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
Jan 22, 2018
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
HDD HOSPITAL DE DIA DE DIABETES
HOSPITAL VIRGEN MACARENA. SEVILLA
AÑOS
@C
risto
b_M
oral
es
CR.MORALES2016
GRACIAS POR SER COMPAÑEROS EN NUESTRO SUEÑO DE CAMBIAR LA DIABETES
DISEÑO DEL ESTUDIO RESULTADOS CVASCULARES RESULTADOS GLUCEMICOS DEVOTE SPAIN
DEVO
TE-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
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Background to DEVOTE A
dvan
cem
ents
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
DEVOTE Degludec Cardiovascular Outcomes Trial
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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)
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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DEVOTE – a global trial
KOREA 4 sites 61 patients
JAPAN 7 sites 61 patients
MALAYSIA 8 sites 102 patients
THAILAND 6 sites 68 patients INDIA
26 sites 357 patients
SOUTH AFRICA 15 sites 194 patients
ARGENTINA 4 sites 120 patients
BRAZIL 10 sites 303 patients
UNITED STATES 269 sites 5201 patients
MEXICO 7 sites 162 patients
CANADA 6 sites 70 patients
ALGERIA 6 sites 63 patients
RUSSIAN FEDERATION 20 sites 240 patients
SPAIN 6 sites 60 patients
GREECE 6 sites 90 patients
ROMANIA 4 sites 84 patients
UNITED KINGDOM 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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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%)
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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 contact Randomization date
Time to primary endpoint – censored Time to CV death
DISEÑO DEL ESTUDIO RESULTADOS CVASCULARES RESULTADOS GLUCEMICOS DEVOTE SPAIN
DEVO
TE-1 (ADA2017)
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10
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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
Pat
ient
s w
ith a
n ev
ent (
%)
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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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 U100 Favors insulin degludec
1.0 1.3
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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 U100 Favors insulin degludec
1.0
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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 U100 Favors insulin degludec
1.0
DISEÑO DEL ESTUDIO RESULTADOS CVASCULARES RESULTADOS GLUCEMICOS DEVOTE SPAIN
DEVO
TE-1 (ADA2017)
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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)
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Bas
al in
sulin
dos
e (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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
HbA
1c (%
)
75
69
64
59
53
0
HbA
1c (mm
ol/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%
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
mm
ol/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% CI ET
FPG
(mm
ol/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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Mea
n nu
mbe
r of
even
ts/1
00 P
YO
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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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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
Mea
n nu
mbe
r of
even
ts/1
00 P
YO
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
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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Factor N % Rate ratio [95% CI]
Insulin degludec IGlar U100 p-value for interaction E 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
Hazard ratio [95% CI] Favors IGlar U100 Favors insulin degludec
1.0
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
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Factor N % Rate ratio [95% CI]
Insulin degludec IGlar U100 p-value for interaction E 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
Hazard ratio [95% CI] Favors IGlar U100 Favors insulin degludec
1.0
DISEÑO DEL ESTUDIO RESULTADOS CVASCULARES RESULTADOS GLUCEMICOS DEVOTE SPAIN
DEVO
TE-1 (ADA2017)
Mean age (years):
65.6 65.0Females:
31.7% 37.4%Mean diabetes duration (years):
17.2 16.4Established CVD/CKD (age ≥ 50 years):
83.3% 85.2%Mean HbA1c:
7.90% 8.43%Mean BMI (kg/m2):
31.8 33.6Mean FPG (mmol/l):
8.71 9.53Severe renal impairment:
1.7% 2.8%
The average patient at baseline
Spain
SPAIN
Insulin regimen at baseline
CV medicationat baseline
10.0 PATIENTSPER SITE6 SITES60 PATIENTS
RANDOMISED 100%CONFIRMED VITALSTATUS AT END OF TRIAL
MACE rate per 100 PYO*
8.68 5.28
Severe hypoglycaemia
rate per 100 PYO*
2.60 4.97
Spaindata
Globaldata
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%
Antihypertensivetheraphy
Diuretics Lipidlowering
Plateletaggr. inhib.
Anti-thrombotic
96.793.1
56.750.0
82.2
71.9
95.0
75.0
11.77.8
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
HbA 1c
(%)
Months since randomisation
HbA1c (m
mol/m
ol)
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 ofpatients
Mean FPG during trial
0 12 24 End treatment visit
FPG
(mm
ol/l)
Months since randomisation
FPG (m
g/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 ofpatients
Antidiabetic medications at baseline
Spaindata
Globaldata
Spain Global
Spain Global
Spain Global
*Patient Years of Observation
Version 2.0 – 01 u ust 2017Not for further distribution
DISEÑO DEL ESTUDIO RESULTADOS CVASCULARES RESULTADOS GLUCEMICOS DEVOTE SPAIN CONCLUSIONES
DEVO
TE-1 (ADA2017)
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
DE
VO
TE S
TUD
Y A
DA
SY
MP
OS
IUM
120
6201
7 V
er. 1
.0
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
Redu
cció
n en
la
inci
denc
ia d
e
-60
-40
-20
0
Redu
cció
n en
la
inci
denc
ia d
e
-54%* PACIENTES DM2 ALTO RCV
(Población DEVOTE)
NNT HIPOGLUCEMIAS SEVERAS
Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA
DE
VO
TE S
TUD
Y A
DA
SY
MP
OS
IUM
120
6201
7 V
er. 1
.0
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 SWIT
CH
22
(Dou
ble
blin
d)
DEV
OTE
(D
oubl
e bl
ind)
Severe
Nocturnal severe
0,125 0,25 0,5 1 2 Favors IGlar U100 Favors insulin degludec
BEG
IN1
(Poo
led
T2D
O
pen
acce
ss)
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!
