The document summarizes studies on the use of SGLT2 inhibitors in patients with type 1 diabetes. A 18-week study of canagliflozin in 351 patients with type 1 diabetes found reductions in HbA1c of 0.29% and 0.25% for the 100mg and 300mg doses respectively, along with weight reductions of 2.8kg and 4.4kg. Insulin doses were also reduced. Hypoglycemia rates were similar between groups. A study of sotagliflozin found reductions of 0.46% in HbA1c, 2.98kg in weight, 3.5mmHg in blood pressure, and 5.25 units in insulin dose. Two larger

7. 12 AÑOS CUIDANDO, COMUNICANDO E INVESTIGANDO EN DIABETES
HDDHOSPITAL DE DIA DE DIABETES
HUV.MACARENA
R16E N D O C R I N O

10. @cristobMorales
TRABAJO EN EQUIPO
ADMINISTRACION
PACIENTE
MEDICOSASISTENCIALESUNIDADESINVESTIGACION

13. @CristobMorales
CONTROLANDO
LA DM1
HASTA LA
FINAL

14. ¿Estamos
solos en DM1?
@CristobMorales

15. @CristobMorales

17. 23% 22%
17%
14%
30% 29%
0
20
40
60
80
100
<6 6–<13 13–<18 18–<26 26–<50 ≥50
SubjectsreachinggoalHbA1c(%)
Age (years)
HbA1c goal <7.0%HbA1c goal <7.5%
Solo un pequeño porcentaje de pacientes
con DM1 consiguen objetivos de A1c
Miller KM et al. Diabetes Care 2015;38:971.

18. Therapy advances have NOT prevented HbA1c rise
*≤2 years old and ≥80 years old are pooled. Participants required to be in both cohorts with ≥3 years diabetes duration in
2010–2012.; Foster N et al. ADA 2018; 1689-P
7.0
0 10 20 30 40 50 60 70 80
7.5
8.0
8.5
9.0
9.5
Age (years)*
MeanHbA1c(%)
2010–2012
Current

19. K
g
¿NECESITAMOS NUEVOS TRATAMIENTOS EN DM1?
TERAPIAS ORALESSOLO INSULINA
TECNOLOGIA INMUNOMODULACION
@cristobMorales

21. JAMACardiology2017:21:doi:10.1001/jamacardio.2017.1891
iSGLT2
CellMetabolism2013:17;http://dx.doi.org/10.1016/j.cmet.2013.04.008
arGLP1
Propiedades anti-ateromatosas (mejora la función endotelial,
disminuye la placa ateromatosa y la inflamación) +
cardioprotección frente a isquemia
Beneficio en pacientes con insuficiencia cardíaca
(efecto diurético + cambios hemodinámicos)
Disminución del daño renal (albuminuria)
Acción tardía = efectos sobre ateromatosisAcción temprana = cambios hemodinámicos
@cristob.morales

24. MACE

25. MARE

26. 1998
Efecto JordiHurtado
2018
@CristobMorales

28. @CristobMorales
iSGLT2 Y GLP1 HAN
SUBIDO A LOS ALTARES

29. ↓ Mortalidad CV
↓ Hospitalización IC
Y en DM1 PA CUANDO?
SGLT2 fármaco multi-TAREA en DM2
CV, cardiovascular; HF, heart failure
Zinman B et al. N Engl J Med 2015;373:2117 & supplementary appendix; Wanner C et al. N Engl J Med 2016;375:323; Frampton, JE. Drugs 2018; 78:1037. epub
↓ Nuevo o empeoramiento
Enf Renal Diabetica
↓ A1c
↓ Presión Arterial
↓ Peso

