Treating To Target in Type 2 Diabetes
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Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapyin 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
One-year ResultsOne-year Results43rd EASD Meeting, Amsterdam, 200743rd 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: 51125379Controlled Clinical Trials number: 51125379
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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.
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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
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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
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Patient Disposition936
Patients screened
708 Underwent randomization
219 excluded
235Assigned to
biphasic insulin
234Assigned to basal
insulin
239Assigned to
prandial insulin
13 Discontinued
10Discontinued
17Discontinued
222 (94%)Completedone year
224 (96%)Completedone year
222 (93%)Completedone year
9 refused to participate
Patients recruited between1st November 2004 and 31st July 2006N Engl J Med 2007; 357: 1716-30
Demographic Characteristics
Biphasic Prandial BasalN=235 N=239 N=234
Male 68% 64% 61%White Caucasian 94% 90% 93%Asian 5% 6% 4%Black 1% 2% 1%Other or mixed <1% 2% 2%
Retinopathy 15% 19% 18%Neuropathy 17% 23% 17%Nephropathy 9% 10% 10%Macroangiopathy 22% 18% 19%
On sulfonylurea 98% 100% 99%On metformin 96% 95% 97%
No significant differences between groups
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Baseline Characteristics
Biphasic Prandial BasalN=235 N=239 N=234
Age (years) 61.7 ±8.9 61.6 ±10.5 61.9±10.0Diabetes duration (years)* 9 (6-2) 9 (6-4) 9 (6-12)
Body weight (kg) 86.9 ±16.8 84.9 ±14.4 85.5 ±16.3Body mass index (kg/m2) 30.2 ±4.8 29.6 ±4.5 29.7 ±4.6
HbA1c (%) 8.6 ±0.8 8.6 ±0.8 8.4 ±0.8Fasting plasma glucose (mmol/l) 9.7 ±2.8 9.6 ±2.7 9.5 ±2.6
LDL cholesterol (mmol/l) 2.5 ±0.7 2.4 ±0.7 2.3 ±0.7HDL cholesterol (mmol/l) 1.0 ±0.3 1.0 ±0.2 1.0 ±0.3Triglycerides (mmol/l)* 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
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Randomisation
* Intensify to a combinationinsulin regimen in year one if unacceptable hyperglycaemia
708T2DM
on dual OAD
Add biphasic insulintwice a day
Add prandial insulinthree times a dayR
Year 1Comparison of three
single insulin regimens,added to OADs*
Add basal insulinonce (or twice) daily
Add prandial insulinat midday
Add basal insulinbefore bed
Years 2 and 3If HbA1c >6.5%, stop
sulfonylurea and add a second insulin formulation
Add prandial insulinthree times a day
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Study Visits
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
The frequency of contacts was designed to be appropriate for insulin initiation in a primary care setting
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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
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Individual Starting Insulin Doses
*Diabetic Medicine 1985; 5: 45-53
Starting doses in rank order
Advised dose : range 2 to 76 IU/day: median 16 (10–25) IU/day
No grade 3 hypoglycaemic episodes occurred within two weeks of starting insulin
Dose taken : median 15 (10–24) IU/day 77% given >10 IU/day 37% given >20 IU/day
5% given >40 IU/day
Estimated from fasting plasma glucose, body weight and gender*
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Insulin Injections & Glucose Measurements
Injection * Self-measured glucose
* *Biphasic
* * ** ** *Prandial
< >Basal* *
Glucose targets
Fasting and pre-meal: 4.0-5.5 mmol/l
Two-hour post meal: 5.0-7.0 mmol/l
6 6 1212 624186 6 1212 624186 6 1212 62418
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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
