Diabetes is a global diseaseEstimated global prevalence of diabetes

20102013

382 million

2035

592 million

2015

387 million

1. International Diabetes Federation. IDF Diabetes Atlas., 6th edition update 2014

Insulin-secretion (%) in Type 2 Diabetes Mellitus patients

Basal initiation/titration

100

75

50

OADs

Basal-prandial

Diagnostic

T2DM is a progressive disease and requiresprogressive therapy

Diab.Rev. 1999; 7:139-153

IGT

Post-prandial hyper glycemia

25

0

-8 -2 0 +2 +8 +14 (years)

Insulin intensification:Basal/basal+ strategy

Both FBG and PPBG contribute to overallhyperglycaemia

50

60

70

PostprandialFasting

Rela

tive

con

trib

utio

nof

FBG

vs

PPBG

(%)

Contribution of postprandial hyperglycaemia increasesas HbA1c nears target

Adapted from Monnier L, et al. Diabetes Care 2003;26:881–5.

0

10

20

30

40

50

<7.37.3–8.48.5–9.29.3–10.2>10.2

Rela

tive

con

trib

utio

nof

FBG

vs

PPBG

(%)

HbA1c (%)

Anti-hyperglycemic therapy in type 2 diabetes: generalrecommendations. Position Statement of ADA-EASD 2012

Inzucchi et al. Diabetologia. DOI 10.1007/s00125-012-2534-0

Insu

lin E

ffect

Insu

lin E

ffect

Bolus InsulinBolus InsulinBasal InsulinBasal Insulin

Endogenous InsulinEndogenous Insulin

Normal Insulin Secretion:The Basal-Bolus Insulin Concept

BB DDLL HSHS

Insu

lin E

ffect

Insu

lin E

ffect

B,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.

Time of AdministrationTime of Administration

Mean plasma glucoseA1C (%) mg/dl mmol/l

6789101112

126154183212240269298

7.08.610.211.813.414.916.5

6789101112

126154183212240269298

7.08.610.211.813.414.916.5

These estimates are based on ADAG data of 2,700 glucose measurements over 3 months per A1Cmeasurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C andaverage glucose was 0.92 (51). A calculator for converting A1C results into estimated average glucose(eAG), in either mg/dl or mmol/l, is available at http://professional.diabetes.org/eAG. ADA, 2011

• When basal insulin added to oral agents doesnot sustain target A1c

• Add mealtime insulin stepwise:– Basal +1 — 2nd injection before the largest meal– Basal +2 — 3rd injection before 2nd largest meal– Basal +3 — 4th injection before 3rd meal

• When basal insulin added to oral agents doesnot sustain target A1c

• Add mealtime insulin stepwise:– Basal +1 — 2nd injection before the largest meal– Basal +2 — 3rd injection before 2nd largest meal– Basal +3 — 4th injection before 3rd meal

Basal InsulinOnce daily(optimized)

Basal PlusOne prandialfor largest

glucoseexcursion

Basal PlusTwo prandialfor largest

glucoseexcursion

Basal BolusBasal +

three prandial

Raccah D. Diabetes Ob Met 2008; 10: 76-82

Basal InsulinOnce daily(optimized)

Basal PlusOne prandialfor largest

glucoseexcursion

OHAmono or

combinationtherapy

Diet andexercise

HbA1cuncontrolled

HbA1c uncontrolled, FBG on targetPPBG>8.8 mmol/l (>160 mg/dl)

Time

Fix the FPG first using basal insulin (dose optimisation)Goal: FPG 70-130 mg/dlConsider adding bolus insulin when:A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2

Fix the FPG first using basal insulin (dose optimisation)Goal: FPG 70-130 mg/dlConsider adding bolus insulin when:A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2

Add bolus 2U at each mealTitrate to next pre-prandial goals (and bedtime) daily

<70 mg/dl -1U70-130 mg/dl 0>130 mg/dl +1U

Discontinues SU on addition of bolus insulinPatients need to monitor up to 4x per day

Add bolus 4U at the largest mealTitrate to next pre-prandial goals (and bedtime) goal daily

If subsequent pre-meal sugars are:<70 mg/dl -1U70-130 mg/dl 0>130 mg/dl +1U

Discontinues SU on addition of bolus insulinPatients need to monitor up to 4x per day

Straight to three bolus doses Sequential addition of bolus doses

A. Pfu¨ tzner, T. ForstInt. J Clin Pract, October 2009, 63 (Suppl. 164), 11–14

Add bolus 2U at each mealTitrate to next pre-prandial goals (and bedtime) daily

<70 mg/dl -1U70-130 mg/dl 0>130 mg/dl +1U

Discontinues SU on addition of bolus insulinPatients need to monitor up to 4x per day

Add bolus 4U at the largest mealTitrate to next pre-prandial goals (and bedtime) goal daily

If subsequent pre-meal sugars are:<70 mg/dl -1U70-130 mg/dl 0>130 mg/dl +1U

Discontinues SU on addition of bolus insulinPatients need to monitor up to 4x per day

If A1C >7% after 3 months despite titrating bolus dose, or bolusdoses are more than 30 U per meal:Resume titration of basal insulin and/or consider performing a 7point profile

If A1C >7% after 3 months despite titrating bolus dose, or bolusdose is more than 30 U per meal:Add 2nd bolus of 4U at 2nd largets meal and titrate as befor.Repeat for 3rd dose at final meal of the day

Why premixed insulin?

