basal vs premix

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



6-596-59


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


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


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


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


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


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.


Study design

• 12-week • Open-label, non-interventional, multicentre (n = 1791),

observational study • Based on everyday clinical practice.


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


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).


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


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


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


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.


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.

THANK YOU

basal vs premix

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