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SAGLB.TJO.16.02.0087
Remaining unmet needs and challenges with
basal insulin therapy
Less than 50% of insulin-treated patients with T2DM are at their glycemic
target1,2 due to key unmet needs and challenges
Incidence of
PK/PD Behavioral challenges
hypoglycemia
Hypoglycemia
has important Fear of
Intra-patient Sub-optimal doses
short- and hypoglycemia and
glucose variability3 and early treatment
long-term insulin-associated
discontinuation4,5
consequences4 weight gain4
SAGLB.TJO.16.02.0087
SAGLB.DIA.15.02.0083 / 2015.03
Effective therapy requires a balance between the benefits of glycemic
control and the risk of hypoglycemia
Pogach L & Aron D. JAMA. 2010;303:2076-7; Khunti K et al. Diabetes Obes Metab. 2016;18:907-15; Riddle M et al. Diabetes Technol Ther. 2016;18:252-7; Peyrot M et al. Diabet Med. 2012;29:682-689;
Davies MJ et al. Diabet Med. 2013;30:512-24; Willis WD et al. Expert Rev Pharmacoecon Outcomes Res. 2013;13:123-130; Ahrén B. Vasc Health Risk Manag. 2013;9:155-163
SAGLB.TJO.16.02.0087
Evolution of basal insulin development:
Overcoming limitations
• Insulin glargine 100 U/mL (Gla-100)
Comparison of action after a single dose for NPH and Gla-100 and for Gla-100 and insulin detemir; comparison at steady state for Gla-100 and Gla-300 and for Gla-100 and insulin degludec
NPH, neutral protamine Hagedorn
1. Eliaschewitz FG, Barreto T. Diabetol Metab Syndr. 2016;8:2; 2. Adapted from Pettus J et al. Diabetes Metab Res Rev. 2016;32:478-96
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Clinical benefits of an ideal PK/PD profile
Once-daily injection
Duration of action (≥24 h)
Becker RHA et al. Diabetes Care 2015;38:637−43; Riddle M et al. Diabetes Technol Ther. 2016;18:252-7
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EDITION program
Introduction
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EDITION program objective and design1-6
T2DM1-4 T1DM5,6
EDITION 1 EDITION 2 EDITION 4
N=807 N=811 N=549
BB BOT BB
Basal insulin (>42 U/day)* Basal insulin (>42 U/day)* Basal insulin plus mealtime
plus mealtime bolus insulin plus OAD (excl. SU) bolus insulin (fast-acting
(fast-acting analogue) analogue)
*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;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
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;38:2217-25; 6. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83
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EDITION program: Study designs
EDITION 11 EDITION 22 EDITION 33 EDITION JP 24 EDITION 45 EDITION JP 16
BB BOT switch BOT start BOT switch BB BB
Gla-300: n=404 Gla-300: n=404 Gla-300: n=439 Gla-300: n=121 Gla-300: n=274 Gla-300: n=122
Gla-100: n=403 Gla-100: n=407 Gla-100: n=439 Gla-100: n=120 Gla-100: n=275 Gla-100: n=121
Flexible injection time M6 to M9: M6 to M9: Not applicable Not applicable Not applicable Not applicable
fixed time ± 3 h7 fixed time ± 3 h7
Primary endpoint:
HbA1C (change from baseline ✔ ✔ ✔ ✔ ✔ ✔
to endpoint [Month 6])
Thorough hypoglycemia ✔ ✔ ✔ ✔ ✔ ✔
analysis
Evening: between pre-dinner and bedtime; morning: between pre-breakfast and pre-lunch
BB, basal-bolus therapy; BOT, basal-oral therapy; HbA1C, glycated hemoglobin A1C; M, month; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
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;38:2217-25; 6. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83; 7. Riddle M et al. Diabetes Technol Ther. 2016;18:252-7
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Basal insulin titration in EDITION studies in T2DM
Gla-300 was always given in the evening1-7
Titration steering committee was in place
Adjustments at investigators’ discretion for safety
• Dose adjustment was generally once weekly, but no more often than every 3 to 4 days1,3,5,7
• The dose of basal insulin was generally unchanged at entry; however, the dose was reduced by 20% if two
daily NPH injections were previously used1,3,7
NPH, neutral protamine Hagedom; SMPG, self-measured plasma glucose; T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Data on file, EDITION 1 CSR (6 months) pg 26-28; 3. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
4. Data on file, EDITION 2 CSR (6 months) pg 26-28; 5. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 6. Data on file, EDITION 3 CSR (6 months) pg 30-31;
7. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74 (main article and Supplementary Table 1)
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Basal insulin titration in EDITION studies in T1DM
<60 mg/dL (<3.3 mmol/L) or occurrence of severe Stop upward titration for Stop upward titration for
hypoglycemia episode without adequate explanation 1 week, decrease dose at 1 week, decrease dose at
in the preceding week investigator’s decision investigator’s decision
• Dose adjustment should be done once weekly, but no more often than every 3 to 4 days2,3
• The dose of basal insulin was generally unchanged at entry; however, the dose was reduced by 20% if
two daily NPH or detemir injections were previously used1,3
NPH, neutral protamine Hagedom; SMPG, self-measured plasma glucose; T1DM, type 1 diabetes mellitus
1. Data on file, EDITION 4 CSR (6 months) pg 32-34; 2. Home PD et al. Diabetes Care. 2015;38:2217-25;
3. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83
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EDITION program
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Summary of baseline characteristics of T2DM studies
Age, years 60.1 59.8 57.9 58.5 58.2 57.2 61.1 60.5
BMI, kg/m² 36.6 36.6 34.8 34.8 32.8 33.2 25.7 24.8
Duration of diabetes, years 15.6 16.1 12.7 12.5 10.1 9.6 14.0 13.9
Prior use of metformin, % 56.2 58.6 94.8 93.6 90.6 92.0 57.9 59.2
SUs were not permitted post-randomization in EDITION 1, EDITION 2, EDITION 3 but were allowed in EDITION JP 2
BB, basal-bolus therapy; BOT, basal-oral therapy; BMI, body mass index; HbA1C, glycated hemoglobin A1C; SU, sulfonylurea; T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74
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Summary of baseline characteristics of T1DM studies
Basal / mealtime / total insulin dose, U/kg 0.38 / 0.34 / 0.71 0.37 / 0.33 / 0.72 0.28 / 0.45 / 0.73 0.30 / 0.45 / 0.74
BB, basal-bolus therapy; BMI, body mass index; HbA1C, glycated hemoglobin A1C; T1DM, type 1 diabetes mellitus
1. Home PD et al. Diabetes Care. 2015;38:2217-25; 2. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83
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Primary endpoint was successfully achieved in
all EDITION trials
-0.30
-0.5 -0.45 -0.40 -0.44 -0.43
-0.57 -0.56 -0.55
T2DM
-1.0 -0.83 -0.83
T1DM
Gla-300
-1.5 -1.42 -1.46 Gla-100
mITT population
BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; HbA1C, glycated hemoglobin A1C; LSM, least squares mean; mITT, modified intention-to-treat; T1DM, type 1 diabetes mellitus; T2DM,
