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Insulin glargine 300 U/mL (Gla-300)

Clinical evidences summary

Aimee Andag-Silva, MD, FPCP, FPSEDM


Chief, Section of Endocrinology & Diabetes
De La Salle University Medical Center
Asst. Professor, De La Salle College of Medicine
Cavite, Philippines

NOT FOR PROMOTIONAL USE


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DISCLOSURES

• Advisory Board Member:


–Sanofi, Merck Inc, Astra-Zeneca, Menarini
• CME Module Consultant:
–Servier, Nestle, Novo Nordisk
• Speaker Bureau:
–Boehringer Ingelheim, Pfizer, LRI-Thera Philippines
• CME grant:
–Cathay YSS Philippines, Natrapharm Philippines

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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

PD, pharmacodynamic; PK, pharmacokinetic; T2DM, type 2 diabetes mellitus


1. Davis KL et al. Curr Med Res Opin. 2013;29:1083-91; 2. Baser O et al. Clinicoecon Outcomes Res. 2013;5:497-505;
3. Maiorino MI et al. Expert Opin Biol Ther. 2014;14:799-808; 4. Ahrén B. Vasc Health Risk Man. 2013;9:155-63; 5. Wei W et al. Endocr Pract. 2014;20:52-61
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Introduction to
pharmacological
properties of basal
insulin analogues
Aspiration for a new basal insulin product

> 24-hour coverage Long duration of action

Reduced hypoglycaemic risk Flat time-action profile

Stable glucose lowering High day-to-day reproducibility

Flat time-action profile


Dosing flexibility Long duration of action

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Effective therapy requires a balance between the benefits of glycemic
control and the risk of hypoglycemia

Effective and stable Low risk of


glycemic control hypoglycemia

• Improved achievement of HbA1C • Reduced fear of hypoglycemia


targets • May allow for more optimal
• Prevention of complications and dose titration and improved
lower healthcare utilization glycemic control
• May allow for flexible dosing • May improve adherence
time, less restrictive regimens • Reduced morbidity and
may improve adherence healthcare utilization

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

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Evolution of basal insulin development:
Overcoming limitations
• Insulin glargine 100 U/mL (Gla-100)

Relative insulin effect

Relative insulin effect


and insulin detemir were developed NPH insulin
to overcome some limitations of Insulin detemir
early basal insulins such as Gla-100 Gla-100

NPH insulin, with less variable


absorption and longer duration of 0 12 24 0 12 24
Time, h Time, h
action1,2

Relative insulin effect

Relative insulin effect


• Longer-acting basal insulins,
insulin glargine 300 U/mL (Gla-300)
and insulin degludec, have since Gla-100
Gla-100

been developed with less variability Insulin degludec Gla-300


and more prolonged durations of
0 12 24 0 12 24
action (>24 h)1,2 Time, h Time, h

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

Ideal characteristic Potential clinical benefit

Once-daily injection
Duration of action (≥24 h)

Flexible injection timing

Flat PK and PD profile

Low risk of hypoglycemia

Low variability in insulin


exposure and action Facilitates insulin titration

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

• 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
Randomized
Participants 6 months 6-month
(1:1) 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;37:2755-62; 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
Testing Gla-300 vs Gla-100 in several populations

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)

EDITION 3 EDITION JP 2 EDITION JP 1


N=878 N=241 N=243
BOT – insulin naïve BOT BB
Basal insulin plus OAD Basal insulin plus OAD; Basal insulin plus mealtime
(excl. SU) Japanese patients 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;37:2755-62; 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

T2DM on T2DM on T2DM T2DM on T1DM T1DM


Population high-dose high-dose insulin-naïve basal insulin
basal insulin* basal insulin*

Dosing basal insulin Evening Evening Evening Evening Morning or Evening


evening
Time basal insulin injection Fixed every 24 h

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])

Main secondary (efficacy) ✔ ✔ ✔ Not applicable Not applicable Not applicable


endpoint: Hypoglycemia†

Thorough hypoglycemia ✔ ✔ ✔ ✔ ✔ ✔
analysis

*High dose: ≥42 U daily basal insulin


†Main secondary hypoglycemia endpoint: Percentage of patients with at least one episode of nocturnal (00:00–05:59 h)
confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia from Week 9 to Month 6

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 adjustments, U/day


EDITION 1, 2 & 3 EDITION JP 2
Median fasting SMPG from last 3 days in the range of:2,4,6,7
Gla-100 or Gla-300 Gla-300 Gla-100
≥140 mg/dL (≥7.8 mmol/L) +6 +3 +2

>100 and <140 mg/dL (5.6–7.8 mmol/L) +3 +1.5 +1

Glycemic target: 80–100 mg/dL (4.4–5.6 mmol/L) No change


≥60 and <80 mg/dL (3.3–4.4 mmol/L) -3
<60 mg/dL (<3.3 mmol/L) or occurrence of ≥2 symptomatic or 1
-3 or at investigator’s discretion
severe hypoglycemia episode(s) in the preceding week

