2008/09
Trials Ignite
Debate about
Regimen for
Type 2
Diabetes
by David W.
Sharp
Medicine
Top
Ten
Papers
Rank
Papers
Cites
This
Period
Nov-Dec
08
Rank
Last
Period
Sep-Oct
08
1
J. Yu,
et
al.,
"Induced
pluripotent
stem
cell
lines
derived
from
human
somatic
cells,"
Science,
318(5858):
1917-20,
21
December
2007.
[Genome
Ctr.
Wisconsin,
Madison;
U.
Wisconsin,
Madison]
*243HE
87
5
2
R.J.
Motzer,
et
al.,
"Sunitinib
versus
interferon
alfa
in
metastatic
renal-cell
carcinoma,"
New
Engl.
J.
Med.,
356(2):
115-24,
11
January
2007.
[10
institutions
worldwide]
*124NE
65
1
3
B.
Escudier,
et
al.,
"Sorafenib
in
advanced
clear-cell
renal-cell
carcinoma,"
New
Engl.
J.
Med.,
356(2):
125-34,
11
January
2007.
[15
institutions
worldwide]
*124NE
63
2
4
L.J.
Scott,
et
al.,
"A
genome-wide
association
study
of
type
2
diabetes
in
Finns
detects
multiple
susceptibility
variants,"
Science,
316(5829):
1341-5,
1
June
2007.
[12
U.S.
and
Finland
institutions]
*173PS
63
8
5
E.
Zeggini,
et
al.,
"Replication
of
genome-wide
association
signals
in
UK
samples
reveals
risk
loci
for
type
2
diabetes,"
Science,
316(5829):
1336-41,
1
June
2007.
[10
U.K.
institutions]
*173PS
56
9
6
S.E.
Nissen,
K.
Wolski,
"Effect
of
rosiglitazone
on the
risk of
myocardial
infarction
and
death
from
cardiovascular
causes,"
New
Engl.
J.
Med.,
356(24):
2457-71,
14
June
2007.
[Cleveland
Clinic,
OH]
*178DR
55
3
7
T.M.
Frayling,
et
al.,
"A
common
variant
in
the
FTO
gene
is
associated
with
body
mass
index
and
predisposes
to
childhood
and
adult
obesity,"
Science,
316(5826):
889-94,
11
May
2007.
[19
institutions
worldwide]
*166HM
53
7
8
The
ACCORD
Study
Group
(H.C.
Gerstein,
et
al.),
"Effects
of
intensive
glucose
lowering
in
type
2
diabetes,"
New
Engl.
J.
Med.,
358(23):
2545-59,
12
June
2008.
[Writing
Group:
10
U.S.
and
Canadian
institutions]
*311IJ
49
†
9
R.
Sladek,
et
al.,
"A
genome-wide
association
study
identifies
novel
risk
loci
for
type
2
diabetes,"
Nature,
445(7130):
881-5,
22
February
2007.
[14
institutions
worldwide]
*138CR
48
6
10
G.
Hudes,
et
al.,
"Temsirolimus,
interferon
alpha,
or
both
for
advanced
renal-cell
carcinoma,"
New
Engl.
J.
Med.,
356(22):
2271-81,
31
May
2007.
[17
institutions
worldwide]
*172PO
Citations processed in the last
two months of 2008 are dominated by
diabetes and
insulin. At #4, #5, and #9 we have
the genetics of this disease; at #6
lies the antidiabetic drug
rosiglitazone; still outside the Top
Ten but rising at #15 is the New
England Journal of Medicine
paper by Brunkhorst et al.
discussed in the March/April issue
(20[2]: 5, 2009); and now we have
two newcomers, related trials with
differing results but very similar
citation records. The study called
ADVANCE, an acronym of astonishing
clumsiness even for this genre, is
at #11 (A. Patel, et al.,
New Engl. J. Med., 358[24]:
256-72, 2008; total cites 67, latest
count 45), while at #8 is ACCORD
(Action to Control Cardiovascular
Risk in Diabetes). At the time of
counting these papers had been in
print for only six months.
Insulin
Before looking at the above two
newcomers let us tidy up something from
the
previousScience Watch.
Studies of intensive blood-glucose
control in intensive-care settings had
indicated that there could be problems
with this approach. A clearer picture
was expected from the results of a
large international trial, not then
published. It is now. The NICE-SUGAR
investigators (S. Finfer, et
al., New Engl. J. Med.,
360[13]: 1283-97, 2009) compared
glucose targets of 4.5-6.0 mmol/L
(intensive control) and 10.0 mmol/L or
less (conventional) and found that
mortality was significantly higher in
the intensive group; so was the
frequency of severe hypoglycemia. This
trial increases by about a half the
number of patients available for a
meta-analysis, and that too has been
re-done (D.E. Griesdale, et
al., Can. Med. Assoc. J.,
e-pub March 24, 2009). In 26 trials
mortality was not significantly
different for intensive-care patients
put on intensive or conventional
insulin regimens for glucose control.
The latest meta-analysis suggests a
benefit for intensive insulin in
surgical intensive care while
NICE-SUGAR found no difference here.
The American Diabetes Association and
the American Association of Clinical
Endocrinologists, in a joint statement
in March 2009, expressed worry lest
NICE-SUGAR "swing[s] the pendulum of
glucose control too far in the other
direction" so that hospital staff
become "complacent" about uncontrolled
hyperglycemia with its attendant risks
of dehydration and infection. A similar
concern accompanies publication of the
ADVANCE and ACCORD studies (#11 and #8)
of more stringent targets for blood
glucose in patients with type 2
diabetes. ACCORD compared targets of
below 6.0% and 7.0-7.9% for glycated
hemoglobin but the trial was stopped
when a significant increase in
mortality in the intensive group
emerged. Such a mortality difference
was not found in ADVANCE, and rates of
major macrovascular events such as
fatal and non-fatal myocardial
infarctions did not differ between the
two treatment groups. In ADVANCE the
primary endpoint was a combination of
the microvascular and the
macrovascular, but it is the effect of
glucose lowering on the latter that
physicians need the answer to.
In recent years there has been much
pressure to produce guidelines for good
practice in the management of patients
with specific diseases. The ACCORD
study group set the scene for their
trial with the argument that although
there are plenty of hints that lowering
glycated hemoglobin levels (a standard
measure of disease severity in
diabetes) should reduce the risk of
cardiovascular events, guidelines
recommending near-normal levels as a
target for therapy have lacked the
support of large randomized trials.
ACCORD is such a trial and so is
ADVANCE, with more than 10,000 patients
taking part in each. There are many
differences between the two studies,
conveniently tabulated in the first of
two accompanying editorials (R.G.
Dluhy, G.T. McMahon, New Engl. J.
Med., 358[24]: 2630-3,
2008) and providing fuel for much
further discussion. The rapid rise in
the citation listings is hardly
surprising. The results will be seen by
many as negative, but guidelines have
not changed overnight and commentators
on ACCORD and ADVANCE have been
stressing the need for judgement in
individual cases; that glucose targets
should not be abandoned; and that more
could be done about cholesterol and
blood-pressure levels in the battle
against cardiovascular disease in
people with type 2
diabetes.
A former deputy editor of
The Lancet, Mr. David W.
Sharp, M.A. (Cambridge), is a freelance
writer living in Minchinhampton,
Gloucestershire, U.K.
KEYWORDS: SEPSIS, INTENSIVE INSULIN
THERAPY, GRETA VAN DEN BERGHE, F.M.
BRUNKHORST, NICE-SUGAR, HYPOGLYCEMIA.