type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94;
4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74 (main article and Supplementary Table 2); 5. Home PD et al. Diabetes Care. 2015;38:2217-25;
6. Data on file, EDITION 4 CSR (6 months) pg 88; 7. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83 (main article and Supplementary Table 1)
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Mean change in FPG from baseline to Month 6
Mean (SD)* Mean (SD)* Mean (SD)† Mean (SD)* Mean (SD)† Mean (SD)*
0
-0.42
-1 -0.83
from baseline, mmol/L
Mean change in FPG
-5
mITT population
*Last observation carried forward; †mixed model for repeated measurements
BB, basal-bolus therapy; BOT, basal-oral therapy; FPG, fasting plasma glucose; HbA1C, glycated hemoglobin A1C; mITT, modified intention-to-treat; SD, standard deviation; T1DM, type 1 diabetes
mellitus;T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62 (Supplementary Table 1); 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43 (Supplementary Table 1);
3. Data on file, EDITION 3 CSR (6 months) pg 96; 4. Data on file, EDITION JP 2 CSR (6 months) pg 92; 5. Home PD et al. Diabetes Care. 2015;38:2217-25 (mg/dL data were calculated in mmol/L);
6. Data on file, EDITION JP 1 CSR (6 months) pg 86
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Incidence of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe
hypoglycemia in T2DM studies at Month 6: Nocturnal (00:00–05:59 h)
EDITION 11
BB 0.78 (0.68 to 0.89) 0.79 (0.64 to 0.98) 0.79 (0.67 to 0.93)
Main
EDITION 22
secondary
0.71 (0.58 to 0.86) 0.53 (0.39 to 0.72) 0.77 (0.61 to 0.99) endpoint*
BOT switch
EDITION 33
0.76 (0.59 to 0.99) 0.74 (0.48 to 1.13) 0.89 (0.66 to 1.20)
BOT start
EDITION JP 24
0.62 (0.44 to 0.88) 0.83 (0.45 to 1.52) 0.58 (0.40 to 0.85)
BOT switch
*mITT population for main secondary endpoint for EDITION 1, 2 and 3; safety population for the other timepoints
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
BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; mITT, modified intention-to-treat; T2DM, type 2 diabetes mellitus
1. Adapted from Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94;
4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74
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Incidence of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe
hypoglycemia in T2DM studies at Month 6: Any time of day (24 h)
Baseline to Month 6 Baseline to Week 8 Week 9 to Month 6
Favors Favors Favors Favors Favors Favors
Favors
Gla-300 Gla-100
Favors Favors
Gla-300 Favors
Gla-100 Favors
Gla-300 Favors
Gla-100
Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100
EDITION 11
0.93 (0.88 to 0.99) 0.86 (0.78 to 0.94) 0.96 (0.89 to 1.04)
BB
EDITION 22
0.90 (0.83 to 0.98) 0.78 (0.69 to 0.89) 0.91 (0.82 to 1.02)
BOT switch
EDITION 33
0.88 (0.77 to 1.01) 0.83 (0.67 to 1.03) 0.86 (0.74 to 1.00)
BOT start
EDITION JP 24
0.86 (0.73 to 1.01) 0.69 (0.52 to 0.91) 0.84 (0.70 to 1.01)
BOT switch
0.3 Relative risk (95% CI) 3.0 0.3 Relative risk (95% CI) 3.0 0.3 Relative risk (95% CI) 3.0
% Participants experiencing ≥1 severe hypoglycemic event from baseline to Month 6: Any time of day (24 h)
Gla-300 Gla-100 Relative risk (95% CI)
EDITION 11 5.0 5.7 0.87 (0.48 to 1.55)
EDITION 22 1.0 1.5 NA
EDITION 33 0.9 0.9 NA
EDITION JP 24 2.5 1.7 1.25 (0.31 to 4.98)
Safety population; BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; NA, not available; T2DM, type 2 diabetes mellitus
1. Adapted from Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43 (main article and Supplementary Table 2);
3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94 (main article and Supplementary Table 1); 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74 (main article and Supplementary Table 4);
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Rate of nocturnal (00:00–05:59 h) confirmed (≤70 mg/dL [≤3.9 mmol/L])
or severe hypoglycemia in T2DM studies at Month 6
2.5 2.5
EDITION 11 Gla-300 EDITION 22
BB Gla-100 BOT switch
2.0 2.0
1.5 1.5
(≤70 mg/dL [≤3.9 mmol/L]) or severe events
Cumulative mean numbers of confirmed
1.0 1.0
4 5
EDITION 33 EDITION JP 24
BOT start BOT switch
4
3 Rate ratio (95% CI) Rate ratio (95% CI)
0.98 0.45
(0.64 to 1.48) 3 (0.21 to 0.96)
2
2
1
1
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
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
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;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 3. Bolli GB et al. Diabetes Obes Metab 2015;17:386-394
(main article and Supplementary Figure 3); 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74
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Rate of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia at
any time of day (24 h) in T2DM studies at Month 6
14 12
EDITION 11 Gla-300 EDITION 22
12 BB Gla-100 10 BOT switch
10
8
8
(≤70 mg/dL [≤3.9 mmol/L]) or severe events
6
Cumulative mean numbers of confirmed
6
4
4
Rate ratio (95% CI) Rate ratio (95% CI)
2 0.95 2 0.77
(0.80 to 1.13) (0.63 to 0.96)
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
16 16
EDITION 33 EDITION JP 24
14 BOT start 14
Rate ratio (95% CI)
BOT switch Rate ratio (95% CI)
12 0.75 12 0.64
(0.57 to 0.99) (0.43 to 0.96)
10 10
8 8
6 6
4 4
2 2
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
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
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;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 3. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94
(main article and Supplementary Figure 3); 4. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74
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Incidence of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe
hypoglycemia in T1DM studies at Month 6
Nocturnal (00:00–05:59 h) Any time of day (24 h)
Favors Favors Favors Favors
Gla-300 Gla-100 Gla-300 Gla-100
← → ← →
Baseline to Month 6 0.98 (0.88 to 1.09) 1.00 (0.95 to 1.04)
EDITION 41
BB
Baseline to Week 8 0.82 (0.70 to 0.96) 0.98 (0.92 to 1.04)
% Participants experiencing ≥1 severe hypoglycemic event from baseline to Month 6: Any time of day (24 h)
Safety population; BB, basal-bolus therapy; CI, confidence interval; T1DM, type 1 diabetes mellitus
1. Home PD et al. Diabetes Care. 2015;38:2217-25 (Supplementary Table 2); 2. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83 (Supplementary Table 3)
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Rate of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe
hypoglycemia in T1DM studies at Month 6
Nocturnal (00:00–05:59 h) Any time of day (24 h)
6 45
EDITION 41 EDITION 41
BB Gla-300 40 BB
5 Gla-100 35
4 30
(≤70 mg/dL [≤3.9 mmol/L]) or severe events
25
Cumulative mean numbers of confirmed
3
20
2 15