Premixed insulin•40% of human insulinused world over

Advantages of premixed•Increased dosage accuracy•Increased efficacy•Enhanced convenience

Increased compliance &

better long-term outcomes1

Premixed insulin•40% of human insulinused world over

Advantages of premixed•Increased dosage accuracy•Increased efficacy•Enhanced convenience

Efficacy of Biphasic Insulin Aspart 30in Patients with T2DM Not Achieving

Glycemic Targets on OADs with/withoutBasal Insulin Therapy

The 1-2-3 Study

Efficacy of Biphasic Insulin Aspart 30in Patients with T2DM Not Achieving

Glycemic Targets on OADs with/withoutBasal Insulin Therapy

The 1-2-3 Study

Garber et al. Diabetes Obes Metab 2006;8(1):58-66

1-2-3 Study: InvestigationOf Once-, Twice-, Thrice-Daily BIAsp 30

Pre-dinner x 16 weeksStart with 12 U at dinner

HbA1c ≤6.5%OD

Phase 1Endof

Study

If HbA1c >6.5%, go to BID,d/c secretagogues

Phase 2Endof

Study

Pre-breakfast & dinner x 16 weeksAdd 3 U at breakfast and titrateBID

Endof

StudyHbA1c ≤6.5%

If HbA1C >6.5%, go to TID

TID x 16 weeksAdd 3 U at lunch and titrateTID

Phase 3

Titrate according to schedule every 3 daysn=100 type 2 DM 12 months with 7.5 HbA1c 10%, 2 OADs or1 OAD plus basal insulin OD (max 60 U)

Garber et al. Diabetes, Obesity & Metabolism 2006; 8:58–66.

A1C ≤ 6.5(AACE, IDF goal)

A1C < 7%(ADA goal)

QD 21% 41%

Results: Cumulative Percentage of PatientsAchieving A1C Goals

QD 21% 41%

BID 52% 70%

TID 60% 77%

Total 60/100 77/100

Baseline A1C was 8.6%

Garber et al. Diabetes Obes Metab 2006;8(1):58-66

Effect of Biphasic Insulin Aspart 30 on FPGand PPG

*P < 0.001

FPG

(mg/

dL)

175

160

180

200

-15

-10

-5

0

QD(dinner)

TID(lunch)

PPG

Incr

emen

ts:

Cha

nges

from

Bas

elin

e

BID(breakfast)

FPG

(mg/

dL)

*125

100

120

140

Baseline End of Study -45

-40

-35

-30

-25

-20

-15

PPG

Incr

emen

ts:

Cha

nges

from

Bas

elin

e-35.3

-42.8

-16.1

*

*Garber et al. Diabetes Obes Metab 2006;8(1):58-66

Intensification to BIAsp30When glycaemic targets can no longer be achieved withbasal insulin in type 2 diabetes, can simpleintensification with a modern premixed insulin help?Results from a subanalysis of the PRESENT studyH. C. Jang,1 S. Guler,2 M. Shestakova3, on behalf of the PRESENT study groupInt J Clin Pract, July 2008, 62, 7, 1013–1018

When glycaemic targets can no longer be achieved withbasal insulin in type 2 diabetes, can simpleintensification with a modern premixed insulin help?Results from a subanalysis of the PRESENT studyH. C. Jang,1 S. Guler,2 M. Shestakova3, on behalf of the PRESENT study groupInt J Clin Pract, July 2008, 62, 7, 1013–1018

Intensification to biphasic insulin aspart 30/70 (BIAsp 30,NovoMix 30) can improve glycaemic control in patientstreated with basal insulins: a subgroup analysis of theIMPROVE TM observational studyJ. Gumprecht,1 M. Benroubi,2 V. Borzi,3 R. Kawamori,4 J. Shaban,5 S. Shah,6 M. Shestakova,7

Y. Wenying,8 R. Ligthelm,9 P. Valensi,10 on behalf of the IMPROVETM Study Group Expert Panel.Int J Clin Pract, June 2009, 63, 6, 966–972

Step up with BIAsp 30 from basal analogueinsulin significantly reduced HbA1c after 6

months

9.4%

7.8%

9.3%

7.5%

Jang HC et al. Int J Clin Pract 2008;62(7);1013-1018; Gumprecht J et al., Int J Clin Pract, June 2009; 63, 6, 966-972

