InsulinAspart by Dr Shahjada Selim_BSMMU

1. SCIENTIFIC SEMINAR
on
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University
ORGANIZED BY:
Rapid acting analog:
Use and Optimization

2. Diabetes is a huge and growing problem, and the costs to
society are high and escalating
382 million people have diabetes
By 2035, this number will rise to
592 million

3. The worldwide challenge of glycaemic
control: mean HbA1C in type 2 diabetes
Canada 7.36–8.7%11
Latin America 7.6%1
US 7.2%7
China 9.5%11
India 8.7–9.6%9,11
Japan 7.05–9.6%11
Korea 7.9–8.7%4
Russia 9.6%11
Spain 9.2%8
Sweden 8.7%3
Turkey 10.6%3
UK 8.510–9.8%2
Germany 8.42–9.2%8
Greece 8.911–9.7%3,8
Italy 8.4%11
Poland 9.0%11
Portugal 9.7%3
Romania 9.9%3
1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Kostev & Rathmann Primary Care Diabetes 2013;7:229–33; 3. Oguz et al. Curr Med Res Opin
2013;29:911–20; 4. Ko et al. Diabet Med 2007;24:55–62; 5. Arai et al. Diabetes Res Clin Prac 2009;83:397–401; 6. Harris et al. Diabetes Res Clin Pract 2005;70:90–7;
7. Hoerger et.al. Diabetes Care 2008;31:81–6; 8. Liebl et al. Diabetes Ther 2012;3:e1–10; 9. Shah et al. Adv Ther 2009;26:325–35; 10. Blak et al. Diabet Med
2012;29:e13–20; 11. Valensi et al. Int J Clin Pract 2008;62:1809–19

5. Diabetes is a progressive disease that
requires reassessment to reach target
Europe
(CODE-2)3
HbA1c <6.5%
31%
69%
Canada
(DICE)2
HbA1c <7%
51%49%
Latin America
(DEAL)1
HbA1c <7%
43%
57%
Achieving glycaemic target
Failed to achieve glycaemic target
US
(NHANES)4
HbA1c <7%
57%43%
• Diabetes progresses
and requires
treatment
reassessment
• Insulin used to help
achieve control
England and Wales
(NDA5)
HbA1c <6.5%
25%
75%57%
43% 31%
69%
49% 51% 57%43%
DEAL, Diabetes En America Latina; CODE-2, The Cost of Diabetes in Europe - Type II; DICE, Diabetes in Canada Evaluation; NDA, National Diabetes Audit;
NHANES, National Health and Nutrition Examination Survey
1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Harris et al. Diabetes Res Clin Pract 2005;70:90–7;
3. Liebl et al. Diabetologia 2002;45:S23–8; 4. Hoerger et.al. Diabetes Care 2008;31:81–6; 5. HSCIC et al. National Diabetes Audit Report, 2011–12

6. Intensification of glucose-lowering
treatment delayed despite OAD failure
Avoidable glycaemic burden = time remaining on
therapy after exceeding HbA1c target
12
17
2626
37
51
0
10
20
30
40
50
60
Metformin
monotherapy
Sulphonylurea
monotherapy
Combination
(Metformin + SU)
Months
7% HbA1c target
8% HbA1c target
OAD, oral antidiabetic drug; SU, sulphonylurea
Brown et al. Diabetes Care 2004;75:1535–40

7. Good glycaemic control matters:
20 and 30 year follow-up results
1977–1991
Randomisation
2007
(30 years)
10-year post-trial follow-up
(non-interventional)
UKPS original results:
Intensive vs. conventional
treatment
12%*
25%*
16%
1997
(20 years)
Any diabetes-related endpoint
Myocardial infarction
Microvascular disease
9%*
24%*
15%*
In T2D, improvements
in glycaemic control
reduce the risk of
complications
*p<0.05; intensive vs. conventional treatment
T2D, type 2 diabetes; UKPDS, UK Prospective Diabetes Study
Adapted from Holman et al. N Engl J Med 2008;359:1577–89; UKPDS Study Group. Lancet 1998;352:837–53

8. Treating T2D and its complications
creates major economic burdens
€1373 1.3x
increase
€1723
€3355
2.4x
increase
€3436
2.5x
increase
€ 5642
4.1x
increase
All insured
patients
Diabetes, no
complications
Diabetes,
microvascular
complications
Diabetes,
macrovascular
complications
Diabetes, micro-
and macrovascular
complications
Annual costs per patient3
In 2011, ~11% (~$465B) of the total
healthcare expenditure worldwide
was spent on treating diabetes1
In 2007, only 10.6% of
US expenditure on
managing diabetes was
on diabetes medication2
Based on an exchange rate of 1 Euro = 1.4156 US dollars. Exchange rate as of 30 Oct 2011
1. IDF Diabetes Atlas, 5th Edition. http://www.idf.org/diabetesatlas/5e/healthcare-expenditures. Accessed November 2013;
2. American Diabetes Association Diabetes Care 2008;31:596–615; 3. Liebl et al. Dtsch Med Wochenschr 2001;126:585–89 (CODE-2 Study)

