Treating To Target in Type 2 Diabetes
Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy
in Type 2 Diabetes
Rury R. Holman, Kerensa I. Thorne, Andrew J. Farmer, Melanie J. Davies,
Joanne F. Keenan, Sanjoy Paul, Jonathan C. Levy, for the 4-T Study Group
N Engl J Med 2007; 357: 1716-30
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One-year Results
43rd EASD Meeting, Amsterdam, 2007
Treating To Target in Type 2 Diabetes
 The 4-T trial is designed, run and reported by an
independent academic group
 Funded by Novo Nordisk
 Continuous glucose monitoring sub study
funded by Diabetes UK
Controlled Clinical Trials number: 51125379
N Engl J Med 2007; 357: 1716-30
RATIONALE
AND DESIGN
Rationâle
 Type 2 diabetes is a progressive condition with the
majority of patients requiring insulin therapy in the
longer term
 The rapidly rising diabetes prevalence means that
insulin initiation will increasingly be undertaken in
primary care
 There is no evidence-based consensus about how
best to initiate insulin therapy, in particular which insulin
formulation should be used.
N Engl J Med 2007; 357: 1716-30
Trial Design
 Three-arm trial in 708 patients with type 2 diabetes from
58 UK and Irish centres
 Evaluating addition of three different analogue insulin
regimens to dual oral antidiabetic therapy
 Open-label randomisation to:
• Twice a day biphasic insulin (NovoMix 30)
• Three times a day prandial insulin (NovoRapid)
• Once a day basal insulin (Levemir) before bed, with
a morning injection added if necessary
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Sample Size and Analysis Methods
Sample Size
 700 patients required to detect a 0.4% difference in
achieved HbA1c, allowing for 15% loss to follow up
Statistical Methods
 Missing data handled by multiple imputation
 Analyses by intention to treat (ITT)
 Mixed-effect regression or logistic models used to
compare treatment groups overall
 Closed-test procedure allows pair wise comparisons
when overall treatment effect was significant
N Engl J Med 2007; 357: 1716-30
Outcomes at One Year
Primary
 To compare HbA1c levels achieved by the three regimens
Secondary outcomes include:
 Proportion with HbA1c ≤6.5%
 Proportion with unacceptable hyperglycemia
i.e. HbA1c >10% or two successive values >8.5%
at or after 24 weeks
 Hypoglycaemia rates
 Impact on body weight
 Quality of Life (EQ-5D)
 Eight-point self-measured capillary glucose profiles
 Proportion requiring a morning basal insulin injection
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Major Inclusion Criteria
 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 four months or more
 HbA1c 7.0% to 10.0% inclusive
 Body mass index not more than 40 kg/m2
 Written informed consent
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Major Exclusion Criteria
 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
N Engl J Med 2007; 357: 1716-30
Patient Disposition
936
Patients screened
9 refused to participate
219 excluded
708 Underwent randomization
235
Assigned to
biphasic insulin
239
Assigned to
prandial insulin
13
Discontinued
222 (94%)
Completed
one year
N Engl J Med 2007; 357: 1716-30
17
Discontinued
222 (93%)
Completed
one year
234
Assigned to basal
insulin
10
Discontinued
224 (96%)
Completed
one year
Patients recruited between
1st November 2004 and 31st July 2006
Demographic Characteristics
Biphasic Prandial
N=235
N=239
Basal
N=234
Male
White Caucasian
Asian
Black
Other or mixed
68%
94%
5%
1%
<1%
64%
90%
6%
2%
2%
61%
93%
4%
1%
2%
Retinopathy
Neuropathy
Nephropathy
Macroangiopathy
15%
17%
9%
22%
19%
23%
10%
18%
18%
17%
10%
19%
On sulfonylurea
On metformin
98%
96%
100%
95%
99%
97%
No significant differences between groups
N Engl J Med 2007; 357: 1716-30
Baseline Characteristics
Biphasic
N=235
Prandial
N=239
Basal
N=234
Age (years)
Diabetes duration (years)*
61.7 ±8.9
9 (6-2)
Body weight (kg)
Body mass index (kg/m2)
86.9 ±16.8 84.9 ±14.4 85.5 ±16.3
30.2 ±4.8 29.6 ±4.5 29.7 ±4.6
HbA1c (%)
Fasting plasma glucose (mmol/l)
LDL cholesterol (mmol/l)
HDL cholesterol (mmol/l)
Triglycerides (mmol/l)*
8.6 ±0.8
9.7 ±2.8
61.6 ±10.5 61.9±10.0
9 (6-4)
9 (6-12)
8.6 ±0.8
9.6 ±2.7
2.5 ±0.7
2.4 ±0.7
2.3 ±0.7
1.0 ±0.3
