What to do when basal bolus therapy fails in Type 2 Diabetes

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UKHMG00596a February 2012Prescribing information can be found on the last slide

UKHMG00596a February 2012

This meeting has been developed and sponsored by

Cerebrovascular event**

UKPDS: A 1% decrease in HbA1c is associated with a reduction in complications

Deaths related to diabetes*

Stratton IM et al (2000) BMJ 321: 405–12

Microvascular complications e.g. Renal disease and blindness*

Amputation or fatal peripheral vascular disease*

Myocardial infarction*

*P<0.0001; ** P=0.035.UKPDS=United Kingdom Prospective Diabetes Study.

HbA1c

1%

37%

43%

21%

14%

12%

UKHMG00596a February 2012

Beta-cell dysfunction – a core defect in type 2 diabetes

• Genetic and environmental pathophysiology• One of the two core defects in type 2 diabetes

• Therapeutic strategies should ideally target both defects

Del Prato S, Marchetti P (2004) Diabetes Technol Ther 6: 719–31

Insulin resistance

Beta-cell dysfunction

Type 2 diabetes

+ =

Impaired ability to secrete insulin and compensate for insulin resistance

UKHMG00596a February 2012

Insulin and glucose patterns: Basal vs. mealtime hyperglycaemia in type 2 diabetes

Plas

ma

gluc

ose

conc

entr

ation

(mm

ol/L

)

10.0

5.0

00600 1200

Time of day (hours)

1800 0000 0600

7.5

12.5

2.5

15.0

Adapted from Riddle MC (1990) Diabetes Care 13: 676–86UKHMG00596a February 2012

Diagram shows 24-hour plasma glycaemic pattern typical of healthy people (lower border of grey area) and those with mild non-insulin dependent diabetes mellitus (upper border of grey area). Red area shows part of the glycaemic abnormality of diabetes accounted for by excessive postprandial hyperglycaemia, whereas grey area shows part due to elevated basal glycaemia.

As people with diabetes get closer to HbA1c targets, the need to manage postprandial glucose (PPG) increases

100

0

50

Rela

tive

cont

ributi

on (%

)

>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: 881–5UKHMG00596a February 2012

There are several ways of addressing PPG and FPG with insulin

• Basal–bolus insulin therapy

• Premixed insulin therapy (with various ratios of longer- and shorter-acting insulin components)

FPG=fasting plasma glucose; PPG=postprandial glucose.UKHMG00596a February 2012

In Non-diabetic Individuals, Basal Secretion Represents Approximately 50% Total Daily Insulin

Normal

Obese

Polonsky KS et al. (1988) J Clin Invest; 81:442-48

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Perc

ent B

asal

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lin S

ecre

tion

0600 1000 1400 1800 2200 0200 0600

Clock 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.

UKHMG00596a February 2012

0

50

100

1 2

Basal Dose Bolus Dose

% T

otal

Dai

ly In

sulin

Dos

e

Multiple Daily Injection (n=50)

Continuous Subcutaneous Insulin Infusion (n=48)

Patients With Type 2 Diabetes on Intensive Insulin Therapy Regimens Use 50% Basal and 50% Bolus Insulin

Doses adjusted to achieve target preprandial and bedtime BG levels

Herman WH et al. (2005) Diabetes Care; 28:1568-73

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

UKHMG00596a February 2012

Is basal–bolus always the gold standard?

• High injection frequency can lead to poor adherence, causing inadequate glycaemic control1

• 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)2

1. Donnelly LA et al (2007) Q J Med 100: 345–502. Hollander P et al (2008) Clin Ther 30: 1976–87

*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.

UKHMG00596a February 2012

Currently available human and analogue premixed insulins

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

Biphasic human insulin (Insuman® Comb 25) 25% soluble insulin 75% isophane insulin

Biphasic human insulin (Insuman® Comb 50) 50% soluble insulin 50% 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.

