original article
T h e
n e w e n gl a n d j o u r n a l
o f
m e d i c i n e
n engl j med 357;17 www.nejm.org october 25, 2007
1716
Addition of Biphasic, Prandial, or Basal
Insulin to Oral Therapy in Type 2 Diabetes
Rury R. Holman, M.B., Ch.B., F.R.C.P., Kerensa I. Thorne, M.Sc.,
Andrew J. Farmer, D.M., F.R.C.G.P., Melanie J. Davies, M.D., F.R.C.P.,
Joanne F. Keenan, B.A., Sanjoy Paul, Ph.D., and Jonathan C. Levy, M.D., F.R.C.P.,
for the 4-T Study Group*
From the Diabetes Trials Unit, Oxford
Centre for Diabetes, Endocrinology, and
Metabolism (R.R.H., K.I.T., A.J.F., J.F.K.,
S.P., J.C.L.) and the Department of Primary
Health Care (A.J.F.), University of Oxford,
Oxford; and the Department of Cardiovas-
cular Sciences, University of Leicester,
Leicester (M.J.D.) — all in the United King-
dom. Address reprint requests to Dr. Hol-
man at the Diabetes Trials Unit, Oxford
Centre for Diabetes, Endocrinology, and
Metabolism, Churchill Hospital, Heading-
ton, Oxford OX3 7LJ, United Kingdom, or
at rury.holman@dtu.ox.ac.uk.
*Investigators in the Treating to Target in
Type 2 Diabetes (4-T) study group are
listed in the Appendix.
This article (10.1056/NEJMoa075392) was
published at www.nejm.org on Septem-
ber 21, 2007.
N Engl J Med 2007;357:1716-30.
Copyright © 2007 Massachusetts Medical Society.
A b s t r a c t
Background
Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glyce-
mic control is suboptimal, though evidence supporting specific insulin regimens is
limited.
Methods
In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with
a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maxi-
mally tolerated doses of metformin and sulfonylurea to receive biphasic insulin
aspart twice daily, prandial insulin aspart three times daily, or basal insulin de-
temir once daily (twice if required). Outcome measures at 1 year were the mean
glycated hemoglobin level, the proportion of patients with a glycated hemoglobin
level of 6.5% or less, the rate of hypoglycemia, and weight gain.
Results
At 1 year, mean glycated hemoglobin levels were similar in the biphasic group
(7.3%) and the prandial group (7.2%) (P = 0.08) but higher in the basal group (7.6%,
P<0.001 for both comparisons). The respective proportions of patients with a gly-
cated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective
mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3;
and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse
events were similar among the three groups.
Conclusions
A single analogue-insulin formulation added to metformin and sulfonylurea resulted
in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year.
The addition of biphasic or prandial insulin aspart reduced levels more than the
addition of basal insulin detemir but was associated with greater risks of hypogly-
cemia and weight gain. (Current Controlled Trials number, ISRCTN51125379.)
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Addi tion of Insulin to Oral Ther a py in T ype 2 Di abetes
n engl j med 357;17 www.nejm.org october 25, 2007
1717
T
ype 2 diabetes mellitus is a progres-
sive condition in which the glycated hemo-
globin level rises inexorably over time and
the function of beta cells declines.
1,2
The mainte-
nance of nearly normal glycemic levels reduces
the risk of diabetic complications
3-5
but is diffi-
cult to achieve, despite the administration of es-
calating doses of oral antidiabetic drugs, such as
metformin, sulfonylureas, and thiazolidinedi-
ones.
6-8
Most patients eventually require insulin,
6
which usually is added when glycemic control
with a regimen of oral antidiabetic agents be-
comes suboptimal.
9
The addition of insulin can
result in a clinically relevant improvement in a
patient’s glycated hemoglobin level.
