The document contains demographic and baseline characteristic data from the DEVOTE clinical trial comparing insulin degludec to insulin glargine in patients with type 2 diabetes at high risk for cardiovascular events. A total of 7637 patients from 20 countries across 5 continents were enrolled in the trial. At baseline, the mean age was approximately 65 years for both treatment groups. Slightly over 60% of patients were male. Patients had a mean duration of diabetes of approximately 16 years and the majority (over 84%) had established cardiovascular or chronic kidney disease and were aged 50 years or older.

4. PABLO
PEREZ
CRISTOBAL
MORALES
F.JAVIER
AMPUDIA
RICARDO
G.HUELGA
FERNANDO
G.PERALTA
JAVIER
ENA
F.JAVIER
CARRASCO

6. 2000 AÑOS
ANTES DE
CRISTO
2000 AÑOS
DESPUES DE
CRISTO

7. “TENGO UN POCO DE
AZUCAR”
“Pero de la buena”
FUMO LO
NORMAL
NO SOY HIPERTENSO, PERO
TOMO 2 PASTILLAS PA LA
TENSION (CUANDO ME ACUERDO)
COMO VOY A TENER EL COLESTEROL
ALTO SI NO COMO NADA CON GRASA
( Y ME TOMO TODOS LOS DIAS UN DANACOL)
@cristob.morales

8. “TENGO UN POCO DE
AZUCAR”
“Pero de la buena”
FUMO LO
NORMAL
NO SOY HIPERTENSO, PERO
TOMO 2 PASTILLAS PA LA
TENSION (CUANDO ME ACUERDO)
COMO VOY A TENER EL COLESTEROL
ALTO SI NO COMO NADA CON GRASA
( Y ME TOMO TODOS LOS DIAS UN DANACOL)
@cristob.morales

9. GRACIAS STEVEN NISSEN,
CONTIGO EMPEZO TODO…

10. LA DECADA DE LOS
ESTUDIOS DE SEGURIDAD
CARDIOVASCULAR EN DM2

11. 11 AÑOS CUIDANDO, FORMANDO E INNOVANDO EN DIABETES
HDDHOSPITAL DE DIA DE DIABETES
HOSPITAL VIRGEN MACARENA. SEVILLA
AÑOS
Cristob_Morales

12. DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARES
RESULTADOS
GLUCEMICOS
DEVOTE2&3
VARIABILIDAD
HIPOGLUCEMIAS
SEGURIDADCARDIOVASCULARDEGLUDEC

15. Fuente:www.doctablet.com
Insulin degludec IGlar U100
Type of insulin New generation long-acting basal insulin analog First generation basal insulin analog
Mode of protraction Forms soluble multihexamers Precipitates as microcrystals
Half life ~25 hours ~12 hours
Day-to-day variability (AUCGIR,0–24h) Coefficient of variation 20% Coefficient of variation 80%
Study drugs

16. Insulin degludec
Rationally designed, beyond sequence modification
Jonassen et al. Pharm Res 2012;29:2104–14
N
H
O
OH
O NH
O
OH
O
DesB30 insulin
DesB30
T
Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin
s
s
s
s
A1
B1
A21
s s
T YG EE CYCC NLQLSISQVI NC
PTYY FFF GGG REE CC VLLAVLHSLHQNV K
L-γ-Glu
Glutamic acid
‘spacer’
N
H
O
OH
O NH
O
Hexadecandioyl
Fatty diacid side
chain
NUEVA
INSULINA

17. Insulin degludec
Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
Monomers are absorbed from
the depot into the circulation
Zinc diffuses slowly causing
individual hexamers to disassemble,
releasing monomers
[ Zn2+]

18. La vida media de insulina degludec es el doble de la de insulina
glargine (25.4 h vs 12)
1
10
100
0 24 48 72 96 120
Insulin
concentration
(%ofmaximum)
Time since injection (hours)
*
IDeg 0.8 U/kg
IGlar 0.8 U/kg
*Insulin glargine was undectable after 48 hours Results from 66 patients with T1D
IDeg, insulin degludec; IGlar, insulin glargine Heise et al. Diabetes 2011;60(Suppl. 1):LB11; Heise et al. Diabetologia 2011;54(Suppl. 1):S425
IDeg IGlar
0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg
Vida Media (hours) 25.9 27.0 23.6 11.5 12.9 11.9
Media (vida media) 25.4 12.1

20. 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
0
1
2
3
4
5
6
GIR(mg/kg/min)
PERFIL FARMACODINAMICO
PLANO en estado de equilibrio
IDeg
DOSIS AUCGIR,0–12h AUCGIR,12-24h
0.4 U/kg 50% 50%
Insulin degludec = 0.4 U/kg; AUC, area under the curve; GIR, glucose
infustion rate; n=66
Heise et al. Diabetologia 2011;54(Suppl. 1):S425
0
1
2
3
4
5
0 4 8 12 16 20 24
GIR(mg/kg/min)
Time since injection (hours)
0.8 U/kg
0.6 U/kg
0.4 U/kg
T2D, 49 patients, randomised, 2-period, 12-day trial
Variability was assessed at steady state by clamps on days 6 and 12
Heise et al. Diabetes Obes Metab 2012; 2012;14:944–50
DM1 DM2

