Nines P Bautista, Md, Ms

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes OBJECTIVES 1.Loco-regional data on T2DM  Epidemiology  Quality of glucose control

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

2.Target HbA1c  Which target for HbA1c?  HbA1c <6.0%?

3.Lowering glucose & tackling CV risk factors A consensus algorithm for the initiation and adjustment of therapy

4.Consensus algorithm  Basal , Basal plus and Basal Bolus in Diabetes Management  Tier 1: well validated therapies

ADA / EASD Update of January 2009

3

IC.DIA.08.12.01

Diabetes is an increasing healthcare epidemic throughout the world

National Diabetes Survey 1982 WHO - MOH

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

Eastern Mediterranean and Middle East

67.0 99.4 +48%

Europe 24.5 44.5 +81%

North America South and Central America South-East Asia Western Pacific

10.4 18.7 +80%

16.2 32.7 +102%

IDF. Diabetes Atlas 3rd Edition – 2006

1 M Diabetics in R.P. 1 M I.G.T. 270,000 in Metro Manila Prevalence: 8.4% NCR 6.5% urban 2.5% rural 4.1% National (20 - 65 yrs) peak: 45-55

53.2 64.1 +21%

28.3 40.5 +43%

Africa

46.5 80.3 +73%

Worldwide: 246 million people in 2007 380 million projected for 2025 55% increase

4

Philippine Data 2007 COS

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

Developing Countries

60



Incidence rate of IFG = 10% Prevalence rate of DM = 18%



Prevalence rate of IFG = 31%



Prevalence rate of IGT = 26%

160 140

50

diabetes (millions)



Incidence rate of DM = 12%

Estimatednumber of peoplewith



120 40

100

30

80 60

20

40 10

20

0

0

20–44

PHILCOS 2007 UNITE FOR DIABETES D IABETES

45–64

65+

20–44

2000

PHIL J INT MED 45;211-218

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

45–64

65+

2030 7

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes NHANES reveals the under-management of diabetes 

NHANES 1999 – 2000 population with diabetes



Mean HbA1c value was 7.8%

Is glycemic control improving over time? % 40

1999-2000

35

2001-2002

 37% had an HbA1c value <7.0%

30

2003-2004

 26% had an HbA1c value of 7.0–8.0%

25

 37% had an HbA1c value >8.0%

20 15



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

10 5 0

<6.0%

6.0 – 6.9% 7.0 – 7.9%

8.0 – 8.9%

≥10.0%

9.0 – 9.9%

HbA1c levels 8

Saydah S, et al. JAMA 2004;291:335–42.

US data in adults

Change over time in guidelines for evaluating hyperglycemia

Clinical inertia Failure to advance therapy when required Percentage of subjects advancing when HbA1C >8% 

70

Time period

 5 years with HbA1C >8%  10 years with HbA1C >7%

<1993 (pre-DCCT)

60 %of Subjects

Type of guideline

At insulin initiation, the average patient had:

66.6%

>1993 (post-DCCT)

50

44.6%

40

35.3%

1997 to present

30

Threshold for initiating or changing treatment Threshold for initiating or changing treatment Recommended treatment goals (UKPDS)

18.6%

20 10

2000

0 Diet

Sulfonylurea

Metformin

Combination 10

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

HbA1c targets in current guidelines

<7.0 ≤6.5 <6.5 ≤6.5 <6.5* ≤7.0 ≤7.0 <6.5

FPG (mg/dL)

HbA1c (%)

200

-

9-10

140

150

8

80-120

90-130

<7

New diagnostic criteria for diabetes

-

126

-

Definition of normoglycemia

99

109

<6

FBG: fasting blood glucose FPG: fasting plasma glucose DCC T: Diabetes Control and Complications Trial Hollander PA. Postgrad Med 2000;Special Report:4-10.



11

Glycemic goals of therapy are based on:  Clinical studies

-

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

 Epidemiological data 

"Normal" HbA1c



Goals of therapy in DCCT and UKPDS

 Upper limit of nondiabetic range: 6.1%

For sanofi-aventis affiliates: Add local guidelines as needed

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

FBG (mg/dL)

Rationale for glycemic goals

HbA1c target (%) ADA/EASD IDF NICE AACE France Canada Australia Latin America

9

NHANES Diabetes Care 2008;31:81–86.