1.0 ±0.2
1.0 ±0.3
1.6 (1.2-2.1) 1.5 (1.2-2.3) 1.5 (1.1-2.2)
No significant differences between groups
*interquartile range
N Engl J Med 2007; 357: 1716-30
8.4 ±0.8
9.5 ±2.6
Randomisation
708
T2DM
on dual
OAD
Year 1
Years 2 and 3
Comparison of three
single insulin regimens,
added to OADs*
If HbA1c >6.5%, stop
sulfonylurea and add a
second insulin formulation
R
*
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
Intensify to a combination
insulin regimen in year one
if unacceptable hyperglycaemia
N Engl J Med 2007; 357: 1716-30
Study Visits
The frequency of contacts was designed to be appropriate
for insulin initiation in a primary care setting
Week
0Randomisation
2Two-week visit
6Six-week visit
12Three-month visit
24Six-month visit
38Nine-month visit
52One-year visit
With eight interim telephone contacts
N Engl J Med 2007; 357: 1716-30
Hypoglycaemia and Safety Measures
Hypoglycaemia
 Categorised as:
• Grade 1: symptoms only (glucose 3.1 mmol/l or more)
• Grade 2: symptoms with glucose <3.1 mmol/l
• Grade 3: third party assistance required
Safety Measures
 Unexpected and/or serious adverse events
 Plasma ALT, creatinine and lipid levels
 Blood pressure
 Metformin discontinued if plasma creatinine rose to
150 µmol/l or more on two successive occasions
 Data Safety Monitoring Board
N Engl J Med 2007; 357: 1716-30
Individual Starting Insulin Doses
Estimated from fasting plasma glucose, body weight and gender*
Advised dose : range 2 to 76 IU/day
: median 16 (10–25) IU/day
Dose taken : median 15 (10–24) IU/day
77% given >10 IU/day
37% given >20 IU/day
5% given >40 IU/day
No grade 3 hypoglycaemic
episodes occurred within
two weeks of starting insulin
Starting doses in rank order
N Engl J Med 2007; 357: 1716-30
*Diabetic Medicine 1985; 5: 45-53
Insulin Injections & Glucose Measurements
Glucose targets
Fasting and pre-meal: 4.0-5.5 mmol/l
Two-hour post meal: 5.0-7.0 mmol/l
12
Biphasic
6
12
18
*
24
*
Prandial
Basal
* *
< >
*
Injection
N Engl J Med 2007; 357: 1716-30
*
*
*
*
*
*
* Self-measured glucose
6
Insulin Titration
 The online Trial Management System suggested dose
adjustments using a common algorithm for all groups
 Doses increased if 1/3 or more of glucose values were
above target, and in proportion to the gap from target
 Doses reduced in the presence of hypoglycaemia
 Investigators encouraged to amend suggested doses, as
necessary, on clinical grounds in consultation with
patients
 Patients also educated how to modify doses between
visits
N Engl J Med 2007; 357: 1716-30
ONE YEAR
RESULTS
Insulin Dose Adjustments
Adherence to dose adjustment suggestions (±10%)
 Biphasic 89.7%
 Prandial 80.4%
 Basal
90.2%
Morning injection of basal insulin
 34% (n=79) of patients randomised to pre-bedtime
basal insulin required, per protocol, an additional
morning injection by one year
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Need for a Second Insulin Formulation
Patients with “unacceptable” hyperglycaemia (HbA1c values
above 10%, or above 8.5% on two successive occasions, at
or after 24 weeks therapy) given a second type of insulin
were:
 Biphasic 8.9% (n=21)
 Prandial 4.2% (n=10)
 Basal
17.9% (n=42), P<0.001 vs. biphasic or prandial
N Engl J Med 2007; 357: 1716-30
Primary Outcome: HbA1c at One Year
Glycated haemoglobin (%)
Baseline to 1 year (%)
Mean ±SD at 1 year (%)
— Biphasic 7.3±0.9
-1.3±1.1
— Prandial 7.2±0.9, p=0.08 vs. biphasic
-1.4±1.0
— Basal
7.6±1.0, p<0.001 vs. biphasic or prandial
-0.8±1.0
P<0.001
Months since randomisation
N Engl J Med 2007; 357: 1716-30
Distribution of HbA1c Values
Proportion <6.5%
Proportion <7.0%
— Biphasic 17.0%
41.7%
— Prandial 23.9%, p=0.08 vs. biphasic
48.7%
— Basal
27.8%
8.1%, p=0.001 vs. biphasic, <0.001 vs. prandial
0.5
0.4
Density
— At baseline
0.3
0.2
0.1
0.0
4
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6
8
HbA1c (%)
10
Likelihood of Achieving HbA1c ≤6.5%
Odds ratio, 95% CI
p
Basal vs. Biphasic
0.21, 0.07-0.65
0.007
Prandial vs. Biphasic
1.24, 0.62-2.51
0.54
Basal vs. Biphasic
0.50, 0.24-1.03
0.06
Prandial vs. Biphasic
1.76, 0.96-3.26
0.07
Baseline HbA1c >8.5%
Baseline HbA1c ≤8.5%
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Glucose Profiles Before & After Starting Insulin
