4-T Final Three-year Results Slides
© University of Oxford Diabetes Trials Unit
Three-Year Efficacy of Complex Insulin Regimens
in Type 2 Diabetes
N Engl J Med 2009;361:1736-47
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Treating-To-Target in Type 2 Diabetes
The 4-T trial
 Three-year study in 708 people with type 2 diabetes
from 58 UK and Irish centres
 Sponsored and funded by Novo Nordisk
 Independently designed, run and reported
by an academic group
 Two sub studies funded by Diabetes UK
 One-year results were published in 2007
Current Controlled Trials no: ISRCTN51125379
N Engl J Med 2009;361:1736-47
Rationale for 4-T
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Type 2 diabetes is a progressive condition with
the majority of patients requiring insulin therapy
in the longer term
Approaches to insulin therapy for type 2 diabetes
vary considerably across the world, but large-scale
direct comparisons of complex insulin regimens
have not been performed
There is no evidence-based consensus about which
insulin formulation should be used to initiate insulin
therapy, or which complex insulin regimen might be
most appropriate
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Aims
First Phase

One-year head-to-head comparison of the efficacy
of three different types of analogue insulins, when
given in addition to dual oral antidiabetic therapy
Second Phase

Evaluation over two further years of the need for
more complex insulin regimens, and the overall
efficacy of three different randomized insulin
treatment strategies
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Statistical Methods
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A sample size of 700 patients was calculated to
detect a 0.4% difference in achieved HbA1c, allowing
for a loss-to-follow up of 15%
Missing data are handled by multiple imputation
Medians are presented with 95% confidence
intervals
Analyses are by intention to treat
Mixed-effect regression or logistic models are used
to compare treatment groups overall
A prespecified closed-test procedure, which adjusts
p values appropriately, allows for three pair-wise
comparisons between groups
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Major Inclusion Criteria
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Aged 18 years or more
Male and female
Type 2 diabetes for one year or more
On maximal tolerated doses of metformin and
sulfonylurea for at least four months
HbA1c 7.0% to 10.0% inclusive
Body mass index not more than 40 kg/m2
Written informed consent
N Engl J Med 2009;361:1736-47
Major Exclusion Criteria
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Taking insulin therapy
Taking oral antidiabetic therapies, other than
sulfonylurea and/or metformin
Plasma creatinine >130 µmol/l
ALT ≥2x upper limit of normal
Life threatening cardiovascular disease
Lactating or potentially pregnant females
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Patient Disposition
235
Assigned to
biphasic insulin
(biphasic aspart)
34
Discontinued
201 (86%)
Completed
three years

