insulin therapy of type 2 diabetes jack l. leahy university of vermont college of medicine division...
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Insulin Therapy of Type 2 Diabetes
Jack L. LeahyUniversity of Vermont College of Medicine
Division of Endocrinology, Diabetes and MetabolismBurlington, Vermont
Global Projections for the Diabetes Epidemic: 2003-2025
23.0 M36.2 M↑57.0%
14.2 M26.2 M↑85%
48.4 M58.6 M↑21% 43.0 M
75.8 M ↑79%
7.1M15.0 M↑111%
39.3 M81.6 M
↑108%
M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western PacificDiabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.
World
2003 = 194 M2025 = 333 M
↑ 72%
AFR
NA
SACA
EUR
SEA
WP
19.2 M39.4 M↑105%
EMME
2003 2025
Standards of Care - American Diabetes Association
• Glycemia: HbA1c <7.0%, FPG 90-130 mg/dL, PP <180 mg/dL.
• Blood Pressure: <130/80.
• Lipids: LDL <100 mg/dL; TG <150 mg/dL.
• Yearly:
– Dilated eye exam; urinary protein; foot exam; flu shot.
• Other:
– Aspirin usage; pneumococcal vaccine.
AACE goals - HbA1c 6.5%, FPG 110 mg/dL, PP 140 mg/dL
NCEP - LDL ≤ 70 mg/dL
ADA. Diabetes Care 2005;29:S4-S42
Nathan DM et al. Diabetes Care 2009;32:193-203..
Consensus Algorithm Update 2009
Check A1C every3 months until <7%. Change treatment if
A1C is ≥7%
Step 3
Tier 1: Well-validated core therapies
At diagnosis:
Lifestyle+
Metformin
Lifestyle + Metforminplus
Basal Insulin
Lifestyle + Metformin plus
Sulfonylureaa
Lifestyle + Metforminplus
Intensive Insulin
Step 1 Step 2
Lifestyle + Metformin plus
PioglitazoneNo hypoglyceamia
Oedema / CHFBone Loss
Lifestyle + Metformin plus
GLP-1 agonistNo hypoglyceamia
Weight lossNausea / vomiting
Tier 2: Less well-validated therapies
Lifestyle + Metformin plus
Pioglitazone plus
Sulfonylurea
Lifestyle + Metformin plus
Basal Insulin
Brown JB et al. Diabetes Care 2004;27:1535-1540.
0
20
40
60
80
100
% o
f Su
bje
cts
Percentage of subjects advancing when A1C < 8%
Clinical Inertia: Failure to Advance Therapy When Required
Diet
66.6%
Sulfonylurea Metformin
35.3%44.6%
Combination
18.6%
At insulin initiation, the average patient had:• 5 years with A1C > 8%• 10 years with A1C > 7%
Learning Objectives
• To discuss the “nuts and bolts” of successful insulin therapy strategies in type 2 diabetes:
– Highlight and discuss timely and controversial topics.
• Use clinical trial data to:
– Compare available long-acting (basal) insulins.
– Identify expected dosages of basal insulins.
– Discuss the importance of patient-driven algorithms for adjustment of basal insulin dosages.
• Introduce the concept of “incomplete” basal-bolus insulin therapy - so called “Basal Plus”.
B = breakfast; L = lunch; D = dinner.
Polonsky KS et al. N Engl J Med 1988;318:1231-1239.
100
200
300
400Glucose Insulin
6:00 10:00 18:0014:00 2:0022:00 6:00
Time
6:00 10:00 18:0014:00 2:0022:00 6:00
Time
20
40
60
80
100
120
B L DB L D
Nondiabetic Type 2 diabetes
mg
/dL
U/m
L
Basal insulin
Basal Insulin Therapy
Lepore M et al. Diabetes 2000;49:2142-2148.
Time (hours)
Basal Insulin ProfilesGlucose Infusion Rates
N=20 T1DM
Mean SEM
0
4
8
Mg/Kg/min
mol/Kg/min
s.c. insulin
NPH
Glargine
4.0
3.0
2.0
1.0
0
40 128 2016 24
12
16
20
24
≈15% with some peak
NPH Glargine
Insulin Detemir: Structure
Lys
Thr Tyr
Thr
Phe Phe Gly ArgGlu
Gly
Val
LeuTyr
Leu
AlaGlu
ValLeu
HisSer
GlyLeuHis
Gln
Val
ValPheB1B3
A21B29
ProCys
TyrAsn
Glu
Cys
Gln
Leu
GlnTyr
LeuSerCys
CysThr Ser lle
Gly
lle
Glu
Gln
Cys
Cys
Asp
A1
C14 fatty acid chain
(Myristic acid)
Plank J et al. Diabetes Care 2005;28:1107-1112.
