Association of Body Weight Time in Target Range With the Risk of Kidney Outcomes in Patients With Overweight/Obesity and Type 2 Diabetes Mellitus

One of the driving forces behind the escalating prevalence of type 2 diabetes mellitus (T2DM) is the global pandemic of obesity (1). The twin epidemics of T2DM and obesity are important factors contributing to the increase in chronic kidney disease (CKD) (2–4). Obesity and weight management have been reported to be associated with improved outcomes in adults with T2DM (5). Behavioral lifestyle weight loss intervention is an effective noninvasive weight loss strategy. The Look AHEAD (Action for Health in Diabetes) trial, the largest multicenter clinical trial designed to examine the effect of an intensive lifestyle intervention (ILI) (here, achieving and maintaining weight loss of ≥7% by focusing on reduced caloric intake and increased physical activity) on the prevention of cardiovascular disease (CVD) in individuals with overweight/obesity and T2DM, showed that the incidence of very-high-risk CKD was significantly reduced in the ILI group, compared with the diabetes support and education (DSE) group (6). Notably, a subset of participants in the Look AHEAD trial typically recovered one-third of their weight loss within the first year of treatment, and returned their weight to baseline levels within 3–5 years (7). Weight regain results in the reduction or loss of cardiometabolic benefits associated with weight loss (8,9). Therefore, we speculate that long-term weight maintenance within a certain target range is more beneficial for kidney health.

Body weight time in target range (TTR) is a novel metric of body weight management. It is the proportion of time that body weight is within a specified range. It incorporates average body weight values and body weight variability over a period of time to quantify weight control. However, the association between body weight TTR and the kidney outcomes remains unknown. To address this knowledge gap, using data from the Look AHEAD trial, we assessed the association between body weight TTR (a weight loss of ≥7% from baseline) and kidney outcomes in people with overweight/obesity and T2DM.

The details about the design and methods of the Look AHEAD trial have been described elsewhere (10,11). In brief, the Look AHEAD trial, including 16 clinical sites in the United States, is a multicenter, randomized controlled trial that evaluated the effects of an ILI versus DSE on cardiovascular morbidity and mortality among 5,145 adults with a BMI >25 kg/m² (or >27 kg/m² if taking insulin) and a T2DM diagnosis.

Eligible patients were randomly assigned to participate in ILI or to receive DSE (control group). The goal of the ILI was to achieve and maintain weight loss of ≥7% through reduced caloric intake and increased physical activity. The program included both group and individual counseling sessions, occurring weekly during the first 6 months, with decreasing frequency over the course of the trial. DSE featured three group sessions per year that focused on exercise, diet, and social support during years 1 through 4. In subsequent years, the frequency was reduced to one session annually.

This study is a post hoc analysis of the Look AHEAD trial. Of the total 5,145 participants, 244 who had consent restrictions were excluded from the present study. Of the remaining 4,901 participants, those who had fewer than three weight measurements during the first 4 years of the study; had self-reported kidney failure; had baseline estimated glomerular filtration rate (eGFR) data missing, or baseline eGFR levels <60 mL/min/1.73 m², or had no eGFR measurements after the first 4 years of the study; or developed composite kidney outcome during the first 4 years were further excluded. Therefore, a total of 3,601 participants were included in the final analysis (Supplementary Fig. 1). Participants included in the analysis did not differ in in population characteristics from those not included (n = 1,300) (Supplementary Table 1).

The Look AHEAD trial was approved by the local institutional review boards, and written informed consent was obtained from all participants.

At annual visits, certified staff members measured participants’ weight and waist circumference, and assessed medication use (10). Weight and height were measured twice separately with a digital scale and a standard range finder, and the average of these repeated measurements was used for analysis.

The primary exposure of interest was body weight TTR during the first 4 years, defined as the proportion of time during the first 4 years that body weight was within the weight loss target (a weight loss of ≥7% from baseline). The first 4 years were chosen because during this time, more weight measurements were available to calculate the individual TTR, and participants had more frequent individual supervision and group sessions. TTR was calculated by linear interpolation using the Rosendaal method (12,13). The data on the first 4 years of body weight TTR distribution of participants in the two groups are shown in Supplementary Fig. 2. Owing to the large proportion of participants who had a TTR of zero in the first 4 years, participants with a TTR of 0% were used as the reference category in the analysis of this study, and the remaining participants were divided by tertiles of body weight TTR during the first 4 years.

Information on age, sex, race/ethnicity, smoking status, alcohol use status, education, duration of diabetes, medical history, and medication use was ascertained by standardized questionnaires. Mean body weight is the mean of weight measurements over the previous 4 years, and body weight variability is the SD of these weight measurements.