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

12

 Neither study was able to maintain HbA1c level in the nondiabetic range  HbA1c ~ 7% in intensive treatment groups

-

i.e., 4 SD above nondiabetic mean

DCC T 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.

13

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes Benefits of intensive vs conventional glycemic management

Risk of complications Benefits of lowering hemoglobin HbA1c

10

16 RelativeRisk

HbA1c (%)

UKPDS conventional UKPDS intensive

8 7

DCCT intensive

of complications

DCCT conventional 9

6

12 8 4 0

6

7

8

5

9

10

11

12

270

300

Hemoglobin HbA1c (%)

0

1

2

3

4

5

6

7

8

9 Average Glucose mg/dl

Time (y) 14

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

Epidemiologic data from the UKPDS

80 Myocardial infarction

150

180

210

240

15

Fasting blood glucose is an important determinant of CVD burden

No HbA1c threshold in Type 2 Diabetes Adjusted incidenc e per 1000 person years (%)

120

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

4.0

Total stroke

Total ischemic Heart disease

CV death

Hazardratio(95%CI)

Microvascular endpoints 60

ADA goal 40

?

2.0

1.0

20 0.5

Risk

Risk

Risk

21% (CI 18-24) rise per 1 mmol/L rise in glucose

23% (CI 19-27) rise per 1 mmol/L rise in glucose

19% (CI 15-22) rise per 1 mmol/L rise in glucose

4.5 5.0 5.5

0 5

6

7

8

9

10

6.0

6.5 7.0

7.5

11

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

Usual fasting glucose (mmol/L)

Updated mean HbA 1C (%) Stratton IM, et al. BMJ. 2000;321:405-412.

16

Glucose lowering to prevent CVD

Why not aiming for lower HbA1c?

Trials in people with dysglycemia Yrs from Dx





17

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

-10

-5

0

5

Normal HbA1c levels are difficult to achieve with present therapies

10

15

ACCORD VADT

Intensive therapy increases the risk of weight gain and hypoglycemia

ADVANCE ORIGIN



The absolute risks and benefits of lower HbA1c are largely unknown… Eye, Kidney, Nerve Disease CVD

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

18

19

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes T2DM guidelines focus on glycaemic control and CVD risk factors

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 action to initiate or change therapy



HbA1c levels correlate with the development of diabetic complications



Multiple CVD risk factors cluster in T2DM  Dyslipidaemia  Hypertension  Obesity



Goal: HbA1c <7%

 Hypercoagulability

 But need for an individualised target

 Insulin resistance 

20

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

Recommendations for BP and CV risk factors ADA

IDF

ESC/EASD

Annually (at every visit if above target)

-

<130/80 mmHg

<130/80 mmHg

<130/80 mmHg

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)

BP targets Lipid measurements

HDL target

50 mg/dl (1.3 mmol/l)

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.

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

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



Guidelines interpret existing evidence in order to help all physicians



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

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



Guidelines should be revised as new evidence accrues

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



Guidelines do not replace clinical judgement in the individual patient

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

BP: blood pressure CV: cardiovascular

22

Rationale for this updated consensus

First Consensus algorithm



 But very few head-to-head comparisons 

Clinical judgment  Medical knowledge

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.

Clinical trials  Effectiveness & safety

1st Update  January 2008: Update regarding thiazolidinediones2



23

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

 August 20061 

21



History of ADA/EASD consensus algorithm



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.

Why guidelines for the treatment of T2DM?

At every visit

BP measurement

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

 Clinical experience

24

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

Benefits, risks, costs

25

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

HbA1c targets should be individualized 

Goal of therapy





Call to action: HbA1c 7%



Less stringent goals may be appropriate for:

-



 

 Individuals with co-morbid conditions

  26

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

Overarching principles Early intervention Patient’s empowerment

 

27

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

Intervention

 Education, SMBG, treatment adjustment 

Safety profiles Tolerability Ease of use Cost

Expected HbA1c reduction according to intervention

ADA/EASD consensus algorithm



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

- Potentially earlier initiation of combination therapy Extraglycemic effects that may reduce long-term complications

 Hypertension, dyslipidemia, BMI, insulin resistance, insulin secretory capacity

 Patients with a history of severe hypoglycemia  Patients with limited life expectancies  Very young children or older adults



Effectiveness in lowering blood glucose  When high HbA1c (≥8.5%)

 In general: HbA1c <7%  In the individual patient: HbA1c as close to 6% as possible without significant hypoglycemia

