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Weight Loss Intervention Fails to Reduce Cardiovascular Events in Type 2 Diabetes, but Has Positive Effect on Other Measures

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Although an intensive lifestyle intervention (ILI) designed for weight loss did not reduce the risk of cardiovascular (CV) events after a decade in overweight/obese patients with type 2 diabetes compared with diabetes support and education (DSE), it did reduce the risk of the development of advanced kidney disease and depression, and it resulted in a lower rate of hospitalizations.

These findings from the Look AHEAD (Action for Health in Diabetes) study were presented at the 73rd Scientific Sessions of the American Diabetes Association held in Chicago. The CV endpoints of the trial were published online on June 24, 2013, in the New England Journal of Medicine.

Look AHEAD was conducted at 16 centers in the United States. It enrolled 5145 overweight and obese patients with type 2 diabetes who were randomly assigned to ILI promoting weight loss or DSE.

ILI was aimed at achieving and maintaining weight loss of at least 7% by focusing on reduced caloric intake and increased physical activity. The program included group and individual counseling sessions over the course of the trial. The calorie goal was 1200 kcal to 1800 kcal per day and the physical activity goal was at least 175 minutes of moderate-intensity physical activity per week.

DSE featured 3 group sessions per year focused on nutrition, exercise, and social support during the first 4 years, subsequently reduced to 1 session annually.

Medication changes were made by the subjects’ own physicians.

The primary endpoint was the composite outcome of death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for angina during a maximum of 13.5 years of follow-up.

The interventions were stopped prematurely after a maximum follow-up of 11 years (median, 9.6 years); short of the planned maximum follow-up of 13.5 years on the basis of futility for finding a difference between groups on the primary outcome.

Patients in the ILI group lost more weight compared with the DSE group. At 1 year, mean weight loss was 8.6% versus 0.7% for the ILI and DSE groups, respectively, said Rena Wing, PhD, professor of psychiatry and human behavior at the Alpert Medical School of Brown University in Providence, Rhode Island. By the end of the study, mean weight loss was 6% and 3.5% in the ILI and DSE groups, respectively. Improvement in fitness as measured in METS was significantly greater with ILI.

“This weight loss had many beneficial effects on glycemic control and on CV risk factors,” she said. “However, it did not affect the risk of CV disease.”

Patients assigned to ILI had greater reductions in hemoglobin A1c (HbA1c) despite less use of insulin, and sustained improvements in systolic blood pressure (SBP) and high-density lipoprotein cholesterol levels relative to those assigned to DSE. Levels of low-density lipoprotein (LDL) cholesterol, however, decreased significantly more in the DSE participants, who also had greater use of statins, said Dr Wing, who added that the use of antihypertensive drugs was also significantly greater in the DSE group.

Occurrence of the primary outcome was not significantly different between the groups—1.83 events per 100 person-years in the ILI group versus 1.92 per 100 person-years in the DSE group, for a hazard ratio of 0.95 (P = .51). ILI and DSE did not differ significantly in the event rates for death from all causes of CV causes, MI, hospitalized angina, stroke, congestive heart failure, and rates of carotid endarterectomy and coronary artery bypass graft surgery.

The education sessions and the greater use of statins in the DSE group, along with intensive medical management of CV risk factors, may have obscured differences in outcomes between the 2 groups, Dr Wing explained. The education provided to the control group may also have reduced any differences in events between the 2 arms.

“CV risk factors were improved particularly in the first year of the trial, and although some of these differences remained statistically significant, the difference between the 2 arms did lessen over the course of the trial,” said Dr Wing. “It’s possible that we needed sustained differences in CV risk factors to produce a difference in CV events. And for LDL cholesterol, the control group had greater lowering than the intervention group.”

Rate of Microvascular Complications Reduced with ILI

As part of Look AHEAD, the subjects’ level of chronic kidney disease was classified using estimated glomerular filtration rate and measures of albumin.

Over the course of the study, advanced kidney disease developed in 172 participants in the DSE group versus 123 in the ILI group, corresponding to a 31% reduction in risk with ILI (P = .002), reported William Knowler, MD, a research physician at the National Institute for Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona. There were no significant difference between the interventions’ effects according to age, race/ethnicity, duration of diabetes, or other medical conditions, although ILI was significantly more effective in women than in men (P = .02).

The rate of self-reported retinopathy was 14% lower in the ILI group relative to DSE (P = .027); there was no significant difference between groups in the occurrence of symptoms of neuropathy (P = .23).

Most Quality of Life Measures Favor ILI

ILI ameliorated the symptoms of depression and improved health-related quality of life (QoL) measures, said Lucy Faulconbridge, PhD, director of research at the Center for Weight and Eating Disorders, Perelman School of Medicine, at the University of Pennsylvania in Philadelphia.

The rate of incident depression as determined by scores on the Beck Depression Inventory was 20% lower in subjects randomized to ILI compared with DSE (17.5% vs .20.9%; P = .0019), “suggesting that weight loss was protective against development of depression,” she said.

Resolution of significant symptoms of depression was not different between the groups, with remission rates of 83.7% in the ILI group and 87.2% in the DSE group. Initiation of antidepressant medications also did not differ over the course of the study (23% with ILI vs 21.3% with DSE; P = .2315).

Physical health-related QoL was significantly better in the ILI group versus the DSE group during the first 8 years of the study, although the Physical Component Summary score on the Short Form-36 declined in both groups as the participants aged.

ILI Reduced Hospitalization Rate

The rate of hospitalizations was 11.9% lower in the ILI group relative to the DSE group (0.193 vs 0.17 hospitalizations per year; P = .003), which translated into an annual reduction in cost of $294 (P = .03), said Henry A. Glick, PhD, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

Last modified: August 30, 2021