The Unmet Need of Current Basal Insulin

Therapy in the Diabetes Management

SAID..TJO.17.02.0021
Speaker Disclosures
Outline of This Talk

1. 25 years of experience with basal insulins

2. Better pharmacokinetics of new basal insulins
25 YEARS OF EXPERIENCE WITH BASAL
INSULINS: 1990-2015
 24-hour Pattern of Hyperglycemia
in Type 2 Diabetes

Basal and postprandial components

300
Plasma glucose (mg/dL)

Postprandial
200 hyperglycemia
Basal
hyperglycemia
100
Normal
glucose exposure
0
0600 1200 1800 2400 0600
Time of day

Riddle MC. Lancet 1985;1:192-195.

Riddle MC. Diabetes Care 1990;13(6):676-686.
 Structured Basal Insulin Titration in
The Treat-to-Target Trial
Glargine vs. NPH added to 1-2 oral agents
756 T2DM participants
9
Percentage (%)

8.6 8.6 Glargine NPH

Mean A1c
8

6.9, 6.9 %
Usual target 7

Upper normal

6
0 4 8 12 16 20 24
Weeks of treatment

Riddle MC, et al. Diabetes Care 2003;26:3080-3086.

 A1c Attained After Initiating Titrated
Insulin Glargine
Baseline Study end
9.5
9.0 8.7 8.8 8.7
8.6 8.6
8.5
∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7
A1c (%)

8.0
7.5
7.0 7.0 7.0 6.8 7.0
7.0
6.5
6.0
5.5
T-T-T1 INSIGHT2 APOLLO3 INITIATE4 Observational5
n = 367 n = 206 n = 174 n = 58 n = 11,511

Typically ~50% of people attain <7%.

1.
2.
Riddle MC, et al. Diabetes Care 2003;26:3080-3086.
Gerstein HC, et al. Diabetes Med 2006;23:736-742.
Similar results are obtained
3. Bretzel RG, et al. Lancet 2008;371:10731084. with insulin detemir.
4. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364-1369.
5. Schreiber SA, Haak T. Diabetes Obes Metab 2007;9:31-38.
 Baseline A1c Predicts Attainment of 7%
A1c After Initiation of Glargine
2193 people with type 2 diabetes after 24 weeks of systematically
titrated glargine added to 1 or 2 oral agents.
Percentage of patients attaining A1c <7%
80 75
70
60 56
% of ppts

50
40 34
30
20
10
0
<8 8 - 8.4 8.5 - 8.9 9 - 9.4 ≥9.5

75% attain target A1c when baseline <8.0%.

Riddle MC, et al. Diab Obes Metab 2013;15:819-825.

 Median A1c by Subgroups in ORIGIN
8.0
Median A1c (%) 7.5
No diabetes
7.0
6.5 Standard
6.0
5.5 Glargine
Std 717 683 664 632 604 577 419 92 578
5.0 Glar 731 692 674 634 614 581 436 109 571

8.0
7.5 Diabetes
Median A1c (%)

7.0 Standard
6.5
6.0 Glargine
5.5
Std 5476 5239 5089 4800 4593 4353 2945 626 4155
5.0 Glar 5451 5149 4990 4757 4565 4359 2995 632 4158

0 1 2 3 4 5 6 7 End
Years of treatment
Timely treatment to target can maintain good A1c for years.
The ORIGIN Trial Investigators. Diabetes Care 2013;36:2915-2922.
 Summary of Important Outcomes in ORIGIN

Hazard ratios for glargine vs. standard care

1st CV composite 1.02

2nd CV composite 1.04
All-cause mortality 0.98
Cancer 1.00
Conversion IFG/IGT to DM 0.72 (P=0.006)

Glargine has neutral effects on CV and cancer risk.

The ORIGIN Trial Investigators. N Engl J Med 2012;367:319-328.

 Insulin Dose and CV Mortality in ACCORD

Hazard ratios for updated average insulin 1U/kg/d

Unadjusted Adjusted
Model 1 Model 2 Model 3 Model 4
Baseline +hypo, ∆ +A1c +Int vs. Std

Total insulin 1.83* (1.45, 2.31) 1.21 1.21 1.12 0.99

Basal insulin 2.29* (1.62, 3.23) 1.30 1.29 1.13 0.94

Bolus insulin 3.36* (2.00, 5.66) 1.65 1.63 1.48 1.23

Association between insulin dose and CV risk does not

persist after adjustment for baseline characteristics.
Siraj ES, et al. Diabetes Care 2015;38:2000-2008.
 Frequency of Hypoglycemia with Glargine
in Treat-to-Target Studies
2251 study participants with 24 weeks of systematically titrated
glargine added to 1 or 2 oral agents.