Blood samples were obtained after a fast of ≥12-h fast, and laboratory tests were performed at the Central Biochemistry Laboratory (Northwest Lipid Research Laboratories, University of Washington, Seattle, WA). Serum and urine creatinine concentrations were measured with the Roche Creatinine Plus enzymatic reagent on a Roche Modular Pautoanalyzer. The value of the assay calibrator is traceable to the isotope dilution mass spectrometry reference method. These measures were performed annually through year 4 and every other year thereafter. Urine albumin to creatinine ratio (UACR) was calculated from urine albumin and creatinine concentrations. The eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration equation based on serum creatinine and includes race (Black versus non-Black individuals) (14).

The primary outcome was the composite kidney outcome, defined as a decrease in eGFR of ≥30% from baseline and to a level <60 mL/min/1.73 m² at follow-up visit, or end-stage kidney disease (ESKD; eGFR <15 mL/min/1.73 m² or self-reported kidney failure) (15,16).

The secondary outcome was a doubling of UACR, defined as a doubling of UACR from <10 mg/g to ≥10 mg/g (16). This outcome is defined because, in people with T2DM, even UACR levels of 10–30 mg/g may increase the risk of cardiovascular events compared with UACR levels of 10 mg/g (17). A total of 1,592 participants who had weight measurements at least three times during the first 4 years of the study, had a UACR <10 mg/g at baseline, had UACR measurements after the first 4 years of the study, and did not develop a doubling of UACR during the first 4 years of the study were included for the analysis of a doubling of UACR (Supplementary Fig. 3).

Baseline characteristics were presented as the mean ± SD or median (25, 75th quantiles) for continuous variables and number (percent) for categorical variables. The differences in population characteristics according to the categories of body weight TTR during the first 4 years (0%, and tertiles of body weight TTR: >0% to <29.9% [tertile 1], 29.9% to <69.7% [tertile 2], and 69.7% to <100% [tertile 3]) were compared using ANOVA tests, Kruskal–Wallis tests, or χ² tests, accordingly.

The follow-up time for each participant was defined as the middle time between the date of follow-up visit at which the study outcome was first diagnosed and the most recent follow-up visit date before the diagnosis, the last examination when the participant was lost from the study, or the end of follow-up (Y10), whichever occurred first. The cumulative rate of the primary outcome according to the categories of body weight TTR during the first 4 years was estimated using the Kaplan-Meier method. The association of body weight TTR during the first 4 years with subsequent study outcomes was estimated using hazard ratios (HRs) and 95% CIs derived from Cox proportional hazards regression models with adjustments for age, sex, race, intervention group, education levels, systolic blood pressure (SBP), smoking and alcohol use status, eGFR, UACR, low-density lipoprotein cholesterol (LDL-C), fasting blood glucose level, history of CVD, insulin use, antihypertensive drug use, and diabetes duration at baseline; as well as mean body weight and body weight variability during the first 4 years. Proportional hazard assumptions for Cox models were verified using Schoenfeld residuals; no violation of this assumption was detected. Restricted cubic splines with three knots were used to explore the dose–response association between body weight TTR during the first 4 years expressed as the continuous variable (with 0% as the reference) and composite kidney outcome with adjustments for the covariates described above.

As additional exploratory analyses, stratified analyses and interaction testing were used to evaluate possible modifications of the association between body weight TTR during the first 4 years and composite kidney outcome in various subgroups, including age (<60 or ≥60 years), sex (male or female), intervention group (ILI or DSE), SBP (<140 or ≥140 mmHg), eGFR (<90 or ≥90 mL/min/1.73 m²), UACR (<30 or ≥30 mg/g), diabetes duration (<5 or ≥5 years), insulin use (no or yes), and history of CVD (no or yes) at baseline, as well as mean body weight (<96 [median] or ≥96 kg), and BMI (<34 [median] or ≥34 kg/m²) during the first 4 years.

A series of sensitivity analyses were performed. First, the association of mean body weight and body weight variability during the first 4 years and the percentage of body weight loss from baseline to year 4 with composite kidney outcome was examined. Second, we examined the association of body weight TTR during the first 4 years with very-high-risk CKD, the primary outcome in the parent Look AHEAD study (6), which was defined by eGFR <30 mL/min/1.73 m² regardless of UACR; or eGFR <45 mL/min/1.73 m² and UACR ≥30 mg; or eGFR <60 mL/min/1.73 m² and UACR >300 mg/g; or received renal replacement therapy regardless of measured eGFR or UACR (6) and a doubling of UACR, which was redefined as a doubling of UACR from <30 mg/g to ≥30 mg/g. Third, according to the American Diabetes Association’s Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Care in Diabetes–2023 clinical guidelines (18), body weight TTR was recalculated as the proportion of time during the first 4 years that body weight was within a weight-loss target of ≥5% from baseline. Fourth, we further adjusted for the average levels of several variables, including SBP, eGFR, UACR, LDL-C, and fasting blood glucose level during the first 4 years in the regression models. Fifth, only the primary outcome that was reconfirmed using a second eGFR measurement during the follow-up period was included in the analysis. Sixth, body weight TTR was recalculated on the basis of all weight measurements taken before the study outcome occurred or the end of follow-up. Data were analyzed with R, software version 4.2.2 (https://www.r-project.org), and a two-tailed P < 0.05 was regarded as being statistically significant in all analyses.

