Early Insulin Initiation

EARLY INSULIN INITIATION:
does it really matter ?
Dr SANJAY KALRA, D.M. (AIIMS)

AGENDA
• Present burden of hyperglycemia

• Definition of early insulin initiation
• Mechanisms of glucotoxicity
• Why intensive glucose control ?
• Why insulin ?
• Why early insulin ?
• A suggested strategy
08/24/08 www.bhartihospital.com 2
BURDEN OF UNTREATED
HYPERGLCEMIA
• By the time insulin is

begun, the average
patient accumulates 5
years of HbA1c > 8%
and 10 years of HbA1c
>7%
• Brown JP, et al. Diab
Care 2004; 27 : 1535 -40
Diabetes in clinical reality – Europe & USA
Mean HbA1c (%)1 Mean HbA1c (%)2
8
(US)
7 9
ADA
6 target 8
7%
5 7
7.7 7.9
4 6
0 0
Belgium
Sweden
Germany
Holland
mean
France
Total
Italy
1988-1994 1999-2000
UK
Spain
Patients receiving lifestyle

advice, OADs or insulin
1
Massi-Benedetti M. Diabetologia 2002;45: S1-4 (CODE-2). 2
Koro CE. Diabetes Care 2004; 27:17-20 (NHANES)
UK GENERAL PRACTICE RESEARCH DATA
• 2200 patients treated with Met for > 3 m before initiating Met + SU
were studied in UK . Age 62 yrs.(31-96 yrs) 54% men Duration of
diabetes 3-8 yrs. (1.9 - 6.9 yrs)
• Mean A1c 8.8 %
• Annualized increase in A1c 0.32% from 3 y to 6 m before met + SU
1.21% from 6m to 0 m before met + SU

A1c ↓ 8.8 % to 7.3 % at 6 mths post – SU
• After 6 mths, A1c again rose by 0.61%
(Cook MN et al, 2005)

NEED FOR INTENSIFICATION
• In n = 2220, over person years =3810
123 started insulin
155 added 3rd OHA
155 switched one OHA
Mean A1c 9.5 % at time of therapy intensification
Mean time from A1c >8.0 % to intensification : 331 days (143 -582)
Similar results at 4207 person - years follow – up.
% patients with A1c ≥ 8% after SU addition
1y 44%
2y 68%
3y 79%
4y 85%
% of patients given oral therapy intensification
1y 8%
2y 20%
3y 32%
4y 42%
% of patients given insulin therapy
1y 2%
2y 8%
3y 14%
4y
08/24/08 20% www.bhartihospital.com 7
A1c/ THERAPY CHANGE IN PATIENTS
90
80
70
60
50 A1c>8
40 OAD+
30 insulin
20
10
0
YEAR 1 Y2 Y3 Y4
Early insulin can never be too early!
EARLY INSULIN SAVES HEALTH; SAVES MONEY

Fight clinical inertia
i n 1 9 9 9
r e s e n t ed
d ta i l o r, p f 7 . 8 % BID
ye a r o l .A 1 c o o1 0 mg
s h , 3 8 m g B I D i n c r t
ka 5 ide
Om Pra benclamide 2. r s g lib e n c l a m
g l i 6y e a n
Put on u bse q u e n t
es – v e d on h i s ow
th e s k e t o n t op p e
Over . U r i n e 0 0 , b u ts y r s
s 1 0 % i n 2 0 k g / 4
•A1C i e tf o r m in
gh t l o s s 20
s g i ve nm 2 4 . w e i 2 y rs
•W a g . BM I l i m bs x
7 0 K lo w e r
•Weighs nd tingling in
b n e s s a th s
•Num ti s x 3 m
p o s th i
•Balano
AGENDA

• Why insulin ?
a t e d ?
i ndi c
her a p y
o f t
f i c a t ion c a t e d ?
i n t e nsi l i n i ndi ?
Is s i n s u A T O R Y
I
l i n M AND i c e ?
s u f c h o
Is in d r u g o
n t h e
s i n s uli r ?
I ea r l i e
d i c a t e d
r t u n i ty’
u l i n in o f o p po
s ws
Was in r e ‘ w i n d o
t i o n ?
e t h e n iti a
/ a r i n i
Were o r i n sul
f
DEFINITION
• A. Insulin at diagnosis of type 2 diabetes

