American Diabetes Association Scientific Sessions

American Diabetes Association Scientific Sessions

Perspective from M. Sue Kirkman, MD
June 24, 2013
6 min read

Look AHEAD: Intensive lifestyle intervention failed to prevent CV events in obese patients with diabetes

Perspective from M. Sue Kirkman, MD
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CHICAGO — A long-term, intensive lifestyle intervention targeting weight loss in overweight and obese patients with type 2 diabetes did not reduce the rate of cardiovascular events, including nonfatal myocardial infarction and nonfatal stroke, according to primary results from the Look AHEAD trial. The intervention, however, yielded other benefits in this patient population.

The data were presented here at the ADA Scientific Sessions and simultaneously published in the New England Journal of Medicine.

“The rationale for Look AHEAD is that we did not know whether weight loss achieved through a behavioral intervention program could help people with diabetes, specifically type 2 diabetes, live longer and develop less CVD,” Mary Evans, PhD, director of Look AHEAD and from the special projects in nutrition, obesity and digestive diseases at the NIDDK, said at a press conference.

CVD outcomes

In the Look AHEAD (Action for Health in Diabetes) trial, Evans and colleagues randomly assigned 5,145 overweight and obese patients with type 2 diabetes at 16 centers in the United States to an intensive lifestyle intervention promoting weight loss or a combination of diabetes support and education. The intervention included decreased caloric intake and increased physical activity. A composite of death from CV causes, nonfatal MI, nonfatal stroke or hospitalization for angina during a maximum of 13.5 years follow-up comprised the primary endpoint.

The trial was terminated early based on futility at a median follow-up of 9.6 years, according to Rena Wing, PhD, chair of Look AHEAD and professor of psychiatry and human behavior at the Alpert Medical School, Brown University. Patients in the intervention group experienced greater weight loss, when compared with the control group. Mean weight loss was 8.6% vs. 0.7% for the intervention and control groups, respectively, at 1 year and 6% vs. 3.5% at the study’s conclusion. Further, data linked the intensive lifestyle intervention to greater decreases in glycated hemoglobin, greater improvements in fitness and overall CV risk factors, with the exception of LDL cholesterol levels, vs. the control group.

However, results indicated that the primary outcome was not significantly different between the groups, with the primary outcome occurring in 403 patients (1.83 events per 100 person-years) in the intervention and 418 (1.92 events per 100 person years) in the control study arms. These data translated to an HR of 0.95 (95% CI, 0.83-1.09) in the intervention group.

“Look AHEAD showed that participants with diabetes can lose weight and maintain it,” Wing said. “This weight loss has many beneficial effects on glycemic control and CVD risk factors; however, it did not affect the risk of CVD.”

Complications of diabetes

Although the intensive lifestyle intervention did not reduce the risk for CVD events, William Knowler, MD, PhD, MPH, of the diabetes epidemiology and clinical research section at the NIDDK, said patients experienced improvements in other common complications of diabetes.

Over the 10 years of the study, advanced kidney disease developed in 172 participants in the diabetes support and education group compared with 123 in the intensive lifestyle intervention group. The annual rate at which this degree of kidney disease developed was 31% lower in the weight loss group, Knowler said, with no significant difference in the intervention’s effects in subgroups according to age, race/ethnicity, duration of diabetes or other medical conditions. The intervention, however, was significantly more effective in women than in men.

The researchers also evaluated two other complications of diabetes: retinopathy and neuropathy. The rate of self-reported retinopathy was 14% lower in the weight loss group, but there were no significant difference between groups in symptoms of neuropathy, according to Knowler.

“The intensive lifestyle weight-loss intervention substantially reduced the development of advanced kidney disease,” Knowler said at the press conference. “Based on other studies showing this to be a major factor associated with higher mortality rates in diabetic persons, such an effect, if it persists long-term, might eventually result in improved quality of life and longevity.”

Quality of life measures

Lucy Faulconbridge, PhD, assistant professor of psychology and director of research at the Center for Weight and Eating Disorders, Perelman School of Medicine at the University of Pennsylvania, said the intervention ameliorated depressive symptoms and improved quality of life, as well.