DETEMIR DOSE (U/kg) 0.1 0.2 0.4 0.8 1.6
DURATION OF ACTION (h)
5.7 12.1 19.9 22.7 23.2
Time since insulin injection (h)
0 2 4 6 8 10 12 14 16 18 20 22 24
Glu
cose
infu
sio
n
rate
(m
g/k
g/m
in)
Detemir 0.1 U/kgDetemir 0.2 U/kgDetemir 0.4 U/kgDetemir 0.8 U/kgDetemir 1.6 U/kg
0
1
2
3
4
5
6
7
Dose Dependency of Action Profiles of
Insulin Detemir
Insulin Glargine Trials Showing Effective Reduction in HbA1c
Hb
A1
c (%
)
APOLLO LAPTOP Triple Therapy
LANMET
10
9
8
7
6
5Treat-To-
TargetINITIATE
7.147.156.96
7.146.80
8.71 8.85 8.809.5
8.808.61
6.96
Baseline Study endpoint
Mullins P et al. Clin Ther 2007;29:1607−19.
Less Hypoglycemia with Insulin Glargine vs NPH
6 7 8 9 10HbA1c
3500
3000
2500
2000
1500
1000
Hyp
ogly
cem
ia
even
ts p
er 1
00
patie
nt-y
ears
NPH Insulin glargine
200
150
100
50
06 7 8 9 10
HbA1c
Hyp
ogly
cem
ia
even
ts p
er 1
00
patie
nt-y
ears
T1DM
T2DM
p=0.004 between treatments
p=0.021 between treatments
Key Questions
• Is there a difference between Glargine and Detemir?
Rosenstock J et al. Diabetologia 2008;51:408-416
Head to Head Comparison of Glargine Versus Detemir in Type 2 Diabetes
52-weeks. Once daily Glargine or Detemir - could be titrated to
BID Detemir (55%). Baseline A1c 8.6% n = 582
Hem
oglo
bin
A1c
(%
)
4
6
8
5
7 7.2 7.1
P = NS
Glargine Detemir
Summary of Results
• 55% of patients on insulin Detemir were titrated to twice daily injections
• All patients on insulin Glargine received only 1 injection per day
• Average daily doses:
– Detemir once daily 0.78 U/kg.
– Detemir twice daily 1.0 U/kg.
– Glargine once daily 0.44 U/kg
• 3.9 kg weight gain with Glargine versus 3.0 kg with Detemir - no difference between Glargine and twice daily Detemir.
Rosenstock J et al. Diabetologia 2008;51:408-416
Key Questions• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
Nathan DM et al. Diabetes Care 2009;32:193-203..
Consensus Algorithm Update 2009
Check A1C every3 months until <7%. Change treatment if
A1C is ≥7%
Step 3
Tier 1: Well-validated core therapies
At diagnosis:
Lifestyle+
Metformin
Lifestyle + Metforminplus
Basal Insulin
Lifestyle + Metformin plus
Sulfonylureaa
Lifestyle + Metforminplus
Intensive Insulin
Step 1 Step 2
Lifestyle + Metformin plus
PioglitazoneNo hypoglyceamia
Oedema / CHFBone Loss
Lifestyle + Metformin plus
GLP-1 agonistNo hypoglyceamia
Weight lossNausea / vomiting
Tier 2: Less well-validated therapies
Lifestyle + Metformin plus
Pioglitazone plus
Sulfonylurea
Lifestyle + Metformin plus
Basal Insulin
Heine RJ et al. Ann Intern Med 2005;143:559-569.
Prebreakfast
Both medications lowered A1C from 8.2% to 7.1% from baselineWeight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n=549)
Blo
od
glu
cose
(m
g/d
L)
3 AM
100
120
140
160
180
200
220
240
Baseline (week 0)Endpoint (week 26)
3 AM
100
120
140
160
180
200
220
240
Baseline (week 0)Endpoint (week 26)
Exenatide5 µg bid 1st 4 weeks, then 10 µg bid
Insulin glargine10 U/d, titrated to target FPG <100 mg/dL
Prebreakfast
Prelunch
Predinner
Prelunch
Predinner
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
Combined Effects of Metformin with Insulin Therapy in Type 2 Diabetes
Sasali A and Leahy JL. Curr Diab Rep 2003;3:378-385.
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
– Continue OHA - “add on” therapy, not “substitution” therapy.
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
– Continue OHA - “add on” therapy, not “substitution” therapy.
• What are expected doses of basal insulin (Glargine or NPH)?
1. Riddle M, et al. Diabetes Care 2003;26:3080−6.2. Gerstein HC, et al. Diabet Med 2006;23:736−42.3. Yki-Järvinen H, et al. Diabetologia 2006;49:442−51.4. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364-9.
Treat-to-Target1 INSIGHT2 LANMET3 INITIATE4
Target FBG <100 mg/dL ≤100 mg/dL <100 mg/dL <100 mg/dL
Algorithm + 2 to 8 U
every week
+ 1 U every day +2 U or + 4 U
every 3 days
+2 U
every 3 days
Final dose Glargine
0.48 U/kg
0.42 U/kg (NPH)0.41 U/kg
0.69 U/kg
0.66 U/kg (NPH)0.60 to 0.64
U/kg
Published Insulin Glargine Doses and Titration Algorithms
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
– Continue OHA - “add on” therapy, not “substitution” therapy.
• What are expected doses of basal insulin (Glargine or NPH)?
– Average dosage of Glargine or once daily NPH 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
– Continue OHA - “add on” therapy, not “substitution” therapy.
• What are expected doses of basal insulin (Glargine or NPH)?
– Average dosage of Glargine or once daily NPH 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
• How to start and titrate?
Recommendations for Starting and Adjusting
Basal Insulin Bedtime or morning long-acting insulin OR
Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 U/kg
Increase dose by 2 units every 3 days until FBG is 70–130 mg/dL.
If FBG is >180 mg/L, increase dose by 4 units every 3 days.
CheckFBGdaily
Continue regimen and check HbA1c every 3 months
In the event of hypoglycemia or FBG level <70 mg/dL.
Reduce bedtime insulin dose by 4 units, or by 10% if >60 units.
Nathan DM et al. Diabetes Care 2009;32:193-203.
1. Riddle M, et al. Diabetes Care 2003;26:3080−6.2. Gerstein HC, et al. Diabet Med 2006;23:736−42.3. Yki-Järvinen H, et al. Diabetologia 2006;49:442−51.4. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364-9.
Treat-to-Target1 INSIGHT2 LANMET3 INITIATE4
Target FBG <100 mg/dL ≤100 mg/dL <100 mg/dL <100 mg/dL
Algorithm + 2 to 8 U
every week
+ 1 U every day +2 U or + 4 U
every 3 days
+2 U
every 3 days
Final dose Glargine
0.48 U/kg
0.42 U/kg (NPH)0.41 U/kg
0.69 U/kg
0.66 U/kg (NPH)0.60 to 0.64
U/kg
Published Insulin Glargine Doses and Titration Algorithms
Optimizing Dose of Glargine Allows Achievement of FPG Target (LANMET study)
Study in 110 insulin-naïve subjects with type 2 diabetes receiving insulin glargine plus metformin
Adapted from Yki-Järvinen H, et al. Diabetologia 2006;49:442–51Time (weeks)
FP
G /
wee
kly
mea
ns (
mg/
dL)
0
30
60
90
120
180
-4 0 4 8 12 16 20 24 28 3632
210
0
20
40
60
80
150
Insulin dose (IU/day)
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
– Continue OHA - “add on” therapy, not “substitution” therapy.
• What are expected doses of basal insulin (Glargine or NPH)?
– Average dosage of Glargine or once daily NPH 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
• How to start and titrate?
• Why not start with premixed insulins?
Split-Mixed/Pre-Mixed Insulin Therapy
4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
12:0012:008:008:00
TimeTime
Pla
sma
Insu
lin
Pla
sma
Insu
lin Regular
NPH
LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures
Janka H et al. Diabetes Care 2005;28:254−259.