• 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

Titration steering committee was in place


Adjustments at investigators’ discretion for safety

Dose adjustments, U/day


Median fasting SMPG from last 3 days in the EDITION 4 and JP 1
range of:1-3
Gla-300 Gla-100
>130 mg/dL (>7.2 mmol/L) ≥10% of daily dose in the ≥10% of daily dose in the
or > individual target range +1.5 to +4.5 U range +1.0 to +4.0 U
Glycemic target: 80–130 mg/dL (4.4–7.2 mmol/L)
No change No change
or within individual target
-1.5 U at investigator’s -1.0 U at investigator’s
<80 mg/dL (<4.4 mmol/L) or below individual target
discretion discretion

<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

6-month core data results

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Summary of baseline characteristics of T2DM studies

Mean unless otherwise EDITION 11 EDITION 22 EDITION 33 EDITION JP 24


stated BB BOT switch BOT start BOT switch

Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100


n=404 n=403 n=404 n=407 n=439 n=439 n=121 n=120

Age, years 60.1 59.8 57.9 58.5 58.2 57.2 61.1 60.5

Male, % 53.7 52.1 46.3 45.5 57.6 57.9 63.6 58.3

BMI, kg/m² 36.6 36.6 34.8 34.8 32.8 33.2 25.7 24.8

Weight, kg 106.2 106.4 98.7 98.0 95.1 95.6 67.4 65.9

Duration of diabetes, years 15.6 16.1 12.7 12.5 10.1 9.6 14.0 13.9

Previous basal insulin


0.67 0.67 0.66 0.68 – – 0.25 0.24
dose, U/kg

Prior use of metformin, % 56.2 58.6 94.8 93.6 90.6 92.0 57.9 59.2

HbA1C, % 8.15 8.16 8.26 8.22 8.51 8.57 7.99 8.06

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

Mean unless otherwise EDITION 41 EDITION JP 12


stated BB BB

Gla-300 Gla-100 Gla-300 Gla-100


n=274 n=275 n=122 n=121

Age, years 46.4 48.2 44.1 46.3

Male, % 54.4 59.6 45.9 46.3

BMI, kg/m² 27.6 27.6 23.8 23.2

Weight, kg 81.9 81.8 63.9 61.0

Duration of diabetes, years 20.5 21.4 12.2 13.9

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

HbA1C, % 8.11 8.14 8.06 8.07

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

EDITION 11 EDITION 22 EDITION 33 EDITION JP 24 EDITION 45,6 EDITION JP 17


BB BOT switch BOT start BOT switch BB BB

LSM difference 0.00% -0.01% 0.04% 0.10% 0.04% 0.13%


(95% CI) (-0.11 to 0.11) (-0.14 to 0.12) (-0.09 to 0.17) (-0.08 to 0.27) (-0.10 to 0.19) (-0.03 to 0.29)
0.0
LSM HbA1C change
from baseline, %

-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

Primary endpoint: non-inferiority in HbA1C change with Gla-300


vs Gla-100 at Month 6

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

EDITION 11 EDITION 22 EDITION 33 EDITION JP 24 EDITION 45 EDITION JP 16


BB BOT switch BOT start BOT switch BB BB

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

-1.14 -1.06 -1.12 -1.03


-1.28
-1.48 -1.45
-2 -1.69
T2DM
T1DM
-3
Gla-300
-3.29
Gla-100
-4
-3.91

-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)

Baseline to Month 6 Baseline to Week 8 Week 9 to Month 6*


Favors Favors Favors Favors Favors Favors
Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100

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

0.3 3.0 0.3 3.0 0.3 3.0


Relative risk (95% CI) Relative risk (95% CI) Relative risk (95% CI)

*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

Rate ratio (95% CI) Rate ratio (95% CI)


0.5 0.5
0.75 0.52
(0.58 to 0.95) (0.35 to 0.77)
0.0 0.0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 28

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)

Week 9 to Month 6 1.06 (0.92 to 1.23) 0.98 (0.91 to 1.06)

Baseline to Month 6 0.85 (0.73 to 0.99) 0.99 (0.95 to 1.04)


EDITION JP 12
BB Baseline to Week 8 0.71 (0.56 to 0.91) 0.91 (0.84 to 0.99)

Week 9 to Month 6 0.84 (0.70 to 1.00) 1.01 (0.95 to 1.08)

0.4 2 0.6 1.5


Relative risk (95% CI) Relative risk (95% CI)

% 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 41 6.6 9.5 0.71 (0.41 to 1.24)

EDITION JP 12 5.7 9.9 0.58 (0.24 to 1.42)

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)
23
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SAGLB.TJO.16.02.0087
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
24
NOT FOR PROMOTIONAL USE
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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

