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 2.Target HbA1c
Type 2 Diabetes  Which target for HbA1c?
 HbA1c <6.0%?
3.Lowering glucose & tackling CV risk factors
A consensus algorithm for 4.Consensus algorithm
the initiation and adjustment of therapy
 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
Global projections for the number of people with diabetes
National Diabetes Survey
(20–79 age group), 2007–2025 (millions)
1982 WHO - MOH
28.3
53.2 1 M Diabetics in R.P.
64.1

Africa
40.5
+43%
+21% 1 M I.G.T.
Eastern Mediterranean
and Middle East
67.0
270,000 in Metro Manila
Europe 99.4
North America
24.5
44.5
+48% Prevalence: 8.4% NCR
+81%
South and Central America
South-East Asia
46.5
80.3
6.5% urban
10.4 +73%
Western Pacific
16.2
32.7
18.7
+80%
2.5% rural
+102%
4.1% National (20 - 65 yrs)
Worldwide:
246 million people in 2007
peak: 45-55
380 million projected for 2025
55% increase 4
IDF. Diabetes Atlas 3rd Edition – 2006

In developing countries, diabetes will affect

Philippine Data 2007 people aged 45−65 years

COS Developed Countries Developing Countries

60 160

 Incidence rate of DM = 12%

Estimatednumber of peoplewith

140
50

 Incidence rate of IFG = 10% 120

diabetes (millions)

40
100

30 80

 Prevalence rate of DM = 18% 60

20

 Prevalence rate of IFG = 31% 40

10
20
 Prevalence rate of IGT = 26%
0 0
PHILCOS 2007 UNITE FOR DIABETES
D IABETES 20–44 45–64 65+ 20–44 45–64 65+

2000 2030
7
PHIL J INT MED 45;211-218 Wild S, et al. Diabetes Care 2004;27(5):1047–1053.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
NHANES reveals the under-management
Is glycemic control improving over time?
of diabetes

%
 NHANES 1999 – 2000 population with diabetes 40 1999-2000
35 2001-2002
 Mean HbA1c value was 7.8%
30 2003-2004
 37% had an HbA1c value <7.0%
25
 26% had an HbA1c value of 7.0–8.0%
20
 37% had an HbA1c value >8.0%
15

 27% were receiving insulin therapy with or without Oral 10

Glucose Lowering Drugs
5

0
<6.0% 6.0 – 6.9% 7.0 – 7.9% 8.0 – 8.9% 9.0 – 9.9% ≥10.0%

HbA1c levels
8 US data in adults 9
Saydah S, et al. JAMA 2004;291:335–42. NHANES Diabetes Care 2008;31:81–86.

Clinical inertia Change over time in guidelines

Failure to advance therapy when required for evaluating hyperglycemia
Percentage of subjects advancing when HbA1C >8% FBG FPG HbA1c
Time period Type of guideline
(mg/dL) (mg/dL) (%)
 At insulin initiation, the average patient had:
 5 years with HbA1C >8% Threshold for
66.6%
<1993 (pre-DCCT) initiating or changing 200 - 9-10
70  10 years with HbA1C >7% treatment
60 Threshold for
>1993 (post-DCCT) initiating or changing 140 150 8
50 treatment
%of Subjects

44.6%
Recommended
40 35.3% treatment goals 80-120 90-130 <7
(UKPDS)
30 1997 to present
18.6% New diagnostic
20 - 126 -
criteria for diabetes
10
Definition of
2000 normoglycemia
99 109 <6
0
Diet Sulfonylurea Metformin Combination
FBG: fasting blood glucose
FPG: fasting plasma glucose
DCC T: Diabetes Control and Complications Trial
10 11
Brow n et al. Diabetes Care 2004;27:1535-1540. Hollander PA. Postgrad Med 2000;Special Report:4-10.

