DEVOTE: CARDIOVASCULAR SAFETY OF INSULIN DEGLUDEC (ADA2017 Y EASD2017)

DEVOTE
Comparing Cardiovascular Safety of
Insulin Degludec
versus Insulin Glargine in Patients
with Type 2 Diabetes at High
Risk of Cardiovascular Events
Degludec Cardiovascular Outcomes Trial

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

GRACIAS POR SER COMPAÑEROS EN NUESTRO SUEÑO
DE CAMBIAR LA DIABETES

DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARES
RESULTADOS
GLUCEMICOS
DEVOTE
SPAIN
DEVOTE-1(ADA2017)

ESTUDIOS DE SEGURIDAD
CARDIOVASCULAR EN DM2

Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
DEVOTESTUDYADASYMPOSIUM12062017Ver.1.0
Background to DEVOTE
Advancements
Time
Animal
insulin
preparations
Recombinant
human
insulin Rapid-acting
analogs
Basal
analogs
First patient
treated with
insulin
(Banting & Best)
Biphasic
analogs
2010s
1990s
1977
1922
New generation
analogs
2000s
2008
FDA guidance released
2003
ORIGIN initiated
2011
ORIGIN completed
2012
NDA submitted and additional
analyses requested
2013
Request for dedicated CVOT
DEVOTE initiated
2016
DEVOTE completed
CVOT, cardiovascular outcomes trial; FDA, Food and Drug Administration; NDA, new drug application. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER). December 2008 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm071627.pdf); The ORIGIN Trial Investigators. N Engl J Med 2012;367:319-28

DEVOTEDegludec Cardiovascular Outcomes Trial

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
AUCGIR, area under the curve for glucose infusion rate; IGlar U100, insulin glargine U100
Insulin glargine image data on file; Jonassen et al. Pharm Res. 2012;29:2104–14; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; Heise et al. Diabetes
Obes Metab 2012;14:859–64

Trial description
Secondary
objective
To assess the efficacy and safety of insulin degludec in patients
with type 2 diabetes at high risk of cardiovascular events
Primary
objective
To confirm the cardiovascular safety of insulin degludec
compared to that of insulin glargine U100
Trial
characteristics
•  Randomized, double blinded, active controlled
•  Treat-to-target
•  Event driven

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)

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

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

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%)

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

Baseline medications
*Nine patients have missing initiation drug date; they are assumed to be on treatment at baseline
Parameter Insulin degludec IGlar U100
Total number of patients, n 3818 3819
Antihyperglycemic treatment (excluding insulins), %
Metformin 60.1 59.4
Sulfonylurea 29.3 29.1
Dipeptidyl peptidase-4 inhibitors 12.1 12.6
Glucagon-like peptide-1 receptor agonists 7.9 8.0
Thiazolidinedione 3.8 3.2
Sodium-dependent glucose transporter-2 inhibitors 2.1 2.3
Alpha-glucosidase inhibitors 1.7 1.8
Others 1.3 1.8
Insulins, %
Any insulin 84.2 83.7
Basal insulin only 38.1 37.7
Basal–bolus insulin (including bolus-only and pre-mix) 46.1 46.0
Cardiovascular medications, %
Antihypertensive therapy* 93.2 93.0
Lipid-modifying medications* 82.4 81.9
Platelet aggregation inhibitors* 72.0 71.8
Anti-thrombotic medication* 8.1 7.6

Primary endpoint and analysis of 3-point MACE
*CV death includes undetermined cause of death
CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction
Primary endpoint
•  Time to first event of adjudication-confirmed 3-point MACE (CV death*,
non-fatal MI, non-fatal stroke)
Test of non-inferiority for primary endpoint
•  Confirmed if upper bound of the 95% CI is below 1.3
1.0
HR [95% CI]
1.3
Randomization
date
Non-fatal MI CV death
Patient with event(s)
Non-fatal stroke
Time to 1st MACE event
Time to 1st Non-fatal MI Time to 1st
non-fatal stroke
Patient without event(s)
Last contactRandomization
date
Time to primary endpoint – censoredTime to CV death