30. #SGLT2inDM1
@CristobMorales
CANA
SOTA
EMPA
DAPA

37. -0,42 %
-0,45 %

39. -8,80 %
-13,17 %

40. -2,5 Kg
-3,2 Kg

48. #SGLT2inDM1
@CristobMorales
CANA
SOTA
EMPA
DAPA

49. Henry R et al. Diabetes Care. 2015 Oct 20.

50. Diseño del estudio
• EC F2, doble ciego, aleatorizado, controlado con placebo, de 18
semanas de duración y que incluyó a 351 pacientes con DM1 tratados
con canagliflozina 100, 300 mg o placebo.
• Tratamiento previo: insulina, en tratamiento estable (MDI o CSII).
• PARA EVITAR HIPOGLUCEMIAS:
• Si partían de A1C ≤8% se les redujo la dosis de insulina basal un 20%, y a los >8%, se les redujo un
10%.
Henry R et al. Diabetes Care. 2015 Oct 20.
Objetivo primario
• Porcentaje de pacientes que conseguía reducir su A1C ≥0,4% sin
ver aumentado su peso al mismo tiempo.

51. Henry R et al. Diabetes Care. 2015 Oct 20.

52. Resultados A1c
Henry R et al. Diabetes Care. 2015 Oct 20.
Figure 1—Proportion of patients with HbA1c reduction$0.4% ($4.4mmol/mol) from baseline and no weight gain (A), change from baseline in HbA1c
(B), percentage change from baseline in body weight (C), change from baseline in FPG (D), and change from baseline in insulin dose at week 18 (E).
Data are LS mean change 6 SE from baseline unless otherwise indicated. Statistical testing of comparisons of canagliflozin versus placebo was not
performed (not prespecified) for end points other than the primary end point. *P ,0.001 vs. placebo. †Total baseline insulin dose is the sum of the
baseline basal and the baseline bolus insulin dose. ‡Baseline basal insulin dose is the total daily dose of basal insulin after downtitration before day 1.
§Baseline bolus insulin dose is the mean of the total bolus insulin doses per day before day 1 during week 21.
-0,29 %
-0,25 %

53. Resultados Peso
Henry R et al. Diabetes Care. 2015 Oct 20.
Figure 1—Proportion of patients with HbA1c reduction$0.4% ($4.4mmol/mol) from baseline and no weight gain (A), change from baseline in HbA1c
(B), percentage change from baseline in body weight (C), change from baseline in FPG (D), and change from baseline in insulin dose at week 18 (E).
Data are LS mean change 6 SE from baseline unless otherwise indicated. Statistical testing of comparisons of canagliflozin versus placebo was not
performed (not prespecified) for end points other than the primary end point. *P ,0.001 vs. placebo. †Total baseline insulin dose is the sum of the
baseline basal and the baseline bolus insulin dose. ‡Baseline basal insulin dose is the total daily dose of basal insulin after downtitration before day 1.
§Baseline bolus insulin dose is the mean of the total bolus insulin doses per day before day 1 during week 21.
-2,8 Kg
-4,4 Kg

54. Resultados Dosis de Insulina
Henry R et al. Diabetes Care. 2015 Oct 20.
Reducción de la insulina total en -8,9% con cana 100 mg y de -12,9% con cana 300 mg.
Figura E pertenecientes a la figura 1 del estudio
-4,1 UI
-7,6 UI

55. Efectos
adversos
• En relación a las
hipoglucemias, las
tasas fueron
similares entre
grupos (96,6%,
98,3% y 99,1% con
placebo, cana 100 y
cana 300 mg
Henry R et al. Diabetes Care. 2015 Oct 20.

57. #SGLT2inDM1
@CristobMorales
CANA
SOTA
EMPA
DAPA

59. SOTAGLIFLOZIN
First in class Dual SGLT2 and SGLT1 Inhibitor

62. TANDEM-3

63. TANDEM-3

64. TANDEM-3

65. TANDEM-3
-0,46 %

66. TANDEM-3
-2,98 Kg

67. TANDEM-3
-3,5 mm Hg

68. TANDEM-3
-5,25 UI

70. #SGLT2inDM1
@CristobMorales
CANA
SOTA
EMPA
DAPA

71. Rosenstock J, et al. Diabetes Care 2018; epub.

72. EASE-2 and EASE-3: Trial design
*CGM performed as sub-study in ~20% patients; R, randomisation
Screening
6 weeks
T1D therapy
intensification
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
1 week 3 weeks52 weeks
Placebo
run-in
2 weeks
Follow-up
Screening
T1D therapy
intensification
Placebo
Empagliflozin 2.5 mg
Empagliflozin 10 mg
Empagliflozin 25 mg
26 weeks
(primary endpoint)
Placebo
run-in Follow-up
CGM*
CGM CGM
26 weeks
CGM
CGM* CGM*
3 weeks
EASE-2
EASE-3
R
R