HbA1c targets in current guidelines Rationale for glycemic goals

HbA1c target (%)

 Glycemic goals of therapy are based on:
ADA/EASD <7.0  Clinical studies
IDF ≤6.5 - Type 1: DCCT, Stockholm Diabetes Intervention Study
- Type 2: UKPDS, Kumamoto
NICE <6.5  Epidemiological data
AACE ≤6.5
France <6.5*  "Normal" HbA1c
 Upper limit of nondiabetic range: 6.1%
Canada ≤7.0
Australia ≤7.0  Goals of therapy in DCCT and UKPDS
For sanofi-aventis
Latin America <6.5 affiliates:  Neither study was able to maintain HbA1c level
in the nondiabetic range
Add local guidelines as  HbA1c ~ 7% in intensive treatment groups
needed
- i.e., 4 SD above nondiabetic mean
*If on single or double therapy; if on triple therapy or insulin, then HbA1c <7%
DCC T Research Group. N.Eng.J.Med.1993;329:977-986.
Nathan DM, et al. Diabetes Care 2009;32 193-203 Drouin P, et al. Diabetes & Metabolism (Paris) 1999;25:72-83. Raichard P, et al. Acta Medica Sandinavica 224(2):115-122.
http://www .idf.org/home/index.cfm?node=1457 Canadian Diabetes Association Canadian J Diab:32(suppl. 1):S1-201 UKPDS Group Lancet 1998;352:837-53.
http://www .nice.org.uk/nicemedia/pdf/CG66diabetesfullguideline.pdf http://www.nhmrc.gov.au/publications/synopses/_files/di10.pdf 12 Ohkubo Y, et al. Diabetes Res Clin Pract 1995;28:103–117. 13
Endocrine Practice Vol 13 (Suppl 1) May/June 2007 http://www.revistaalad.com.ar/guias/GuiasALAD_DMTipo2_v3.pdf Nathan DM, et al. Diabetes Care 2009;32 193-203.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
Benefits of intensive vs conventional Risk of complications
glycemic management Benefits of lowering hemoglobin HbA1c

10
16
DCCT conventional
9

of complications
RelativeRisk
12
HbA1c (%)

8 UKPDS conventional
UKPDS intensive 8

7
DCCT intensive 4

6
0
6 7 8 9 10 11 12
5 Hemoglobin HbA1c (%)
0 1 2 3 4 5 6 7 8 9
Average Glucose
Time (y) 120 150 180 210 240 270 300
mg/dl

14 Adapted from UKPDS 33: Lancet 1998;352:837-853. 15

Turner R, et al. Ann Intern Med. 1996;124:136-145. Adapted from DCCT Study Group. N Engl J Med 1993;329:977.

Fasting blood glucose is an important

No HbA1c threshold in Type 2 Diabetes
determinant of CVD burden
Adjusted incidenc e per
1000 person years (%) Epidemiologic
80 data from Total stroke Total ischemic CV death
Myocardial infarction 4.0
the UKPDS Heart disease
Microvascular endpoints
Hazardratio(95%CI)

60
2.0

ADA goal
40
1.0
?

20
Risk Risk Risk
0.5 21% (CI 18-24) rise per 23% (CI 19-27) rise per 19% (CI 15-22) rise per
1 mmol/L rise in glucose 1 mmol/L rise in glucose 1 mmol/L rise in glucose

0 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 4.5 5.0 5.5 6.0 6.5 7.0 7.5
5 6 7 8 9 10 11
Usual fasting glucose (mmol/L)
Updated mean HbA 1C (%)
16 CVD: cardiovascular disease 17
Stratton IM, et al. BMJ. 2000;321:405-412. Asia Pacific Cohort Studies Collaboration. Diabetes Care 2004;27:2836-2842.

Why not aiming for lower HbA1c? Glucose lowering to prevent CVD
Trials in people with dysglycemia

Yrs from Dx -10 -5 0 5 10 15

 Normal HbA1c levels are difficult to achieve with present
therapies 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

18 19
American Diabetes Association. Diabetes Care 2008;31(Suppl 1):S12-S54.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
T2DM guidelines focus on glycaemic
HbA1c- How low is low enough?
control and CVD risk factors

 Benefit of intensive glycemic control on CVD outcomes  HbA1c levels correlate with the development of diabetic
not proven complications
 Multiple CVD risk factors cluster in T2DM
 HbA1c level of ≥7% should serve as a call to action  Dyslipidaemia
to initiate or change therapy  Hypertension
 Obesity
 Goal: HbA1c <7%  Hypercoagulability
 But need for an individualised target  Insulin resistance
 Thus, control of hyperglycaemia and CVD risk factors
is the focus of T2DM treatment

IDF Clinical Guidelines Task Force. Brussels, 2005.

