1. CAN WE IMPROVE POSTPRANDIAL GLUCOSE CONTROL WITH FAST-ACTING INSULINS?
Faculty
Antonio Ceriello, MD, PhD
Professor of Medicine
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Bruce W. Bode, MD
Associate Professor of Medicine
Emory University School of Medicine; President and CEO
Atlanta Diabetes Associates
Piedmont Hospital
Atlanta, USA

2. Controlling Glucose in T1DM
415 million adults worldwide have diabetes
> 540,000 children have T1DM
Significant morbidity and mortality in people with elevated glucose levels
Improving glucose control improves outcomes
Guideline-Recommended Glycemic Targets
ADA, 2017[a,b]
IDF, 2012[c]
HbA1c
53 mmol/mol (< 7%)
FPG
4.4 to 7.2 mmol/mol ( mg/dL)
6.5 mmol/mol (115 mg/dL)
PPG
10.0 mmol/mol (< 180 mg/dL)
9.0 mmol/mol (< 160 mg/dL)
International Diabetes Federation. Diabetes Atlas - 7th edition, Accessed February 21, 2017.
International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Accessed February 21, 2017.
ADA = American Diabetes Association
FPG = fasting plasma glucose
HbA1c = glycated hemoglobin
IDF = International Diabetes Federation
PPG = postprandial glucose
T1DM = type 1 diabetes mellitus
T2DM = type 2 diabetes mellitus
* More or less stringent targets may be set according to patient or disease factors.
ADA. Diabetes Care. 2017;40(suppl 1):S1-S135.
IDF website. Diabetes atlas.
IDF website. Global guidelines for T2DM.

3. Patient Case: Profile Gender, age Female, 22 Duration of T1DM
Diagnosed 3 years ago
Current medication
Insulin glargine once daily
Insulin aspart with each meal
HbA1c
Current
56.3 mmol/mol (7.3%)
Target
< 53 mmol/mol (< 7%)
FPG
5.1 to 6.7 mmol/L ( mg/dL)
PPG
9.9 to 11.3 mmol/L ( mg/dL)
Monitoring
Checks FPG most mornings and PPG 2 to 3 times per week

4. The Importance of Controlling PPG
Normal HbA1c
Controlled FPG
Controlled PPG
PPG after 2 hours is a risk factor for overall mortality and CVD in diabetes[a,b]
Treatment guidelines recommend:[c,d]
Food with low glycemic index in diet
Adding specific glucose-lowering agents for targeting elevated PPG
International Diabetes Federation Guideline for management of post meal glucose in diabetes. Accessed February 21, 2017.
CVD = cardiovascular disease
a. Cavalot F, et al. Diabetes Care. 2011;34: ; b. Raz I, et al. Diabetes Care. 2009;32: ;
c. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135; d. IDF website. Postmeal glucose management guidelines.

5. Insulins That Target PPG: Aspart4 9
Time, min
Time, min
Pooled analysis of 6 randomized, double-blind, crossover trials
Adults aged 18 to 64 with T1DM; treated with insulin ≥ 12 months; HbA1c ≤ 86 mmol/mol (≤ 10%); BMI 18 to 28 kg/m2
PK analysis: n = 218; PD analysis: n = 119
BMI = body mass index
GIR = maximum glucose infusion rate
PD = pharmacodynamics
PK = pharmacokinetics
Newer insulin aspart vs regular aspart
Onset twice as fast
2-fold higher insulin exposure after 30 minutes
74% greater action within first 30 minutes
Heise T, et al. ADA Poster 929-P.

6. Onset® 1 Trial: Faster Aspart Effective Whether Given Before or After a Meal
-0.32%
-0.17%
-0.13%
Change in HbA1c (%)
ETD: -0.15%* (95% CI: -0.23, -0.07)
ETD: 0.04% (95% CI: -0.04, 0.12)
Study Design:
T1DM ≥ 12 months
Male or female ≥ 18 years
Basal-bolus insulin ≥ 12 months
Insulin detemir or insulin glargine ≥ 4 months
HbA1c 53 to 80 mmol/mol (7.0%-9.5%)
BMI ≤ 35.0 kg/m2
Primary endpoint: change in HbA1c after 26 weeks
CI = confidence interval
ETD = estimated treatment difference *
Weeks
*Statistically significant
Russell-Jones D, et al. Diabetologia. 2016;59(suppl 1):S6.

7. Onset 1 Trial: Faster Aspart Controlled 1-Hour and 2-Hour PPG
2-hour ETD:* mmol/L (95% CI: -1.29, -0.04) mg/dL (95% CI: -23.3, -0.7)
126
108 † 90 * 72
PPG Increment (mmol/L)
PPG Increment (mg/dL) 54
1-hour ETD:† mmol/L (95% CI: -1.65, -0.71) mg/dL (95% CI: -29.7, -12.8) 36 18
Time (min)
Bolus dose 0.1 U/kg
No significant differences in the overall rate of hypoglycemia
Similar overall safety profiles
*P = .0375; †P < .0001
Standardized meal test: mealtime comparison
Russell-Jones D, et al. Diabetologia. 2016;59(suppl 1):S6.