73. Key inclusion and exclusion criteria
CSII, continuous subcutaneous insulin infusion; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR,
estimated glomerular filtration rate; MDI, multiple dose injections
• Adults with type 1 diabetes ≥12 months
• On MDI (≥12 months) or CSII (≥5 months) prior to screening
• eGFR (CKD-EPI formula) ≥30 ml/min/1.73m2
• HbA1c ≥7.5–≤10.0% after insulin intensification
• Severe hypoglycaemia 3 months before screening
• DKA occurrence 3 months before screening and until randomisation
Key inclusion criteria
Key exclusion criteria

74. Baseline characteristics
* >80% had a diagnosis >10 years; † >75% above 0.5 U/kg; ‡ >80% above 0.5 U/kg
Main baseline parameter EASE-2 EASE-3
Sex, female, % 53 51
Race, white, % 94 95
Main regions, % of randomized patients
Europe
North America
54
39
63
25
Mean age, years 45 43
Mean BP, SBP/DB, mmHg 125/76 124/76
Mean BMI, kg/m2 29 28
Mean eGFR, CKD-EPI creatinine, ml/min/1.73m2 95 97
Time since diagnosis of T1D, years 23* 21*
Mean HbA1c, %
<8.0%
≥8.0%
8.1
45
55
8.2
42
58
Insulin needs, Mean insulin dose (range), U/kg 0.71 (0.1–1.9)† 0.70 (0.5–1.7)‡
Insulin therapy, %
MDI
CSII
59
41
66
34

75. 6-weekintensification
2-weekrun-in
EASE-2: HbA1c reduction over time
*Adjusted mean change from baseline vs placebo; Screening and week 0: descriptive data in full analysis set. Week 4–52:
adjusted data based on mixed model repeated measures in full analysis set (observed cases); SE, standard error
238
243
241
239
243
241
238
242
241
223
227
235
217
230
234
210
225
231
203
212
225
193
204
220
n with data at visit
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
Week
4 12 180 26 43Screening
A1c reduction is sustained
10 and 25 mg doses almost identical
52
9.0
8.8
8.6
8.4
8.2
8.0
7.8
7.6
7.4
-0.53*
(95% CI:-0.65, -0.42)
p<0.0001
-0.54*
(95% CI:-0.65, -0.42)
p<0.0001
Mean(SE)HbA1c(%)
Placebo Empagliflozin 10 mg Empagliflozin 25

76. Empagliflozin 10 mg
Empagliflozin 2.5 mg
6-weekintensification
2-weekrun-in
EASE-3: HbA1c reduction over time
*Adjusted mean change from baseline vs placebo; Screening and week 0: descriptive data in full analysis set. Week 4–26:
adjusted data based on mixed model repeated measures in full analysis set (observed cases).
Week
238
237
244
242
238
237
244
242
236
237
243
241
227
234
234
231
222
228
225
226
217
225
225
221
n with data at visit
Placebo
Empagliflozin 2.5 mg
Empagliflozin 10 mg
Empagliflozin 25 mg
A1c reduced with all
three doses versus
placebo
-0.28*
(95% CI:-0.42, -0.15)
p<0.0001
-0.45*
(95% CI:-0.58, -0.32)
p<0.0001
-0.52*
(95% CI:-0.66, -0.39)
p<0.0001
Placebo
Empagliflozin 25 mg
4 12 180 26Screening
8.9
8.7
8.5
8.3
8.1
7.9
7.7
7.5
Mean(SE)HbA1c(%)

