Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomised clinical trial

Abstract

Background: Long-term effects of behavioural weight loss interventions on diabetes complications are unknown. In a secondary analysis of the Look AHEAD (Action for Health in Diabetes) multicentre randomised clinical trial, we assessed whether an intensive lifestyle intervention (ILI) affects the development of nephropathy in people with type 2 diabetes.

Methods: Overweight or obese people aged 45-76 years with type 2 diabetes were randomly assigned (1:1) to ILI or to a diabetes support and education (DSE) group by a central web-based data management system, stratified by clinical centre and blocked with random block sizes. The ILI was designed to achieve and maintain weight loss through reduced caloric consumption and increased physical activity. The interventions were terminated early because of absence of effect on the primary outcome of cardiovascular disease events in the main Look AHEAD trial. Albuminuria and estimated glomerular filtration rate were prespecified as two of many other outcomes and were assessed from baseline until the interventions ended. They were combined post hoc to define the main outcome for this report, very-high-risk chronic kidney disease (CKD), based on the 2013 Kidney Disease Improving Global Outcomes (KDIGO) classification. Outcomes assessors and laboratory staff were masked to treatment, but participants and interventionists were not masked. Time-to-event data were analysed by intention to treat by the Kaplan-Meier method and proportional hazards models. The Look AHEAD trial is registered with ClinicalTrials.gov, NCT00017953.

Findings: Of the 5145 participants randomly assigned in the Look AHEAD trial (2570 to ILI and 2575 to DSE), analyses for very-high-risk CKD were done in 2423 (94%) of patients in the ILI group and 2408 (94%) of those in the DSE group. After a median of 8·0 years (IQR 7·9-9·9) of follow-up, the incidence of very-high-risk CKD was lower in the ILI group than in the DSE group, with incidence rates of 0·91 cases per 100 person-years in the DSE group and 0·63 per 100 person-years in the ILI group (difference 0·27 cases per 100 person-years, hazard ratio 0·69, 95% CI 0·55-0·87; p=0·0016). This effect was partly attributable to reductions in bodyweight, HbA1c, and systolic blood pressure. There were no safety concerns regarding kidney-related adverse events.

Interpretation: Weight loss should be considered as an adjunct to medical treatments to prevent or delay progression of CKD in overweight or obese people with type 2 diabetes.

Funding: National Institute of Diabetes and Digestive and Kidney Diseases.

Figure 1

Flowchart showing recruitment, randomization, and follow-up.

Figure 2

Cumulative incidence of very-high-risk CKD by treatment group through year 10. Too few observations were available beyond year 10 for reliable estimates. DSE is the Diabetes Support and Education group, and ILI is the Intensive Lifestyle Intervention group. The numbers of persons at risk at the beginning of the even-numbered years since randomization are shown. The hazard ratio (ILI vs. DSE) is 0.69, 95% confidence interval = 0.55 to 0.87, p=0.002.

Figure 3

Numbers of first occurrence of very-high-risk CKD and incidence rates (events per 100 person-years) by treatment group, hazard ratios, and treatment by subgroup interaction tests by subgroups defined by age, sex, race/ethnicity, body mass index (BMI, kg/m²), history of CVD, insulin use, and diabetes duration. The p-values denoted “*” are for the tests of interaction between the subgroups and the intervention group. The dotted reference line refers to the overall hazard ratio. DSE is the Diabetes Support and Education group, and ILI is the Intensive Lifestyle Intervention group. The race/ethnicity variables are abbreviated as: AA=African American, AI=American Indian. Further details are in a footnote to Table 1.