Gla-300 0.97 0.92 0.62 0.35 0.47 0.35

Gla-100 0.88 0.84 0.53 0.30 0.40 0.29

Mean weight change from baseline, kg

EDITION 11 EDITION 22 EDITION 33 EDITION JP 24 EDITION 45 EDITION JP 16


1.5

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
25
NOT FOR PROMOTIONAL USE
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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

TEAEs 56.4 54.2 58.8 50.7 57 56 58 57 61 58 62 64

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

• No between-treatment differences in tolerability or safety were identified

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
26
NOT FOR PROMOTIONAL USE
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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

Participants with ≥1 confirmed (≤70 mg/dL


Mean (SE) HbA1C, % Mean (SE) HbA1C, mmol/mol [≤3.9 mmol/L]) or severe hypoglycemia event at Month 6
8.4 69
Favors Favors
LS mean difference at 67 Gla-300 Gla-100
8.2
Month 6: 0.00%
65 ← →
95% CI –0.08 to 0.07%
8.0 Nocturnal 0.75 (0.68 to 0.83)
63 (00:00 h–05:59 h)
7.8
61
Any time of day 0.91 (0.87 to 0.96)
7.6
59 (24 h)
7.4
57 0.5 1 1.5

7.2 Gla-300 n=1247 Relative risk (95% CI)


55
Gla-100 n=1249
7.0 53
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
27
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
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
28
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SAGLB.TJO.16.02.0087
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

Any time of day (24 h) Nocturnal (00:00–05:59 h)


(≤70 mg/dL [≤3.9 mmol/L]) or severe events
Cumulative mean numbers of confirmed

10 2.0
Gla-300 Gla-300
Gla-100 Gla-100
8

1.0

Rate ratio (95% CI) Rate ratio (95% CI)


2 0.86 0.69
(0.77 to 0.97) (0.57 to 0.84)
P=0.0116 P=0.0002
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
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
-14% 29
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
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

• Diabetes duration (<10 years and ≥10 years)1

• Number of previous basal insulin injections (once or twice daily)2


EDITION 1 and 2
• Duration of prior basal insulin therapy3

• 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
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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

Participants with ≥1 confirmed (≤70 mg/dL


Mean (SE) HbA1C, % Mean (SE) HbA1C, mmol/mol [≤3.9 mmol/L]) or severe hypoglycemia event at Month 12
8.8 73
Favors Favors
8.6 Gla-300 Gla-100
8.4 ← →
68
Nocturnal 0.85 (0.77 to 0.92)
8.2 LS mean difference at (00:00 h–05:59 h)
Month 12: –0.10%
8.0
95% CI –0.18 to –0.02% 63
7.8 P=0.0174 Any time of day
(24 h) 0.94 (0.90 to 0.98)
7.6
58
7.4 0.5 1 1.5
Gla-300
7.2
Gla-100 Relative risk (95% CI)
7.0 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
32
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
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

Month 6, mean (SD) 7.30 (0.93) 7.30 (0.96) 30

Month 6–9, LS mean 0.05 (0.06) 0.00 (0.07) 20

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

*Flexible dosing time: Once-daily injection intervals of 24 ± 3 h


CGM, continuous glucose monitoring; CI, confidence interval; HbA1C, glycated hemoglobin A1C; LS, least squares; mITT, modified intention-to-treat; SD, standard deviation; SE, standard error;
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
1. Home PD et al. Diabetes Care. 2015;38:2217-25; 2. Bergenstal RM et al. Diabetes Technol Ther 2015;17:A16–A17; 3. Adapted from Riddle M et al. Diabetes Technol Ther. 2016;18:252-7
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SAGLB.TJO.16.02.0087
A pragmatic self-titration 1 unit/day (INSIGHT) algorithm for
insulin glargine 300 U/mL (Gla-300) is safe and effective

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

0.1–0.2 U/kg if HbA1c <8%


Initial dose/ day 10 U or – 10 U
0.2–0.3 U/kg if HbA1c >8% Diabetes &
its complications
Titration 2 U every 3 days 1-4 U every 2-3 days caused
2 U every 3 days5.1 million
1 U every day
deaths
Target FPG, in 2013
70–130 <110 <115 72–126
mg/dL

Target HbA1c, % <7.0 <7.0 <6.5 ≤7.0

• However, inadequate dose titration remains a barrier to optimal insulin therapy in


clinical practice5–8
– Poor target achievement suggests suboptimal titration by patients and/or their
physicians in the real-world setting8
*ADA/EASD 2012 guidelines do not provide a prescriptive algorithm for titration
CDA, Canadian Diabetes Association
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972; 2. Garber AJ et al. Endocr Pract. 2013;19:327-36;3. IDF. Global Guideline for Type 2 Diabetes. Available at;
http://www.idf.org/global-guideline-type-2-diabetes-2012 Accessed August 2014; 4. 2013 CDA Clinical Practice Guidelines. Available at: http://guidelines.diabetes.ca/Browse.aspx
Accessed August 2014; 5. Garber AJ. Diabetes Obes Metab. 2009;11 Suppl 5:10-3; 6. Riddle MC et al. Diabetes Care 2003;26:3080–3086;
7. Baser O et al. Clinicoecon Outcomes Res. 2013;5:497-505; 8. Hamaty M. Cleve Clin J Med. 2011;78:332-42