77. -0,35
-0,53
-0,62
-1,0
-0,8
-0,6
-0,4
-0,2
0,0
0,2
-0,18
-0,35
-0,39
-1,0
-0,8
-0,6
-0,4
-0,2
0,0
0,2
Adjustedmean(95%CI)difference
vsplaceboinchangefrombaseline
inHbA1catweek26(%)
HbA1c reductions according to baseline HbA1c
HbA1c <8.0% at baseline HbA1c ≥8.0% at baseline
†
†
Empagliflozin 2.5 mg (n=101)
Empagliflozin 10 mg (n=106)
Empagliflozin 25 mg (n=98)
Empagliflozin 2.5 mg (n=136)
Empagliflozin 10 mg (n=138)
Empagliflozin 25 mg (n=144)
‡
‡
‡
Mixed model repeated measures in full analysis set (observed cases).
†p<0.001; ‡p<0.0001 for difference vs placebo.
Highest HbA1c reduction observed in subgroup
of patients with HbA1c ≥8% at baseline
~60% of patients

78. 0.0
-4.0
-3.0
-2.0
-1.0
1.0
Week
4 12 26 43 520
Adjustedmean(SE)change
frombaselineinweight(kg)
-2.7*
(95% CI:-3.3, -2.1)
p<0.0001
-3.3*
(95% CI:-3.8, -2.7)
p<0.0001
-2.7*
(95% CI:-3.3, -2.1)
p<0.0001
-3.3*
(95% CI:-3.8, -2.7)
p<0.0001
*Adjusted mean change from baseline vs placebo. Screening and week 0: descriptive data in full analysis set. Week 4–52:
adjusted data based on mixed model repeated measures in full analysis set (observed cases).
EASE-2: Body weight reductions over time
238
243
240
238
242
240
224
237
239
211
228
232
200
211
226
194
203
218
n analysed
Placebo
Empa 10 mg
Empa 25 mg
Body weight reduction
is sustained
10 and 25 mg doses
almost identical
Placebo Empagliflozin 10 mg Empagliflozin 25 mg

79. EASE-3: Body weight reduction over time
0.0
-4.0
-3.0
-2.0
-1.0
1.0
Week
4 12 260 1
Adjustedmean(SE)change
frombaselineinweight(kg)
*Adjusted mean change from baseline vs placebo; Screening and week 0: descriptive data in full analysis set. Week 4–26:
adjusted data based on mixed model repeated measures in full analysis set (observed cases).
238
237
243
240
232
234
239
239
237
236
242
237
219
223
225
223
n analysed
Placebo
Empa 2.5 mg
Empa 10 mg
Empa 25 mg
All three doses
significantly reduced
body weight
227
233
233
231
-1.8*
(95% CI:-2.3, -1.2)
p<0.0001
-3.0*
(95% CI:-3.6, -2.5)
p<0.0001
-3.4*
(95% CI:-4.0, -2.9)
p<0.0001
Placebo Empagliflozin 10 mg Empagliflozin 25 mgEmpagliflozin 2.5 mg

80. CGM: A powerful tool to understand glycaemic control
§ Ambulatory Glucose Profile:
Ø Diurnal graphical and quantitative representation of pooled interstitial glucose readings
obtained from CGM over time (e.g. ~288 readings per day and up to 4000 readings in 2
weeks)
§ Time in range is a gold-standard CGM-based measurement for the assessment of glycaemic
control
Median
180 mg/dl
Time
in
Range
Glucose
(mg/dl)
00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00
Time of day (24-hour clock)
70 mg/dl

81. EASE-2: Full analysis CGM results
6%
47
%
47
%
Baseline Week 26 Week 52
6%
48
%46
%
6%
47
%
47
%
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
ER
[P
E
[P
E
[P
E
Placebo
Empagliflozin
10 mg
Empagliflozin
25 mg
Full analysis set (observed cases – excluding data after paracetamol intake).
Glucose ≤70 mg/dl Glucose >70–≤180 mg/dl Glucose >180 mg/dl
Empagliflozin
increased time in
target glucose
range by
~3 hrs/day

