THE NEW EVIDENCE OF

BASAL INSULIN TREATMENT

 β-cell Function Continues to Decline Regardless of
Intervention in T2DM

Progressive Loss of β-cell Function Sulfonylurea (n=511)

100 Occurs prior to Diagnosis Diet (n=110)
Metformin (n=159)

80
β-cell Function (%)*

60

40

20

0
–5 –4 –3 –2 –1 0 1 2 3 4 5 6
Years since Diagnosis
T2DM=type 2 diabetes mellitus
*β-cell function measured by homeostasis model assessment (HOMA)
Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.
 Clinical Inertia: Failure to Advance
Therapy When Required

Percentage of Patients Intensifying

Therapy Before A1C >8.1%
100

It took 1-2 years before a

80 second medication was
Patients (%)

66.6%
added!
60
44.6%

40 35.3%

20 18.6%

0
Diet
Sulfonylurea Metformin Combination
OAD
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
 Effect of Adding Sulfonylurea to
Metformin When Monotherapy Fails
Addition of
sulfonylurea (N=2220)
10.0

9.5
A1C (%)

Upper quartile
9.0
Upper quartile
8.5

8.0 Median
Median
7.5
Lower quartile
7.0
Lower quartile
6.5
-3 -2 -1 0 1 2 3
Time from sulfonylurea initiation (years)

Cook MN et al. Diabetes Care. 2005;28:995-1000.

4-Year Failure Rate With Combination
OADS

90
n-2220; 4 yrs after initiation
80
% patients (HbA1c>8%)

70
60
50 SU
40 SU+Met
30
20
10
0
SU SU+Met

Cook MN et al. Diabetes Care. 2005;28:995-1000.

 ADA/EASD Consensus Algorithm
Call to action if HbA1c is 7%
Tier 1:
well-validated therapies
Lifestyle + Lifestyle +
Metformin Metformin
At + Basal insulin + Intensive
diagnosis: insulin
Lifestyle +
Metformin Lifestyle +
Metformin
+ Sulfonylurea

STEP 1 STEP 2 STEP 3

Tier 2: Lifestyle +
Metformin Lifestyle +
Less well Metformin
validated + Pioglitazone
No hypoglycaemia + Pioglitazone
therapies Oedema/CHF + Sulfonylurea
Bone loss
Lifestyle +
metformin Lifestyle +
+ GLP-1 agonist metformin
No hypoglycaemia + Basal insulin
Weight loss
Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.
LONG ACTING (BASAL) INSULIN
 Ideal Basal Insulin

Closely mimic normal pancreatic

basal insulin secretion
No distinct peak effect
Continued effect over 24 hours
Reduce nocturnal hypoglycemia
Once-daily administration for
patient compliance
Predictable absorption pattern
 Duration of Action: Type 1 and Type 2
Results From a Review of Clamp
Studies Levemir®
Insulin glargine
30

25 24 24 24 24 24
23
22 21.5 22
Duration (h)

20
17.5

15

10

0
Luzio Klein Lepore Heise Plank Porcellati Porcellati
2006 2007 2000 2004 2005 2007* 2006
Unit/kg 0.5 0.4 0.3 0.4 0.4 0.3 0.35

Type 2 Study
*Day 1 value.

Heise T, Pieber TR. Diabetes Obes Metab.

2007;9:648-659.
 CGMS Data Show That Just Like
Glargine, Detemir Acts Up to 24 Hours

King AB. Diabetes obesity and Metabolism 2009, 11: 69-71

VARIABILITY/PREDICTABILITY
 Major Factors Influencing
Predictability
Drug
 Suspension
 Precipitation
Suspension
Precipitation
Patient
 absorption
Absorption
(Drug effect)
 Insulin Detemir
LysB29(N-tetradecanoyl)des(B30)human insulin
C1
4
cha fatt
ya
(My in cid
ris Phe Gly Arg
tic Phe
aci Glu
d) Tyr
Thr Gly
Pro Cys
Lys
Thr Val
Lys Asn Cys
B29 A21
Tyr Leu
A1 Gly Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu
Gln Glu
Gln
Tyr Val
Cys Leu Leu
Cys Ser
Thr Ser Ile Cys
His
Myristic acid
Ser
Gly
Cys
Leu
B1 Phe Val Asn Gln His
 Insulin Detemir: Mode of
Prolonging Action

Self association
Protracted
(hexameric) absorption
Fatty acid side chains
bind to albumin in ‘Buffering’ effect
injection depot and minor
contribution to
protraction

Albumin binding in
circulation
 How Does Insulin Detemir Address
Predictability?
Clear solution

Hexamer stability
Dilution → disassociation Dihexamerisation
Albumin binding
hexamers dimers monomers
–3 –5 –8
10 M 10 M 10 M

Capillary membrane
insulin detemir in blood
Sli
de
Plasma albumin
5th Oct’05 binding
Insulin Detemir 15
Detemir Demonstrated More Consistent Insulin Action
54 Type 1 Diabetic Subjects Randomly Assigned
to receive one type of Insulin, single dose 0.4 u/kg, 4 Different Times

NPH NPH NPH

Glargine Glargine Glargine

Detemir Detemir Detemir

Adapted from Heise T et al. Diabetes.