10
However,
many patients do not reach targets for glycated
hemoglobin
6
with conventional insulin regimens,
and there is often concern regarding hypoglyce-
mia and weight gain. Large-scale, direct compari-
sons of various regimens of insulin analogues in
combination with oral antidiabetic agents have
been lacking.
Treating to Target in Type 2 Diabetes (4-T) is
a 3-year, multicenter, open-label, randomized, con-
trolled clinical trial. We report the results of the
first year, which compared the efficacy and
safety of adding analogue biphasic, prandial, or
basal insulin to the treatment of patients with
type 2 diabetes who had suboptimal glycemic con-
trol while receiving maximally tolerated doses of
metformin and sulfonylurea.
M e t hod s
Patients
From November 1, 2004, to July 31, 2006, we re-
cruited men and women 18 years of age or older
who had had type 2 diabetes mellitus for at least
12 months and who had not been treated with
insulin. Recruitment took place in 58 clinical
centers in Ireland and the United Kingdom. All
patients had suboptimal glycemic control (a gly-
cated hemoglobin level of 7.0 to 10.0%) while re-
ceiving maximally tolerated doses of metformin
and sulfonylurea for at least 4 months (or one
agent if the other was not tolerated) and had a
body-mass index (the weight in kilograms divid-
ed by the square of the height in meters) of 40.0 or
less. Exclusion criteria were a history of thiazoli-
dinedione therapy or triple oral antidiabetic treat-
ment within the previous 6 months, sight-threat-
ening retinopathy, a plasma creatinine level of
1.47 mg per deciliter (130 μmol per liter) or more,
cardiac disease (a history of unstable angina or
myocardial infarction within the previous 6 months
or New York Heart Association class III or IV con-
gestive heart failure), hepatic disease or an ala-
nine aminotransferase level at least two times as
high as the upper limit of the normal range, un-
awareness of hypoglycemia or recurrent major hy-
poglycemia, anticipated changes in concomitant
medication affecting glucose regulation, uncon-
trolled hypertension (systolic pressure ≥180 mm Hg
or diastolic pressure ≥105 mm Hg), and the likeli-
hood of pregnancy.
All patients provided written informed consent
and confirmed their willingness to inject insulin
and perform glucose self-monitoring. The proto-
col was approved by local and national ethics and
regulatory agencies and was implemented in ac-
cordance with provisions of the Declaration of
Helsinki and Good Clinical Practice guidelines.
Study Design
The Diabetes Trials Unit ran the study with the
use of an online trial-management system, Macro,
version 3 (Infermed), which was configured to
validate data on entry, acquire laboratory results
electronically, and track adherence to the proto-
col. Randomization was performed in permuted
blocks of six according to center with the use of
an interactive voice-response system. A total of
235 patients were assigned to receive twice-daily
biphasic insulin aspart 30 (NovoMix 30), 239 to
receive thrice-daily prandial insulin aspart (Novo-
Rapid), and 234 to receive once-daily (twice if
required) basal insulin detemir (Levemir). All
three preparations were supplied by Novo Nor-
disk in 3-ml disposable-pen devices (FlexPen).
The steering committee that supervised the
study consisted of five academic members who
designed the trial, one lay member, and three rep-
resentatives of the sponsor. Data (with the excep-
tion of data regarding safety) were held and ana-
lyzed only by the Diabetes Trials Unit. All authors
had full access to the data and vouch for its ac-
curacy and integrity.
Insulin Initiation and Titration
The trial-management system estimated start-
ing doses of insulin according to the following
formulas
11
: for men, [(fasting plasma glucose
[mmol/liter] − 5) × 2] × (weight [kg] ÷ (14.3 × height
[m]) − height [m]); for women, [(fasting plasma
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T h e
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1718
glucose [mmol/liter] − 5) × 2] × (weight [kg] ÷ (13.2 ×
height [m]) − height [m]).