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ONE YEARRESULTS
Insulin Dose Adjustments
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
Adherence to dose adjustment suggestions (±10%) Biphasic 89.7% Prandial 80.4% Basal 90.2%
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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
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Primary Outcome: HbA1c at One Year
— Biphasic— Prandial— Basal
Mean ±SD at 1 year (%)7.3±0.9
Baseline to 1 year (%)-1.3±1.1
7.2±0.9, p=0.08 vs. biphasic7.6±1.0, p<0.001 vs. biphasic or prandial -0.8±1.0
-1.4±1.0
Months since randomisation
Gly
cate
d ha
emog
lobi
n (%
)
P<0.001
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Distribution of HbA1c Values
— At baseline
HbA1c (%)
— Biphasic— Prandial— Basal
De
nsi
ty23.9%, p=0.08 vs. biphasic 8.1%, p=0.001 vs. biphasic, <0.001 vs. prandial
Proportion <6.5%17.0%
4 6 8 10
0.1
0.2
0.3
0.4
0.5
0.0
Proportion <7.0%41.7%
27.8%48.7%
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Likelihood of Achieving HbA1c ≤6.5%
Odds ratio, 95% CI p
Baseline HbA1c >8.5%
Basal vs. Biphasic 0.21, 0.07-0.65 0.007
Prandial vs. Biphasic 1.24, 0.62-2.51 0.54
Baseline HbA1c ≤8.5%
Basal vs. Biphasic 0.50, 0.24-1.03 0.06
Prandial vs. Biphasic 1.76, 0.96-3.26 0.07
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Glucose Profiles Before & After Starting Insulin
— Biphasic— Prandial— Basal
Change in FPG (mmol/l))-2.5±3.1
Change in PPG (mmol/l)-3.8±3.5
-1.3±2.7-3.3±2.9 -2.6±3.0
-4.6±3.0p<0.001 vs. biphasicp<0.001 vs. biphasic or prandial
0
— At baseline
Body Weight Over One Year
Months since randomisation
Bod
y w
eigh
t (k
g)
P<0.001
— Biphasic— Prandial— Basal
Baseline to 1 year (kg)+4.7±4.0+5.7±4.6, p<0.005 vs. biphasic+1.9±4.2, p<0.001 vs. biphasic or prandial
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Insulin Doses Over One Year
Months since randomisation
Insu
lin d
ose
(U/k
g/da
y)
P=0.04
— Biphasic— Prandial— Basal
Median at 1 year (U/kg/day)0.53 (0.36 to 0.70)
Total per day (U)48 (30 to 71)
0.61 (0.37 to 0.88), p<0.006 vs. biphasic0.49 (0.34 to 0.73), p<0.02 vs. prandial 42 (28 to 72)
56 (34 to 78)
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Hypoglycaemia (≥ Grade 2) Over One Year
Months since randomisation
Pro
port
ion
with
eve
nts
(%)
P=0.001
— Biphasic— Prandial— Basal
Mean at 1 year (events/patient/year) 5.712.0, p<0.002 vs. biphasic 2.3, p=0.01 vs. biphasic, p<0.001 vs.prandial
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Serious Adverse Events
Biphasic Prandial Basal p(N=235) (N=239) (N=234)
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 1 3 1 0.63
Deaths
3 Biphasic (heart failure, myocardial infarction, ischaemic heart disease)
1 Prandial (myocardial infarction)0 Basal
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Adverse events
No clinically relevant changes in albumin creatinine ratio, ALT or plasma creatinine were observed
Biphasic Prandial Basal pN=235 N=239 N=234
All 209 203 207 0.37
Upper respiratory tract infection 81 74 91 0.19
Reaction at injection or infusion site 37 33 52 0.04
Musculoskeletal/connective-tissue 43 37 35 0.59
Lower respiratory/lung infection 36 40 29 0.40
Nausea and vomiting 36 32 32 0.83
Diarrhoea 27 26 34 0.45
Headache 16 27 20 0.23
Upper respiratory tract symptom 17 20 26 0.33
Cough 22 26 17 0.39
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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
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Mean One-year Changes
Biphasic Prandial Basal
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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
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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
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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