21. Variabilidad dia a dia
AUC GIR (intervalo tiempo, horas)
IDeg CV
(%)
IGlar CV
(%)
p value
AUCGIR,0-24h 20 82 p<0.0001
54 patients
with T1D
CV, coefficient
of variation
Heise et al.
Diabetes Obes
Metab
2012;14:859-
64

23. Farmacocinética de insulina degludec en poblaciones
especiales:
Edad
Función Hepática
Función Renal
Ancianos (≥65)
Adultos jóvenes (18–
35)
La FC de insulina degludec no se
ven afectadas por el aumento de
la edad, alteraciones renales o
hepáticas.
0
2000
4000
6000
8000
10000
0 4 8 12 16 20 24
IDegConcentración
(pmol/L)
Time since injection (hours)
Normal
Mild
Moderate
Severe
0
2000
4000
6000
8000
10000
0 4 8 12 16 20 24
IDegConcentración
(pmol/L)
Time since injection (hours)
Normal
Child-Pugh A
Child-Pugh B
Child-Pugh C
0 4 8 12 16 20 24
Time since injection (hours)
2000
4000
6000
8000
10000
IDegConcentración
(pmol/L)
0
PK, pharmacokinetic
Kupčová et al. Clin Drug Investig 2014;34:127–33; Kiss et al. Clin Pharmacokinet 2014;53:175–83; Korsatko et al. Drugs Aging 2014;31:47–
53

24. Desarrollo clinico Ideg (F3a – F3b)
*Simple vs. step-wise titration algorithm or U100 vs. U200 formulation
BOT, basal-oral therapy; DPP-4, dipeptidyl peptidase 4; IDeg, insulin degludec; IGlar U100, insulin glargine U100; T1D, type 1 diabetes; T2D, type 2 diabetes
Phase 3a Phase 3b
BB
Basal–bolus, n=1006
ONCE LONG
Basal start,
n=1030
BB T1 LONG
Basal–bolus,
n=629
FLEX T1
Basal–bolus,
n=493
EARLY
Basal start, n=458
LOW VOLUME
U200 basal start,
n=460
ONCE ASIA
Basal start, n=435
FLEX
BOT, n=687
BB T1
Basal–bolus,
n=456
vs. insulin detemir vs. DPP-4 inhibitors andT1D vs. IGlar U100T2D
SWITCH 1
Basal switch, n=501
Exercise study
n=40
YOUNG 1
Basal–bolus, n=350
ONCE SIMPLE USE
Basal start, n=222
Simple vs. step-wise
Flexibility and
simple titration
in Japan, n=458
SWITCH 2
Basal switch, n=721
HIGH DOSE
IDeg U200 vs. IGlar
U100, n=145
VICTOZA® ADD-ON
BOT, n=413
COMPARE
BOT, n=373
IDeg U100 vs. U200
DEVOTE
Cardiovascular
outcomes study
ADD-ON TO GLP-1
BOT, n=346
IDeg + liraglutide
Comparators
Type 1 diabetesType 2 diabetes
vs. IDeg*
9225 PACIENTES

25. DM1
Basal/Bolo
(3583+3770)
1.13
0.83
(18% Reducción Eventos)
1.12
DM2
Terapia Basal Oral
(3579, 3586, 3672)
DM2
Basal/Bolo
(3582)
0.90
0.64
(36% Reducción Eventos)
0.14
(86% Reducción Eventos)
0.83
(17% Reducción Eventos)
0.75
(25% Reducción Eventos)
1.14
Eventos Nocturnos
(No-Graves)
Eventos Diurnos
(No-Graves)
Eventos Graves
(Nocturnos y Diurnos)
-0.61
[-1.13;-0.10]
-0.34
[-0.54;-0.15]
-0.29
[-0.65; 0.06]
Cambios en: Glucosa Plasmática en
Ayunas (mmol/L)
No-Inferioridad HbA1c
No diferencia en estudios de tratar hasta
el objetivo (TTT)
  
5 vs 11* 10 vs 12 12 vs 12Tiempo para Alcanzar
Objetivos (Mediana en Semanas)
Indicadores
Control
Glucémico
Hipoglucemias
(Ratios Relativos)
0.88
(12% Reducción Dosis)
0.90
(10% Reducción Dosis)
1.03Ratio Dosis Diaria
(Ratio Unidades/kg)
Dosis Insulina
(Ratios Relativos)
*Only 3583 (full meta-
analysis pending. 4 vs. 6
weeks in 3370)
IDegludec
Significantly Better
Iglargine
Significantly Better
No Statistical
Difference
Meta-Análisis:
Resumen de resultados I.Deg vs. I.Glar

