early insulin initiation

EARLY INSULIN INITIATION: does it really matter ?

Dr SANJAY KALRA, D.M. (AIIMS)

04/11/23 www.bhartihospital.com 2

AGENDA

1) Present burden of hyperglycemia

2) Definition of early insulin initiation

3) Mechanisms of glucotoxicity

4) Why intensive glucose control ?

5) Why insulin ?

6) Why early insulin ?

7) A suggested strategy


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

http://images.google.co.in/imgres?imgurl=http://www.faluninfo.net/torturemethods2/children/Why_big.jpg&imgrefurl=http://www.faluninfo.net/torturemethods2/children/&h=1263&w=1000&sz=258&tbnid=Hs5FzjT_NKVYWM:&tbnh=150&tbnw=118&hl=en&start=13&prev=/images%3Fq%3Dchildren%26svnum%3D10%26hl%3Den%26lr%3D


Diabetes in clinical reality – Europe & USA

Mean HbA1c (%)2

(US)

1 Massi-Benedetti M. Diabetologia 2002;45: S1-4 (CODE-2). 2 Koro CE. Diabetes Care 2004; 27:17-20 (NHANES)

Patients receiving lifestyle advice, OADs or insulin

7.7 7.9

0

6

7

8

9

1988-1994 1999-2000

Belg

ium

France

Germ

any

Italy

Holla

nd

Sp

ain

Sw

ed

en

UK

Tota

lm

ean

8

7

6

5

4

0

Mean HbA1c (%)1

ADA target 7%


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

1 y 44%

2 y 68%

3 y 79%

4 y 85%

% of patients given oral therapy intensification

1 y 8%

2 y 20%

3 y 32%

4 y 42%

% of patients given insulin therapy

1 y 2%

2 y 8%

3 y 14%

4 y 20%


A1c/ THERAPY CHANGE IN PATIENTS

0

10

20

30

40

50

60

70

80

90

YEAR 1 Y2 Y3 Y4

A1c>8

OAD+

insulin


Early insulin can never be too early!

EARLY INSULIN SAVES HEALTH; SAVES MONEY

Fight clinical inertia


•Om Prakash, 38 year old tailor, presented in 1999

• Put on glibenclamide 2.5 mg BID .A1c of 7.8%

•Over the subsequent 6 years glibenclamide incr to 10 mg BID

•A1C is 10% . Urine ketones –ve

•Was given metformin in 2000, but stopped on his own

•Weighs 70 Kg. BMI 24. weight loss 20 kg/4 yrs

•Numbness and tingling in lower limbs x 2 yrs

•Balanoposthitis x 3 mths


AGENDA





5) Why insulin ?




Is intensifica

tion of therap

y indicated ?

Is insulin ind

icated ?

Is insulin MAN

DATORY ?

Is insulin the

drug of choic

e ?

Was insulin in

dicated earlie

r ?

Were /are the

re ‘windows of

opportunity’

for insulin i

nitiation ?


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

Time

Beta cellfunction

Chronic,gradual decline

Sudden, acute, ?reversible declineDue to physical/mental stress


THE NATURAL HISTORY OF DIABETES

Time

Beta cellfunction

Chronic,gradual decline

Sudden, acute, ?reversible decline

Elective/intermittent insulin

Inevitable/long terminsulin


AGENDA



3) Mechanisms of beta cell dysfunction


5) Why insulin ?




•Se cholesterol : 245 mg%, se triglycerides 240 mg%

•se creatinine 1.6 mg%

•Urine r/e: 10 - 15 pus cells

•Metformin was added in 2000, but stopped

•on his own

•He recently lost his father

•WHY HAS THE H

bA1c WORSENED

?

•WILL THE PATIE

NT NEED INSULI

N ?

•WILL HE NEED P

ERMANENT INSU

LIN ?


