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.