20 ADA. Diabetes Care 2008;31(Suppl. 1):S12–54. 21
Nathan DM, et al. Diabetes Care 2009;32 193-203. Ryden L, et al. Eur Heart J 2007;28:88–136.

Recommendations for BP and

Why guidelines for the treatment of T2DM?
CV risk factors

ADA IDF ESC/EASD  Diabetes is a complex and progressive disease, requiring

Annually timely treatment escalation
BP measurement At every visit (at every visit if -
above target)
 Guidelines interpret existing evidence in order to help
BP targets <130/80 mmHg <130/80 mmHg <130/80 mmHg all physicians
Lipid measurements Annually Annually -
 The increase in the number of available therapies has
100 mg/dl <95 mg/dl <70 mg/dl
LDL target
(2.6 mmol/l) (2.5 mmol/l) (1.8 mmol/l) increased treatment options
150 mg/dl <200 mg/dl <150 mg/dl
Triglyceride target
(1.7 mmol/l) (<2.3 mmol/l) (<1.7 mmol/l)  Guidelines should be revised as new evidence accrues
male >40 mg/dl
50 mg/dl >39 mg/dl (>1.0 mmol/l)  Guidelines do not replace clinical judgement in
HDL target
(1.3 mmol/l) (>1.0 mmol/l) female >46 mg/dl the individual patient
(>1.2 mmol/l)

IDF Clinical Guidelines Task Force. Brussels, 2005.

BP: blood pressure
ADA. Diabetes Care 2008;31(Suppl. 1):S12–54. 22 23
Ryden L, et al. Eur Heart J 2007;28:88–136. CV: cardiovascular Nathan DM, et al. Diabetes Care 2009;32 193-203.

History of ADA/EASD consensus algorithm Rationale for this updated consensus

 First Consensus algorithm  Clinical trials

 August 20061
 Effectiveness & safety

 1st Update  But very few head-to-head comparisons

 January 2008: Update regarding thiazolidinediones2
 Clinical judgment
 2nd Update  Medical knowledge
Benefits, risks, costs
 January 20093  Clinical experience

1. Nathan DM, et al. Diabetes Care 2006;29(8):1963-72.

2. Nathan DM, et al. Diabetes Care 2008;31(1):173-5. 24 25
3. Nathan DM, et al. Diabetes Care 2009;32:193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
Principles in selecting antihyperglycemic
HbA1c targets should be individualized
interventions

 Goal of therapy  Effectiveness in lowering blood glucose

 In general: HbA1c <7%  When high HbA1c (≥8.5%)
- Classes with greater and more rapid glucose-lowering
 In the individual patient: HbA1c as close to 6% as possible effectiveness are recommended
without significant hypoglycemia - Potentially earlier initiation of combination therapy
 Call to action: HbA1c 7%  Extraglycemic effects that may reduce long-term
complications
 Less stringent goals may be appropriate for:  Hypertension, dyslipidemia, BMI, insulin resistance, insulin
 Patients with a history of severe hypoglycemia secretory capacity
 Patients with limited life expectancies  Safety profiles
 Very young children or older adults  Tolerability
 Individuals with co-morbid conditions
 Ease of use
 Cost
26 27
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.

ADA/EASD consensus algorithm Expected HbA1c reduction according

Overarching principles to intervention

 Early intervention Intervention Expected ↓ in HbA1c (%)

 Patient’s empowerment Lifestyle interventions 1 to 2%
 Education, SMBG, treatment adjustment Metformin 1 to 2%
 Shorten delays in treatment changes Sulfonylureas 1 to 2%
 Achieve and maintain normal glycemic goals Insulin 1.5 to 3.5%
 Add medications, transition to new regimens quickly Glinides 1 to 1.5%1
 Whenever HbA1c levels are ≥7% Thiazolidinediones 0.5 to 1.4%
-Glucosidase inhibitors 0.5 to 0.8%
STEP 1: Lifestyle intervention + metformin
GLP-1 agonist 0.5 to 1.0%
STEP 2: Add another agent – basal insulin or SU
Pramlintide 0.5 to 1.0%
STEP 3: Intensify therapy
DPP-IV inhibitors 0.5 to 0.8%
Timely basal insulin therapy for patients not meeting targets
SMBG: self-monitoring blood glucose 1. Repaglinide is more effective than nateglinide
28 29
Nathan DM, et al. Diabetes Care 2009;32:193-203. 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 Lifestyle + Metformin
+ Basal insulin + Intensive insulin
At diagnosis:
Lifestyle +
Metformin
Lifestyle + Metformin
+ Sulfonylurea
Lifestyle modifications
STEP 1 STEP 2 STEP 3