The data underlying this article are available in National Institute of Diabetes and Digestive and Kidney Diseases Central Repository (https://repository.niddk.nih.gov/). Study materials that support the findings of this study will be available from the corresponding authors on request.

Of the 3,601 participants included, the mean age (SD) was 59.0 (6.6) years, and 2,140 (59%) were women. Participants with higher TTR were older, more likely to be White and from the ILI group, had lower fasting glucose levels and LDL-C concentrations at baseline, and had lower mean body weight levels during the first 4 years (Table 1).

During a median follow-up duration of 8.0 years (30,436 person-years), 435 participants reached the composite kidney outcome after the first 4 years, including 415 cases of eGFR decline of ≥30% and to a level <60 mL/min/1.73 m², and 20 cases of ESKD.

Body weight TTR during the first 4 years was inversely associated with the subsequent risk of composite kidney outcome (per SD increment; adjusted HR 0.81; 95% CI 0.70–0.93; overall P < 0.001; P for nonlinearity = 0.576) (Fig. 1). Accordingly, when body weight TTR during the first 4 years was assessed as categories, the adjusted HRs (95% CI) of composite kidney outcome were 1.00 (reference), 0.73 (0.54–1.00), 0.71 (0.52–0.99), and 0.54 (0.36–0.80) for participants with body weight TTR of 0%, >0% to <29.9%, 29.9% to <69.7%, and 69.7% to <100%, respectively (Table 2). Cumulative incidence curves also showed that lower body weight TTR was associated with a higher risk of composite kidney outcome (Supplementary Fig. 4).

Mean body weight and body weight variability during the first 4 years were not significantly associated with the risk of composite kidney outcome (Supplementary Table 2). However, there was a significant, nonlinear, L-shaped association between the percentage of body weight loss and composite kidney outcome, with an inflection point of ∼5% of body weight loss (Supplementary Fig. 5). That is, when the percentage of body weight loss was less than ∼5%, the percentage of body-weight loss was negatively associated with the composite kidney outcome, and when the percentage of body-weight loss was >5%, the risk of composite kidney outcome reached a plateau. Of note, including the mean body weight, body weight variability during the first 4 years, and the percentage of body weight loss from baseline to year 4 in the regression models did not materially change the association between body weight TTR during the first 4 years and composite kidney outcome risk (Supplementary Table 3), suggesting that the association between body weight TTR and composite kidney outcome was independent of these three standard weight measures.

Moreover, although some results were not significant, compared with participants with body weight TTR during the first 4 years of 0%, a lower risk of a doubling of UACR was found in those with body weight TTR of >0% to <29.4% (adjusted HR 0.91; 95% CI 0.68–1.23), 29.4% to <73.6% (adjusted HR 0.88; 95% CI 0.63–1.24), and 73.6% to <100% (adjusted HR 0.58; 95% CI 0.38–0.88) (Table 2).

A stronger inverse association of body weight TTR during the first 4 years with composite kidney outcome was found among participants in the ILI group (per SD increment; adjusted HR 0.77, 95% CI 0.66–0.89; versus DSE group: adjusted HR 1.00, 95% CI 0.79–1.27; P for interaction = 0.048) (Fig. 2). Consistently, when body weight TTR during the first 4 years was assessed as categories in different intervention groups, the inverse association of body weight TTR with the risk of composite kidney outcome (Supplementary Table 4) and a doubling of UACR (Supplementary Table 5) was found in the ILI group but not in the DSE group.

None of other variables, including age, sex, SBP, eGFR, UACR, diabetes duration, insulin use, and history of CVD at baseline, as well as mean body weight and BMI during the first 4 years, significantly modified the association of body weight TTR during the first 4 years with the subsequent risk of composite kidney outcome (for all, P for interaction >0.05) (Fig. 2).

