Insulin Therapy

in Type 2 Diabetes:
Current and Future
Directions
Issues in the Management of
Type 2 Diabetes

Type 2: Deterioration of beta cells over time

Increasing prevalence with increasing risk factors, eg, obesity

Hyperglycemia afects morbidity, mortality, and resorces

Tight glycemic control with inslin may redce costly

complications

!"# to $"# of patients ltimately re%ire inslin

&egimen'related limitations with crrent inslin formlations

and delivery systems

(ewer semisynthetic inslins and delivery systems may

improve compliance and achieve better glycemic control with
less hypoglycemia
Prevalence of Type 2 Diabetes
Mellitus
MMWR) *++,-$.:*"*$'*"*/)
29.8
25.2
20
25
30
35
1990 1992 1994
CDC NHIS Results
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Incidence of Type 2 Diabetes
Mellitus
MMWR) *++,-$.:*"*$'*"*/)
3.7
2.1
1
2
3
4
5
1990 1992 1994
CDC NHIS Results
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Ris Factors for Type 2 Diabetes
(onmodi0able

1enetic factors

2ge

3thnicity
4odi0able

5eight

6hysical activity
Trend in Prevalence of !besity":
#$%#&' Data
7c8marski &9, et al) JAMA) *++$-2,2:2":'2**)
;<4I 2,)! mg=m
2
for women- 2,)/ kg=m
2
for men
20
22
24
2
28
30
32
34
3
NH!S (190"
192)
NH#N!S I
(1971"1974)
NH#N!S II
(197"1980)
NH#N!S III$
(1988"1994)
%
S

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(in )et*een !besity and Type 2
Diabetes:
#urses+ $ealth 'tudy
>oldit8 12, et al) Ann Intern Med) *++:-*22:$/*'$/.)
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(in )et*een !besity and Type 2
Diabetes:
#urses+ $ealth 'tudy ,cont+d-
>oldit8 12, et al) Ann Intern Med) *++:-*22:$/*'$/.)
0
10
20
30
40
50
0
70
80
(22.0 22.0"24.9 25.0"28.9 29)
*+I (,-./
2
) at #-e 18 0ears
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4oss o5 5"10 ,-
4oss or -ain o5 4.9 ,- or less
6ain o5 5".9 ,-
6ain o5 7"10.9 ,-
6ain o5 11"19.9 ,-
6ain o5 20 ,- or /ore
%D% Treatment .uidelines
<iochemical IndeD (ormal 1oal 2ction Eggested
6reprandial glcose?+" mg=dF /"'*2" mg=dF ?/" or @*$" mg=dF
<edtime glcose ?*2" mg=dF *""'*$" mg=dF?*"" or @*."
mg=dF
Hb2
*c
?.#; ?,# @/#
;Depending on assay norms
Medical #utrition Therapy
for Type 2 Diabetes

Diet
G
Improved food choices
G
Epacing meals
G
Individali8ed carbohydrate
content
G
4oderate calorie restriction

3Dercise
Pharmacologic Therapy
for Type 2 Diabetes

Elfonylreas Aglybride, glipi8ide, glimepirideB

<iganides AmetforminB

2lpha'glcosidase inhibitors Aacarbose, miglitol,

vogliboseB

<en8oic acid analoges ArepaglinideB

Thia8olidinediones Atroglita8one, rosiglita8one,

pioglita8oneB

Inslin Ahman inslin, inslin analogesB

Treatment %lgorithm
(onpharmacologic therapy
4onotherapy
Elfonylreas=<en8oic
acid analoge
<iganide
2lpha'glcosidase
inhibitors
Thia8olidinediones
Inslin
>ombination therapy
Inslin
Hery symptomatic
Eevere hyperglycemia
7etosis
Fatent atoimmne
diabetes
6regnancy
Considerations in Pharmacologic
Treatment of Type 2 Diabetes

3Icacy AHb2
*c
lowering capacityB

4echanisms of action of drgs

Impact on weight gain

>omplications=tolerability

Jre%ency of hypoglycemia

>ompliance=compleDity of regimen

>ost
Tight .lycemic Control:
Reducing the Ris of
Complications

3pidemiologic evidence in type 2 diabetes to link

microvasclar disease and hyperglycemia K 0rst
sggested in D>>T

Type 2 diabetes stdies: Heterans 2fairs >ooperative

Etdy on Type 2 Diabetes AH2 >ED4B, Lnited 7ingdom
6rospective Diabetes Etdy AL76DEB, and 7mamoto trial
G
Intensive blood glcose control with inslin, slfonylrea, or
metformin redced risk of micro' and macrovasclar complications
G
1lycemic threshold to prevent onset and progression of
microvasclar complications: Hb2
*c
?.):#, J<1 ?**" mg=dF,
2'hr postprandial glcose ?*/" mg=dF
Improvement in $b%
/c
in the 0%
C'DM
P?")""* vs) placebo in intensive treatment grop
2braira >, et al) Diabetes Care) *++:-*/:***!'**2!)

