Early Initiation of Insulin: - PowerPoint Presentation

Slide1

Early Initiation of Insulin:

Basal Bolus versus Premixed

Slide2

ADA Diabetes Management Algorithm 2015

Slide3

Slide4

Slide5

Slide6

Slide7

Slide8

Slide9

Slide10

Slide11

Need for Early and aggressive treatment

Slide12

Slide13

Legacy effect: early vs late glycemic control and complications risk

Aggressive glycemic control:

‘Modestly reduced macro-vascular complication risk while posed additional complication’

In Early stage T2 DM

Inzucchi

et al., 2012; Skyler,

Bergenstal

,

Bonow

, et al., 2009,

Stratton IM et al. BMJ 2000;321:405–412

Slide14

Insulin at Diagnosis

Handelsman

, Y. et al.

Endocr

. Pract.17 (Suppl. 2), 1–53 (2011).

Bhattacharyya

, O. K. Can. Fam. Physician. 55, 39–43 (2009).

Slide15

Early

Insulinization

is

Recommended by the ADA/EASD

to Avoid Clinical Inertia

If HbA

1c

targets are not achieved after

~3 months

of initial treatment, alternative therapy such as basal insulin should be

initiated

1,2

Early insulin therapy has the potential to achieve near-normal glucose control & prevent progression of glucose intolerance

3

1.

Inzucchi

SE, et al.

Diabetologia

2012;

55

:1577–96

2. Nathan DM, et al.

Diabetes Care

2009;

32

:193–203

3. ORIGIN Trial Investigators. N Engl J Med 2012;367:319–28

ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes

Slide16

The legacy of

basal

insulin

Diabetes Care in 2012: Current Trends and Future Directions

Slide17

4-T Study:

Insulins Relative Changes

over 3

Years and

Hypoglycaemia

N

Engl

J Med 2009; 361: 1736-47

Differential effects of basal vs prandial insulin components of dysglycemia, body weight and hypoglycemia risk: the 4T study

Slide18

Biphasic

Prandial

Basal

Median HbA

1c

level achieved

+

+

+

HbA

1c

targets achieved

+

++

++

Mean SMBG level achieved

+

++

++

Fewer

hypoglycaemic

episodes

++

+

+++

Less weight gain

+

+

++

Less increase in waist circumference

+

+

++

Overview of Main Results

Slide19

1

Riddle M, et al.

Diabetes

Care 2003;26:3080–6;

2

Yki-Järvinen H, et al.

Diabetologia

2006;49:442–51;

3

Bretzel RG, et al. Lancet

2008;371:1073–84;

4

Janka H, et al. Diabetes Care 2005;28:254–9;

5

Rosenstock J, et al. Diabetes Care 2006;29:554–9;

6

Yki-Jarvinen H

, et al. Diabetes 2006;55 Suppl. 1:A30

HbA

1c

(%)

APOLLO

3

LAPTOP

4

Triple

Therapy

5

LANMET

2

Treat-To-Target

1

INITIATE

6

7.14

7.15

6.96

7.14

6.80

8.71

8.85

8.80

9.5

8.808.616.96BaselineStudy endpoint58.0Target HbA1c≤7% (%)49.448.057.0

NA

NA

7

8

9

10

6

The most

studied

basal insulin

With established

CV safety,

10

million patients,

>

60 million patient-years,

>

59,000 participants in clinical trials

Consistent achievement of glycaemic targets with basal

insulin GLARGINE

Slide20

0

100

200

300

400

0

4

8

12

16

20

24 hrs

Isoglycemic clamp study

Plasma Insulin (pM)

Inadequate prandial insulin :

Postprandial

Hyperglycemia

Excess inter-prandial supply:

Increased risk of Hypoglycemia

risk

HYPO

risk

HYPO

HYPER

HYPER

HYPER

Luzio S et al, Diabetologia 49:1163-8, 2006

Insulin Profiles: Premixed 30/70

Aspart

pre-mixes

are NOT suitable to

Treat-to-target A1C <7.0%

Slide21

2015 – Basal & “Premix”

Fixed ratio.

2

Premix :

Less flexible.

1

Less studied alternative.

1

Less adaptable.

2

Less desirable to intensify.

3

More Hypos & weight gain

Unable to titrate individually

1. Diab Care 38; 38:140–149 Jan 2015. 2.

Owens DR. Diabet. Med. 30, 276–288; 2013. 3. AACE Algorithm 2013

“The fixed-ratio nature of premixed formulations make them less flexible & adaptable to the individual’s specific needs than a basal-plus strategy”.

