Post on 03-Aug-2015
SCIENTIFIC SEMINARon
Dr Shahjada SelimAssistant Professor
Department of EndocrinologyBangabandhu Sheikh Mujib Medical
University
ORGANIZED BY:
Rapid acting analog: Use and
Optimization
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
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
Type 2 Diabetes Is Progressive
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
Intensification of glucose-lowering treatment delayed despite OAD failure
Avoidable glycaemic burden = time remaining on therapy after exceeding HbA1c target
Metforminmonotherapy
Sulphonylureamonotherapy
Combination(Metformin + SU)
0
10
20
30
40
50
60
1217
2626
37
51
Mon
ths
7% HbA1c target8% HbA1c target
OAD, oral antidiabetic drug; SU, sulphonylureaBrown et al. Diabetes Care 2004;75:1535–40
Good glycaemic control matters: 20 and 30 year follow-up results
1977–1991Randomisation
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 treatmentT2D, type 2 diabetes; UKPDS, UK Prospective Diabetes StudyAdapted from Holman et al. N Engl J Med 2008;359:1577–89; UKPDS Study Group. Lancet 1998;352:837–53
Treating T2D and its complications creates major economic burdens
€1373 1.3xincrease
€1723
€3355
2.4xincrease
€3436
2.5xincrease
€ 5642
4.1xincrease
All insuredpatients
Diabetes, nocomplications
Diabetes,microvascularcomplications
Diabetes,macrovascularcomplications
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 20111. 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)
Hypoglycaemia rates are higher than expectedResults from the HAT study
T1D, type 1 diabetesKhunti 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)
Any hypoglycaemia Severe hypoglycaemia0
5
10
15
20
25
16.5
0.9
19.3
2.5
Hyp
ogly
caem
ia in
cide
nce,
eve
nts
per
patie
nt y
ear
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)
Hypoglycaemia continues to be a main obstacle for HCPs to treat effectively with insulinResults from the GAPP™ study
GAPP™• A global internet survey of patient and
physician beliefs regarding insulin therapy
• n=1250 physicians
0 10 20 30 40 50 60 70 80 90 100
72%
79%
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 providerPeyrot et al. Diabet Med 2012;29:682–9
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
Patie
nts
with
A1C
<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
Patie
nts
with
A1C
<7%
(%)
Most Patients With T2D Will Eventually Need Insulin
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.
Types of insulin
Name of Insulin
Onset DurationRole 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
Types of insulin
Type of Insulin Onset Peak DurationRole 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
InhalerExubera Banned
Afrezza With in min 12 to 15 min 2-3 hoursPost 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).
Basal and Bolus Insulin
6-16
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
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/m
L
6-17
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
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
Structure of insulin aspart
Glu
Thr
Lys
ThrTyr Phe Phe Gly Arg
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
GlyCysLeuHisGlnAsnValPheB1
Asn CysTyr
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21B28B30
AspPro
Asp
Insulin aspart: more physiological insulin profile than soluble human insulin
Lindholm et al. Diabetes Care 1999;22:801-5
Plas
ma
insu
lin (p
mol
/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
00 1 2 3 4 5 6
n = 22
Prandial increment isthe mean increase in blood glucose from pre-meal to 90 min post-meal
European trial North American trial
Bloo
d gl
ucos
e in
crem
ent (
mm
ol/l
)
p < 0.001
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Insulin aspartHuman 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
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)
Post-breakfast
Post-lunch Post-dinner
0123456789
10
IAsp HI
Post
pran
dial
glu
cose
(mm
ol/l
)
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
Change in HbA1c
-2-10123456789
Baseline End of trial Difference
HbA
1c (%
)
IAspHIBHI
Bretzel et al. Diabetologia 2001;44(Suppl. 1):A209 1197
n = 222
Insulin aspart significantly reduces the rate of severe nocturnal hypoglycaemia
0
0.5
1
1.5
2
2.5
3
Totalevents
Nocturnalevents
Diurnalevents
Hyp
ogly
caem
ia e
vent
rate
(eve
nts
per p
atien
t-ye
ar)
Heller et al. Diabetic Medicine 2004, in press 066
IAspHI
n = 155
72% risk reduction with IAsp
• 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
• 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
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
Bloo
d gl
ucos
e ex
curs
ion
0– 5
h (m
mol
/l h
)
31
Improved postprandial glucose after 3 months
*
Bloo
d gl
ucos
e (m
mol
/l)
*
0Pre-
10
12
Post-
8
6
BIAsp 30
BHI 30 * p < 0.05*
*
LunchPre- 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%)
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
HbA
1c (%
)
0
33
Blood glucose levels did not differ between treatment groups
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 afterdinner
Bloo
d gl
ucos
e le
vels
(mg/
dl)
n = 91
p = NS in all cases
• 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)
• 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)
Thank you
Thank You All