Lifestyle-Based Diabetes Prevention Seen to Endure for at Least a Decade

October 30, 2009

October 30, 2009 (Bethesda, Maryland) — A number of prospective studies have shown that behavioral and lifestyle interventions can provide lasting protection against new type 2 diabetes in people at increased risk, but the question remains: For how long?

What might be the longest follow-up yet of patients from such a randomized controlled trial comes this week from the Diabetes Prevention Program (DPP) Research Group, which saw protective effects of both lifestyle intervention and treatment with metformin last as long as 10 years [1].

Their findings, now published online in the Lancet, come from an unblinded, extended follow-up of most patients from the original DPP, published in 2002 [2], that compared an intensive lifestyle intervention program with metformin or placebo in 3234 nondiabetic patients with elevated fasting glucose and impaired glucose tolerance.

As reported by heartwire at the time, the rate of new diabetes (defined according to American Diabetes Association criteria) fell by 58% with intensive lifestyle intervention and by 31% with metformin only, compared with placebo, over a mean of 2.8 years (p<0.001 for both differences). Compared with outcomes with metformin, lifestyle intervention--which included diet modification, exercise, and weight-reduction targets--lowered the rate by 39% (p<0.001).

The clearest message is that the lifestyle intervention was very effective in a short time, as we showed in the DPP study a number of years ago.

After a one- to two-week washout period for the metformin and placebo groups, the blinding was lifted and results were disclosed to participants. Then, 88% of the total group continued in their respective randomization groups in the separately designed Diabetes Prevention Program Outcomes Study (DPPOS). For that, 910 lifestyle subjects continued with their intervention, and a similar one was offered to the 924 metformin subjects (who continued on that drug) and the 932 subjects previously in the placebo group.

Over the subsequent median follow-up of 5.7 years, the original lifestyle-intervention subjects--whose rate of new diabetes had plummeted in the first trial relative to placebo--maintained their low diabetes-onset rate during the DPPOS phase. "It's been remarkably stable throughout the study," lead author Dr William C Knowler (National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ) told heartwire .

In the metformin and former placebo groups, new diabetes rates fell sharply from what they had been in the first trial, so that "there was no significant difference between the three treatment groups, not because the lifestyle group changed, but because the other two groups improved to match it," Knowler said.

In a combined analysis of the consecutive studies, the new diabetes rate fell by 34% in the lifestyle-intervention group and by 18% in the metformin group over 10 years, compared with the placebo group.

Incidence of New-Onset Diabetes (95% CI) Per 100 Person-Years in the DPP and DPPOS Studies, and During 10-Year Combined Follow-up

Study period Lifestyle intervention, n=910 Metformin, n=924 DPP placebo, n=932
DPP 4.8 (4.1-5.7) 7.8 (6.8-8.8) 11.0 (9.8-12.3)
DPPOS 5.9 (5.1-6.8) 4.9 (4.2-5.7) 5.6 (4.8-6.5)
DPP + DPPOS 5.3 (4.8-5.8) 6.4 (5.9-7.1) 7.8 (7.2-8.6)
DPP=Diabetes Prevention Program; DPPOS=Diabetes Prevention Program Outcomes Study

The "mostly healthy," mostly nonelderly DPP cohort had too few cardiovascular events to show anything conclusive about the effect of lifestyle intervention on coronary disease, Knowler said. "We certainly hypothesized that this would have an effect on more than just diabetes and, in the next phase of DPPOS . . . we're looking at microvascular complications, cardiovascular disease, and even mortality."

"The clearest message is that the lifestyle intervention was very effective in a short time, as we showed [in the DPP study] a number of years ago," according to Knowler. Those participants, he said, gained most of their protection against new diabetes in the early phase "and were able to maintain it and some weight loss for a long time--10 years on average." Although their weight dropped rapidly during the first year of DPP, some of it--but not all-- returned during the DPPOS phase.

Knowler pointed out that the 10-year DPP/DPPOS results are consistent with the long-term follow-up of 522 initially nondiabetic subjects in the Finnish Diabetes Prevention Study [3], who had been randomized to a lifestyle-intervention group or a nonintervention control group. As reported by heartwire , that analysis extended the primary study's three-year follow-up out to seven years.

In the current analysis, the diabetes-onset rates for the metformin and placebo patients ultimately matched those of the lifestyle group, possibly because all DPPOS subjects were offered a lifestyle intervention much like the one used in DPP.

I consider this lifestyle intervention an important step in the right direction, but it's clearly not sufficient. Because still, after 10 years, half the people developed diabetes.

"We can't say with certainty why the rates in the metformin and placebo groups fell during the DPPOS, but that's certainly a plausible hypothesis," Knowler said. His group's report says that 58% of metformin patients and 57% of placebo patients attended "at least some sessions" of the intervention's educational program. An unknown number of others likely exercised more.

"What does this study add?" asks Dr Anoop Misra (Fortis Hospitals, New Delhi, India) in an accompanying editorial [4]. "We now know from DPP and DPPOS that an intensive lifestyle intervention is effective over 10 years, and remains the best bet for prevention of diabetes. Further, during DPPOS, metformin did as well as an intensive lifestyle intervention, which might be due to the addition of the lifestyle intervention to the drug group," he speculates. "Finally, some weight loss could be sustained over the 10 years of the lifestyle intervention and metformin, although during DPPOS, the loss of weight was not as impressive as that during DPP."

Results of trials that have tested lifestyle modification for diabetes prevention, including the current study and the Finnish study, have been "remarkably similar," Misra observed. "A carefully followed diet-exercise combination seemed to be superior in preventing or delaying the development of diabetes compared with the effect of antihyperglycemic drugs other than the thiazolidinediones."

Knowler offered a caution about the DPP/DPPOS findings. "I consider this lifestyle intervention an important step in the right direction, but it's clearly not sufficient. Because still, after 10 years, half the people developed diabetes. We've cut that rate, but obviously there's much more to do."

According to the report, the DPPOS study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases , with further support from other institutes of the National Institutes of Health , the Center for Disease Control and Prevention , and the American Diabetes Association ; medicine and other materials were provided by Merck-Santé and LifeScan.


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