What to do when basal bolus therapy fails in Type 2 Diabetes
[insert name]
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
0
100
200
300
400
500
600
Perc
ent B
asal
Insu
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*
12.5
10
7.5
5
2.5
0
–2.5
Chan
ge in
blo
od g
luco
se fr
om F
BG (m
mol
/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
9
8
7
6
5
4
3
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.
9
8
7
6
5
4
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
11
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
[insert name]
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
Top Related