Rate ratio (95% CI) Rate ratio (95% CI)
0.90 10 1.09
1 (0.71 to 1.14)
5 (0.94 to 1.25)
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
10 60
EDITION JP 12 EDITION JP 12
9 54
BB BB
8 48
7 42
6 36
5 30
4 24
3 18
Rate ratio (95% CI) Rate ratio (95% CI)
2 12 0.80
0.66
1 (0.48 to 0.92) 6 (0.65 to 0.98)
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
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
BB, basal-bolus therapy; CI, confidence interval; T1DM, type 1 diabetes mellitus
The steep increase in the Gla-300 group during the last 8 days of the main 6-month treatment period in EDITION JP 1 is explained by the very low number of patients exposed to treatment during this time
who experienced only 1 event on each of Day 187, Day 189 and Day 190
1. Adapted from Home PD et al. Diabetes Care. 2015;38:2217-25 (main article and Supplementary Figure 3); 2. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83
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Basal insulin doses and weight change at Month 6
Basal insulin
EDITION 11 EDITION 22 EDITION 33 EDITION JP 24 EDITION 45 EDITION JP 16
dose at M6,
BB BOT switch BOT start BOT switch BB BB
U/kg/day
1.0
0.9 0.9
1.0
0.7 0.7
0.5 0.5
Gla-300 0.5 0.4 0.4
Gla-100 0.1
0.0
-0.1
-0.5
-0.6
-1.0
BB, basal-bolus therapy; BL, baseline; BOT, basal-oral therapy; M6, Month 6
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 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;38:2217-25; 6. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83
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Similar AE profile of Gla-300 and Gla-100 at Month 6
T2DM studies T1DM studies
Proportion of EDITION 11,2 EDITION 23 EDITION 34,5 EDITION JP 26 EDITION 47 EDITION JP 18
patients, % BB BOT switch BOT start BOT switch BB BB
Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100
Serious TEAEs 6.4 5.2 3.7 3.7 6 6 4.2 3.3 6.2 8.0 2.5 2.5
TEAEs
leading to 1.5 1.7 1.5 1.0 1 1 2.5 0.8 1.1 1.1 0.8 0
discontinuation
TEAEs
0.2 0.5 0.5 0.2 0.2 0 0 0 0.4 0 0 0
leading to death
Injection site
2.2 1.5 0.7 2.7 4 5 1.7 0.8 2.2 1.5 0 0
reactions
AE, adverse event; BB, basal-bolus therapy; BOT, basal-oral therapy; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TEAEs, treatment-emergent adverse events
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Data on file, EDITION 1 CSR (6 months) pg 125; 3. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
4. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 5. EDITION 3 CSR (6 months) pg 139; 6. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74;
7. Home PD et al. Diabetes Care. 2015;38:2217-25 (main article and Supplementary Table 4); 8. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83
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EDITION 1+2+3 T2DM
Patient-level meta-analysis, M6
Similar HbA1C reduction with lower hypoglycemia
and less weight gain with Gla-300 vs Gla-100 at 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
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EDITION 1+2+3 T2DM
Patient-level meta-analysis, M6
Rate of hypoglycemia by time of the day
at Month 6
Annualized rates of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia
4.5 Gla-300
4.0 Gla-100
Events per participant-year
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0 to 2 2 to 4 4 to 6 6 to 8 8 to 10 10 to 12 12 to 14 14 to 16 16 to 18 18 to 20 20 to 22 22 to 24
Clock time, h
• A lower rate of hypoglycemia was shown during the night and beyond the predefined nocturnal
period (00:00–05:59 hours) up to the afternoon with Gla-300 compared with Gla-100
Safety population
T2DM, type 2 diabetes mellitus
Adapted from Ritzel R et al. Diabetes Obes Metab. 2015;17:859-67
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EDITION 1+2+3 T2DM
Patient-level meta-analysis, M6
Rate of confirmed (≤70 mg/dL [≤3.9 mmol/L])
or severe hypoglycemia at Month 6
10 2.0
Gla-300 Gla-300
Gla-100 Gla-100
8
1.0
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
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EDITION T2DM
Post hoc
Post hoc subpopulation analyses of EDITION T2DM studies analyses M6
• Comparable glycemic control with hypoglycemia benefit with Gla-300 and Gla-100
regardless of:
• Age (<65 years and ≥65 years)1
Patient-level meta-analysis
• BMI (<30 and ≥30 kg/m2)1 of EDITION 1, 2 and 3
• A greater percentage of older adults aged ≥65 years achieved HbA1C targets
without confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia in the
Gla-300 vs Gla-100 group during the night and at any time of day (24 h) in a
post hoc patient-level meta-analysis of EDITION 1, 2 and 34
BMI, body mass index; HbA1C, glycated hemoglobin A1C; T2DM, type 2 diabetes mellitus
1. Twigg SM et al. Poster presentation at ATTD 2016; Abstract 0381; 2. Roussel R et al. Poster presentation at ATTD 2016; Abstract 0207;
3. Bonadonna RC et al. Oral presentation at ATTD 2016; Abstract 0385; 4. Yale J-F et al. Poster presentation at ADA 2015; Abstract 991-P
30
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
EDITION program
12-month results
31
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
EDITION 1+2+3 T2DM
Patient-level meta-analysis, M12
More sustained HbA1C reduction with lower
hypoglycemia and weight gain with Gla-300 vs Gla-100 at Month 12
• 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
32
NOT FOR PROMOTIONAL USE
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Flexibility of dosing injection time
33
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
Flexibility of dosing injection time with Gla-300
• Morning vs evening injection in T1DM
– In EDITION 4, there were no clinically relevant differences in HbA1C improvement or hypoglycemia with
morning or evening Gla-300 injections1 (further confirmed by findings from the T1DM CGM trial)2
• In EDITION 1 and 2 substudies in T2DM (Months 6–9) administration of Gla-300 with a flexible
dosing* time had no effect on glycemic control and incidence of hypoglycemia3
Pooled data of EDITION 1 and 2 substudies Pooled data of EDITION 1 and 2 substudies
(mITT population) (safety population)
60
% participants experiencing
Flexible dosing Fixed dosing Flexible dosing
≥1 hypoglycemic event
n=99 n=95 50
Fixed dosing
HbA1C,% 40
change (SE) 10
LS mean difference 0.05
0
(95% CI) (–0.13 to 0.23) Any time of day (24 h) Nocturnal (00:00 to 05:59 h)
Confirmed (≤70 mg/dL [≤3.9 mmol/L])
or severe hypoglycemia
The EDITION titration algorithm has shown to be effective and safe to bring patients to target. The INSIGHT pragmatic
1 U/day self-titration algorithm, widely used in Canada, has been compared with the EDITION program algorithm in the
primary care setting. This study demonstrates that the application of a self-titration of 1 U/day algorithm with Gla-300 is
safe, effective and comparable to the previously tested EDITION algorithm.
