Nines P Bautista, MD, MS

Basal Bolus tandem in the Management of hyperglycemia in Type 2 Diabetes

A consensus algorithm forthe initiation and adjustment of therapy

ADA / EASDUpdate of January 2009

IC.DIA.08.12.01 3

OBJECTIVES

1.Loco-regional data on T2DMEpidemiologyQuality of glucose control

2.Target HbA1cWhich target for HbA1c?HbA1c <6.0%?

3.Lowering glucose & tackling CV risk factors

4.Consensus algorithmBasal , Basal plus and Basal Bolus in Diabetes ManagementTier 1: well validated therapies

4

Diabetes is an increasing healthcare epidemic throughout the world

Global projections for the number of people with diabetes (20–79 age group), 2007–2025 (millions)

AfricaEastern Mediterraneanand Middle EastEurope

North America

South and Central America

South-East Asia

Western Pacific

28.340.5

+43%

16.232.7

+102%

10.418.7

+80%

24.544.5

+81%

53.264.1

+21%

67.099.4

+48%

46.580.3

+73%

IDF. Diabetes Atlas 3rd Edition – 2006

Worldwide:246 million people in 2007

380 million projected for 202555% increase

National Diabetes Survey1982 WHO - MOH1 M Diabetics in R.P.

1 M I.G.T.270,000 in Metro Manila

Prevalence: 8.4% NCR6.5% urban2.5% rural

4.1% National (20 - 65 yrs)peak: 45-55

Philippine Data 2007

Incidence rate of DM = 12%Incidence rate of DM = 12%

Incidence rate of IFG = 10%Incidence rate of IFG = 10%

Prevalence rate of DM = 18% Prevalence rate of DM = 18%

Prevalence rate of IFG = 31%Prevalence rate of IFG = 31%

Prevalence rate of IGT = 26%Prevalence rate of IGT = 26%PHILCOS 2007 UNITE FOR DIABETESPHILCOS 2007 UNITE FOR DIABETES

COS

PHIL J INT MED 45;211-218 7

In developing countries, diabetes will affect people aged 45−65 years

Wild S, et al. Diabetes Care 2004;27(5):1047–1053.

Estim

ated

num

ber o

f peo

ple with

diab

etes

(milli

ons)

Developed Countries

0

20

40

60

80

100

120

140

160

20–44 45–64 65+0

10

20

30

40

50

60

20–44 45–64 65+

2000 2030

Developing Countries

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes

8

NHANES reveals the under-managementof diabetes

NHANES 1999 – 2000 population with diabetes

Mean HbA1c value was 7.8%37% had an HbA1c value <7.0%

26% had an HbA1c value of 7.0–8.0%

37% had an HbA1c value >8.0%

27% were receiving insulin therapy with or without Oral Glucose Lowering Drugs

Saydah S, et al. JAMA 2004;291:335–42.9

Is glycemic control improving over time?

NHANES Diabetes Care 2008;31:81–86. US data in adults

1999-2000

2001-2002

0

5

10

15

20

25

30

35

40

<6.0% 6.0 – 6.9% 7.0 – 7.9% 8.0 – 8.9% 9.0 – 9.9% ≥10.0%

HbA1c levels

2003-2004

%

10

Percentage of subjects advancing when HbA1C >8%

Brown et al. Diabetes Care 2004;27:1535-1540.

Clinical inertiaFailure to advance therapy when required

0

10

20

30

40

50

60

70

Diet Sulfonylurea Metformin Combination

At insulin initiation, the average patient had: 5 years with HbA1C >8% 10 years with HbA1C >7%

18.6%

66.6%

35.3%44.6%

% o

f Sub

jects

11

Change over time in guidelinesfor evaluating hyperglycemia

Time period Type of guideline FBG (mg/dL)

FPG (mg/dL)

HbA1c(%)

<1993 (pre-DCCT)Threshold for

initiating or changing treatment

200 - 9-10

>1993 (post-DCCT)Threshold for

initiating or changing treatment

140 150 8

1997 to present

Recommended treatment goals

(UKPDS)80-120 90-130 <7

New diagnostic criteria for diabetes - 126 -

2000 Definition of normoglycemia 99 109 <6

FBG: fasting blood glucoseFPG: fasting plasma glucoseDCCT: Diabetes Control and Complications Trial Hollander PA. Postgrad Med 2000;Special Report:4-10.