Tier 2: Medical Nutrition Therapy (MNT)

Less well validated Lifestyle + Metformin
therapies + Pioglitazone Lifestyle + Metformin
No hypoglycaemia + Pioglitazone Weight loss
Oedema/CHF + S ulfonylurea
Bone loss
Physical activity
Lifestyle + metformin
+ GLP-1 agonist Lifestyle + metformin
No hypoglycaemia + Basal insulin
Weight loss
Nausea/vomiting
30
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
ADA/EASD consensus algorithm: step 2 ADA/EASD consensus algorithm: step 2

 If step 1 fails to achieve or sustain HbA1c <7%, another

STEP 1 STEP 2
medication should be added within 2-3 months
 The HbA1c level will determine (in part) which agent is
Lifestyle
+ Metformin selected next:
+ Basal insulin
 Most of newly diagnosed Type 2 Diabetic patients will usually
At diagnosis: respond to sulfonylurea*
Lifestyle HbA1c 7%
+  Basal insulin if HbA1c >8.5% or symptoms of hyperglycemia
Metformin
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
* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide
32 33
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203. Nathan DM, et al. Diabetes Care 2009;32:193-203.

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
HbA1c 7%
At diagnosis: At diagnosis:
Lifestyle Lifestyle
+ + HbA1c 7%
Metformin Metformin
HbA1c 7%
Lifestyle Lifestyle
+ Metformin + Metformin
+ Sulfonylurea* + Sulfonylurea

* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide

34 35
Nathan DM, et al. Diabetes Care 2009;32:193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.

ADA/EASD recommend early initiation of

Attributes of insulin
insulin therapy to meet HbA1c targets

 Basal insulin therapy initiated when lifestyle modification

plus metformin, or combination with sulfonylurea, How it works Direct compensation for lack of insulin sensitivity
does not maintain HbA1c <7.0% • 1.5 to 3.5%
Expected HbA1c
reduction
 Insulin therapy may be particularly beneficial in patients • No maximum dose +++
with HbA1c values of >8.5% Adverse events Hypoglycemia

 Insulin regimens should be designed taking lifestyle and Weight effects Weight gain of ~ 2–4 kg
meal schedules into account • Beneficial effect on TG and HDL
CV effects
• Weight gain may have an adverse effect on CV risks

HDL:
TG: triglycerides
CV: cardiovascular
36 37
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32:193-203.
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  Weight gain ~ 2-4 kg

 ± proportional to the correction of glycemia
 Most effective in lowering glycemia  Predominantly the result of  glycosuria
 Can decrease any level of elevated HbA1c
 Hypoglycemia
 No maximum dose of insulin
 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
- Type 1 DM: 61 events per 100 patient-years
- Type 2 DM: 1 to 3 events per 100 patient-years

38 39
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.

INSULIN TACTICS INSULIN TACTICS

Normal Insulin Secretion Ideal Treatment

Insulin
Insulin

N N
BCF

B L S B B L S B
Meals Meals

Initiating and adjusting insulin A Simple way to add & titrate basal insulin

Bedtime intermediate-acting insulin, or

Continue regimen; check
HbA1c every 3 months
Pre-lunch BG out of range: add
rapid-acting insulin at breakfast
bedtime or morning long-acting insulin Initiate insulin with a single injection of a basal insulin
(initiate with 10 units or 0.2 units per kg)
Target range:
Check FG and increase dose until in target range 3.89-7.22 mmol/L • Bedtime or morning long-acting insulin OR
(70-130mg/dL) INITIATE • Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 units/kg
If HbA1c < 7% If HbA1c 7%
Check
FPG
If FBG in target range, check BG before lunch, dinner, and bed. daily
Depending on BG results, add second injection
(can usually begin with ~4 units and adjust by 2 u nits every 3 days until BG in range)
• Increase dose by 2 units every 3 days In the event of hypoglycemia or
until FPG is 3.89–7.22 mmol/L FPG level <3.89 mmol/L
(70–130 mg/dL) (<70 mg/dL)
Pre-dinner BG out of range: add NPH insulin at Pre-bed BG out of range: add TITRATE • Reduce bedtime insulin dose
breakfast or rapid-acting insulin at lunch rapid-acting insulin at dinner • If FPG is >10 mmol/L (>180 mg/dL), by 4 units, or by 10% if >60
increase dose by 4 units every 3 days units