• B. Insulin before β cell failure.
• Insulin before secondary OHA failure.
• Insulin at half –maximal OHA dose failure.
• C. Insulin when 2 drugs fail.
• Insulin when 3 drugs fail.
• D. Insulin for short term/ to correct glucotoxicity.
THE NATURAL HISTORY OF DIABETES
Sudden, acute, ?reversible decline

Due to physical/mental stress
Beta cell
function
Chronic,gradual decline
Time
THE NATURAL HISTORY OF DIABETES
Elective/intermittent insulin
Sudden, acute, ?reversible decline
Beta cell
function
Chronic,gradual decline
Inevitable/long term
insulin
Time
AGENDA

• Mechanisms of beta cell dysfunction
• Why insulin ?
40 m g %
c e r i d es2
, s e t r igly
2 4 5 m g%
l e s t e r o l:
•Se cho i ne 1 . 6 m g%
c r e a ti n u s c e l ls s t o p p ed
•se 1 0 - 1 5p 0 0 0 , b ut
/e: n2
•Urine r w a sa d d e d i
i n
•Metform n
n h i s o w i s fa t h er
•o l y l o st h
n t
•He rece S E N E D ?
c WO R
T H E H b A 1
N S U L I N ?
H Y H AS T N E E D I I N ?
•W PA T I E N I N S U L
L T H E A N E N T
•WIL E D P E RM
L H E NE
•WI L
Terminology
• Beta cell exhaustion • Beta cell failure
• Beta cell
desensitization • ?permanent
• Apoptosis has occurred
• Temporary • Beta cells need
• Can recover with short permanent support
period of normoglycemia
• Beta cells need rest from
sulfonylureas
GLUCOTOXICITY
• Acute or chronic adverse effects of hyperglycemia on cellular

structure and function.
• Glucose reacts non specifically with structural, metabolic and
immune components of tissues.
• Alterations :
basement membrane thickening
protein glucation
microtubule function
contractile apparatus
cellular immunity
cell growth differentiation
BIOCHEMICAL ABNORMALITIES
• Beta cell dysfunction is worsened by glucotoxicity

 β cell exhaustion
 β cell desensitization –(Robertson RP, et al .
Diabetes 2003; 52 :581-87)

 ROS -(Grankvist K et al, Biochem J,
1981;199;393-98)
 FFA -(Shimabu Koro et al , PNAS
1998:95;2498-2502)
MECHANISMS OF BETA CELL
DYSFUNCTION
• Reduced beta cell mass*
– Increased apoptosis
– Decreased regeneration
• Glucotoxicity#
• Lipo toxicity#
• Beta- cell exhaustion*#
• Amyloid deposition*
• Oxidative stress#
• * = worsened by sulfonylurea administration
• # = improved by insulin
PREDICTORS OF EARLY INSULIN USE
• high A1c
• younger age
• lower BMI
• white race
• high se creatinine
• short duration of disease at time of 2nd OHA addition
• ex – smoking
Donnan PT et al, 2002, Matthews DR et al, 1998,

Cook MN et al, 2005
AGENDA

• Why insulin ?
Glucose control : recommended goals
Measurement Normal IDF ADA AACE
A1c* <6% <6.5% <7% <6.5%

Preprandial <100 <110 90-130 <110
Postprandial <140 <155** <180** <140
(2h)
* DCCT-referenced assays- Normal Range 4-6%; ** Peak value
•Realistic Target--- Lowest A1c possible without unacceptable adverse effects
. 08/24/08 www.bhartihospital.com 24
Target A1c
AGENDA

• Why insulin ?
A C T ? Y ?
O H A s I E N T L
•WILL C T E F FIC T ?
H A s A T A R G E
•WILL O s REACH THE O F C H O I CE ?
O H A R U G
•WILL I N T H E D
M E T F ORM H E L P ?
•IS I N S U LIN
O W W I LL
•H
ESTIMATED IMPROVEMENT WITH OHAs
Drug HbA1c (%) FBG (mg%)

SU 1.5 – 2 50-60
Met 1-2 50-60
Pio 0.6-1.9 55-60
Rosi 0.7-1.5 55-60
Repaglinide 1-2 30-40
ESTIMATED IMPROVEMENT WITH OHAs
Drug HbA1c (%) FBG (mg%)
Acarbose 0.5-1 20-30
SU + met 1.7 65
SU + pio 1.2 50
Pio +met 0.7 40
Insulin Open to target