12

HbA1c targets in current guidelines

HbA1c target (%)

ADA/EASD <7.0IDF ≤6.5NICE <6.5AACE ≤6.5France <6.5*Canada ≤7.0Australia ≤7.0Latin America <6.5

*If on single or double therapy; if on triple therapy or insulin, then HbA1c <7% Nathan DM, et al. Diabetes Care 2009;32 193-203http://www.idf.org/home/index.cfm?node=1457http://www.nice.org.uk/nicemedia/pdf/CG66diabetesfullguideline.pdfEndocrine Practice Vol 13 (Suppl 1) May/June 2007

Drouin P, et al. Diabetes & Metabolism (Paris) 1999;25:72-83. Canadian Diabetes Association Canadian J Diab:32(suppl. 1):S1-201http://www.nhmrc.gov.au/publications/synopses/_files/di10.pdfhttp://www.revistaalad.com.ar/guias/GuiasALAD_DMTipo2_v3.pdf

For sanofi-aventis affiliates:

Add local guidelines as needed

13

Rationale for glycemic goals

Glycemic goals of therapy are based on:Clinical studies

- Type 1: DCCT, Stockholm Diabetes Intervention Study- Type 2: UKPDS, Kumamoto

Epidemiological data

"Normal" HbA1cUpper limit of nondiabetic range: 6.1%

Goals of therapy in DCCT and UKPDSNeither study was able to maintain HbA1c level

in the nondiabetic range HbA1c ~ 7% in intensive treatment groups

- i.e., 4 SD above nondiabetic mean

DCCT Research Group. N.Eng.J.Med.1993;329:977-986.Raichard P, et al. Acta Medica Sandinavica 224(2):115-122.UKPDS Group Lancet 1998;352:837-53.Ohkubo Y, et al. Diabetes Res Clin Pract 1995;28:103–117. Nathan DM, et al. Diabetes Care 2009;32 193-203.


14

Benefits of intensive vs conventional glycemic management

Turner R, et al. Ann Intern Med. 1996;124:136-145.

DCCT conventional

UKPDS conventionalUKPDS intensive

DCCT intensive

Time (y)

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9

HbA

1c(%

)

15

Risk of complicationsBenefits of lowering hemoglobin HbA1c

0

4

8

12

16

6 7 8 9 10 11 12Hemoglobin HbA1c (%)

Relat

ive Risk

of com

plicat

ions

Adapted from UKPDS 33: Lancet 1998;352:837-853.Adapted from DCCT Study Group. N Engl J Med 1993;329:977.

Average Glucose mg/dl 120 150 180 210 240 270 300

16

No HbA1c threshold in Type 2 DiabetesAdjusted incidence per 1000 person years (%)

Stratton IM, et al. BMJ. 2000;321:405-412.

Epidemiologic data fromthe UKPDS

40

60

80

20

05 6 7 8 9 10 11

Myocardial infarction

Microvascular endpoints

ADA goal

Updated mean HbA1C (%)

?

17

Usual fasting glucose (mmol/L)

Haz

ard

ratio

(95%

CI)

Risk21% (CI 18-24) rise per

1 mmol/L rise in glucose

Total ischemic Heart disease

CVD: cardiovascular diseaseAsia Pacific Cohort Studies Collaboration. Diabetes Care 2004;27:2836-2842.

Total stroke4.0

2.0

1.0

0.5

4.5 5.0 5.5 6.0 6.5 7.0 7.5

CV death

4.5 5.0 5.5 6.0 6.5 7.0 7.5 4.5 5.0 5.5 6.0 6.5 7.0 7.5





Fasting blood glucose is an important determinant of CVD burden

18

Why not aiming for lower HbA1c?

Normal HbA1c levels are difficult to achieve with present therapies

Intensive therapy increases the risk of weight gain and hypoglycemia

The absolute risks and benefits of lower HbA1c are largely unknown…

American Diabetes Association. Diabetes Care 2008;31(Suppl 1):S12-S54.19

Glucose lowering to prevent CVD Trials in people with dysglycemia

Yrs from Dx 0 5-10 -5 10 15

ACCORD

VADT

Eye, Kidney, Nerve Disease

CVD

ORIGIN

ADVANCE


20

HbA1c- How low is low enough?