Percentage of participants affected

60 52 Non-severe hypo
50
Incidence (%)

40
30
20 17 Severe hypo
10 7
1.5
0
≥1 symptomatic ≥1 event ≥2 event ≥1 severe event
event confirmed <50 confirmed <50
mg/dL mg/dL

Karl DM, et al. Diab Obes Metab 2013;15:622-628.

 Hypoglycemia with NPH vs. Glargine
Cumulative events confirmed <72 mg/dL in the
Treat-To-Target Trial
2500

2000
Cumulative number of

NPH
1500 Glargine
events

1000
29% lower
500 with glargine
than NPH
0
0 24 48 72 96 120 144 168

Days of treatment

Basal insulins differ mainly in the frequency of hypoglycemia.

Riddle MC, et al. Diabetes Care 2003;26:3080-3086.
 Hypoglycemia by Time of Day
in the Treat-to-Target Trial
Events confirmed <72 mg/dL per patient-year

1.4 * 44% lower

* with glargine
1.2 *
than NPH
*
1 * Glargine
Insulin *
0.8 injection
NPH

0.6
* * p <0.05

0.4

0.2

0
20 21 22 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Time of day
Hypoglycemia with basal insulins is mostly at night.
Riddle MC, et al. Diabetes Care 2003;26:3080-3086.
 Independent Predictors of Non-Severe
Hypoglycemia in Treat-to-Target Studies
2251 study participants with 24 weeks of systematically titrated
glargine added to 1 or 2 oral agents.

Multivariable model analysis of hypoglycemia

confirmed by glucose measurement <2.9 mmol/L (50 mg/dL).

P value

Younger age 0.0014

Use of both metformin and a sulfonylurea 0.0024
Lower attained A1c <0.0001
Lower body mass index <0.0001
Lower dose of glargine (U/kg) <0.0001

Karl DM, et al. Diab Obes Metab 2013;15:622-628.

 Independent Predictors of Hypoglycemia
in the ORIGIN Study
12,537 study participants followed a median 6.2 years during
treatment with glargine or standard oral-step therapy.
Multivariable model analysis
Non-severe (<3mM) Severe
HR p HR p
Allocation to glargine 4.53 <0.001 3.57 <0.001
Sulfonylurea at baseline 2.07 0.01 1.35 0.01

Younger age 0.98 <0.001 ---

Higher baseline A1c 1.24 <0.001 ---
Lower attained A1c 0.85 <0.001 ---
Lower body mass index 0.97 <0.001 ---

Older age --- 1.04 <0.001

Less education --- 1.81 <0.001
Cognitive function --- 0.96 <0.02
Serum creatinine --- 1.01 <0.001
The ORIGIN Trial Investigators. Diabetes Care 2015;38:22-28.
 Lower Insulin Dose Leads to
Shorter Duration
Single-dose studies of insulin detemir in 12 type 1 patients (BMI 23.3)

2.0 For a 70 kg person these doses

GIR (mg/kg/min)

would be 7, 14, 28 units.

1.5

1.0
0.4 U/kg
0.5 0.2 U/kg
0.1 U/kg
0
0 4 8 12 16 20 24
Hours after injection

Lower doses of basal insulin have shorter duration.

Plank J, et al. Diabetes Care 2005;28:1107-1112.
 Basal Insulin Dose Distribution in a Global
Population in ORIGIN

Mean body weight 83.2 kg

Mean BMI 29.9

Median insulin dose

U/kg/d 0.40
U/d 33

Lower 25% <0.27 U/kg/d (<23 U/d)

Upper 25% >0.56 U/kg/d (>47 U/d)

About 25% used <25 units basal insulin.

