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

Only 7.3% of adults with diabetes in NHANES 1999-2000 attained recommended HbA1C goals of <7%, BP < 130/80 mmHg and total cholesterol <200 mg/dl

Saydah et al JAMA 291(3):335-342

DICE: Primary care management of diabetes

One in two diabetes patients were not at target 7%

Uncontrolled A1C 49% Controlled A1C 51%

Most recent A1C test results (n = 2,337)

Harris SB et al. Diabetes Res Clin Pract 2005; 70: 90-97.

Standard Approaches to Therapy Result in Prolonged Exposure to Elevated Glucose

10% Mean A1C at Last Visit 9% 9.0% 8.6% 8% 7% 6% Diagnosis Diet/Exercise Sulfonylurea or Metformin Monotherapy Combination Therapy Insulin 9.6%

ADA Goal <7% 2 3 4 5 Years 6 7 8 9 10

At insulin initiation, the average patient had: 5 years with A1C >8% 10 years with A1C >7%
Brown JB, et al. Diabetes Care. 2004;27:1535-1540.

Deterioration of Glycemic Control with Combination Therapy Over Time

Deterioration in glycemic control begins within 6 months of starting combination therapy, particularly when initiated at higher A1C values
1.0

Proportion with A1C 8.0%

0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 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%

Time from Sulfonylurea Initiation (Years)

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

Glycemic management
Metformin
Sulfonylureas net TZDs net Other oral agents net Insulin Lifestyle only

61% 48%

15%
4% 12% 15%

20

40

60

80

100

Patients currently taking medication (%)

Despite suboptimal control, only 12% of patients were receiving insulin

Base: Patients (n = 2,473). Sulfonylureas: Glimepiride, glyburide, chloropropamide, gliclazide, tolbutamide. TZDs: Pioglitazone, rosiglitazone. Other oral agents: Repaglinide, acarbose, nateglinide.

Harris SB et al. Diabetes Res Clin Pract 2005; 70: 90-97.

Insulin Coverage at Different Stages: All Diabetes Types

100 -Cell Function (% )

80 Early type 2 Late type 2, type 1 Basal replacement Basal and meal replacement -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

60

40

20

Time (Years)

DeFronzo RA. Diabetes Rev. 1997;5:178-269.

Treating Fasting Hyperglycemia Lowers the Entire 24-Hour Plasma Glucose Profile
400

Plasma Glucose (mg/dL)

Type 2 diabetes
300

20

Plasma Glucose (mmol/L)

15

200 Hyperglycemia due to increase in fasting glucose

10 100

Normal
0
6
Meal Meal Meal

0 22 2 6

10

14

18

Time of Day (h)

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

Insulin Glargine : Mechanism of Action

Clear Solution pH4

pH 7.4

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

Precipitation Dissolution Hexamers 10-3 M Dimers 10-5M Monomers 10-8 M

Capillary Membrane Insulin in Blood Adapted from: Kramer W. Exp Clin Endocrinol Diabetes 107(1999) Suppl 2

Insulin Detemir

Thr Lys

Lys

Pro

Thr

Tyr

Phe

Phe

Gly

Arg

Glu

Gly

Cys Val Leu Tyr Leu Ala Glu Val

B29

A21

Asn

Cys

A1

Gly Ile Val

Tyr Asn

Glu
Leu Gln Cys Tyr Cys Thr Ser Ile Cys Ser Leu Ser His Gly

Glu
Gln

Leu

B1

Phe

Val

Asn

Gln

His

Leu

Cys

Relative Benefits of

Glargine NPH Detemir Pre-Mix (70/30, 75/25)

Treatment to Target Study

Study Design Continue oral hypoglycemic agent(s) + insulin glargine at bedtime Patients inadequately controlled on oral hypoglycemic agent(s) HbA1c 7.5-10%

24 weeks of treatment Continue oral hypoglycemic agent(s) + NPH insulin at bedtime Target FPG 100 mg/dL
Riddle MC et al. Diabetes Care. 2003;26:3080-3086

Treat-to-Target Trial: Efficacy Results

Glargine 200 NPH 9 8.5 Glargine NPH

FPG (mg/dL)

150

A1C (%)
0 4 8 12 16 20 24

8 7.5 7 6.5

100

6 0 4 8 12 16 20 24

Weeks of Treatment

Weeks of Treatment

*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.

Insulin Dosage During Study

(Both treatment groups)
50 40
Total Daily Dose (Units)

36 37 31 33 0.37 0.39 28 25 21 16 10 0.17 0.11 0.26 0.22 0.33 0.35 0.3

39

41

43

44

0.6 0.5

Total Daily Dose (Units/kg)

30 20 10 0 0 1* 2

0.41

0.43

0.44

0.46

0.4 0.3 0.2

Units Units/kg 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

0.1 0

Weeks in Study
Riddle MC et al. Diabetes Care. 2003;26:3080-3086

Symptomatic Hypoglycemic Events

Events per patient exposureyear
1.4 1.2 1.0

* * * *
Basal insulin

* *

NPH Glargine

0.8
0.6 0.4 0.2

Breakfast

Lunch

Dinner

0
20 22 24 2 4 6 8 10 12 14 16 18

Time of day (h)

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.