Benefit of intensive glycemic control on CVD outcomes not proven

HbA1c level of ≥7% should serve as a call to actionto initiate or change therapy

Goal: HbA1c <7%But need for an individualised target

Nathan DM, et al. Diabetes Care 2009;32 193-203.21

T2DM guidelines focus on glycaemic control and CVD risk factors

HbA1c levels correlate with the development of diabetic complications

Multiple CVD risk factors cluster in T2DMDyslipidaemiaHypertensionObesityHypercoagulability Insulin resistance

Thus, control of hyperglycaemia and CVD risk factorsis the focus of T2DM treatment

IDF Clinical Guidelines Task Force. Brussels, 2005.ADA. Diabetes Care 2008;31(Suppl. 1):S12–54.Ryden L, et al. Eur Heart J 2007;28:88–136.

22

Recommendations for BP andCV risk factors

ADA IDF ESC/EASD

BP measurement At every visitAnnually

(at every visit if above target)

-

BP targets <130/80 mmHg <130/80 mmHg <130/80 mmHg

Lipid measurements Annually Annually -

LDL target 100 mg/dl(2.6 mmol/l)

<95 mg/dl(2.5 mmol/l)

<70 mg/dl(1.8 mmol/l)

Triglyceride target 150 mg/dl(1.7 mmol/l)

<200 mg/dl(<2.3 mmol/l)

<150 mg/dl(<1.7 mmol/l)

HDL target 50 mg/dl(1.3 mmol/l)

>39 mg/dl(>1.0 mmol/l)

male >40 mg/dl(>1.0 mmol/l)

female >46 mg/dl(>1.2 mmol/l)

BP: blood pressureCV: cardiovascular

IDF Clinical Guidelines Task Force. Brussels, 2005.ADA. Diabetes Care 2008;31(Suppl. 1):S12–54.Ryden L, et al. Eur Heart J 2007;28:88–136.

23

Why guidelines for the treatment of T2DM?

Diabetes is a complex and progressive disease, requiring timely treatment escalation

Guidelines interpret existing evidence in order to helpall physicians

The increase in the number of available therapies has increased treatment options

Guidelines should be revised as new evidence accrues

Guidelines do not replace clinical judgement inthe individual patient

Nathan DM, et al. Diabetes Care 2009;32 193-203.

24

History of ADA/EASD consensus algorithm

First Consensus algorithmAugust 20061

1st Update January 2008: Update regarding thiazolidinediones2

2nd Update January 20093

1. Nathan DM, et al. Diabetes Care 2006;29(8):1963-72. 2. Nathan DM, et al. Diabetes Care 2008;31(1):173-5. 3. Nathan DM, et al. Diabetes Care 2009;32:193-203. 25

Rationale for this updated consensus

Clinical trialsEffectiveness & safetyBut very few head-to-head comparisons

Clinical judgmentMedical knowledgeClinical experience

Benefits, risks, costs



26

HbA1c targets should be individualized

Goal of therapy In general: HbA1c <7% In the individual patient: HbA1c as close to 6% as possible

without significant hypoglycemia

Call to action: HbA1c 7% Less stringent goals may be appropriate for:

Patients with a history of severe hypoglycemiaPatients with limited life expectanciesVery young children or older adults Individuals with co-morbid conditions


Principles in selecting antihyperglycemic interventions

Effectiveness in lowering blood glucoseWhen high HbA1c (≥8.5%)

- Classes with greater and more rapid glucose-lowering effectiveness are recommended

- Potentially earlier initiation of combination therapy

Extraglycemic effects that may reduce long-term complicationsHypertension, dyslipidemia, BMI, insulin resistance, insulin

secretory capacity

Safety profiles Tolerability Ease of use Cost


28

ADA/EASD consensus algorithmOverarching principles

Early intervention Patient’s empowerment

Education, SMBG, treatment adjustment Shorten delays in treatment changes Achieve and maintain normal glycemic goals Add medications, transition to new regimens quickly

Whenever HbA1c levels are ≥7%

STEP 1: Lifestyle intervention + metforminSTEP 2: Add another agent – basal insulin or SUSTEP 3: Intensify therapy

Timely basal insulin therapy for patients not meeting targetsSMBG: self-monitoring blood glucoseNathan DM, et al. Diabetes Care 2009;32:193-203.