The ORIGIN Trial Investigators. N Engl J Med 2012;367:319-328.
Lessons from Studies of Basal Insulin

1990-2015
1. Standardized titration can often keep
A1c <7% (>50%).
2. Timely initiation (A1c <8%) improves success (~75%).
3. Basal insulin does not increase CV or cancer risk.
4. Hypoglycemia is more likely:
• with NPH than glargine U100.
• with lower BMI.
• with lower insulin dose.
Persisting Problems
with Basal Insulin Therapy

1. Many people using insulin still have A1c >7%.

2. Hypoglycemia limits attainment of glycemic targets.
3. Mealtime hyperglycemia remains poorly controlled.
BETTER PHARMACOKINETICS OF NEW
BASAL INSULINS
 New Longer-Acting Insulins with Longer
and Flatter Profiles of Action
Insulin glargine U300
• New low-volume formulation of glargine molecule
• Further delay of absorption, rapid clearance
PEG-lyated insulin lispro (Development has been discontinued)
• Insulin lispro with polyethylene glycol attachment
• Prolonged absorption and clearance
• Relatively specific action at liver

Insulin degludec
• Insulin analogue with fatty acid side chain
• Prolonged absorption and clearance
• Developed as U100 and U200 formulations
Disclaimer : U300, Degludec have not been approved yet in Indonesia.
This presentation is intended for Medical purpose only in the scientific Exchnge
Meeting
* Development has been discontinued.
What’s the difference between Gla-300 and Gla-100?
Reduction of volume by 2/31

Same number
Smaller volume of
of units
injection for
Gla-300 vs Gla-1001 Gla-100 Gla-300

Smaller surface area1,2

Gla-100 Gla-300
More compact smaller
SC depot with Gla-300
vs Gla-1001,2

For illustrative purposes only2

Different absorption kinetics:

More gradual and slower release1-4 Gla-300 has a distinct PK/PD profile vs Gla-
100:
More stable, prolonged duration
of action beyond 24 hours4

• Insulin glargine metabolism is the same regardless of Gla-100 or Gla-300 administration; M1

metabolite was confirmed as the prinicpal active moiety circulating in blood3
PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous
1. Pettus J, et al. Diabetes Metab Res Rev. 2015 Oct 28. doi: 10.1002/dmrr.2763. [Epub ahead of print]; 2. Adapted from Sutton G et al. Expert Opin Biol Ther. 2014;14:1849-60; 3. Steinstraesser A
et al. Diabetes Obes Metab. 2014;16:873-6; 4. Becker RH et al. Diabetes Care. 2015;38:637-43
23
 basal insulin
s.c. injection
205
205 detemir
Long-acting analogs
Plasma Glucose

150 post-NPH ERA 150

mg/dl

NPH
glargine
95 95

Subjects with Type 1 DM

Mean±SE
4
Glucose Infusion Rate

NPH
3
INSULIN ACTION
mg/Kg/min

1 glargine
0
detemir
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
Rossetti P. et al., Arch. Physiol. Biochem., 114:3-10, 2008
 Steady-state
study T1DM
More stable and prolonged (beyond 24 hours)
PK/PD profile with Gla-300 vs Gla-100
Gla-300 0.4 U/kg, n=16
Insulin concentration,

25 Gla-100 0.4 U/kg, n=17

20
µU/mL

15
10
5 LLOQ

0
0 6 12 18 24 30 36
3
Glucose infusion rate,
mg/kg/min

0
0 6 12 18 24 30 36
Time, hours

LLOQ, lower limit of quantification; PD, pharmacodynamic; PK, pharmacokinetic; T1DM, type 1 diabetes mellitus
Becker RH et al. Diabetes Care. 2015;38:637-43
25
Insulin glargine 300 U/mL (Gla-300) provides more stable
and more evenly distributed steady-state PK/PD profiles
compared with insulin degludec in type 1 diabetes
 Clamp variability
study T1DM
Even distribution of glucose-lowering effect
with Gla-300
• Even distribution of glucodynamics – within-day fluctuation

Within-day distribution of GIR-AUC as 6- and 12-hour fractions of total AUC

3
53% 47%
GIR, mg/kg /min

2
Average GIR
1
29% 24% 23% 23%
0

0–6 hours 6–12 hours 12–18 hours 18–24 hours Period 1

Period 2

AUC, area under the curve; GIR, body weight standardized glucose infusion rate; T1DM, type 1 diabetes mellitus
Adapted from Becker RH et al. Diabetes Obes Metab. 2015;17:261-7 (main article and Supplementary Table 1)
27
 Low between-day variability with Gla-300

High PK/PD reproducibility – between-day variability

Within-subject CV% (90% CI)