*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])
N=371 insulin-naïve patientsInsulin glargine + OADs vs twice-daily human NPH insulin (70/30)Follow-up: 24 weeks
Hypoglycaemia* (events/patient year)
0
1
2
3
4
5
p=0.0009
5
6
7
8
9
HbA1c (%)
7.5%7.2%
1.3% 1.7%
p=0.0003
Twice-daily premixed insulinInsulin glargine + OADs
2.6
5.7
Analog Pre-Mixed Insulin Therapy
4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
12:0012:008:008:00
TimeTime
Pla
sma
Insu
lin
Pla
sma
Insu
lin
Raskin P et al. Diabetes Care 2005;28:260-265.
Change in A1C From Baseline to Study End
9.8%
6.9%7.4%
5
6
7
8
9
Insulin Glargine + OADs PreMix
Baseline
Endpoint
P<0.01
A1C
(%
)
- 2.4% - 2.8%
10
9.7%
HypoglycemiaDocumented Hypoglycemic Episodes (<56 mg/dL)
0.7
3.4
0
1
2
3
4
Epi
sode
s pe
r pa
tient
yea
r
P<0.05
Insulin Glargine PreMix
Raskin P et al. Diabetes Care 2005;28:260-265.
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin
Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
– Continue OHA - “add on” therapy, not “substitution” therapy.
• What are expected doses of basal insulin (Glargine or NPH)?
– Average dosage of Glargine or once daily NPH 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
• How to start and titrate?
• Why not start with premixed insulins?
• What if basal insulin is not enough?
350
300
250
200
150
100
50
Raskin P et al. Diabetes Care 2005;28:260-265.
*
Pla
sma
Glu
cose
(m
g/dL
)
Week 28
Baseline
GlarginePremix†
Time of DayBB B90 BL L90 BD D90 Bed 3AM
**
**
Blood Glucose Profiles
Lifestyle changes + Metformin
Additional Oral agents
BasalAdd basal insulin and titrate
Basal PlusAdd prandial insulin at main meal
Basal BolusInsulin Initiation
Intensification
Further intensification
Progressive deterioration of -cell function
Stepwise Treatment of Type 2 Diabetes
Eleonor Study
• Aim: To determine if a Telecare program facilitates optimization of basal insulin Glargine followed by addition of one mealtime insulin injection of insulin Glulisine.
• Protocol:
– 24-week, open label, multicenter, randomized study in Italy.
– 200 patients with type 2 diabetes.
– Poor glycemic control (A1C 8.9±0.9%) on one or more oral hypoglycemic agents.
– Adjust Glargine to FBG <126 mg/dL followed by adding Glulisine to meal with highest PPG value.
Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452
Hb
A1c
(%
)
Group 1Group 2
9.0
6.5
7.0
7.5
8.0
8.5
0 12 36
ADA/EASD target
Weeks
Glargine + OHAs
Glargine + 1 Glulisine + OHAs
20
40
60
80
100
pts
ach
ievi
ng
Hb
A1c
<7.
0 (%
)
51%55%
0
p=NS
Group1
Group2
Eleonor Study Results
No clinically significant weight gain. Low rate of severe hypoglycemia
Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452
Basal Plus Mealtime Insulin• Use rapid-acting analogs, not regular insulin
– Easier timing, less postprandial hypoglycemia
– Can be taken up to 20 minutes after start eating
• Start with 1 shot, at largest meal:– 4 units, and titrate, OR
– By weight - 0.1 U/kg
• Titrate to:
– <160 mg/dL 2 hours post-prandial OR
– <130 mg/dL next meal or bedtime
• Continue oral secretagogues until full basal-bolus regimen
HoursRHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes 1994;43:396-402.
10
8
6
4
2
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Insu
lin
Act
ivit
y
RHI
Timing offood
absorbed
Analog insulin
Lispro, Aspart, Glulisine vs Regular Insulin
Basal Plus Mealtime Insulin• Use rapid-acting analogs, not regular insulin
– Easier timing, less postprandial hypoglycemia
– Can be taken up to 20 minutes after start eating
• Start with 1 shot, at largest meal:– 4 units, and titrate.
– By weight - 0.1 U/kg
• Titrate to:
– <160 mg/dL 2 hours post-prandial OR
– <130 mg/dL next meal or bedtime
• Continue oral secretagogues until full basal-bolus regimen
“We don’t start insulin early enough, or use it aggressively
enough”
Robert Turner MA, MD, FRCPProfessor of MedicineUniversity of Oxford
1938-1999