2

Slide22

CLINICAL EVIDENCES for

basal/basal-plus/basal-bolus

strategy versus premixed

Slide23

LAPTOP study: Comparison of insulin

glargine

added to an

OAD

regimen versus switching to premixed insulin

RANDOMISATION

Patients

with

T2DM

HbA

1c

: 7.5% to 10.5%

and FBG: ≥6.7

mmol

/L (≥120 mg/

dL

) and

treated

with

OADs

(

n

= 364)

Insulin

glargine

+

OADs

(

n

= 177)Initial dose: 10 IU once daily in the morning

Human premixed insulin (70/30) (

n

= 187)

Initial dose: 10 IU before breakfast and 10 IU before dinner

Treatment phase

Screening

24 weeks

Run-in phase

3–14 weeks

Subjects taking sulphonylurea and metformin for at least a month were enrolled. Sulphonylurea was replaced with 3 or 4 mg glimepiride during run-in phase. OHA dose remained the same throughout the study in the insulin glargine arm, while OHAs were discontinued in the premixed insulin arm.

Janka

H, et al. Diabetes Care 2005;28:254–9.

Slide24

24

Significantly greater reduction in FBG and PPBG with insulin

glargine

vs premix

4

6

8

10

12

14

16

Endpoint

Fasting

After

breakfast

Lunch

After

lunch

Dinner

After

dinner

Bedtime

03.00

*

*

*

*

*

Blood glucose (mmol/L)

Baseline

Insulin glargine + OHAs

Premixed insulin twice daily

Time of day

*

p

< 0.05 for treatment comparison of changes from baseline to endpoint

Janka

H,

et al. Diabetes Care

2005;28:254–9.

Slide25

Insulin

glargine

provided better glycaemic control and less weight gain than premix

Premixed insulin

†

Insulin glargine

‡

0

-0.5

-1.0

-1.5

-2.0

-1.31

Premixed insulin

†

Insulin glargine

‡

Weight gain (kg)

1.4

2.1

2.5

2.0

1.5

1.0

0.5

0

-1.64

HbA

1c

change from baseline (%)

Final daily dose:

Premixed insulin 64.5 IU

Insulin glargine 28.2 IU

p

= 0.0003

p

= NS

†

Twice daily;

‡

plus OHAs

Janka

H,

et al. Diabetes Care 2005;28:254–9.

Slide26

26

Lower incidence of hypoglycaemia with insulin

glargine

versus

premixed

0.51

0

2

4

6

8

10

12

Events per patient per year

Premixed insulin

Insulin glargine*

All confirmed

hypoglycaemia

Confirmed

symptomatic

Confirmed

nocturnal

p

< 0.0001

p

= 0.0009

p

= 0.0449

Hypoglycaemia confirmed by blood glucose <60 mg/

dL

(3.3

mmol

/L)

Janka

H,

et al. Diabetes Care

2005;28:254–9.

*Plus

ODAs

1,04

2,62

9.87

5.73

4.07

Slide27

INITIATE (

Raskin

) study: Comparative study of insulin

glargine

versus premix added to an

OAD

regimen

RANDOMISATION

Insulin-naïve patients with T2DM previously

treated with

metformin

(>1,000 mg/day) alone

or plus other

OADs

HbA

1c

≥8%

(

n

= 222)

Insulin

glargine

+

OADs

(

n

= 114): Initiated at 10–12 U once daily at bedtime

Premixed insulin

aspart

(

BIAsp

70/30) +

OADs

(

n

= 108)

Initiated at 5–6 U twice daily, before breakfast and dinner

Treatment phase

Screening

28 weeks

Run-in phase

3–14 weeks

During run-in, metformin was optimised to 1,500

–2,550 mg/day, secretagogues and -glucosidase inhibitors were discontinued. Pioglitazone was continued (if taken pre-study) and subjects taking rosiglitazone were changed to pioglitazone.Raskin P, et al. Diabetes Care 2005;28:260–5.

Slide28

HbA1c was reduced in both groups with a significantly greater effect with

premixed

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

*FPG target of 80–110 mg/dL (4.4–6.1 mmol/L)

p

< 0.01

p

= NS

Target FPG* achieved by 57%

of insulin glargine group and

36% of premix group

HbA

1c

<7% achieved by 40%

of insulin glargine group and

66% of premix group

Premix

Insulin glargine

14,0

7,1

13,5

6,5

Baseline

Study end

FPG (mmol/L)

9,7

6,9

9,8

7,4BaselineStudy endHbA1c (%)Raskin P, et al. Diabetes Care 2005;28:260–5.

Slide29

Hypoglycaemia, weight gain and daily dose all lower with insulin

glargine

vs premix

0

10

20

30

40

50

0

1

2

3

4

5

6

0

20

40

60

80

100

*Minor hypoglycaemia: <56 mg/dL (<3.1 mmol/L) with or without symptoms

p

< 0.05

p

< 0.01

Raskin

P,

et al. Diabetes Care

2005;28:260–5.