SAGLB.DIA.14.06.0065a(1) / 2014.09
GLA 300 Special Population Studies

NOT FOR PROMOTIONAL USE


SAGLB.TJO.16.02.0087
Subgroup analysis:
Renal function

Comparable glycemic control and lower risk of nocturnal


hypoglycemia with Gla-300 vs Gla-100 in T2DM regardless of renal function*
Subgroups by Favors Favors
baseline eGFR LS mean difference in Gla-300 Gla-100
Similar HbA1C (mL/min/1.73 m2) HbA1C (95% CI)
reductions with Gla-300 Overall (n=2,468) –0.01 (–0.08 to 0.06)
and Gla-100 regardless No evidence of
of renal function ≥30 to <60 (n=399) 0.10 (–0.09 to 0.28) heterogeneity of
treatment effect across
≥60 to <90 (n=1,386) –0.03 (–0.12 to 0.07) subgroups: p=0.46

≥90 (n=683) –0.03 (–0.17 to 0.11)

–1 –0.5 0 0.5 1

LS mean difference (95% CI), %

Numerically lower Nocturnal (00:00–05:59 h) Anytime (24 h)


Subgroups by
hypoglycemia Participants with ≥1 event, n (%) Participants with ≥1 event, n (%)
baseline eGFR
incidence with Gla-300 (mL/min/1.73 m2) Gla-300 Gla-100 Gla-300 Gla-100
vs Gla-100 regardless
of renal function Overall (n=2,468) 30.0 39.7 65.7 71.7

≥30 to <60 (n=399) 39.5 51.3 79.5 80.4

≥60 to <90 (n=1,386) 32.1 40.0 67.0 71.4

≥90 (n=683) 20.1 32.7 54.8 67.3

*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

FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY


SAGLB.TJO.17.07.XXXApproved
SAGLB.TJO.17.09.1196 ApprovedSeptember
August 2017
2017 INTERNAL USE ONLY
EDITION 1-2-3: Older, M6
Lower confirmed (≤70 mg/dL [≤3.9 mmol/L) or severe
hypoglycemia with Gla-300 vs Gla-100 in elderly (>65 y.o.)

Protocol-defined Clinically defined Hypoglycemia at any


nocturnal hypoglycemia nocturnal hypoglycemia time (24 h)
(00:00–05:59 h) (22:00 h to pre-breakfast SMPG*)
Favors Favors Favors Favors Favors Favors
Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100

% participants % participants % participants


Participants with ≥1 hypoglycemic
event Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100
n=327 n=332 n=327 n=332 n=327 n=332
Confirmed (≤70 mg/dL) or severe 31.8 44.9 58.4 72.0 71.6 77.4
Confirmed (<54 mg/dL) or severe 9.8 13.9 19.6 25.9 30.0 36.4
Documented symptomatic (≤70 mg/dL) 24.8 31.6 40.1 47.3 51.4 57.5
Documented symptomatic (<54 mg/dL) 7.6 11.4 14.1 19.3 23.9 26.8

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

NOT FOR PROMOTIONAL USE


SAGLB.TJO.16.02.0087
SAAS.TJO.17.03.0005c SAAS.TJO.16.09.0027c
Pregnancy

Gla-300 was not associated with any specific AEs in pregnancy


• Review of post-marketing pharmacovigilance data during pregnancy provided cumulative
event data: 90,860,252 pt-y for Gla-100 and 572,667 pt-y for Gla-300
Gla-100 Gla-300
• Low AE rate during pregnancy: Number of
Reporting
Number of
Reporting
Medical Dictionary for
rateb,d rateb,d
Gla-100: 29.51 per 1,000,000 pt-y Regulatory Activities events
(per 1,000,000
events
(per 1,000,000
search term (%)b,d (%)b,d
pt-y) pt-y)
Gla-300: 73.34 per 1,000,000 pt-y
Total number of pregnancy
2681 (N/A) 29.51 42 (N/A) 73.34
exposures
• Low rates of spontaneous
Abortion induced 12 (0.4) 0.13 0 (0.0) N/A
abortions, consistent with general
Abortion spontaneous 114 (4.3) 1.25 0 (0.0) N/A
population (10%)
Congenital, familial and
82 (3.1) 0.9 0 (0.0) N/A
genetic disorders
• Congenital, familial and genetic
Ectopic pregnancy 5 (0.2) 0.06 0 (0.0) N/A
anomalies were low with Gla-100;
Exposures via breast milk 78 (2.9) 0.86 2 (5.0) 3.49
none with Gla-300
Premature birth 82 (3.1) 0.9 1 (2.0) 1.75

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

FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY


SAGLB.TJO.17.07.XXXApproved
SAGLB.TJO.17.09.1196 ApprovedSeptember
August 2017
2017 INTERNAL USE ONLY
Gla-300 clinical profile: Conclusions