82. EASE-3: Subanalysis CGM results
Baseline Week 26
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
Empagliflozin 2.5 mg [PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
48,
0
[PE
RC
48%
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
[PE
RC
Full analysis set (observed cases – excluding data after paracetamol intake).
Empagliflozin 2.5 mg
increased time in
target glucose range
by ~1 hr/day
Glucose ≤70 mg/dl Glucose >70–≤180 mg/dl Glucose >180 mg/dl

83. 0 26 43 524 12 18
Adjustedmean(SE)changefrom
baselineintotaldailyinsulindose(U/kg)
0.0
-0.12
-0.10
-0.06
-0.02
0.02
-0.04
-0.08
34
Week
*Adjusted mean change from baseline vs placebo. Screening and week 0: descriptive data in full analysis set. Week 4–52:
adjusted data based on mixed model repeated measures in full analysis set (observed cases).
EASE-2: Total daily insulin dose reduction over time
223
227
226
217
224
224
204
216
221
189
199
210
161
180
189
165
178
186
n analysed
Placebo
Empa 10 mg
Empa 25 mg
188
204
215
179
188
200
-0.09* (-13%)
(95% CI:-0.11, -0.07)
p<0.0001
-0.09* (-13%)
(95% CI:-0.11, -0.07)
p<0.0001
Early reduction in
total daily insulin
dose is sustained
(Half the reduction in basal dose and half in bolus dose)
Placebo
Empagliflozin 10 mg Empagliflozin 25 mg

84. -0.12
-0.10
-0.08
-0.06
-0.04
-0.02
0.00
0.02
-0.14
0 4 26
Week
12 18
EASE-3: Total daily insulin dose reduction over time
Adjusted mean change from baseline vs placebo. Screening and week 0: descriptive data in full analysis set. Week 4–26:
adjusted data based on mixed model repeated measures in full analysis set (observed cases).
217
223
217
220
217
222
215
218
201
208
195
206
189
189
177
187
n analysed
Placebo
Empa 2.5 mg
Empa 10 mg
Empa 25 mg
Reduction in total daily
insulin dose with all
doses
196
202
187
195
-0.05* (-6%)
(95% CI:-0.07, -0.03)
p<0.0001
-0.07* (-10%)
(95% CI:-0.09, -0.05)
p<0.0001
-0.09* (-13%)
(95% CI:-0.11, -0.07)
p<0.0001
(Half the reduction in basal dose and half in bolus dose)
Placebo
Empagliflozin 10 mg Empagliflozin 25 mgEmpagliflozin 2.5 mg
Adjustedmean(SE)changefrom
baselineintotaldailyinsulindose(U/kg)

85. EASE-2 and EASE-3: Systolic blood pressure changes
MMRM in FAS (observed cases excluding values after changes in anti-hypertensive medication). *p=0.0397 for
empagliflozin 10 mg; †p=0.0270; ‡p<0.001 for difference vs placebo, significant in confirmatory testing hierarchy 85
[VALUE]
-3,7
-6,0
-5,0
-4,0
-3,0
-2,0
-1,0
0,0
1,0
2,0
Adjustedmean(95%CI)
differencevsplaceboinchange
frombaselineinSBP(mmHG)
Empagliflozin 10 mg (n=206)
Empagliflozin 25 mg (n=218)
-2,1
[VALUE] [VALUE]
-6,0
-5,0
-4,0
-3,0
-2,0
-1,0
0,0
1,0
2,0
Empagliflozin 2.5 mg (n=218)
Empagliflozin 10 mg (n=216)
Empagliflozin 25 mg (n=208)
*
‡
†
‡ ‡
All doses associated with a reduction in SBP

86. Patient-reported
>23,000 events*
Hypoglycaemia reporting in EASE-2 and EASE-3 trials
*Symptomatic hypoglycaemic events with blood glucose <54 mg/dl.
Investigator-reported events
• Are a subset of all events
• Subjective judgement
influences reporting
Patient-reported events
• Considers totality of data
• Supported by EASD/ADA guidance
Investigator-
reported
~13,000 events*
In EASE both
approaches were tested

