1. Why the new U300 EDITION of Glargine
will become a Real Life improvement
for our patients
ralph de fronzo for the pathogenesis of diabetes
Andrea Giaccari, MD, PhD
Center for Endocrine
and Metabolic Diseases
Fondazione Policlinico Universitario A. Gemelli
Università Cattolica del Sacro Cuore
Rome, Italy
Capri - Italy

4. AT.LANTUS: titration protocols
Study population: patients with T2DM suboptimally controlled on OADs and requiring insulin
Study duration: 24 weeks
Starting basal insulin dose
Mean FBG for previous 3 consecutive days
Daily dose increase
Target FBG
by physiciana or by patient
≥5.5 and <6.7 mmol/L (≥100 and <120 mg/dL)
0–2 Ub
0–2 Ub
10 U/day
≥6.7 and <7.8 mmol/L (≥120 and <140 mg/dL)
2 U
2 U or
≤5.5 mmol/L (≤100 mg/dL)
Numerical equivalent of highest FBG in mmol/L over previous 7 days
≥7.8 and <10 mmol/L (≥140 and <180 mg/dL)
4 U
2 U
≥10 mmol/L (≥180 mg/dL)
6–8 Ub
2 U
ATLANTUS study design1
The ATLANTUS study was a prospective, multicenter (n=611), multinational (n=59), open-label, 24-week, randomized trial in 4961 patients with suboptimally controlled T2DM (Algorithm 1 [investigator-led], n=2493; Algorithm 2 [patient-led], n=2468)
The primary objective was to compare the 2 algorithms in terms of incidence of severe hypoglycemia, defined according to criteria used in the Diabetes Control and Complications Trial
ATLANTUS results1
A greater proportion of patients reached target HbA1c at the end of the study with patient-led titration (30%) versus physician-led titration (26%) (p=0004)
Greater reductions in HbA1c and FBG were found with patient- versus physician- managed titration (p<0.001 for both)
Reference
Davies M et al. Diabetes Care 2005;28(6):1282–8; p. 1282, abstract; p. 1283, Research Design and methods, 1st and 5th paras and Basal insulin algorithms, 1st para and Table 1; p. 1284, Objectives, 1st para; p. 1285, HbA1c; p. 1285, FBG
By physician: titration at every visit By patient: titration every 3 days
aReviewed by physician at each visit, either in person or over the telephone; titration occurred only in the absence of blood glucose levels <4 mmol/L (<72 mg/dL); bMagnitude of daily basal dose was at the discretion of the investigator FBG, fasting blood glucose
Davies et al. Diabetes Care 2005;28(6):1282–8

5. AT.LANTUS: patients reach target easier than physicians24 * 8 16 50 45 40 35 30 25 20
170
150
130
110 90
HbA1c
patients
-0.25
FastingBloodGlucose (mg/dl)
Insulin dose (units/day)
physicians
-0.50 %
-0.75
-1.00
-1.25
weeks
Davies M, et al. Diabetes Care 2005;28:1282, 2005

6. ORIGIN: no difference in CV outcomes with insulin glargine vs
ORIGIN: no difference in CV outcomes with insulin glargine vs. standard care
Rates of cardiovascular events
First co-primary outcome per 100 person-yearsa
Second co-primary outcome per 100 person-yearsb
Insulin glargine
2.94
5.52
Standard care
2.85
5.28
HR (95% CI)
1.02 (0.94–1.11)
1.04 (0.97–1.11)
p value
0.63
0.27
rates of incident CV outcomes were similar in the insulin glargine and standard-care groups
Early use of basal insulin neither increases nor reduces the risk of cardiovascular outcomes compared with standard care1
Rates of cardiovascular events were similar between the groups. For the first co-primary outcome, rates were 2.94 (glargine) and 2.85 (standard care) per person-years, with a risk ratio of For the second co-primary outcome, rates were 5.52 (glargine) and 5.28 (standard care) per 100 person- years, with a risk ratio of 1.041
Intervention reduced incident diabetes in participants with impaired fasting glucose or impaired glucose tolerance, although it was associated with modest weight gain and more episodes of hypoglycemia1
Treatment with glargine for >6 years had a neutral effect on cardiovascular outcomes and cancers1
Reference
ORIGIN Trial Investigators. N Engl J Med 2012;367(4):319–28; p. 319, abstract; p. 320, 2nd col, 2nd para; p. 324, 2nd col, 2nd para; p. 325, Figure 1; p. 327, 2nd para
aFirst co-primary outcome: death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke; bSecond co-primary outcome: composite of any of the events in the first co-primary outcome, plus revascularization procedure (cardiac, carotid, or peripheral), or hospitalization for heart failure
HR, hazard ratio
ORIGIN Trial Investigators. N Engl J Med 2012;367(4):319–28