• Comparable HbA1C reductions to Gla-100,1-7 but with lower risk of confirmed or


severe hypoglycemia in T2DM7 and lower or similar risk in T1DM,5,6 also during
the titration period1-6

• Flexibility to select the timing of injections to either am or pm dosing and within a


± 3 hours window when needed9

• Comparable glycemic control and similar hypoglycemia benefits in


special populations11-13

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

FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY


SAGLB.TJO.17.07.XXXApproved
SAGLB.TJO.17.09.1196 ApprovedSeptember
August 2017
2017 INTERNAL USE ONLY
Real World Evidence of GLA-300 & Titration
(DELIVER 1, 2, 3 Studies)

NOT FOR PROMOTIONAL USE


SAGLB.TJO.16.02.0087
What is real-world evidence?

“Data derived from


“A measure in “Everything that goes
medical practice
understanding beyond what is
among
health care data normally collected in
heterogeneous
collected under the Phase 3 clinical
sets of patients in
real-life practice trials program in terms
real-life practice
circumstances.”1 of efficacy.”1
settings.”2

FDA: “Real-world evidence can inform therapeutic


development, outcomes research, patient care, research
on health care systems, quality improvement, safety
surveillance, and well-controlled effectiveness studies..”3

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.

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
Continuum of clinical research: RCTs and RWE
Real-world evidence (RWE):
Usual-care settings with a broad population

Broad

RCTs: Tightly controlled Observational


in a narrow population studies
Population

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

Highly controlled Pragmatically Observational


controlled

RCT, randomized controlled trial


Adapted from Roche N et al. Ann Am Thorac Soc 2014;11:99-104
44

FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY


SAGLB.TJO.17.09.1196 Approved September 2017 INTERNAL USE ONLY
FDA view on real-world evidence

“We believe that Real-World evidence can be used


across a wide spectrum of research, ranging from
observational“..the
studies to studies
agency that incorporate
will initiate activities to address key
planned interventions,
concerns and whether withdraft
publish or without
guidance on how such
randomisation at the point
evidence “..one of care.”
can beofused to assess safety and
the most important advances in clinical trial
effectiveness in both premarketing
methodology and
may be the broadening of the
post-marketing regulatory requirements.”
application of randomization outside more typical
venues for clinical trials, such as academic research
centers.”
Sherman RE et al. N Engl J Med. 2016;375:2293-2297.
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
Sources of real-world data

RCT supplement1 Health survey1


Patient registry1,2
• Resource utilisation • Health status
• Observational
• PROs • Healthcare utilisation
• Specified outcomes
• Defined population • Treatment patterns

Real- Claims database1


Real-
Real • Administrative data
Randomized real-life studies1,3 world data
world
• Prospective, randomized
world • Reimbursement
data
data • Some diagnoses and
• Large, diverse population
procedures
• Long follow-up
• Resource utilization
• Pragmatic/practical design
and costs

Electronic medical records


• Disease-specific symptoms/
treatments
• Patient-level outcomes

PRO, patient-reported outcome; RCT, randomised controlled trial


1. ISPOR Using ‘Real World’ Data Task Force. At: www.ispor.org/workpaper/RWD_TF/RWTFDraftReport.pdf. Accessed June 2017; 2. Gliklich & Dreyer (eds). Registries for evaluating patient
outcomes: a user’s guide. 2nd ed. Rockville, MD: AHRQ. 2010; 3. Tunis SR et al. JAMA 2003;290:1624‒1632. 4. Sherman RE et al. N Engl J 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
Challenges with RCTs -
Most patients are not represented in RCTs
Example:
How many real world patients with type 2 diabetes would
be eligible to landmark diabetes RCTs?

Eligibility for RCTs evaluated in Total Scottish Care Information –


Diabetes Collaboration population - includes ∼99% of patients in Scotland
n = 180,590 patients with T2DM (100%)

ACCORD ADVANCE PROactive RECORD VADT

11.4% 35.7% 3.5% 9.2% 18.3%

T2DM, type 2 diabetes mellitus; Saunders C et al. Diabetic Med 2012;30:300-8


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
Different stakeholders may have different interest in
real-world evidence

PRESCRIBER REGULATORY PAYER PATIENT


How a treatment AUTHORITY Economic impact To what extent a
performs in real life How clinical setting (budget impact model, treatment is likely
practice across and provider and short term models, to work for patients
different age groups, health-system health care resource like them in real life 3
genders, races and characteristics utilization/cost data),
ethnicities, disease influence treatment reimbursement;2
severities and effects and pricing;2
comorbid conditions to outcomes4 cost-effectiveness;1
inform use in everyday Real-world safety1 formulary placement1
clinical practice1