29

Expected HbA1c reduction accordingto intervention

Intervention Expected ↓ in HbA1c (%)Lifestyle interventions 1 to 2%Metformin 1 to 2%Sulfonylureas 1 to 2%Insulin 1.5 to 3.5%Glinides 1 to 1.5%1

Thiazolidinediones 0.5 to 1.4%-Glucosidase inhibitors 0.5 to 0.8%GLP-1 agonist 0.5 to 1.0%Pramlintide 0.5 to 1.0%DPP-IV inhibitors 0.5 to 0.8%

1. Repaglinide is more effective than nateglinideAdapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

30

ADA/EASD consensus algorithm

At diagnosis:Lifestyle + Metformin

Lifestyle + Metformin+ Basal insulin

Lifestyle + Metformin+ Sulfonylurea

Lifestyle + Metformin+ Intensive insulin

Tier 1:well-validated therapies

STEP 1 STEP 2 STEP 3

Call to action if HbA1c is 7%

Tier 2:Less well validated therapies

Lifestyle + Metformin+ PioglitazoneNo hypoglycaemiaOedema/CHFBone loss

Lifestyle + Metformin+ Pioglitazone+ Sulfonylurea

Lifestyle + metformin+ Basal insulin

Lifestyle + metformin+ GLP-1 agonistNo hypoglycaemiaWeight lossNausea/vomiting


Lifestyle modifications

Medical Nutrition Therapy (MNT)

Weight lossPhysical activity


32

ADA/EASD consensus algorithm: step 2

Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

At diagnosis:Lifestyle

+Metformin

Lifestyle+ Metformin

+ Basal insulin


+ Sulfonylurea

STEP 1 STEP 2

HbA1c 7%

When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effectiveness,or potentially earlier initiation of combination therapy, are recommended

33

ADA/EASD consensus algorithm: step 2

If step 1 fails to achieve or sustain HbA1c <7%, another medication should be added within 2-3 months

The HbA1c level will determine (in part) which agent is selected next:Most of newly diagnosed Type 2 Diabetic patients will usually

respond to sulfonylurea*Basal insulin if HbA1c >8.5% or symptoms of hyperglycemia

* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamideNathan DM, et al. Diabetes Care 2009;32:193-203.

34

ADA/EASD consensus algorithm: step 2Addition of sulfonylurea


+Metformin


+ Sulfonylurea*

STEP 1 STEP 2

HbA1c 7%

* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamideNathan DM, et al. Diabetes Care 2009;32:193-203.

35

ADA/EASD consensus algorithm: step 2Insulin initiation


+Metformin


+ Basal insulin


+ Sulfonylurea

STEP 1 STEP 2

HbA1c 7%

HbA1c 7%


36

ADA/EASD recommend early initiation of insulin therapy to meet HbA1c targets

Basal insulin therapy initiated when lifestyle modification plus metformin, or combination with sulfonylurea,does not maintain HbA1c <7.0%

Insulin therapy may be particularly beneficial in patients with HbA1c values of >8.5%

Insulin regimens should be designed taking lifestyle and meal schedules into account


How it works Direct compensation for lack of insulin sensitivity

Expected HbA1creduction

• 1.5 to 3.5%

• No maximum dose +++

Adverse events Hypoglycemia

Weight effects Weight gain of ~ 2–4 kg

CV effects• Beneficial effect on TG and HDL

• Weight gain may have an adverse effect on CV risks

Attributes of insulin

HDL: TG: triglyceridesCV: cardiovascularNathan DM, et al. Diabetes Care 2009;32:193-203.


38

Advantages of insulin therapy

Oldest medication, with most clinical experience

Most effective in lowering glycemiaCan decrease any level of elevated HbA1c

No maximum dose of insulin

Beneficial effects on triglyceride and HDL-c


Disadvantages of insulin therapy

Weight gain ~ 2-4 kg± proportional to the correction of glycemia Predominantly the result of glycosuria

HypoglycemiaRates of severe hypoglycemia in patients with T2DM are low in

treat-to-target clinical trials (compared to T1DM):- Type 1 DM: 61 events per 100 patient-years- Type 2 DM: 1 to 3 events per 100 patient-years


INSULIN TACTICS

Normal Insulin Secretion

B L S B

Insu

lin

Meals

N NN

INSULIN TACTICS

Ideal Treatment

B L S B

Insu

lin

Meals

BCF

42

Bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin

(initiate with 10 units or 0.2 units per kg)

Initiating and adjusting insulin

If HbA1c < 7%

Check FG and increase dose until in target range

If HbA1c 7%

If FBG in target range, check BG before lunch, dinner, and bed. Depending on BG results, add second injection

(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)

