company confidential © 2012 eli lilly and company therapeutic options for patients sub-optimally...

Company Confidential © 2012 Eli Lilly and Company

Therapeutic options for patients sub-optimally controlled on human premix insulin

Speaker name and affiliation

Prescribing information is available on the last slide.UKHMG00716 September 2013

Meetings developed by Eli Lilly & Company Ltd in conjunction with SB Communications Group. Eli Lilly & Company Ltd fully funded these meetings



Key factors

HbA1cSMBG

Body Weight

Age

Cognitive ability

Hypo’s

Co-morbidity

Diet & exerciseLifestyle

Occupation

Injection freq/

device

Carb awareness

Dose adjustment

Motivation

Langauge

Some practical factors to consider when changing a patient’s insulin regimen

The factors that determine a

patient’s regimen will be individual

and vary from patient to patient.

SMBG=self-monitoring of blood glucose.

What options exist for those with suboptimal control on biphasic human insulin 30/70?

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Some commonly considered options*

4

*Assuming Humulin® M3 has been optimised appropriately.

Options for people with suboptimal control

on Human premix 30/70

Move to an analogue premix

with a similar ratio of basal/prandial

coverage?

Consider using basal plus bolus

insulin?

Move to a premixed preparation with greater prandial

coverage?

Moving to an analogue premix with a similar ratio of basal/prandial coverage

Evidence from randomised trials and considerations


Comparison of human insulin 30/70 with insulin lispro 25/75

6

Roach P et al (1999) Diabetes Care 22: 1258–61

Six-month, randomised, open-label, two-period crossover study. Included 89 individuals with type 2 diabetes. Each insulin administered twice daily. Conclusion:

In comparison to treatment with human insulin 30/70, twice daily administration of analogue premix

25/75 resulted in improved postprandial glycemic control, similar overall glycemic control, and the

convenience of dosing immediately before meals


Consider premixed preparations that include short-acting insulin

analogues, rather than premixed preparations that include short-

acting human insulin preparations, if:

The person prefers injecting insulin

immediately before a meal.

Hypoglycaemia is a problem.

Blood glucose levels rise markedly after

meals.

Initiating pre-mixed insulin therapy: NICE guidance*

7

NICE (2009) Type 2 Diabetes. The Management of Type 2 Diabetes. NICE Clinical Guideline 87. Available at: http://www.nice.org.uk/CG87 (accessed (3.10.2013)

*Note: When insulin is initiated, NICE recommends beginning with human neutral protamine Hagedorn insulin injected at bed-time or twice daily according to need.

http://www.nice.org.uk/CG87


Summary

Switching from human insulin 30/70 to an analogue premixed insulin with a similar ratio:

– May not yield overall improvement in HbA1c.

– May be useful if PPG is a concern or hypoglycaemia is a problem.

– May be useful if a person wishes to “inject and eat”.

8

PPG=postprandial plasma glucose.


Summary

9

Options for people with suboptimal

control on Human premix 30/70



coverage?


insulin?


coverage?

Moving to using basal and bolus insulin

Evidence from randomised trials and considerations


Premixed insulin compared with basal–bolus: The GINGER study

11

GINGER=Glulisine in Combination with Insulin Glargine in an Intensified Insulin Regimen.Fritsche A et al (2010) Diabetes Obes Metab 12: 115–23

A 52-week, open-label, randomised, multinational, multicentre trial that included 310 subjects with type 2 diabetes on premixed insulin (human or analogue – either 25/75 or 30/70), with or without metformin.

Participants randomised to a basal–bolus regimen (with glargine and glulisine) or twice-daily premixed insulin (either human 30/70, or aspart 30/70).


Main results of the GINGER study

12

GINGER=Glulisine in Combination with Insulin Glargine in an Intensified Insulin Regimen.Fritsche A et al (2010) Diabetes Obes Metab 12: 115–23

At study end: Number of overall

hypoglycaemic events per year were higher in the premix group, but the difference was not significant (P=0.2385).

Weight gain was significantly greater in the basal–bolus group (+3.6 vs. +2.2 kg; P=0.0073).


In “Real World” Practice, Is Basal–Bolus Always The Gold Standard?

13

1. Donnelly LA et al (2007) Q J Med 100: 345–502. Currie CJ et al (2012) Diabetes Care 35(6):1279-84. 3. Hollander P et al (2008) Clin Ther 30: 1976–87

High injection frequency can lead to poor adherence, causing inadequate glycaemic control in insulin treated type 2 patients.1

Noncompliance in insulin treated type 2 patients is associated with increased all-cause mortality.2

Many people with type 2 diabetes on basal–bolus therapy have suboptimal glycaemic control. In one large study*, almost two thirds of people failed to achieve HbA1c ≤7% (≤53 mmol/mol).3

*This was a multinational, 52-week, open-label, parallel-group, non-inferiority, treat-to-target trial, designed to compare the efficacy and safety profiles of detemir and glargine as the basal insulin component of a basal–bolus regimen in people with type 2 diabetes. Insulin aspart was used as the bolus insulin. The intention-to-treat population included 319 participants.


