1. New Insulin Formulations
Guillermo Umpierrez, MD, FACP, FACE
Professor of Medicine
Emory University School of Medicine
Part 3 1

2. New Insulin Formulation GLAR-300a vs GLAR-100 in Patients on Basal Plus Mealtime Insulin
GLAR-100 (n = 403)
Noninferior A1C change for GLAR-300 vs GLAR-100 (both groups, -0.83%)
No between-group differences in adverse events
Significantly fewer with nocturnal hypoglycemia (≥ 1 severe or confirmedb) with GLAR-300 (graph)
GLAR-300 (n = 404)
RR 0.79 (CI, )
P = .0070
FXCX:
Riddle 2013: abstract
GLAR, glargine.
a GLAR-300 is not FDA approved for clinical use.
b Confirmed hypoglycemia, ≤ 70 mg/dL.
Riddle M, et al. ADA 73rd Scientific Sessions. 2013;43-LB.

3. Meta-Analysis: U300 Glargine vs U100 Glargine: Safety and Efficacy
HbA1c (%) Mean ± SE
7.6
8.4
7.0
Baseline
6 Mon
Week 12
7.2
8.2
8.0
7.4
7.8
U100
U300
LS mean difference (95% CI)
between groups:
000 (-0.08 to 0.07)%
Nocturnal Hypo-Events* per Participant-Year 2 6 5 4 1 3
3.06
2.10
p=0.0002 RR
31%
U100
U300 M6
U100
U300
Weight Change (Kg) Mean ± SE
1.5
-0.5
Base line
1.0
0.5
0.0 M4
W12 W8 W4 W2
LOV
p=0.039
*Confirmed (≤70 mg/dL) or severe hypoglycemia from 00:00–05:59 h. SE = standard deviation; LOV = last on-treatment value.
Ritzel R, et al. Presentation 90-LB 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. Accessed August 15, 2014.

4. Flexible vs Fixed Dosing U300 Glargine: Sub-Studies of Phase III Trials
6 Months (randomization, sub-study)
U300 once daily every 24 ± 3h
U300 once daily every 24 h
9 Months (end of sub-study)
sub-study
6 Month Treatment Period (main study)
6 Month Extension Period (main study)
Edition 1 Sub-Study N=109
Edition 2 Sub-Study N=89
No difference in A1C between flexible- vs fixed-dosing
No difference in severe or nocturnal hypoglycemia within each sub-study
100 80
Flexible Dosing
Fixed Dosing
Percentage of Injections (%) 60 40 20
24 ± <1 h
24 ± 1-3 h
24 ± >3 h
24 ± <1 h
24 ± 1-3 h
24 ± >3 h
Ritzel R, et al. Presentation 919-P 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. Accessed August 15, 2014.

5. U300 Glargine vs U100 Glargine: Meta-Analysis of 3 Phase III Trials
Edition 1
Edition 2
Edition 3
Meta-Analysis
Trial description and treatment
U300 vs U100 (+RAI+Met)
U300 vs U100 (+Met+OADs*)
U300 vs U100 (+Met+OADs†)
N/A
No. of participants
Gla-300
Gla-100
404
403
407
439
1,247 1,249
Therapy at screening
Basal + mealtime insulin + OADs
Basal insulin + OADs
Insulin naïve + OADs
Inclusion criteria
Insulin dose HbA1c Age
≥42U ≥7.0%, ≤10.0% ≥18 years old
≥7.0%, ≤11.0% ≥18 years old
Mean baseline characteristics
BMI, kg/m2 Age, years
Duration of DM, yrs
HbA1c, %
U300
U100 U
*Use of sulfonylureas prohibited within 2 months prior to screening and during the study; †Except sulfonylureas, glinides and other OADs not approved for use with insulin.
Ritzel R, et al. Presentation 90-LB 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. Accessed August 15, 2014.

6. Insulin Degludec Dihexamers form soluble multihexamers after injection
CO2H H HN
HO2C
Dihexamers form soluble multihexamers after injection
Multihexamers disassemble slowly
Monomers are released rapidly after hexamers disassemble
Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res Aug;29(8): doi: /s z. Epub 2012 Apr 7. PubMed PMID: ; PubMed Central PMCID: PMC
Beals JM, et al, inventors; Eli Lilly and Company, Indianapolis, IN, assignee. Pegylated insulin lispro compounds. Patent US 2011/ A1. May 5, Patent filing, fig 2 and brief explanation, p 2. Patent was published 5/5/2011.
Mode of prolongation: Rosenstock ADA 2012 poster 1026-P (first column)
a Polyethylene glycol (PEG)
group may be attached at any of 3 points.
Jonassen I, et al. Pharm Res. 2012;29:

7. Insulin Degludec*
desB30 insulin acylated (16 carbon fatty acid chain) at LysB29
Duration of action >42 hours
Half-life ~25 hours
Detectable for at least 5 days
Steady state in 2-3 days
FDA denied approval in 2013, research continues
FXCX:
Garber page 6-7
Garber page 6
Garber page 3
Owens p
*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):

8. Pharmacodynamics of Degludec
Ideg 0.4 U/kg
Ideg 0.8 U/kg
Ideg 0.6 U/kg 6 5 4
Glucose Lowering Effect on Day 6 (mg/kg/min) 3 2 1
FXCX:
Simon pdf in Zotero
Grunberger pef in Zotero 4 8 12 16 20 24
Time since Injection (hours)
Josse RG and Woo V. Diabetes Obes Metab. 2013;15(12):

9. Degludec vs Glargine In Type 2 DM16 40 28 52 4 32 20 44 12 36 24 48 8
8.6
7.8
A1C (%)
7.0
8.2
8.4
7.6
7.4
8.0
7.2 70 62
A1C (mmol/mol) 54 66 68 60 58 64 56
Insulin Degludec once-daily (N=744)
Insulin Glargine once-daily (N=248)
Time (weeks)
2.0
1.0
Cumulative Events per Participant 16
Time (weeks) 40 28
0.2 52
1.4
1.8
0.8
1.6
0.6
1.2
0.4 4 32 20 44 12 36 24 48 8
Nocturnal Hypoglycemia
Equal Efficacy, Less Nocturnal Hypoglycemia with Degludec but no difference in severe hypoglycemia
FXCX:
Permissions for reuse of figures
pdf in Zotero
Graph A = Graph A page 1502
Graph B = Graph B (Noctural confirmed hypoglycemic episodes)
Graph C = Graph C (Diurnal confirmed hypoglycemic episodes) all on page 1503
Garber AJ, et al. Lancet. 2012;379(9285):