87. Investigator reported hypoglycaemic events: Week 1-26
Negative binomial model
Empagliflozin Placebo
Event Rate Ratio
(95% CI)
Event Rate Ratio
(95% CI) p-valueN
Events,
n N
Events,
n
EASE-2 (week 1–26)
Empagliflozin 10 mg 243 1327 239 1870 0.77 (0.57, 1.05) 0.0972
Empagliflozin 25 mg 241 1333 239 1870 0.78 (0.58, 1.06) 0.1180
EASE-3 (week 1–26)
Empagliflozin 2.5 mg 237 976 238 1339 0.93 (0.68, 1.27) 0.6587
Empagliflozin 10 mg 244 1423 238 1339 1.26 (0.93, 1.71) 0.1438
Empagliflozin 25 mg 242 1216 238 1339 1.05 (0.77, 1.43) 0.7543
0,25 0,5 1 2 4
Favours placeboFavours empagliflozin

88. Empagliflozin Placebo
Event Rate Ratio
(95% CI)
Event Rate Ratio
(95% CI) p-valueN
Events
, n N
Events
, n
All patient-reported (symptomatic and asymptomatic) hypos with BG <54 mg/dl
Empagliflozin 2.5 mg 241 2531 241 2976 0.83 (0.67, 1.04) 0.0978
Empagliflozin 10 mg 491 9133 484 11446 0.81 (0.70, 0.94) 0.0043
Empagliflozin 25 mg 489 9022 484 11446 0.81 (0.70, 0.93) 0.0035
Patient-reported symptomatic hypos with BG <54 mg/dl
Empagliflozin 2.5 mg 241 1936 241 2236 0.85 (0.67, 1.08) 0.1876
Empagliflozin 10 mg 491 6281 484 8501 0.77 (0.65, 0.90) 0.0014
Empagliflozin 25 mg 489 6429 484 8501 0.79 (0.67, 0.92) 0.0035
0,25 0,5 1 2 4
Patient-reported hypoglycaemia
EASE-2 data up to 52 weeks and EASE-3 data up to 52 weeks.
Negative binomial model. Treated set; Data from further analysis, no confirmatory testing.
ADA, American Association of Diabetes; EASD, European Association for the Study of Diabetes
International Hypoglycemia Study Group. Diabetes Care. 2016;doi:10.2337/dc16-2215
Overall patient-reported hypoglycaemic events with blood glucose <54 mg/dl
Favours placeboFavours empagliflozin

89. Patient-reported nocturnal hypoglycaemia
*Onset between 0:00 and 5:59 hours; EASE-2 data up to 52 weeks and EASE-3 data up to 52 weeks. Negative binomial
model. Treated set; Data from further analysis, no confirmatory testing.
Nocturnal* patient-reported hypoglycaemic events with blood glucose <54 mg/dl
Empagliflozin Placebo
Event Rate Ratio
(95% CI)
Event Rate Ratio
(95% CI) p-valueN
Events
, n N
Events
, n
All nocturnal patient-reported (symptomatic and asymptomatic) hypos with BG <54 mg/dl
Empagliflozin 2.5 mg 241 331 241 514 0.65 (0.48, 0.86) 0.0030
Empagliflozin 10 mg 491 1166 484 1844 0.65 (0.54, 0.78) <0.0001
Empagliflozin 25 mg 489 1310 484 1844 0.72 (0.60, 0.87) 0.0005
Nocturnal patient-reported symptomatic hypos with BG <54 mg/dl
Empagliflozin 2.5 mg 241 292 241 443 0.66 (0.48, 0.91) 0.0114
Empagliflozin 10 mg 491 973 484 1587 0.63 (0.52, 0.78) <0.0001
Empagliflozin 25 mg 489 1114 484 1587 0.72 (0.59, 0.88) 0.0014
Favours placeboFavours empagliflozin
0,25 0,5 1 2 4
*Onset between 0:00 and 5:59 hours

90. DKA adjudication in the EASE program
Case definitionParameters for adjudication
Acidosis
pH ≤ 7.30
or
bicarbonate ≤ 18
Ketosis
BHB
>1.5 mmol/l
or urine ketones
Clinical
Manifestations
suggestive of DKA
1
1
1. Certain ketoacidosis: Acidosis and ketosis
2 2
2. Potential ketoacidosis: Acidosis or ketosis with
clinical manifestations
3 3. Ketosis: High ketones without acidosis and
without clinical manifestations

