1. WHY WE NEED NEW INSULIN ANALOG
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2. Diabetes: Global Scenario
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3. Diabetes – Growing Threat in Myanmar
Diabetes has been noted to be increasingly
common in Myanmar!

5. Patients achieving targets (%)
Uncontrolled Hyperglycemia is a Global
Problem In Clinical Practice
HbA1c <7%
56
HbA1c <7%
51
USA (NHANES) CANADA (DICE)
HbA1c <6.5%
31
EUROPE
(CODE-2)
HbA1c <6.5%
36
Emerging
countries
(IDPMS)

6. Progressive nature of Type 2 diabetes
Normal
Impaired
glucose
tolerance
Late type 2
diabetes
complications
Type 2
diabetes
Insulin
sensitive
Hyperglycaemia
Normal insulin
secretion
Insulin
resistance
Normoglycaemia
β-cell
exhaustion
Insulin resistance
Fasting plasma glucose
Insulin sensitivity
Insulin secretion
Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876.
Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7.
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7. ADA/ACE Targets for Glycemic control1
FPG
PPG
HBA1c
90-130 mg/dL
<180 mg/dL
<7.0%
<110 mg/dL
<140 mg/dL
<6.5%
For certain patients, a more stringent goal of <6.0% can be considered. 2
1.
2.
ADA, Standards of Medical Care in Diabetes, Diabetes Care 2003;26(Suppl 1): S33S50/AACE, Endocrine Practice 2002;8(Suppl 1):5-11
ADA, Standards of Medical Care in Diabetes, Diabetes Care 2004;27(Suppl 1): S15-S35
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8. Contributions of FPG and PPG On
Glycosylated Haemoglobin
Increasing Contribution of FPG as A1C Increases
100%
30%
%
Contribution
80%
60%
70%
60%
55%
50%
FPG
PPG
40%
20%
70%
30%
40%
45%
50%
0%
< 10.2
10.2 to 9.3 9.2 to 8.5 8.4 to 7.3
A1C Range (%)
Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and
postprandial plasnma glucose increments to the overall diurnal hyper glycemia
of Type 2 diabetic patients: variations with increasing levels of HBA(1c).
Diabetes Care. 2003;26:881-885.
< 7.3

9. Evidence of good glycemic control
• Several landmark trials viz;
– United Kingdom Prospective Diabetes Study (UKPDS)
– Diabetes Control and Complications trial (DCCT)
– Diabetes Control and Complications Trial/Epidemiology of
Diabetes Interventions and Complications (DCCT/EDIC)
– ADVANCE study
– All reinstate the importance of good glycemic control in
reducing the risk of microvascular & macrovascular
complications of diabetes
– Decrease of 1% in HBA1c levels is associated with a 21%
reduction in risk for any diabetes related end points
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10. ß-Cell Function (% ß)
The United Kingdom Prospective Diabetes Study demonstrated that a
great majority of patients with Type 2 diabetes will eventually require
Insulin and have provided level IA evidence that intensive glycemic
control improves patient outcomes*
Early Type 2
Late Type 2/
Type 1
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11. INSULIN
The Most Powerful Agent We Have To
Control Glucose
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12. Indications of Insulin
• Absolute
– Type 1 diabetic patients
– GDM (Gestational Diabetes Mellitus)
– Ketoacidosis
• Relative
–
–
–
–
–
–
–
–
–
Type 2 diabetic patient with primary or secondary failure to OHA
Surgery under general anesthesia
Type 2 diabetes with symptoms of glucose toxicity
Acute illness
Acute infections, e.g., Pneumonia, septicemia, etc.
Active pulmonary tuberculosis
Acute MI, CVA
Diabetic nephropathy
Chronic liver disease, etc.
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13. • Traditionally insulin is introduced to patients with only after
combination of two or three OHA failed to provide adequate
glycemic control
• General trend of insulin usage is last resort for Type 2
Diabetes
• Superior efficacy of insulin over oral agents in reducing
HbA1C levels is augmented by beneficial profile of new
insulin analogs versus human insulin
•
Difference of current treatment guideline is they all
recommend to initiate insulin therapy earlier than usual in
patients not achieving HbA1C targets
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14. Algorithm to initiate Insulin Therapy
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15. Traditionally, insulin is used only when OADs fail to
control glucose
Lifestyle changes
E.g. diet and exercise
Adequate in only ~15% of people
Oral antidiabetic agents
E.g. metformin, sulphonylurea
(or glitazone)
Poor glycaemic control
Oral combination therapy
E.g. metformin plus
sulphonylurea, metformin plus
glitazone
Poor glycaemic control
INSULIN
With/without oral
agent*
*Glitazones are contraindicated in combination with insulin
Bergenstal RM et al. In: Degroot et al. (eds) Endocrinology 2001: pp. 821–35

16. Diabetologia 2009; 52:17-30
Diabetes Care 2009;32:193-203
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17. Beta cell function loss is earlier and greater than
expected
By the time that the diagnosis of
diabetes is made, the patient has lost
over 80% of his/her β-cell function
DeFronzo RA. Diabetes. 2009 58:773–95.

18. Need of insulin increases over time
Patients
requiring
additional
insulin
(%)
60
40
20
0
1
2
3
4
5
6
Years from randomization
Chlorpropamide
Glipizide
~53% of patients required additional insulin therapy by year 6
Wright A , Burden A.C, Paisey R.B, Cull C. Holman R.R. Ukpds. Sulfonylurea Inadequacy Diabetes Care. 2002;25:330-6.

19. Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]

20. Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]

21. Time to insulin initiation and incidence of
complications are increasing
Median duration until insulin
initiation (years)
Patients with at least 1 macrovascular
event before initiation (%)
Kotav K, et al, Diabetologia 2011; 54 Suppl.1)374

22. “Ideal” & “Real Course” of
“Treated” Type-2-Diabetes
9,5
9,0
HbA1c (%)
(First) cardiovascular event
e.g. Myocardial Infarction
 New therapy attempt
There is golden window period
in diabetes; in first 3 - years
Real course
Build-up of
metabolic memory
Ideal course
8,5
Increasing the
risk of diabetic
late
complications
8,0
7,5
7,0
6,5
6,0
1
2
3
4
5
6
7
8
9 10
Time (years after diagnosis)
11
12
13
22
14
15
16
Del Prato, Diabetologia (2009) 52(7),1219- 1226

23. Need for Insulin
EARLY INSULIN SAVES HEALTH; SAVES MONEY
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24. Insulin Usage
Number of diabetics using medication:
25-30 million
Oral products
66%
Oral/insulin
Insulin
7%
27%
Patients treated with Insulin were 1.68 times more likely to acheive 2
consecutive HbA1c levels of 6.5% or less, sooner than those on OADs*
* Gerstein et al, Diabet Met. 2006;23:736-742
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25. Types of Insulin
*Leahy JL, Intensive Insulin Therapy in Type 1 diabetes
mellitus, in Lehay JL: Insulin Therapy. New
York, NY, Marcel Dekker, Inc.2002, p 87-112
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26. Normal Insulin Secretion:
The Basal-Bolus Insulin Concept
Endogenous Insulin
Bolus Insulin
Insulin Effect
Basal Insulin
B
L
D
HS
Time of Administration
B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.
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27. Insulin regimen:
Once-daily regimen
• Long- or intermediate-acting insulin is given at bedtime.
• It is suitable only for patients with type 2 diabetes and may be
used in combination with oral hypoglycaemic agents.
• This regimen may be used when starting insulin in type 2 diabetes
NICE Clinical Guideline (July 2004), NICE Clinical
Guideline (May 2009)
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28. Insulin regimen…
Twice-daily regimen
• A biphasic insulin is injected twice a day (pre-breakfast and preevening meal).
• The peak action varies directly with the proportion of soluble
insulin in the combination.
• The peak and trough of the evening dose of longer-acting insulin
can lead to the combination of nocturnal hypoglycaemia and then
fasting hyperglycaemia in the morning.
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29. Insulin regimen…
Three times per day
• In uncontrolled FPG
• 2/3 in BF, of which 2/3 NPH, 1/3 Regular
• 1/6 before EM, Regular
• 1/6 HS, NPH
Four times per day
• Either NPH & Regular (¼ X 3 R and ¼ HS NPH)
• Ultrashort and Long analogues (1/6 X 3 Aspart / Lispro and
½ HS Glargine)
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30. Insulin regimen….
Basal bolus regimen
•
Regular and Intermediate/long acting insulin is used.
•
Basal requirement is met by intermediate acting insulin
given twice a day before breakfast and dinner.
•
The regular insulin is given before each meal thrice a day.
Out of the total daily requirement 50% is given as basal
(intermediate/long) and 50% as regular insulin.
Continuous subcutaneous insulin infusion
•
Only short acting insulin by insulin pump.
•
It is neither practical, nor are the results better than twice
daily or bolus regimen.
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31. When to start the regimens?
A. Once daily regimen
• In type 2 diabetes patients with secondary failure to OHA: used in
combination with OHA.
B. Twice daily regimen
•
In type l, 2, and GDM patients.
•
When HbA1c is >9%
C. Basal Bolus regimen
•
When adequate control is not achieved by premixed insulin alone
D. Continuous subcutaneous insulin infusion
• When the patient is very much compliant
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32. Current Diabetes Therapy Falls Short
Inadequate control of Fasting Blood Glucose
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33. Key of insulin therapy
• Control of both FPG and PPBS is essential to improve
microvascular and macrovascular outcomes
• Ideal goal of insulin therapy is to mimic the pattern of
physiologic insulin secretion to control FPG & PPBG
• In order to achieve the normal physiological profile, Long
acting basal insulin suppress endogenous hepatic glucose
output therefore reducing FBG and short acting insulin to
address PPG
• Newer insulin analogs mimic the profile of endogenous
insulin more closely than recombinant human insulin
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34. Shortfalls of Current Regimen
• Unpredictable in insulin absorption
• Mismatch between glycemic excursions and insulin levels
• Lack of a truly basal insulin
• Poor FBG / PPBG control
• Events of Hypoglycemia
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35. Fasting Plasma Glucose
• Predicts the degree of post-meal hyperglycemia and the
magnitude of the post-meal excursion from baseline*
• FPG is a determinant of PPG excursion
*Diab Care 25: 1247-1248,2002
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36. FPG & Complications…
• FPG shows a positive association with the incidence of
diabetes related morbidity and mortality
• A study showed*
FPG
Risk of mortality
<110 mg/dl
No increased risk
110 – 125 mg/dl
40% increased risk
125 – 140 mg/dl
Double the risk
*Diab Care 2005;28(11):2626-32
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37. Insulin Regimen: Balancing Act
Can somebody
help me ??????
Hyperglycemia
Hypoglycemia
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38. Basal Insulin Supplements
NPH has…..
• Erratic absorption
• Unfavorable plasma
insulin profiles with
unwanted peaks
• Nocturnal
hypoglycemia
NPH
Insulin
Glargine
Insulin
Detemir
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39. Physiology of basal Insulin
• Suppresses lipolysis
• Restrains hepatic glucose output
• Prevents hypo-neuroglycopenia (in concert with glucagon)
• Not relevant to glucose utilization by muscle
An adipose-hepato-centric hormone
Large metabolic effects for small
changes in plasma
concentration

40. Basal Insulin Supplements
Basal Insulin
Preparations
Onset
(hours)
Peak
(hours)
Duration
(hours)
Remarks
NPH
2–4
6 – 10
10 – 16
•
•
•
•
•
•
•
Glargine
1–2
Peakless
24
• No Unpredictable peaks
• No Unpredictable glucose fluctuations
• Decreased hypoglycemia
Detemir
3–4
Peakless
Upto 14
hrs
• Injection site reactions and allergic
reactions
• Higher insulin dosage required
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Does not mimic basal insulin release profile
Component of Premixed
Does not provide enough flexibility
Unexpected time–action profiles
Unpredictable peaks
Unpredictable glucose fluctuations
Increased hypoglycemia
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41. Ideal basal insulin
• The ideal basal insulin should have…
– Mimic the physiological Insulin secretion pattern
– Square-wave action profile, i.e., no peak, long-lasting
– Reproducible effects
– Pharmacodynamic effects similar to pump insulin
This need is fulfilled by:
INSULIN GLARGINE
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42. Insulin Glargine: Structure
Phe Gly Arg
Tyr Phe
Glu
Thr
Gly
Pro
Arg Arg
Extension
Lys
A21 Gly Cys
Thr
A1 Gly
lle
Asp
Glu
Gln
Cys
B30
Asp
Gly
Substitution
Tyr
Gln
Glu
Leu
Gln
Tyr
Cys Thr Ser
lle Cys Ser
Leu
Cys
B1 Phe Val Asn Gln His Leu
Insulin Glargine:
21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin
pH = 4; Clear solution; Do not mix
Cys
Val
Leu
Tyr
Leu
Ala
Glu
Val
Leu
His
Ser
Gly

43. WHAT HAPPENS AFTER GLARGINE
INJECTION ?
Glargine
Clear
Solution
pH 4.0
pH
7.4
Precipitation
Dissolution
Hexamers
10-3 M
Dimers
10-5M
Monomers
10-8 M
S.c. Injection of
an acidic solution (pH
4.0)
Precipitation of glargine in
subcutaneous tissue (pH
7.4)
Slow dissolution of free
glargine hexamers from
precipitated Glargine
Capillary Membrane
Insulin in Blood
Protracted action

44. Are all insulin
analogs equally
effective?
-Pharmacokinetics
and
pharmacodynamics
of insulin glargine
and insulin detemir
in patients with type
35 IU insulin; PG-Clamp
1 mg/dL X 24h
100 diabetes.
Duration of action :
(PG < 150 mg/dL)
Insulin glargine: >24h
Insulin detemir: 17.5 h
Porcellati et al, DIABETES CARE , 30,OCTOBER 2007

45. Factors affecting PK / PD profile of insulin analog
• Insulin dose :
• area under the curve (AUC) and DOA for long & rapid acting
analog increases with dose elevation
• Injecting site
• Deeper subcutaneous injections cause more rapid insulin
diffusion and absorption
• High Sc fat slow absorption, altering or delaying the time
action profile
• Glargine has no clinically significant differences in DOA
whether injected in abdomen, thigh or deltoid where as in
Determer , bioavailabilty differs, 64%in abdomen, 59%in
thigh and 65% in deltoid
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46. Changes of PK /PD in special patient population
Elderly patients
Obesity – high subcutaneous fat slow the absorption
Renal dysfunction – 30 to 80% of insulin is removed by renal
excretion
Hepatic dysfunction – liver mainly controls hepatic glucose
output and uptake
Pregnancy – PK not altered but insulin resistance increased so
needing higher dose of insulin
Exercise –conditions causing greater blood flow
( exercise, massage, hot bath ) is associated with rapid insulin
absorption
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47. How has insulin Glargine changed the
treatment paradigm of diabetes?
• Once daily administration
• Easy titration algorithm
• Sustained glycemic control
• Less hypoglycemia
• Easy to use for specialist, GP, and patient

48. Mean HbA1c (%)
Insulin glargine: rapid and sustained glycemic
control.
A 32 month extension of a 9 month, open
label, uncontrolled, multicenter, observational study
(n=12216)
-----------
Months of treatment
Insulin glargine + OADs provides sustained glycemic control
Schreiber SA et al, Diabetes Techno Ther 2008; 10 121-7

49. Effect of insulin glargine on β-cell function
Insulin Secretion (mU/kg per min)
Insulin Secretion (mU/kg per
min)
First phase (t=0 to 10 min minus basal levels) and second phase insulin
secretion (t=-10 to 120 min minus basal levels) in response to IV glucose
administration in T2DM(n=14) before and after 8 weeks of insulin glargine
treatment
Pennartz C, et al, Diabetes Care 2011; 34-204

50. Insulin glargine has demonstrated effective
HbA1c reductions across a wide range of
RCTs in T1DM
Raskin
(2000)
n=619,
16 weeks
Bolli
(2009)
n=175, 2
4 weeks
Fulcher
(2005)
n=125, 3
0 weeks
Ashwell
(2006)
n=56, 3
2 weeks
Chatterje
e (2007)
n=53, 3
6 weeks
Porcellati
(2004)
n=121, 5
2 weeks
HbA1c reduction with insulin glargine in RCTs of varying duration and size

51. Lower risk of hypoglycemia for insulin glargine vs
NPH at any level of HbA1c in T1DM
Rate of hypoglycemia (events
per patients-year)
Meta-analysis of 5 randomized trails comparing insulin glargine and NPH
in HbA1c in T1DM
P=0004
HbA1c (%; LOCF)
Mullins P, et al, Clin ther 2007; 29; 1607-19

52. APOLLO: Insulin glargine vs prandial insulin lispro
44 week open label study on 412 T2DM patients treated with OHAs and
Glargine (OD) or Lispro (TID)
Change in HbA1c
30
Glargine
Lispro
-1.65
-1.7
-1.71
-1.75
-1.8
-1.85
Difference=.157
95% Cl -.008 to
0.332
-1.87
Hypoglycemic events
Change in HbA1c (%)
-1.6
24
25
Glargine
Lispro
20
13.6
15
10
5.2
5
4.2
0.520.34
0.030.08
0
-1.9
Overall
Symptomatic Nocturnal
Severe
Significant better treatment satisfaction with glargine compare to lispro
Bratzel RG et al Lancet 2008; 371:1073-8

53. THE
LANCET
• The first clinically available
long acting analog
*addition of insulin glargine to therapies
with oral hypoglycemic agents can be
regarded as a first-line insulin initiation
approach in type 2 diabetes mellitus*
• 42 million patient-years of
experience
• 80,000 individuals in clinical
development programs
worldwide
• Available in over 100
countries

54. Setting standards for basal insulin therapy : The
contribution of insulin glargine
Peak less, 24 hours insulin coverage
Effective, sustained glycemic control with the low
incidence of hypoglycemia in clinical trail and in real life
clinical practice.
Favorable impact on quality of life
Benefits proven across a wide range of patients
populations in T1DM & T2DM.
Easy to use, flexible titration algorithms
12 years of clinical experience.
Wealth of evidence to support a basal insulin treatment
regimen with insulin glargine.