7
8
9
10
0 3 9 12 15 18 21 24 27 30
+ont7s
H
$
#
1
8

(
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Stan1ar1
Intensi3e
0% C'DM: Results at &ndpoint
<aseline 3ndpoint P Hale
Hb2
*c
+)!# .)+# ?")""*
Jasting serm glcose 2". mg=dF **/ mg=dF ?")""*
Inslin dose 22)+ L *!!)" L
<lood pressre; *!.=/* mmHg *!,=/" mmHg
Total cholesterol; :)+ mg=dF :)2 mg=dF ")""!
HDF cholesterol; *)* mg=dF *)" mg=dF
FDF cholesterol; !): mg=dF !)$ mg=dF
Triglycerides; 2)! mg=dF 2)" mg=dF ")".
;&eslts at 2 years
2braira >, et al) Diabetes Care) *++:-*/:***!'**2!)
The 1umamoto Trial: &2ects of
Conventional vs3 Intensive Insulin
Therapy
Mhkbo N, et al) Diabetes Res Clin Pract) *++:-2/:*"!'**,)
32'
44'
28'
32'
7.7'
19.2'
7.7'
11.5'
0
10
20
30
40
50
&ri/ar9
&re3ention
Se8on1ar9
&re3ention
&ri/ar9
&re3ention
Se8on1ar9
&re3ention
Retinopat79 Nep7ropat79
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Con3entional
Intensi3e
41PD': &2ect of Intensive Therapy on
.lycemia
L76DE 1rop) Lancet) *++/-!:2:/!,'/:!)

7
8
9
10
0 1 3 5 7 9 0ears
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:&6; Con3entional (N<1138)
:&6; Sul5on9lurea (N<1573) or Insulin (N<115)
H$#18; Con3entional
H$#18; Sul5on9lurea or Insulin
41PD' /567ear Cohort Data: Reductions
8ith Intensive vs3 Conventional Therapy
L76DE 1rop) Lancet) *++/-!:2:/!,'/:!)
"'
"10'
"1'
(P< 0.052)
"25'
(P< 0.0099)
"12'
(P< 0.029)
"11'
"30
"20
"10
0
H$#18 #ll"Cause +ortalit9 Dia$etes"Relate1
Deat7
#n9 Dia$etes"
Relate1
Co/pli8ation
+9o8ar1ial
In5ar8tion
+i8ro3as8ular
Co/pli8ation
'ummary of 1ey Findings

H2 >ED4:
G
1lycemic control achievable with intensive inslin treatment: control
maintained @2 years
G
Intensive treatment not associated with severe hypoglycemia,
weight gain, hypertension, or dyslipidemia

7mamoto trial:
G
Intensive inslin treatment redced microvasclar complications
G
3stablished glycemic threshold to prevent onset and progression of
complications

L76DE:
G
Diet therapy alone inade%ate in two thirds of patients
G
6harmacologic therapy pls ntrition=eDercise necessary
G
5eigh bene0t:risk ratio
G
(o threshold for Hb2
*c
redction in redcing complications
G
Inslin does not increase macrovasclar disease
3fective
Mnset 6eak Dration
Inslin lispro ?*: min * hr ! hr
&eglar "):'* hr 2'! hr !'. hr
(6H=Fente 2'$ hr .'*2 hr *"'*. hr
Lltralente $'/ hr Haries */'2" hr
Pharmacoinetics of Current
Insulin Preparations
<arnett 2H, Mwens D&) Lancet) *++,-!$+:+,':*) 5hite 9&, et al) Postgrad Med) *++,-*"*::/',")
7ahn >&, Echechter N) In: Goodman and Gilmans The Pharmacological Basis of Therae!tics)
*++":*$.!'*$+:)
Clinical &9cacy of Insulin (ispro

5orldwide clinical trials of inslin lispro in

@*",""" patients with type * or type 2
diabetes

*'year parallel grop comparisons or .'month

crossovers A! months on each inslinB stdies
G
Dosage regimen: inslin lispro *" min before and
solble hman inslin !" to $: mintes before meals,
with (6H or ltralente inslin as the basal inslin
spplement
'trategies for Insulin Therapy in &lderly
Patients

Inslin therapy often considered a last resort in

the elderly

Therapetic goals:
G
&elieve symptoms
G
6revent hypoglycemia
G
6revent acte complications of hyperglycemia

5ays to facilitate inslin treatment:

G
Eimple dose schedles
G
6remiDed preparations
G
Improved, more convenient delivery systems
Combination Therapy:
!ral %gents Plus Insulin

&ationale
G
>ombination of two agents with diferent mechanisms of action
G
4ore convenient and may be safer