Glargine vs Detemir

6-59

Insulin Glargine Plus Oral Agents vs. Insulin Detemir Plus Oral Agents
Study Design Detemir 12 U HS 582 Patients inadequately controlled on 1 or 2 oral agents HbA1c 8.6% FPG ~194 mg/dl Detemir Q HS (45%) Detemir AM and HS (55%)

Target FPG pre-breakkfast<108 mg/dl pre-dinner <126 mg/dl Glargine 12 U HS

52 weeks of treatment
Diabetologia. 2008 Mar;51(3):408-16

Insulin Glargine Plus Oral Agents vs. Insulin Detemir Plus Oral Agents
52 week results
Glargine + OAD HbA1C (%) FPG (mg/dl) HbA1C<7% with no hypos Overall + Nocturnal Hypos Weight gain 7.1 126 35% Same 3.9 Kg Detemir + OADs 7.2 128 35% Same 3.0 Kg

Diabetologia. 2008 Mar;51(3):408-16

6-59

Insulin Glargine Plus Oral Agents vs. Insulin Detemir Plus Oral Agents
52 week insulin use & weight gain results
Insulin use (Units/Kg) Glargine + Oral agents Detemir + Oral agents Detemir HS Detemir BID 0.4 0.6 0.4 0.8 Weight gain (Kg) 3.9 3.0 2.25 3.71

Diabetologia. 2008 Mar;51(3):408-16

6-59 6-59

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
Lantus + OAD 0 Premix (70/30)

Reduction in FBG (mg/dL)

10 20 30 40 50
P<0.0001

39

60

56

43% greater reduction in Lantus + OAD group as compared to premix twice daily

Decrease in A1C
Lantus + OAD 0 Premix (70/30)

Reduction in A1C (%)

0.4 0.8 1.2 1.3 1.6 1.64

p=0.0003

26% greater reduction in Lantus + OAD group as compared to premix twice daily

Glycemic control without hypos

50 40 45
p=0.0013

Patients (%)

30 20 10 0 Lantus + OAD

29

Premix (70/30)

55% patients in the Lantus group achieved target glycemic control (A1C <7%) without a single incident of nocturnal hypoglycemia

Insulin dose
Mean insulin dose at endpoint (IU)
70 60 50 40 30 20 10 0 Lantus + OAD Premix (70/30) 28.2 64.5

Superior Glycemic control at one third the insulin dose

Mean Number of Confirmed hypoglycemic events per patient-years

Type of Hypo All Symptomatic Nocturnal Lantus + OAD 4.07 2.62 0.51 Pre Mix 9.87 5.73 1.04 P value < 0.0001 0.0009 0.0449

Severe

0.00

0.05

0.0702

Almost 50% less hypoglycaemia with Lantus + OAD seen for all classifications
Hypoglycemia was confirmed by blood glucose levels <60 mg% Severe hypoglycemia was glycemic levels <36 mg% and which required third party assistance

Hypoglycemia
5 4.5
P<0.0001

Mean total event rate/patient

4 3 2 1 0 Lantus + OAD Premix (70/30) 1.9

Mean event rate/patient of documented hypoglycemic (<60mg/dL) episodes

Weight change
3
P=0.08

Change in weight (kg)

2.1 2 1.4 1

0 Lantus + OAD Premix (70/30)

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-nave 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 +/- TZD

Raskin, P, Diabetes Care 28(2):260, 2005

Insulin Glargine vs 70/30 Premix A1C Reduction

Baseline Endpoint

10
9 A1C (%) 9.8%

P<0.01

2.36%

9.7%

2.79%

8
7 7.41% 6 5 Insulin Glargine 70/30 Aspart Premix 6.91%

Raskin P et al. Diabetes Care. 2005;28:260-265

Insulin Glargine vs Premix : Hypoglycemia

Documented hypoglycemic episodes (<56 mg/dL)
P<0.05

Episodes per Patient-Year

4
3 2 1 0

3.4

0.7
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) Baseline A1c Week 28 Results A1c ? % Patients with A1c 6.5% % Patients with A1c< 7.0% Total Daily Insul in Dose (U/kg) Total Weight Gain (lbs) Minor Hypoglycemia (BG <56 mg/dL) 9.7 1.5* 6.9 1.2* 42% 66% 0.82 0.40 11.9 ? 10.6 43% Glargine (N=116) 9.8 1.4* p=0.0026 7.4 1.2* 28% 40% 0.55 0.27 7.7 ? 9.9 16% p=0.0356 p=0.0002 Not reported p=0.0013 Not reported p- value p=0.4782

*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. Rapidacting 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

Limitations of Twice-Daily Premix 30/70

Endogenous Insulin Regular Insulin NPH Insulin Hyperglycaemia Risk

Dawn phenomenon

HS

Time of Administration
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.

