 |
54.5 |
NR |
Empagliflozin (10 mg or 25 mg) |
Placebo |
Assessed through the reporting of adverse events up to 7 days after the last dose of the study drug; coded using MedDRA version 16.0 |
Tikkanen, 2015 (16) |
12 weeks |
823 |
60.2 |
39.9 |
NR |
Empagliflozin (10 mg or 25 mg) |
Placebo |
Assessed through the reporting of adverse events; coded using MedDRA version 15.0 |
Wilding, 2013 (17) |
52 weeks |
469 |
56.8 |
49.0 |
9.6 |
Canagliflozin (100 mg or 300 mg) |
Placebo |
Assessed through the reporting of adverse events; coded using MedDRA version 14.0 for week 26 and MedDRA version 15.0 for week 52 |
Zinman, 2015 (18) |
206 weeks |
7,020 |
63.1 |
28.5 |
NR |
Empagliflozin (10 mg or 25 mg) |
Placebo |
Assessed on the basis of adverse events that occurred during treatment or within 7 days after the last dose of the study drug; coded using MedDRA version 18.0 |
Perkovic, 2019 (19) |
245 weeks |
4,401 |
36.0 |
33.9 |
15.8 |
Canagliflozin (100 mg) |
Placebo |
All ketone-related events, adjudicated by an independent adjudication committed on the basis of clinical presentation and predefined biochemical parameters; coded using MedDRA version 21.0 |
Wiviott, 2019 (20) |
280 weeks |
17,160 |
63.9 |
37.4 |
10.5 |
Dapagliflozin (10 mg) |
Placebo |
Adjudicated by the TIMI Clinical Events Committee, who were unaware of treatment assignments; coded using MedDRA version 21.0 |
Neal, 2017 (21) |
52 weeks |
10,142 |
63.0 |
36.0 |
13.5 |
Canagliflozin (100–300 mg) |
Placebo |
Events adjudicated by the Baim Institute for Clinical Research (Boston, Massachusetts); coded using MedDRA version 19.1 |
McMurray, 2019 (22) |
127 weeks |
4,744 |
66.0 |
24.0 |
NR |
Dapagliflozin (5 mg or 10 mg) |
Placebo |
Independent, blinded DKA adjudication committee assessed all potential ketoacidosis events (definite or probable); coded using MedDRA version 22.0 |
Pollock, 2019 (23) |
24 weeks |
461 |
64.5 |
29.3 |
17.9 |
Dapagliflozin (10 mg) |
Placebo |
Assessed through the reporting of adverse events; coded using MedDRA version 21.0 |
Lavalle-González, 2013 (24) |
52 weeks |
1,284 |
55.4 |
52.9 |
6.9 |
Canagliflozin (100 mg or 300 mg) |
Placebo/sitagliptin (100 mg) |
Assessed through the reporting of adverse events; coded using MedDRA version 14.0 for week 26 and MedDRA version 15.0 for week 52 |
Frías, 2016 (25) |
28 weeks |
685 |
54.2 |
52.1 |
7.4 |
Dapagliflozin (10 mg) |
Exenatide (2 mg) |
Assessed through the reporting of adverse events; coded using MedDRA version 20.1 |
Hollander, 2018 (26) |
52 weeks |
1,325 |
58.2 |
51.5 |
7.5 |
Ertugliflozin (5 mg or 15 mg) |
Glimepiride |
Assessed through the reporting of adverse events; coded using MedDRA version 20.0 |
Gallo, 2019 (27) |
104 weeks |
621 |
56.6 |
53.6 |
7.9 |
Ertugliflozin (5 mg or 15 mg) |
Placebo/glimepiride |
Potential cases of ketoacidosis were reviewed by a blinded internal case review committee; coded using MedDRA version 20.0 |
Pratley, 2018 (28) |
52 weeks |
1,232 |
55.1 |
46.1 |
6.9 |
Ertugliflozin (5 mg or 15 mg) |
Sitagliptin (100 mg) |
Assessed through the reporting of adverse events; coded using MedDRA version 19.0 |
Haering, 2015 (29) |
76 weeks |
666 |
57.1 |
49.1 |
NR |
Metformin + sulfonylureas + empagliflozin (10 mg or 25 mg) |
Metformin + sulfonylureas |
Assessed through the reporting of adverse events; coded using MedDRA version 16.0 |
Observational Studies |
Fralick, 2017 (30)a |
180 days |
76,090 |
54.6 |
47.3 |