9. Hypoglycaemia rates are higher
than expected
Results from the HAT study
T1D, type 1 diabetes
Khunti et al. Diabetologia 2014;57 (Suppl. 1):S201
Prospective data suggests higher than expected rates of hypoglycaemia in both
T1D and T2D, in particular severe events
T2D, retrospective (n=19,563)
T2D, prospective (n=19,563)
16.5
0.9
19.3
2.5
0
5
10
15
20
25
Any hypoglycaemia Severe hypoglycaemia
Hypoglycaemiaincidence,events
perpatientyear
HAT study
• Non-interventional, global,
6-month retrospective and
1-month prospective study
of patient self-reported
hypoglycaemic events
• n=27,585 (T1D: 8,022;
T2D: 19,563)

10. Hypoglycaemia continues to be a main obstacle for HCPs to treat
effectively with insulin
Results from the GAPP™ study
GAPP™
• A global internet survey of patient and
physician beliefs regarding insulin
therapy
• n=1250 physicians
72%
79%
0 20 40 60 80 100
Percentage
I would treat my patients more
aggressively if there was no
concern about hypoglycaemia
p<0.05
Diabetes specialistsPrimary care physicians
GAPP, Global Attitudes of Patients and Physicians; HCP, health care provider
Peyrot et al. Diabet Med 2012;29:682–9

11. 50%
24%
34%
0
10
20
30
40
50
3 years 6 years 9 years
Glycemic Control Declines Over Time With
Traditional Monotherapy
Adequately controlled and
treated with sulfonylureas†
13%
44%
34%
0
10
20
30
40
50
3 years 6 years 9 years
PatientswithA1C<7%(%)
Adequately controlled and
treated with metformin*
Turner RC, et al. JAMA. 1999;281:2005-2012.
*Overweight drug-naïve patients. †Normal weight and overweight drug-naïve patients
PatientswithA1C<7%(%)

14. Types of insulin
Type of Insulin
& Brand Names
Onset Peak Duration
Role in Blood Sugar
Management
Rapid-Acting
Lispro 15-30 min. 30-90 min 3-5 hours Covers insulin needs for
meals eaten at the same
time as the injection.Aspart 10-20 min.
40-50
min.
3-5 hours
Glulisine 20-30 min.
30-90
min.
1-2½ hours
Short-Acting
Regular
30 min- 60
min
2-5 hours 5-8 hours
Covers insulin needs for
meals eaten within 30-60
minutes
Intermediate-Acting
NPH (N) 1-2 hours
4-12
hours
18-24
hours
Covers insulin needs for
about half the day or
overnight.

15. Types of insulin
Name of
Insulin
Onset Duration
Role in Blood
Sugar
Management
Long-Acting
Long-acting
insulin covers
insulin needs
for about one
full day.
Degludec 30-90 min No peak:
insulin is
delivered at
a steady
level.
Longer than 24
hours
Glargine 30-90 min Up to 24 hours
Detemir 1-120 min 20-24 hours

16. Types of insulin
Type of Insulin Onset Peak Duration
Role in Blood Sugar
Management
Pre-Mixed*
30/70 30 min. 2-4 hours 14-24 hours These products are
generally taken two
or three times a day
before mealtime.
50/50 30 min. 2-5 hours 18-24 hours
25/75 15 min.
30 min.-2½
hours
16-20 hours
Inhaler
Exubera Banned
Afrezza With in min 12 to 15 min 2-3 hours
Post prandial
effects.
*Premixed insulins are a combination of specific proportions of intermediate-
acting and short-acting insulin in one bottle or insulin pen (the numbers the brand
name indicate the percentage of each type of insulin).

17. Basal and Bolus Insulin
6-16

18. The Basal Bolus Insulin Concept
• Basal Insulin
– Suppresses glucose production between meals and overnight
– Nearly constant levels
– 50% of daily needs
• Bolus Insulin (Mealtime or Prandial)
– Limits hyperglycemia after meals
– Immediate rise and sharp peak at 1 hour
– 10% to 20% of total daily insulin requirement at each meal
6-20
Ideally, for insulin replacement therapy, each
component should come from a different insulin with
a specific profile

19. Insulin and Glucose Patterns: Normal and Type 2 Diabetes
Polonsky, et al. N Engl J Med. 1988;318:1231-1239.
100
200
300
400
Glucose Insulin
0600 1000 18001400 02002200 0600
Time of Day
0600 1000 18001400 02002200 0600
Time of Day
20
40
60
80
100
120
B L SB L S
Normal
Type 2 Diabetes
mg/dL
U/mL
6-17

20. Limitations of Human NPH, Lente, and
Ultralente
• Do not mimic basal insulin profile
– Variable absorption
– Pronounced peaks
– Less than 24-hour duration of action
• Cause unpredictable hypoglycemia
– Major factor limiting insulin adjustments
– More weight gain
6-30

21. Rapid-acting Analogues: Clinical Features
• Insulin profile more closely mimics normal physiology
• Convenient administration immediately prior to meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
– Reduced late postprandial hypoglycemia
– But more frequent late postprandial hyperglycemia
• Need for basal insulin replacement revealed
6-27