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

Key barriers to achieving glucose goals

Fear of hypoglycaemia

Weight gain
Fear of injections

Barnett AH. Eur J Endocrinol 2004;151(Suppl.15):T3T7 41

Status of diabetes management

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
lack of tolerability with previous therapy 13.3 insufficient mixtures of insulin suspensions available frequent occurrence of hypoglycaemia with previous therapy ability to give up between meal snacks 13.7

23.5

37.1

patient wanting a more flexible lifestyle

55.6

lack of efficacy of premixed insulin 0 10 20 30

68.8 40 50 60 70

% 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

200 180 160 140 120
mg/dl 178.2

100 80 60 40 20 0

196.2

FBS Start of observation

124.2

2h-Postprandial 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.

140.4

Change in A1c
- 1.1 1.0 *

8 7 6

HbA1C (%)

5 4 3 2 1 0 Start of observation End of observation 8.3 7.2

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.

100 90 80 70 60 50

Proportion of patients who achieved clinically relevant FBG, PPBG and HbA1c at week 12

%patients

30 20 10 0 FBG total < 120 mg/dl PPBG total < 160 mg/dl HbA1C < 7.5%

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
Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.

48.9

73.9

40

81.6

Body weight at the start & end of 12-week observation period

85.2 78 68 58 48 83.6

Kg
38 28 18 8 -2 -1.5

Start

End

Change

Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.

Physicians assessment of therapy

90 80 70

%patients

60

30 20 10 0 QOL Blood Glucose Control

Weight Management

68.8

40

87.5

Safety

Demand on time

Hammer H, Klinge A. Int J Clin Pract. 2007 Dec;61(12):2009-18.

90.3

50

94.3

96.3

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 glargine optimal titration (0.50.7 U/kg) Premixed insulin x 1

Premixed insulin x 2

Insulin glargine + 1 insulin glulisine: Basal Plus Basalbolus

Barnett A, et al. Pract Diabetes 2003;20:97102. Dailey G, et al. Diabetes 2004;27:23638.

Premixed insulin x 3

Premixed (biphasic) insulin 1-2-3 study

N=100 T2DM individuals poorly controlled with OADs or basal insulin plus OADs Open-label, single-arm, observational study with 48 weeks follow-up Step-up premixed insulin regimen: once to three-times daily

Patients
90 80 Phase1 Phase 2 Phase 3

Minor hypoglycaemia (%) Major hypoglycaemia (n)

84 7

Patients achieving HbA1c <7% (%)

70 60 50 40 30 20 10 0

Insulin dose

Weight gain

Phase 1
Phase 2 Phase 3

0.6 U/kg
1.15 U/kg 1.53 U/kg

3 kg
Not specified Not specified

Garber A, et al. Diabetes Obes Metab 2006;8:5866.

Basal Plus achieves control of glycaemia in patients failing premixed insulin therapy
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)

0.2
0.4

HbA1c (%)

0.6 0.8 1.0 1.2 1.4

*p<0.001 from baseline to endpoint

-0.74 * -1.21 *

1.6
Weight change from baseline to study end (kg)

-1.35 *

-1.39 *

0.4

1.4

1.7

1.5

Davies M, et al. Diabetes 2006;55(suppl). Abstract 455-P.

Rationale for Basal Plus strategy: Add one bolus of rapid-acting insulin at main meal 300
Plasma glucose (mg/dl)

200

If PPBG >180 mg/dl, add bolus insulin

100

FBG (controlled with basal insulin) Normal

6 am

noon

6 pm
Time of day

midnight

6 am

OPAL study design

Individuals with T2DM treated with insulin glargine + OADs FBG <120 mg/dl (<6.7 mmol/l) HbA1c >6.59.0% (444 patients enrolled) Pre-screening 12 weeks Screening 13 weeks
5 days FBG measurement * Main meal determined based on 2-h PPBG values
Lankisch M, et al. Diabetes 2006;55(suppl.). Abstract 514-P.

Insulin glargine + OADs + 1 bolus of insulin glulisine 015 mins before breakfast Insulin glargine + OADs + 1 bolus of insulin glulisine 015 mins before the main meal* of the day Treatment 24 weeks Follow-up 1 week

Titration targets: FBG 100 mg/dl 2-h PPBG 135 mg/dl

OPAL: First study supporting the Basal Plus regimen*

Addition of 1 x insulin glulisine significantly improves glycaemic control

Baseline Insulin glargine dose (U) FPG (mg/dl) Insulin glulisine dose (U) 30 125 5

Study end (Week 26) 31 125 11

HbA1c (%)

7.4

7.0

*Interim analysis of 158 patients from all subgroups

Lankisch M, et al. Diabetes 2006;55(suppl). Abstract 514-P.

Mode of administration and titration of Basal Plus insulin regimen Vs Premixed insulin
Insulin glargine/ Insulin glulisine Number of injections Timing of injections Two Insulin glargine: Morning OR pre dinner OR bedtime Insulin glulisine: Major meal Insulin glargine: 10 U Insulin glulisine: 4 U Insulin glargine: Based on FPG Insulin glulisine: 2-hr PPBG or pre-meal BG

Premixed insulin
Two/three Pre-breakfast and predinner and pre-lunch

Initial insulin dose

Premixed 15 U BID1

Insulin dose titration

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;8:5866.

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