NR |
New users of SGLT-2 inhibitors between April 1, 2013, and December 31, 2014 |
New users of DPP-4 inhibitors between April 1, 2013, and December 31, 2014 |
Hospitalization for DKA (using the primary position ICD-9 code) within 180 days after drug initiation |
Kim, 2018 (31)a |
3.5 years |
112,650 |
53.2 |
44.8 |
NR |
New use of SGLT-2 inhibitors, from 2014 to 2017, with no use in the prior 365 days |
New use of DPP-4 inhibitors, from 2014 to 2017, with no use in the prior 365 days |
Hospitalization for DKA |
Hamblin, 2019 (32)b |
26 months |
162 |
64.8 |
41.9 |
≤NR |
Users of SGLT-2 inhibitors |
Nonusers of SGLT-2 inhibitors |
Emergency department visit with DKA or development of DKA during hospital admission using the Australian modification of the ICD-10 (codes E1010, E1012, E1015, E1016, E1111, E1112, E1115, E1116, E1311, E1312, E1411, and E1412); then verified by study physicians to confirm that DKA was present as defined by the ADA criteria (blood pH < 7.30, bicarbonate concentration ≤ 18 mmol/L, and elevated ketone levels). Euglycemic DKA was defined as blood glucose concentration < 250 mg/dL (<14 mmol/L). |
McGurnaghan, 2019 (33) |
12 years |
238,876 |
65.8 |
43.5 |
9.0 |
Any initiation of dapagliflozin between November 2012 and 2016 |
No prescription for dapagliflozin from 2004 to 2016 |
DKA events were captured using linkage to national hospitalization records and death data; ICD-10 codes were used for cause of admission (code E10.0 or E10.1) |
Ueda, 2018 (34)a |
3.5 years |
34,426 |
61.0 |
39.0 |
NR |
First prescription for an SGLT-2 inhibitor during the study period, without any previous use |
First prescription for GLP-1 receptor agonists during the study period, without any previous use |
Any hospital admission using ICD-10 codes (Sweden: codes E110A and E111A; Denmark: codes E111, E131, and E141) |
Wang, 2017 (35)a |
18 months |
60,196 |
53.8 |
NR |
NR |
First prescription for SGLT-2 inhibitors with no use in at least the prior 12 months |
First prescription for sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, thiazolidinedione, insulin, and other miscellaneous antidiabetic agents with no use in at least the prior 12 months |
DKA ascertained by hospital or emergency room diagnosis |
Wang, 2019 (36)a |
Approximately 4–4.5 years |
739,993 |
56.4 |
47.1 |
NR |
New prescription dispensing record for SGLT-2 inhibitors, without prior use of the respective AHA ever recorded in the database |
New prescription dispensing record for an insulinotropic AHA (DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas, meglitinides) without prior use of the respective AHA ever being recorded in the database |
DKA event that occurred after the index date of an AHA therapy, identified from a diagnosis code recorded in inpatient or emergency room claims. To be considered an incident event, DKA occurring after exposure to a new AHA had to occur ≥30 days after any preindex DKA event. |
Douros, 2020 (37)a |
5 years |
417,514 |
63.9 |
41.5 |
NR |
New user of an SGLT-2 inhibitor, alone or in combination with other antidiabetic drugs, between 2013 and 2018 |
New users of DPP-4 inhibitors from 2013 to 2018, with no use in the prior 365 days |
Hospitalization with a primary diagnosis of DKA or an emergency department visit using ICD-10 (Canadian adaptation) diagnostic codes E11.10, E11.12, E13.10, E13.12, E14.10, and E14.12 (or E11.1, E13.1, and E14.1 in the CPRD). |