Lifestyle changes, not drugs, should be the main focus for preventing
type 2 diabetes: that was the conclusion of a lively debate here at
the European Association for the Study of Diabetes 2008 Meeting.
While Dr Paul Zimmet (Baker IDI Heart and Diabetes Institute,
Melbourne, Australia) argued nimbly that glucose-lowering drugs could
play an important role in preventing progression to diabetes, the
audience, in a show of hands, ultimately voted to feed him to the
lions following what both speakers, in a nod to their Roman
surroundings, called a "gladiatorial debate."

In defense of lifestyle interventions, Dr Nick Wareham (Institute of
Metabolic Science, Cambridge, UK), pointed to the fundamental,
philosophical problem of treating patients who have no overt disease
with pharmaceutical agents that have no proven benefits as preventive
medications.

"As a physician I know that drug therapy is hugely beneficial in
certain circumstances. The question is whether it is beneficial for
people who don't have a disease to be treated with drugs," Wareham
said. "I do not contest the notion that this group is at risk, but I
think there is a profound philosophical question we're facing: when
we as physicians seek out people who don't come to us to offer them
help, we'd better be damn sure that what we're doing is actually
going to do so."

But taking the counterposition, Zimmet cited the American Diabetes
Association (ADA) consensus panel guidelines for people with impaired
fasting glucose and impaired glucose tolerance, pointing out that
while lifestyle changes are recommended, the writing group also "goes
straight to metformin" in the presence of a wide range of risk
factors common in the general population, relating to age, weight,
family history, blood pressure, and lipid parameters. "This is a
basic rejection of the idea that lifestyle alone works," Zimmet said.

Indeed, citing the ProACTIVE UK study, for which his opponent was an
investigator, Zimmet pointed out that Wareham's own paper
acknowledged that "it's very, very hard" to achieve a lifestyle
intervention. In ProACTIVE UK, a behavioral intervention was no more
effective than an "advice leaflet" for promoting physical activity in
an at-risk group [1].

Forces Work Against Lifestyle

Backing up this claim, Zimmet showed a photograph of people attending
the ADA annual meeting crammed onto escalators, while the stairs
stood empty. "If we can't get the people pushing for lifestyle
interventions to use the stairs themselves, then we really have a
problem," Zimmet quipped.

Zimmet pointed to environmental, cultural, economic, and
sociopolitical forces that work against lifestyle changes in
developed countries, many of which are amplified in other parts of
the world. "I'm a strong believer that lifestyle interventions can
work, but maybe only in Alcatraz, where you can put people in prison
and then rigorously control their exercise and diet regimen," he said.

If we can't get the people pushing for lifestyle interventions to use
the stairs themselves, then we really have a problem.

The real reason, Zimmet reminded the audience, for preventing onset
of type 2 diabetes is to reduce the risk of cardiovascular disease,
but as he points out, "the clock starts ticking long before the line
we actually call diabetes." And whether lifestyle changes alone will
be enough to alter long-term effects remains unproven. In the 20-year
follow-up from the Da Qing diabetes study, Zimmet noted, any
significant differences between lifestyle intervention and control
groups for cardiovascular or all-cause mortality that were apparent
up to 14 years had disappeared after two decades [2].

But referring to the same study in his counterargument, Wareham
pointed out that the Da Qing study was underpowered to detect these
kinds of late-term differences, and, if anything, the totality of
data overwhelmingly suggests that the effects of lifestyle
interventions, once stopped, are far more durable than those of
drugs. Zimmet had anticipated this point and suggested that the
solution would be to just to stay on the drugs. Wareham, however,
cited a comparison of lifestyle interventions and metformin by Herman
et al, arguing that lifestyle changes are significantly more cost-
effective in the first few years and, extrapolating over a lifetime,
incur negligible costs per quality-associated life-year gained [3].

But perhaps most important, Wareham pointed out, lifestyle changes
actually tackle the root cause of type 2 diabetes, not its
consequences. And not only are they effective at reducing diabetes
risk, Wareham noted, but they also have "halo effects," including
anthropometric, physiological, metabolic, psychological, behavioral,
and quality-of-life benefits.

