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Basal Vs. Pre-Mix
Introduction
• Pharmacological therapy of type 2 diabetes mellitus typically starts with oral agents, including metformin or sulfonylurea.
• However, the natural progression of type 2 diabetes mellitus means that combination therapy is often required.
• One option to starting insulin therapy is the addition of a ‘basal’ insulin to help manage fasting blood glucose.
Quality of Diabetes Care – NHANES 1999-2000
Saydah et al JAMA 291(3):335-342
Only 7.3% of adults with diabetes in Only 7.3% of adults with diabetes in
NHANES 1999-2000 attained recommended NHANES 1999-2000 attained recommended
HbA1C goals of <7%, BP < 130/80 mmHgHbA1C goals of <7%, BP < 130/80 mmHg
and total cholesterol <200 mg/dland total cholesterol <200 mg/dl
DICE: Primary care management of diabetes
Controlled A1C
51%
Uncontrolled A1C
49%
Most recent A1C test results (n = 2,337)
Harris SB et al. Diabetes Res Clin Pract 2005; 70: 90-97.
One in two diabetes patientswere not at target ≤7%
At insulin initiation, the average patient had:At insulin initiation, the average patient had: 5 years with A1C >8%5 years with A1C >8% 10 years with A1C >7%10 years with A1C >7%
Standard Approaches to Therapy Result inProlonged Exposure to Elevated Glucose
Brown JB, et al. Diabetes Care. 2004;27:1535-1540.
Sulfonylurea or Sulfonylurea or Metformin Metformin
MonotherapyMonotherapy
ADA Goal <7%
CombinationCombinationTherapyTherapy
Diet/ExerciseDiet/Exercise
Mea
n A
1C a
t L
ast
Vis
it
YearsDiagnosis 2 3 4 5 6 7 8 9 10
9.6%
9.0%8.6%
6%
7%
8%
9%
10% InsulinInsulin
Cook MN, et al. Diabetes Care. 2005;28:995-1000.
Deterioration of Glycemic Control with Combination Therapy Over Time
Pro
po
rtio
n w
ith
A
1C ≥
8.0%
Time from Sulfonylurea Initiation (Years)0 1 2 3 4
1.0
0.6
0.4
0.0
0.8
0.2
Pre-SU A1C ≥10%
Pre-SU A1C 9.0%−9.9%
Pre-SU A1C 8.0%−8.9%
Pre-SU A1C 5.0%−7.9%
Deterioration in glycemic control begins within 6 months of starting combination therapy, particularly when initiated at higher A1C values
Glycemic management
0 20 40 60 80 100
61%
48%
15%
4%
12%
15%
Patients currently taking medication (%)
Base: Patients (n = 2,473). Sulfonylureas: Glimepiride, glyburide, chloropropamide, gliclazide, tolbutamide. TZDs: Pioglitazone, rosiglitazone. Other oral agents: Repaglinide, acarbose, nateglinide.
Metformin
Sulfonylureas net
TZDs net
Other oral agents net
Insulin
Lifestyle only
Harris SB et al. Diabetes Res Clin Pract 2005; 70: 90-97.
Despite suboptimal control, only 12%of patients were receiving insulin
-C
ell F
un
ctio
n (
%
)
Basal replacement
Early type 2
Late type 2,type 1
0
20
40
60
80
100
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
DeFronzo RA. Diabetes Rev. 1997;5:178-269.
Basal and meal replacement
Time (Years)
Insulin Coverage at Different Stages: All Diabetes Types
Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (P<0.001).