26. Fuente: www.doctablet.com

27. DEVOTE: trial design
Insulin degludec once daily (blinded vial) +
Standard of care
IGlar U100 once daily (blinded vial) +
Standard of care
Randomization
7637 patients
randomized
End of treatment
(633 MACE accrued)
Follow-up
period
30 days
Follow-up
period
*Confirmed by the Event Adjudication Committee; †cardiovascular death includes undetermined cause of death; ‡severe defined as an episode requiring the assistance of another
person to actively administer carbohydrate, glucagon, or take other corrective actions. BG concentrations may not be available during an event, but neurological recovery following the
return of BG to normal is considered sufficient evidence that the event was induced by a low BG concentration
BG, blood glucose; MACE, major adverse cardiovascular event
Secondary endpoints
• Rate of severe hypoglycemic episodes*‡
• Incidence of severe hypoglycemic episodes*‡
Primary endpoint
Time from randomization to first occurrence of a 3-point MACE:
cardiovascular death*†, non-fatal myocardial infarction* or non-fatal stroke*
Interim analysis
(150 MACE accrued)

28. Key inclusion criteria: cardiovascular profile
Type 2 diabetes
Current treatment with ≥1 oral or injectable
antidiabetic agent(s)
HbA1c <7.0% and basal
insulin treatment ≥20 U/day
High cardiovascular
risk profile
HbA1c
≥7.0%
OR
• cardiovascular or
chronic kidney
disease and aged ≥50
OR
• risk factors for
cardiovascular
disease and aged ≥60
U, units

29. DEVOTE – a global trial
KOREA
4 sites
61 patients
JAPAN
7 sites
61patients
MALAYSIA
8 sites
102 patients
THAILAND
6 sites
68 patientsINDIA
26sites
357 patients
SOUTHAFRICA
15 sites
194 patients
ARGENTINA
4 sites
120 patients
BRAZIL
10 sites
303 patients
UNITEDSTATES
269 sites
5201 patients
MEXICO
7 sites
162patients
CANADA
6 sites
70 patients
ALGERIA
6 sites
63patients
RUSSIAN
FEDERATION
20 sites
240 patients
SPAIN
6 sites
60 patients
GREECE
6 sites
90 patients
ROMANIA
4 sites
84 patients
UNITEDKINGDOM
8 sites
80 patients
POLAND
8 sites
135 patients
ITALY
10 sites
140 patients
CROATIA
5 sites
46 patients
GLOBALLY
5 continents
20 countries
438 sites
7637 patients

30. Randomized patient disposition
*7644 patients were randomized in total. Of these, seven patients were randomized at two different sites. Data from the second site were not included in the full
analysis set; **status during trial closure: from the first patient's follow-up visit (29 Jun 2016) to the last patient/last visit (16 Oct 2016); FAS, full analysis set
Completed trial
N=3742 (98.0%)
Completed trial
N=3747 (98.1%)
IGlar U100
N=3819 (100.0%)
Insulin degludec
N=3818 (100.0%)
Screened
N=8205
Screening failures
N=561
Duplicate randomization
identities excluded
N=7*
Randomized (FAS)
N=7637
Did not complete trial
• Vital status known**
- Alive
- Dead
• Vital status unknown**
- Withdrawal of consent
- Lost to follow-up
N=76 (2.0%)
N= 71 (1.9%)
N= 71 (1.9%)
N= 0 (0.0%)
N= 5 (0.1%)
N= 1 (0.0%)
N= 4 (0.1%)
Did not complete trial
• Vital status known**
- Alive
- Dead
• Vital status unknown**
- Withdrawal of consent
- Lost to follow-up
N=72 (1.9%)
N= 69 (1.8%)
N= 69 (1.8%)
N= 0 (0.0%)
N= 3 (0.1%)
N= 2 (0.1%)
N= 1 (0.0%)

31. Baseline characteristics
*Mean value. HbA1c and FPG measured at randomization. All other parameters measured at the screening visit
BMI, body mass index; CKD, chronic kidney disease; CV, cardiovascular; FPG, fasting plasma glucose; IGlar U100, insulin glargine U100
Parameter Insulin degludec IGlar U100
Total number of patients, n 3818 3819
Age, years* 64.9 65.0
Sex, Male, % 62.8 62.4
Duration of diabetes, years* 16.6 16.2
CV risk profile
Established CV or CKD and age ≥50 years, % 85.5 84.9
With CV risk factors and age ≥60 years, % 14.1 14.8
BMI, kg/m2* 33.6 33.6
HbA1c, %* 8.4 8.4
FPG, mg/dL* 169.8 173.5

36. DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARES
RESULTADOS
GLUCEMICOS
DEVOTE2&3
VARIABILIDAD
HIPOGLUCEMIAS
SEGURIDADCARDIOVASCULARDEGLUDEC

37. 0
2
4
6
8
10
12
0 3 6 9 12 15 18 21 24 27 30
Time to first 3-point MACE
Full analysis set; Cox regression analysis accounting for treatment. Analysis includes events between randomization date and follow-up date.
Patients without an event are censored at the time of last contact (phone or visit)
EAC, Event Adjudication Committee; N, number of patients at risk; PYO, patient-years of observation
HR: 0.91
[0.78; 1.06]95% CI
Non-inferiority confirmed
p<0.001
Patientswithanevent(%)
Insulin degludec (N) 3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217
IGlar U100 (N) 3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205
Time to first EAC-confirmed event (months)
IGlar U100
Insulin degludec
356 patients
325 patients
Rate:
4.71/100 PYO
Rate:
4.29/100 PYO
-9 % (NS)

38. Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
DEVOTESTUDYADASYMPOSIUM12062017Ver.1.0
3-point MACE, 4-point MACE and all-cause death
*CV death includes undetermined cause of death; †4-point MACE defined as cardiovascular death*, non-fatal myocardial infarction, non-fatal stroke or
unstable angina requiring hospitalization
Hazard ratio
[95% CI]
Insulin degludec IGlar U100
N % N %
3-point MACE 0.91 [0.78; 1.06] 325 8.5 356 9.3
CV death* 0.96 [0.76; 1.21] 136 3.6 142 3.7
Non-fatal MI 0.85 [0.68; 1.06] 144 3.8 169 4.4
Non-fatal stroke 0.90 [0.65; 1.23] 71 1.9 79 2.1
4-point MACE† 0.92 [0.80; 1.05] 386 10.1 419 11.0
Unstable angina requiring hospitalization 0.95 [0.68; 1.31] 71 1.9 74 1.9
All-cause death 0.91 [0.76; 1.11] 202 5.3 221 5.8
Hazard ratio [95% CI]
Favors IGlar U100Favors insulin degludec
1.0 1.3

39. Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
DEVOTESTUDYADASYMPOSIUM12062017Ver.1.0
Subgroup analyses of time to first 3-point MACE
*As per CKD-EPI
CKD-EPI, chronic kidney disease epidemiology collaboration equation
Factor N %
Hazard ratio
[95% CI]
Insulin degludec IGlar U100 p-value for
interaction
N % N %
Primary analysis 7637 100.0 0.91 [0.78; 1.06] 325 8.5 356 9.3
Sex 0.0989
Women 2859 37.4 0.76 [0.59; 0.99] 99 7.0 131 9.1
Men 4778 62.5 0.99 [0.83; 1.20] 226 9.4 225 9.5
Age at baseline 0.3570
<65 years 3682 48.2 0.84 [0.67; 1.05] 140 7.6 167 9.0
≥65 years 3955 51.7 0.97 [0.79; 1.19] 185 9.3 189 9.6
BMI 0.8335
<30 kg/m2 2499 32.7 0.93 [0.71; 1.21] 107 8.4 111 9.1
≥30 kg/m2 5127 67.1 0.90 [0.75; 1.08] 217 8.6 245 9.5
Renal function* 0.5785
Normal 1486 19.4 0.73 [0.50; 1.08] 44 6.0 61 8.2
Mild impairment 3118 40.8 0.97 [0.76; 1.24] 132 8.3 129 8.5
Moderate impairment 2704 35.4 0.96 [0.75; 1.21] 130 9.8 141 10.2
Severe impairment 214 2.8 0.76 [0.39; 1.50] 15 13.9 19 17.9
Hazard ratio [95% CI]
Favors IGlar U100Favors insulin degludec
1.0

40. Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
DEVOTESTUDYADASYMPOSIUM12062017Ver.1.0
Subgroup analyses of time to first 3-point MACE
†Includes basal/bolus, bolus only and premix
Factor N %
Hazard ratio
[95% CI]
Insulin degludec IGlar U100 p-value for
interaction
N % N %
Primary analysis 7637 100.0 0.91 [0.78; 1.06] 325 8.5 356 9.3
Diabetes duration 0.5699
≤15 years 3740 49.0 0.95 [0.76; 1.18] 149 8.2 166 8.6
>15 years 3895 51.0 0.87 [0.71; 1.07] 176 8.8 190 10.0
CV risk group 0.5742
Established CV disease 6509 85.2 0.89 [0.76; 1.04] 293 9.0 325 10.0
Risk factors for CV disease 1105 14.5 1.03 [0.62; 1.72] 29 5.4 30 5.3
Previous insulin regimen 0.1917
Basal only 2894 37.9 1.10 [0.84; 1.43] 111 7.6 101 7.0
Basal–bolus† 3515 46.0 0.80 [0.66; 0.98] 172 9.8 210 12.0
Insulin naïve 1228 16.1 0.96 [0.63; 1.46] 42 7.0 45 7.2
Region 0.0052
North America 5271 69.0 0.96 [0.81; 1.15] 244 9.3 254 9.6
Europe 875 11.4 1.40 [0.88; 2.23] 43 9.8 31 7.1
Asia 649 8.5 0.42 [0.22; 0.81] 13 4.1 31 9.4
South America 585 7.7 0.80 [0.43; 1.47] 19 6.3 22 7.8
Africa 257 3.4 0.30 [0.12; 0.77] 6 4.6 18 14.4
Hazard ratio [95% CI]
Favors IGlar U100Favors insulin degludec
1.0

41. DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARES
RESULTADOS
GLUCEMICOS
DEVOTE2&3
VARIABILIDAD
HIPOGLUCEMIAS
SEGURIDADCARDIOVASCULARDEGLUDEC

42. Similar mean HbA1c
Full analysis set
CI, confidence interval; ET, end treatment visit; ETD, estimated treatment difference
-0.86 -0.84
-1.0
-0.5
0.0
%
Observed mean change
from baseline at month 24
Insulin degludec IGlar U100
Post hoc ETD:
0.01% [-0.05; 0.07]95% CI
6.5
7.0
7.5
8.0
8.5
9.0
0 3 6 9 12 15 18 21 24 27 30
HbA1c(%)
75
69
64
59
53
0
HbA1c(mmol/mol)
Insulin degludec (N) 3774 3656 3608 3535 3525 2458 3344
IGlar U100 (N) 3776 3640 3562 3516 3500 2424 3277
0.0
Months since randomization
ET
Insulin degludec
IGlar U100
7.55%
7.50%