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
239
Assigned to
prandial insulin
(aspart)
234
Assigned to
basal insulin
(detemir)
51
Discontinued
188 (79%)
Completed
three years
45
Discontinued
189 (81%)
Completed
three years
Overall, 18.4% of patients did not complete three years
No difference in proportions between groups (p=0.15)
No difference in baseline characteristics between those
who completed or did not complete three years follow up
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Demographic Characteristics
Biphasic
N=235
68%
Prandial
N=239
64%
Basal
N=234
61%
94%
90%
93%
9 (6-12)
9 (6-14)
9 (6-12)
Taking sulfonylurea
98%
100%
99%
Taking metformin
96%
95%
97%
Age (years)
61.7±8.9
61.6
±10.5
61.9±10.
0
Body mass index (kg/m2)
30.2 ±4.8 29.6 ±4.5 29.7 ±4.6
HbA1c (%)
8.6 ±0.8
Male
White Caucasian
*Diabetes duration (yrs)
*interquartile range
N Engl J Med 2009;361:1736-47
8.6 ±0.8
8.4 ±0.8
No significant differences between groups
Visit Schedule in Year One
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The visit schedule was designed to mirror
a primary care setting
Visits were undertaken at two weeks, six weeks and
three months after starting insulin therapy
Visits were then three-monthly
In addition, eight interim telephone contacts
were scheduled
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Hypoglycaemia
Categorised as
 Grade 1
- Symptoms only
with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl)
 Grade 2
- Symptoms plus glucose <3.1 mmol/l (<56 mg/dl)
 Grade 3
- Third party assistance required
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Glycaemic targets and Insulin Injections
Fasting and pre-meal: 4.0-5.5 mmol/l (72-99 mg/dl)
Two-hours post meal: 5.0-7.0 mmol/l (90-126 mg/dl)
12
6
Biphasic
Prandial
*
Basal
* Twice a day if required
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12
18
24
6
Transition to a Complex Insulin Regimen
From one year onwards, if HbA1c levels were >6.5%, sulfonylurea
therapy was stopped and a second type of insulin was added
708 T2DM
on dual
oral agents
R
First Phase
Second Phase
Add biphasic insulin*
twice a day
Add prandial insulin
at midday
Add prandial insulin*
three times a day
Add basal insulin
before bed
Add basal insulin*
once (or twice) daily
Add prandial insulin
three times a day
*
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Intensify to a complex insulin regimen in
year one if unacceptable hyperglycaemia
Starting Doses for Second Type of Insulin
Biphasic group
 Add midday prandial insulin
- 10% of current total daily biphasic insulin dose
(limited to 4-6 units)
Prandial group
 Add basal insulin at bedtime
- 10 units
Basal group
 Add prandial insulin at breakfast, lunch and dinner
- 10% of current total daily basal insulin dose at each
time point (limited to 4-6 units)
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Titrate to Target
Glycaemic targets as for Phase 1 of the study
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Fasting and pre-meal 4.0-5.5 mmol/l (72-99 mg/dl)
Two-hours post meal 5.0-7.0 mmol/l (90-126 mg/dl)
The 4-T Online Trial Management System
suggested dose adjustments using a common
algorithm for all groups
Investigators encouraged to amend suggested doses
on clinical grounds and in consultation with patients
Patients encouraged to modify doses between visits
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Complex Insulin Regimens
Proportion eligible for a second
type of insulin per protocol
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Proportion taking
two types of insulin
Insulin Doses Over 3 Years
Median±95% confidence interval
Biphasic
±prandial
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Prandial
±basal
Basal
±prandial
Total Daily Insulin Doses at 3 Years
Median±95% confidence interval
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HbA1c Values Over 3 Years
Median±95% confidence interval
Overall
6.9%
(6.8 to 7.1)
Biphasic
±prandial
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Prandial
±basal
Basal
±prandial
Primary Outcome: HbA1c at 3 Years
Median±95% confidence interval
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Distribution of HbA1c Values at 3 Years
Proportion ≤6.5%
Proportion ≤7.0%
Biphasic
31.9% p=0.006
Biphasic
49.4% p<0.001
p=0.03 Prandial
p=0.02
Prandial
44.8%
67.4%
Basal
43.2% p=0.55
Basal
63.2% p=0.22
6.5 7.0
Biphasic
±prandial
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Prandial
±basal
Basal
±prandial
Baseline
Decrease in SMBG Levels Over 3 Years
Mean±1SD
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Body Weight over 3 Years
Median±95% confidence interval
Biphasic
±prandial
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Prandial
±basal
Basal
±prandial
Increase in Body Weight Over 3 Years
Mean±1SD
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Increase in Waist Circumference Over 3 Years
Mean±1SD
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Grade 2 or 3 Hypoglycaemia Over 3 Years
Biphasic
±prandial
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Prandial
±basal
Basal
±prandial
Grade 2 or 3 Hypoglycaemia Over 3 Years
Median±95% confidence interval
All
patients
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Patients with
HbA1c ≤6.5%
EQ-5D Quality of Life Scores at 3 Years
Winzorized mean±95% confidence interval
Biphasic: 0.76 (0.71 to 0.80)
p=0.73
Prandial: 0.77 (0.73 to 0.81)
p=0.86
p=0.86
Basal:
0.80 (0.77 to 0.83)
N Engl J Med 2009;361:1736-47
Adverse Events
Biphasic
N=235
Prandial
N=239
Basal
N=234
p
value
Any serious event
105
(44.7%)
79
(33.1%)
78
(33.3%)
0.011
Death from any cause
7
(3.0%)
9
(3.8%)
4
(1.7%)
0.23
Cardiovascular death
4
(1.7%)
9
(3.8%)
1
(0.4%)
0.002
Any adverse event
228
(97.0%)
235
(98.3%)
227
(97.0%)
0.58
No significant differences were seen between groups in:
 Serious adverse events occurring in more than 1% in any group
 Non-serious adverse events occurring in more than 10% in any group
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Safety Data
No clinically relevant differences were seen between
the groups with respect to changes in:
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Blood pressure
Lipid profiles
Alanine aminotransferase
Plasma creatinine
Ratio of urinary albumin to creatinine
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Relative Changes over 3 Years and Hypoglycaemia
Mean±1SD
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Overview of Main Results
Biphasic Prandial Basal
Median HbA1c level achieved
+
+
+
HbA1c targets achieved
+
++
++
Mean SMBG level achieved
+
++
++
++
+
+++
Less weight gain
+
+
++
Less increase in waist circumference
+
+
++
Fewer hypoglycaemic episodes
N Engl J Med 2009;361:1736-47
Summary
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Three quarters of patients added a second insulin
Those commencing therapy with a basal or prandial
insulin more often achieved glycaemic targets than
patients commencing with a biphasic insulin
Patients commencing therapy with basal insulin had
fewer hypoglycaemic episodes and less weight gain
These findings provide clear evidence in people with
type 2 diabetes to support starting insulin therapy
with a once a day basal insulin, and then adding
a mealtime insulin if glycaemic targets are not met
N Engl J Med 2009;361:1736-47