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 patientsRate:
4.71/100 PYO
Rate:
4.29/100 PYO

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]
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

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
1.0

Subgroup analyses of time to first 3-point MACE
†Includes basal/bolus, bolus only and premix
Factor N %
Hazard ratio
[95% CI]
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
1.0

Treat-to-target titration algorithms
The alternative titration algorithm was not specified in the protocol
SMBG, self-measured blood glucose
Protocol guidance to
achieve glycemic targets
(71–90 mg/dL)
Lowest of three pre-breakfast SMBG values
once weekly
Basal insulin
adjustment
mg/dL mmol/L Units
<71 <4.0 -2
71–90 4.0–5.0 0
91–126 5.1–7.0 +2
>126 >7.0 +4
Lowest of three pre-breakfast SMBG values
once weekly
Basal insulin
adjustment
mg/dL mmol/L Units
<90 <5.0 -2
91–126 5.1–7.0 0
>126 >7.0 +2
Alternative titration guidance
(91–126 mg/dL)

Basal insulin dose (U/kg)
Full analysis set
IGlar U100, insulin glargine U100; N, number of patients; U, units
0,0
0,2
0,4
0,6
0,8
1,0
1,2
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Basalinsulindose(U/kg)
Insulin degludec (N) 3724 3575 3424 3290 1125 55
IGlar U100 (N) 3717 3542 3385 3239 1134 61
Months since randomization
Insulin degludec
IGlar U100

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
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
ET
Insulin degludec
IGlar U100
7.55%
7.50%

Significant reduction of FPG with insulin degludec
compared with 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
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
Insulin degludec
IGlar U100

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

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

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

Factor N %
Rate ratio
[95% CI]
interactionE R E R
Confirmatory secondary analysis 7637 100.0 0.60 [0.48; 0.76] 280 3.70 472 6.25
Sex 0.038
Women 2859 37.4 0.46 [0.32; 0.66] 110 3.91 244 8.59
Men 4778 62.5 0.76 [0.56; 1.02] 170 3.57 228 4.83
Age at baseline 0.834
<65 years 3662 48.2 0.59 [0.42; 0.82] 126 3.47 219 5.99
≥65 years 3955 51.7 0.62 [0.45; 0.85] 154 3.91 253 6.49
BMI 0.254
<30 kg/m2 2499 32.7 0.73 [0.49; 1.11] 97 3.92 131 5.51
≥30 kg/m2 5125 67.1 0.55 [0.41; 0.73] 183 3.60 341 6.59
Renal function* 0.992
Normal 1486 19.4 0.63 [0.37; 1.08] 48 3.31 80 5.42
Mild impairment 3118 40.8 0.62 [0.43; 0.91] 97 3.05 150 4.96
Moderate impairment 2704 35.4 0.63 [0.43; 0.92] 121 4.63 205 7.51
Severe impairment 214 2.8 0.77 [0.21; 2.85] 13 6.19 15 7.42
Subgroup analyses of severe hypoglycemic events
*As per CKD-EPI
BMI, body mass index; CKD-EPI, chronic kidney disease epidemiology collaboration equation
1.0