Adapted from Polonsky K et al. N Engl J Med. 1988;318:1231-1239
Treating Fasting Hyperglycemia Lowers the Entire 24-Hour Plasma Glucose
Profile
Time of Day (h)
400
300
200
100
0
6 610 14 18 22 2
Pla
sm
a G
luc
os
e (
mg
/dL
)
Normal
Meal Meal Meal
20
15
10
5
0
Plas
ma G
luc
os
e (m
mo
l/L)
Hyperglycemia due to increase in fasting glucose
Type 2diabetes
Insulin Glargine : Mechanism of Action
Clear Solution pH4
pH 7.4
Precipitation
Dissolution
Capillary Membrane
Insulin in Blood
Hexamers Dimers Monomers
10-3 M 10-5M 10-8 M
Injection of an acidic solution (pH 4.0)
Precipitation of glargine in subcutaneous tissue (pH 7.4)
Slow dissolution of free glargine hexamers from precipitated glargine (stabilized aggregates)
Protracted action
Adapted from: Kramer W. Exp Clin Endocrinol Diabetes 107(1999) Suppl 2
Insulin Detemir
Thr
Glu
Lys
ValPhe
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerCys
Cys
Gln
Glu
Val
Ile
GlyTyr
CysAsnLys
ProThr
TyrPhe Phe ArgGly
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
SerGly
Cys
Asn Gln LeuHisB1
A21
A1
B29
14-carbon fatty acid
chain(Myristic acid)
Thr
Glargine
NPH
Detemir
Pre-Mix (70/30, 75/25)
Relative Benefits of
Treatment to Target Study
Patients inadequately controlled on oral hypoglycemic agent(s)
Continue oral hypoglycemic agent(s) + insulin glargine at bedtime
Continue oral hypoglycemic agent(s) + NPH insulin at bedtime
HbA1c 7.5-10%
Target FPG ≤ 100 mg/dL
24 weeks of treatment
Study Design
Riddle MC et al. Diabetes Care. 2003;26:3080-3086
Treat-to-Target Trial:Efficacy Results
*In both groups, FPG decreased from 194 or 198 to 117 or 130 mg/dL by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
100
150
200
0 4 8 12 16 20 24
Weeks of Treatment
FP
G (
mg
/dL
)
Glargine NPH
6
6.5
7
7.5
8
8.5
9
0 4 8 12 16 20 24
Weeks of Treatment
A1C
(%
)
Glargine NPH
Insulin Dosage During Study(Both treatment groups)
To
tal D
aily
Do
se (
Un
its)
4341
393736
3331
2825
21
1610
44
0.370.350.33
0.30.26
0.220.17
0.11
0.39 0.41 0.43 0.440.46
0
10
20
30
40
50
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
0
0.1
0.2
0.3
0.4
0.5
0.6
UnitsUnits/kg
Weeks in Study
To
tal Daily D
ose (U
nits/kg
)
*
Riddle MC et al. Diabetes Care. 2003;26:3080-3086
Hypoglycemia defined as plasma glucose 72 mg/dL*P<0.05 vs insulin glargine.NPH=neutral protamine Hagedorn
Adapted from Riddle M et al. Diabetes Care. 2003;26:3080-3086. Used with permission.
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
20 22 24 2 4 6 8 10 12 14 16 18
Time of day (h)
*
*
*
*
*
*
*GlargineNPH
Basal insulin
Breakfast Lunch Dinner
Eve
nts
per
pat
ien
t ex
po
sure
–yea
rSymptomatic Hypoglycemic Events
Glargine vs
Detemir
6-59
582 Patients inadequately controlled on 1 or 2 oral agents
Detemir
12 U HS
Glargine 12 U HS
Target FPG pre-breakkfast<108 mg/dl
pre-dinner <126 mg/dl
52 weeks of treatment
Study Design
Detemir Q HS (45%)
Detemir AM and HS (55%)
Insulin Glargine Plus Oral Agents vs. Insulin Detemir Plus Oral Agents
HbA1c 8.6%
FPG ~194 mg/dl
Diabetologia. 2008 Mar;51(3):408-16
6-59
Glargine + OAD Detemir + OADs
HbA1C (%) 7.1 7.2
FPG (mg/dl) 126 128
HbA1C<7% with no hypos 35% 35%
Overall + Nocturnal Hypos Same Same
Weight gain 3.9 Kg 3.0 Kg
52 week results
Insulin Glargine Plus Oral Agents vs. Insulin Detemir Plus Oral Agents
Diabetologia. 2008 Mar;51(3):408-16
6-596-59
Insulin Glargine Plus Oral Agents vs. Insulin Detemir Plus Oral Agents
Detemir HS 0.4 2.25
Detemir BID 0.8 3.71
Insulin use Weight gain
(Units/Kg) (Kg)
Glargine + Oral agents 0.4 3.9
Detemir + Oral agents 0.6 3.0
52 week insulin use & weight gain results
Diabetologia. 2008 Mar;51(3):408-16
Results
• Lantus MRP @ Rs 840
Detemir MRP @ Rs 933
Glargine vs
Pre-Mix Insulin
6-59
“Laptop Trial”Lantus + Amaryl + metformin vs. premixed