91. DKA: classification of adjudicated cases
On-treatment analysis.
Adjudicated cases (196)
Severe
(9)
Moderate
(25)
Mild (13) Mild (39)
• pH <7.00 Or
• Bicarbonate <10 mEq/l Or
• Stupor/coma
• pH 7.00-7.24 Or
• Bicarbonate 10–<15 mEq/l Or
• pH 7.25-7.30 Or
• Bicarbonate 15-18 mEq/l Or
• No neurological symptoms
• pH <7.00 Or
• Bicarbonate <10 mEq/l Or
• Stupor/coma
Severe
• pH 7.25-7.30 Or
• Bicarbonate 15-18 mEq/l Or
• No neurological symptoms
Mild
• pH 7.00-7.24 Or
• Bicarbonate 10–<15 mEq/l Moderate
Severe
(9)
Moderate
(25)
Mild (13)
Mild (39)
Severe
(9)
Moderate
(25)
Mild (13) Mild (39)
Certain
(47)
Potential
(39)
Unlikely DKA, but
ketosis (100)
Unlikely
(10)
Unclassifiable
(0)
Certain
(47)
Potential
(39)
Ketosis
(100)
Unlikely
(10)

92. Pooled*
placebo
(n=484)
Pooled*
empagliflozin
10 mg
(n=491)
Pooled*
empagliflozin
25 mg
(n=489)
EASE-3
placebo
(n=241)
EASE-3
empagliflozin
2.5 mg
(n=241)
Patients with certain DKA, n (%) 6 (1.2) 21 (4.3) 16 (3.3) 3 (1.2) 2 (0.8)
Certain DKA events, n 6 21 18 3 2
Incidence rate per 100 patient-years 1.77 5.94 5.05 2.52 1.65
Events by severity, n
Severe 1 2 6 1 0
Moderate 4 13 8 1 0
Mild 1 6 4 1 2
Outcome of event
Fatal 0 0 1 0 0
Adjudication results: Certain DKA
*Consists of EASE-2 and EASE-3 data up to 52 weeks; Treated set. On-treatment analysis.

93. Baseline characteristics associated with increased
risk of DKA
*Consists of EASE-2 and EASE-3 data up to 52 weeks; Treated set. On-treatment analysis.
Pooled*
Placebo
Pooled*
Empagliflozin
10 mg
Pooled*
Empagliflozin
25 mg
Patients with certain or potential DKA,
n/N (%)
Sex
Male
7/226 (3.1) 6/234 (2.6) 6/237 (2.5)
Female 4/258 (1.6) 27/257 (10.5) 22/252 (8.7)
Insulin therapy
MDI 4/305 (1.3) 10/309 (3.2) 10/308 (3.2)
CSII 7/179 (3.9) 23/182 (12.6) 18/181 (9.9)

94. Resumen DKA
• Increased risk of DKA with empagliflozin 10 and 25 mg
– Consistent with other SGLT inhibitor T1D programs
• DKA risk correlated with concomitant illness or inadequate insulin administration
(e.g. pump failure); the risk appears to be higher in female patients and with insulin
pump use
• The rate of certain DKA in empagliflozin 2.5 mg was low and similar to placebo
– This suggests that lower SGLT2 inhibitor doses may help to minimize risk in T1D

95. Resumen de efectos de Empagliflozina como terapia
adyuvante a la insulina
§ Empagliflozin 10 and 25 mg led to clinically meaningful
effects:
Ø HbA1c (> -0.5%)
Ø Body weight (up to -3.4 kg)
Ø Insulin dose (up to -13%)
Ø Systolic blood pressure (up to -3.9 mmHg)
Ø Glucose time in range (up to +3 hrs/day)
§ Similar effects observed for empagliflozin 2.5 mg:
Ø HbA1c: -0.28% (HbA1c ≥8.0% at baseline -0.35%)
Ø Body weight (-1.8 kg)
Ø Insulin dose (-6.4%)
Ø Systolic blood pressure (-2.1 mmHg)
Ø Glucose time in range (+1 hr/day)