8. Onset® 2: Mean Change in HbA1c Over Time
Basal optimization
Bolus intensification
Patients with T2DM:
Basal insulin (glargine 100) and metformin ± other glucose-lowering agents
Basal insulin dose optimization
Bolus intensification for 26 weeks with insulin aspart (n = 344) or faster aspart (n = 345)
HbA1c 7.0% to 9.5% (53-80 mmol/mol)
HbA1c, %
0.0
Time Since Randomization, Weeks
Bowering K, et al. Diabetologia. 2016;59(suppl 1):S399.

9. Related Agents in Development
Afrezza® (insulin human) - inhaled insulin (United States only)
BioChaperone® - molecular delivery system
Hylenex® - hyaluronidase adjuvant
Others - eg, hepatic specific insulins
Note to CME - I checked with the lead SD, Anne, and she said it is ok to use trade names here.
Afrezza website. Accessed February 28, 2017.
BioChaperone website. Accessed February 28, 2017.
Hylenex website. Accessed February 28, 2017.
Afrezza website.
BioChaperone website.
Hylenex website.
Madsbad S. Diabetes. 2014;63:

10. Patient Case: Progression
Continued with insulin regimen
Focused on changing her diet to include foods with a low glycemic index
But her PPG remains elevated after 6 months
1-hour PPG 11.2 to 13.3 mmol/L ( mg/dL)
Insulin dose needs to increase
Using an insulin pump will reduce the risk for hypoglycemia
Grunberger G, et al. Endocr Pract. 2014;20:

11. Earlier Insulin Exposure and Action With Faster Aspart in CSII
Cmax
1.11 [1.03, 1.19]a†
AUC0-30 min
2.95 [2.32, 3.73]a*
AUCTotal
0.97 [0.90, 1.05]a
Randomized, double-blind, crossover trial
CSII in 48 patients with T1DM receiving faster aspart or insulin aspart as a CSII bolus dose in addition to basal CSII
AUC0-1 h
1.52 [1.37, 1.69]a*
AUC0-2 h
1.18 [1.10, 1.26]a*
Onset of action (t50%Cmax)
0.64 [0.57, 0.71]a*
AUC = area under the concentration-time curve
Cmax = maximum concentration
CSII: continuous subcutaneous insulin infusion 21 32
*P < .001; †P = .01; a Treatment ratio, 95% CI
Onset of action
~3-fold greater insulin exposure within the first 30 minutes, with faster aspart vs insulin aspart
Study also found greater glucose-lowering effect with faster aspart in first 2 hours; similar total glucose-lowering effect
Heise T, et al. Diabetes. 2015;64(suppl 1):A256.

12. Better PPG Control in CSII With Faster Aspart
Double-blind, randomized, 14-day crossover trial of 43 adults with T1DM
Improved PPG after a meal test in CSII with faster aspart vs insulin aspart
∆PPG0-2 h†
-0.99 [-1.95, -0.03] mmol/L*‡
∆PPG0-1 h†
-0.50 [-1.07, 0.07] mmol/L‡
*P < .05
† PPGav,0-1 (2)h calculated as AUCPG,0-2 h / 2 h - PPGPre-dose where AUCPG,0-2h was the area under the plasma glucose concentration time profile based on observed values and actual measurement times in relation to injection time between 0 and 2 h
‡ Treatment difference, 95% CI
Bode B, et al. Diabetes. 2015;64(suppl 1):A253.

13. Other Trials With Faster Aspart
Onset® 4[a]
37 patients with T1DM
6-week pump compatibility
Faster aspart vs insulin aspart
Onset® 5[b]
Phase 3B
T1DM pump
ClinicalTrials.gov. Efficacy and safety of continuous subcutaneous insulin infusion of faster-acting insulin aspart compared to NovoRapid® in adults with type 1 diabetes (Onset® 5). Accessed February 28, 2017.
EASD = European Association for the Study of Diabetes
a. Bode B, et al. EASD Abstract 39.
b. ClinicalTrials.gov. NCT

14. Conclusions
FPG and PPG need to be controlled in order to get HbA1c to goal
Several methods available for achieving this
Fast-acting insulin aspart is available in many countries
It can be used in T1DM and T2DM with no increased risk for hypoglycemia
Several clinical trials with faster aspart completed
Can be used with pump therapy and as a post-meal bolus

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16. Abbreviations
ADA = American Diabetes Association AE = adverse event AUC = area under the concentration-time curve BMI = body mass index CI = confidence interval Cmax = maximum concentration CSII = continuous subcutaneous insulin infusion CVD = cardiovascular disease EASD = European Association for the Study of Diabetes ETD = estimated treatment difference FPG = fasting plasma glucose GIR = glucose infusion rate HbA1c = glycated hemoglobin IDF = International Diabetes Federation

17. Abbreviations (cont)
PD = pharmacodynamic PK = pharmacokinetic PPG = postprandial glucose SC = subcutaneous T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus t50%Cmax = time to 50% of maximum insulin concentration