Drugs, by contrast, may effectively reduce diabetes risk but often
have adverse effects on some of these other factors and in some cases
may actually have the effect of discouraging people from making
meaningful lifestyle changes," Wareham argued.

Asked during the question period whether he had any specific
recommendations for clinicians, Wareham acknowledged that a public-
health problem requires sweeping changes in public-health policies--a
point that both gladiators agreed upon. And conceding a point to
Zimmet on the lack of long-term, hard-end-point studies for specific,
clinically applicable lifestyle interventions, Wareham called for any
funding agency representatives in the audience to sit up and take
notice.

Controlling Risk Factors and Public Health Solutions

Before we embark on pharmacological therapy I would ask you whether
you are doing that on the basis of evidence, or on assumption.

In his concluding remarks, Zimmet emphasized that in the
future "preventive genomics" may prove useful for identifying
individuals who could benefit from lifestyle changes and those in
whom pharmacotherapy is appropriate. He also underscored the need for
optimal control of other risk factors--lipids and blood pressure,
through drugs as well as lifestyle--for preventing future disease.

For the time being, Zimmet concluded, "We must consider all options
for prevention and drugs that are likely to magnify the benefit
obtained from attempts at lifestyle measures."

Wareham, for his part, reiterated that the "true solution" to the
problem of type 2 diabetes will be a public-health solution that
encompasses transportation, school and workplace characteristics, and
family activity levels and influences personal attitudes and choices.
But in the meantime, he stressed, "before we embark on
pharmacological therapy, I would ask you whether you are doing that
on the basis of evidence or on assumption. There is evidence
supporting lifestyle interventions. They can work, and they can be
effective in the long term."

In a show of hands following the debate, Zimmet's prodrug arguments
received a smattering of votes, while Wareham was the overwhelming
winner.

Being Surer Than We Are

Speaking with heartwire after the debate, session cochair Dr Edwin
Gale (Bristol University, UK) explained that while pharmacotherapy
for type 2 diabetes prevention is "not really taking place"
clinically, at present, it is a topic of major interest and debate
among endocrinologists and diabetologists.

"We're looking closely at the evidence, because starting someone on a
drug before they have a diagnosis is problematic. Impaired glucose
intolerance is a soft diagnosis, because it can be made only with a
glucose-tolerance test, and not many people are going to get this,"
he said. "I think that both speakers agreed that in the long term, it
needs to be lifestyle changes for the whole population and not just
directed at high-risk individuals. But we need better ways of
identifying high-risk individuals, so we can intervene earlier."

Today, asymptomatic individuals typically undergo automatic glucose
testing at age 45, Gale said, but he believes testing will start to
be performed earlier, particularly in people with other diabetes risk
factors, like obesity. "In reality, we will always start with
lifestyle interventions, but if you see that someone is progressing
toward diabetes, then you're going to start to see the use of drugs,"
he said.

But Gale reiterated that the evidence supporting a beneficial effect,
in terms of hard diabetes and cardiovascular end points, of lowering
glucose in people who are prediabetic, is lacking. And he agreed with
Wareham that the creation of a label like "prediabetic," diagnosing a
disease before it's present, is "a major worry." One issue, as both
he and Zimmet suggested during the session, is that the definition of
diabetes may need to be reconsidered so that people can be identified
earlier in the disease process.

"This has to be risk-based treatment," Gale told heartwire, "and we
have to have ways of being surer than we are at present that someone
has risk before we start adding on drugs and changing their lives."


1.Kinmonth AL, Wareham NJ, Hardeman W, et al. Efficacy of a theory-
based behavioural intervention to increase physical activity in an at-
risk group in primary care (ProActive UK): a randomised trial. Lancet
2008; 371:41-48. Abstract

2.Li G, Zhang P, Wang J, Gregg EW, et al. The long-term effect of
lifestyle interventions to prevent diabetes in the China Da Qing
Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008;
371:1783-1789. Abstract

3.Herman WH, Hoerger TJ, Brandle M, et al. The cost-effectiveness of
lifestyle modification or metformin in preventing type 2 diabetes in
adults with impaired glucose tolerance. Ann Intern Med 2005; 142:323-
332. Abstract