1. New Insulin Formulations
Guillermo Umpierrez, MD, FACP, FACE
Professor of Medicine
Emory University School of Medicine
Part 2 1

2. Hypoglycemia* (events/patient year)
Insulin Glargine vs 70/30 Premixed Insulin in OHA Failures
N=371 insulin-naïve patients Insulin Glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks
Twice-daily premixed insulin
Insulin Glargine + OADs
p=0.0003 9 5
5.7
1.3%
1.7% 4 8
Hypoglycemia* (events/patient year)
p=0.0009 3
7.5%
HbA1c (%) 7
7.2%
2.6 2
70/30 IS NOT BETTER THAN BASAL AND IS ASSOCIATED WITH HIGHER RATE OF HYPOGLYCEMIA 6 1 5
*Confirmed symptomatic hypoglycemia (blood glucose <60 mg/dl [<3.3 mmol/l])
Janka H, et al. Diabetes Care 2005;28:254−259.

3. Stepwise Intensification: 1-2-3 Study Design
Group 1:GLAR + OADs
+ 1GLU
Poorly controlled on OADs
(N=785)
A1C >7.0%
(n=343)
N=113
Group 2: GLAR + OADs
+ 2GLU
Switched to GLAR for 14 weeks
Group 3: GLAR + OADs
+ 3GLU
N=115
Randomization and 24 week F/U
Multicenter, open-label, randomized, 3-arm, parallel-group (1:1:1) study in adult patients with T2DM
On a stable dose of 2 or 3 OADs (rosiglitazone reduced from 8mg to 4mg per label)
Had an A1C >8.0% at screening visit
14-week run-in treatment phase
Added insulin glargine to current OAD regimen
Insulin glargine initiated at 10 U/d and titrated every 2 days to target FG mg/dL
Patients with A1C >7.0% at end of run-in were randomized to receive prandial injections of insulin glulisine
Randomized treatment phase
3 arms: Insulin glargine + insulin glulisine before
The meal with greatest glycemic index (1)
The 2 meals with greatest glycemic index (2)
All 3 meals (3)
Insulin glulisine was administered 0-15 minutes before meals
Initial glulisine dose was 1/10th of the glargine does at randomization
Weekly titration to target PPG mg/dL and HS level mg/dL
Insulin glulisine was administered 0-15 minutes before greatest glycemic index meal
Initial glulisine dose was 1/10th of the glargine does at randomization
Weekly titration to target PPG mg/dL and HS level mg/dL
OADs were continued.
GLAR = insulin glargine; GLU = insulin glulisine; OADs=oral antidiabetic agents.
Davidson MB et al. Endocr Pract. February 16, 2011. 3 3

4. A1C Change From Baseline to Week 24
Following 14-week run-in with insulin glargine
Mean A1C decreased from >10.0% to ~8.0%
288 patients achieved A1C 7.0%
Final dose was 0.55 U/kg regardless of reaching target
Figure 3
mITT = modified intent to treat.
Davidson MB et al. Endocr Pract 2011

5. Characteristics of Available Basal Insulin Analogs
Benefits over NPH
Longer duration of action
Less variability
Less weight gain
Less hypoglycemia
Room for Improvement
More consistent 24+ hour coverage
Flat time-action profile
Less day-to-day variability
Less weight gain
Less hypoglycemia
More suppression of hepatic glucose production
FXCX:
Simon pdf in Zotero
Grunberger pef in Zotero
Simon ACR. Diabetes Technol Ther. 2011;13(suppl 1):S Grunberger G. Diab Obes Metab. 2013; 15(suppl 1):1-5.

6. *Glargine U-300 *Degludec *Pegylated Lispro
New Basal Insulin Formulations
*Glargine U *Degludec *Pegylated Lispro
* Not FDA Approved

7. High concentration glargine (U300)*
U300 insulin glargine offers a smaller depot surface area leading to a reduced rate of absorption
Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency
Half-life is ~23 hours
Steady state in 4 days
Duration of action ≤36 hours
FXCX:
Simon pdf in Zotero
Grunberger pef in Zotero
*Not FDA approved
Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2): Steinstraesser A, et al. Diabetes Obes Metab Feb 26. [Epub ahead of print]. Accessed March 11, 2014.

8. Pharmacokinetics of U-300 Insulin Glarginea in Healthy Volunteers35 30 25 20 15 10 5 2 4 6 8 12 14 16 18 22 24 26 28
Concentration (uIV/mL)
Time
U U/kg (n = 24)
U U/kg (n = 23)
Becker R, Hahn A, Boderke P, Fuerst C, Mueller W, Tertsch K, Werner U, Loos P. Long-acting formulations of insulin. Sanofi-Aventis Deutschland GmbH, Frankfurt am Main. Filed 5/17/2011.
0.4 U/kg dose: [0010]
Healthy volunteers: [0565]
a U-300 insulin glargine is not FDA approved for clinical use.
Becker R, et al. European Patent EP A

9. Pharmacodynamics of U300 Glargine vs U100 Glargine
3.0
SC Injection
U U/kg-1
U U/kg-1
U U/kg-1
U U/kg-1
2.5
2.0
GIR (mg/kg-1 min-1)*
1.5
1.0
0.5 6 12 18 24 30 36
Time (hours)
The U-300 glargine has a flatter more prolonged effect
The time it takes for 50% of the effect of a single injection
U-100 = 12.1 hours
U-300 = 16.7 hours
FXCX:
Bullet 1=Found i abstract 920-P
Could not find figure
Permissions needed to reuse figure
Bullet 2 could not find data in abstract 920-P
GIR = glucose infusion rate.
Tillner J, et al. Poster 920P 73rd ADA Scientific Sessions June 21-25, 2013, Chicago, IL. Accessed March 21, 2014.

10. U300 Glargine vs U100 Glargine in Type 2 Diabetes
Mean A1C (%)
8.5
6.5
Baseline
Month 6 LOCF
Time
Month 6
Week 12
8.0
U300
U100
7.5
7.0
Mean change in A1C
for both treatment groups
-0.83%
No difference in A1C change
Lower rate of severe or confirmed hypoglycemia, particularly overnight
Time period
U100
U300
RR with U300 CI
0-6 months
Nocturnal
57.5%
44.6%
0.78
0.68 – 0.89
9 weeks – 6 mo
46.0%
36.1%
0.79
0.67 – 0.93
24 hours
87.8%
81.9%
0.93
0.89 – 1.04
FXCX:
Abstract 43-LB in zotero
Cannot find the figure
Found abstract 43-LB; A1C data contained in abstract but not the graph itself
Hypoglycemia data in table: abstract contains data for 9weeks-6mo only; does not contain other time points (nocturnal or 24 hours)
Permissions needed to reuse figure and table
Riddle MC et al. Presentation 43-LB 73rd ADA Scientific Sessions June 21-25, 2013, Chicago, IL. Accessed March 21, 2014.