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.
Bibliographical noteFunding Information:
JPB has received grants from the National Institutes of Health (NIH). GAB has received grants from the NIH; personal fees from Herb life Nutrition Institute, Jason Pharmaceuticals, and Theracos Pharmaceuticals; personal fees for lectures from the American Association of Clinical Endocrinologists; and royalties for Handbook of obesity from Informa Healthcare, for A guide to treatment of obesity from CRC Press, and for Up-to-date, an electronic source of information primarily for health professionals, from Wolters Kluwer. LC has received personal fees from Medifast and Vivus. JMC has received grants from the NIH. FLG has received grants from the NIH and the NIDDK; personal fees from Diabetic Living, Jenny Craig, Baronova, Basic Research, Eisai, General Nutrition Corporation, Japan Tobacco, Microbiome Therapeutics, Novo Nordisk, Obalon Therapeutics, Orexigen Therapeutics, Pam Lab, Plensat, and Zafgen. FLG also holds the following US patents: 5952026, 6417231, 7150141, 7709031, and 8334000. HPH has received grants from the NIDDK. ESH has received grants from the NIH and NIDDK. JMJ has received grants from the NIH and American Heart Association; and personal fees from Kaiser Permanente. SEK has received grants from the NIH. MK has received grants from Sanofi. CEL has received grants from the NIH, NIDDK, and Novo Nordisk. AP has received grants from the NIH, NIDDK, and Medtronic Foundation; personal fees from Novo Nordisk, from AstraZeneca, Bristol-Myers Squibb, Lilly Pharmaceuticals, and Sanofi. XP-S has received grants from Novo Nordisk and personal fees from Zafgen, Weight Watchers, Johnsons & Johnson, and Novo. TAW has received personal fees from Nutrisystem, Orexigen Pharmaceutical, Novo Nordisk, Boehringer Ingelheim, and Guilford Press; and grants from Novo Nordisk, Weight Watchers, and NutriSystem. WCK, JLB, AGB, HC, CE, ME, JPF, SPG, EWG, JOH, VSH, RWJ, KCJ, AEK, JK, AK, BJM-C, SM, MGM, DMN, EN, JP, HP, LEW, DFW, RRW, HW, and SZY declare no competing interests.
We acknowledge the contributions of Frederick Brancati and Richard Rubin, who passed away during the completion of this manuscript. Both colleagues were fundamental to the successful development and implementation of the trial. This study was funded by the NIH and other Department of Health and Human Services agencies through cooperative agreements with the NIDDK : DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992 . Additional funding was provided by the National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; and the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the NIDDK. The Indian Health Service (IHS) provided personnel, medical oversight, and use of facilities. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the IHS or other funding sources. Additional support was received from the Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (GCRC) (M01RR000056), the Clinical Translational Research Center (CTRC) funded by the Clinical and Translational Science Award (UL1 RR 024153) and NIH grant (DK 046204); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C Bartter General Clinical Research Center (M01RR01346). The following organisations have committed to make major contributions to Look AHEAD: FedEx Corporation; Health Management Resources; LifeScan, a Johnson & Johnson Company; OPTIFAST of Nestle HealthCare Nutrition; Hoffmann-La Roche; Abbott Nutrition; and Slim-Fast Brand of Unilever North America. Some of the information contained herein was derived from data provided by the Bureau of Vital Statistics, New York City Department of Health and Mental Hygiene.
© 2014 Elsevier Ltd.