The only risk factor that remained unimproved at four years with the intensive program of exercise and a calorie-reduced diet was LDL cholesterol.

Lead investigator Dr. Rena Wing (Brown University, Providence, RI) stated that, "If you look at the averages across the four years, we see that a lifestyle intervention produced significantly greater improvements across all four years for all of the cardiovascular-disease risk factors, except LDL cholesterol.... The intensive lifestyle-intervention group spent considerably less cumulative time with lower cardiovascular disease risk, so we're hoping the intensive intervention will reduce cardiovascular morbidity and mortality. We're hoping people will live longer."

Sponsored by the National Institutes of Health, the Look AHEAD study is a large cardiovascular-outcomes study comparing the long-term effects of an intensive program designed to achieve and maintain weight loss through a calorie-restricted diet and increased physical activity in 5,145 overweight or obese individuals with Type 2 diabetes mellitus.

During the first year, patients randomly assigned to the intensive lifestyle intervention lost approximately 10% of their weight through physical activity, up to three hours of exercise weekly, and reduced caloric intake. Through a combination of group and individual appointments, patients met weekly during the first six months and continue to meet monthly for individual counseling sessions and to participate in periodic refresher courses designed to reinforce the intensive lifestyle changes.

Patients randomly assigned to the diabetes support and education study group, which served as the control arm, met three to four times yearly but were not required to lose weight or exercise.

Individuals assigned to the intensive program lost significantly more weight in the first year and maintained greater weight loss throughout the four-year study period. At four years, patients assigned to active therapy lost approximately 6.15% of their body weight, compared with 0.88% in the control arm. Similarly, fitness levels, as measured by metabolic equivalents (METs), were greater in the intensive lifestyle-intervention arm at four years than in the support-and-education arm.

Regarding cardiovascular risk factors, Wing reported four-year data showing marked benefits among those assigned to the intensive lifestyle intervention. HDL-cholesterol levels increased 3.67 mg/dL from baseline, compared with just 1.77 mg/dL among those in the education arm. LDL-cholesterol levels were improved in the first year, but there was no significant difference between treatments at year four, a finding Wing attributes to greater increases in statin use among those assigned to support and education only.

Also, improvements in systolic blood pressure were greater in the active arm, as were reductions in glycated hemoglobin A_1c (HbA_1c) levels. Diastolic blood pressure improved but was significantly better in the active-therapy arm only through years two and three. Wing pointed out that more individuals in each of the four years stopped using antihypertensive medications because they were able to get their blood pressure under control. Similarly, more patients in the control arm were prescribed a diabetes medication or insulin, but more patients in the intensive lifestyle intervention were able to stop taking these drugs.

She added that individuals in the intensive lifestyle intervention were far more likely to achieve the ADA goals of HbA_1c and also more likely to achieve blood-pressure and HDL-cholesterol goals.

During the session, Wing noted that differences in HbA_1c levels "waned" a little over time, although the reduction was still significant from baseline at four years and might be attributed to some weight gain among patients. Other curves, including triglyceride levels, also appeared to wane with time, she noted, but suspects that the intervention will have a positive effect on outcomes.

"Look AHEAD is designed to look at these individuals over 13 years," said Wing. "So we're interested in understanding, even if some of that effect goes away, whether it will still have an impact on cardiovascular morbidity and mortality. It's been the type of effect that's been shown in other trials -- for example, the [Diabetes Control and Complications Trial] DCCT, where we know that the hemoglobin A_1c levels come back, yet it still showed long-term health benefits."

The primary end point of Look AHEAD is cardiovascular death, nonfatal MI, and nonfatal stroke. Secondary end points include all-cause mortality, revascularization, carotid endarterectomy, hospitalization for congestive heart failure, and peripheral vascular disease.

Wing R. Reduction in weight and cardiovascular disease (CVD) risk factors in subjects with Type 2 diabetes (T2DM): Four-year results of Look AHEAD. Obesity 2009; October 25, 2090; Washington, DC. Abstract 06-OR.