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

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


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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


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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


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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)


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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


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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


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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%)


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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


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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


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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


DEVO

TE-1 (ADA2017)


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2

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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


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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]


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


Favors IGlar U100 Favors insulin degludec

1.0 1.3


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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


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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


1.0


DEVO

TE-1 (ADA2017)


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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)


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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



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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


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


7.55%

7.50%


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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


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



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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


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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


Rate ratio: 0.60 [0.48; 0.76]95% CI

p<0.001


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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



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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


1.0


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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


1.0


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)


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)


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


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


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.


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



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.


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.


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



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


40 years 90 years

15 %

30 years

5 %

0 years

Gender

Insulin treatment

?


10

5

0




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


40 years 90 years

15 %

30 years

5 %

0 years

Gender

Insulin treatment

?


Insulin naïve

Basal only


10

5

0



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


15 %

30 years

5 %

0 years

Gender

Insulin treatment

?

Risk of having a severe hypoglycaemic episode within 2 years Age 40 years 90 years


10

5

0



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


15 %

30 years

5 %

0 years

Gender

Insulin treatment

?

Risk of having a severe hypoglycaemic episode within 2 years Age 40 years 90 years


10

5

0



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

Health & Medicine

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