43. Significant reduction of FPG with insulin degludec
vs IGlar U100
Full analysis set
FPG, fasting plasma glucose
108
117
126
135
144
153
162
171
180
0 12 24 36
FPG(mg/dL)
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
-40
-30
-20
-10
0
mmol/L
mg/dL
Observed mean change
from baseline at month 24
Insulin degludec IGlar U100
Post hoc ETD:
-7.2 mg/dL [-10.3; -4.1]95% CIET
FPG(mmol/L)
10.0
9.5
9.0
8.0
7.5
7.0
6.5
0.0
8.5
Insulin degludec (N) 3757 3521 2457 3345
IGlar U100 (N) 3760 3498 2425 3277
-39.9 mg/dL
-
-34.9 mg/dL
0
Months since randomization
Insulin degludec
IGlar U100

44. Event Adjudication Committee-confirmed severe
hypoglycemia in this double-blinded trial
ADA, American Diabetes Association; EAC, Event Adjudication Committee
1. Seaquist et al. Diabetes Care 2013;36:1384–95
Events sent for severe
hypoglycemia adjudication
1005 events
EAC-confirmed severe hypoglycemia
752 events
Severe hypoglycemia
(ADA definition):
An episode requiring the
assistance of another person
to actively administer
carbohydrate, glucagon, or
take other corrective actions
with neurologic recovery1

45. Rates of severe hypoglycemia
Full analysis set; Mean number of confirmed severe hypoglycemic episodes. The number of events is analyzed using a negative binomial regression model using a log link
and the logarithm of the observation time (100 years) as offset
E, number of events; R, events per 100 patient-years of observation; PYO, patient-years of observation
0
4
8
12
16
0 3 6 9 12 15 18 21 24 27 30
Meannumberof
events/100PYO
Time from randomization (months)
Insulin degludec (N=3818) IGlar U100 (N=3819)
E R E R
EAC-confirmed episodes 280 3.70 472 6.25
IGlar U100
Insulin degludec
Rate ratio: 0.60
[0.48; 0.76]95% CI
p<0.001

46. Rates of nocturnal severe hypoglycemia
Full analysis set; Nocturnal hypoglycemia: EAC-confirmed severe hypoglycemic episode with an investigator-reported onset between 00:01 and 05:59.
Mean number of nocturnal EAC-confirmed severe hypoglycemic episodes. The number of events is analyzed using a negative binomial regression
model using a log link and the logarithm of the observation time (100 years) as offset
0
1
2
3
4
5
0 3 6 9 12 15 18 21 24 27 30
Meannumberof
events/100PYO
Time from randomization (months)
Insulin degludec (N=3818) IGlar U100 (N=3819)
N % E R N % E R
EAC-confirmed episodes 37 1.0 48 0.64 73 1.9 106 1.39
Rate ratio: 0.47
[0.31; 0.73]95% CI
p<0.001
IGlar U100
Insulin degludec

47. Resultados:
desenlaces cardiovasculares,eficacia y seguridad
IDeg, insulin degludec; IGlar U100, insulin glargine U100; MACE, major adverse cardiovascular event
Novo Nordisk Company announcement 29 November 2016
Control
Glucémico
Reducciones Similares en A1c con Ideg
vs IGlar U100
Seguridad
IDeg parece tener un buen perfil de
seguridad y tolerabilidad
Desenlace
primario
Logrado
no inferioridad en MACE
Ideg vs IGlar U100
cuando se agrega a terapia estándar 1.0
Hazard ratio
0.91

48. Resultados: hipoglucemia adjudicada
*Reducción Significativa
IDeg, insulina degludec; IGlar U100, insulina glargina U100
-40%*
HIPOs
Severa
-40%
reducción
significativa
de la tasa
HIPOs
Nocturna
severa
-54%
reducción
significativa
de la tasa
-60
-50
-40
-30
-20
-10
0
Reducciónenla
incidenciade…
-60
-50
-40
-30
-20
-10
0
Reducciónenla
incidenciade…
-54%*
PACIENTES DM2 ALTO RCV
(Población DEVOTE)
NNT HIPOGLUCEMIAS SEVERAS