Patients injected biphasic insulin twice daily,
prandial insulin immediately before meals, and
basal insulin at bedtime. Visits with patients were
scheduled at 2, 6, 12, 24, 38, and 52 weeks, with
interim telephone contact. For each visit and tele-
phone contact, patients were asked to perform in
advance three capillary glucose profiles (Medi-
sense Optium, Abbott) obtained before break-
fast and before the evening meal for patients in
the biphasic and basal groups and before meals
and 2 hours after meals and at bedtime in the
prandial group. Using these glucose readings and
self-reported hypoglycemia, the trial-management
system suggested changes in insulin doses, aiming
for values before meals of 72 to 99 mg per deci-
liter (4.0 to 5.5 mmol per liter) and values 2 hours
after meals of 90 to 126 mg per deciliter (5.0 to
7.0 mmol per liter). A morning basal dose was
advised, either when glucose readings were at tar-
get before breakfast but not before the evening
meal and when nocturnal hypoglycemia limited
dose increases at bedtime (for details, see
Table
1
of the Supplementary Appendix, available with
the full text of this article at www.nejm.org).
Investigators and patients were encouraged to
vary suggested insulin doses if such a change was
deemed to be appropriate and to amend doses
between visits if necessary. Hypoglycemia was
categorized as grade 1 if a patient had symp-
toms with a self-measured capillary glucose level
of 56 mg per deciliter (3.1 mmol per liter) or more,
grade 2 (minor) if the patient had symptoms with
a self-measured capillary glucose level of less than
56 mg per deciliter, or grade 3 (major) if third-
party assistance was required.
If unacceptable hyperglycemia (a glycated he-
moglobin level of more than 10.0% or two con-
secutive values of 8.0% or more) occurred at or
after 24 weeks of therapy, a second type of insu-
lin was added and sulfonylurea (if the patient was
taking it) was discontinued. Aspart was added
with the midday meal to biphasic insulin, detemir
was added to prandial insulin at bedtime, and
aspart was added three times daily with meals to
basal insulin.
Biochemical and Clinical Measurements
Investigators recorded any diabetic complications
and race (as reported by patients) at study entry.
Blood pressure was measured at baseline and at
24 and 52 weeks, waist circumference at baseline
and at 52 weeks, and body weight at all visits ex-
cept at week 2. Body-mass index was calculated
at baseline. A quality-of-life questionnaire, the
EuroQol Group 5-Dimension Self-Report Ques-
tionnaire,
12
was administered at baseline and at
12 and 52 weeks.
Glycated hemoglobin levels were measured,
eight-point glucose profiles were requested, and
the ratio of urinary albumin to creatinine was
calculated at baseline and at 12, 24, 38, and 52
weeks; plasma creatinine levels were measured
at baseline and at 2, 6, 12, 24, 38, and 52 weeks;
and lipid levels and alanine aminotransferase lev-
els were measured at baseline and at 52 weeks.
Plasma samples were sent by overnight surface
mail at ambient temperatures to a central labo-
ratory. Glycated hemoglobin was measured by
high-performance liquid chromatography (Biorad
Variant II, Biorad) (normal range, 4.5 to 6.2%),
and plasma insulin by enzyme-linked immuno-
sorbent assay (Dako). An Olympus AU400 analyzer
(Olympus Optical) was used to measure levels of
low-density lipoprotein cholesterol (Genzyme
kit, Biostat), high-density lipoprotein cholesterol
(Olympus HDL-cholesterol kit), and triglycerides
(glycerol phosphate oxidase-p-aminophenazone
[GPO-PAP]); urinary albumin was measured by
immunoturbidimetry, urinary creatinine by the
Jaffe method, and alanine aminotransferase by a
kinetic ultraviolet test.