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 + metformin STEP 2: Add another agent – basal insulin or SU STEP 3: Intensify therapy

Expected ↓ in HbA1c (%)

Lifestyle interventions Metformin Sulfonylureas Insulin

1 1 1 1.5

to 2% to 2% to 2% to 3.5%

Glinides Thiazolidinediones -Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors

1 0.5 0.5 0.5 0.5 0.5

to to to to to to

1.5%1 1.4% 0.8% 1.0% 1.0% 0.8%

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

28

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

ADA/EASD consensus algorithm Tier 1:

Call to action if HbA1c is 7%

well-validated therapies

Lifestyle + Metformin + Basal insulin At diagnosis: Lifestyle + Metformin

STEP 1

Lifestyle + Metformin + Intensive insulin

Lifestyle modifications

Lifestyle + Metformin + Sulfonylurea STEP 2

STEP 3

Tier 2: Less well validated therapies

Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss

Lifestyle + metformin + GLP-1 agonist No hypoglycaemia Weight loss Nausea/vomiting Nathan DM, et al. Diabetes Care 2009;32 193-203.

Medical Nutrition Therapy (MNT) Lifestyle + Metformin + Pioglitazone + S ulfonylurea

Weight loss Physical activity

Lifestyle + metformin + Basal insulin 30

29

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes ADA/EASD consensus algorithm: step 2

STEP 1

ADA/EASD consensus algorithm: step 2

Lifestyle + Metformin + Basal insulin At diagnosis: Lifestyle + Metformin



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:

STEP 2

 Most of newly diagnosed Type 2 Diabetic patients will usually respond to sulfonylurea*

HbA1c 7%

 Basal insulin if HbA1c >8.5% or symptoms of hyperglycemia Lifestyle + Metformin + Sulfonylurea

When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effectiveness, or potentially earlier initiation of combination therapy, are recommended 32

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

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

33

ADA/EASD consensus algorithm: step 2

ADA/EASD consensus algorithm: step 2

Addition of sulfonylurea

Insulin initiation

STEP 1

STEP 2

STEP 1

STEP 2

Lifestyle + Metformin + Basal insulin At diagnosis: Lifestyle + Metformin

HbA1c 7%

At diagnosis: Lifestyle + Metformin

HbA1c 7%

HbA1c 7%

Lifestyle + Metformin + Sulfonylurea*

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

Lifestyle + Metformin + Sulfonylurea

34

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





35

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

Attributes of insulin

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

How it works Expected HbA1c reduction

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

Direct compensation for lack of insulin sensitivity • 1.5 to 3.5% • No maximum dose +++

Adverse events

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

Hypoglycemia

Weight effects

Weight gain of ~ 2–4 kg • Beneficial effect on TG and HDL

CV effects • Weight gain may have an adverse effect on CV risks

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

36

HDL: TG: triglycerides CV: cardiovascular Nathan DM, et al. Diabetes Care 2009;32:193-203.

37

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

Disadvantages of insulin therapy



Oldest medication, with most clinical experience



Most effective in lowering glycemia



 ± proportional to the correction of glycemia  Predominantly the result of  glycosuria

 Can decrease any level of elevated HbA1c



 No maximum dose of insulin 

Weight gain ~ 2-4 kg

Hypoglycemia  Rates of severe hypoglycemia in patients with T2DM are low in treat-to-target clinical trials (compared to T1DM):

Beneficial effects on triglyceride and HDL-c

-

38

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

Type 1 DM: 61 events per 100 patient-years Type 2 DM: 1 to 3 events per 100 patient-years

39

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

INSULIN TACTICS

INSULIN TACTICS

Ideal Treatment

Insulin

Insulin

Normal Insulin Secretion

N BCF

N

B

L

S

B

B

L

S Meals

Meals

Initiating and adjusting insulin

A Simple way to add & titrate basal insulin

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

Target range: 3.89-7.22 mmol/L (70-130mg/dL)

INITIATE

If HbA1c 7%

• Bedtime or morning long-acting insulin OR • Bedtime intermediate-acting insulin Daily dose: 10 units or 0.2 units/kg Check FPG daily

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

Continue regimen; check HbA1c every 3 months

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

Initiate insulin with a single injection of a basal insulin

(initiate with 10 units or 0.2 units per kg)