EFFICACY AND SAFETY
Study 1
TITRATE® Trial Design
Levemir® once daily
Self-adjusted target FPG 70-90 mg/dL
Main inclusion criteria
• Insulin naïve, on OAD therapy (n=122)
• Type 2 diabetes, ≥3 months
• 7%A1C9% Levemir® once daily
Self-adjusted target FPG 80-110 mg/dL
• BMI 45 kg/m2 Screening
period (n=122)
• Age 18 years

Week -2 0 20

 Levemir® was initiated at 0.1-0.2 unit/kg or 10 units once daily

at dinner or bedtime
 Dose titration was based on the PREDICTIVE® 303 patient-directed
self-titration algorithm
 Patients continued current OAD therapy
 Mean duration of diabetes: 8.4 years
 Mean A1C: 8.0%

Blonde L et al. Diabetes Obes Metab. 2009;

11(6):623-631.
 Levemir® Dose Titration Guidelines:
3-0-3 Algorithm
Dose Adjustment for Each Arm

Mean 3-day FPG

(mg/dL) increase dose

FPG>90 mg/dl (5.0 mm/L) 3 units FPG>110 mg/dL (6.1 mmol/L)

FPG target range FPG target range

70-90 mg/dL 0 maintain
dose
80-110 mg/dL

FPG <70 mg/dL (3.8 mmol/L) decrease dose FPG <80 mg/dL (4.4 mmol/L)
3 units

• Patients who experienced hypoglycemia reduced their daily dose by 3 units

Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-

Insulin Doses of Levemir® Between Target
Groups

0.6 0.57 unit/kg

0.5 0.51 unit/kg

Dose (unit/kg)

0.4

0.3

0.2
FPG 70-90 mg/dL
0.1 FPG 80-110 mg/dL

0
Week 0 Week 20

Time (study week)

Blonde L et al. Diabetes Obes Metab. 2009;

11(6):623-631.
 Levemir® Once Daily Reduced FPG
Levels by 54 mg/dL (Combined Target
Groups)
0
Change in FPG (mg/dL)

-10

-20

-30 FPG 70-90 mg/dL

FPG 80-110 mg/dL
-40

-50
-49.7
-60
-57.4
-70

Blonde L et al. Diabetes Obes Metab. 2009;

11(6):623-631.
 Rates of Hypoglycemia

FPG 70-90 mg/dL

FPG 80-110 mg/dL

subject/month

0.42
Events per

0.2

Minor hypoglycemic events

• A single event of major hypoglycemia was reported in the 70-90 mg/dL group
• No major hypoglycemic events were reported in the 80-110 mg/dL group

Blonde L et al. Diabetes Obes Metab. 2009;

11(6):623-631.
Study 2
Comparison of Detemir and Glargine in
a
Treat-to-Target Protocol
 52-week, open-labelled, randomised (1:1), parallel group trial.
Patients with type 2 diabetes from 80 sites in seven countries

Detemir once or twice-daily

n = 291 n = 231
Prior OAD treatment maintained
Stratified at randomisation by current OAD treatment:
mono- or combination therapy
2 weeks’
screening Glargine once-daily
n = 291
52 weeks’ continued titration to target. n = 252
Titration at contacts (weekly, 0-12; monthly 12-52)

• Per study protocol, a second dose of Levemir ® could be added in the

morning if BG level before dinner was greater than 7.0 mmol/l)

Rosenstock J et al Diabetologia Jan 2008;51, DOI 10.1007/s00125-007-0911-x

 Detemir and Glargine Improvement in
Glycemic Control
Detemir
9.0 Glargine
HbA1c (%)

7.16%, -1.48%,
8.0
7.12%, -1.50%,
ns
7.0

0
-2 0 12 28 36 52

12.0
FPG (mmol/l)

7.14 mmol/l, -3.6

10.0 6.98 mmol/l -3.6 mmol/l
mmol/l

8.0
ns
6.0

0
-2 0 12 28 36 52
Study week
Rosenstock J et al Diabetologia Jan 2008;51, DOI 10.1007/s00125-007-0911-x
 Detemir and Glargine 10-Point SBGM
Data

Detemir
Glargine
10.0
Plasma Glucose

9.0
8.0
mmol/L

7.0
6.0
5.0

er 90 . . st
t ch e hr hr
a s 90 n 90 n a
kf ay)
k f
t + -lu +
n
di er
+
d tim .0
0
.0
0 a
a e - re t d
r e a s P r c h e
Pr in
n Be 02 04 b x
-b kf n e- n e
r e e a Lu D r
P (
P Br