Factor N %
Rate ratio
[95% CI]
interactionE R E R
Confirmatory secondary analysis 7637 100.0 0.60 [0.48; 0.76] 280 3.70 472 6.25
Diabetes duration 0.580
≤15 years 3740 48.9 0.64 [0.46; 0.91] 115 3.19 194 5.08
>15 years 3895 51.0 0.56 [0.41; 0.77] 165 4.16 278 7.44
CV risk group 0.014
Established CV disease 6509 85.2 0.52 [0.40; 0.66] 228 3.51 438 6.82
Risk factors for CV disease 1105 14.5 1.24 [0.65; 2.38] 38 3.62 34 3.03
Baseline insulin regimen 0.562
Basal only 2894 37.9 0.50 [0.34; 0.75] 73 2.54 145 5.08
Basal–bolus† 3297 46.0 0.63 [0.46; 0.87] 184 5.27 294 8.50
Insulin naïve 1228 16.1 0.73 [0.37; 1.45] 23 1.91 33 2.65
Region 0.090
North America 5271 69.0 0.54 [0.41; 0.70] 203 3.81 385 7.19
Europe 875 11.4 0.73 [0.32; 1.71] 15 1.79 20 2.38
Asia 649 8.5 1.23 [0.55; 2.76] 28 4.61 24 3.86
South America 585 7.7 1.33 [0.56; 3.18] 26 4.76 18 3.54
Africa 257 3.4 0.31 [0.09; 1.09] 8 3.19 25 10.71
Subgroup analyses of severe hypoglycemic events
†Includes basal/bolus, bolus only and premix
CV, cardiovascular
1.0

Mean age (years):
65.6 65.0
Females:
31.7% 37.4%
Mean diabetes
duration (years):
17.2 16.4
Established CVD/CKD
(age ≥ 50 years):
83.3% 85.2%
Mean HbA1c:
7.90% 8.43%
Mean BMI (kg/m2
):
31.8 33.6
Mean FPG (mmol/l):
8.71 9.53
Severe renal impairment:
1.7% 2.8%
The average
patient at baseline
Spain
SPAIN
Insulin regimen
at baseline
CV medication
at baseline
10.0PATIENTS
PER SITE6SITES60PATIENTS
RANDOMISED 100%CONFIRMED VITAL
STATUS AT END OF TRIAL
MACE rate
per 100 PYO*
8.68
5.28
Severe
hypoglycaemia
rate per 100 PYO*
2.60
4.97
Spain
data
Global
data
0%
10%
20%
30%
40%
50%
60%
70%
Insulin-naïve
16.1
37.9 36.7
11.7
51.7
46.0
Basal only Basal-bolus
0%
20%
40%
60%
80%
100%
Antihypertensive
theraphy
Diuretics Lipid
lowering
Platelet
aggr. inhib.
Anti-
thrombotic
96.7
93.1
56.7
50.0
82.2
71.9
95.0
75.0
11.7
7.8
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Metformin SU Alpha
glucosidase inhib.
TZD DPP-4 GLP-1 SGLT2 Other
59.8
86.7
6.7
29.2
12.3
33.3
7.91.70.0
20.0
1.7 3.33.51.7 2.2 1.5
Mean HbA1c during trial
7,550 7,296 7,170 7,051 7,025 4,882 6,621
0 3 6 9 12 24 End treatment visit
HbA1c
(%)
Months since randomisation
HbA1c
(mmol/mol)
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Total
47.6
53.0
58.5
63.9
69.4
74.9
80.3
85.8
60 59 58 58 60 39 54ESP
GlobalSpain
Number of
patients
Mean FPG during trial
0 12 24 End treatment visit
FPG(mmol/l)
FPG(mg/dl)
5
6
7
8
9
10
11
90.1
108.1
126.1
144.2
162.2
180.2
198.2
60 60 41 57ESP
7,517 7,019 4,882 6,622Total
GlobalSpain
Number of
patients
Antidiabetic
medications at baseline
Spain
data
Global
data
Spain Global
Spain Global
Spain Global
*Patient Years of Observation
Version 2.0 – 01 u ust 2017
Not for further distribution

DISEÑO
DEL ESTUDIO
RESULTADOS
CVASCULARES
RESULTADOS
GLUCEMICOS
DEVOTE
SPAIN
CONCLUSIONES
DEVOTE-1(ADA2017)