The researchers compared incidence rates of new cases of depression between the intervention and control groups.

“We found that participants in the intervention group were 20% less likely than those in the diabetes support and education group to develop symptoms of depression over the course of the study, suggesting that weight loss was protective against developing depression in this population,” Faulconbridge said.

Results revealed incidence rates of 17.5% in the intervention group and 21% in the control group at the end of the study. This difference, she said, was statistically significant. The researchers also examined resolution of significant symptoms of depression among study participants but found no differences, with remission rates of about 85% in both groups. Use of antidepressant medications also did not differ over the course of the study.

Physical health-related quality of life also appeared to be significantly better in the intervention group than the control group during the first 8 years of the study, although it declined in both groups over the 10 years as the participants aged, according to Faulconbridge. There was also a 3.1% difference between study arms in physical health-related quality of life across the entire trial, indicating that this type of intervention may mitigate the effects of aging on physical health-related quality of life. However, the researchers observed no significant differences in mental health-related quality of life measures.

“The take home message is that participation in this 10-year intensive lifestyle weight loss intervention protected overweight or obese individuals with type 2 diabetes from developing potentially significant symptoms of depression as well as impairments in quality of life,” Faulconbridge said.

Cutting costs

The intensive lifestyle intervention yielded financial benefits as well, according to Henry A. Glick, PhD, health economist from the Perelman School of Medicine at the University of Pennsylvania.

“Compared to the diabetes support and education group, the intensive lifestyle intervention reduced the average number of hospitalizations per year and the average number of medications per year,” he said at the press conference. “Hospitalizations were reduced by 11.9% from 0.193 to 0.17 hospitalizations per year, which translated into savings of $294 per year and $2,600 discounted over 10 years.”

Moreover, the number of medications was reduced by 6.3% from 4.9 to 4.6 medications per year, translating into a savings of $278 per year and $2,487 discounted over 10 years. Average costs per year were $8,807 for the control group vs. $8,205 for the intervention group, leading to a significant reduction of $602 per year and $5,378 discounted over 10 years.

Significant reductions in hospitalizations occurred mainly among CV and pulmonary hospitalization, and significant reductions in medications occurred mainly among diabetes, lipid-lowering and antihypertensive medications, according to Glick.

The intervention treatment effect did significantly differ for outpatient medications and total costs among those with and without a history of CVD. Among participants with no history of CVD, the intervention significantly decreased outpatient medication and total costs compared with the control group. Among those with a history of CVD, however, the intervention increased outpatient costs and had no effect on medication or total costs.

“Look AHEAD is one of, if not the first, randomized trial of weight loss and exercise that documents significant, long-term reductions in hospitalizations and medical costs,” Glick said.


In an accompanying editorial also published in the New England Journal of Medicine, Hertzel C. Gerstein, MD, of the department of medicine and Population Health Research Institute at McMaster University, said the findings suggest that weight loss may not mitigate significant CV risks but confer other benefits for patients with type 2 diabetes.

“[The researchers] can clearly assert that changes in activity and diet safely reduce weight, reduce the need for and cost of medications, reduce the rate of sleep apnea, improve well-being, and (in some cases) achieve a diabetes remission,” he wrote.

“With respect to cardiovascular outcomes, inspection of the confidence intervals should allow clinicians to reassure their patients that intensive lifestyle interventions are unlikely to cause harm and may provide a modest benefit. However, even with no clear evidence of cardiovascular benefit, the Look AHEAD investigators have shown that attention to activity and diet can safely reduce the burden of diabetes and have reaffirmed the importance of lifestyle approaches as one of the foundations of modern diabetes care.” – by Melissa Foster

For more information:

Look AHEAD Research Group. N Engl J Med. 2013;doi:10.1056/NEJMoa1212914.

Gerstein HC. N Engl J Med. 2013;doi:10.1056/NEJMe1306987.

Clark JM. Primary results of the Look AHEAD randomized controlled trial of a lifestyle intervention in overweight and obese individuals with type 2 diabetes. Presented at: ADA Scientific Sessions; June 21-25, 2013; Chicago.