N = 348P<0.0001

9.4%

7.8%

9.3%

7.5%

N = 245P<0.0001

Comparison of insulin analogue regimens in peoplewith type 2 diabetes mellitus in the PREFER Study:

a randomized controlled trial

Aims: Compared two such regimens in type 2 diabetes mellitus (T2DM)uncontrolled by oral antidiabetic agents (OADs) with or without basalinsulin.Methods: In a 26-week multinational, multicentre, randomized treat-to-target trial, OADs were discontinued and subjects randomized toanalogue basal–bolus therapy (insulin detemir once daily and insulinaspart mealtimes) or biphasic insulin aspart 30 (30% rapid-actinginsulin aspart), twice daily. Insulin was titrated to targets for fasting,predinner and postprandial plasma glucose (PG), as appropriate.Conclusions: Modern insulin analogue regimens, adjusted to PGtargets, enable a majority of people with T2DM to reach HbA1c<7.0% after failure of OADs and OAD-basal insulin therapy.Insulin-treated patients may benefit more from transfer toanalogue basal–bolus therapy, while insulin-naive individualsbenefit equally well from the more convenient biphasic analogueregimen.Liebl A et al. Diabetes Obes Met 2008; 11: 45-52

Practical guideline on intensification of insulintherapy with BIAsp 30: a consensus statement

A simple algorithm for the intensification of basal insulin th. OD or BiD to BIAsp 30 BID

Basal insulin OD or BID

HbA1c 7-8%

Titrate basal insulin to achieveFPG <110 mg/dl

FPG >110 mg/dl FPG: 73-110 mg/dl

HbA1c >8%

Unnikrishnan AG et al. Int J Clin Pract, 2009

Practical guideline for swiching from basal insulin OD or BID to BIAsp 30 BID

• 1:1 Total dose transfer to BIAsp 30• Split the dose 50:50 prebreakfast and predinner• Titrate the dose preferably once a week• Discontinue sulfonylureas (SUs)• Continue metformin• Consider discontinuing TZDs as per local guideline and practice• Administer BIAsp 30 just before meals

Switch to BIAsp 30 BIDTitrate basal insulin to achieveFPG <110 mg/dl

Practical guideline on intensification of insulintherapy with BIAsp 30: a consensus statement

A simple algorithm for the intensifying therapy from BIAsp 30 OD or BID to BID or TID

BIAsp 30 OD (pre dinner) or BIAsp 30 BID

HbA1c >7%Titrate BIAsp 30 OD or BID to achieveFPG and/or pre dinner BG < 110 mg/dl

FPG and/or pre dinner BG: 73-110 mg/dl FPG and/or pre dinner BG > 110 mg/dl

If Hypoglycemia occurs

Unnikrishnan AG et al. Int J Clin Pract, 2009

Practical guideline for swiching from BIAsp 30 OD to BID

• Split the OD dose into equal breakfast and dinner doses (50:50)• Titrate the dose preferably once a week according to the algoritm below• Discontinue sulfonylureas (SUs)• Continue metformin• Consider discontinuing TZDs as per local guideline and practice• Administer BIAsp 30 just before meals

Switch to BIAsp 30 BID or TID

If Hypoglycemia occurs

Practical guideline for swiching from BIAsp 30 BID to TID• Add 2-6 U or 10% of total daily BIAsp 30 dose before lunch• Down-titration of morning (-2 to 4 U) may be needed after adding the lunch dose• Titrate the dose preferably once a week according to the algoritm below• Discontinue sulfonylureas (SUs)• Continue metformin• Consider discontinuing TZDs as per local guideline and practice• Administer BIAsp 30 just before meals

Practical guideline on intensification of insulintherapy with BIAsp 30: a consensus statement

• Add 2-6 U or 10% of total daily BIAsp 30 dose before lunch• Down-titration of morning (-2 to 4 U) may be needed after adding the lunch dose• Titrate the dose preferably once a week according to the algoritm below• Discontinue sulfonylureas (SUs)• Continue metformin• Consider discontinuing TZDs as per local guideline and practice• Administer BIAsp 30 just before meals

Unnikrishnan AG et al. Int J Clin Pract, 2009

Preprandial blood glucose value Dose change

<80 mg/dl80-110 mg/dl110-140 mg/dl141-180 mg/dl>180 mg/dl

-2U0

+2 U+4 U+6 U

• When the daily insulin dose in a OD regimen nears 40-50 U, intensifying the regimen to BID• BIAsp 30 distribution = 2:1:3 (breakfast:lunch:dinner)• BIAsp 30 TID: alternative to basal-bolus (fewer daily injection and only one device need)

Summary

• Basal insulin is a choice if monotherapy fail to achievetarget

• Basal-bolus insulin therapy is considered the optimaltreatment regimen for intensification after OADs+basal insulin fail

• Premix insulin also has a place for intensification afterbasal insulin fail:

– Simple

– Effective

– Low rate of hypoglycemia

• Basal insulin is a choice if monotherapy fail to achievetarget

• Basal-bolus insulin therapy is considered the optimaltreatment regimen for intensification after OADs+basal insulin fail

• Premix insulin also has a place for intensification afterbasal insulin fail:

– Simple

– Effective

– Low rate of hypoglycemia

Carmela D’Avella, BSc N, CDESource: Novo Nordisk Inc.