June 24, 2013

CHICAGO, Illinois — Physicians looking forward to the Action for Health Diabetes (Look AHEAD) study, a trial comparing an intensive lifestyle-intervention program aimed at achieving and maintaining weight loss and fitness in patients with type 2 diabetes, need wait no longer as researchers presented the final results of the trial today at the American Diabetes Association (ADA) 2013 Scientific Sessions [1].

As reported by heartwire in October, the 5145-patient National Institutes of Health (NIH)–sponsored trial was stopped for futility after a median follow-up of 9.6 years when researchers failed to show that weight loss did not reduce the risk of cardiovascular events in overweight or obese adults with type 2 diabetes.

The primary end point, which was the first occurrence of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for angina, occurred in 403 patients in the intervention arm and 418 patients in the control arm. This difference was not statistically significant. In addition, there was no statistically significant difference between the treatment arms with regard to secondary outcomes.

Dr William Knowler (National Institute of Diabetes and Digestive Kidney Diseases [NIDDK], Phoenix, AZ), one of the investigators of the Look AHEAD study, said the goal in presenting the results is to give information to patients and their physicians. "Weight loss does have many long-term benefits," said Knowler, "but one of them, at least over this 10-year period, is not a reduction in the risk of heart attack and stroke. So people shouldn't embark on a weight-loss program with that expectation."

Knowler presented data from the trial showing that the intensive lifestyle intervention was associated with a 31% reduction in the risk of advanced kidney disease. As defined, the classification of advanced kidney disease used in the trial, which was based on a classification system recommended by the National Kidney Foundation, is associated with a high risk of progression to kidney failure, cardiovascular disease, or death. There was a significant 14% reduction in the risk of diabetic retinopathy with the intensive lifestyle intervention, but no difference in the rate of diabetic neuropathy between the groups.

In addition to being presented at the ADA meeting, the study is now published online in the New England Journal of Medicine.

Some Beneficial Aspects to Lifestyle Changes

The Look AHEAD trial showed there was some benefit of reducing calories and exercising more, however, with investigators reporting that patients in the intensive lifestyle-intervention arm had significantly greater weight loss than the patients in the control arm. At one year, patients in the lifestyle-intervention arm lost 8.6% of their body weight compared with just 0.7% in the control arm. As time went on, the weight-loss differences narrowed but remained statistically significant. At the study's completion, the mean weight loss from baseline was 6.0% in the treatment arm vs 3.5% in the control arm (which comprised diabetes support and education).

Fitness levels were also improved, as were other markers of metabolic risk, such as glycated hemoglobin levels and systolic blood pressure. LDL cholesterol levels, on the other hand, were not improved with the lifestyle-intervention program.

Dr Rena R Wing (Brown University, Providence, RI), the lead investigator of Look AHEAD, said the weight loss achieved in the trial was some of the best ever reported in the clinical-trial literature. Stopped at 9.6 years, she said, Look AHEAD answered its primary research question--that an intensive lifestyle intervention, one that recommended 1200 to 1800 calories per day and 175 minutes of moderate-intensity physical activity per week, did not reduce the risk of cardiovascular events.

"Look AHEAD showed that participants with diabetes can lose weight and maintain it," said Wing. "This weight loss has many beneficial effects: on glycemic control and on cardiovascular disease risk factors. However, it did not affect the risk of cardiovascular disease."

Despite the lack of benefit of clinical outcomes, Dr Lucy Faulconbridge (University of Pennsylvania, Philadelphia) presented data, not unlike the renal outcomes, showing weight loss does have an upside. Faulconbridge reported that the lifestyle intervention resulted in a significant 20% reduction in cases of new depression as well as significant improvements in the quality of life. In analyzing patients who had depression at baseline, the researchers found no significant difference between treatment arms with regard to the resolution of depression.

"We know that diabetes and obesity are each independently associated with high rates of morbidity and mortality, as well as with an increased risk of depression and [reduced] quality of life," she said during a press conference at the ADA. Depression in diabetic individuals, she added, appears to be particularly harmful and is associated with poor self-management, persistent hyperglycemia, and high rates of diabetes-related complications. "Reducing depression and improving quality of life in obese diabetic individuals is a crucial clinical objective."

To heartwire , Knowler said that the improvement in the microvascular outcomes but not clinical events is not surprising, especially since the relationship between reductions in blood pressure and better glycemic control are stronger with regard to these outcomes than macrovascular events.

Why No Clinical Impact on Cardiovascular Disease?

In speculating as to why the study failed to show a difference in cardiovascular outcomes, the Look AHEAD investigators note that the differential weight loss between the intervention and control arms averaged 4.0% over the course of the study but just 2.5% at the end. Such a small difference might not have been sufficient to have an effect on cardiovascular events.

In addition, "the intensification of medical management of cardiovascular risk factors in routine medical care in the two study groups may have made the relative benefit of the intensive lifestyle intervention more difficult to demonstrate," they add. In Look AHEAD, the use of antihypertensive medications, statins, and insulin was significantly lower in the intervention arm than in the control arm.

In an editorial accompanying the published study [2], Dr Hertzel Gerstein (McMaster University, Hamilton, ON) said that such differences in the use of cardioprotective drugs might have had an impact on the lack of effect on clinical outcomes. He added that while lifestyle interventions might have a real effect on cardiovascular outcomes, the reduction in risk is likely in the 10% to 15% range, which would be similar to glucose-lowering therapy.

Overall, Gerstein said that while the study showed no benefit on clinical outcomes, clinicians can tell their patients that a lifestyle intervention, one that reduces caloric consumption and increases physical activity, can safely lower weight and improve fitness. In addition, other studies have shown that lifestyle changes can decrease the rate of sleep apnea, improve well-being, and "in some cases achieve a diabetes remission."

Dr Mary Evans (NIDDK, Bethesda, MD), the project scientist for Look AHEAD, said that if current trends continue, nearly one in three Americans could be diabetic by 2050. Today, roughly 26 million people are diabetic, or 8% of the population. These rates are even higher in racial/ethnic minorities, she said. At present, 70% of the US population is either overweight or obese, something she labeled an epidemic constituting a public-health crisis.


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