INS-AUC0-24* 17.4 (15–21)
Excluding outliers† 15.3 (13–19)
INS-Cmax* 33.4 (28–41)
Excluding outliers† 19.4 (17–24)
GIR-AUC0-24‡ 34.8 (30–42)
GIRmax‡ 27.9 (24–34)

• Crossover euglycemic clamp study of Gla-300 0.4 U/kg in 50 patients with T1DM

*Coefficient of variation (CV%) is of geometric type

†One parTcipant on reference and two on test treatment were excluded with INS-Cmax >31.4 µU/mL
‡CV% is based on un-transformed data
AUC, area under the curve; GIR, body weight standardized glucose infusion rate; INS, serum insulin concentration; T1DM, type 1 diabetes mellitus
Adapted from Becker RH et al. Diabetes Obes Metab. 2015;17:261-7
28
Do not duplicate, distribute externally or use in promotion
SAGLB.DIA.15.08.0581
 CGM T1DM
More constant glucose profile with Gla-300 vs
Gla-100 when administered in the morning or evening

Gla-300 Gla-100

200 200 Gla-300

Morning injection
190 190
180 180
170 170
160 160

Mean (SE) glucose, mg/dL

Mean (SE) glucose, mg/dL

150 150
140 140
Morning Evening
130 130
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
200 Evening injection 200 Gla-100
190 190
180 180
170 170
160 160
150 150
140 140
130 Morning Evening
130
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Time, h Time, h

• In addition, all measured intra-subject variability metrics were consistently lower with Gla-
300 vs Gla-100

Average 24-h glucose profiles during the last 2 weeks of each treatment period (CGM population; pooled data period A + B)
CGM, continuous glucose monitoring; SE, standard error; T1DM, type 1 diabetes mellitus
Adapted from Bergenstal RM et al. Diabetes Technol Ther 2015;17:A16–A17
29
 Phase 1 and phase 2 Gla-300 studies

• Phase 1 and 2 studies in T1DM demonstrated that Gla-300 has:

– A more constant and prolonged PK and PD profile compared
with
Gla-100, maintaining blood glucose control beyond 24 h and
up to 36 h
– Low within-day fluctuation and between-day variability
– More constant glucose profile independent of the time of
injection (morning or evening) compared with Gla-100

PD, pharmacodynamic; PK, pharmacokinetic; T1DM, type 1 diabetes mellitus

Becker RH et al. Diabetes Care. 2015;38:637-43; Becker RH et al. Diabetes Obes Metab. 2015;17:261-67;
Bergenstal RM et al. Oral presentation at ATTD 2015; Abstract 39
30
 EDITION program objective and design

• OBJECTIVE: To assess the clinical efficacy and safety of Gla-300 vs Gla-100

• Randomized 1:1, open-label, parallel-group, multicenter studies
• EDITION program 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; OAD, oral antihyperglycemic drugs

Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; Terauchi Y et al. Oral presentation at ADA 2015; Abstract 98-OR
Home PD et al. Diabetes Care. 2015 Jun 17. pii: dc150249. [Epub ahead of print]; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975

31

SAGLB.DIA.15.08.0581 Do not duplicate, distribute externally or use in promotion

 EDITION program
Testing Gla-300 vs Gla-100 in several populations

T2DM T1DM
EDITION 1* EDITION 2*
EDITION 4
N=807 N=811
N=549
BB BOT
Basal insulin plus OAD (excl. BB
Basal insulin plus mealtime
SU) Basal insulin plus mealtime bolus
bolus insulin (fast-acting
insulin (fast-acting analogue)
analogue)

EDITION 3 EDITION JP 2 EDITION JP 1

N=878 N=241 N=243
BOT BOT BB
Basal insulin plus OAD (excl. Basal insulin plus OAD Basal insulin plus mealtime bolus
SU) and/or GLP-1 receptor insulin (fast-acting analogue)
agonists

All Phase 3, age of participants ≥18 years, randomization ratio 1:1

BB, basal-bolus therapy; BOT, basal only therapy; GLP-1, glucagon-like peptide-1; OAD, oral antihyperglycemic drug; SU, sulfonylurea
T2DM – type 2 diabetes mellitus, T1DM – type 1 diabetes mellitus, * in EDITION 1 and EDITION 2, people being treated with basal insulin ≥42U/day were recruited
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976;
Home PD et al. Oral presentation at EASD 2014; Abstract 148; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975
 EDITION program
Testing Gla-300 vs Gla-100inacross
T2DM the spectrum of treatment