22. Structure of insulin aspart
Glu
Thr
Lys
Thr
Tyr
Phe
Phe Gly Arg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Leu
HisGlnAsnValPheB1
Asn Cys
Tyr
Asn
Glu
Leu
Gln
Tyr
Leu
Ser
CysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
B28
B30
Asp
Pro
Asp

23. Insulin aspart: more physiological insulin
profile than soluble human insulin
Lindholm et al. Diabetes Care 1999;22:801-5
Plasmainsulin(pmol/l)
Time (hours)
Insulin aspart, t = 0 min
Human insulin, t = 0 min
Human insulin, t = –30 min
(insulin dose 0.15 U/kg)
600
500
400
300
200
100
0
0 1 2 3 4 5 6
n = 22

24. Prandial increment is
the mean increase in blood
glucose from pre-meal to
90 min post-meal
European trial North American trial
Bloodglucoseincrement(mmol/l)
p < 0.001
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Insulin aspart
Human insulin
Postprandial blood glucose increment:
mean over the three meals at 6 months
Home et al. Diabetic Med 2000;17:762-70, Raskin et al. Diabetes Care 2000;23:583-8
p < 0.001
n = 1070 n = 884

25. Postprandial glucose control in type
1 diabetes
• Patients with type 1 diabetes (n =
368) were randomised to receive
either IAsp or HI as the meal-
related part of a basal-bolus
regimen
• IAsp reduced postprandial blood
glucose levels when compared to HI
(at 3 and 15 months)
0
1
2
3
4
5
6
7
8
9
10
Post-
breakfast
Post-lunch Post-dinner
Postprandialglucose(mmol/l)
IAsp
HI
DeVries et al. Diabet Med 2003 Apr;20(4):312-8
p = 0.0137
p = 0.0037
p = 0.081
N = 368
At 3 months

26. Change in HbA1c
-2
-1
0
1
2
3
4
5
6
7
8
9
Baseline End of trial Difference
HbA1c(%)
IAsp
HI
BHI
Bretzel et al. Diabetologia 2001;44(Suppl. 1):A209 1197
n = 222

27. Insulin aspart significantly reduces the
rate of severe nocturnal hypoglycaemia
0
0.5
1
1.5
2
2.5
3
Total
events
Nocturnal
events
Diurnal
events
Hypoglycaemiaeventrate
(eventsperpatient-year)
Heller et al. Diabetic Medicine 2004, in press 066
IAsp
HI
n = 155
72% risk
reduction
with IAsp

28. • Insulin Aspart provides improved
postprandial glycaemia through a rapid
onset, rapid time to maximum effect and a
gentle return to baseline insulin levels.
• Insulin Aspart significantly improves and
maintains lower HbA1c levels over 3 years
without increasing major hypoglycaemia.
Insulin Aspart

29. • Insulin Aspart is the only analogue to show
a 72% reduction in major nocturnal
hypoglycaemia
• Insulin Aspart can be administered
immediately before or after a meal
offering convenience and flexibility
• Insulin Aspart is safe and efficacious in
pumps
Insulin Aspart

30. Reduced glucose excursions vs.
Insulin Lispro and BHI 30
30
Hermansen K et al. Diabetes Care 2002;25:883–888
p < 0.05
–10%
p < 0.001
–17%
0
13
14
15
16
17
18
19
20
21
Humalog® Mix 25 BIAsp BHI 30
Bloodglucoseexcursion0–5h
(mmol/lh)

31. Improved postprandial glucose after 3
months
31
*
Bloodglucose(mmol/l)
*
0
Pre-
10
12
Post-
8
6
BIAsp 30
BHI 30
* p < 0.05
*
*
Lunch
Pre- Post-
Breakfast
Pre- Post-
Dinner
Bedtime 0200 h
Boehm B et al. Diabet Med 2002;19(5):393–399

32. Superior glycaemic control with BIAsp+ metformin in
poorly controlled patients (HbA1c > 9%)
32
p = 0.037 p = 0.033
Kvapil M et al. Diabetes 2002;51(Suppl 2):A104
7
7.5
8
8.5
BIAsp BIAsp+met Met+SU
Treatment group
HbA1c(%)
0

33. Blood glucose levels did not differ between treatment groups
33
Warren et al. Diab Res Clin Pract, in press 2004
Preprandial dosing
(BIAsp, bid)
Postprandial dosing
(BIAsp, bid)
0
20
40
60
80
100
120
140
160
180
200
Before
breakfast
Before
dinner
2 hrs after
breakfast
2 hrs after
dinner
Bloodglucoselevels(mg/dl)
n = 91
p = NS in all cases

34. • BIAsp provides improved postprandial
glycaemic control compared to biphasic
human insulin and Insulin Lispro.
• BIAsp provides a superior hypoglycaemic
profile to biphasic human insulin
Biphasic Insulin Aspart (BIAsp)

35. • BIAsp improves HbA1c when used in
combination with oral medications
• BIAsp is simple and convenient to use in
clinical practice
• BIAsp is effective and well tolerated in
adolescents
Biphasic Insulin Aspart (BIAsp)

36. Thank you
Thank You All