1. Advanced Insulin Therapy: Achieving Better PPG Control in T1DM and T2DM
Moderator
Stephen Atkin, MBBS, MD, PhD
Professor of Medicine
Weill Cornell Medicine - Qatar
Education City, Qatar Foundation
Doha, Qatar
T1DM = type 1 diabetes mellitus
T2DM = type 2 diabetes mellitus

2. Faculty Thomas R. Pieber, MD Eric Renard, MD, PhD Tim Heise, MD
Professor of Medicine
Chair, Department of Internal Medicine
Chair, Division of Endocrinology and Diabetology
Medical University of Graz
Graz, Austria
Eric Renard, MD, PhD
Head, Department of Endocrinology, Diabetes, and Nutrition
University Hospital of Montpellier
Montpellier, France
Tim Heise, MD
Lead Scientist
Science and Administration
Profil Institute for Metabolic Research
Neuss, Germany

3. Introduction/Overview
Elevated PPG in both T1DM and T2DM has been associated with poor glycemic control as well as a number of cardiometabolic risk factors and comorbidities
Rapid-acting insulins are useful in the treatment of PPG, but their onset of action is slow and PD/PK profiles may not correspond to physiologic insulin secretion
Ultra-fast-acting prandial insulins address these short-comings, with the added benefit of more flexible dosing
Clinical trial data suggest ultra-fast-acting prandial insulins can better control PPG and reduce HbA1c, with safety comparable to current prandial insulins
HbA1c = glycated hemoglobin
PPG = postprandial glucose
PD = pharmacodynamic
PK = pharmacokinetic

4. Case Study Patient characteristics
Male; diabetes duration 10 years
Age: 62 years
BMI: 30 kg/m2
HbA1c: 8.2%
FPG: 6.8 mmol/L (120 mg/dL) 
PPG: 10.5 mmol/L (189 mg/dL)
eGFR: 66
Treatment: Metformin
Basal insulin 30 units in the evening
How should we advance treatment for this patient?
BMI = body mass index
FPG = fasting plasma glucose
eGFR = estimated glomerular filtration rate

5. PPG, HbA1c, and Risk Factor Exacerbation
Elevated PPG has been associated with poor HbA1c control and other risk factors, for example:
Exacerbation of insulin resistance
Diabetes disease progression (increased PPG drives an increase in HbA1c)
CV disease
Recent data from a meta-analysis suggest that PPG has a stronger correlation with HbA1c than FPG
CV = cardiovascular
Ketema L, et al. Arch Pub Health. 2015;73:43.

6. Impact of Postprandial Hyperglycemia
Associated with:
Microvascular complications[a,b]
CV events[c]
CV and all-cause mortality[c,d]
Can affect mood and cognitive function[e]
San Luigi Gonzaga Diabetes Study: 14-Year Follow-Up of 505 Patients With T2DM[c]
Outcome
HR (95% CI)
P Value
CV events
1.45 (1.06, 1.99)
.021
All-cause mortality
1.85
(1.31, 2.61)
.001
Postprandial hyperglycemia was a significant predictor of CV events and mortality
Medscape slide OUS
CI = confidence interval
HR = hazard ratio
a. Shichiri M, et al. Diabetes Care. 2000;23:B21-B29; b. UKPDS Group. Lancet. 1998;352: ; c. Cavalot F, et al. Diabetes Care. 2011;34: ; d. DECODE Study Group. Arch Intern Med. 2001;161: ; e. Sommerfield AJ, et al. Diabetes Care. 2004;27:

7. Major Mechanisms Linking Elevated PPG to Diabetes Complications
Hyperglycemia[a,b]
Elevated PPG[a,b]
Oxidative Stress[a,b]
Vascular Inflammation[a,b]
Endothelial Dysfunction[a,b]
Diabetic Complications[a,b]
a. Ceriello A, et al. Rev Endocr Metab Disord. 2016;17:
b. de Vries MA, et al. Adv Exp Med Biol. 2014;824:

8. When Should Glycemic Treatment Focus on PPG?
When does PPG become a concern?
When the FPG is at goal and HbA1c remains elevated
When large differences appear between bedtime and morning/AM ("BeAM" factor)
When there are large glucose drops overnight or between meals
When there is increased variability of FPG values
Yacoub T. Postgrad Med. 2017;14:1-10.