If HbA1c < 7% If HbA1c 7%

Continue regimen; check Recheck pre-meal BG levels and if out of range, may need to add another Continue regimen and
HbA1c every 3 months injection; if HbA1c continues to be out of range, check 2-hr postprandial levels MONITOR check HbA1c every 3 months
and adjust preprandial rapid-acting insulin

FPG, fasting plasma glucose

42 43
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32:193-203.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
Basal insulin analogues offer advantages
Types of basal insulin
over basal human insulins

 Compared with human basal insulins, basal insulin analogues:

 Have more physiological action profiles
Intermediate- Long-Acting
Acting
Long-Acting
Analogues  Exhibit less variability
(e.g. ultralente)  Reduce the risk of hypoglycaemia
(e.g. NPH, lente) (glargine, detemir)
 Are associated with less weight gain
Onset 1-3 hr(s) 3-4 hrs 1.5-3 hrs
Insulin analogue (long ac ting) Human insulin (intermediate acting)
No peak with glargine,
Peak 5-8 hrs 8-15 hrs dose-dependent peak
with detemir

Insulinlevel

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

0 4 8 12 16 20 24 0 4 8 12 16 20 24
Hours post dose Hours post dose

44 Adapted from Tibaldi J, and Rakel R, Int J Clin Pract 2007;61:633–44. 45

Rossetti P, et al. Arch Physiol Biochem 2008;114(1): 3 – 10. Adapted from Choe C, et al. J Natl Med Assoc 2007;99:357–67.

Adding basal insulin to metformin is

Basal insulin analogues
particularly effective in lowering HbA1c

T1DM patients (n=20)1 T1DM patients (n=24)2 10 9.59%

SC injection NPH
SC injection 0.35 IU/kg
4 24 4 24 9 9.49% Glargine
Glucoseinfusionrate(µmol/kg/min)
Glucoseinfusionrate(mmol/kg/min)
Glucose infusionrate (µmol/kg/min)
Glucoseinfusionrate(mg/kg/min)

HbA1c (%)
NPH 0.3 IU/kg 20 20
3 3
16 16 8
CSII (insulin lispro) 12 12 7.16%
2 0.3 IU/kg/24h 2

8 8
Insulin glargine 7
1 1
Insulin glargine
4 4 7.14%
0.3 IU/kg Insulin detemir Reference range 4.0- 6.0%
0 0 0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 6
-4 0 12 24 36
Time (hours) Time (hours)

Time (weeks)

1. Lepore M, et al. Diabetes 2000;49:2142–8. 46 47

2. Porcellati F, et al. Diabetes Care 2007;30:2447–52. Yki-Järvinen H, et al. Diabetologia 2006;49:442–451.

Insulin glargine has proven efficacy in Choosing a basal insulin with a lower risk
combination with metformin + sulfonylurea of hypoglycemia
9.5
Baseline  Insulin analogues with longer, non-peaking profiles
9.0 8.9 8.8 8.8
8.7
8.6
8.5
Endpoint decrease the risk of hypoglycemia…
8.0
HbA1c(%)

7.6
7.5 7.2 7.1
7.0 7.0 6.8 6.8
7.0

6.5

6.0

5.5

5.0
T-T-T1 LAPTOP2 Triple APOLLO4 INITIATE5 TULIP6
Therapy3

SU: sulfonylurea
1. Riddle M, et al. Diabetes Care 2003;26:3080–3086. 4. Bretzel RG, et al. Lancet 2008;371:1073-84.
2. Janka H, et al. Diabetes Care 2005;28:254–259. 5. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364-69. 48 49
3. Rosenstock J, et al. Diabetes Care 2006;29:554–559. 6. Bickle J et al. Diabetes 2008;57(Suppl 1):A139 Nathan DM, et al. Diabetes Care 2009;32 193-203.
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
Less hypoglycemia with glargine vs NPH
target range
Meta-Regression Analysis 11 randomized controlled trials; n=3,083
• Bedtime or morning long-acting insulin OR
INITIATE • Bedtime intermediate-acting insulin
200
Daily dose: 10 units or 0.2 units/kg