Change in FPG (mmol/l))
Change in PPG (mmol/l)
— Biphasic -2.5±3.1
-3.8±3.5
— Prandial -1.3±2.7
p<0.001 vs. biphasic
-4.6±3.0
-3.3±2.9 p<0.001 vs. biphasic or prandial -2.6±3.0
— Basal
— At baseline
0
Body Weight Over One Year
Body weight (kg)
Baseline to 1 year (kg)
— Biphasic +4.7±4.0
— Prandial +5.7±4.6, p<0.005 vs. biphasic
— Basal
+1.9±4.2, p<0.001 vs. biphasic or prandial
P<0.001
Months since randomisation
N Engl J Med 2007; 357: 1716-30
Insulin Doses Over One Year
Insulin dose (U/kg/day)
Median at 1 year (U/kg/day)
— Biphasic 0.53 (0.36 to 0.70)
— Prandial 0.61 (0.37 to 0.88), p<0.006 vs. biphasic
— Basal
0.49 (0.34 to 0.73), p<0.02 vs. prandial
Total per day (U)
48 (30 to 71)
56 (34 to 78)
42 (28 to 72)
P=0.04
Months since randomisation
N Engl J Med 2007; 357: 1716-30
Hypoglycaemia (≥ Grade 2) Over One Year
Proportion with events (%)
Mean at 1 year (events/patient/year)
— Biphasic 5.7
— Prandial 12.0, p<0.002 vs. biphasic
— Basal
2.3, p=0.01 vs. biphasic, p<0.001 vs.prandial
P=0.001
Months since randomisation
N Engl J Med 2007; 357: 1716-30
Serious Adverse Events
Biphasic Prandial Basal
(N=235) (N=239) (N=234)
p
All
41
30
30
0.25
Gastro intestinal and abdominal pain
4
0
0
0.02
Lower respiratory & lung infection
4
0
0
0.02
Ischaemic & coronary artery disorder
3
4
3
0.99
Abdominal and gastrointestinal infection 3
0
2
0.21
Other infection
3
1
0.63
1
Deaths
3 Biphasic (heart failure, myocardial infarction,
ischaemic heart disease)
1 Prandial (myocardial infarction)
0 Basal
N Engl J Med 2007; 357: 1716-30
Adverse events
Biphasic Prandial
N=235
N=239
All
209
203
Upper respiratory tract infection
81
74
Reaction at injection or infusion site 37
33
Musculoskeletal/connective-tissue
43
37
Lower respiratory/lung infection
36
40
Nausea and vomiting
36
32
Diarrhoea
27
26
Headache
16
27
Upper respiratory tract symptom
17
20
Cough
22
26
Basal
N=234
207
91
52
35
29
32
34
20
26
17
p
0.37
0.19
0.04
0.59
0.40
0.83
0.45
0.23
0.33
0.39
No clinically relevant changes in albumin creatinine ratio, ALT or plasma
creatinine were observed
N Engl J Med 2007; 357: 1716-30
Quality of Life
Baseline
Change at one year
Biphasic
0.81 (0.78 to 0.84)
0 (-0.15 to 0.03)
Prandial
0.79 (0.76 to 0.82)
0 (-0.08 to 0.03)
Basal
0.78 (0.75 to 0.82)
0 (-0.09 to 0.04)
p=0.48
N Engl J Med 2007; 357: 1716-30
Mean One-year Changes
Biphasic
N Engl J Med 2007; 357: 1716-30
Prandial
Basal
SUMMARY AND
CONCLUSIONS
Biphasic Insulin Summary
 Two injections a day, with two capillary glucose tests for
dose titration
 HbA1c lowering equivalent to Prandial insulin
 Greater weight gain and more hypoglycaemia than with
Basal insulin but less for both than with Prandial insulin
 No change in QoL as assessed by EQ-5D
N Engl J Med 2007; 357: 1716-30
Prandial Insulin Summary
 Three injections a day, with up to seven capillary glucose
tests for dose titration
 HbA1c lowering equivalent to Biphasic insulin
 Greater weight gain and more hypoglycaemia than with
Biphasic or Basal insulin
 No change in QoL as assessed by EQ-5D
Basal Insulin Summary
 One injection a day, with two capillary glucose tests for
dose titration
 One third of patients require a morning insulin injection
in addition
 More patients require a second insulin formulation than
with Biphasic or Prandial insulin
 Less HbA1c lowering than with Biphasic or Prandial
insulin
 Less weight gain and less hypoglycaemia than with
Biphasic or Prandial insulin
 No change in QoL as assessed by EQ-5D
N Engl J Med 2007; 357: 1716-30
Conclusions
 Addition of a single analogue insulin formulation to
metformin and sulfonylurea can lower HbA1c by
between 0.8 and 1.4%, and sustain these values over
one year
 Regimens using biphasic or prandial insulin reduced
HbA1c to a greater extent than basal, but were
associated with greater risks of hypoglycemia and more
weight gain
 The one-year results of the 4-T study suggest that most
patients are likely to need more than one type of insulin
to achieve target glucose levels in the longer term
 The final two years of the trial will examine specifically
the use of complex insulin regimens in these patients
N Engl J Med 2007; 357: 1716-30