9. Recommended Targets for PPG
PPG Target
(1-2 hours post meal)
ADA/EASD[a,b]
< 10 mmol/L
< 180 mg/dL
AACE[c]
< 7.8 mmol/L
< 140 mg/dL
IDF[d]
< 9.0 mmol/L < 160 mg/dL
International Diabetes Federation. Guideline for Management of Postmeal Glucose in Diabetes. Available at: Accessed September 18, 2017.
AACE = American Association of Clinical Endocrinologists ADA = American Diabetes Association EASD = European Association for the Study of Diabetes IDF = International Diabetes Federation
a. Inzucchi SE, et al. Diabetologia. 2015;58: ; b. ADA Guidelines. Diabetes Care. 2017;40:S48-S56; c. Garber AJ, et al. Endocr Pract. 2017;23; ; d. IDF website. Management of Postmeal Glucose.

10. Strategies for Treating PPG: Type 1 and Type 2 Diabetes
CGM: increasing patient awareness of PPG spikes post meal
Improving the matching of bolus insulin dose to meal size
Appropriate injection time; too many patients are still injecting after the meal, not before
Addition of other compounds; eg, GLP-1 receptor agonists, or SGLT2 inhibitors
Application of ultra-fast-acting prandial insulins
CGM = continuous glucose monitoring
GLP-1 = glucagon-like peptide-1
SGLT2 = sodium-glucose co-transporter-2

11. Case Study (cont) Patient characteristics
Male; diabetes duration 10 years
Age: 62 years
BMI: 30 kg/m2
HbA1c: 8.2%
FPG: 6.8 mmol/L (120 mg/dL) 
PPG: 10.5 mmol/L (189 mg/dL)
eGFR: 66
Treatment: Metformin
Basal insulin 30 units in the evening
How should we advance treatment for this patient?

12. Flat basal insulin profile
Insulin Replacement Therapy Aims to Recreate the Normal Blood Insulin Profile
0800
1200
1600
2000
2400 10 20 30 40 50
0400
Time, h
Serum Insulin, mU/L
Flat basal insulin profile
Breakfast
Lunch
Dinner
Mealtime (prandial) insulin excursions
Rapid rise; short duration
Medscape slide OUS
Kruszynska YT, et al. Diabetologia. 1987;30:16-21.
INTERNAL USE ONLY

13. PK Profile of Insulin Replacement Therapy (Schematic Representation)
Time, h 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Rapid (aspart, lispro, glulisine, insulin human)[a]
Short (regular U-100) [a]
Mixed short/intermediate (regular U-500) [a]
Intermediate (NPH) [a]
Long (detemir) [a]
Long (U-100 glargine) [a]
Glargine U-300[a]
Plasma Insulin Levels
Ultra-long (degludec U-100 & U-200)[b]
Medscape slide OUS
a. Hirsh IB. N Engl J Med. 2005;352: ; b. Haahr H, et al. Clin Pharmacokinet. 2014;53:

14. Insulin Action (At Mealtime)*
Ultra-Fast-Acting Insulin: Approaching a More Exact Physiological Insulin Profile
First-generation rapid-acting insulins had improved action profile vs RHI
Ultra-fast-acting insulins:
Better approach physiological insulin secretion in T1DM
Replace early insulin secretion in T2DM
Have a better profile for pump therapy
Rapid-acting insulin
Time, h
Insulin Action (At Mealtime)*
From the normal pancreas
'Faster-acting' insulin
RHI
RHI = regular human insulin
*Schematic representation.
Home PD. Diabetes Obes Metab. 2015;17: 14

15. Adocia: BioChaperone® Technology
Insulin,
Growth factors, mAbs…
BioChaperone-Protein
Complex
Protein
CE: shortened ref; added registered symbol to BioChaperone; added mAb abbreviation
mAb = monoclonal antibody
Adocia BioChaperone. Available at: Accessed 12/18/17.
Adocia website. BioChaperone®.