Check FG and increase dose until in target range

If HbA1c < 7%

B

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

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

If HbA1c < 7%

Continue regimen; check HbA1c every 3 months

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

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

TITRATE

• 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

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

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

42

MONITOR

Continue regimen and check HbA1c every 3 months

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

43

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes Basal insulin analogues offer advantages over basal human insulins

Types of basal insulin



Long-Acting (e.g. ultralente)

1-3 hr(s)

3-4 hrs

1.5-3 hrs

5-8 hrs

8-15 hrs

No peak with glargine, dose-dependent peak with detemir

Up to 18 hrs

22-26 hrs

9-24 hrs (detemir); 20-24 hrs (glargine)

Onset

Compared with human basal insulins, basal insulin analogues:    

IntermediateActing (e.g. NPH, lente)

Long-Acting Analogues (glargine, detemir)

Have more physiological action profiles Exhibit less variability Reduce the risk of hypoglycaemia Are associated with less weight gain

Insulinlevel

Duration

Human insulin (intermediate acting)

(long ac ting)

Insulinlevel

Insulin analogue

Peak

0

4

8

12

16

20

24

0

Hours post dose

44

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

8 1 4

Insulin glargine 0.3 IU/kg

0 0

4

8

12

0 16

20

10

9.59%

9

9.49%

24 20

3 16 12

2

8

Insulin glargine

1

4 Insulin detemir 0

0

24

0

4

8

Time (hours)

12

16

20

HbA1c (%)

Glucoseinfusionrate(mmol/kg/min)

Glucoseinfusionrate(mg/kg/min)

12

20

24

NPH

4

Glucoseinfusionrate(µmol/kg/min)

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

2

Glucose infusionrate (µmol/kg/min)

20

NPH 0.3 IU/kg 3

16

45

SC injection 0.35 IU/kg 24

12

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.

T1DM patients (n=24)2

SC injection 4

8

Hours post dose

Adding basal insulin to metformin is particularly effective in lowering HbA1c

Basal insulin analogues

T1DM patients (n=20)1

4

Glargine

8

7.16% 7

7.14%

Reference range 4.0- 6.0% 6

24

-4

Time (hours)

0

12

24

36

Time (weeks)

46

1. Lepore M, et al. Diabetes 2000;49:2142–8. 2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.

Insulin glargine has proven efficacy in combination with metformin + sulfonylurea

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

47

Choosing a basal insulin with a lower risk of hypoglycemia

9.5 9.0

8.9

8.8

Baseline

8.8

8.7

8.6



Endpoint

HbA1c(%)

8.5 8.0

7.6

7.5 7.0

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

7.2 7.0

7.1

7.0

6.8

6.8

6.5 6.0 5.5 5.0 T-T-T1

LAPTOP2

SU: sulfonylurea 1. 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.

Triple Therapy3

APOLLO4

INITIATE5

TULIP6

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

48

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

49

Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes Titrate basal insulin as long as FPG above target range

Less hypoglycemia with glargine vs NPH 11 randomized controlled trials; n=3,083

Meta-Regression Analysis

Rate of Hypoglycemia

(Events/100 Patient-Years)

• Bedtime or morning long-acting insulin OR • Bedtime intermediate-acting insulin Daily dose: 10 units or 0.2 units/kg

INITIATE

200

Check FPG daily

p=0.021

150

NPH insulin

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

• Increase dose by 2 units every 3 days

100

TITRATE

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

50

Insulin glargine 0 6

7

8

9

MONITOR

10

Continue regimen and check HbA1c every 3 months

HbA1c (%) 50

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

The patient: A key player in the diabetes care team

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

51

After 2-3 months…

Need for training and empowerment 

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

Self-Monitoring Blood Glucose (SMBG)



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

To determine whether blood glucose targets are achieved

Medication Self-Adjustment (under HCP guidance)

-

Titrate basal insulin

 If FPG within target range:

Achieve glycemic targets

Prevent and treat hypoglycemias

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.