DEVOTE summary
CI, confidence interval; EAC, Event Adjudication Committee; HR, hazard ratio; IGlar U100, insulin glargine U100; MACE, major adverse cardiovascular events;
N, number of patients at risk; PYO, patient-years of observation
•  DEVOTE confirmed the cardiovascular safety of insulin degludec
in comparison with insulin glargine (both U100)
•  DEVOTE reported 752 adjudication-confirmed severe
hypoglycemic events in a blinded head-to-head trial
•  A 40% lower rate of severe hypoglycemia was confirmed at similar
levels of HbA1c
•  A 53% lower rate of nocturnal severe hypoglycemia was confirmed
at a lower fasting plasma glucose
3-point MACE (primary)
HR: 0.91
[0.78; 1.06]95% CI
Non-inferiority confirmed
p<0.001
Severe hypoglycemia
Rate ratio: 0.60
[0.48; 0.76]95% CI
Superiority confirmed
p<0.001
Nocturnal severe hypoglycemia
Rate ratio: 0.47
[0.31; 0.73]95% CI
p<0.001

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

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
-40
-20
0
Reducciónenla
incidenciade
-60
-40
-20
0
Reducciónenla
incidenciade
-54%*
PACIENTES DM2 ALTO RCV
(Población DEVOTE)
NNT HIPOGLUCEMIAS SEVERAS

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
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

u DEVOTE Es el primer ensayo doble ciego de
resultados cardiovasculares con una
comparación directa de dos insulinas basales
u DEVOTE confirma la seguridad cardiovascular
de Ideg en DM2
u Se confirman los hallazgos previos en
beneficio hipoglucémico a un nivel similar de
control glucémico demostrados en BEGIN y
SWITCH 2

Muchas Gracias IDeg Spanish TEAM!

@cristob_morales
DEVOTE 2-3
EXSCEL CANVASODYSSEY-DM TANDEM TOSCA-IT DEPICT-1 CONCEPTT J-DOIT3 EMPAREG

VARIABILIDAD
GLUCEMICA Y ECV
HIPOGLUCEMIAS
SEVERAS Y ECV
IMPLICACIONES
CLINICAS
RESULTADOS DEVOTE 2&3
DEVOTE-23(EASD2017)

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

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%
(61.7 mmol/mol)
8
0
Patient A
Low variability
Patient B
High variability

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%
(61.7 mmol/mol)
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.

The relationship between glycaemic variability
and hypoglycaemia is established
Bode et al. Diabetologia 2013;56(Suppl. 1):S423

Lower day-to-day variability in glucose-lowering
effect for IDeg versus IGlar U100
*CV% was pre-specified.
AUC, area under the curve; CV, coefficient of variation; GIR, glucose infusion rate; SMPG, self-measured plasma glucose.
Heise T et al. Diabetes Obes Metab 2012;14:859-64.
0
25
50
75
100
125
150
175
200
225
250
275
Day-to-dayvariabilityin
AUCGIR(CV%)
Injection Time interval (hour)
CV% ratio*
IGlar U100/IDeg 4.10
IDeg vs. IGlar U100
SMPG
IDeg
IGlar U100

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

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
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.

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.
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

Outcomes by variability tertile
Rate, events per 100 patient-years of observation.
MACE, major adverse cardiovascular event.
0
1
2
3
4
5
6
Severe hypoglycaemia MACE All-cause mortality
Rate(events/100patient-years
ofobservation)
Low variability
Medium variability
High variability

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.