Primary and Secondary Outcomes
The primary outcome was the glycated hemoglo-
bin level at 1 year. Secondary outcomes were the
proportion of patients with a glycated hemoglo-
bin level of 6.5% or less, the proportion of patients
with a glycated hemoglobin level of 6.5% or less
but without hypoglycemia (grade 2 or more) dur-
ing weeks 48 to 52, the rate of hypoglycemia,
weight gain, the eight-point self-measured capil-
lary glucose profile, the proportion of patients
requiring twice-daily detemir insulin, the propor-
tion of patients with unacceptable hyperglyce-
mia, the ratio of albumin to creatinine, and qual-
ity of life.
Statistic al Analysis
We calculated that 198 patients per study group
would need to be enrolled to detect an absolute
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Addi tion of Insulin to Oral Ther a py in T ype 2 Di abetes
n engl j med 357;17 www.nejm.org october 25, 2007
1719
difference of 0.4% in the achieved glycated hemo-
globin level, assuming an SD of 1.1% on the basis
of trial data regarding detemir insulin,
13
with a
power of 95%. The recruitment target was 700 pa-
tients (233 per group), allowing for a discontinu-
ation rate of 15%.
Missing data were imputed with the use of
the Bayesian Markov chain Monte Carlo multiple-
imputation technique.
14
All analyses were ad-
justed according to clinical center. Mixed regres-
sion models
15
were used for continuous data, with
baseline values, oral antidiabetic agents, and gly-
cated hemoglobin levels as covariates. Mixed-effect
logistic models were used for the proportion of
patients who had glycated hemoglobin levels of
6.5% or more or 7.0% or more, with calculations
repeated for patients with baseline glycated he-
moglobin levels of 8.5% or less or more than
8.5%, and with baseline values, oral antidiabetic
agents, and baseline glycated hemoglobin levels
as potential covariates. The proportion of patients
with hypoglycemia was analyzed in a similar
fashion without adjustment. Generalized mixed-
effect models with Poisson and negative bino-
mial distributions were used for rates of hypo-
glycemia, and an approach with unstructured
correlation was used for self-measured capillary
glucose profiles, with baseline values and oral
antidiabetic agents as covariates. Ratios of uri-
nary albumin to creatinine were analyzed with
the use of a generalized mixed-effect model with
gamma distribution, adjusted for baseline values,
oral antidiabetic agents, and glycated hemoglo-
bin levels. Quality-of-life data are presented as
Winsorized means with 95% confidence inter-
vals, with a Kruskal–Wallis analysis of variance
for treatment comparisons.
A prespecified closed-test procedure allowed
for a pairwise comparison of groups only if the
overall treatment effect was significant. A two-
sided P value of less than 0.05 was considered to
indicate statistical significance; all P values are
based on adjusted analyses but have not been
adjusted for multiple testing.
R e s ul t s
Patients
Of 936 patients who underwent screening, 708
were assigned randomly at baseline to the three
study groups (Fig. 1). The patients had a mean
(±SD) age of 61.7±9.8 years and a median dura-
tion of disease of 9 years; most were white and
overweight, with no significant differences in
baseline variables among the groups (
Table 1
).
The total numbers of patients who did not
complete 52 weeks did not differ significantly
among the biphasic group (13 of 235, or 5.5%),
the prandial group (17 of 239, or 7.1%), or the
basal group (10 of 234, or 4.3%) (P = 0.40 for all
comparisons). However, of these patients, 13 in
the prandial group (5.4%) withdrew from the
study, as compared with 4 in the biphasic group
(1.7%) and 3 in the basal group (1.3%) (P<0.002
for all comparisons). Demographic, anthropomet-
ric, and metabolic characteristics of the 40 pa-
tients who did not complete the study (Fig. 1)
differed from those of patients who continued
only in that they had a lower median triglyceride
level (113 vs. 137 mg per deciliter [1.3 vs. 1.6
mmol per liter], P = 0.02).
Starting insulin doses were 2 to 76 IU per day.