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 quality and


delivery of care1

Improve outcomes1

Reduce overall cost1

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

Real-world evidence (RWE) is the knowledge created when answering specific


research questions through the rigorous scientific analysis of real-world data

Types of RWE studies


Supporting Gla-300

Prospective Data Retrospective Data


Collection Collection

Observational Interventional RWE using existing


Unmet needs / hypo Randomized Real-Life Studies databases
Basal insulin registry

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)

Study objective: To assess the clinical characteristics


and outcomes of patients with T2D who switched to 0.64% reduction
Gla-300 from other basal insulin analogs in the US [95% CI 0.45-0.84]; P<0.0001
10 8.97
Methods: Retrospective, observational pre-post cohort 8.33
study of patient-level EMR data in the Predictive Health 8

Mean A1C (%)


Intelligence Environment (PHIE) diabetes dataset
6
Key Findings:
• Baseline clinical characteristics of 881 patients 4
switching to Gla-300 from other basal insulins:
2
– Mean A1C level of 8.97%
– Hypertension (86%) and dyslipidemia (88%) as 0
the most frequent comorbidities Baseline Follow-up
– T2D-related complications including neuropathy
• Reduction in A1C levels was seen as early as the first 3
(35%), nephropathy (17%), and retinopathy months following Gla-300 initiation
(11%)
• Switching to Gla-300 was associated with a 0.9%
• Mean reduction in A1C levels from baseline to reduction in hypoglycemia from baseline to follow-up
follow up (0-6 months) was 0.64% among 267 (0-3 months)
patients with A1C measures at baseline and at • A cost-comparison model estimated that switching to
follow-up Gla-300 was associated with cost savings of $116.41
per patient per year

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

Ye F, Agarwal R, Kaur A, et al. Poster presented at ADA 2016 (Diabetes. 2016;65(1):A243)


Lower Risk of Hypoglycemia After Switch to Gla-300 vs Other Basal Insulins in
Patients With T2D on Basal Insulin in Real-World Clinical Settings (DELIVER 2)
19
Study objective: To evaluate clinical outcomes of patients with T2D P=0.01
(aOR 0.78, 95% CI: 0.65, 0.94) 18.2

Hypoglycemia Incidence at 6 months


using basal insulin who switched to either Gla-300 or other basal
insulins in real-world clinical practice 18
Methods: A retrospective observational study using data from the
Predictive Health Intelligence Environment (PHIE) database of

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

LS Means estimate at 6 months follow-up


patients with T2D in real-world clinical settings focusing on glycemic 10.31
control and hypoglycemia risk LS-mean difference:
10

(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.

Zhou FL, Ye F, Gupta V, et al. Abstract submitted to ADA 2017


Summary Real World Evidence Studies of GLA 300

● Real-world evidence is of increasing importance to decision


makers

● Understanding differences between RCTs, RWE from databases


and randomized real-life studies and the different questions they
answer is key for understanding the value of the data

● GLA 300 RWE studies compliment of RCT studies which showed


consistency of efficacy and safety profile of GLA-300

Date of approval June 2017


FOR MEDICAL AND SCIENTIFIC PURPOSES ONLY
SUBJECT TO LOCAL REVIEW AND APPROVAL
SAGLB.TJO.17.06.0651 DO NOT USE IN PROMOTIONAL PURPOSES
THANK YOU for your KIND ATTENTION

NOT FOR PROMOTIONAL USE


SAGLB.TJO.16.02.0087
Back up

59
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
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

Gla-300 1.03 0.97 0.36 0.36

Gla-100 0.90 0.87 0.30 0.28

Mean weight change from baseline, kg T2DM


1.5 1.4
1.2 1.2
T1DM

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
SAGLB.TJO.16.02.0087
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

Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100

TEAEs 71.5 69.2 69.0 60.1 78.3 73.3 79.5 77.7


Similar safety profiel
Serious TEAEs M1 metabolite
13.1 15.4 7.4 7.4 10.0 6.7 5.7 7.4

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

• No between-treatment differences in tolerability or safety were identified


Safety population
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 Obes Metab. 2015;17:835-42 (Supplementary Table 1); 2. Yki-Järvinen H et al. Diabetes Obes Metab. 2015;17:1142-9; 3. Terauchi Y et al. Oral
presentation at ADA 2015; Abstract 98-OR; 4. Matsuhisa M et al. Oral presentation at EASD 2015; Abstract 4
61
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
Primary endpoint was successfully achieved in
all EDITION trials
LS mean difference (95% CI) LS mean difference (95% CI)
for Gla-300 vs Gla-100 for Gla-300 vs Gla-100
HbA1C change from baseline HbA1C change from baseline
to Month 6, % to Month 6, %
T2DM T1DM

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

-0.5 0.0 0.5 -0.5 0.0 0.5

Primary endpoint: non-inferiority in HbA1C change with


Gla-300 vs Gla-100 at Month 6
modified intention-to-treat population
BB, basal-bolus therapy; BOT, basal-oral therapy; CI, confidence interval; HbA1C, glycated hemoglobin A1C; LS, least squares; 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
62
NOT FOR PROMOTIONAL USE
SAGLB.TJO.16.02.0087
Comparable HbA1C reductions from baseline to Month 12
with Gla-300 and Gla-100