7. effect of insulin glargine versus standard care on cancer by site
ORIGIN study: no difference in cancer outcomes with insulin glargine versus standard care
effect of insulin glargine versus standard care on cancer by site
Insulin glargine
Standard care
HR (95% CI)
p value
n (%)
/100 p-y
Breast
1.01 (0.60–1.71)
0.95
28 (0.4)
0.08
Lung
1.21 (0.87–1.67)
0.27
80 (1.3)
0.22
66 (1.1)
0.18
Colon
1.09 (0.79–1.51)
0.61
76 (1.2)
0.21
70 (1.1)
0.19
Prostate
0.94 (0.70–1.26)
0.70
88 (2.1)
0.36
89 (2.2)
0.38
Melanoma
0.88 (0.44–1.75)
0.71
15 (0.2)
0.04
17 (0.3)
0.05
Other
0.95 (0.80–1.14)
0.59
233(3.7)
0.64
245 (3.9)
0.67
There was no significant difference in the incidence of any cancer (HR 1.00; 95% CI: 0.88–1.13; p=0.97), death from cancer (HR 0.94; 95% CI: 0.77–1.15; p=0.52), or cancer at specific sites1,2
Individual values for cancer by site are given in the table. There was no significant difference in cancer incidence between glargine and standard care for any of the sites described2
Treatment with glargine for >6 years had a neutral effect on cardiovascular outcomes and cancers1
References
ORIGIN Trial Investigators. N Engl J Med 2012;367(4):319–28; p. 319, abstract; p. 324, 1st col, 2nd para
ORIGIN Trial Investigators. N Engl J Med 2012;367(4):319–28. Supplementary appendix; 1–42. p. 42, Table S4
There was no significant difference in the incidence of any cancer (HR 1.00; 95% CI 0.88–1.13; p=0.97), death from cancer (HR 0.94; 95% CI 0.77–1.15; p=0.52), or cancer at specific sites
ORIGIN Trial Investigators. N Engl J Med 2012;367(4):319–28;
ORIGIN Trial Investigators. N Engl J Med 2012;367(4):319–28. Summary appendix; 1–42
p-y, patient-years

8. glargine U100 as active comparator in clinical trials: a sistematic review
all GLP-1 RA have been compared with glargine U100
Exe GWAA – Ann intern Med 143:559, 2005
Exe Barnett AH Clin Ther 29:2333, 2007
Exe HEELA – DOM 11:1153, 2009
Lira LEAD-5 Diabetologia 52:2046, 2009
Exe-LAR DURATION-3 Lancet D&E 2:464, 2014
Albi HARMONY-4 – Diabetologia 57:2475, 2014
Dula AWARD-4 Lancet 385:2057, 2015
Dula AWARD-2 Diabetes Care 38:2241, 2015
glargine U100 is considered the state-of-the-art insulin

9. some early considerations
basal insulin is a valid therapeutic option for T2DM
for safety (CV and cancer), stability, pharmacodynamics, low hypoglycemia, easy titration and other considerations, glargine U100 has been considered the state-of-the-art insulin (biosimilars)
are there unmet needs?