Rosenstock J et al Diabetologia Jan 2008;51, DOI 10.1007/s00125-007-0911-x

 Multicenter, open-label, randomized,
Study 3

controlled, non-inferiority, treat-to-

target trial
Study design
Levemir® initiated once daily at bedtime* + NovoLog® (n=25
Main inclusion criteria
• Age ≥18 years • Insulin secretagogues and -glucosidase inhibitors
discontinued; TZDs or MET continued
• Type 2 diabetes • Insulin aspart administered as part of
• 7%≤ A1C ≤11% basal-bolus regimen
• History of OAD
Insulin glargine once daily at bedtime + NovoLog®
and/or insulin use
(n=131)
• BMI ≤40 kg/m2 Titration and treatment:
Prebreakfast/predinner goal PG ≤108 mg/dL

Screening 2:1 randomization 26 weeks

9 visits, 13 telephone contacts

*Per study protocol, a second dose of Levemir ® could be added in the morning; 87.4% of
patients remained on a once-daily basal insulin regimen throughout the study.

Raskin P et al. Diabetes Metab Res Rev. 2009 Jun 29; [Epub ahead
 A1C Reduction With Levemir® vs Insulin
Glargine at 26 Weeks
10
Mean A1C (%)

9
8.42 8.42
* †
8
7.33 * †
7.13 7.02
7
6.92

0
BaselineWeek 26 LOCF BaselineWeek 26 LOCF
Levemir ®
Insulin glargine
Noninferiority outcomes were interpreted based on the CONSORT (Consolidated Standards of
Reporting Trials) reporting guideline. The value of the delta (treatment difference) used in
determining the noninferiority outcome was 0.4. The results based on the 26­week data
showed that noninferiority criteria were met, since the upper confidence limit was less than
delta (0.4). The results based on the LOCF approach were inconclusive regarding possible
inferiority of magnitude 0.4 (delta) or more, since the confidence interval included delta (0.4).
*
P=.035, LS mean of [Det-gla]: 0.207; 95% CI: 0.0149, 0.3995; noninferiority criteria met.
†
P=.004, LS mean of [Det-gla]: 0.307; 95% CI: 0.1023, 0.5109; results inconclusive.
CI=confidence interval; LOCF=last observation carried forward; LS=least squares.

Raskin P et al. Diabetes Metab Res Rev. 2009 Jun 29; [Epub ahead of
 Reduction in FPG With Levemir® and
Insulin Glargine
300

250
Mean FPG (mg/dL)

200
174.0 P=NS 172.2 P=NS
P=NS P=NS
150 129.7 135.4 134.3 136.7

100

50

0
BaselineWeek 26 LOCF BaselineWeek 26 LOCF
Levemir® Insulin glargine

All statistical comparisons vs insulin glargine.

Raskin P et al. Diabetes Metab Res Rev. 2009 Jun 29; [Epub
 Significantly Less Weight Gain With
Levemir® vs Insulin Glargine
7.0 P=.001
5.94±8.67
6.0
Weight gain after

5.0
26 weeks (lb)

4.0

3.0 2.64±8.71

2.0

1.0

0
Levemir® Insulin glargine

Raskin P et al. Diabetes Metab Res Rev. 2009 Jun 29; [Epub
ahead of print]
 36 patients with T2DM receiving basal insulin therapy Study 4
 Randomized, double-blind, crossover study

King CGMS: Study Design

Levemir® once daily Levemir® once daily

Insulin glargine once daily Insulin glargine once daily

CGMS data for the last 24-hour period were recorded for comparison between treatments

Week 0 Week 1 Week 2

CGMS=continuous glucose monitoring system (Medtronic CGMS ® System GoldTM)

Insulin was titrated to achieve BG goals of <120 mg/dL
with <5% of their BG values <70 mg/dL between 12 AM and 6 AM.

King AB. Diabetes Obes Metab.

 Comparable CGMS Profiles With
Levemir® vs Insulin Glargine
Daily Blood Glucose Measured by CGMS
200
(Mean ± SE) Insulin Glargine vs Levemir ®
180
Mean glucose (mg/dL)

160
140
120
100
80
Levemir® (n=29)
60
Insulin glargine (n=29)
40
20
0
3 AM
4 AM
5 AM
6 AM

1 PM
2 PM

5 PM
1 AM
2 AM

7 AM
8 AM
9 AM

3 PM
4 PM

6 PM
7 PM
8 PM
9 PM

10 AM
11 AM
12 PM
12 AM
10 PM
11 PM

Timemonitoring
CGMS=continuous glucose of day system. (Medtronic CGMS ® System
GoldTM)

King AB. Diabetes Obes Metab.

 Conclusions
 Variability and non-predictability is
disadvantages of conventional basal insulin
 Lack of precipitation formation or
precipitation dissolution of detemir insulin
may contribute to less within patient
variability in day-to day blood glucose value
 Insulin detemir was effective to control blood
glucose in diabetic patients
 Insulin detemir reduced risk of nocturnal
hypoglycemia
 Insulin detemir significantly less weight gain
THANK YOU