The Role of Rapid Acting Analogue

in Basal-Bolus Strategy
Outlines
Presentation structure

Progressiveness of Diabetes
The role of basal insulin analogue
Introduction of rapid acting analogue (NovoRapid)
Insulin Intensification : Basal Bolus Strategy
Conclusion
The Importance of treating Type 2 Diabetes
Type 2 diabetes is a progressive disease

Postprandial glucose

Diagnosis

Glucose Fasting glucose

Insulin Insulin resistance

Inadequate
-cell function Insulin secretion
Microvascular changes
Macrovascular changes

Prediabetes
NGT Diabetes
(IFG/IGT)

Adapted from Type 2 Diabetes BASICS. International Diabetes Center 2000

 Type 2 diabetes is progressive
disease

Over time,
most patients need insulin to achieve
glycemic control
 Slide 5

Main pathophysiological defects in type 2 DM

pancreatic Brain
Intestines Pancreas insulin
incretin secretion
effect
pancreatic
glucagon ? Kidney
secretion
gut
carbohydrate Glucose
reabsorpsion
delivery and
absorption Hyperglycemia
Muscle
Liver

peripheral
glucose
uptake
hepatic Adipose
glucose
production
Adapted from:Inzucchi SE, Sherwin RS. Diabetes Mellitus. In: Goldman L, Ausiello D, eds. Cecil Textbook of
Medicine. 23rd Edn. Philadelphia, Pa: Saunders Elsevier; 2007.
 Type 2 diabetes is a progressive disease

HOMA: homeostasis model assessment

Lebovitz. Diabetes Reviews 1999;7:13953 (data are from the UKPDS population: UKPDS 16.
Diabetes 1995;44:124958)
 Why does the -cell fail?
Oversecretion of
insulin to
compensate for
insulin resistance1,2

Glucotoxicity2 Lipotoxicity3

Pancre High
Chronic
as circulating
hyperglycemia
free fatty acids

-cell dysfunction
1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:1423.
2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:522.
3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20S27.
Insulin can be initiated at any time

Traditionally, insulin has been reserved as the last line of

therapy
However, considering the benefits of normal glycemic
status, Insulin can be initiated earlier and as soon as
possible

Inadequate
+ 1 OAD + 2 OAD + 3 OAD
Lifestyle

INITIATE INSULIN
Outlines
Presentation structure

Progressiveness of Diabetes
The role of basal insulin analogue
Introduction of rapid acting analogue (NovoRapid)
Insulin Intensification : Basal Bolus Strategy
Conclusion
 PPG

Influenced by:
Pre-prandial glucose
Glucose load from meal
Incretin level
Insulin secretion
Insulin sensitivity in peripheral tissues
Decrease in glucagon suppression
1. IDF. International Diabetes Foundation. Guidelines for Postmeal Glucose. Available at:
http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan 2009. 2. Monnier L, et al. Diabetes Metab.
2006;32:2S11-16. 3. Woo V, et al. Int J Clin Pract. 2008;62:1935-42.
 of patients on basal insulin +/- OAD are
well controlled at 1 year1

But what next for the patients whose diabetes has progressed and are no longer in
control?

Effective glycaemic control is achieved when both fasting

plasma glucose (FPG) and postprandial glucose (PPG) are
targeted3

2. Holman RR et al. Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes. N Engl J Med. 2007; 357(17): 1716-1730.
3. Monnier L et al. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic
patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003; 26(3): 881-885
 Keluhan Klasik (+) Keluhan Klasik (-)

GDP GDP <100

126 <126 126 100 - <126
atau atau
<140
GD2J 200 <200 GD2J 200

140-199
Ulang GDS atau GDP
TTGO
GDP GD 2 jam
126 <126
atau
GD2J 200 <200

200 140 - 199 100-126

DIABETES MELLITUS TGT GDPT NORMAL

Modifying insulin to achieve rapid action:
NovoRapid (Insulin Aspart )