16. 994-P/994 - Ultra-Fast-Acting Lispro (BCLIS) vs Insulin Lispro: Blood Glucose and PK Parameters
LS Means
P value
BCLIS vs LIS
All Days
Parameter
Treatment
Days 1- 2
Days 13-14
Blood glucose parameters
BG_0-2h (mg*h/dL)
BCLIS
47.7
39.7
43.6
.0041
LIS
50.3
62.0*
56.1
BGmax (mg/dL) 51
.0107 56 61 59
PK parameters
AUCLIS_0-2h (pg*h/mL)
4434
4548
4520
<.0001
3872
3965
3946
BG = blood glucose
AUC = area under the curve
AUCLIS = area under the curve lispro
LS = least squares
LIS = lispro
BCLIS = BioChaperone® lispro
*indicates a significant difference within treatment between days 1-2 and days
Heise T, et al. ADA Abstract 994.

17. Faster-Acting Insulin Aspart: A New Formulation of Insulin Aspart
Thr
Lys
Asp
Tyr
Phe
Gly
Arg
Glu
Cys
Val
Leu
Ala
His
Ser
Gln
Asn
Ile A1
A21 B1
B30
B28 SS
Nicotinamide: absorption modifier
L-Arginine: added for stability
Insulin aspart: reduced strength of the insulin dimer leading to fast absorption[a]
Faster-acting insulin aspart is a new formulation of insulin aspart, which contains 2 excipients, nicotinamide and arginine[b]
Nicotinamide acts as an absorption modifier; arginine acts as a stabilizing agent
Both ingredients are "generally recognized as safe" by the FDA
The excipients result in a stable formulation and faster initial absorption after SC injection
Abbreviations:
FDA = United States Food and Drug Administration
SC = subcutaneous
a. Brange J, et al. Diabetes Care. 1990;13:
b. Heise T, et al. Diabetes Obes Metab. 2015;17: Figure courtesy of Tim Heise, MD.

18. Faster-Acting Insulin Apart Pooled Analysis: Onset and Offset of Insulin Exposure
Ratio (95% CI)
Cmax (pmol/L)
1.04 (1.00, 1.08)
AUCIAsp, 0-12h (pmol·h/L)
1.01 (0.98, 1.04)
AUCIAsp, 2-12h (pmol·h/L)
0.89 (0.85, 0.93)*
Treatment Difference (95% CI)
t50%Cmax (min)
-9.5 (-10.7, -8.3)*
tlate50%Cmax (min)
-12.2 (-17.9, -6.5)*
Faster aspart
Insulin aspart 50
100
150
200
250
300
Insulin aspart serum conc. (pmol/L) 1 2 3 4
Time (h) 5 6 7 8
–10/–12 min
Cmax = peak serum concentration
AUCIAsp = area under the curve insulin aspart
t50%Cmax = time to 50% peak serum concentration
tlate50%Cmax = time to late 50% peak serum concentration
IAsp = insulin aspart
CSII = continuous subcutaneous insulin infusion
*statistically significant.
(Faster-acting insulin aspart is approved in the US, Canada, EU, Australia [CSII only in the EU].)
Reproduced from Heise T, et al. Clin Pharmacokinet. 2017;56:

19. Faster-Acting Insulin Aspart Pooled Analysis: Early Exposure
Faster aspart/IAsp
Ratio (95% CI)
AUCIAsp, 0-15min
3.83 (3.41, 4.29)*
AUCIAsp, 0-30min
2.01 (1.87, 2.17)*
AUCIAsp, 0-1h
1.32 (1.26, 1.39)*
AUCIAsp, 0-1.5h
1.16 (1.12, 1.21)*
AUCIAsp, 0-2h
1.10 (1.06, 1.14)*
Favors insulin aspart
Favors faster aspart
*statistically significant; all P values were <.001
Heise T, et al. Clin Pharmacokinet. 2017;56:

20. Treatment difference (95% CI)
Faster-Acting Insulin Aspart Pooled Analysis: Onset and Offset of Insulin Action
Ultra-fast-acting aspart has a 4.9 min earlier peak than standard aspart.
Faster aspart
Insulin aspart
GIR (mg/(kg·min)) 2 4 6 8 1 3 5 7
Time (h)
–10/–14 min
Ratio (95% CI)
GIRmax (mg/kg·min)
1.01 (0.96, 1.05)
AUCGIR, 0-12h (mg/kg)
0.98 (0.94, 1.03)
Treatment difference (95% CI)
t50%GIRmax (min)
-9.5 (-12.5, -6.4)*
tlate50%GIRmax (min)
-14.3 (-22.1, -6.5)*
GIR = glucose infusion rate
GIRmax = maximum glucose infusion rate
t50%GIRmax = time to half maximum glucose infusion rate
tlate50%GIRmax = time to late half maximum glucose infusion rate
*statistically significant
(Faster-acting insulin aspart is approved in the US, Canada, EU, Australia [CSII only in the EU].)
Reproduced from Heise T, et al. Clin Pharmacokinet. 2017;56:

21. Faster-Acting Insulin Aspart in Insulin Pumps: PK Results
Cmax [1.03; 1.19]
26 min
Faster aspart
Endpoint
Treatment Difference (min; 95% CI)
tEarly50%Cmax
-11.8 (-14.4, -9.2)
tmax
-25.7 (-34.3, -17.1)
tLate50%Cmax
-35.4 (-47.0, -23.8)*
12 min
35 min
AUCIAsp,0-6h [0.90; 1.05]
Tmax = time to maximum insulin aspart concentration
tEarly50%Cmax = time to early 50% peak serum concentration
* All P values were <.001. Faster-acting insulin aspart is approved in the US, Canada, EU, Australia (CSII only in the EU).
Heise T, et al. Diabetes Obes Metab 2017;19: © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

22. Faster-Acting Insulin Aspart in Insulin Pumps: Improved 2-Hour PPG (CGM)
IG Increment, mmol/L
P <.001
P = .004
P = .015
All Meals
After Breakfast
Faster aspart
Insulin aspart
IG = interstitial glucose
Graphs show LS mean values Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33.

23. Patients With T1DM Who May Be Candidates for Ultra-Fast-Acting Insulins
Patients who may fail to follow the recommendation to inject bolus insulin before the meal
Patients with irregular eating habits who may want to use post meal dosing of faster aspart
Patients who experience hypoglycemia following a meal when injecting rapid-acting insulin analogs before the meal

24. Onset® 1: Study Design Double-blind Faster aspart (mealtime) + detemir
Insulin aspart + insulin detemir
Faster aspart (mealtime) + detemir
Insulin aspart (mealtime) + detemir
Faster aspart (post meal) + detemir
n = 381
n = 380
n = 382
Run-in
Randomization (1:1:1)
End of treatment Partial DBL
Additional treatment period
8 weeks
26 weeks FU
Patients with T1DM on basal-bolus treatment:
T1DM ≥ 12 months
Male or female ≥ 18 years
Basal-bolus insulin ≥ 12 months
Insulin detemir or insulin glargine ≥ 4 months
HbA1c 7.0% to 9.5% (53 to 80 mmol/mol)
BMI ≤ 35.0 kg/m2
Medscape slide OUS
DBL = database lock
FU = follow-up
Russell-Jones D, et al. Diabetes Care. 2017;40:
The primary endpoint was change from baseline in HbA1c after 26 weeks of treatment

25. Onset® 1: Postprandial Plasma Glucose (Test Meal)
Week 26
2-h ETDŦ:
–0.67 mmol/L [95% CI: –1.29; –0.04]
–12.0 mg/dL [95% CI: –23.3; –0.7]
1-h ETD*:
–1.18 mmol/L [95% CI: –1.65; –0.71]
–21.2 mg/dL [95% CI –29.7; –12.8]
Faster-acting insulin aspart significantly reduced HbA1c vs standard aspart (P =.0003)
*P <.001; ŦP = .0375
American Diabetes Association Russell-Jones D, et al. Diabetes Care. 2017;40: Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

26. Onset® 1: Severe and Confirmed Hypoglycemia
Faster aspart (meal-time)
Insulin aspart (meal-time)
Faster aspart (post-meal)
NS = not significant
Estimated Ratio
95% CI
Faster aspart (meal-time)/
Insulin aspart (meal-time)
1.01
0.88, 1.15
Faster aspart (post-meal)/
0.92
0.81, 1.06
Russell-Jones D, et al. Diabetes Care. 2017;40:

27. Patients With T2DM Who May Be Candidates for Ultra-Fast-Acting Insulins
Patients with cognitive disturbances, and/or unsure how much the patient will eat at a meal
Patients who habitually forget to inject prandial insulins pre-meal
CE: added Patients to first bullet