52

ADA/EASD consensus algorithm step 3

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

Tier 1: Well-validated therapies STEP 2

53

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

Intensify insulin if HbA1c is still ≥7%

Intensifying insulin therapy

STEP 1

Intensify insulin therapy…

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

STEP 3

add Lifestyle + Metformin + Basal insulin At diagnosis: Lifestyle + Metformin

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

HbA1c 7%

Lifestyle + Metformin + Intensive insulin

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

or

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

or

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

Lifestyle + Metformin + Sulfonylurea

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Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes Rapid-acting insulin analogues reduce risk of PP hyperglycaemia and late hypoglycaemia

Attributes of prandial insulin

Meal 80

Short-Acting

(e.g. aspart, lispro, glulisine)

(e.g. regular human insulin)

Onset

5 - 15 mins

30 - 60 mins

Peak

30 - 90 mins

2 - 3 hrs

4 - 6 hrs

8 - 10 hrs

Duration

Normal post-prandial values

Better PPBG control

Subcutaneous insulin Plasma-free insulin(µU/mL)

Rapid-Acting

Regular human insulin (RHI) Insulin lispro, insulin aspart, or insulin glulisine

60

40 Lower risk of late post-prandial hypoglycaemia 20

0 0

2

4

6

8

10

12

Time after insulin injection or meal ingestion (hours) Adapted from Hirsch IB, N Engl J Med 2005;352:174-83.

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Initiation & titration of prandial insulin

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

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After 2-3 months…



Can usually begin with ~4 units



If HbA1c is <7%



Adjust by 2 units every 3 days until plasma glucose is in range



If HbA1c is ≥7%



 Continue regimen and check HbA1c every 3 months

 Recheck pre-meal blood glucose

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

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

 If premeal blood glucose is out of range, continue to intensify insulin therapy with introduction of a second injection of prandial insulin

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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%

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A logical stepwise approach

Basal bolus Basal plus Basal plus Basal insulin

Bas al + 2 prandial

Basal + 3 prandial

Basal + 1 prandial

once daily (treat-to-target)

 Check 2-hr postprandial levels  Adjust preprandial rapid-acting insulin

Lifestyle + Metformin

± SU

HbA1c ≥7.0%, FBG on target PPG ≥160 mg/dL

HbA1c ≥7.0% Time

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

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

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Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes Potential limitations of premixed insulin analogues in clinical practice

Place of premixed insulins



Premixed insulins are not recommended



Lack of flexibility: ratio of the 2 insulin components cannot be adjusted separately



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)

 For initiation or during adjustment of doses 

 Structured meal content and timing needed

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

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

ADA/EASD consensus algorithm Tier 2:

4b

Call to action if HbA1c is 7%

Less well validated therapies

Lifestyle + Metformin + Intensive insulin At diagnosis: Lifestyle + Metformin

Tier 2 STEP 1

ADA/EASD consensus algorithm for the initiation and adjustment of therapy for the management of hyperglycemia in Type 2 Diabetes

STEP 2

Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss

Lifestyle + Metformin + GLP-1 agonist No hypoglycaemia Weight loss Nausea/vomiting

STEP 3

Lifestyle + Metformin + Pioglitazone + S ulfonylurea

Lifestyle + Metformin + Basal insulin

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

ADA/EASD consensus algorithm

Conclusions

Summary

A new sense of urgency Timely basal insulin therapy for patients not meeting targets

STEP 1

Lifestyle intervention + metformin

STEP 2

Add basal insulin or SU

STEP 3



Early intervention



Patient’s empowerment

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 Education, SMBG, treatment adjustment

Intensify therapy



Shorten delays in treatment changes



Achieve and maintain normal glycemic goals



Add medications, transition to new regimens quickly  Whenever HbA1c levels are ≥7%

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Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes Summary of glucose-lowering interventions

SALAMAT PO

Expected decrease in HbA1C with monotherapy ( %)

Advantages

Lifestyle to decrease weight and increase activity

1.0-2.0

Broad benefits

Insufficient for most within first year

Metfor min

1.0-2.0

W eight neutral

GI side effects, contraindicated with renal insufficiency

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)

TZDs

0.5-1.4

Improved lipid profile (pioglitazone), potential decrease in MI (pioglitazone)

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

GLP-1 agonist

Two injections daily, frequent GI side effects, longterm safety not established, expensive

Intervention

Disadvantages

Tier 1: well-validated core Step 1: initial therapy

HbA1c 7%

Step 2: additional therapy

=

Tier 2: less well validated

Call to action

0.5-1.0

Weight loss

-Glucosidase inhibitor

0.5-0.8

W eight neutral

Frequent GI side effects, three times/day dosing, expensive

Glinide

0.5-1.51

Rapidly effective

W eight 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

W eight neutral

Long-term safety not established, expensive

Other therapy

1.Repaglinide more effective in lowering HbA 1C than nateglinide. CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction. Nathan DM, et al. Diabetes Care 2009;32 193-203.

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