Glycemic control/
composite endpoint Hypoglycemia
INSIGHT algorithm
Mean HbA1c at
35 EDITION algorithm
Week 12: 60
7.6 7.6
30
Percentage of patients
50
Percentage of patients
25
40
20
30
15
20
10
5 10
0 0
FSMPG ≤5.6 HbA1c ≤7% at Week Confirmed or Symptomatic Confirmed* Nocturnal Nocturnal
mmol/L without 12 severe (before 6:00 (before 8:00
nocturnal AM) AM)
hypoglycemia
*Confirmed hypoglycemia: SMPG ≤3.9 mmol/L [≤70 mg/dL].
INSIGHT algorithm: self-titration 1 U daily; EDITION algorithm: EDITION 1, 2 and 3: dose adjusted at least once weekly Yale et al. ADA 2016.
Insulin titration in clinical practice
• When initiated, insulin is ideally titrated from a low starting dose (usually
10 U/day) to achieve therapeutic efficacy using various titration algorithms
ADA/EASD 20061* AACE 20132 IDF 20123 CDA 20134
SAGLB.DIA.14.06.0065a(1) / 2014.09
GLA 300 Special Population Studies
–1 –0.5 0 0.5 1
*Post hoc patient-level meta-analysis of people with T2DM treated with Gla-300 or Gla-100 for 6 months in the EDITION 1, 2 and 3 studies by estimated glomerular filtration rate (eGFR)
Adapted from Halimi S et al. Poster presentation at ATTD 2017
38
Annualized rate of hypoglycemic Events per participant-year Events per participant-year Events per participant-year
events Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100
Confirmed (≤70 mg/dL) or severe 2.2 3.6 7.7 10.3 18.0 21.3
Confirmed (<54 mg/dL) or severe 0.3 0.7 0.9 1.5 2.1 2.5
Documented symptomatic (≤70 mg/dL) 1.4 2.6 3.3 5.1 8.4 10.1
0.2 0.6 0.5 1.1 1.4 1.7
Documented symptomatic (<54 mg/dL)
0.2 1.0 1.5 0.2 1.0 1.5
0.2 1.0 1.5
RR (95% CI) RR (95% CI) RR (95% CI)
• Incidence of severe events was low and similar with Gla-300 and Gla-100
• Nocturnal (00:00–05:59 h) events: 1.5% vs 1.2% (RR 1.11; 95% CI: 0.40 to 3.08)
• Anytime (24 h) events: 3.1% vs 4.2% (RR 0.71; 95% CI: 0.33 to 1.49)
Safety population. *Median (IQR) time of pre-breakfast SMPG 07:45 (07:00 to 08:30) h
Adapted from Yale J-F et al. Poster presentation at ADA 2015; Abstract 991-P
The use of Gla-300 may be Exposure via father 5 (0.2) 0.06 2 (5.0) 3.49
considered during pregnancy Stillbirth 19 (0.7) 0.21 0 (0.0) N/A
if clinically needed
Live birth/unknown outcome 2284 (85.2) 25.14 37 (88) 64.61
aSome cases may be counted more than once owing to multiple events reported in one case; bThe reporting rate is based on cumulative exposure as there are no data by gender
cPercentage calculation is based on total number of pregnancy/lactation-related cases and events; dData collected from International Marketing Services Health; AE, adverse event; N/A, not applicable; pt-y, patient-years
Bertolini M et al. Poster to be presented at EASD 2017; Abstract XXX
40
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 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. Ritzel R et al. Diabetes Obes Metab. 2015;17:859-67; 6. Home PD et al. Diabetes Care. 2015;38:2217-25; 7. Matsuhisa M et al. Diabetes Obes Metab.
2016;18:375-83; 8. Bergenstal RM et al. Diabetes Care. 2017;40:554-560; 9. Riddle M et al. Diabetes Technol Ther. 2016;18:252-7; 10. Klonoff D et al. J Diabetes Sci Technol. 2015;10:125-30;
11. Ritzel R et al. Poster presentation at Abstract 469; 12. Halimi S et al. Poster presentation at ATTD 2017; 13. Bertolini M et al. Poster presentation at EASD 2017; abstract number to be added when available
41
1. ISPOR. Real-Life Data: A Growing Need. Available at: https://www.ispor.org/News/articles/Oct07/RLD.asp. Last accessed June 2017; 2. Network for Excellence in Health Innovation 2015. Real World Evidence: A
New Era for Health Care Innovation. Available at: http://www.nehi.net/publications/66-real-world-evidence-a-new-era-for-health-care-innovation/view. Last accessed June 2017. 3 Sherman RE et al. N Engl J Med 2016:
375:2293-7.
Broad
Pragmatic
trials RWE: Helps to answer questions that
RCTs do not address
Long-term
phase III
Matching and/or adjustment strategies
Registration can be used to account for potential
RCTs
confounders and minimize bias
Narrow
1. Cziraky M, Pollock M. Applied Clinical Trials 2015. Available at: http://www.appliedclinicaltrialsonline.com/real-world-evidence-studies. Last accessed June 2017; 2.