insulin in patients with type 2 diabetes mellitus after failing oral treatment pathways
Janka,HU, Diab Care 28(2):254, 2005
Decrease in FBG
39
56
0
10
20
30
40
50
60
Lantus + OAD Premix (70/30)R
educ
tion
in F
BG
(m
g/dL
)
P<0.0001
43% greater reduction in Lantus + OAD group as compared to premix twice daily
Decrease in A1C
1.3
1.64
0
0.4
0.8
1.2
1.6
2
Lantus + OAD Premix (70/30)
Red
ucti
on in
A1C
(%
)
p=0.0003
26% greater reduction in Lantus + OAD group as compared to premix twice daily
Glycemic control without hypos
29
45
0
10
20
30
40
50
Lantus + OAD Premix (70/30)
Pat
ient
s (%
)
55% patients in the Lantus group achieved target glycemic control (A1C <7%) without a single incident of nocturnal hypoglycemia
p=0.0013
Insulin dose
64.5
28.2
0
10
20
30
40
50
60
70
Lantus + OAD Premix (70/30)
Mea
n in
suli
n do
se a
t en
dpoi
nt (
IU)
Superior Glycemic control at one third the insulin dose
Mean Number of Confirmed hypoglycemic events per patient-years
Type of Hypo Lantus + OAD Pre Mix P value
All 4.07 9.87 < 0.0001
Symptomatic 2.62 5.73 0.0009
Nocturnal 0.51 1.04 0.0449
Severe 0.00 0.05 0.0702
Hypoglycemia was confirmed by blood glucose levels <60 mg%Severe hypoglycemia was glycemic levels <36 mg% and which required third party assistance
Almost 50% less hypoglycaemia with Lantus + OAD seen for all classifications
Hypoglycemia
4.5
1.9
0
1
2
3
4
5
Lantus + OAD Premix (70/30)
Mea
n to
tal e
vent
rat
e/pa
tien
t
Mean event rate/patient of documented hypoglycemic (<60mg/dL) episodes
P<0.0001
Weight change
2.1
1.4
0
1
2
3
Lantus + OAD Premix (70/30)
Cha
nge
in w
eigh
t (k
g)
P=0.08
50% greater greater chances of weight gain with premix twice daily as compared to Lantus
The Initiate Study
Initiating insulin therapy in type 2 diabetes
Raskin, P, Diabetes Care 28(2):260, 2005
Initiate Study Design
28 week, multicenter, randomized, open-label, parallel-group study conducted at 25 sites in US
233 insulin-naïve patients with T2DM inadequately controlled (A1c 8.0%) on Metformin + Glitazone
Randomized to:• Insulin BIAsp 70/30 (5-6 units) BID + MET +/- TZD
• Glargine (10-12 units) HS + MET +/- TZDRaskin, P, Diabetes Care 28(2):260, 2005
9.8%
6.91%7.41%
5
6
7
8
9
Insulin Glargine 70/30 Aspart Premix
Baseline EndpointP<0.01
A1C
(%
)
–2.36% –2.79%
10
9.7%
Insulin Glargine vs 70/30 Premix A1C Reduction
Raskin P et al. Diabetes Care. 2005;28:260-265
Documented hypoglycemic episodes (<56 mg/dL)
Insulin Glargine vs Premix : Hypoglycemia
0.7
3.4
0
1
2
3
4
Ep
iso
des
per
Pat
ien
t-Y
earP<0.05
Insulin Glargine + OADs Premix
16% patients 43% patients
Raskin P et al. Diabetes Care. 2005;28:260-265.
Mean weight gain: 70/30 Aspart Premix, 5.4 ±4.8 kg, vs. glargine, 3.5 ±4.5 kg, P<0.01
Initiate Results
BIAsp 70/30
(N=117)
Glargine
(N=116)
p- value
Baseline
A1c
9.7 ± 1.5*
9.8 ± 1.4*
p=0.4782
Week 28 Results
A1c
6.9 ± 1.2*
7.4 ± 1.2*
p=0.0026
% Patients with A1c? 6.5% 42% 28% p=0.0356
% Patients with A1c< 7.0% 66% 40% p=0.0002
Total Daily Insul in Dose (U/kg) 0.82 ± 0.40 0.55 ± 0.27 Not
reported
Total Weight Gain (lbs) 11.9 ? 10.6 7.7 ? 9.9 p=0.0013
Minor Hypoglycemia (BG <56
mg/dL) 43% 16%
Not
reported
*Reported values for n=110 for BIAsp 70/30 group and n=114 for glargine group
Raskin, P, Diabetes Care 28(2):260, 2005
Problems with Premix
NPH/Regular 70/30 has the problems associated with both components. Rapid-acting analogs are safer
It locks the patient into eating when the insulin peaks, limiting flexibility
Available premixes often do not have enough rapid insulin to cover a large evening meal
In our experience it is difficult to achieve an A1C <7% without hypoglycemia
BB DDLL HSHS BB
Limitations of Twice-Daily Premix 30/70
Dawn Dawn phenomenonphenomenon
B, breakfast; L, lunch; D, dinner; HS, bedtime.B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.