EDITION 11 EDITION 22 EDITION JP 23 EDITION JP 14


BB BOT switch BOT switch BB
LSM difference -0.17% -0.06%
NA NA
(95% CI) (-0.30 to -0.05) (-0.22 to 0.10)
P=0.007
0.0
change from baseline, %

-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

EDITION JP 23 0.73 (0.55 to 0.97) 0.97 (0.85 to 1.10)


BOT switch

EDITION JP 14 0.93 (0.83 to 1.05) 1.00 (0.96 to 1.04)


BB
0.30 3.00 0.80 1.2

Relative risk (95% CI) Relative risk (95% CI)

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

EDITION JP 23 0.41 (0.18 to 0.92) 0.64 (0.44 to 0.94)


BOT switch

EDITION JP 14 0.82 (0.58 to 1.15) 0.86 (0.71 to 1.04)


BB
0.10 1.00 5.00 0.30 3.00

Rate ratio (95% CI) Rate ratio (95% CI)

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
SAGLB.TJO.16.02.0087
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-100 glargine 55% lower


with U300
p=0.038

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

Mean (SE) insulin dose, U/kg/day (LOCF)1


1.2

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

Gla-100 15.8 20.1

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

Lower rate of confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe


hypoglycemia with Gla-300 vs Gla-100 at any time of day (24 h)
and during the predefined nocturnal period at Month 6
At any time of day (24 h) Nocturnal (00:00–05:59 h)
Cumulative mean numbers of confirmed Cumulative mean numbers of confirmed
(≤70 mg/dL [≤3.9 mmol/L]) or severe events (≤70 mg/dL [≤3.9 mmol/L]) or severe events
16 5
Gla-300 Gla-300
Gla-100 Gla-100
4
12

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®

Mean (SE) weight change from baseline, kg


LS mean difference at Month 6:
1.0
U300 –1.0 (95% CI –1.5 to −0.5) kg
P=0.0003
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

SAGLB.DIA.14.06.0065a(1) / 2014.09 FOR INTERNAL USE ONLY – DO NOT DISTRIBUTE


EDITION JP 1
Lower confirmed and/or severe hypoglycemia at night
and at any time (24 h)

Hypoglycemia at any time (24 h)


events per participant-year Nocturnal hypoglycemia (00:00–05:59 h)
events per participant-year

-20% -34%

Footer:

FOR INTERNAL USE ONLY – DO NOT DISTRIBUTE


EDITION JP 1

Lower or similar rate of nocturnal hypoglycemia with U300 vs


Lantus®

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

7.5 7.5 7.5

5.7

5 4.1
3.3

2.0 2.1 1.9

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

Rate ratio 0.66 0.58 0.71 0.49 0.37 0.58


Not estimated Not estimated Not estimated
(95% CI) 0.48-0.92 0.41-0.84 0.49-1.01 0.31-0.76 0.22-0.64 0.36-0.94

Rate ratio (95% CI)


Data on file, u300-EFC12449_RR_event_patient_year pg 1-12

SAGLB.DIA.14.06.0065a(1) / 2014.09 FOR INTERNAL USE ONLY – DO NOT DISTRIBUTE


EDITION JP 1

Less weight gain with U300 vs Lantus®

Mean (SE) weight change from baseline, kg


LS mean difference at Month 6:
1.0
–0.6 (95% CI –1.1 to –0.0) kg
P=0.0347

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

SAGLB.DIA.14.06.0065a(1) / 2014.09 FOR INTERNAL USE ONLY – DO NOT DISTRIBUTE


EDITION 1, 2: BID switchers, M6
Switching from twice-daily basal insulin to
once-daily Gla-300
• Objective: To explore the effect of switching from basal insulin BID to once-daily Gla-300 or Gla-100 in
people with T2DM in a post hoc analysis of EDITION 1 and 2
• At randomization, 16.9% and 20.0% of people were receiving basal insulin BID in EDITION 1 and
EDITION 2, respectively

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

HbA1c (mmol/mol) mean ± SE


8.8 between prior BID groups in change 73
once-daily Gla-300 or Gla-100 led 8.6
from baseline: –0.01 (–0.27 to 0.24) %

HbA1c (%) mean ± SE


69
to comparable HbA1c reductions in 8.4 Gla-100: prior BID (n=65)
8.2 Gla-300: prior BID (n=70)
both groups at Month 6 8.0 Gla-100: overall (n=400)
65

7.8 Gla-300: overall (n=404)


61
• HbA1c reductions in participants 7.6
7.4 57
who switched from BID to 7.2 EDITION 1
once-daily basal insulin were 7.0 53
Baseline Week 12 Month 6
comparable with the overall study
population for EDITION 1 LS mean difference (95% CI)
between prior BID groups in change
from baseline: 0.16 (–0.25 to 0.57) %