28. Onset® 2: Study Design Basal insulin dose optimization
Bolus intensification
Faster aspart + insulin glargine U100 + metformin
Patients with T2DM on basal insulin and metformin ± other OADs
Insulin glargine U100 + metformin
n = 345
Insulin aspart + insulin glargine U100 + metformin
n = 344
8 weeks
26 weeks
1 week/30 days
Medscape slide OUS
Abbreviations:
OAD = oral antidiabetic drug
Run-in
Randomization (1:1)
Follow-up
End of treatment
Randomization criteria: HbA1c 7.0% to 9.5% (53 to 80 mmol/mol), using HbA1c measured at visit 9 (week-1).
Bowering K, et al. Diabetes Care. 2017;40:

29. Onset® 2: Postprandial Plasma Glucose (Test Meal)
Week 26
1-h ETD:*
−0.59 mmol/L [95% CI: −1.09; −0.09]
−10.6 mg/dL [95% CI: −19.6; −1.7]
2-h ETD:†
−0.36 mmol/L [95% CI: −0.81; 0.08]
−6.6 mg/dL [95% CI: −14.5; 1.4]
HbA1c was reduced by -1.38% with faster-acting insulin aspart and by -1.36% with standard aspart
*P =.0198; †confirmatory secondary endpoint, not statistically significant.
American Diabetes Association Bowering K, et al. Diabetes Care. 2017;40: Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

30. Onset® 2: Treatment-Emergent Hypoglycemia
No Difference in Rates of Severe or BG-Confirmed Hypoglycemia*
Faster aspart (meal-time)
Insulin aspart (meal-time)
Estimated Ratio
95% CI
Faster aspart/
insulin aspart
1.09
0.88, 1.36
Medscape slide: OUS
No differences in hypoglycemia rates or body weight
No differences in safety data
*BG-confirmed hypoglycemia: plasma glucose value < 56 mg/dL (3.1 mmol/L)
Bowering K, et al. Diabetes Care. 2017;40:

31. Patient Satisfaction With New Ultra-Fast-Acting Prandial Insulins
Greater control of PPG even in patients who use the insulin post meal (not recommended)
No increased risk for hypoglycemia; physicians can more securely intensify therapy, if needed
More consistent insulin level increase and action, leading to more consistent PPG control
Potential for reducing treatment burden
Likelihood for quality of life improvements

32. Summary and Conclusions
PPG in T1DM and T2DM is sometimes difficult to treat and, uncontrolled, has been associated with disease exacerbation and increased CV risk
First-generation rapid-acting (prandial) insulins have been helpful in controlling PPG, but only at best approximate normal mealtime insulin profiles
New, ultra-fast-acting prandial insulins more exactly match mealtime insulin physiology, and thus may more effectively control PPG, with safety comparable to that of currently available prandial insulins

33. Abbreviations
AACE = American Association of Clinical Endocrinologists ADA = American Diabetes Association AUC = area under the curve AUCLIS = area under the curve lispro AUCIAsp = area under the curve insulin aspart BCLIS = BioChaperone® lispro BG = blood glucose BMI = body mass index CGM = continuous glucose monitoring CI = confidence interval Cmax = peak serum concentration CSII = continuous subcutaneous insulin infusion CV = cardiovascular DBL = database lock DPP-4 = dipeptidyl peptidase-4 EASD = European Association for the Study of Diabetes eGFR = estimated glomerular filtration rate ETD = estimated treatment difference

34. Abbreviations (cont)
FDA = United States Food and Drug Administration FPG = fasting plasma glucose FU = follow-up GIR = glucose infusion rate GIRmax = maximum glucose infusion rate GLP-1 = glucagon-like peptide-1 HbA1c = glycated hemoglobin HR = hazard ratio IAsp = insulin aspart IG = interstitial glucose IDF = International Diabetes Federation LIS = lispro LS = least squares mAb = monoclonal antibody NS = not significant OAD = oral antidiabetic drug PD = pharmacodynamic PK = pharmacokinetic

35. Abbreviations (cont)
PPG = postprandial glucose RHI = regular human insulin SC = subcutaneous SGLT2 = sodium-glucose co-transporter-2 t50%Cmax = time to 50% peak serum concentration t50%GIRmax = time to 50% maximum glucose infusion rate tearly50%Cmax = time to early 50% peak serum concentration tlate50%Cmax = time to late 50% peak serum concentration tlate50%GIRmax = time to late 50% maximum glucose infusion rate Tmax = time to maximum IAsp concentration T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus