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1 Glaritus 2012
WHY WE NEED NEW INSULIN ANALOG
Glaritus 2012 2
Diabetes: Global Scenario
Pandemic rise in Diabetes,
especially in developing countries !!!
Diabetes – Growing Threat in Myanmar
Increasing Diabetes
Making Headlines!
Diabetes has been noted to be increasingly common in Myanmar!
Uncontrolled Hyperglycemia is a Global Problem In Clinical Practice
HbA1c <7%56 HbA1c <7%
51
HbA1c <6.5%31
HbA1c <6.5%36
Patie
nts
achi
evin
g ta
rget
s (%
)
Glaritus 2012 6
Normal
Progressive nature of Type 2 diabetes
Impaired glucose
toleranceType 2
diabetes
Fasting plasma glucoseInsulin sensitivityInsulin secretion
Insulin sensitive
Normal insulin secretion
Normoglycaemia
Hyperglycaemia
β-cell exhaustion
Insulin resistance
Late type 2 diabetes
complications
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.
Insulin resistance
Glaritus 2012 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. ADA, Standards of Medical Care in Diabetes, Diabetes Care 2003;26(Suppl 1): S33-S50/AACE, Endocrine Practice 2002;8(Suppl 1):5-11
2. ADA, Standards of Medical Care in Diabetes, Diabetes Care 2004;27(Suppl 1): S15-S35
Increasing Contribution of FPG as A1C Increases
30%40% 45% 50%
70%
60% 55% 50%30%
70%
0%
20%
40%
60%
80%
100%
< 10.2 10.2 to 9.3 9.2 to 8.5 8.4 to 7.3 < 7.3A1C Range (%)
%
Con
trib
utio
n
FPGPPG
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.
Contributions of FPG and PPG On Glycosylated Haemoglobin
Glaritus 2012 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
Glaritus 2012 10
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
ß-Ce
ll Fu
nctio
n (%
ß)
Glaritus 2012 11
INSULINThe Most Powerful Agent We Have To Control Glucose
Glaritus 2012 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.
Glaritus 2012 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
Glaritus 2012 14
Algorithm to initiate Insulin Therapy Early Insulin
Gets Results !
Traditionally, insulin is used only when OADs fail to control glucose
E.g. metformin, sulphonylurea (or glitazone)
E.g. metformin plus sulphonylurea, metformin plus glitazone
With/without oral agent*
Lifestyle changes
Oral combination therapy
INSULIN
E.g. diet and exercise
*Glitazones are contraindicated in combination with insulinBergenstal RM et al. In: Degroot et al. (eds) Endocrinology 2001: pp. 821–35
Oral antidiabetic agents
Poor glycaemic control
Poor glycaemic control
Adequate in only ~15% of people
Glaritus 2012 16
Diabetologia 2009; 52:17-30 Diabetes Care 2009;32:193-203
Early Insulin
Gets Results !
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.
Need of insulin increases over time
Wright A , Burden A.C, Paisey R.B, Cull C. Holman R.R. Ukpds. Sulfonylurea Inadequacy Diabetes Care. 2002;25:330-6.
Chlorpropamide
60
40
20
0
Patie
nts
requ
iring
ad
ditio
nal
insu
lin
(%)
1 2 3 4 5 6
Glipizide
Years from randomization
~53% of patients required additional insulin therapy by year 6
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Patients with at least 1 macrovascular event before initiation (%)
Time to insulin initiation and incidence of complications are increasing
Median duration until insulin initiation (years)
Kotav K, et al, Diabetologia 2011; 54 Suppl.1)374
161514131211109876543216,0
6,5
7,0
7,5
8,5
8,0
9,5
9,0
“Ideal” & “Real Course” of “Treated” Type-2-Diabetes
Time (years after diagnosis)
HbA
1c (
%)
(First) cardiovascular evente.g. Myocardial Infarction New therapy attemptReal course
Ideal courseBuild-up ofmetabolic memory
Increasing the risk of diabetic
late complications
Del Prato, Diabetologia (2009) 52(7),1219- 122622
There is golden window period in diabetes; in first 3 - years
Glaritus 2012 23
Need for Insulin
EARLY INSULIN SAVES HEALTH; SAVES MONEY
Glaritus 2012 24
Insulin Usage
Number of diabetics using medication: 25-30 million
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
Oral products Oral/insulin Insulin
66% 7% 27%
Glaritus 2012 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
Disadvantages: NPH / Ultralente
Insulins*
@ Peak action profile
@ Unpredictable nocturnal
hypoglycemic episodes
@ High Inter-patient variability,
varying glycemic control
@ Multiple dosing-Decreased
patient compliance & Skin
reactions
Glaritus 2012 26
B DL HS
Insu
lin E
ffect
Bolus Insulin
Basal Insulin
Endogenous Insulin
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.
Normal Insulin Secretion: The Basal-Bolus Insulin Concept
Time of Administration
Glaritus 2012 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)
In type 2 diabetes patients with secondary failure to OHA: used in combination with OHA.
Glaritus 2012 28
Insulin regimen…
Twice-daily regimen• A biphasic insulin is injected twice a day (pre-breakfast and pre-
evening 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.
In type l, 2, and GDM patients when HbA1c is >9%
Glaritus 2012 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)
Glaritus 2012 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.
30
When adequate control is not achieved by premixed insulin alone.