ISPOR. Real-Life Data: A Growing Need. Available at: https://www.ispor.org/News/articles/Oct07/RLD.asp. Last accessed June 2017; 3. de Lusignan S et al. J
Innov Health Inform 2015;22:368-73. 4. Sherman RE et al. N EnglJ Med 2016:375:2293-7.
Date of approval June 2017
FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY
SUBJECT TO LOCAL
FOR MEDICAL REVIEW
AND AND APPROVAL
SCIENTIFIC PURPOSES ONLY
SAGLB.TJO.17.06.0651
SAGLB.TJO.17.06.0585 June 2017 DO NOT USE IN PROMOTIONAL PURPOSES
DO NOT DISTRIBUTE OR USE IN PROMOTION
Real-world evidence can inform our understanding
to enhance clinical practice
Improve outcomes1
1. Cziraky M, Pollock M. Applied Clinical Trials 2015. Available at: http://www.appliedclinicaltrialsonline.com/real-world-evidence-studies. Last accessed June 2017.
Date of approval June 2017
FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY
SUBJECT TO LOCAL
FOR MEDICAL REVIEW
AND AND APPROVAL
SCIENTIFIC PURPOSES ONLY
SAGLB.TJO.17.06.0651
SAGLB.TJO.17.06.0585 June 2017 DO NOT USE IN PROMOTIONAL PURPOSES
DO NOT DISTRIBUTE OR USE IN PROMOTION
Types of RWE being used in Gla-300 studies
Real-world data (RWD) is the raw information about patients’ characteristics, their care,
the resources-consumed, and the outcomes achieved during actual medical practice
HbA1c, hemoglobin A1c; HEDIS, Healthcare Effectiveness Data and Information Set; T2DM, type 2 diabetes mellitus
Oster G et al. Postgrad Med. 2016;128:731-739; https://clinicaltrials.gov/ct2/show/NCT0245113; https://clinicaltrials.gov/ct2/show/NCT02967224;
https://clinicaltrials.gov/ct2/show/NCT02967211 (accessed June 2017)
Date of approval June 2017
FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY
SUBJECT TO LOCAL
FOR MEDICAL REVIEW
AND AND APPROVAL
SCIENTIFIC PURPOSES ONLY
SAGLB.TJO.17.06.0651
SAGLB.TJO.17.06.0585 June 2017 DO NOT USE IN PROMOTIONAL PURPOSES
DO NOT DISTRIBUTE OR USE IN PROMOTION
Result
Results and Conclusions
Conclusions
• In this real-world study of patients with T2DM, switching to Gla-300 from another basal insulin resulted in
significantly lower A1C, hypoglycemic events and frequency of dosing, with numerically lower daily insulin
dose.
• This findings are consistent with those of the EDITION clinical trial program and also suggest that in the
real-life setting, without observing any dose increases and with less frequent daily dosing. Gla-300 provides
an advantage in terms of better efficacy and safety than are obtained with the standard of care.
• Prospective studies using a larger number of subjects are needed to confirm these findings
Real-World Assessment of Patient Characteristics and Clinical Outcomes of Early
Users of the New Insulin Glargine 300 U/ml (DELIVER 1)
Real-world patients with T2D who switched to Gla-300 from other basal insulin analogs showed improved
glycemic control and a trend towards fewer hypoglycemia events
follow-up (%)
electronic medical records for adults with T2D on basal insulin and 17
switching to either Gla-300 or another basal insulin
Key Findings: 15.9
• 1,827 patients switching to Gla-300 were matched to 1,827 16
patients switching to another basal insulin
• Comparable change in mean A1C from baseline, 6 months after
switching to Gla-300 or other basal insulin (P=0.14): 15
– Gla-300: -0.55%
– Other basal insulins: -0.47%
14
• Hypoglycemia incidence was lower in patients switching to Gla- Gla-300 Other basal insulins
300 than other basal insulins (15.9% vs 18.2%; aOR 0.78, 95% CI:
0.65, 0.94) at 6 month follow-up • Switching to Gla-300 was associated with a lower
hypoglycemia event rate (LS-mean difference: −0.225
events/PPPY, 95%CI: −0.379,−0.072; P<0.01)
• The lower hypoglycemia risk is associated with lower
health care resource utilization, and associated costs.
In real-world clinical settings, switching to Gla-300 is associated with a significantly lower risk of hypoglycemia than
switching to other basal insulins, while delivering comparable glycemic control
Zhou FL, Ye F, Gupta V, et al. Late-breaking poster presented at AACE 2017 (abstract published in Endocrine Practice)
Older Adults with T2D Experience Less Hypoglycemia When
Switching to Gla-300 vs Other Basal Insulins (DELIVER 3)
Hypoglycemia event rates
Study objective: To examine the performance of Gla-300 in older 12
(event/100 patient-months)
Methods: A retrospective study of data from the Predictive Health –4.94 events/100
Intelligence Environment (PHIE) database of electronic medical records patient-months;
for adults ≥65 years with T2D on basal insulin and switching to Gla-300 8 P = 0.0002
or another basal insulin
Key Findings 6 5.37
• Baseline clinical characteristics of 468 patients switching to Gla-300
and 1,142 patients switching to another basal insulin, respectively: 4
– Mean age 71.8 and 73.1 years
– Mean A1C level 8.52% and 8.34%
2
• Switching led to comparable change in mean A1C from baseline, 6
months after switching to Gla-300 or another basal insulin (LS-
mean difference: -0.09; P=0.24) 0
• Similar proportions of patients reached A1C <8% (OR: 0.967; 95% Gla-300 Other basal insulins
CI 0.749-1.248; P=0.797) • Patients switched to Gla-300 were 57% less likely to have
hypoglycemia at 6-mo follow-up
• (OR: 0.432; 95% CI 0.307-0.607; P<0.0001)
• Hypoglycemia event rates were also significantly lower in
the Gla-300 cohort
In real-world clinical settings, switching to Gla-300 in older patients with T2D is associated
with significantly lower hypoglycemia risk and similar glycemic control vs other basal insulins.
