Dr Paul Zimmet

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].

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].

Dr Nick Wareham

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.

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.

Dr Edwin Gale

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."