Glaritus 2012 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
32 Glaritus 2012
Current Diabetes Therapy Falls Short
Inadequate control of Fasting Blood Glucose
Glaritus 2012 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
Glaritus 2012 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
Glaritus 2012 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
Fix the Fasting First !
Glaritus 2012 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
Glaritus 2012 37
Insulin Regimen: Balancing Act
Hypoglycemia
Can somebodyhelp me ??????
Hyperglycemia
Glaritus 2012 38
Basal Insulin Supplements
NPH
Insulin Detemir
Insulin Glargine
NPH has…..• Erratic absorption• Unfavorable plasma
insulin profiles with unwanted peaks
• Nocturnal hypoglycemia
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
Glaritus 2012 40
Basal Insulin Supplements
Basal Insulin Preparations
Onset (hours)
Peak(hours)
Duration(hours)
Remarks
NPH 2 – 4 6 – 10 10 – 16 • 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
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
Glaritus 2012 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
Insulin Glargine:21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin
Insulin Glargine: Structure
Arg Thr Lys
Tyr
Thr
Phe Phe Gly Arg GluGly
ValLeu
TyrLeuAlaGluVal
LeuHis
SerGly
LeuHis
Gln
Asp
ValPheB1
B30A1A21
ProCys
TyrGly
Glu
Cys
Gln
LeuGln
TyrLeuSerCys
CysThr Ser lle
Glylle
Asn
GluGln
Cys
Cys
GlyAsp
Substitution
ExtensionArg
pH = 4; Clear solution; Do not mix
WHAT HAPPENS AFTER GLARGINE INJECTION ?
Clear SolutionpH 4.0 S.c. Injection of
an acidic solution (pH 4.0)
Glargine
Capillary MembraneInsulin in Blood
pH 7.4
PrecipitationPrecipitation of glargine in subcutaneous tissue (pH 7.4)Dissolution
Hexamers Dimers Monomers10-3 M 10-5M 10-8 M Slow dissolution of
free glargine hexamers from precipitated GlargineProtracted action
Are all insulin analogs equally
effective?-Pharmacokinetics
and pharmacodynamics of insulin glargine
and insulin detemir in patients with type
1 diabetes.35 IU insulin; PG-Clamp 100 mg/dL X 24h
Duration of action : (PG < 150 mg/dL)
Insulin glargine: >24h
Insulin detemir: 17.5 hPorcellati et al, DIABETES CARE , 30,OCTOBER 2007
Glaritus 2012 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
Glaritus 2012 46
Changes of PK /PD in special patient population
Elderly patients Obesity – high subcutaneous fat slow the absorptionRenal dysfunction – 30 to 80% of insulin is removed by renal
excretionHepatic dysfunction – liver mainly controls hepatic glucose
output and uptakePregnancy – PK not altered but insulin resistance increased so
needing higher dose of insulinExercise –conditions causing greater blood flow( exercise, massage, hot bath ) is associated with rapid insulin
absorption
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
Insulin glargine: rapid and sustained glycemic control.
A 32 month extension of a 9 month, open label, uncontrolled, multicenter, observational study (n=12216)
- - - - - - - - - - -Mea
n H
bA1c
(%)
Months of treatmentInsulin glargine + OADs provides sustained glycemic control
Schreiber SA et al, Diabetes Techno Ther 2008; 10 121-7
Effect of insulin glargine on β-cell functionFirst 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
Insu
lin S
ecre
tion
(mU
/kg
per
min
)
Insu
lin S
ecre
tion
(mU
/kg
per m
in)
Pennartz C, et al, Diabetes Care 2011; 34-204
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,
24 weeks
Fulcher (2005) n=125,
30 weeks
Ashwell (2006) n=56,
32 weeks
Chatterjee (2007) n=53,
36 weeks
Porcellati(2004) n=121,
52 weeks
HbA1c reduction with insulin glargine in RCTs of varying duration and size
Lower risk of hypoglycemia for insulin glargine vs NPH at any level of HbA1c in T1DM
Meta-analysis of 5 randomized trails comparing insulin glargine and NPH in HbA1c in T1DM
Rat
e of
hyp
ogly
cem
ia (e
vent
s pe
r pat
ient
s-ye
ar)
HbA1c (%; LOCF)
Mullins P, et al, Clin ther 2007; 29; 1607-19
P=0004
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)
Significant better treatment satisfaction with glargine compare to lispro
Glargine Lispro
-1.9
-1.85
-1.8
-1.75
-1.7
-1.65
-1.6
-1.71
-1.87
Change in HbA1c
Difference=.157 95% Cl -.008 to 0.332
Overall Symptomatic Nocturnal Severe0
5
10
15
20
25
30
5.2 4.2
0.52 0.03
24
13.6
0.34 0.08
GlargineLispro
Hyp
ogly
cem
ic e
vent
s
Cha
nge
in H
bA1c
(%)
Bratzel RG et al Lancet 2008; 371:1073-8
THE LANCET
• The first clinically available long acting analog
• 42 million patient-years of experience
• 80,000 individuals in clinical development programs worldwide
• Available in over 100 countries
*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*
Setting standards for basal insulin therapy : The contribution of insulin glargine
Peak less, 24 hours insulin coverageEffective, sustained glycemic control with the low
incidence of hypoglycemia in clinical trail and in real life clinical practice.
Favorable impact on quality of lifeBenefits proven across a wide range of patients
populations in T1DM & T2DM.Easy to use, flexible titration algorithms12 years of clinical experience.Wealth of evidence to support a basal insulin treatment
regimen with insulin glargine.