49. DEVOTE confirmed the results from BEGIN and
SWITCH with regards to hypoglycemia in T2D
*p<0.05; BG, blood glucose; T2D, type 2 diabetes
1. Ratner et al. Diabetes Obes Metab 2013;15:175–84; 2. Wysham et al. Diabetologia 2016;59(Suppl.1):S43
Maintenance period Full treatment period
0.68 [0.57; 0.82]*
Estimated rate ratio [95% CI]
0.83 [0.74; 0.94]*Overall confirmed
Nocturnal confirmed
0.81 [0.42; 1.56]Severe
0.58 [0.46; 0.74]*
0.60 [0.48; 0.76]*
0.47 [0.31; 0.73]*
0.54 [0.21; 1.42]
0.70 [0.61; 0.80]*Overall confirmed
Nocturnal confirmed
Severe
SWITCH22
(Double
blind)
DEVOTE
(Double
blind)
Severe
Nocturnal severe
0.125 0.25 0.5 1 2
Favors IGlar U100Favors insulin degludec
BEGIN1
(PooledT2D
Openaccess)
Severe or BG <56 mg/dL
00.01–05.59, both inclusive
Requiring third-party assistance
Severe or BG <56 mg/dL with symptoms
Severe or BG <56 mg/dL with symptoms,
00.01–05.59, both inclusive
Requiring third-party assistance and adjudicated
Requiring third-party assistance and adjudicated
00.01–05.59, both inclusive, requiring third-party
assistance and adjudicated

50. DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARES
RESULTADOS
GLUCEMICOS
DEVOTE2&3
VARIABILIDAD
HIPOGLUCEMIAS
SEGURIDADCARDIOVASCULARDEGLUDEC

51. @cristob_morales
DEVOT
EXSCEL CANVASODYSSEY-DMTANDEMTOSCA-IT DEPICT-1CONCEPTT J-DOIT3 EMPAREG

52. Association between glycaemic variability,
hypoglycaemia and outcomes: the hypo-triad
1. Desouza CV et al. Diabetes Care 2010;33:1389–94; 2. Driesen NR et al. J Neurosci Res 2007;85:575–82;
3. Mooradian AD. Brain Res Brain Res Rev 1997;23:210–8; 4. Sanon VP et al. Clin Cardiol 2014;37:499–504;
5. Dhalla NS et al. J Hypertens 2000;18:655–73.
Glycaemic
variability
Hypoglycaemia
Outcomes

53. Hyperglycaemia
Glycaemic control: variability
BG, blood glucose; HbA1c, glycated haemoglobin.
Image adapted from Penckofer S et al. Diabetes Techno Ther 2012;14:303–10; Vora J & Heise T. Diabetes Obes Metab 2013;15:701–12.
Hypoglycaemia
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24
0
6
2
4
10
12
14
16
18
22
Time (hours)
BG(mmol/L)
36
72
108
144
180
216
252
288
324
BG(mg/dL)
Mean BG ≈ HbA1c 7.8%
8
0
Patient A
Low variability
Patient B
High variability

54. Hyperglycaemia
Hypoglycaemia
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24
0
6
2
4
10
12
14
16
18
22
Time (hours)
BG(mmol/L)
36
72
108
144
180
216
252
288
324
BG(mg/dL)
Mean BG ≈ HbA1c 7.8%
8
0
Patient A
Low variability
Patient B
High variability
Glycaemic control: similar HbA1c, different profile
BG, blood glucose; HbA1c, glycated haemoglobin.
Image adapted from Penckofer S et al. Diabetes Techno Ther 2012;14:303–10; Vora J & Heise T. Diabetes Obes Metab 2013;15:701–12.

55. VARIABILIDAD GLUCÉMICA

56. Measuring day-to-day fasting
glycaemic variability
Pre-specified analysis
Standard deviation of the pre-
breakfast SMBG measurements
=
Day-to-day fasting glycaemic
variability measurement
Mean monthly
variances

57. 0 5 10 15 20
0
2
4
6
8
10
12
14
16
0 5 10 15 20
Pre-breakfastSMBG
(mmol/L)
0
50
100
150
200
250
0 5 10 15 20
(mg/dL)
Patient with
high variability
Patient with
low variability
Patient with
medium variability
Months since randomisation
Patients with low, medium, and high
day-to-day variability
Representative fasting SMBG profiles from three separate DEVOTE patients.
SMBG, self-measured blood glucose.
Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z.

58. Patient characteristics by tertile
Full analysis set (all randomised patients); data listed are number (proportion [%]) or mean ± standard deviation. Percentage refers to the
proportion of patients on IDeg or IGlar U100 treatment. aIncluding 2 patients with age <50 years. bIncluding 1 patient with age <50 years. cPatients
with missing age information or age <50 years, but who fulfilled at least one of the inclusion criteria for established CVD/CKD were included.
dPatients with missing age information and who only fulfilled the inclusion criteria for CVD risk factors were not included.
CKD; chronic kidney disease; CKD-EPI, CKD epidemiology collaboration formula; CVD, cardiovascular disease; eGFR, estimated glomerular filtration
rate; HbA1c, glycated haemoglobin.
Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z.
Low variability
n=2528
Medium variability
n=2530
High variability
n=2528
Age, years 64.7 ± 7.4a 65.0 ± 7.3b 65.3 ± 7.4
Men, n (%) 1617 (64.0) 1621 (64.1) 1515 (59.9)
Region, n (%)
North America 1506 (59.6) 1760 (69.6) 1973 (78.0)
Europe 456 (18.0) 278 (11.0) 131 (5.2)
South America 143 (5.7) 194 (7.7) 247 (9.8)
India 204 (8.1) 100 (4.0) 51 (2.0)
Asia excluding India 136 (5.4) 95 (3.8) 60 (2.4)
Africa 83 (3.3) 103 (4.1) 66 (2.6)
Age ≥50 years and established CVD or CKDc 2147 (84.9) 2148 (84.9) 2172 (85.9)
Diabetes duration, years 14.1 ± 8.1 16.3 ± 8.6 18.8 ± 9.3
HbA1c, %
[mmol/mol]
8.1 ± 1.6
[65.4 ± 17.3]
8.4 ± 1.6
[68.2 ± 17.5]
8.8 ± 1.7
[72.2 ± 18.6]
Change in HbA1c from baseline to 24 months, %
[mmol/mol]
-0.8 ± 1.4
[-8.6 ± 15.8]
-0.9 ± 1.6
[-10.0 ± 17.2]
-0.8 ± 1.6
[-9.3 ± 17.5]
Fasting plasma glucose, mmol/L
[mg/dL]
9.2 ± 3.5
[165.8 ± 63.1]
9.5 ± 3.7
[171.2 ± 66.7]
9.9 ± 4.4
[178.4 ± 79.3]
eGFR (ml/min/1.73m2) based on CKD-EPI 70.5 ± 21.1 68.7 ± 21.3 64.7 ± 21.8