59
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Basal insulin doses and weight change at Month 12
Basal insulin
EDITION 11 EDITION 22 EDITION JP 23 EDITION JP 14
dose at M12,
BB BOT switch BOT switch BB
U/kg/day
1.0
0.5
Gla-300 0.5 0.4 0.4
Gla-100 0.1
0.0
-0.5
-0.7
-1.0
EDITION 11 EDITION 22 EDITION JP 23 EDITION JP 14
BB, basal-bolus therapy; BL, baseline; BOT, basal-oral therapy; M12, Month 12; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Obes Metab. 2015;17:835-42; 2. Yki-Järvinen H et al. Diabetes Obes Metab. 2015;17:1142-9; Terauchi Y et al. Oral presentation at ADA 2015; Abstract 98-OR;
4. Matsuhisa M et al. Poster presentation at ADA 2015; Abstract 987-P
60
NOT FOR PROMOTIONAL USE
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Similar AE profile of Gla-300 and Gla-100 at Month 12
T2DM studies T1DM studies
Proportion of EDITION 11 EDITION 22 EDITION JP 23 EDITION JP 14
patients, % BB BOT switch BOT switch BB
TEAEs
leading to 2.2 3.5 2.7 1.7 3.3 1.7 1.6 0.8
discontinuation
TEAEs leading to
0.5 1.0 1.0 0.5 0 0 0 0.8
death
Injection site
3.0 1.5 1.2 3.0 1.7 0.8 0 0
reactions
EDITION 11 EDITION 45
BB 0.00% (–0.11 to 0.11) BB 0.04% (–0.10 to 0.19)
EDITION 22 EDITION JP 16
–0.01% (–0.14 to 0.12) BB 0.13% (–0.03 to 0.29)
BOT switch
EDITION 33
BOT start 0.04% (–0.09 to 0.17)
EDITION JP 24
0.10% (–0.08 to 0.27)
BOT switch
-0.20
-0.28 -0.25
-0.33
Gla-300
LSM HbA1C
-0.5
-0.50
-0.55 Gla-100
-0.69
T2DM
-0.86
-1.0 T1DM
-1.5
mITT population
BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; HbA1C, glycated hemoglobin A1C; LSM, least squares mean; mITT, modified intention-to-treat; NA, not available; T1DM, type 1 diabetes mellitus;
T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Obes Metab. 2015;17:835-42; 2. Yki-Järvinen H et al. Diabetes Obes Metab. 2015;17:1142-9;
3. Terauchi Y et al. Poster presentation at EASD 2015; Abstract 959; 4. Matsuhisa M et al. Poster presentation at ADA 2015; Abstract 987-P
63
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
Lower or similar incidence of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or
severe hypoglycemia with Gla-300 vs Gla-100 at Month 12
T2DM
Nocturnal (00:00–05:59 h) Any time of day (24 h)
T1DM
Favors Favors Favors Favors
Gla-300 Gla-100 Gla-300 Gla-100
← → ← →
EDITION 11
BB 0.84 (0.75 to 0.94) 0.94 (0.89 to 0.99)
EDITION 22
0.84 (0.71 to 0.99) 0.96 (0.89 to 1.02)
BOT switch
Safety population; 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
BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
1. Adapted from Riddle MC et al. Diabetes Obes Metab. 2015;17:835-42; 2. Yki-Järvinen H et al. Diabetes Obes Metab. 2015;17:1142-9 (Supplementary Table 1);
3. Terauchi Y et al. Oral presentation at ADA 2015; Abstract 98-OR; 4. Matsuhisa M et al. Poster presentation at ADA 2015; Abstract 987-P
64
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
Lower or similar rate of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or
severe hypoglycemia with Gla-300 vs Gla-100 at Month 12
T2DM
Nocturnal (00:00–05:59 h) Any time of day (24 h)
T1DM
Favors Favors Favors Favors
Gla-300 Gla-100 Gla-300 Gla-100
← → ← →
EDITION 11
0.90 (0.70 to 1.16) 1.06 (0.89 to 1.27)
BB
EDITION 22
0.63 (0.42 to 0.96) 0.88 (0.71 to 1.09)
BOT switch
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
BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
1. Adapted from Riddle MC et al. Diabetes Obes Metab. 2015;17:835-42; 2. Yki-Järvinen H et al. Diabetes Obes Metab. 2015;17:1142-9 (Supplementary Table 1);
3. Terauchi Y et al. Oral presentation at ADA 2015; Abstract 98-OR; 4. Matsuhisa M et al. Poster presentation at ADA 2015; Abstract 987-P
65
NOT FOR PROMOTIONAL USE
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Poster 2:
- Japanese Patients JP1 and JP2
- BID Switch- EDITION Subanalyses
Insulin glargine U-300 vs U-100
(EDITION JP-2)
241 basal insulin using Asian patients with T2DM
Cumulative mean number of nocturnal
severe or confirmed (≤3.9 mmol/L) events per participant
RR (95% CI)
0.45 (0.21 to 0.96)
U-300 glargine
Difference
after 12 wk
67
With long-term use U300 may reduce noc hypoglycemia >50%
Terauchi Y et al. Diab Obes Metab 21 JAN 2016 DOI: 10.1111/dom.12618 CONFIDENTIAL- for Advisor Discussion only
EDITION JP 2, M6
Insulin dose from baseline to Month 6
1.0
0.8
Gla-300 Mean basal insulin dose, U/day (OC)2
Gla-100 BL M6
0.6 Gla-300 16.1 24.2
0.4
Relative difference for
Gla-300 vs Gla-100 at
0.2 Month 6 (based on U/kg/day)2:
+17.87%
LOCF
0.0
BL W12 M6
mITT population
LOCF, last observation carried forward
1. Data on file, EDITION JP 2 CSR (6 months) Appendix 16-2-6-eff-reponse_data_6_month-2014 pg 261
2. Data on file, Sanofi response to D80 CHMP List of Questions (post-hoc analysis): E19_Insulin dose_Absolute and Relative differences_M12_2014-09-03. doc pg 43, 44
EDITION JP 2, M6
Rate ratio 0.64 (0.43 to 0.96) Rate ratio 0.45 (0.21 to 0.96)
3
8
4
1
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
Time, weeks Time, weeks
Safety population
Adapted from Data on file, EDITION JP 2 CSR (6 months) pg 145, 147; EDITION JP 2 Ad-hoc analyses (6 months) efc12512-hypo-adhoc-jp pg 5, 8
EDITION JP 2
Less weight gain with U300 vs Lantus®
0.5
0.0
–0.5
–1.0
BL W2 W4 W8 W12 M4 M6 LOV
Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976 Available at: http://www.easdvirtualmeeting.org/resources/19078 Accessed September 2014
-20% -34%
Footer:
Confirmed (≤70 mg/dL [3.9 mmol/L]) Confirmed (<54 mg/dL [3.0 mmol/L])
and/or severe and/or severe Severe
15
12.8 U300
Events per patient-year
11.2 Lantus®
10.5
10
5.7
5 4.1
3.3
0.05 0 0 0 0.07 0
0
BL to M6 BL to W8 W9 to M6 BL to M6 BL to W8 W9 to M6 BL to M6 BL to W8 W9 to M6
0.5
U300
Lantus®
–0.5
BL W4 W8 W12 M4 M6 LOV
Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975 Available at: http://www.easdvirtualmeeting.org/resources/18532 Accessed September 2014
EDITION 1 EDITION 2
Gla-300 Gla-100 Gla-300 Gla-100
(n=404) (n=403) (n=404) (n=407)
Prior basal insulin type*†, %
Gla-100 92.5 91.5 74.9 82.8
NPH 7.5 8.5 25.1 17.2
Prior basal insulin BID¶, % 16.9‡ 20.0‡
Gla-300 BID Gla-100 BID Gla-300 BID Gla-100 BID
(n=70) (n=65) (n=84) (n=77)
Age, years 60.3 59.0 57.9 58.7
BMI, kg/m2 37.5 38.1 34.6 35.0
Duration of diabetes, y 15.7 17.3 14.9 13.9
HbA1C, % 8.22 8.14 8.37 8.41
Prior basal insulin type*, %
Gla-100 74.3 73.8 19.0 24.7
NPH 25.7 26.2 81.0 75.3
Mean unless otherwise indicated; BID, twice daily
*None of the participants in EDITION 1 and 2 were receiving detemir BID before the start of the studies. †Randomized population.