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

UKHMG00596a February 2012

UKHMG00596a February 2012

“Mid-mix” analogue insulins: Clinical data

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

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

After switching to biphasic insulin lispro 50/50

*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)

AB=after breakfast; AL=after lunch; AS=after supper; BL=before lunch; BS=before supper; FBG=fasting blood glucose; NPH=neutral protamine Hagedorn. *P<0.05; **P<0.01.

Before switching to biphasic insulin lispro 50/50*

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–2.5

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BG (m

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/L)

FBG AB BL AL BS AS Bedtime

**

*

*

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

UKHMG00596a February 2012

Cucinotta D et al (2009) Diabetes Obes Metab 11: 700–8

*Participants received twice-daily biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) throughout the study (ITT=200); **Participants received thrice-daily biphasic insulin aspart 50/50 (50% aspart, 50% aspart protamine) throughout the study (ITT=114), or switched their dinner insulin to biphasic insulin aspart 30/70 at 12 weeks (ITT=87); ***Participants received thrice-daily biphasic insulin aspart 70/30 (70% aspart, 30% aspart protamine) throughout the study (ITT=91), or switched their dinner insulin to biphasic insulin aspart 30/70 at 12 weeks (ITT=107). All regimens were in combination of metformin. NS=not significant; ITT=intent-to-treat.

Comparison of thrice-daily biphasic insulin aspart 70/30, thrice-daily biphasic insulin aspart 50/50, and twice-daily biphasic insulin aspart

30/70

0

−0.5

−1

−1.5

−2 −0.30% (P=0.0004)

NS

Biphasic insulin aspart 30/70* 50/50 (30/70)** 70/30 (30/70)***

8.9

7.3

8.8

7.2

8.9

7.0

Redu

ction

in H

bA1c

(%)

Glycaemic control improved with thrice-daily biphasic insulin aspart 50/50 without higher incidence of hypoglycaemia compared with twice-daily insulin aspart 30/70

Reduction in mean HbA1c (%) at 36 weeks of treatment, intent-to-treat population

UKHMG00596a February 2012

UKHMG00596a February 2012

Thrice-daily biphasic insulin lispro 50/50 was non-inferior to basal–bolus therapy

In people with type 2 diabetes uncontrolled on insulin glargine or lispro mix 25/75 (25% lispro, 75% lispro protamine): a non-inferiority intensification substudy of the DURABLE trial

HbA1c remained stable in both treatment groups

Miser WF et al (2010) Clin Ther 32: 896–908

Biphasic insulin lispro 50/50 (n=174) Basal–bolus therapy* (n=171)

HbA

1c (%

)

DURABLE=assessing durability of basal versus lispro mix 25/75 insulin efficacy. *Glargine plus mealtime insulin lispro.

Baseline

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2

1

3 60

Time (months)

P=0.660 P=0.566 P=0.990

Thrice-daily biphasic insulin aspartwas non-inferior to basal–bolus therapy

HbA1c decreased from 9.1±0.7% to 7.8±1% in both treatment groups

Ligthelm RJ et al (2006) Exp Clin Endocrinol Diabetes 114: 511–9

Biphasic insulin aspart* (n=196) Basal–bolus therapy** (n=198)

HbA

1c (%

)

* BMI≤30 kg/m2: biphasic insulin aspart 70/30 (70% aspart, 30% aspart protamine) at breakfast and lunch and biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) at supper;

BMI>30 kg/m2: biphasic insulin aspart 50/50 (50% aspart, 50% aspart protamine) at breakfast and lunch and biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) at supper; ** NPH plus mealtime aspart. BMI=body mass index; NPH=neutral protamine Hagedorn.

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0 2 4 6 8 10 12 14 160

Time (week)

10

UKHMG00596a February 2012

Twice-daily biphasic insulin lispro 50/50 vs. basal–bolus therapy: Glycaemic control

Masuda H et al (2008) Diabetes Obes Metab 10: 1261–5

Participants were insulin-naïve people with type 2 diabetes who had suboptimal glycaemic control on maximal doses of oral antidiabetes drugs.

