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.
Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes
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
Risk23% (CI 19-27) rise per
1 mmol/L rise in glucose
Risk19% (CI 15-22) rise per
1 mmol/L rise in glucose
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
Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes
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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
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
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
Nathan DM, et al. Diabetes Care 2009;32 193-203.27
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
Nathan DM, et al. Diabetes Care 2009;32 193-203.
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
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Lifestyle modifications
Medical Nutrition Therapy (MNT)
Weight lossPhysical activity
Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes
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
Lifestyle+ Metformin
+ 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
At diagnosis:Lifestyle
+Metformin
Lifestyle+ 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
At diagnosis:Lifestyle
+Metformin
Lifestyle+ Metformin
+ Basal insulin
Lifestyle+ Metformin
+ Sulfonylurea
STEP 1 STEP 2
HbA1c 7%
HbA1c 7%
Nathan DM, et al. Diabetes Care 2009;32 193-203.
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
Nathan DM, et al. Diabetes Care 2009;32 193-203.37
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.
Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes
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
Nathan DM, et al. Diabetes Care 2009;32 193-203.39
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
Nathan DM, et al. Diabetes Care 2009;32 193-203.
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)
Nathan DM, et al. Diabetes Care 2009;32 193-203.43
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
Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes
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…
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
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…
Nathan DM, et al. Diabetes Care 2009;32 193-203.
54
ADA/EASD consensus algorithm step 3Intensifying insulin therapy
At diagnosis:Lifestyle + Metformin
Lifestyle + Metformin+ Basal insulin
Lifestyle + Metformin+ Sulfonylurea
Lifestyle + Metformin+ Intensive insulin
STEP 1 STEP 2 STEP 3
Tier 1: Well-validated therapies
HbA1c 7%
Nathan DM, et al. Diabetes Care 2009;32 193-203.55
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
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
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
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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
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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% Check 2-hr postprandial levels Adjust preprandial rapid-acting insulin
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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
Nines P. Bautista, MD, FPCP Basal Bolus Tandem in the Management of Hyperglycemia in Type 2 Diabetes
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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
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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
At diagnosis:Lifestyle + Metformin
Lifestyle + Metformin+ Intensive insulin
STEP 1 STEP 2 STEP 3
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
Lifestyle + Metformin+ Basal insulin
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
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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%
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
68
HbA1c 7%
Call to action
=
68Nathan DM, et al. Diabetes Care 2009;32 193-203.
SALAMAT PO
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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.
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