Continue regimen; check HbA1c every 3 months

Pre-lunch BG out of range: add rapid-acting insulin at breakfast

Pre-dinner BG out of range: add NPH insulin at breakfast or rapid-acting insulin at lunch

Pre-bed BG out of range: add rapid-acting insulin at dinner

If HbA1c < 7% If HbA1c 7%

Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA1c continues to be out of range, check 2-hr postprandial levels

and adjust preprandial rapid-acting insulin

Continue regimen; check HbA1c every 3 months

Target range:3.89-7.22 mmol/L

(70-130mg/dL)


A Simple way to add & titrate basal insulin

FPG, fasting plasma glucoseNathan DM, et al. Diabetes Care 2009;32:193-203.

Initiate insulin with a single injection of a basal insulin

CheckFPGdaily

In the event of hypoglycemia or FPG level <3.89 mmol/L(<70 mg/dL)

• Reduce bedtime insulin dose by 4 units, or by 10% if >60 units

• Bedtime or morning long-acting insulin OR• Bedtime intermediate-acting insulin

Daily dose: 10 units or 0.2 units/kgINITIATE

• Increase dose by 2 units every 3 days until FPG is 3.89–7.22 mmol/L(70–130 mg/dL)

• If FPG is >10 mmol/L (>180 mg/dL), increase dose by 4 units every 3 days

TITRATE

Continue regimen and check HbA1c every 3 monthsMONITOR


44

Types of basal insulin

Intermediate-Acting

(e.g. NPH, lente)Long-Acting

(e.g. ultralente)Long-Acting Analogues

(glargine, detemir)

Onset 1-3 hr(s) 3-4 hrs 1.5-3 hrs

Peak 5-8 hrs 8-15 hrsNo peak with glargine, dose-dependent peak

with detemir

Duration Up to 18 hrs 22-26 hrs 9-24 hrs (detemir); 20-24 hrs (glargine)

Rossetti P, et al. Arch Physiol Biochem 2008;114(1): 3 – 10. 45

Hours post dose

Insu

lin le

vel

0 4 8 12 16 20 24

Basal insulin analogues offer advantages over basal human insulins

Compared with human basal insulins, basal insulin analogues: Have more physiological action profiles Exhibit less variability Reduce the risk of hypoglycaemia Are associated with less weight gain

Adapted from Tibaldi J, and Rakel R, Int J Clin Pract 2007;61:633–44.Adapted from Choe C, et al. J Natl Med Assoc 2007;99:357–67.

Hours post dose

Insu

lin le

vel

0 4 8 12 16 20 24

Insulin analogue (long acting) Human insulin (intermediate acting)

46

Basal insulin analogues

1. Lepore M, et al. Diabetes 2000;49:2142–8.2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.

Glu

cose

infu

sion

rate

(mg/

kg/m

in)

Glucose infusion rate (µm

ol/kg/min)

Time (hours)

0

8

16

4

12

20

24

0

2

4

1

3

0 4 8 12 16 20 24

SC injection

T1DM patients (n=20)1

Glu

cose

infu

sion

rate

(mm

ol/kg/

min) G

lucose infusion rate (µmol/kg/m

in)

Time (hours)

0

8

16

4

12

20

24

0

2

4

1

3

0 4 8 12 16 20 24

SC injection0.35 IU/kg

T1DM patients (n=24)2

Insulin detemir

Insulin glargine

NPH 0.3 IU/kg

CSII (insulin lispro)0.3 IU/kg/24h

Insulin glargine 0.3 IU/kg

47Yki-Järvinen H, et al. Diabetologia 2006;49:442–451.

Adding basal insulin to metformin is particularly effective in lowering HbA1c

-4 0 12 24 366

7

8

9

10

HbA

1c(%

)

Time (weeks)

Reference range 4.0- 6.0%

NPH

Glargine

7.16%

9.59%

9.49%

7.14%

48

Insulin glargine has proven efficacy in combination with metformin + sulfonylurea

HbA

1c (%

)

APOLLO4LAPTOP2T-T-T1 INITIATE5

8.68.9 8.7 8.8

7.07.2

Triple Therapy3

8.8

7.17.0 6.8

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

7.6

6.8

TULIP6

Endpoint

Baseline

SU: sulfonylurea1. Riddle M, et al. Diabetes Care 2003;26:3080–3086.2. Janka H, et al. Diabetes Care 2005;28:254–259.3. Rosenstock J, et al. Diabetes Care 2006;29:554–559.

4. Bretzel RG, et al. Lancet 2008;371:1073-84.5. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364-69.6. Bickle J et al. Diabetes 2008;57(Suppl 1):A139

49

Choosing a basal insulin with a lower riskof hypoglycemia

Insulin analogues with longer, non-peaking profiles decrease the risk of hypoglycemia…



50

Less hypoglycemia with glargine vs NPH

Adapted from Mullins P, et al. Clin Ther 2007;29:1607-1619.

p=0.021

NPH insulin

Insulin glargine

Rat

e of

Hyp

oglyc

emia

(Eve

nts/

100

Patie

nt-Y

ears

)

200

150

100

50

0

6 7 8 9 10

HbA1c (%)

Meta-Regression Analysis 11 randomized controlled trials; n=3,083

51

Titrate basal insulin as long as FPG above target range

FPG, fasting plasma glucoseNathan DM, et al. Diabetes Care 2009;32:193-203.

CheckFPGdaily

In the event of hypoglycemia or FPG level <3.89 mmol/L(<70 mg/dL)

• Reduce bedtime insulin dose by 4 units, or by 10% if >60 units

• Bedtime or morning long-acting insulin OR• Bedtime intermediate-acting insulin

Daily dose: 10 units or 0.2 units/kg INITIATE

• Increase dose by 2 units every 3 days until FPG is 3.89–7.22 mmol/L(70–130 mg/dL)

• If FPG is >10 mmol/L (>180 mg/dL), increase dose by 4 units every 3 days

TITRATE

Continue regimen and check HbA1c every 3 monthsMONITOR

52

The patient: A key player in the diabetes care team

Self-Monitoring Blood Glucose(SMBG)

To determine whether blood glucose targets are achieved

Medication Self-Adjustment(under HCP guidance)

Nathan DM, et al. Diabetes Care 2009;32:193-203. Davies M, et al. Diabetes Care 2005;28:1282-8.Meneghini L, et al. Diabetes Obes Metab 2007;9(6),:902-13.Garber AJ, et al. Diabetes Obes Metab 2006;8:58-66.

Need for training and empowerment

Prevent and treat hypoglycemiasAchieve glycemic targets

53

After 2-3 months…

If HbA1c is <7%Continue regimen and check HbA1c every 3 months

If HbA1c is ≥7% If FPG > target range:

- Titrate basal insulin

If FPG within target range:- Intensify insulin therapy…


54

ADA/EASD consensus algorithm step 3Intensifying insulin therapy



Lifestyle + Metformin+ Sulfonylurea



Tier 1: Well-validated therapies

HbA1c 7%


Intensify insulin if HbA1c is still ≥7%

ADA/EASD recommend the stepwise addition of prandial insulin to intensify a basal insulin regimen

If pre-lunch blood glucose is out of range...

If pre-dinner blood glucose is out of range...

If pre-bed blood glucose is out of range...

If fasting blood glucose (FBG) levels are in target range but HbA1c 7%,check blood glucose before lunch, dinner, and bedtime and

or or

add



56

Attributes of prandial insulin

Adapted from Hirsch IB, N Engl J Med 2005;352:174-83.

Rapid-Acting(e.g. aspart, lispro, glulisine)

Short-Acting(e.g. regular human insulin)

Onset 5 - 15 mins 30 - 60 mins

Peak 30 - 90 mins 2 - 3 hrs

Duration 4 - 6 hrs 8 - 10 hrs

57

Rapid-acting insulin analogues reduce risk of PP hyperglycaemia and late hypoglycaemia

Lower risk of late post-prandial hypoglycaemia

Plas

ma-

free

insu

lin (µ

U/m

L)

Time after insulin injection or meal ingestion (hours)

Better PPBGcontrol

PPBG=post-prandial blood glucoseBolli GB, Av Diabetol 2007;23:326–32.

0

20

40

60

80

0 2 4 6 8 10 12

Subcutaneous insulin

Meal

Normal post-prandial values

Regular human insulin (RHI)

Insulin lispro, insulin aspart,or insulin glulisine

58

Initiation & titration of prandial insulin

Can usually begin with ~4 units

Adjust by 2 units every 3 days until plasma glucoseis in range

When prandial insulin is started, insulin secretagogues (SU or glinides) should be discontinued


After 2-3 months…

If HbA1c is <7%Continue regimen and check HbA1c every 3 months

If HbA1c is ≥7%Recheck pre-meal blood glucose If premeal blood glucose is out of range, continue to intensify

insulin therapy with introduction of a second injection of prandial insulin


60

Further intensifying insulin to basal bolus

Recheck pre-meal blood glucose

If out of range, may need to add a third injection of prandial insulin

If HbA1c is still ≥7% Check 2-hr postprandial levels Adjust preprandial rapid-acting insulin


Basal plusBasal +

1 prandial

A logical stepwise approach

Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.

Basal insulinonce daily

(treat-to-target)

Basal plusBasal +

2 prandial

Basal bolus Basal +

3 prandial

Lifestyle+

Metformin

± SU

HbA1c ≥7.0%, FBG on targetPPG ≥160 mg/dLHbA1c ≥7.0%

Time


62

Place of premixed insulins

Premixed insulins are not recommended For initiation or during adjustment of doses

If the proportion of rapid- and intermediate-acting insulin is similar to the fixed proportions available Can be used before breakfast and/or dinner


Potential limitations of premixed insulin analogues in clinical practice

Lack of flexibility: ratio of the 2 insulin components cannot be adjusted separatelyStructured meal content and timing needed

No flexible regimen of self-titration Regimens based on carbohydrate counting difficult to

devise

Insulin coverage may not address early-morning and/or postlunch hyperglycemia

Not suitable when food intake is held (eg, in the inpatient setting)

Rizvi AA, et al. Insulin 2007;2:68–79.

ADA/EASD consensus algorithmfor the initiation and adjustmentof therapy for the managementof hyperglycemia in Type 2 Diabetes

4b

Tier 2

65

ADA/EASD consensus algorithm




Call to action if HbA1c is 7%

Lifestyle + Metformin+ PioglitazoneNo hypoglycaemiaOedema/CHFBone loss

Lifestyle + Metformin+ GLP-1 agonistNo hypoglycaemiaWeight lossNausea/vomiting

Lifestyle + Metformin+ Pioglitazone+ Sulfonylurea


Tier 2:Less well validated therapies


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ADA/EASD consensus algorithmSummary

STEP 3

Timely basal insulin therapy for patients not meeting targets

STEP 2

STEP 1 Lifestyle intervention + metformin

Add basal insulin or SU

Intensify therapy


ConclusionsA new sense of urgency

Early intervention

Patient’s empowermentEducation, SMBG, treatment adjustment

Shorten delays in treatment changes

Achieve and maintain normal glycemic goals

Add medications, transition to new regimens quicklyWhenever HbA1c levels are ≥7%



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HbA1c 7%

Call to action

=

68Nathan DM, et al. Diabetes Care 2009;32 193-203.

SALAMAT PO

69

Summary of glucose-lowering interventions

Intervention Expected decrease in HbA1Cwith monotherapy (%) Advantages Disadvantages

Tier 1: well-validated coreStep 1: initial therapy

Lifestyle to decrease weight and increase activity 1.0-2.0 Broad benefits Insufficient for most within first year

Metformin 1.0-2.0 Weight neutral GI side effects, contraindicated with renal insufficiency

Step 2: additional therapy

Insulin 1.5-3.5 No dose limit, rapidly effective, improved lipid profile

One to four injections daily, monitoring, weight gain, hypoglycemia, analogues are expensive

Sulfonylurea 1.0-2.0 Rapidly effective Weight gain, hypoglycemia (especially with glibenclamide or chlorpropamide)

Tier 2: less well validated

TZDs 0.5-1.4Improved lipid profile

(pioglitazone), potential decrease in MI (pioglitazone)

Fluid retention, CHF, weight gain, bone fractures, expensive, potential increase in MI (rosiglitazone)

GLP-1 agonist 0.5-1.0 Weight loss Two injections daily, frequent GI side effects, long-term safety not established, expensive

Other therapy

-Glucosidase inhibitor 0.5-0.8 Weight neutral Frequent GI side effects, three times/day dosing, expensive

Glinide 0.5-1.51 Rapidly effective Weight gain, three times/day dosing, hypoglycemia, expensive

Pramlintide 0.5-1.0 Weight loss Three injections daily, frequent GI side effects, long-term safety not established, expensive

DPP-4 inhibitor 0.5-0.8 Weight neutral Long-term safety not established, expensive

1.Repaglinide more effective in lowering HbA1C than nateglinide. CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction.



Documents

Nines P Bautista, MD, MS