10. unmet needs with insulin
a significant portion of patients complains
PD < 24 h
variable
absorption
intra-day
variability
fear of
hypoglycemia
large
volumes
risk for
lipodystrophy
Lajara R, et al.: Curr Med Res Opin 33:1045, Maiorino MI et. al: Expert Opin Biol Ther. 14:799, Wang F et al.: Diabetes Metab Syndr Obes 9:425, Hurren KM, O'Neill JL: Expert Opin Drug Metab Toxicol 12:1521, Heise T, Mathieu C. Diabetes Obes Metab 19:3, Lamos EM et al.: Ther Clin Risk Manag 12:389, Goldman J, White JR Jr.: Ann Pharmacother 49:1153, Woo VC. Can J Diabetes 39:335, Sutton G et al.: Expert Opin Biol Ther 14:1849, Garber AJ: Diabetes Obes Metab 16:483, Owens DR et al.: Diabetes Metab Res Rev 30:104, 2014

11. glargine U100 vs. U300 Gla-100 Gla-300
Sutton, Expert Opin. Biol. Ther 14:1849, 2014

12. More even and prolonged profile with GLA-300 vs GLA-100 in T1DM after 8 days’ treatment25
Insulin concentration, µU/mL 20
GLA U/kg
GLA U/kg 15 10 5
LLOQ 3
Glucose infusion rate, mg/kg/min 2 1
160
Blood glucose, mg/dL
140
Clamp level +18 mg/dL (1 mmol/L)
120
100
Clamp level
Becker RHA et al. Diabetes Care. 2014
time, hours

13. Low within-day variability Exposure and activity was nearly evenly distributed over 24 h
INS-AUC0-6/INS-AUC0-24
INS-AUC6-12/INS-AUC0-24
INS-AUC12-18/INS-AUC0-24
INS-AUC18-24/INS-AUC0-24
0.28 (0.26 – 0.30)
0.27 (0.26 – 0.29)
0.24 (0.23 – 0.26)
0.20 (0.19 – 0.22)
0.55 (0.53 – 0.57)
0.45 (0.43 – 0.47)
53%
(48-58)
47%
(42-52) 3
0-12 hours
12-24 hours 2
Average GIR
GIR (mg.kg-1,min-1) 1
29%
(23 -34)
24%
(20-28)
23%
(20-28)
23%
(19-27)
0-6 hours
6-12 hours
12-18 hours
18-24 hours
Becker RH, et al. DOM 17:261, 2015

14. more constant glucose profile with glargine U300 vs. U100
morning injection
glargine U 300 11 11 10 10 9 9 8 8
morning
evening 7 7 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24
evening injection
glargine U 100 11 11 10 10 9 9 8 8
morning
evening 7 7 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24
Average glucose profiles, mean (SE), mmol/L
Time, h
Bergenstal RM et al. EASD 2014;

15. some early considerations (2)
glargine U300 inherits safety (CV and cancer) from U100
does improved stability, and prolonged pharmacodynamics reflect on hypoglycemia and control?

16. EDITION program: objective and design1-6
OBJECTIVE: To assess the clinical efficacy and safety of Gla-300 vs Gla-100
Randomized 1:1, open-label, parallel-group, multicenter phase 3 studies
EDITION program was built with similar study design across trials to confirm results
Gla-300 ± OADs ± Mealtime insulin
Participants
Randomized
(1:1)
6 months
6-month
Extension period
Gla-100 ± OADs ± Mealtime insulin
Non-inferiority to Gla-100 in HbA1C reduction at 6 months was the primary endpoint in all trials
HbA1C, glycated hemoglobin A1C; OADs, oral antihyperglycemic drugs 1. Riddle MC et al. Diabetes Care. 2014;37: ; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37: ; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74; 5. Home PD et al. Diabetes Care. 2015;38: ; 6. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83

17. EDITION program Testing Gla-300 vs Gla-100 in several populations
T2DM1-4
T1DM5,6
EDITION 1
N=807 BB
Basal insulin (>42 U/day)* plus mealtime bolus insulin (fast-acting analogue)
EDITION 2
N=811
BOT
Basal insulin (>42 U/day)* plus OAD (excl. SU)
EDITION 4
N=549 BB
Basal insulin plus mealtime bolus insulin (fast-acting analogue)
EDITION 3
N=878
insulin naïve
Basal insulin plus OAD (excl. SU)
EDITION JP 2
N=241
BOT
Basal insulin plus OAD; Japanese patients
EDITION JP 1
N=243 BB
Basal insulin plus mealtime bolus insulin (fast-acting analogue); Japanese patients
All phase 3, age of participants ≥18 years, randomization ratio 1:1
*In EDITION 1 and EDITION 2, people being treated with basal insulin ≥42 U/day were recruited BB, basal-bolus therapy; BOT, basal-oral therapy; OAD, oral antihyperglycemic drug; SU, sulfonylurea; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus 1. Riddle MC et al. Diabetes Care. 2014;37: ; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37: ; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74; 5. Home PD et al. Diabetes Care. 2015;38: ; 6. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83