Elfonylrea O Inslin
G
<IDE therapy: bedtime inslin=daytime slfonylrea
G
Lsefl in patients early in corse of disease

4etformin O Inslin
G
Improves inslin sensitivity

2lpha glcosidase inhibitor AacarboseB O Inslin

G
Decreases postprandial glycemia

Thia8olidinediones O Inslin
G
Improves inslin resistance, improves inslin action in peripheral
tisses
G
&edces inslin re%irement
Meta6%nalysis of
'ulfonylurea:Insulin
Combination Therapy
9ohnson 9F, et al) Arch Intern Med" *++.-*:.:2:+'2.$)
= P( 0.05 3s. $aseline 3al ue
1.4
"0.
"0.25
0.8
"2.5=
"1.1=
"3
"2
"1
0
1
2
:asti n- Seru/ 6lu8ose
(/-.14)
H$#18 (') >ei-7t (,-)
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sSul5on9lurea ) Insuli n
Insulin @nl9
Comparison of Insulin Regimens
%mong !ral Treatment Failures
Nki'9arvinen H, et al) # $ngl J Med) *++2-!2,:*$2.'*$!!)
"0.9
"1.7=
2.2=
"1.9=
1.2= A
"1.8=
1.8=
"1.=
2.9=
"0.5
"4
"2
0
2
4

8
10
C7an-e in H$#18 (') >ei-7t C7an-e (,-)
= P( 0.001 3s. 8ontrol -roup
AP( 0.05 3s. ot7er insulin treat/ent -roups
+ornin- N&H (N< 32)
!3enin- N&H (N< 28)
BCi8e"1ail9 in2e8tions (N< 29)
+ultiple"1ail9 in2e8tions (N< 30)
Control (N< 30)
Total Direct Costs of Type 2
Diabetes
&athman 5) Dr!g Bene%t Trends) *++/-*":2$'2,)
15.
1.8
.2
37.2
0 10 20 30 40
&res8ription Costs
Nursin- Ho/e
@utpatient Care
Hospital
%S D *illions
Total Indirect Costs of Type 2
Diabetes
&athman 5) Dr!g Bene%t Trends) *++/-*":2$'2,)
27
11.2
8.5
0 10 20 30
+ortalit9
4on-"Ber/
+or$i1it9
S7ort"Ber/
+or$i1it9
%S D *illions
Ideal )asal Insulin

>losely mimic normal pancreatic basal inslin

secretion

(o distinct peak efect

>ontined efect over 2$ hors

&edce noctrnal hypoglycemia

Mnce'daily administration for patient

compliance

6redictable absorption pattern

3fective
Mnset 6eak Dration
Inslin lispro ?*: min * hr ! hr
&eglar "):'* hr 2'! hr !'. hr
(6H=Fente 2'$ hr ,'/ hr *"'*2 hr
Lltralente $ hr Haries */'2" hr
Inslin glargine; *'2 hr Jlat=6redictable 2$ hr
;Investigational
Pharmacoinetics of Current Insulin
Preparations Compared 8ith Insulin
.largine
<arnett 2H, Mwens D&) Lancet) *++,-!$+:+,':*) 5hite 9&, et al) Postgrad Med) *++,-*"*::/',")
7ahn >&, Echechter N) In: Goodman and Gilmans The Pharmacological Basis of Therae!tics)
*++":*$.!'*$+:)
>oates 62, et al) Diabetes) *++:-$$AEppl *B:*!"2)
'tructure of Insulin .largine:
% #e* (ong6%cting Insulin
%nalogue

4odi0cations to hman inslin chain

G
Ebstittion of glycine at position 22*
G
2ddition of two arginines at position <!"
G
Lni%e release pattern from inCection site
*
*
*: *" :
: *" *: 2"
2" 2sn
2: !"
1ly
2rg 2rg
Ebstittion
3Dtension
Characteristics of Insulin
.largine

3glycemic clamp stdies vs) (6H

G
Emooth continos release from inCection site
G
Fonger dration of action
G
>ontined efect at end of 2$'hor clamp stdy