Terminology

• Beta cell exhaustion• Beta cell

desensitization

• Temporary • Can recover with short

period of normoglycemia• Beta cells need rest from

sulfonylureas

• Beta cell failure

• ?permanent• Apoptosis has occurred• Beta cells need

permanent support


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





5) 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 (2h)

<140 <155** <180** <140

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

* DCCT-referenced assays- Normal Range 4-6%; ** Peak value


Target A1c


AGENDA





5) Why insulin ?




•WILL OHAs ACT

?

•WILL OHAs ACT

EFFICIENTLY ?

•WILL OHAs REAC

H THE TARGET ?

•IS METFORMIN T

HE DRUG OF CHO

ICE ?

•HOW WILL INSUL

IN HELP ?


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


0

0

40

60

80

Bet

a-ce

ll fu

nct

ion

(%

)

20

2 4 6Years from diagnosis

0

0

40

60

Insu

lin s

ensi

tivi

ty (

%)

20

2 4 6

Patients with diet failure 5–7 years after diagnosis

β-cell defect vs insulin resistance

Levy J et al. Diabet Med 1998;15:290

β-cell defect more progressive than insulin resistance

Target

β-cell

decline

04/11/23 www.bhartihospital.com

• Endogenous insulin production decreases as the disease progresses

• At diagnosis, only 50% of beta-cell function remains (UKPDS, Diabetes 1995)

• At FPG >140, only 25% of beta cell function remains

Polonsky KS et al. New Engl J Med 1988; 318:1231–1239.

Time

0600 1000 1400 1800 2200 0200 0600

800

700

600

500

400

300

200

100Insu

lin s

ecr

eti

on (

pm

ol/m

in)

Healthy individuals

0

Patients with type 2 diabetes

Blunted 1st phase insulin secretion


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 -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





5) Why insulin ?




•BP 160 /110 mm Hg

•Bl urea 46 mg%, urine albumin +

•ECG non-specific changes, TMT mildly positive

•Biothesiometry : mean VPT 30 mV both feet

•Should insulin

have been sta

rted earlier ?

•How can we mot

ivate the pati

ent ?


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

response (AIR) with aspart in 20

new onset T2 DM patients showed

reduction of PPBG increment to

non diabetic levels.

Gredal C et al: Diabetologia 48

S1,Aug 2005.

Time

0600

1000

1400

1800

2200

0200

0600

800700600500400300200100

Insu

lin s

ecr

eti

on

(pm

ol/m

in)

Healthy individuals

0

Patients with type 2 diabetes


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





5) Why insulin ?




How should we

treat this pat

ient ?

Are there any

dangers in adv

ising insulin

?

How should we

counsel this p

atient for ins

ulin ?

Which complica

tions will he

be worried abo

ut ?

(tailor; young

44 male; infe

ction; no fath

er)


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

Basal once-daily start*

Premix once- daily start*

Disease progression

Increasing inability to produce insulin

*continue with appropriate OAD


Strategies for initiation of insulin therapy

Basal once daily start*

Premix once daily start*

Increasing need to cover PPGDisease

progression

MDIBasal bolus

therapy

Intensification

Premix twice-daily

MDIBasal bolus

therapy

Intensification

Premix three- times daily

*continue with appropriate OAD

MDI: Multiple Daily Injections


INDICATIONS OF EARLY INSULIN

– Preconception– Pregnancy– Ketosis, HHNKC,

lactic acidosis– OHA failure– Renal/hepatic

compromise

– Impending OHA failure– Intercurrent illness:

trauma, infection, stroke, MI, frozen shoulder, foot, p vulvae, balanoposthitis

– Asthenia/ sudden weight loss

– Newly diagnosed diabetes


A person with diabetes will eventually find a diabetologist who fits his/her style.

diabetologist

Patient insulin patientpatient

diabetologist insulin


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• Pre-empt the

complication• Act before it’s too

late: pre-empt OHA failure

• Prevent apoptosis of -cells

Don’t be reactive

BE PROACTIVE


Let us all speak the same language:

EARLY INSULIN INITIATION

DOES MATTER

& CERTAINLY HELPS


Be dynamic. Be proactive.Innovate constantly. Upgrade constantly

FOR OUR PARENTS, and FOR US

early insulin initiation

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