18. primary endpoint was successfully achieved in all EDITION trials
T2DM
T1DM
EDITION 11 BB
EDITION 22
BOT switch
EDITION 33
BOT start
EDITION JP 24
BOT switch
EDITION 45 BB
EDITION JP 17 BB
LSM difference
(95% CI)
0.00 %
( )
-0.01 %
( )
0.04 %
( )
0.10 %
( )
0.04 %
( )
0.13 %
( )
-0.30
-0.5
-0.40
-0.44
-0.42
-0.45
-0.55
LSM HbA1c change
from baseline
-0.57
-0.56
primary endpoint for ALL studies:
non-inferiority in HbA1c change at month 6
glargine U300 vs. glargine U100
-0.83
-0.83
-1.0
-1.5
-1.42
-1.46
*In EDITION 1 and EDITION 2, people being treated with basal insulin ≥42 U/day were recruited BB, basal-bolus therapy; BOT, basal-oral therapy; OAD, oral antihyperglycemic drug; SU, sulfonylurea; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus 1. Riddle MC et al. Diabetes Care. 2014;37: ; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37: ; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74; 5. Home PD et al. Diabetes Care. 2015;38: ; 6. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83

19. rate of confirmed (≤70 mg/dL) or severe hypoglycemia at any time of day (24 h) in T2DM studies at Month 6 4 6 8 14 2 12 24 20 16 10 4 6 10 12 2 24 8 20 16 28
EDITION 11 BB
EDITION 22
BOT switch
Rate ratio (95% CI) 0.95 (0.80 to 1.13)
Rate ratio (95% CI) 0.77 (0.63 to 0.96)
Cumulative mean numbers of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe events
Time, weeks 12 14 16 2 24 4 8 20 28 6 10 12 24 4 8 20 16 28
Time, weeks 14 2 6 10
EDITION 33
BOT start
EDITION JP 24
BOT switch
Rate ratio (95% CI) 0.75 (0.57 to 0.99)
Rate ratio (95% CI) 0.64 (0.43 to 0.96)
glargine U300
glargine U100
rate ratio and 95% CI are based on annualized rates per patient-year for confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; T2DM, type 2 diabetes mellitus 1. Adapted from Riddle MC et al. Diabetes Care. 2014;37: ; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37: ; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17: (main article and Supplementary Figure 3); 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74

20. rate of nocturnal (00:00–05:59 h) confirmed (≤70 mg/dL) or severe hypoglycemia in T2DM studies at Month 6
2.5
2.5
EDITION 11 BB
EDITION 22
BOT switch
2.0
2.0
Rate ratio (95% CI) 0.52 (0.35 to 0.77)
1.5
1.5
1.0
1.0
Rate ratio (95% CI) 0.75 (0.58 to 0.95)
0.5
0.5 4 8 12 16 20 24 12 24 4 8 20 16 28
Cumulative mean numbers of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe events 4 5
EDITION 33
BOT start
EDITION JP 24
BOT switch
Rate ratio (95% CI) 0.98 (0.64 to 1.48) 4 3 3
Rate ratio (95% CI) 0.45 (0.21 to 0.96)
glargine U300
glargine U100 2 2 1 1 12 24 4 8 20 16 28 12 24 4 8 20 16 28
Time, weeks
Time, weeks
rate ratio and 95% CI are based on annualized rates per patient-year for confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; T2DM, type 2 diabetes mellitus 1. Adapted from Riddle MC et al. Diabetes Care. 2014;37: ; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37: ; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17: (main article and Supplementary Figure 3); 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74