Check
(Events/100 Patient-Years)

p=0.021 FPG
Rate of Hypoglycemia

150 daily

NPH insulin • Increase dose by 2 units every 3 days In the event of hypoglycemia or
until FPG is 3.89–7.22 mmol/L FPG level <3.89 mmol/L
100 (<70 mg/dL)
TITRATE (70–130 mg/dL)
• Reduce bedtime insulin dose
• If FPG is >10 mmol/L (>180 mg/dL), by 4 units, or by 10% if >60
increase dose by 4 units every 3 days units
50
Insulin glargine

0
Continue regimen and
6 7 8 9 10 MONITOR check HbA1c every 3 months
HbA1c (%)

FPG, fasting plasma glucose

50 51
Adapted from Mullins P, et al. Clin Ther 2007;29:1607-1619. Nathan DM, et al. Diabetes Care 2009;32:193-203.

The patient:
After 2-3 months…
A key player in the diabetes care team
Need for training and empowerment
 If HbA1c is <7%
Self-Monitoring Blood Glucose  Continue regimen and check HbA1c every 3 months
(SMBG)

 If HbA1c is ≥7%
 If FPG > target range:
Medication Self-Adjustment To determine whether blood glucose
(under HCP guidance) targets are achieved - Titrate basal insulin
 If FPG within target range:
- Intensify insulin therapy…

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. 52 53
Garber AJ, et al. Diabetes Obes Metab 2006;8:58-66. Nathan DM, et al. Diabetes Care 2009;32 193-203.

ADA/EASD consensus algorithm step 3 Intensify insulin if HbA1c is still ≥7%

Intensifying insulin therapy

ADA/EASD recommend the stepwise addition of

Tier 1: Well-validated therapies prandial insulin to intensify a basal insulin regimen

If fasting blood glucose (FBG) levels are in target range but HbA1c 7%,
STEP 1 STEP 2 STEP 3 check blood glucose before lunch, dinner, and bedtime and
add

HbA1c 7%
Lifestyle + Metformin Lifestyle + Metformin
+ Basal insulin + Intensive insulin If pre-lunch blood glucose If pre-dinner blood glucose If pre-bed blood glucose
At diagnosis: is out of range...
or is out of range...
or is out of range...
Lifestyle +
Metformin
Lifestyle + Metformin
+ Sulfonylurea

54 55
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.
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
Attributes of prandial insulin hyperglycaemia and late hypoglycaemia
Meal

80
Normal post-prandial values
Better PPBG
Subcutaneous control Regular human insulin (RHI)
insulin
Rapid-Acting Short-Acting

Plasma-free insulin(µU/mL)
Insulin lispro, insulin aspart,
(e.g. aspart, lispro, glulisine) (e.g. regular human insulin) 60 or insulin glulisine

Onset 5 - 15 mins 30 - 60 mins

40
Peak 30 - 90 mins 2 - 3 hrs Lower risk of late
post-prandial hypoglycaemia
20
Duration 4 - 6 hrs 8 - 10 hrs

0
0 2 4 6 8 10 12
Time after insulin injection or meal ingestion (hours)
PPBG=post-prandial blood glucose
56 57
Adapted from Hirsch IB, N Engl J Med 2005;352:174-83. Bolli GB, Av Diabetol 2007;23:326–32.

Initiation & titration of prandial insulin After 2-3 months…

 Can usually begin with ~4 units  If HbA1c is <7%

 Continue regimen and check HbA1c every 3 months
 Adjust by 2 units every 3 days until plasma glucose
is in range  If HbA1c is ≥7%
 Recheck pre-meal blood glucose
 When prandial insulin is started, insulin secretagogues
(SU or glinides) should be discontinued  If premeal blood glucose is out of range, continue to intensify
insulin therapy with introduction of a second injection of prandial
insulin

58 59
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.

Further intensifying insulin to basal bolus A logical stepwise approach

 Recheck pre-meal blood glucose Basal bolus

Basal plus Basal +
Bas al + 3 prandial
 If out of range, may need to add a third injection of 2 prandial
Basal plus
prandial insulin Basal +
Basal insulin 1 prandial
once daily
 If HbA1c is still ≥7% (treat-to-target)
 Check 2-hr postprandial levels
 Adjust preprandial rapid-acting insulin ± SU
Lifestyle
+
Metformin
HbA1c ≥7.0%, FBG on target
HbA1c ≥7.0% PPG ≥160 mg/dL

Time

60 61
Nathan DM, et al. Diabetes Care 2009;32 193-203. Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
Potential limitations of premixed insulin
Place of premixed insulins
analogues in clinical practice

 Premixed insulins are not recommended  Lack of flexibility: ratio of the 2 insulin components cannot
 For initiation or during adjustment of doses be adjusted separately
 Structured meal content and timing needed
 If the proportion of rapid- and intermediate-acting insulin  No flexible regimen of self-titration
is similar to the fixed proportions available
 Regimens based on carbohydrate counting difficult to
 Can be used before breakfast and/or dinner
devise
 Insulin coverage may not address early-morning and/or
postlunch hyperglycemia
 Not suitable when food intake is held (eg, in the inpatient
setting)

62 63
Nathan DM, et al. Diabetes Care 2009;32 193-203. Rizvi AA, et al. Insulin 2007;2:68–79.

ADA/EASD consensus algorithm

Tier 2: Call to action if HbA1c is 7%
4b Less well validated therapies
Lifestyle + Metformin
+ Intensive insulin
At diagnosis:
Lifestyle +
Metformin

Tier 2
STEP 1 STEP 2 STEP 3

ADA/EASD consensus algorithm

Lifestyle + Metformin
for the initiation and adjustment + Pioglitazone Lifestyle + Metformin
of therapy for the management No hypoglycaemia
Oedema/CHF
+ Pioglitazone
+ S ulfonylurea
of hyperglycemia in Type 2 Diabetes Bone loss

Lifestyle + Metformin
+ GLP-1 agonist Lifestyle + Metformin
No hypoglycaemia + Basal insulin
Weight loss
Nausea/vomiting
65
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  Early intervention

 Patient’s empowerment
STEP 1 Lifestyle intervention + metformin  Education, SMBG, treatment adjustment

 Shorten delays in treatment changes

STEP 2 Add basal insulin or SU
 Achieve and maintain normal glycemic goals

STEP 3 Intensify therapy

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

66 67
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.
 Nines P. Bautista, MD, FPCP
Basal Bolus Tandem in the Management of Hyperglycemia
in Type 2 Diabetes
Summary of glucose-lowering interventions

SALAMAT PO Intervention Expected decrease in HbA1C

with monotherapy ( %)
Advantages Disadvantages

Tier 1: well-validated core

Step 1: initial therapy

HbA1c 7% Lifestyle to decrease weight

and increase activity

Metfor min
1.0-2.0

1.0-2.0
Broad benefits

W eight neutral
Insufficient for most within first year

GI side effects, contraindicated with renal

insufficiency
Step 2: additional therapy
No dose limit, rapidly effective, One to four injections daily, monitoring, weight gain,
Insulin 1.5-3.5
= Sulfonylurea 1.0-2.0
improved lipid profile

Rapidly effective
hypoglycemia, analogues are expensive
Weight gain, hypoglycemia (especially with
glibenclamide or chlorpropamide)
Tier 2: less well validated
Improved lipid profile
TZDs 0.5-1.4 Fluid retention, CHF, weight gain, bone fractures,
(pioglitazone), potential expensive, potential increase in MI (rosiglitazone)
decrease in MI (pioglitazone)
Two injections daily, frequent GI side effects, long-
GLP-1 agonist 0.5-1.0 Weight loss
Call to action Other therapy
term safety not established, expensive

-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
Three injections daily, frequent GI side effects,
Pramlintide 0.5-1.0 Weight loss long-term safety not established, expensive
DPP-4 inhibitor 0.5-0.8 W eight neutral Long-term safety not established, expensive

1.Repaglinide more effective in lowering HbA 1C than nateglinide. CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction.
68 69
Nathan DM, et al. Diabetes Care 2009;32 193-203. Nathan DM, et al. Diabetes Care 2009;32 193-203.