Oral agents only Basal and mealtime insulin

EDITION 3
N=878
BOT
Prior oral therapies alone EDITION JP 2
(insulin naïve) N=241
BOT
Prior basal insulin + oral
therapies; Japanese patients EDITION 2
N=811
BOT
Prior basal insulin (≥42 U/day) +
oral therapies EDITION 1
N=807
BB
Prior basal + mealtime insulin
& prior basal insulin dosage
≥42 U/day

Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
Bolli GB et al. Diabetes Obes Metab 2015;17:386-394; Terauchi Y et al. Oral presentation at ADA 2015; Abstract 98-OR

SAGLB.TJO.15.09.0742
 EDITION program: Study designs
EDITION 1 EDITION 2 EDITION 3 EDITION JP 2 EDITION 4 EDITION JP 1
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: - - - -

fixed time ± 3 h fixed time ± 3 h

Primary endpoint: ✔ ✔ ✔ ✔ ✔ ✔
HbA1C reduction

Main secondary (efficacy) ✔ ✔ ✔ - - -

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
HbA1C, glycated hemoglobin A1C; M, month; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976;
Home PD et al. Diabetes Care. 2015 Jun 17. pii: dc150249. [Epub ahead of print]; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975;
Riddle M et al. Poster presentation at ATTD 2015; Diabetes Tech Ther. 2015; 17 (Suppl1): A102-103 (abstract no. 234)
34

SAGLB.DIA.15.08.0581 Do not duplicate, distribute externally or use in promotion

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

-0.30
-0.5
baseline, %

-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)
35
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
36
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
37
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
38
 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
39
 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
Flexible dosing Fixed dosing

% participants experiencing
Flexible dosing
n=99 n=95 50

≥1 hypoglycemic event
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
40
 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
41
 Gla-300, in comparison to Gla-100, provides:
• More constant and prolonged PK/PD profile, low glycemic variability andAge 20 to 79 years old
stable
blood glucose control beyond 24 hours1-3
• Comparable HbA1C reduction in the treat-to-target randomized clinical trial setting4-9
• Lower risk of confirmed or severe hypoglycemia during the 6-month treatment period
including the titration phase in T2DM, with similar or lower risk in T1DM4-9
• Generally more pronounced hypoglycemia reductions during the first 8 weeks when most
titration occurred in T2DM and T1DM studies4-9
• Flexibility to select the timing of injections to either am or pm dosing and within
a ± 3 hours window when needed10
• Slightly lower or similar weight gain4-9
• Increase in basal insulin dose with Gla-300 vs Gla-100, mostly during the first
12 weeks4-9
• Similar overall safety and tolerability4-9
• The same metabolism as Gla-100 (M1) supporting long-term CV safety11,12

CV, cardiovascular; HbA1C, glycated hemoglobin A1C; PD, pharmacodynamic; PK, pharmacokinetic; SMPG, self-monitored plasma glucose; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
1. Becker RH et al. Diabetes Care. 2015;38:637-43; 2. Becker RH et al. Diabetes Obes Metab. 2015;17:261-7; 3. Bergenstal RM et al. Diabetes Technol Ther 2015;17:A16–A17;
4. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 5. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; 6. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94;
7. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74; 8. Home PD et al. Diabetes Care. 2015;38:2217-25; 9. Matsuhisa M et al. Diabetes Obes Metab. 2016;18:375-83;
10. Riddle M et al. Diabetes Technol Ther. 2016;18:252-7; 11. Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; 12. ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-28
42
Lessons from Studies of New Basal Insulin

2012-2016
1. Degludec and U300 glargine have longer and flatter
profiles of action and are safe and effective.
2. Both global and Asian populations have lower rates
of hypoglycemia with degludec and U300 glargine.
3. Peglispro is discontinued due to safety issues.
4. Biosimilar U100 glargine is coming soon.
Conclusions

1. Basal insulin is well-tested, effective, safe,

and can be used whenever needed to control
basal glucose.
2. Newer basal insulins can be helpful when
hypoglycemia limits glycemic control.
3. Basal insulin is a platform for additional
mealtime treatment with rapid-acting insulins
or GLP-1 agonists.
THANK YOU!