21. patient-level meta-analysis, M6
Similar HbA1C reduction with lower hypoglycemia and less weight gain with Gla-300 vs Gla-100 at Month 6
EDITION T2DM
patient-level meta-analysis, M6
Mean (SE) HbA1C, %
Mean (SE) HbA1C, mmol/mol
8.4 69
Participants with ≥1 confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia event at Month 6
LS mean difference at Month 6: 0.00% 95% CI –0.08 to 0.07% 67
8.2
Favors Gla-300
Favors Gla-100 ← → 65
8.0
Nocturnal (00:00 h–05:59 h)
Any time of day (24 h) 63
7.8 61
0.75 (0.68 to 0.83)
7.6 59
0.91 (0.87 to 0.96)
7.4 57
7.2
Gla-300 n=1247 Gla-100 n=1249 55
0.5 1
1.5
7.0 53
Relative risk (95% CI)
Baseline
Week 12
Month 6
Less weight gain with Gla-300 vs Gla-100: LS mean difference −0.28 kg (95% CI −0.55 to −0.01; P=0.039)
The mean basal insulin dose at Month 6 was 0.85 U/kg/day with Gla-300 and 0.76 U/kg/day with Gla-100, representing a 12% higher dose with Gla-300
Relative risk and 95% CI based on % of participants with ≥1 event of one confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia CI, confidence interval; HbA1C, glycated hemoglobin A1C; LS, least squares; SE, standard error; T2DM, type 2 diabetes mellitus Adapted from Ritzel R et al. Diabetes Obes Metab. 2015;17:859-67

22. rate of confirmed (≤70 mg/dL [≤3
rate of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia at Month 6
any time of day
nocturnal 10
2.0
Gla-300 n=1247 Gla-100 n=1249 8
1.5 6
Rate ratio (95% CI) 0.69 (0.57 to 0.84) P=0.0002
1.0 4
Rate ratio (95% CI) 0.86 (0.77 to 0.97) P=0.0116
0.5 2 4 8 12 16 20 24 28 4 8 12 16 20 24 28
Maintenance
Maintenance
Time, weeks
Time, weeks
Safety population; rate ratio and 95% CI are based on annualized rates per patient-year for confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia CI, confidence interval; T2DM, type 2 diabetes mellitus Adapted from Ritzel R et al. Diabetes Obes Metab. 2015;17:859-67

23. More sustained HbA1c reduction with lower hypoglycemia and weight gain with Gla-300 vs Gla-100 at Month 12
EDITION T2DM
Patient-level meta-analysis, M12
Mean (SE) HbA1C, %
Mean (SE) HbA1C, mmol/mol
Participants with ≥1 confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia event at Month 12
8.4 68
8.2
Favors Gla-300
Favors Gla-100 ← →
LS mean difference at Month 12: –0.10% 95% CI –0.18 to –0.02% P=0.0174
Nocturnal (00:00 h–05:59 h)
Any time of day (24 h)
0.85 (0.77 to 0.92)
0.94 (0.90 to 0.98)
8.0 63
7.8
7.6 58
7.4
7.2
glargine U300 glargine U100
0.5 1
1.5
7.0
Relative risk (95% CI) 53
Baseline
W12 M6 M9
M12
3.2% participants on Gla-300 and 3.6% on Gla-100 had ≥1 severe hypoglycemic event at any time of day (24 h) (relative risk 0.89; 95% CI 0.59 to 1.35)
Less weight gain with Gla-300 vs Gla-100: LS mean difference −0.40 kg (95% CI −0.71 to −0.09; P=0.0117)
The mean basal insulin dose at Month 12 was 0.89 U/kg/day with Gla-300 and 0.78 U/kg/day with Gla-100, representing a 14% higher dose with Gla-300
CI, confidence interval; HbA1C, glycated hemoglobin A1C; LS, least squares; M, month; T2DM, type 2 diabetes mellitus; W, week Adapted from Ritzel R et al. Poster presentation at ADA 2015; Abstract 1030-P

24. some more considerations (3)
glargine U300 inherits safety (CV and cancer) from U100
glargine U300 reaches same HbA1c of glargine U100, but with less hypos
glargine U300 reaches same HbA1c of glargine U100, keeping it for a longer time

25. from ORIGIN to DEVOTE
2012 NDA submitted and additional analyses requested
2013 Request for dedicated CVOT DEVOTE initiated
2016 DEVOTE completed
2003 ORIGIN initiated
2011 ORIGIN completed
2003 ORIGIN initiated
2010s
New generation analogs
2000s
Basal analogs
Advancements
1990s
Biphasic analogs
2008 FDA guidance
Recombinant human insulin
First patient treated with insulin
(Banting & Best)
Animal insulin preparations
Rapid-acting analogs
1977
Time
1922
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 ( Information/Guidances/ucm pdf); The ORIGIN Trial Investigators. N Engl J Med 2012;367:319-28

