One could call it the Murphy's
Law of medical research: if you want a definitive answer
to a thorny clinical question, set up a large, well-designed,
prospective clinical trial. But if you want to go right
back to square one, ending up as much in the dark as
when you set out, then set up two such trials.
That's the conundrum facing the
diabetes community after two groundbreaking flagship
trials delivered wholly incompatible answers on the
question of aggressive glucose control in type II diabetics
with cardiovascular risk factors.
TRIAL
ARM HALTED
On February 6, the ACCORD trial (Action to Control Cardiovascular
Risk in Diabetes), a US-Canadian venture set to run
until 2009, shut down the aggressive treatment arm of
its glucose control component, after patient safety
monitoring revealed excess deaths among those patients
whose treatment goal was <6.0% glycated hemoglobin
(the A1c test). One of the main hypotheses underlying
the ACCORD trial was that these patients would fare
better, because their blood sugar was close to that
of a healthy person.
The number of excess deaths was
not huge. The study enrolled 10,251 subjects, of whom
about 1,500 were Canadian. To date, the average patient
in the trial has been followed for about four years.
There were 257 deaths in the aggressive treatment group,
compared to 203 deaths in the standard treatment group,
which aimed for A1c levels in the 7.0-7.9% range. Those
figures translate to a 1.4% annual risk of death in
the aggressive treatment group, and a 1.1% annual risk
of death in the standard treatment group.
Given the subjects' mean age of
62 years, their average diabetes duration of 10 years,
and the fact that all had either multiple CVD risk factors
or previous CVD events, those are death rates that would
make the average physician proud. In fact, the researchers
say, Ontario data suggests that similar patients in
the general population have death rates of about 4-6%
a year. So the mistake in the study hypothesis, if there
was one, cannot be said to have cost people their lives.
As so often happens, the standard of care in such high-profile
trials is so good that all treatment arms do better
than patients in a more typical clinical setting.
But the elevated risk was real,
and rigorous analysis found no obvious cause. So the
experiment in aggressive glucose control comes to an
early end, with all patients transferred to the standard
care arm. The lipid and hypertension control parts of
the study will continue, winding up as planned in June
2009.
STEP
BACK FOR ADVANCE?
Not surprisingly, the news from the ACCORD trial put
the cat among the pigeons in Sydney, Australia, headquarters
of the remarkably similar ADVANCE trial. That international
trial (including sites in Canada) follows 11,140 patients
with type II diabetes and cardiovascular risk factors.
It too seeks to measure the effect of intensive treatment
to lower blood pressure and reduce blood glucose. Like
ACCORD, it has a treatment arm in which the goal is
to achieve blood glucose levels close to those found
in a healthy non-diabetic person. One key difference
is that while the target in ACCORD was < 6.0%, in
ADVANCE it was a more modest < 6.5%.
"Unlike what we saw in ACCORD,
a rigorous review of ADVANCE data by the Data and Safety
Monitoring Committee shows that the treatment strategy
of intensively lowering blood sugar does not pose greater
risk to our patients with type II diabetes" , announced
Canadian lead investigator Dr Pavel Hamet, of the University
of Montreal, on February 28. While the ADVANCE results
are described as interim, there is no prospect that
they will change. "ADVANCE will continue as planned
to completion," added Dr Hamet. The latest interim analysis,
released contains 99% of the study's final data. The
ADVANCE researchers say they have about twice as much
total data as ACCORD generated.
One thing they aren't yet letting
on is whether aggressive glucose control actually lowered
mortality in ADVANCE, in line with the study hypothesis.
APPLES
TO APPLES
Now comes the hard work of meshing together the data
from two studies that were never designed to be analysed
together. Teasing out the cause of excess mortality
will be especially difficult because neither trial specified
treatment methods, but only set treatment goals. Clinicians
were free to use a range of drugs to lower blood glucose.
The groups are now sharing their
data, and the American Diabetes Association (ADA) and
the US National Heart Lung and Blood Institute are also
poring over the two datasets. The number of variables
to be controlled is daunting, and no results are expected
for months. In fact the ADVANCE trial may well finish
before that task can be completed.
Another big trial of aggressive
glucose controlled is also set to end this year, the
Veterans' Affairs Diabetes Trial. It could end up playing
the role of tiebreaker if the discrepancies between
ACCORD and ADVANCE prove impossible to resolve.
One possible cause of the excess
deaths has already been eliminated. Rosiglitizone, once
a widely-used diabetes drug until it was linked to cardiovascular
risk, appears not to have been implicated.
The closure of the intensive treatment
arm in ACCORD coincided with the appearance of a Danish
study in the New England Journal of Medicine
that also tested intensive glucose-lowering therapy,
and found a marked survival benefit. The Danish researchers,
however, were quick to note that their subjects were
younger, far healthier, and newly diagnosed with type
II diabetes. In such patients, there is broad agreement
that the lower the A1c count, the better.
The ACCORD researchers are keeping
mum for the moment. Dr Hertzel Gerstein, endocrinologist
at McMaster and principal investigator of ACCORD, told
NRM that they're in the process of crunching
their mortality data and hope to publish the results
sometime this month.
PROCEED
WITH CAUTION
All of this leaves the guardians of best practice in
a bit of a quandary. Both the American and the Canadian
Diabetes Associations have for some time recommended
aiming for an A1c of less than 7%. They aren't changing
that advice in the light of ACCORD, but are counselling
caution in the presence of cardiovascular disease or
risk factors. At the same time, they leave open the
option of more aggressive treatment if the patient seems
up to it.
The ADA's president of science,
Dr John Buse, who is vice chairman of the ACCORD steering
committee, is the only expert involved who's yet willing
to speculate on what might have caused the excess deaths.
"The intensity of what we did is
done virtually nowhere on the planet," he told the New
York Times, calling it a "brutal program." The program
demanded much of patients, he said, and many had difficulty
reaching blood sugar goals. "At some level I just wonder
if some of them were just overwhelmed by this psychologically,''
Dr Buse said. ''Could it be the stress of 'I'm trying
so hard, but I can't get it done'?"
For more, please see Opinion "Discord
on ACCORD".
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