‡Percentages are calculated based on the numbers of participants with no missing data. ¶mITT population.
Roussel R et al. Poster and e-poster presentations at ADA 2015; Abstract 1021-P
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
EDITION 1, 2: BID switchers, M6
Comparable glycemic control with
Gla-300 vs Gla-100 after switching from BID to
once-daily basal insulin
LS mean difference (95% CI)
• Switching from basal insulin BID to
SAAS.TJO.16.09.0027c
EDITION 1, 2: BID switchers, M6
Lower risk of nocturnal confirmed
(≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia with Gla-300
vs Gla-100 in people switching from BID basal insulin
• Risk of nocturnal confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia was
reduced with once-daily Gla-300 compared with Gla-100 in EDITION 1 and EDITION 2
in people who switched from basal insulin BID
• A benefit in favor of Gla-300 was also seen for confirmed or severe hypoglycemia at
any time of day (24 h) in EDITION 2
• Results were consistent with the overall populations of EDITION 1 and EDITION 2
Prior BID Overall study population
Favors Favors Favors Favors
Confirmed or severe hypoglycemia Gla-300 Gla-100 Gla-300 Gla-100
EDITION 1
Nocturnal (00:00–05:59 h): ≤70 mg/dL (≤3.9 mmol/L)
Nocturnal (00:00–05:59 h): <54mg/dL (<3.0 mmol/L)
EDITION 2
Nocturnal (00:00–05:59 h): ≤70 mg/dL (≤3.9 mmol/L)
Nocturnal (00:00–05:59 h): <54mg/dL (<3.0 mmol/L)
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
Poster 3: BEGIN and EDITION Trial Level Meta-
analysis, Network Meta-Analysis
Clinical perspectives from the BEGIN and
EDITION programmes: Trial-level meta-
analyses outcomes with either IDeg or
Gla-300 vs Gla-100 in T2DM
Based on Roussel R et al. Poster presentation at EASD 2016;
Abstract 914
SAAS.TJO.16.09.0027c
BEGIN & EDITION trial-
level meta-analyses
Objectives and methods T2DM
FDA, Food and Drug Administration; FPG, fasting plasma glucose; T2DM, type 2 diabetes mellitus
1. Novo Nordisk. FDA Briefing document 2012; Available at:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM327017.pdf
(accessed June 2016)
Roussel R et al. Poster presentation at EASD 2016; Abstract 914. Available at: http://www.easdvirtualmeeting.org/resources/clinical-perspectives-from-the-begin-and-edition-
programmes-trial-level-meta-analyses-outcomes-with-either-degludec-or-glargine-300-u-ml-vs-glargine-100-u-ml-in-type-2-diabetes-mellitus (accessed 27 September 2016)
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
BEGIN & EDITION
trial-level
Summary of BEGIN and EDITION trials in meta-analyses T2DM
people with T2DM
BEGIN development program EDITION development program
Trial BEGIN
description BEGIN BEGIN
Basal- BEGIN BEGIN EDITION
and treatment Once Low EDITION 16 EDITION 27 EDITION 38
Bolus Flex (OD)4 Once Asia5 JP 29
Long2 Volume3
Type 21
Number of IDeg, 755 IDeg, 773 IDeg, 228 IDeg, 228 IDeg, 289 Gla-300, 404 Gla-300, 404 Gla-300, 439 Gla-300, 121
participants* Gla-100, 251 Gla-100, 257 Gla-100, 229 Gla-100, 230 Gla-100, 146 Gla-100, 403 Gla-100, 407 Gla-100, 439 Gla-100, 120
Study duration,
52 52 26 26 26 26 26 26 26
weeks
Inclusion
criteria
HbA1C ≥7–≤10% ≥7–≤10% ≥7–≤10% ≥7.0–≤11† or ≥7–≤10% ≥7–≤10% ≥7–≤10% ≥7–≤11% ≥7–≤10%
≤10‡%
Age ≥18 years ≥18 years ≥18 years ≥18 years ≥18 years§ ≥18 years ≥18 years ≥18 years ≥18 years
BMI ≤40 kg/m2 ≤40 kg/m2 ≤45 kg/m2 ≤40 kg/m2 ≤35 kg/m2 N/A N/A N/A <35 kg/m2
From the BEGIN Flex trial only the ‘OD’ arm was included in these trial-level meta-analyses; participants in the ‘OD Flex’ arm received IDeg at intervals of 8–40 h,4 therefore these data
were not included
*Full analysis set for BEGIN trials and randomized population for EDITION trials; †Insulin-naïve participants; ‡Participants on basal insulin; §≥20 years in Japan
BMI, body mass index; HbA1C, glycated hemoglobin A1C; Met, metformin; N/A, not applicable; OAD, oral antihyperglycemic drug; OD, once daily; T2DM, type 2 diabetes
1. Garber AJ et al. Lancet 2012;379:1498-507; 2. Zinman B et al. Diabetes Care 2012;35:2464-71; 3. Gough SC et al. Diabetes Care 2013;36:2536-42;
4. Meneghini L et al. Diabetes Care 2013;36:858-64; 5. Onishi Y et al. J Diabetes Invest 2013;4:605-12; 6. Riddle MC et al. Diabetes Care 2014;37:2755-62;
7. Yki-Järvinen H et al. Diabetes Care 2014;37:3235-43; 8. Bolli GB et al. Diabetes Obes Metab 2015;17:386-94; 9. Terauchi Y et al. Diabetes Obes Metab 2016;18:366-74
Roussel R et al. Poster presentation at EASD 2016; Abstract 914. Available at: http://www.easdvirtualmeeting.org/resources/clinical-perspectives-from-the-begin-and-edition-
programmes-trial-level-meta-analyses-outcomes-with-either-degludec-or-glargine-300-u-ml-vs-glargine-100-u-ml-in-type-2-diabetes-mellitus (accessed 27 September 2016)
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
BEGIN & EDITION
Differences in HbA1C and FPG reduction in BEGIN and trial-level