26. DEVOTE Trial design R trial characteristics
degludec once daily (blinded vial)
+ standard of care
follow-up
period R
N=7653
glargine U100 once daily (blinded vial)
+ standard of care
follow-up
period
interim analysis
(150 MACE events)
end of treatment
(633 MACE accrued)
30 days
trial characteristics
event driven
double blinded
treat-to-target
primary endpoint
time from randomization to first occurrence of a 3-point MACE:
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke
secondary endpoint
rate of severe hypoglycemic episodes
incidence of severe hypoglycemic episodes

27. p-value for interaction
DEVOTE: lower rate of severe hypoglycemia in the subgroup established CV disease, NOT in the subgroup risk factors of CV
Factor N %
Rate ratio
[95% CI]
Insulin degludec
IGlar U100
p-value for interaction 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
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 25
10.71
1.0
Hazard ratio [95% CI]
Favors insulin degludec
Favors IGlar U100
†Includes basal/bolus, bolus only and premix CV, cardiovascular

28. DEVOTE: results summary
3-point MACE (primary)
DEVOTE confirmed the cardiovascular safety of insulin degludec in comparison with insulin glargine U100
Lower rate of severe hypoglycemia was confirmed at similar levels of HbA1c
Lower rate of nocturnal severe hypoglycemia was confirmed
no data on other hypoglycemic events 3 6 9 12 15 18 21 24 30 27
HR: 0.91 (95% CI, 0.78; 1.06)
p<0.001 Non-inferiority confirmed
glargine U100
Patients with an event (%)
degludec
Time to firste EAC-confirmed event (months)
3818
3819
3765
3758
3721
3703
3699
3655
3611
3595
3563
3530
3504
3472
2851
2832
1767
1742
217
205
811
degludec
glargine U100
nocturnal severe hypoglycemia
severe hypoglycemia 3 6 9 12 15 18 21 24 30 27 16 8 4 3 6 9 12 15 18 21 24 30 27 5 4 2 1
Rate ratio 0.60 (95% CI, )
p<0.001 superiority confirmed
Rate ratio 0.47 (95% CI, )
P<0.001
glargine U100
glargine U100
Mean number of events /100 PYO
Mean number of events /100 PYO
degludec
degludec
Months since randomization
Months since randomization
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

29. DEVOTE: Adjustment of basal insulin dose
- The subject should adjust basal insulin dose weekly.
- The basal dose adjustment should be based on the lowest of three pre-breakfast SMPG values measured preferably two days prior to titration and on the day of titration.
mmol/L
mg/dl
Units
< 4.0
< 71
- 2
4.0 – 5.0
71 – 90
5.1 – 7.0
91 – 126
+ 2
> 7.0
> 126
+ 4

30. glargine U300 vs. degludec: within-day fluctuation of GIR profiles
Within-day variability of the smoothed GIR (GIR-smFL0–24) was significantly lower (20%) with Gla-300 versus Deg-100 at the 0.4 U/kg/day dose
2.5
mean GIR (mg·kg-1·min-1)
degludec U100
glargine U300
2.0
1.5
1.0
GIR-smFL0-24 treatment ratio
0.89 (90%CI: ; p=0.047)
0.5 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
hours
Randomized, double-blind, two-treatment, two-period, two-sequence crossover euglycemic clamp study in parallel cohorts with two dose levels in 48 patients with T1DM
For GIR data a smoothing factor (LOESS factor 0.15) was applied.
Gla-100, insulin glargine 100 U/ml; IDeg, insulin degludec; Gla-100, insulin glargine 100 U/ml; CI, confidence interval; GIR, glucose infusion rate; GIR-smFL0–24, fluctuation of the smoothed GIR curve over 24 hours
Bailey T et al. Poster presented at Diabetes Technology Meeting, 11 November 2016.

31. some more considerations (4)
degludec is non-inferior to glargine U100 for CV diseases (don’t know vs. glargine U300)
the burdening clinical question is:
are data coming from clinical trials always applicable to our clinics?