Hypoglycaemia*

Daily insulin dose

Weight gain

p

< 0.05

43

16

Premixed

insulin

Insulin

glargine

% patients

5,43,5PremixedinsulinInsulinglarginekg78,551,3PremixedinsulinInsulinglargineIU at study end

Slide30

GINGER: Basal Bolus provides superior glycemic control vs. intensified premixed insulin therapy

Subjects:

310 with inadequately controlled type 2 diabetes (HbA

1c

8–11%)

Pretreated

with premixed insulin (mean of 5 years),

with some receiving metformin (continued during study)

Fritsche

A, et al.

Diabetologia

2008;51 Suppl. 1:S83

Mean baseline values:

HbA

1c

(%):

8.5

BMI (kg/m

2

): 30.1

Diabetes duration (years): 13.0

52 weeks

Randomization

Insulin glargine + three daily doses of insulin glulisine +/- metformin (n=153)

Twice-daily premixed insulin +/- metformin (n=157)

Slide31

Fritsche

A, et al.

Diabetologia

2008;51 Suppl. 1:S83

p=0.0004

% achieving HbA

1c

<7.0

0

10

20

30

40

50

Glargine

+ glulisine

Premixed

insulin

47

28

Months

7.0

8.0

9.0

6.0

p=0.0001

0

3

6

9

12

8.5

8.6

7.7

7.3

HbA

1c

(%)

Premixed insulin

Glargine + glulisine

GINGER: Basal Bolus provides superior

glycemic

control vs. intensified premixed insulin therapy

Slide32

GINGER: Basal Bolus has an acceptable safety

profile in late stage T2D

0

1

2

3

4

Glargine

+ glulisine

Premixed

insulin

Mean body weight change

from baseline (kg)

3.6

2.2

p=0.007

Symptomatic hypo

(event/patient-year)

0

5

10

15

Glargine

+ glulisine

Premixed

insulin

9.9

13.4

p=NS

Severe hypo

(event/patient-year)

0.00

0.05

0.10

0.15

0.20

0.25

Glargine

+ glulisine

Premixed

insulin

0.1

0.2

p=NS

Fritsche

A, et al.

Diabetologia

2008;51 Suppl. 1:S83

Slide33

Treatment satisfaction

with insulin

glargine

vs premixed insulin analogues

Slide34

LADI – switching from premixed to glargine + glulisine improves treatment satisfaction in T2DM

DTSQ score

p<0.0001

Schreiber S, et al.

Diabetologia

2007;50(

suppl

1):S410

–

1

.

Baseline 12 weeks

Basal-plus and basal-bolus insulin therapy provided

better patient treatment satisfaction

Slide35

Treatment satisfaction is higher with insulin glargine than with premixed human insulin

p = 0.0012

Bradley C, et al.

Diabetes

2005;54(

Suppl

):Abstract 1246-P.

0

5

10

15

Insulin

glargine

+

OADs

Premixed human

insulin 30/70 BID

DTSQc score at endpoint

11.5

14.0

At 24 weeks insulin glargine was associated with a greater increase

in patient treatment satisfaction

Slide36

High physician satisfaction with switching from premixed insulin to insulin glargine

Hammer H and

Klinge

A.

Int

J

Clin

Pract

2007;61:2009–18.

Efficacy

Safety

Very good

Good

Satisfactory

Unsatisfactory

No response given

Most physicians rated the efficacy and safety

of insulin glargine as ‘very good’ or ‘good’

46%

41%

54%

42%

Slide37

Markers of glycemic variability were better in patients treated with BB than in those treated with MIX in better control group.

Conclusion

: These results suggest that BB therapy achieves better glucose profiles than MIX therapy.

Slide38

Subcontinental

Data

Slide39

Addition of insulin

aspart

with basal insulin is associated with improved glycemic control in Indian patients with uncontrolled type 2 diabetes mellitus

Banerjee

S,

Maji

D,

Baruah

M. J

Assoc

Physicians India. 2013 Jan;61(1 Suppl):24-7.

Slide40

Recent 2015 ADA Standard of care

ADA STANDARDS OF MEDICAL CARE IN DIABETES—2015

Slide41

Conclusion

Slide42

Laptop Study1

Initiate Study2

Hammer & Kingler3

AT-LANTUS Study5

Janka

H,

et al. Diabetes Care

2005;28:254

–

9.

2.

Raskin

P,

et al. Diabetes Care

2005;28:260–5.

3.

Davies M, et al. Diabetes Res

Clin

Pract

2008;79:368–75.

4. Hammer H and

Klinge

A.

Int

J

Clin

Pract

2007;61:2009–18

5.

Diabetes Care 34:249–255, 2011

.

DURABLE Study5

Thank you