Regular InsulinRegular InsulinNPH InsulinNPH Insulin
Endogenous InsulinEndogenous Insulin
Hyperglycaemia RiskHyperglycaemia Risk
Time of AdministrationTime of Administration
Strategies for Controlling the Uncontrolled Insulinized Patient
Criteria for successful insulin therapy
• Efficacy: HbA1c <7.0%
• Low rates of hypoglycaemia
• Minimal weight gain
• Flexibility
• Treatment satisfaction
41
Key barriers to achieving glucose goals
Barnett AH. Eur J Endocrinol 2004;151(Suppl.15):T3–T7
Status of diabetes management
Fear of hypoglycaemia
Weight gain
Fear of injections
Present Scenario
• > 40% of patients with T2DM worldwide use premixed insulin
• Newer premixed insulin analogues confer greater improvements in glycaemic control compared with regular human insulin or NPH insulin
• For many patients, premixed insulin alone – is insufficient to maintain adequate glycaemic control and – is associated with significant day-to-day variability.
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Rationale for a mega-observational study
There is limited information regarding therapeutic options for patients for whom premixed insulin provides inadequate glycaemic control or who frequently experience episodes of hypoglycaemia.
Aim of the study
• To evaluate the efficacy and safety of insulin glargine with concomitant OADs in everyday clinical practice when used by patients with T2DM who were previously treated with premixed insulin.
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Study design
• 12-week • Open-label, non-interventional, multicentre (n = 1791),
observational study • Based on everyday clinical practice.
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Eligibility criteria
• Inclusion criteria :– Patients with T2DM on regular human or analogue premixed insulin ± OADs.
– Switch to insulin glargine ± OADs done at the discretion of the physicians and patients, and depended mainly on subjective parameters, as reported by the physician, including:
• lack of efficacy of premixed insulin, • patient wanting a more flexible lifestyle, • ability to give up between-meal snacks, • frequent occurrence of hypoglycaemia with previous therapy,• insufficient mixtures of insulin suspensions available and • lack of tolerability with previous therapy.
• Exclusion criteria :– patients hypersensitive to insulin glargine or any of the excipients
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Reasons given by physicians and patients for switching from premixed insulin to
insulin glargine
68.8
55.6
37.1
23.5
13.7
13.3
0 10 20 30 40 50 60 70
lack of efficacy of premixed insulin
patient wanting a more flexible lifestyle
ability to give up between meal snacks
frequent occurrence of hypoglycaemia with previoustherapy
insufficient mixtures of insulin suspensions available
lack of tolerability with previous therapy
% patients
Of those citing frequent occurrence of hypoglycaemia (n = 1306), the mean number of episodes per person in the 3 months preceding the observation period was 5.0 ± 4.2 (median: 4.0).
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Control of FBG & PPG
178.
2
196.
2
124.
2
140.
4
0
20
40
60
80
100
120
140
160
180
200
FBS 2h-Postprandial
mg
/dl
Start of observation End of observation
• Mean decrease in FBG was 54.7 ± 45.6 mg/dl• Mean decrease in 2-h PPBG levels was 55 mg/dl
*p ≤ 0.001 for the within-group change in FBG from the start to the end of the observation period Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Change in A1c
- 1.1 ± 1.0 *
8.37.2
0
1
2
3
4
5
6
7
8
Start of observation End of observation
Hb
A1
C (
%)
• Mean decrease in HbA1c is 1.1 ± 1.0%
*p ≤ 0.001 for the within-group change in HbA1c from the start to the end of the observation period Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Proportion of patients who achieved clinically relevant FBG, PPBG and HbA1c at week 12
• 48.9% of the patients achieved FBG levels <120 mg/dl at study end• 81.6 % of the patients achieved PPBG levels <160 mg/dl at study end• 73.9% patients achieved HbA1c levels < 7.5% at study end
48
.9
81
.6
73
.9
0
10
20
30
40
50
60
70
80
90
100
FBG total < 120 mg/dl PPBG total < 160 mg/dl HbA1C < 7.5%
%p
ati
en
ts
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Body weight at the start & end of 12-week observation period85.2 83.6
-1.5
-2
8
18
28
38
48
58
68
78
Start End Change
Kg
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
Physicians assessment of therapy
94
.3
87
.5
68
.8
96
.3
90
.3
0
10
20
30
40
50
60
70
80
90
QOL Blood GlucoseControl
WeightManagement
Safety Demand on time
%p
ati
en
ts
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
SUMMARY
• A non-interventional, non-randomised observational study was undertaken to document postmarketing experience of transferring patients with T2DM from premixed insulin to insulin glargine.