96. #SGLT2inDM1
@CristobMorales
CONCLUSIONES

97. Increasing hospitalizations for DKA: A need for prevention
Zhong et al. Diabetes Care 2018;41:1870. Vellanki P, Umpierrez GE. Diabetes Care 2018;41:1839; 2
• Recent (Sept 2018) review of DKA challenges and prevention efforts following publication
reporting increased DKA occurrence in England from 1998-2013
• DKA incidence rates in 2013 were 50% higher than the rates in 1998
Increased DKA rates in:
• Wales
• Australia/New Zealand
• Denmark
• USA

98. Status of other adverse outcomes in persons with T1D
Liu et al. Pediatric Diabetes 2010;11:4; Nathan et al. Arch Intern Med 2009;169:1307; Baskaran et al. Pediatric Diabetes
2015;16:263; Miller et al. Diabetes Care 2015;38:971; DuBose et al. J Pediatr 2015;167:627; Purnell et al. Diabetes Care
2017;40:1756.
• Half to two-thirds of adults with T1D are overweight
or obese
• Overweight / obesity are associated with:
• higher HbA1c levels,
• adverse CVD risk factors
• hypoglycaemia

99. Debate…
“…Using the lowest available dose
of SGLT inhibitor may reduce the
risks of DKA and other adverse
events…”
“…Any added benefits of adjunctive
therapies for T1D must be carefully
balanced against their added
risks…”

100. SGLT2 en DM1: De la evidencia a la practica clinica
• Una oportunidad de mejorar más allá de la
A1c. Peso, Hipoglucemias, tiempo en rango,
dosis de insulina, TA…
• Riesgos (DKA, Infecciones Genitales,
deshidratación) ya existen en DM1
• Balancear riesgos y beneficios
• PLUS: reducir preocupaciones sobre
Hiperglucemias y miedo a hipoglucemias
(especialmente nocturnas)

101. Approach to reduce DKA risk with SGLTis: STICH Protocol
Garg S, et al. Diab Tech Ther 2018; epub.
Wallet Card - front Wallet Card - back

102. @cristobMmorales

103. MURIÓ CON
LA A1c EN
6%
@CristobMorales

104. HIPOs
TIEMPO
EN RANGO
VARIABILIDAD
GLUCEMICA
A1c
@cristob_morales

105. De la evidencia a la practica
• Provide education regarding potential benefits and risks of SGLT2is, especially
related to atypical DKA
• Educate all stakeholders: PWD, family members, HCPs, payers (need to provide
BG/CGM supplies, blood ketone (BHB) supplies (strips/meter), ER/ED staff,
pharmacists, etc.
• Reinforce sick day management and DKA prevention during flu season
• Avoid use of SGLT2is in persons with disordered eating behaviors/eating
disorders, low carbohydrate diets, history of recurrent DKA
• Utilize the lowest dose that balances efficacy with safety (DKA risk minimization)
• Offer opportunities to improve HbA1c and TiR, reduce hypoglycaemia, promote
weight loss, reduce burden / worries related to T1D self-management (improved
post-prandial glucose levels, less fear of hypoglycaemia) and provide HOPE

107. @CristobMorales
La clave del éxito
es la
PERSONALIZACION

108. LA EDUCACION
DIABETOLOGICA
ES EL ARMA
MÁS PODEROSA
DE LA
GALAXIA
@CristobMorales

109. LA EDUCACION
DIABETOLOGICA
ES EL ARMA
MÁS PODEROSA
DE LA
GALAXIA
@CristobMorales

110. MEDICO
EXPERTO
PACIENTE
EXPERTO

111. DIABETES
VAR ROOM
@CristobMorales
DIABETES

112. #SGLT2inDM1
@CristobMorales

113. #MásAlláA1c

116. Disminución
insulina
Seguridad
disminución
HbA1c
sin hipoglucemias
Resultados más allá de la A1c importan al paciente…
Tiempo
en
rango
Perdida
de peso
Disminución
TA