(o diferences in the absorption rate from arm, leg,

or abdominal sites

(o inPammatory reactions at any of the inCection

sites

Jlat inslin pro0le

2s efective in lowering J61 levels as (6H inslin,

with signi0cantly redced noctrnal hypoglycemia
)lood .lucose Pro;le of Insulin
.largine in #ormal 0olunteers
Mwens D&, et al) Diabetologia) *++/-$*Asppl *B:22$:)
70
75
80
85
90
95
100
105
110
"0.5 1 3 9 12 15 18 21 24
Bi/e (7r)
C
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N&H Insuli n -lar-ine (15 E- Fin8) Insul i n -lar-i ne (80 E- Fin8)
&<ogenous Insulin Concentration
of Insulin .largine in #ormal
0olunteers
Mwens D&, et al) Diabetologia) *++/-$*Asppl *B:22$:)
0
25
50
75
0 2 4 8 10 12 14 1 18 20 22 24
Hours a5ter i n2e8tions
!
G
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N&H Insulin -lar-i ne (15 E- Fin8) Insulin -lar-ine (80 E- Fin8)
&9cacy of Insulin .largine
in Type / and Type 2 Diabetes
&askin 6, et al) 6resented at 2D2 :/th 2nnal 4eeting) *++/:2bstract "$"$)
&osenstock 9, et al) 6resented at 2D2 :/th 2nnal 4eeting) *++/:2bstract "!:,)
&PQ")"""*
I/pro3e/ent in :&6 #5ter 4 >ee,s
"50.4
"41.4
"14.4
"4.8
"52.2=
"0
"40
"20
0
Insulin
-lar-ine
N< 18
N&H
N< 88
Insulin
-lar-ine
(30 E-
Fi n8)
N< 55
Insul in
-lar-i ne
(80 E-
Fin8)
N< 51
N&H
N< 49
B9pe 1 B9pe 2
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'afety of Insulin .largine
in Type / and Type 2 Diabetes

Type * Diabetes
G
Eimilar incidence of hypoglycemia between inslin
glargine and (6H after $ weeks of treatment
G
6attern of adverse events and inCection site reactions
also similar

Type 2 Diabetes
G
(o diference in fre%ency of hypoglycemia from (6H
G
(o change in body weight
!ther (ong6%cting Insulin
%nalogues

1lycemic obCectives:
G
6rovide constant, reprodcible spply of basal inslin
G
2de%ately sppress hepatic glcose prodction

(ovoEol <asal
G
Jirst long'acting inslin analoge
G
Discontined becase of local inPammatory reactions

In development
G
Di'arginyl hman inslin analoge A1ly, 2rgB
G
>*. fatty'acid'acylated analoge
#eed for #ovel Delivery 'ystems of
Insulin

Disadvantages of conventional sbctaneos inCection:

G
Discomfort
G
Inconvenience
G
Eystemic delivery
G
Inconsistent pharmacokinetics
G
Irreversible after inCection

Inslin pmps: too compleD, limited eDperience and

tility with type 2

Inslin pen: bene0cial bt ndertili8ed

Eystems in clinical testing

G
Inhaled formlation
G
9et'inCected systems
Insulin Pump

>EII: ses portable infsion pmp connected to

an indwelling sbctaneos catheter to deliver
short'acting inslin

II6 shown to have signi0cant advantages over

mltiple daily inCections
G
&edces glycemic variability, clinical hypoglycemia,
weight gain
G
3Dtreme for rotine practice bt may be sefl in
special circmstances
G
(ot crrently available in the Lnited Etates
Insulin Pump
Insulin Pen

<ene0ts
G
4ore accrate dosing mechanisms
G
Jaster and easier than conventional syringes
G
Improved patient attitde and compliance

2dvantages of newer inslin pens

G
F>D display to show dosage setting
G
Dosage settings change %ickly and easily
G
Eafety btton atomatically resets after drg delivery
Insulin Pen
Inhaled Insulin Formulations
1elfand &2, et al) 6resented at 2D2 :/th 2nnal 4eeting) *++/:2bstract "2!:)
C7an-esin 6l 98e/i8 &ara/eters
"50
"45
"40
"35
"30
"25
"20
"15
"10
"5
0
H$#18 2"7r &6
'

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In7al e1 7u/an insuli n
Su$8utaneousl9 i n2e8te1
insuli n
Continuous .lucose 'ensors

5hen available, may provide only mechanical

means of achieving RnormalS glcose
homeostasis

5ill direct inslin delivery atomatically on

demand ARclosed loopSB

Mne technology ses reverse iontophoresis to

noninvasively eDtract and measre glcose
levels

Technical challenge to develop

Conclusions

Type 2 diabetes: gradal deterioration of glycemic control

Eigni0cant morbidity and mortality- tight glycemic control redces

risk of complications

3arlier instittion of inslin may help attain initial glycemic control

MbCectives of inslin therapy:

G
2chieve normal fasting glcose levels
G
2chieve normal postprandial glcose levels
G
4inimi8e hypoglycemia

Intensive inslin therapy shold:

G
6rovide good glycemic control
G
6rodce little hypoglycemia
G
Improve lipid pro0le
G
&edce risks and costs of treating complications
Conclusions ,cont+d-

(ew delivery systems:

G
&edce limitations of conventional inslin syringes
G
Improve patient compliance and disease
management

(ew long'acting inslin analoges Aeg, inslin

glargineB:
G
6rodce Pat inslin pro0le with no peaks
G
2llow once'daily administration
G
Eigni0cantly redce noctrnal hypoglycemia