32. Unrestricted concomitant medications2
Classical RCTs exclude most real-life patients real-life studies include larger patient population
Real-life studies
Special
population
Unrestricted BMI2
EDITION 1
T2DM on BB
Male / female
HbA1c 7–10%1
BI dose≥42 U/d
Only metformin
Pregnancy
lactation4
Hypoglycemia2,5
HbA1c with no
upper limit1
Severe
comorbidities1,2
Age with no
upper limit3
Age<18
years1
Unrestricted concomitant medications2

33. switching to glargine U300 a retrospective study
hypo
dose
once/twice
Tong L et al.: ADA 2017

34. DELIVER 2: glargine U300 demonstrates a 48% lower rate of hospitalization-related hypoglycemia
Predicted Inpatient/ED Encounter-related hypoglycemia event rate (events/100 patients-months)
-48%
p<0.01
3.82%
1.97%
glargine U300
other basal insulin
Study Design
The Differentiate Toujeo clinical and Economic in reaL-world Via EMR data study (DELIVER 2) is a retrospective matched cohort study.
Data were collected from the Predictive Health Intelligence Environment database of electronic medical records (EMRs) representing 26 integrated health delivery networks.

35. some more considerations (5)
retrospective studies accurately describe insulin efficacy in ALL our patients
still, the choice of the insulin analogue is influenced by
patients’ preferences
physicians’ preferences and habits
other unmeasurable variables
WE NEED RANDOMIZED TRIALS!

36. from DELIVER to ACHIEVE, REACH and REGAIN
Real World Observational Studies
patients with type 2 diabetes switching to Gla-300 vs. another basal insulin.
DELIVER Program:
>3,000
reduction in risk of hypoglycemia with Gla-300, without
compromising HbA1c control (DELIVER 2)
reduction in risk of hypoglycemia with Gla-300, without compromising HbA1c
control in people aged ≥65 years (DELIVER 3)
25% 
57% 
Total saving in healthcare resource with Gla-300:
>$2,000
per patient per year
Randomized Real Life Studies
The Toujeo Real Life Study Program is comparing Gla-300 to other basal insulins in a variety of patient populations with type 2 diabetes. The Toujeo Real Life Study Program, combining the benefits of RCTs (randomization) and Real World Observational Studies, is unique in the diabetes field.
insulin-naïve patients in the U.S.
~3,300
insulin-naïve patients in EU and Brazil
~700
patients uncontrolled on basal insulin in EU and Brazil
~600
The Gla-300 Real Life Studies will report initial findings later in 2017.

37. over 3700 patients already randomized in real life studies
Insulin-naïve T2DM (US)
Primary endpoint: Patients (%) achieving individualized HbA1c target (HEDIS criteria) without hypoglycemia
Target n=3324 (May 17), 77% randomized
6-month interim analysis n=1800 (Mar 2017)
Insulin-naïve T2DM (EU, LATAM)
Primary endpoint: Change in HbA1c
Enrollment Completed n=703
T2DM uncontrolled on basal insulin (EU, LATAM)
Primary endpoint: Change in HbA1c
Enrollment Completed n=609
KEY SECONDARY OUTCOME MEASURES
Hypoglycemia, persistence to insulin treatment, HbA1c target achievement, weight,
basal insulin dose, need for treatment intensification, patient-reported outcomes, healthcare utilization

38. hypoglycemia data collected
Incidence and rate
Incidence and rate
Documented symptomatic
Severe hypoglycemia
Documented symptomatic or severe
Documented symptomatic
Severe hypoglycemia
Blood glucose ≤ 70 and < 54 mg/dl
Blood glucose ≤ 70 and < 54 mg/dl
Nocturnal ( ) and 24 hour
Nocturnal ( ), all day and by sleep status
From baseline to 6 and 12 months
From baseline to 6 and 12 months

39. ACHIEVE: study design
Oster G. et al.:Postgraduate medicine, 2017

40. ACHIEVE: endpoints
Oster G. et al.:Postgraduate medicine, 2017

41. REACH and REGAIN
A 26 week, randomized, open-label, 2-arm parallel group real world pragmatic trial to assess the clinical and health outcomes benefit of glargine U300 compared to standard of care insulin for initiating basal insulin in insulin naïve patients with uncontrolled DMT2, with 6-month extension
A 26 week, randomized, open-label, 2-arm parallel group real world pragmatic trial to assess the clinical and health outcomes benefit of transition to glargine U300 compared to standard of care insulin, in basal insulin treated patients with uncontrolled DMT2, with 6-month extension