Asp

Phe Gly
Phe Arg
Tyr Glu
Thr Gly
Pro Cys
Lys
Thr Val
A21 Asn Cys
B29
Tyr Leu
A1 Gly Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu
Gln Glu
Gln
Tyr Val
Cys Leu Leu
Cys Thr Ser Ile Cys Ser
His
Ser
Gly
Cys
Gln His Leu
B1 Phe Val Asn
 Twice as Rapid onset & as High peak
Doubleblind, cross-over, single dose study in healthy volunteers, N=24

(mU/ (pmol/
l) l)
500 48 min/ 414 pmol/l
NovoRapid
75
400 Human Actrapid
Serum insulin

(0.2 U/kg)

50 300 123 min/ 239 pmol/l

200

2
5 100

0 0
-60 0 60 120 180 240 300 360 420 480 540 600
Time (minutes)
Heinemann L et al. Diabetes Med 1996;13:683-84
 NovoRapid vs Human insulin:
Improved postprandial glycemia in T1 DM

Two long-term, multi-centre trials compared the efficacy

and safety of NovoRapid with human insulin

Design
Open-label, parallel-group comparison between NovoRapid and
human insulin, 6 months basal-bolus treatment (with a 6-month
extension period)
Type 1 diabetes (NovoRapid:HI = 2:1)
European study, 1070 subjects Home et al. 2000
North American study, 884 subjects Raskin et al. 2000

Home et al. Diabetic Med 2000;17:762-70

Raskin et al. Diabetes Care 2000;23:583-8
Self-monitored blood glucose profiles European trial

Type 1 diabetes
12
n = 1070
11 NovoRapid
p < 0.001
Blood glucose (mmol/l)

Human insulin
10
p < 0.01
p < 0.001 p < 0.01
9
p < 0.01
8

0
Before and Before and Before and Bedtime 2 a.m.
90 min after 90 min after 90 min after
breakfast lunch dinner

Home et al. Diabetic Med 2000;17:762-70

 Self-monitored blood glucose profiles
North American trial

12 Type 1 diabetes
n = 884
11 p < 0.001
Blood glucose (mmol/l)

NovoRapid
p < 0.01 Human insulin
10
p < 0.001
p < 0.05
9
p < 0.05

0
Before and Before and Before and Bedtime 2 a.m.
90 min after 90 min after 90 min after
breakfast lunch dinner

Raskin et al. Diabetes Care 2000;23:583-8

 Postprandial blood glucose increment

p < 0.001 p < 0.001

Type 1 diabetes
Mean values
1.8
after 6 months
1.6
Blood glucose increment

1.4 NovoRapid
Human insulin
1.2
(mmol/l)

1.0
Prandial increment is the
0.8 mean increase in blood
glucose from pre-meal to
0.6 90 min post-meal

0.4

0.2

0
European trial North American trial
n = 1070 n = 884
Home et al. Diabetic Med 2000;17:762-70
Raskin et al. Diabetes Care 2000;23:583-8
 Better postprandial control; lower HbA1c in type 1 patients

European trial North American trial

8.5 n = 1070 n = 882
8.5
Type 1 diabetes

p < 0.02 p < 0.005

HbA1c (%)
HbA1c (%)

8.0 8.0

7.5 7.5

0 00
0 3 6 0 3 6
Time (months) Time (months)
NovoRapid
Human insulin
Home et al. Diabetic Med 2000;17:762-70
Raskin et al. Diabetes Care 2000;23:583-8
 Summary on NovoRapid vs RHI

Better PPG control

Stable HbA1c levels in the long term

Less risk of hypoglycemia

Meal time flexibility

Outlines
Presentation structure

Progressiveness of Diabetes
The role of basal insulin analogue
Introduction of rapid acting analogue (NovoRapid)
Insulin Intensification : Basal Bolus Strategy
Conclusion
Outlines
Presentation structure

Progressiveness of Diabetes
The role of basal insulin analogue
Introduction of rapid acting analogue (NovoRapid)
Insulin Intensification : Basal Bolus Strategy
Conclusion
Conclusion

Insulin treatment must be evaluated

because diabetes as progressive disease
Novorapid is an rapid acting insulin
analogue which has better profile than
human insulin