Muchas Gracias IDeg Spanish TEAM!
@cr
isto
b_m
oral
es
DEVOTE 2-3
EXSCEL CANVAS ODYSSEY-DM TANDEM TOSCA-IT DEPICT-1 CONCEPTT J-DOIT3 EMPAREG
VARIABILIDAD GLUCEMICA Y ECV HIPOGLUCEMIAS SEVERAS Y ECV IMPLICACIONES CLINICAS
RESULTADOS DEVOTE 2&3 D
EVOTE-2 3 (EASD
2017)
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
(m
mol
/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
(m
mol
/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.
VARIABILIDAD GLUCÉMICA
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-
day
variab
ility
in
AU
CG
IR (
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-
brea
kfas
t SM
BG
(m
mol
/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.
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
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
(ev
ents
/100
pat
ient
-yea
rs
of o
bser
vatio
n)
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. Zinman B et al. Diabetologia 2017;doi10.1007/s00125-017-4423-z.
Hazard ratio [95% CI]
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
VARIABILIDAD GLUCEMICA Y ECV HIPOGLUCEMIAS SEVERAS Y ECV IMPLICACIONES CLINICAS
RESULTADOS DEVOTE 2&3 D
EVOTE-2 3 (EASD
2017)
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
@Cristob_Morales
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. Pieber TR B et al. Diabetologia 2017;doi10.1007/s00125-017-4422-0.
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 Hazard ratio [95% CI]
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. 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
MACE, major adverse cardiovascular event. Pieber TR B et al. Diabetologia 2017;doi10.1007/s00125-017-4422-0.
• 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
VARIABILIDAD GLUCEMICA Y ECV HIPOGLUCEMIAS SEVERAS Y ECV IMPLICACIONES CLINICAS
RESULTADOS DEVOTE 2&3 D
EVOTE-2 3 (EASD
2017)
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]
RC
Ts
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]*
RW
E
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 1000,1 1 10 1000.1 1 10 100 Hazard ratio [95% CI]
0.1 1 10 100 Hazard ratio [95% CI]
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
Female Male
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
MA
CE
inci
den
ce (
%)
0%
67
10.4%
16
Male
Insulin naïve
3.8%
Basal only
Basal bolus
Insulin naïve
Female Male
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
MA
CE
inci
den
ce (
%)
Total
Total
Medium
Moderately high
High
Very high
3.8%
Basal only
Insulin naïve
4.1%
Basal only
Basal bolus
Insulin naïve
Female Male
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
MA
CE
inci
den
ce (
%)
Total
Total
Medium
Moderately high
High
Very high
4.1%
13.7
4.8%
Basal only
Basal bolus
Insulin naïve
Female Male
HbA1c
Duration of diabetes
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Risk of having a severe hypoglycaemic episode within 2 years Age 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
MA
CE
inci
den
ce (
%)
Total
Total
Medium
Moderately high
High
Very high
4.8%
Female Male
6.7%
Basal only
Basal bolus
Insulin naïve
Female Male
HbA1c
Duration of diabetes
15 %
30 years
5 %
0 years
Gender
Insulin treatment
?
Risk of having a severe hypoglycaemic episode within 2 years Age 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
MA
CE
inci
den
ce (
%)
Total
Total
Medium
Moderately high
High
Very high
Basal only
Basal bolus
6.7% 11.3%
HIPOs
VARIABILIDAD GLUCEMICA
TIEMPO EN
RANGO
A1c
@cr
isto
b_m
oral
es
BORN TO PREVENT
@cr
isto
b_m
oral
es
DIET
A EJ
ERCI
CIO
SGLT
2 /
GLP1
SMOK
ING
HTA
LIP
IDOS
AN
TIAG
REG
VARIABILIDAD CV)
HIPOGLUCEMIAS
TIEMPO EN RANGO (%)
@cr
isto
b_m
oral
es
Más allá de la A1c… La Variabilidad está ahí fuera
@Cristob_Morales
EFICACIA_A1c EFICACIA_A1cNOHIPOs
@cristob.morales
NUESTRASEXIGENCIASAUMENTAN
EFICACIA_A1cNOHIPOs++++VARIABILIDADDURACIONFLEXIBILIDAD
HIPOs
VARIABILIDAD
FLEXIBILIDAD
DISPOSITIVO
5RAZONES PARA ELEGIR 1 INSULINA
@Cristob.Morales
@Cristob_Morales
La clave del éxito es la PERSONALIZACION
MANAGEMENTOFT2DM
PREVENTIONOFMICROVASCULARCOMPLICATIONS
PREVENTIONOFCARDIOVASCULAR
DISEASE
DrivenbyA1creducLonirrespecLvelyoftratmentregimen
Drivenbydrug
strategy(agents)more
thanA1creducLon
@Cristob_Morales Adapted from Guillermo Umpierrez
“ThinkaboutMicro,thinkaboutMacro“
DM2-P2
GUIA DE TRATAMIENTO DE LA DM2
EN PREVENCION SECUNDARIA
By Cardio, Nefro y Endocrino
@cristob.morales
94