Is this for every patient?

14

Too many injections Regimen complexity Patient

– mental capacity– scared of hypos

Frequent BG measurements CHO awareness More injections -> more likely to skip

injections Body weight (not just young women) Tiring, long-tem commitment Not all patients want flexibility

Best regimen for the right patient

Basal bolus a successful regimen

Carb awarene

ss

4-5 injectio

ns a day

Insulin dose

adjustments

Frequent BG

monitoring

1. Donnelly LA et al (2007) Q J Med 100: 345–50


Summary

15

There is some evidence that basal–bolus regimens provide glycaemic benefit compared with twice-daily premixed insulin.

However, there are some practical factors that make basal–bolus regimens unfeasible for some people with type 2 diabetes.


Summary

16

Options for people with suboptimal control

on human premix 30/70



coverage?


insulin?


coverage?

Moving to a premixed insulin with a greater prandial coverage

Rationale for considering “mid-mix” insulins


As people with diabetes get closer to HbA1c targets, the need to manage PPG increases

18

100

0

50

Rel

ativ

e co

ntrib

utio

n (%

)

>10.2 10.2–9.3 9.2–8.5 8.4–7.3 <7.3

HbA1c (%) quintiles

70%

30%

Fasting plasma glucosePostprandial glucose

Adapted from Monnier L et al (2003) Diabetes Care 26: 881–5


In people without diabetes, basal secretion represents approximately 50% of total daily insulin

19

Polonsky KS et al (1988) J Clin Invest 81: 442–8

Normal

Obese

Time (hours)

When the basal insulin secretion rate was extrapolated over a 24-h period and expressed as a percentage of the total 24-h insulin secretion, basal secretion represented 50.1±3.1% of the total 24-h insulin secretion in normal subjects and 45.2±2.2% in obese patients.


Patients with type 2 diabetes on intensive insulin therapy regimens use 50% basal and 50% bolus insulin

20

BG=blood glucose.Herman WH et al (2005) Diabetes Care 28: 1568–73

Doses adjusted to achieve target preprandial and bedtime BG levels.

Basal dose Bolus doses

% T

ota

l da

ily in

sulin

dos

e

Multiple daily injection (n=50)Continuous subcutaneous insulin infusion (n=48)

After titrating doses throughout the study each group independently had a regimen that consisted of approximately 50% basal and 50% preprandial insulin.

100

50

0


Currently available human and analogue premixed insulins

21

BG=blood glucose.Herman WH et al (2005) Diabetes Care 28: 1568–73

Composition

Human insulins

Biphasic human insulin (Humulin® M3) 30% soluble insulin 70% isophane insulin

Biphasic human insulin (Insuman® Comb 15) 15% soluble insulin 85% isophane insulin



Analogue insulins

Biphasic insulin lispro (Humalog® Mix25) 25% lispro 75% lispro protamine

Biphasic insulin lispro (Humalog® Mix50) 50% lispro 50% lispro protamine

Biphasic insulin aspart (NovoMix® 30) 30% aspart 70% aspart protamine

Higher proportion of rapid-acting insulin component provides greater activity in the postprandial period.

Moving to a premixed insulin with a greater prandial coverage

Evidence from clinical trials


Switching from twice-daily premixed insulin 30/70 or 25/75 to premixed insulin 50/50

23

Tanaka M, Ishii H (2010) J Int Med Res 38: 674–80

After switching to biphasic insulin lispro 50/50

Before switching to biphasic insulin lispro 50/50*

12.5

10

7.5

5

2.5

0

–2.5

Ch

an

ge

in b

loo

d g

luco

se f

rom

FB

G (

mm

ol/L

)

FBG AB BL AL BS AS Bedtime

***

**

**

n=13 Switching to twice-daily Mix 50/50 insulin injections controlled post-prandial blood glucose levels and stabilised diurnal blood glucose variations in patients with type 2 diabetes mellitus who had poor glucose control on insulin 30/70 or 25/75.

*Participants were receiving biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine), biphasic human insulin 30/70 (30% rapid-acting insulin, 70% NPH), or biphasic insulin lispro 25/75 (25% lispro, 75% lispro protamine). **<0.05; ***P<0.01.

AB=after breakfast; AL=after lunch; AS=after supper; BL=before lunch; BS=before supper; FBG=fasting blood glucose; NPH=neutral protamine Hagedorn.


Biphasic insulin lispro 50/50 (TID) vs premixed human insulin 30/70 (BID)

24

Study design Primary measure: mean blood glucose (BG) change.

Secondary measures: HbA1c, 7-point BG profile, and hypoglycaemia.

6-month, single-centre, prospective, randomised, open-label, 2-period crossover.

40 candidates (35 completed the study) on conventional insulin therapy received biphasic insulin lispro 50/50 (TID) or human insulin 30/70 (30% regular/70% NPH, BID) for 12 weeks, and then switched to the opposite sequence.

BID=twice-daily; NPH=neutral protamine Hagedorn; TID=three-times-daily. Schernthaner G et al (2004) Horm Metab Res 36: 188–93


Biphasic insulin lispro 50/50 (TID) resulted in greater reduction in HbA1c compared with premixed human insulin 30/70 (BID)

25

BID=twice-daily; TID=three-times-dailySchernthaner G et al (2004) Horm Metab Res 36:188–93

Both treatments reduced HbA1c from

baseline, lispro 50/50 significantly more than

human 30/70.

n=35

Mea

n H

bA

1c (%

)

0

1

5

6

7

8

9

Baseline Human30/70

Lispro50/50

P<0.001

8.4

8.1

7.6

P=0.021P=0.034

2

3

4


Biphasic insulin lispro 50/50 (TID) vs premixed human insulin 30/70 (BID): summary

26

Compared with human 30/70 (BID), lispro 50/50 (TID):

Produced a greater decrease in mean blood

glucose.

Produced a greater reduction in HbA1c.

Was associated with smaller postprandial

blood glucose excursions.

Improved overall glycaemic control, and no

significant difference in hypoglycaemia risk between treatment

groups.

BID=twice-daily; TID=three-times-daily.Schernthaner G et al (2004) Horm Metab Res 36:188–93


Biphasic insulin lispro 50/50 (TID) vs 25/75 or 30/70 analogue mixture (BID)

Primary measure:HbA1c

Secondary measure: Change in HbA1c from baseline to endpoint, percentage of patients who achieved a HbA1c <7% and ≤6.5%, and SMBG

This was a 16-week, multicenter, randomized, open-label, 2-arm parallel study

Patients continued with previous hypoglycemic treatment during the lead-in period for 2 weeks (from visit 1 to 2), Following the clinical assessments, eligible patients were randomized (1:1) at visit 2 (week 0, baseline for the efficacy measures) to 1 of the 2 insulin treatment strategies. One strategy was based on LM50/50 3 times each day (TID group) and the other on continuous progressive dose titration of twice-daily premixed insulin analogue (BID group).Farcasiu E et al. (2011) Clin Ther ; 33:1682-93


Results I

Farcasiu E et al. (2011) Clin Ther ; 33:1682-93

TID Group (n=139) BID Group (n=139)

Baseline End Point Baseline End Point P

HbA1C* 8.71 (1.20) 7.7 (1.10) 8.67 (1.13) 7.84 (1.04) 0.2519ᵻ

HbA1C (%) mean change (95% CI)

-1.0 (-1.17,-0.82)

-0.82 (-0.99,-0.66)

HbA1C of <7% 28.0 (21.4) 25.0 (18.5) 0.6455ᶊ

HbA1C of ≤6.5% 15.0 (11.5) 9.0 (6.7) 0.2024ᶊ

Weight Change, (Kg)

1.3 (2.73) 0.4 (2.45) 0.0009ii

*Data were mean (SD)ᵻTreatment comparison at end point by ANCOVAᶊFisher exact test

ii Treatment comparison at end point by ANCOVA (repeated measures)


Results II.

29

Farcasiu E et al. Clin Ther 2011; 33:1682-93

Hypoglycaemia (episodes/patient/30 days) TID BID P value

overall 0.56 (0.10) 0.61 (0.10) 0.7230

nocturnal 0.04 (0.02) 0.13 (0.02) 0.0063

severe 0.00 (0.004) 0.01 (0.004) 0.8876


Summary

30

When compared with a 30/70 premix BID, lispromix 50 TID therapy was associated with:

Similar decrease in HbA1c

Similar risk of overall hypoglycaemia

Similar overall glycaemic control, while nocturnal hypoglycemia risk improved between treatment groups

Similar total daily insulin doses

Greater weight gain

Farcasiu E et al. Clin Ther 2011; 33:1682-93


Conclusion

31

A number of factors will influence the decision regarding choice of insulin regimen.

A key priority is education for self-management to optimise blood glucose control.

There is a need to discuss and tailor the insulin regimen to the individual.

The patient’s journey will frequently involve change and the role of the healthcare professional is to identify, action and support it.


Conclusion

32

A three-times daily 50/50 analogue regimen comprehensively addresses the postprandial glucose peaks associated with the three main meals.

There is evidence that biphasic insulin lispro 50/50 is associated with glycaemic benefits compared with biphasic human insulin 30/70, without a detrimental effect on rates of hypoglycaemia.

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