Biphasic insulin lispro 50/50 (n=14)

HbA

1c (%

)

14

13

12

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10

9

8

7

6

5

Basal–bolus therapy* (n=14)

*NPH plus mealtime insulin lispro. NPH=neutral protamine Hagedorn.At entry 1 2 3

Time (months)4

0

UKHMG00596a February 2012

Both the premix group and basal bolus group showed significant reduction in HbA1c over the 12 weeks

Twice-daily biphasic insulin lispro 50/50 vs. basal–bolus therapy: Insulin therapy-related quality of life questionnaire

scoresSc

ore

*NPH plus mealtime insulin lispro. **P≤0.05; ***P=NS.NPH=neutral protamine Hagedorn; NS=not significant.

**

** ** **

***

UKHMG00596a February 2012 Masuda H et al (2008) Diabetes Obes Metab 10: 1261–5

These results might suggest that twice-daily injections of premixed rapid-acting insulin analogue therapy could achieve good glycaemic control and better QOL compared with BB therapy in insulin-naıve type 2 diabetes.

Advantages of TDS“mid-mix” premixed insulins

• A thrice-daily “mid-mix” regimen comprehensively addresses the postprandial glucose peaks associated with the three main meals

• Compared with a basal–bolus regimen, a thrice-daily “mid-mix” regimen may be simpler to teach, and the single delivery device may benefit people who find it difficult to cope with the demands of frequent injections, glucose monitoring and necessary dose adjustments

UKHMG00596a February 2012

Summary

• As people with type 2 diabetes get closer to HbA1c targets, the significance of postprandial hyperglycaemia increases

• Biphasic insulin lispro 50/50 is an appropriate option to consider in a selected group of individuals

UKHMG00596a February 2012

Practical factors to consider when changing a patient’s insulin regimen

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UKHMG00596a February 2012

Key Factors

Lifestyle

Occupation

Diet & exercise

Injection Frequency

Self Monitoring of Blood Glucose

Carbohydrate

Awareness

Dose Adjustmen

t

Motivation

Language Barrier

Cognitive ability

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

UKHMG00596a February 2012

Basal–bolus therapy: How you might identify patients as uncontrolled

• Potential signs and clues to look for:– Erratic blood glucose control– Missing injections– Not adjusting doses– People who appear to not be engaged or who are

frustrated

UKHMG00596a February 2012

• Potentially people who might fall into this category:– Those who are unable to dose adjust– Those who are not carbohydrate aware– Those who have problems with frequency of

injections– Those who have problems grasping the concept of

basal bolus

Basal–bolus therapy: How you might identify patients as uncontrolled

UKHMG00596a February 2012

How many of your patients with type 2 diabetes on a basal bolus regimen adjust their insulin based on the amount of carbohydrate they

eat?

UKHMG00596a February 2012

Premixed insulin

• Why might a premix offer an advantage?– Some people may find it a simpler regimen than

basal–bolus therapy– Fewer injections– There can be less self-monitoring of blood glucose

required– In some cases only one type of insulin and device

is used– In some patients it can be less time consuming to

teach than basal bolus

UKHMG00596a February 2012

Premixed insulin

• Potentially people who are likely to benefit from this therapy:– Those who are unable or not wanting to adjust

insulin doses / carbohydrate count– Those who prefer fewer injections

UKHMG00596a February 2012

UKHMG00596a January 2012

Premixed insulin

• Some of the perceived limitations:– In some patients it is a less flexible regimen –

regular meals and a “structured” lifestyle required– There might be the potential to need to “feed”

insulin– In some patients it might be more difficult to

correct for high blood glucose levels

No panacea – need to discuss and tailor the insulin regimen to the individual

UKHMG00596a February 2012