HbA1c, glycated haemoglobin; MACE, major adverse cardiovascular event.
•  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

Severe hypoglycaemia is associated with MACE
and all-cause mortality across CVOTs
CVOT, cardiovascular outcomes trial; MACE, major adverse cardiovascular event.
1. ACCORD Study Group. N Engl J Med 2008;358:2545–59; 2. Zinman B et al. Diabetes. 2017;66(Suppl. 1):A95;
3. Duckworth WC et al. J Diabetes Complications 2011;25:355-61; 4. Duckworth W et al. N Engl J Med 2009;360:129–39;
5. Goto A et al. BMJ 2013;347:f4533; 6. Bonds DE et al. BMJ 2010;340:b4909; 7. Zoungas S et al. N Engl J Med 2010;363:1410–8, for the
ADVANCE Collaborative Group; 8. Mellbin LG et al. Eur Heart J 2013;34:3137–44 for the ORIGIN Trial Investigators.
VADT
ACCORD
ADVANCE
EXAMINE
ORIGIN
LEADER

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

Risk of MACE following a severe hypoglycaemic
event by time period
CI, confidence interval; MACE, major adverse cardiovascular event; n, number of patients; R, events per 100 patient-years of observation.
Window (days)
Hazard ratio
[95% CI]
With prior severe
hypoglycaemia in
window
Without prior severe
hypoglycaemia in
window
n R n R
Any time 1.38 [0.96; 1.96] 32 6.34 649 4.57
365 days 1.15 [0.74; 1.79] 20 5.34 661 4.62
180 days 1.24 [0.72; 2.15] 13 5.74 668 4.62
90 days 1.12 [0.53; 2.37] 7 5.28 674 4.63
60 days 1.16 [0.48; 2.80] 5 5.46 676 4.63
30 days 1.28 [0.41; 3.99] 3 6.10 678 4.63
15 days 0.82 [0.11; 5.80] 1 3.87 680 4.64
0,0625 0,125 0,25 0,5 1 2 4 8
Higher risk of MACE any time following
severe hypoglycaemia

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.
Higher risk of all-cause death any time
following severe hypoglycaemia

MACE, major adverse cardiovascular event.
•  No significant association between severe hypoglycaemia and MACE
•  A significantly higher risk of cardiovascular death following a severe
hypoglycaemic event
•  Significant association between severe hypoglycaemia and
all-cause mortality
•  This includes a temporal relationship between these parameters
•  This indicates severe hypoglycaemia is associated with higher
subsequent mortality
Summary
Severe hypoglycaemia and association to outcomes

Reproducibility in comparative hypoglycaemia
rates with IDeg across RCTs and RWE
*Significant difference. Data are from the full treatment period.
CI, confidence interval; RCT, randomised controlled trial; RWE, real-world evidence; T1D, type 1 diabetes; T2D, type 2 diabetes.
1. Ratner RE et al. Diabetes Obes Metab 2013;15:175–84; 2. Wysham C et al. JAMA 2017;318:45–56;
3. Marso SP et al. N Engl J Med 2017;377:723-732.
Estimated rate ratio [95% CI]
RCTs
Phase 3a
Overall confirmed 0.83 [0.74; 0.94]*
Nocturnal confirmed 0.68 [0.57; 0.82]*
Severe 0.81 [0.42; 1.56]
SWITCH 2
Overall confirmed 0.77 [0.70; 0.85]*
Nocturnal confirmed 0.75 [0.64; 0.89]*
Severe 0.49 [0.26; 0.94]*
DEVOTE
Nocturnal severe 0.47 [0.31; 0.73]*
Severe 0.60 [0.48; 0.76]*
RWE
EU-TREAT
Overall 0.21 [0.11; 0.38]*
Non-severe nocturnal 0.09 [0.03; 0.28]*
Severe 0.08 [0.01; 0.85]*
Favours IDeg Favours comparator
0,01 0,02 0,03 0,06 0,13 0,25 0,50 1,00 2,00

Severe hypoglycaemia, MACE and all-cause
mortality
MACE, major adverse cardiovascular event; T2D, type 2 diabetes.
1. Adapted from Yeh JS et al. Acta Diabetol 2016;53:377–92; 2. Adapted from Bonds DE et al. BMJ 2009;339:b4909;
3. Adapted from Mellbin LG et al. Eur Heart J 2013;34:3137–44 for the ORIGIN Trial Investigators;
4. Adapted from Zoungas S et al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group.
Systematic review: hypoglycaemia is
associated with adverse outcomes1
ACCORD: the association between
hypoglycaemia* and mortality in T2D2
ORIGIN: severe hypoglycaemia is associated
with increased risk of adverse outcomes3
ADVANCE: severe hypoglycaemia is associated
with increased risk of adverse outcomes4