Roenstock J,2001
LIMITATION OF OHAs
• Take home:
• One can not reduce A1c by >2% or FBG by >100 mg%

even with maximal doses of OHAs
• Any patient with A1c > 8% or prolonged FBG >200 mg%

(without obvious reason) should receive insulin
β-cell defect vs insulin resistance
Patients with diet failure 5–7 years after diagnosis
β-cell defect more progressive than insulin resistance
80 60
Insulin sensitivity (%)

60
Beta-cell function (%)
40
40
20
20
r g et
Ta ell
β-c ine
e c l
0 0 d
0 2 4 6 0 2 4 6
Years from diagnosis
08/24/08
Levy J et al. Diabet Med 1998;15:290 www.bhartihospital.com 31
Blunted 1st phase insulin secretion
Healthy individuals
Patients with type 2 diabetes
800
Insulin secretion (pmol/min)
• Endogenous insulin
700
production decreases as
600 the disease progresses
500 • At diagnosis, only 50%
of beta-cell function
400 remains (UKPDS,
300 Diabetes 1995)
200 • At FPG >140, only 25%

of beta cell function
100 remains
0
0600 1000 1400 1800 2200 0200 0600
Time
08/24/08 www.bhartihospital.com
Polonsky KS et al. New Engl J Med 1988; 318:1231–1239.
BENEFITS OF INSULIN
• Avoidance of polypharmacy
(Turner RC et al,1995)
• Avoidance of drug interactions
• Restoration of insulin sensitivity
(Scarlett JA et al, Diab Care 1982;5. 353- 63)

• Improvement in lipid profile
(Romano G et al, Diabetes 1997;46 :1653 -9)
ADVANTAGES OF INSULIN
• Anabolic effect
• Cardioprotective and neuroprotective effect
 reduced neuronal necrosis
 reduced ischemic damage
• Anti inflammatory
 ↓ NF-KB, Egr -1, AP -1
 ↓ ROS generation
 ↓ ICAM -1, MCP -1 ↓ VEGF
 ↓ free fatty acids
PROTECTION AGAINST APOPTOSIS
• Exogenous insulin suppresses β-cell activity; decreases
antigen expression
• Induces immunotolerance to islet antigens
• Regulates IL-4 responsive pathway thru’ common

receptor pathway with IL-4, thus correcting Th1/Th2
imbalance
SUMMARY
• Insulin can meet HbA1c targets in all patients (if used
judiciously)
• Insulin focuses on beta cell dysfunction; protects vs.

apoptosis
• Insulin also corrects insulin resistance
• Insulin (analogues) cover 1st phase defects
• Insulin has pleiotropic effects: neuro, cardio, antiinflam
AGENDA

• Why insulin ?
m m H g i n + e
0 / 1 1 0 a l b u m p os i t i v
•BP 16 g % , u rine T m i l d ly
r e a 4 6 m n g e s , TM t h f e e t
•Bl u i f i c ch a m V b o
o n-s p e c V PT 3 0
•EC G n :m ea n
e tr y
i o t h e s i om
e a r l i er ?
•B
n sta rted
b e e
l i n h av e
a t i e n t ?
o u l d insu a t e t he p
•Sh w e m otiv
n
•How ca
RATIONALE OF EARLY INSULIN USE
• Beta cell dysfunction begins before onset of hyperglycemia

• Therefore, insulin given at time of diagnosis is not too early
 ↓ proinsulin to insulin
 altered patterns of insulin secretion
 ↓ insulin secretion
 all can be corrected by early insulin initiation
FIRST PHASE DEFECT
CORRECTED BY INSULIN
• Substitution of Ist phase insulin
Healthy
individuals
Patients with response (AIR) with aspart in 20
8 type 2 diabetes
new onset T2 DM patients showed
0
7
0
0 reduction of PPBG increment to
60
0
Insulin secretion
0
50 non diabetic levels.
0
40
(pmol/min)
0
30
0
20
0
10 Gredal C et al: Diabetologia 48
00
S1,Aug 2005.
06 10 14 18 22 02 0
00 00 00 Ti00 00 00 600
m
08/24/08 e www.bhartihospital.com 40
BENEFITS OF EARLY INSULIN USE
• Intensive insulin 0.6 U/kg/d x 2 weeks induced a long ‘remission’ upto 13 months,
during which diet alone was sufficient to maintain euglycemia.
Ilkova et al, Diab Care 1997; 20 : 1353-6
Ryan EA et al, Diab Care 2004; 27 :1028
Sellers EA et al, J Pediatr Endo. Met 2004; 17 :1561-64
Sahay et al, Hyderabad; Seshiah et al, Chennai
Best response in young (20-35 y old) obese males:
personal experience
Insulin preserves the surviving β cells (25%) instead of whipping them.
BENEFITS OF INSULIN
• Early insulin better than glibenclamide in
↓HbA1c, ↓ FBG ,↑ C peptide, ↑plasma insulin.