EDITION trials meta-analyses T2DM
IDeg vs Gla-100 (BEGIN trials) Gla-300 vs Gla-100 (EDITION trials)
Favors Favors Estimated LS mean Favors Favors Estimated LS mean
IDeg Gla-100 difference in change Gla-300 Gla-100 difference in change
from baseline to study from baseline to study
HbA1c (%) end (95% CI) HbA1c (%) end (95% CI)
BEGIN Basal-Bolus Type 2 0.08 (−0.12 to 0.28) EDITION 1 −0.03 (−0.14 to 0.08)
BEGIN Once Long 0.09 (−0.05 to 0.23) EDITION 2 −0.03 (−0.16 to 0.10)
BEGIN Low Volume 0.04 (−0.20 to 0.28) EDITION 3 0.04 (−0.09 to 0.17)
BEGIN Flex (OD) 0.18 (−0.04 to 0.40) EDITION JP 2 0.11 (−0.06 to 0.28)
BEGIN Once Asia 0.09 (−0.08 to 0.26)
Overall 0.09 (0.01 to 0.18) Overall 0.01 (–0.06 to 0.08)
-1.5 -1.0 -0.5 0.0 0.5 1.0 -1.5 -1.0 -0.5 0.0 0.5 1.0
• In the BEGIN meta-analysis, HbA1c reduction was significantly better for Gla-100 vs IDeg (p=0.024) despite
FPG reduction being significantly better with IDeg (p<0.001)
• In the EDITION meta-analysis, HbA1c and FPG reduction was comparable with Gla-300 and Gla-100 (p=NS)
• No significant heterogeneity of treatment effect across individual trials was observed in either trial-level
meta-analysis for HbA1c or FPG reduction (p=NS)
CI, confidence interval; FPG, fasting plasma glucose; HbA1C, glycated hemoglobin A1C; LS, least squares; NS, not significant; OD, once daily; T2DM, type 2 diabetes mellitus
Adapted from Roussel R et al. Poster presentation at EASD 2016; Abstract 914. Available at: http://www.easdvirtualmeeting.org/resources/clinical-perspectives-from-the-begin-and-edition-
programmes-trial-level-meta-analyses-outcomes-with-either-degludec-or-glargine-300-u-ml-vs-glargine-100-u-ml-in-type-2-diabetes-mellitus (accessed 27 September 2016)
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
BEGIN & EDITION
Relative risk of ≥1 documented symptomatic trial-level
(≤70 mg/dL [≤3.9 mmol/L]) hypoglycemic event meta-analyses T2DM
in BEGIN and EDITION trials
Confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia Confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia
Anytime Anytime
(24 h) 1.02 (0.97 to 1.06) NS (24 h) 0.89 (0.83 to 0.95) <0.001
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
Safety and efficacy of Gla-300 compared with other
basal or premixed insulin therapies in patients with
T2DM – A network meta-analysis (NMA)
Based on Freemantle N et al. Publication-only presentation at ADA 2016;
Abstract 2237-PUB
T2DM, type 2 diabetes mellitus
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
Gla-300 vs other
Comparable glycemic control and a lower risk of insulins: Network
meta-analysis in T2DM
hypoglycemia compared with other insulin therapies
• A systematic review (1980–2014) of 53 RCTs was conducted to assess the efficacy and safety of Gla-300 vs
other insulin therapies in patients with T2DM with/without basal insulin exposure
• HbA1c changes were comparable between treatments
Documented symptomatic Severe
Comparison hypoglycemia event rate hypoglycemia event rate
Relative risk (95% confidence interval) Relative risk (95% credible interval)
Gla-300 vs Gla-100 0.77 (0.72 to 0.81) NS
Gla-300 vs insulin detemir 0.67 (0.6 to 0.73) NS
Gla-300 vs NPH 0.55 (0.5 to 0.6) 0.38 (0.14 to 0.94)
Gla-300 vs insulin degludec 0.49 (0.44 to 0.54) NS
Gla-300 vs glargine biosimilar 0.76 (0.70 to 0.84) 0.14 (0.02 to 0.75)
Gla-300 vs premixed insulin 0.51 (0.47 to 0.54) 0.21 (0.08 to 0.54)
• The documented symptomatic hypoglycemia event rate was significantly lower with Gla-300 vs all comparators
• The severe hypoglycemia event rate was significantly lower with Gla-300 vs NPH, BIO and PRE
• Body weight change from baseline was lower with Gla-300 vs PRE (-1.82 kg) and higher vs DET (0.79 kg)
CONCLUSIONS
It may be expected that in real life, Gla-300 would lead to better hypoglycemia management
vs other basal insulins in patients with T2DM
BIO, glargine biosimilar; DET, insulin detemir; HbA1C, glycated hemoglobin A1C; NS, not significant; PRE, premixed insulin; RCT, randomized controlled trial;
T2DM, type 2 diabetes mellitus
Freemantle N et al. Publication-only presentation at ADA 2016; Abstract 2237-PUB. Available at: http://www.abstractsonline.com/pp8/#!/4008/presentation/41867
(accessed 25 September 2016)
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
Gla-300 vs other
The per patient-year rate ratio of documented insulins: Network
symptomatic hypoglycemia was significantly lower with meta-analysis in T2DM
Gla- 300 in comparison to other basal insulin therapies
• The results of the indirect treatment comparison revealed that Gla- 300 was associated
with statistically significant reduction in per patient-year rate ratio for documented
symptomatic hypoglycemia compared to all evaluated basal insulin therapies
Gla- 300 vs. RR (95% CI)
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