HbA1c (mmol/mol) mean ± SE


8.8
• HbA1c reductions were greater in 73
HbA1c (%) mean ± SE
8.6 Gla-100: prior BID (n=77)
Gla-300: prior BID (n=84)
the overall population than in those 8.4
Gla-100: overall (n=405) 69
8.2
switching from BID for both Gla- 8.0
Gla-300: overall (n=403)
65
300 and Gla-100 in EDITION 2 7.8
7.6 61
7.4 57
7.2 EDITION 2
7.0 53
Baseline Week 12 Month 6
mITT population. Prior BID, participants switching from twice-daily basal insulin
Adapted from Roussel R et al. Poster presentation at ADA 2015; Abstract 1021-P

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)

Any time (24 h): ≤70 mg/dL (≤3.9 mmol/L)


Any time (24 h): <54 mg/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)

Any time (24 h): ≤70 mg/dL (≤3.9 mmol/L)


Any time (24 h): <54 mg/dL (<3.0 mmol/L)

0.2 0.5 1.0 2.0 0.2 0.5 1.0 2.0


Safety population
Adapted from Roussel R et al. Poster presentation at ADA 2015; Abstract 1021-P Relative risk (95% CI)

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

T2DM, type 2 diabetes mellitus

SAAS.TJO.16.09.0027c
BEGIN & EDITION trial-
level meta-analyses
Objectives and methods T2DM

• To explore comparative glycemic control and hypoglycemia incidence with IDeg or


Gla-300 vs Gla-100 in two trial-level meta-analyses of people with T2DM from the
BEGIN and EDITION programs
• All BEGIN and EDITION trials included in the analyses were randomized, open-label,
phase 3a, treat-to-target trials conducted in adults with T2DM
• Patients were randomized to IDeg vs Gla-100 (BEGIN) and Gla-300 vs Gla-100
(EDITION). Titrated to FPG target:
– BEGIN, 70–90 mg/dL (3.9–5.0 mmol/L)
– EDITION, 80–100 mg/dL (4.4–5.6 mmol/L)
• Trial-level meta-analyses of the EDITION program were performed using patients
data
• Data from the BEGIN trials included in the trial-level meta-analyses were extracted
from the relevant US FDA briefing document1

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

Glucose- Basal ± Insulin naïve


lowering Basal +
mealtime Insulin naïve Insulin naïve + OADs or Insulin naïve Basal insulin Insulin naïve Basal insulin
therapy mealtime
insulin ± + OADs + OADs basal insulin + OADs + OADs +OADs + OADs
at screening insulin ± Met
OADs ± OADs

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)

-0.5 0.0 0.5 -0.5 0.0 0.5


FPG (mmol/L) FPG (mmol/L)
BEGIN Basal-Bolus Type 2 −0.30 (−0.84 to 0.24) EDITION 1 0.05 (−0.29 to 0.39)
BEGIN Once Long −0.47 (−0.79 to −0.15) EDITION 2 0.17 (−0.18 to 0.52)
BEGIN Low Volume −0.42 (−0.97 to 0.13) EDITION 3 0.39 (0.10 to 0.68)
BEGIN Flex (OD) −0.37 (−0.91 to 0.17) EDITION JP2 −0.16 (−0.74 to 0.42)
BEGIN Once Asia −0.13 (−0.53 to 0.27)
Overall −0.35 (−0.55 to −0.15) Overall 0.18 (–0.03 to 0.38)

-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

IDeg vs Gla-100 (BEGIN trials) Gla-300 vs Gla-100 (EDITION trials)

Confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia Confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia

Favors Favors Favors Favors


IDeg Gla-100 Gla-300 Gla-100
Overall Overall
Relative Relative
95% CI p value 95% CI p value
risk risk
Nocturnal Nocturnal
0.87 (0.78 to 0.96) 0.007 0.74 (0.65 to 0.83) <0.001
(00:00–05:59h) (00:00–05:59h)

Anytime Anytime
(24 h) 1.02 (0.97 to 1.06) NS (24 h) 0.89 (0.83 to 0.95) <0.001

0.5 1.0 1.5 0.5 1.0 1.5

• Risk of ≥1 documented symptomatic (≤70 mg/dL [≤3.9 mmol/L]) hypoglycemic


event closely reflected that of confirmed or severe events
– IDeg vs Gla-100 was lower for nocturnal (00:01–05:59 h) but not anytime (24 h) events
– Gla-300 vs Gla-100 was lower for nocturnal (00:01–05:59 h) and anytime (24 h) events
CI, confidence interval; NS, not significant
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
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)

Glargine 0.77 (0.72, 0.81)

Glargine Biosimilar 0.76 (0.70, 0.84)

Degludec 0.74 (0.68, 0.8)

Detemir 0.67 (0.60, 0.73)

NPH 0.64 (0.59, 0.69)

Premix 0.51 (0.47, 0.54)

.4 1

Favors Gla- 300 Favors comparator


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)

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