42. REACH and REGAIN
Multi-center, multi-national, open label randomized active controlled 2-arm parallel group comparative “pragmatic” trial
The two treatment arms will be:
glargine U300
“Standard of care” basal insulin. [ ie all commercially available long acting or Intermediate insulins]
Patients will be offered a patient support program:
a designated patient support program with glargine U300,
a patient support program, if available, with “standard of care” basal insulin according to Investigator’s usual practice

43. REACH and REGAIN
patients with DMT2 insufficiently controlled (HbA1c >7%) with current standard of care with oral agents (metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT-2 inhibitor, glinide) with/without GLP-1 RA
eligible to basal insulin, per investigator’s judgment
patients with DMT2 insufficiently controlled (HbA1c >7%) with current “standard of care” basal insulin therapy (including glargine U100, detemir, NPH or
degludec) with/without oral agents (metformin,
SU, thiazolidinedione, DPP-4 inhibitor, SGLT-2 inhibitor, glinides) and with/without GLP-1 RA

44. ITAS: Italian Titration Approach Study
Gla-300
Titration managed by physician
Inclusion criteria
≥18 years
T2DM (> 1 year)
HbA1c 7.5–10.0%
OADs (except Su-Glin)
Willingness/capability to self-manage titration algorithm (based on Investigator evaluation)
Randomizatio n 1:1
Gla-300
Patient-managed titration
(nurse assisted)
Gla-300 OD (starting dose 0.2 U/kg)
Dose titrated to FPG mg/dL
For both groups will be available:
Educational program (GISED Gruppo Italiano di Studio per l’Educazione sul Diabete) aimed to personalize, follow, monitor patient educational pathway
MSC software patient version, a «patient dashboard» application, supporting the patient self- monitoring and exchanging data with Diabetologist on SBGM and disease situation

45. ITAS: Italian Titration Approach Study
glargine U300 OD in the evening, starting dose: 0.2 U/kg
Dose adjustement: target range for fasting SMPG  mg/dL
glargine U300 dose will be adjusted based on two different approaches (Algorithm 1: managed by phy; Algorithm 2 managed by pt)
Median FBG
3 consecutive days
Algorithm phys
(managed by phy)
Algorithm pat
(managed by pt)
>180 mg/dL
+ 4
> mg/dL
+ 2
80–110 mg/dL
No change
< 80 mg/dL
- 2 2
< 54 mg/dL*
At physician discretion
Contact physician
* or occurrence of ≥2 symptomatic or 1 severe hypoglycemia episode(s) in the preceding week
Patients randomised to algorithm 1 will have basal insulin dose adjusted during visits or telephone contacts
Patients randomised to both algorithm 1 & 2 will  adjust dose at least weekly, and no more frequently than every 3-4 days, as needed

46. unmet needs with insulin
a significant portion of patients complains
PD < 24 h
variable
absorption
intra-day
variability
fear of
hypoglycemia
large
volumes
risk for
lipodystrophy
Lajara R, et al.: Curr Med Res Opin 33:1045, Maiorino MI et. al: Expert Opin Biol Ther. 14:799, Wang F et al.: Diabetes Metab Syndr Obes 9:425, Hurren KM, O'Neill JL: Expert Opin Drug Metab Toxicol 12:1521, Heise T, Mathieu C. Diabetes Obes Metab 19:3, Lamos EM et al.: Ther Clin Risk Manag 12:389, Goldman J, White JR Jr.: Ann Pharmacother 49:1153, Woo VC. Can J Diabetes 39:335, Sutton G et al.: Expert Opin Biol Ther 14:1849, Garber AJ: Diabetes Obes Metab 16:483, Owens DR et al.: Diabetes Metab Res Rev 30:104, 2014

47. needs met with glargine U300
a significant portion of patients will reach or regain
PD < 24 h
variable
absorption
intra-day
variability
fear of
hypoglycemia
large
volumes
risk for
lipodystrophy
stable
absorption
PD > 24 h
low intra-day
variability
less fear of
hypoglycemia
small
volumes
lower risk for
lipodystrophy