(Abivarrson M et al, Diab Care 2003:262:231-7)
EDIC STUDY
• Epidemiology of Diabetes Interventions and Complications (EDIC)

study.
• Multicentre, longitudinal observational study
• 28 centres
• 10 year follow up
• Intensive (early control) vs. late control (conventional control cohort
of DCCT offered intensive control at the end of DCCT)
EDIC STUDY
• At end of study, both groups had similar HbA1c

• Reduction in risk of progressive retinopathy and nephropathy
resulting from intensive therapy persists x > 4 years , despite
increasing hyperglycemia.
• Lower rise in microalbuminuria in intensive group.
• Less progression of carotid IMT in intensive group.
• EARLY INITIATION OF INTENSVE THERAPY HAD AN EFFECT
ON COMPLICATION RATE EVEN THOUGH A1c WAS NOT
DIFFERENT IN BOTH GROUPS
UKPDS 57 STUDY
• Early insulin use, prior to β cell failure helped in

 preserving and sustaining β cell secretory capacity
 achieving smoother, better glycemic control
 lowering incidence of hypo
 Causing less weight gain
EARLY INSULIN
• Adult T2 DM with HbA1c 7.5% -11% on 0,1 or 2 OADs were

allocated to addition of glargine (206) or optimization of OAD (199)
for 24 weeks.
• HbA1c ↓ in glargine group by 1.55% vs 1.25%.
• FBG ↓ by 72.4 mg% in insulin vs 42.9 mg% in OAD group .
• Incidence of hypo same in both groups.
Yale JF et al Diabetologia 48 S1,Aug 2005.
EARLY INSULIN
• 308 T2 DM not controlled on 2 drugs randomized to 3

groups:
• BIAsp tds; BIAsp bd + met ; OADs.
• ↓ HbA1c: -2.88 %, -3.015% ,-2.055%. ( signif diff)
• ↓ Mean BG: -109.92 mg%,-97.09 mg%, -64.91mg%

(signif diff) Diabetologia 48 S1,Aug 2005
AGENDA

• Why insulin ?
i e n t ?
i s pa t
e at t h
e t r
s h o u ld w l i n ?
Ho w g i n s u
i dvisin
n a
e r s
a n y dang i n su l in ?
ere for
Are th s p a ti e n t
a b ou t ?
u ns e l thi
e w o r ried
u ld we co wi l l he b
o ions
How sh mp l ic a t
n o f a t her)
co on;
Which ; in f e c t i
m a l e
; y o u ng 44
r
(tailo
WHICH STRATEGY ?
• Early insulin use
The optimal strategy undefined
At what time ? Which regime ?

 basal
 premixed
 basal-bolus
 combination
Strategies for initiation of insulin therapy
Disease progression
Increasing inability to produce insulin
Premix once-
daily start*
Basal once-
daily start*
*continue with appropriate OAD
Strategies for initiation of insulin therapy
Increasing
need to
Disease cover PPG
progression
Intensification Intensification
Premix once
daily start* Premix twice- Premix three-
daily times daily
MDI MDI
Basal once
Basal bolus Basal bolus
daily start*
therapy therapy
*continue with appropriate OAD
08/24/08 MDI: Multiple Daily Injections

www.bhartihospital.com 52
INDICATIONS OF EARLY INSULIN
– Preconception – Impending OHA failure