LEADER: severe hypoglycaemia, all-cause
mortality and cardiovascular outcomes
*Adjusted for concomitant insulin use during the trial
Zinman B et al. Diabetes 2017;66(Suppl. 1):A95.
Risk of all-cause mortality in
patients with vs. without severe
hypoglycaemia
Risk of MACE in patients with vs.
without severe hypoglycaemia*
Any time
≤365 days after
≤180 days
≤90 days
≤60 days
≤30 days
≤15 days
≤7 days
0,1 1 10 100 0,1 1 10 100 0.1 1 10 100
0.1 1 10 100

1. Marso SP et al. N Engl J Med 2017;377:723-732; 2. Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z;
3. Pieber TR B et al. Diabetologia 2017;doi10.1007/s00125-017-4422-0.
•  Several clinical outcome trials and observational studies have
demonstrated an association between severe hypoglycaemia
and outcomes
•  Potential pathogenic mechanisms could explain a causal association
•  DEVOTE is consistent with data demonstrating an association
between severe hypoglycaemia and mortality
•  It is most likely that hypoglycaemia is a single contributory factor
of cardiovascular events in a much larger multifactorial landscape
Overall summary

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

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%

Basal only
Basal bolus
Insulin naïve
FemaleMale
Age
HbA1c
40 years 90 years
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
0 2 4 6 8 10 12
10
5
0
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
3.8%
Basal only
Insulin naïve
4.1%

Basal only
Basal bolus
Insulin naïve
FemaleMale
Age
HbA1c
40 years 90 years
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Insulin naïve
Basal only
0 2 4 6 8 10 12
10
5
0
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
4.1%
13.7
4.8%

Basal only
Basal bolus
Insulin naïve
FemaleMale
HbA1c
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
10
5
0
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
4.8%
FemaleMale
6.7%

Basal only
Basal bolus
Insulin naïve
FemaleMale
HbA1c
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
10
5
0
MACEincidence(%)
Total
Total
Medium
Moderately high
High
Very high
Basal only
Basal bolus
6.7%11.3%

HIPOs
VARIABILIDAD
GLUCEMICA
TIEMPO EN
RANGO
A1c
@cristob_morales

BORN TO PREVENT
@cristob_morales
DIETA
EJERCICIO
SGLT2/GLP1
SMOKING
HTALIPIDOS
ANTIAGREG

VARIABILIDAD CV)
HIPOGLUCEMIAS
TIEMPO EN RANGO
(%)
@cristob_morales
Más allá de la A1c… La Variabilidad está ahí fuera

EFICACIA_A1c EFICACIA_A1c
NO HIPOs
@cristob.morales
NUESTRAS EXIGENCIAS AUMENTAN
EFICACIA_A1c
NO HIPOs ++++
VARIABILIDAD
DURACION
FLEXIBILIDAD

HIPOs
VARIABILIDAD
FLEXIBILIDAD
DISPOSITIVO
5RAZONES
PARA ELEGIR
1 INSULINA
@Cristob.Morales

@Cristob_Morales
La clave del éxito
es la
PERSONALIZACION

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

DM2-P2
GUIA DE TRATAMIENTO DE LA DM2
EN PREVENCION SECUNDARIA
By Cardio, Nefro y Endocrino
@cristob.morales

DEVOTE: CARDIOVASCULAR SAFETY OF INSULIN DEGLUDEC (ADA2017 Y EASD2017)

DEVOTE: CARDIOVASCULAR SAFETY OF INSULIN DEGLUDEC (ADA2017 Y EASD2017)

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