59. Outcomes by variability tertile
Rate, events per 100 patient-years of observation.
MACE, major adverse cardiovascular event.
Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z.
0
1
2
3
4
5
6
Severe hypoglycaemia MACE All-cause mortality
Rate(events/100patient-years
ofobservation)
Low variability
Medium variability
High variability

60. Hazard ratio [95% CI] p-value
Severe hypoglycaemia
Unadjusted 4.11 [3.15; 5.35] <0.0001
Adjusted for HbA1c 4.15 [3.17; 5.44] <0.0001
Adjusted for HbA1c and BC 3.37 [2.52; 4.50] <0.0001
MACE
Unadjusted 1.36 [1.12; 1.65] 0.0023
Adjusted for HbA1c 1.30 [1.06; 1.58] 0.0101
Adjusted for HbA1c and BC 1.21 [0.98; 1.49] 0.0811
All-cause mortality
Unadjusted 1.58 [1.23; 2.03] 0.0004
Adjusted for HbA1c 1.53 [1.19; 1.98] 0.0011
Adjusted for HbA1c and BC 1.33 [1.01; 1.75] 0.0432
0.5 1.0 2.0 4.0 8.0
Association between day-to-day fasting glycaemic
variability and outcomes on a continuous scale
Adjusted for HbA1c: most recent HbA1c on a continuous scale. Adjusted for HbA1c and BC: most recent HbA1c on a continuous scale and BC (IMP, sex,
region, age, smoking status, diabetes duration, CV risk-group inclusion criteria, insulin-naïve at BL and renal function (eGFR).
BC, baseline characteristics; BL, baseline; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate;
HbA1c, glycated haemoglobin; IMP, investigational medicinal product; MACE, major adverse cardiovascular event.
Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z.
Hazard ratio [95% CI]

61. HbA1c, glycated haemoglobin; MACE, major adverse cardiovascular event.
Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z.
• Day-to-day fasting glycaemic variability was significantly
associated with:
• Severe hypoglycaemia, both before and after adjustments
• All-cause mortality, both before and after adjustments
• MACE before adjustments
• The significant association was lost after adjusting for baseline characteristics with
the most recent HbA1c measurement
• Patients may benefit from a basal insulin that has low day-to-day
variability and therefore provides consistent fasting glycaemia
Summary
Impact of glycaemic variability on outcomes in DEVOTE

62. Association between glycaemic variability,
hypoglycaemia and outcomes: the hypo-triad
1. Desouza CV et al. Diabetes Care 2010;33:1389–94; 2. Driesen NR et al. J Neurosci Res 2007;85:575–82;
3. Mooradian AD. Brain Res Brain Res Rev 1997;23:210–8; 4. Sanon VP et al. Clin Cardiol 2014;37:499–504;
5. Dhalla NS et al. J Hypertens 2000;18:655–73.
Glycaemic
variability
Hypoglycaemia
Outcomes

63. Risk of MACE and all-cause mortality following
a severe hypoglycaemic event
CI, confidence interval; MACE, major adverse cardiovascular event; n, number of patients; R, events per 100 patient-years of observation.
Pieber TR B et al. Diabetologia 2017;doi10.1007/s00125-017-4422-0.
Hazard ratio
[95% CI]
With prior
severe
hypoglycaemia
Without prior
severe
hypoglycaemia
n R n R
First 3-point MACE 1.38 [0.96; 1.96] 32 6.34 649 4.57
First 4-point MACE 1.37 [0.99; 1.91] 37 7.44 768 5.47
Individual components
Non-fatal myocardial infarction 0.74 [0.36; 1.49] 8 1.57 305 2.13
Non-fatal stroke 1.81 [0.92; 3.57] 9 1.76 141 0.97
Cardiovascular death (including unknown) 2.14 [1.37; 3.35] 21 4.05 257 1.76
Unstable angina requiring hospitalisation 1.34 [0.59; 3.04] 6 1.18 139 0.96
All-cause mortality 2.51 [1.79; 3.50] 38 7.32 385 2.64
0.25 0.5 1 2 4
Hazard ratio
[95% CI]
Higher risk of MACE/all-cause mortality
any time following severe hypoglycaemia