– Pregnancy – Intercurrent illness:
– Ketosis, HHNKC, trauma, infection,
lactic acidosis stroke, MI, frozen
– OHA failure shoulder, foot, p
– Renal/hepatic vulvae, balanoposthitis
compromise – Asthenia/ sudden
weight loss
– Newly diagnosed
diabetes
A person with diabetes will eventually find a
diabetologist who fits his/her style.
diabetologist
diabetologist insulin
insulin patient
Patient
A FEW TIPS
• Empowerment
• Transfer of ownership
• Long duration of ‘contemplation’ mode
• Positive communication
 verbal
 non verbal
• Positive communication
 All diabetes care team members
EFFECTIVE COMMUNICATION
• Emphasize control
• Emphasize need for good health
• Prevention is better than cure
• Search for ‘felt needs’
• Search for ‘windows of opportunity’
• Search for situation with ‘high index of perceived severity’
• ADVISE, USE and ENCOURAGE INSULIN AS EARLY AS
POSSIBLE
PREVENTION IS BETTER THAN CURE
• Pre-empt the illness Don’t be reactive

• Pre-empt the
complication
• Act before it’s too
late: pre-empt OHA
failure
BE PROACTIVE
• Prevent apoptosis of
β-cells
Let us all speak the same language:
EARLY INSULIN INITIATION
DOES MATTER
& CERTAINLY HELPS
Be dynamic. Be proactive.
Innovate constantly. Upgrade constantly
08/24/08 www.bhartihospital.com
FOR OUR PARENTS, and FOR US 59

Early Insulin Initiation

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EARLY INSULIN INITIATION:

does it really matter ?

Dr SANJAY KALRA, D.M. (AIIMS)

• Present burden of hyperglycemia

• By the time insulin is

Patients receiving lifestyle

1.21% from 6m to 0 m before met + SU

(Cook MN et al, 2005)

• In n = 2220, over person years =3810

123 started insulin

155 added 3rd OHA

155 switched one OHA

Mean A1c 9.5 % at time of therapy intensification

Similar results at 4207 person - years follow – up.

% of patients given oral therapy intensification

% of patients given insulin therapy

EARLY INSULIN SAVES HEALTH; SAVES MONEY

• Present burden of hyperglycemia

• A. Insulin at diagnosis of type 2 diabetes

Sudden, acute, ?reversible decline

Sudden, acute, ?reversible decline

• Present burden of hyperglycemia

• Acute or chronic adverse effects of hyperglycemia on cellular

• Beta cell dysfunction is worsened by glucotoxicity

 β cell desensitization –(Robertson RP, et al .

Diabetes 2003; 52 :581-87)

Donnan PT et al, 2002, Matthews DR et al, 1998,

• Present burden of hyperglycemia

Measurement Normal IDF ADA AACE

A1c* <6% <6.5% <7% <6.5%

•Realistic Target--- Lowest A1c possible without unacceptable adverse effects

• Present burden of hyperglycemia

Drug HbA1c (%) FBG (mg%)

Pio 0.6-1.9 55-60

Rosi 0.7-1.5 55-60

Repaglinide 1-2 30-40

Drug HbA1c (%) FBG (mg%)

Acarbose 0.5-1 20-30

Pio +met 0.7 40

Insulin Open to target

• One can not reduce A1c by >2% or FBG by >100 mg%

• Any patient with A1c > 8% or prolonged FBG >200 mg%

Insulin sensitivity (%)

200 • At FPG >140, only 25%

(Scarlett JA et al, Diab Care 1982;5. 353- 63)

(Romano G et al, Diabetes 1997;46 :1653 -9)

 reduced ischemic damage

 ↓ ICAM -1, MCP -1 ↓ VEGF

 ↓ free fatty acids

• Regulates IL-4 responsive pathway thru’ common

• Insulin focuses on beta cell dysfunction; protects vs.

• Insulin also corrects insulin resistance

• Insulin (analogues) cover 1st phase defects

• Insulin has pleiotropic effects: neuro, cardio, antiinflam

• Present burden of hyperglycemia

• Beta cell dysfunction begins before onset of hyperglycemia

 altered patterns of insulin secretion

 all can be corrected by early insulin initiation

Ilkova et al, Diab Care 1997; 20 : 1353-6

Ryan EA et al, Diab Care 2004; 27 :1028

Sellers EA et al, J Pediatr Endo. Met 2004; 17 :1561-64

Sahay et al, Hyderabad; Seshiah et al, Chennai