In the subsequent 2 weeks, mean rates of grade
2 hypoglycemia were 0.045 event per patient per
week in the biphasic group, 0.031 event in the
prandial group, and 0.024 event in the basal group;
there were no grade 3 episodes. During the study,
the percentages of patients whose prescribed in-
sulin doses were within ±10% of the recommen-
dation of the trial-management system averaged
89.7% in the biphasic group, 80.4% in the prandial
group, and 90.2% in the basal group. The median
number of capillary glucose readings before visits
were 9.5 (interquartile range, 6 to 12) in the bi-
phasic group, 14 (interquartile range, 9 to 18) in
the prandial group, and 9 (interquartile range, 6 to
12) in the basal group. Of patients assigned to re-
ceive basal insulin, 79 (33.8%) required additional
morning injections. The number of patients with
unacceptable hyperglycemia at or after 24 weeks
who required injection of a second type of insu-
lin differed according to the study group: 21 pa-
tients in the biphasic group (8.9%), 10 in the
prandial group (4.2%), and 42 in the basal group
(17.9%) (P<0.001 for all comparisons).
Primary Outcome
The maximal reduction in the mean glycated he-
moglobin level occurred by 24 weeks and then
remained stable (Fig. 2A). At 52 weeks, the re-
duction from baseline was 1.3% in the biphasic
group, 1.4% in the prandial group, and 0.8% in
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T h e
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1720
the basal group (Fig. 2A and 2B). At that time,
the difference between the levels of 7.3% in the
biphasic group and 7.2% in the prandial group
were not significant (P = 0.08), but the level was
higher (7.6%) in the basal group (P<0.001 for both
comparisons with the basal group) (
Table 2 and
Fig. 2A and 3A
).
Secondary Outcomes
The proportion of patients with a glycated hemo-
globin level of 6.5% or less at 1 year differed
among the groups (P<0.001 for all comparisons).
The proportions of patients in the biphasic group
(17.0%) and the prandial group (23.9%) did not
differ significantly (P = 0.08), but the proportion
in the basal group was lower (8.1%) than that in
either other group (P = 0.001 for the comparison
with the biphasic group and P<0.001 for the com-
parison with the prandial group). The corre-
sponding proportions of patients with a glycated
hemoglobin level of 7.0% or less also differed
significantly between the basal group (27.8%) and
each of the two other groups (biphasic group,
41.7%; prandial group, 48.7%; P<0.001 for both
33p9
708 Underwent randomization
936 Patients were screened
219 Were excluded (could have more than one reason)
126 Had glycated hemoglobin <7% or >10%
27 Had plasma creatinine ≥1.47 mg/dl
20 Had alanine aminotransferase >3 times the
upper limit of normal
11 Had body-mass index >40
8 Had previously received insulin
7 Were not receiving maximally tolerated oral
antidiabetes agents
6 Had had diabetes for <1 yr
5 Had received thiazolidinediones within 6 mo
5 Had uncontrolled hypertension
5 Had received oral therapy for <4 mo
4 Had received oral therapy with 3 or more drugs
within 6 mo
8 Had other reasons
9 Declined to participate
3 Withdrew consent
4 Were unwilling to inject insulin
2 Were unwilling to perform self-
monitored capillary glucose
measurements
10 Discontinued
1 Had poor clinical
response
4 Had adverse
event
1 Had protocol
violation
1 Lost access to
center
3 Withdrew parti-
cipation
17 Discontinued
1 Died
2 Had protocol
violation
1 Was lost to
follow-up
13 Withdrew parti-
cipation
13 Discontinued
2 Had adverse
event
3 Died
2 Had protocol
violation
2 Were lost to
follow-up
4 Withdrew parti-
cipation
235 Were assigned to
biphasic insulin
239 Were assigned to
prandial insulin
234 Were assigned to
basal insulin
222 Completed 1 yr 222 Completed 1 yr 224 Completed 1 yr
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Holman
1 of 3
10-25-07
ARTIST: ts
35717
Figure 1. Enrollment and Outcomes.
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