64. Window (days)
Hazard ratio
[95% CI]
With prior severe
hypoglycaemia in window
Without prior severe
hypoglycaemia in window
n R n R
Any time 2.51 [1.79; 3.50] 38 7.32 385 2.64
365 days 2.78 [1.92; 4.04] 30 7.78 393 2.67
180 days 3.13 [1.99; 4.90] 20 8.56 403 2.71
90 days 3.28 [1.85; 5.83] 12 8.95 411 2.74
60 days 2.74 [1.30; 5.79] 7 7.40 416 2.77
30 days 3.66 [1.51; 8.84] 5 9.84 418 2.77
15 days 4.20 [1.35; 13.09] 3 11.23 420 2.78
0.25 0.5 1 2 4 8 16
Risk of all-cause death following a severe
hypoglycaemic event by time period
CI, confidence interval; n, number of patients; R, events per 100 patient-years of observation.
Pieber TR B et al. Diabetologia 2017;doi10.1007/s00125-017-4422-0.
Hazard ratio [95% CI]
Higher risk of all-cause death any time
following severe hypoglycaemia

65. Introducing the hypoglycaemia risk score
Follow this link to access the
hypoglycaemia risk score:
http://www.hyporiskscore.com/

66. Basal only
Basal bolus
Insulin naïve
FemaleMale
Age
HbA1c
Duration of diabetes
40 years 90 years
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Medium
Moderately high
High
Very high
0 2 4 6 8 10 12
Rate of hypoglycaemia per 100 years
10
5
0
Hypoglycaemia risk group
Medium Moderately high High Very high
Risk of having a severe hypoglycaemic episode within 2 years
Total
Total
Risk of having a major adverse cardiovascular event within 2 years
MACEincidence(%)
0%
67
10.4%
16
Male
Insulin naïve
3.8%

67. Basal only
Basal bolus
Insulin naïve
FemaleMale
Age
HbA1c
Duration of diabetes
40 years 90 years
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
0 2 4 6 8 10 12
Rate of hypoglycaemia per 100 years
10
5
0
Hypoglycaemia risk group
Medium Moderately high High Very high
Risk of having a severe hypoglycaemic episode within 2 years
Risk of having a major adverse cardiovascular event within 2 years
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
3.8%
Basal only
Insulin naïve
4.1%

68. Basal only
Basal bolus
Insulin naïve
FemaleMale
Age
HbA1c
Duration of diabetes
40 years 90 years
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Risk of having a severe hypoglycaemic episode within 2 years
Insulin naïve
Basal only
0 2 4 6 8 10 12
Rate of hypoglycaemia per 100 years
10
5
0
Hypoglycaemia risk group
Medium Moderately high High Very high
Risk of having a major adverse cardiovascular event within 2 years
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
4.1%
13.7
4.8%

69. Basal only
Basal bolus
Insulin naïve
FemaleMale
HbA1c
Duration of diabetes
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Risk of having a severe hypoglycaemic episode within 2 yearsAge
40 years 90 years
0 2 4 6 8 10 12
Rate of hypoglycaemia per 100 years
10
5
0
Hypoglycaemia risk group
Medium Moderately high High Very high
Risk of having a major adverse cardiovascular event within 2 years
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
4.8%
FemaleMale
6.7%

70. Basal only
Basal bolus
Insulin naïve
FemaleMale
HbA1c
Duration of diabetes
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Risk of having a severe hypoglycaemic episode within 2 yearsAge
40 years 90 years
0 2 4 6 8 10 12
Rate of hypoglycaemia per 100 years
10
5
0
Hypoglycaemia risk group
Medium Moderately high High Very high
Risk of having a major adverse cardiovascular event within 2 years
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
Basal only
Basal bolus
6.7%11.3%

71. DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARE
S
RESULTADOS
GLUCEMICOS
DEVOTE2&3
VARIABILIDAD
HIPOGLUCEMIAS
SEGURIDADCARDIOVASCULARDEGLUDEC

72. BORN TO PREVENT
@cristob_morales

73. @cristob_morales
La Variabilidad, las Hipoglucemias están ahí fuera…

74. @Cristob_Morales

75. HIPOs
TIEMPO EN
RANGO
VARIABILIDAD
GLUCEMICA
A1c
@cristob_morales

77. EFICACIA_A1c
EFICACIA_A1c
NO HIPOs
@cristob.morales
NUESTRAS EXIGENCIAS AUMENTAN
EFICACIA_A1c
NO HIPOs ++++
VARIABILIDAD
FLEXIBILIDAD
SEGURIDAD CARDIOVASCULAR

78. VARIABILIDAD
5RAZONES
PARA ELEGIR
1 INSULINA
@Cristob.Morales

79. @Cristob_Morales
La clave del éxito
es la
PERSONALIZACION

80. MANAGEMENT OF T2DM
PREVENTION OF
MICROVASCULAR
COMPLICATIONS
PREVENTION OF
CARDIOVASCULAR
DISEASE
Driven by
A1c
reduction
irrespectively
of tratment
regimen
Driven by
drug
strategy
(agents) more
than A1c
reduction
@Cristob_MoralesAdapted from Guillermo Umpierrez
“Think about Micro, think about Macro “