• This study demonstrates for the first time in daily clinical practice that initiation of insulin glargine with or without OADs improves glycaemic control in patients with T2DM who were poorly controlled with premixed insulin prior to the observation period.
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.
What next?: When simple insulin regimens fail
Failure of combination OADs
Insulin glargineoptimal titration(0.5−0.7 U/kg)
Premixed insulin x 1
Premixed insulin x 2
Premixed insulin x 3Insulin glargine +
1 insulin glulisine: Basal Plus
Barnett A, et al. Pract Diabetes 2003;20:97−102.Dailey G, et al. Diabetes 2004;27:2363−8.
Basal–bolus
Premixed (biphasic) insulin ‘1-2-3 study’
0
10
20
30
40
50
60
70
80
90
Pati
ents
ach
ievi
ng
HbA
1c <
7% (
%)
Phase1
Phase 2
Phase 3
N=100 T2DM individuals poorly controlled with OADs or basal insulin plus OADsOpen-label, single-arm, observational study with 48 weeks’ follow-upStep-up premixed insulin regimen: once to three-times daily
Patients
7Major hypoglycaemia (n)
84Minor hypoglycaemia (%)
Garber A, et al. Diabetes Obes Metab 2006;8:58−66.
Insulin dose Weight gain
Phase 3 1.53 U/kg
Not specifiedPhase 2 1.15 U/kg
3 kgPhase 1 0.6 U/kg
Not specified
Basal Plus achieves control of glycaemia in patients failing premixed insulin therapy
-0.74
-1.21-1.35 -1.39
Hb
A1
c (%
)
Glargine + OAD(n=534)
Glargine + OAD+ prandial insulin x1
(n=47)
Glargine + OAD+ prandial insulin x2
(n=178)
Glargine + OAD+ prandial insulin >2
(n=193)0
–0.2
–0.4
–0.6
–0.8
–1.0
–1.2
–1.4
–1.6
Davies M, et al. Diabetes 2006;55(suppl). Abstract 455-P.
Weight change from baseline to study end (kg)
0.4 1.4 1.7 1.5
*
****p<0.001 from
baseline to endpoint
300
200
100
0
Pla
sma g
luco
se (
mg/d
l)
6 am noon 6 pm midnight 6 am
Time of day
If PPBG >180 mg/dl, add bolus insulin
Normal
FBG (controlled with basal insulin)
Rationale for ‘Basal Plus’ strategy: Add one bolus of rapid-acting insulin at main
meal
OPAL study design
5 days’ FBG measurement* Main meal determined based on 2-h PPBG
values
Titration targets:FBG 100 mg/dl2-h PPBG 135 mg/dl
Follow-up1 week
Pre-screening1−2 weeks
Screening1−3 weeks
Treatment24 weeks
Insulin glargine + OADs + 1 bolus of insulin glulisine 0−15 mins
before the main meal* of the day
Insulin glargine + OADs+ 1 bolus of insulin glulisine 0−15 mins
before breakfast Individuals with T2DM treated
with insulin glargine + OADs
FBG <120 mg/dl (<6.7 mmol/l)
HbA1c >6.5−≤9.0%
(444 patients enrolled)
Lankisch M, et al. Diabetes 2006;55(suppl.). Abstract 514-P.
OPAL: First study supporting the Basal Plus regimen*
*Interim analysis of 158 patients from all subgroups
Lankisch M, et al. Diabetes 2006;55(suppl). Abstract 514-P.
Baseline Study end (Week 26)
Insulin glargine dose (U) 30 31
FPG (mg/dl) 125 125
Insulin glulisine dose (U) 5 11
HbA1c (%) 7.4 7.0
Addition of 1 x insulin glulisinesignificantly improves glycaemic
control
Mode of administration and titration of Basal Plus insulin regimen Vs Premixed insulin
Insulin glargine/Insulin glulisine Premixed insulin
Number of injections Two Two/three
Timing of injections Insulin glargine: Morning OR pre dinner OR bedtime
Insulin glulisine: Major meal
Pre-breakfast and pre–dinner and pre-lunch
Initial insulin dose Insulin glargine: 10 U
Insulin glulisine: 4 U
Premixed 15 U BID1
Insulin dose titration Insulin glargine: Based on FPG
Insulin glulisine: 2-hr PPBG or pre-meal BG
Based on FBG, pre-dinner BG and PPBG at noon2
1. Premixed insulin aspart 70/30 (Novo Mix 30) guidelines. 2. Garber A, et al. Diabetes Obes Metab 2006;8:58−66.
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