Among participants in the ILI group, compared with those with body weight TTR during the first 4 years of 0%, a significantly lower risk of a doubling of UACR from <30 mg/g to ≥30 mg/g was found in participants with body weight TTR of 81.8% to <100% (tertile 3; adjusted HR 0.59; 95% CI 0.35–0.99) (Supplementary Table 6). Moreover, among participants in the ILI group, those with body weight TTR during the first 4 years of 80.8% to <100% (tertile 3) had a nonstatistically significant lower risk of very-high-risk CKD (adjusted HR 0.41; 95% CI 0.15–1.13), compared with participants with a TTR of 0%, partly due to insufficient statistical power (Supplementary Table 7).

Further adjustments for the average levels of SBP, eGFR, UACR, LDL-C, and fasting blood glucose during the first 4 years (Supplementary Table 8), calculating TTR as the proportion of time during the first 4 years that body weight was within a weight loss target of ≥5% from baseline (Supplementary Table 9), defining the primary outcome with reconfirmation using a second eGFR measurement during the follow-up period (Supplementary Table 10), or calculating TTR on the basis of all weight measurements taken before the study outcome occurred or the end of follow-up (Supplementary Table 11) did not substantially change our findings.

In this post hoc analysis of the Look AHEAD trial, we found an inverse association between the body weight TTR during the first 4 years and the subsequent risk of composite kidney outcome, independent of the mean body weight and body weight variability during the first 4 years and the percentage of body weight loss from baseline to year 4. TTR represents an important measure of body weight control beyond the mean body weight, body weight variability, and the percentage of body weight loss, and predicts renal outcomes in people with overweight/obesity and T2DM. In this study, the weight loss target is a weight loss of ≥7% (primary analysis) and 5% (sensitivity analysis) from baseline, indicating that even a single-digit sustained weight loss can bring significant renal benefits.

The Look AHEAD trial showed that compared with DSE, ILI, which was designed to produce weight loss through caloric restriction and physical activity, reduced the incidence of very-high-risk CKD by 31% in individuals with overweight/obesity and T2DM (6). However, in the Look AHEAD trial, a subset of participants regained a third of their body weight within the first year of treatment and returned to baseline body weight within 3–5 years (7). Weight regain leads to a reduction or loss of cardiometabolic benefits associated with weight loss (8,9). Nevertheless, because the study by the Look AHEAD Trial Group (6) mainly focused on the effect of average weight loss on CKD risk and did not simultaneously consider the effect of weight change on CKD risk, the benefits of long-term maintenance of weight loss on the risk of CKD could not be fully assessed. Body weight TTR incorporates average body weight values and body weight variability over a period of time to quantify weight control. We speculate that higher body weight TTR may have more benefits for kidney health. This hypothesis has not been examined, to our knowledge.

The present study did show that a higher body weight TTR with a weight-loss target of ≥7% of initial weight, which is in line with the goal of the ILI in the Look AHEAD trial, is associated with a lower risk of subsequent composite kidney outcome and a doubling of UACR among participants in the ILI group. This association was independent of the mean body weight and body weight variability. Although the results were not significant, due to insufficient statistical power, similar results were found for very-high-risk CKD. These results suggest that although ILI significantly reduced the risk of CKD in the previous Look AHEAD study (6), a higher TTR needs to be further emphasized to maximize the benefits in reducing CKD risk when conducting ILI. Compared with the study end point of very-high-risk CKD, the composite kidney outcome used in the present study was also considered by previous studies to be a surrogate end point for kidney failure (15,16,19), which can identify more high-risk populations.

The mechanism by which weight loss leads to a lower risk of kidney outcomes may be related to reduced oxidative stress, inflammation, fibrosis, and lipotoxicity. The activation of reactive oxygen species as a result of obesity triggers a cascade of apoptotic enzymes and numerous inflammatory mediators, leading to glomerular podocyte damage and a disruption of the structural integrity of the glomerular filtration membrane barrier (20). Conversely, weight loss can improve inflammatory cytokines and oxidative stress markers in people with obesity with T2DM (21). Chronic activation of the renin-angiotensin system is a hallmark of CKD, and a 5% weight loss can lead to a significant reduction in the renin-angiotensin system in plasma and adipose tissue (22). In addition, weight loss improves insulin sensitivity and reduces lipotoxicity and energy stress caused by lipid accumulation in people with obesity with T2DM, which may further contribute to the reduced risk of CKD (23,24).

Of note, a stronger inverse association between body weight TTR during the first 4 years and composite kidney outcome was found in the ILI group, whereas no significant association was found in the DSE group. Similar trends were found for a doubling of UACR with different definitions and very-high-risk CKD. Regular exercise during a diet-induced weight loss program (the ILI group) could result in greater improvement in whole-body insulin sensitivity and muscle strength than matched weight loss achieved solely by calorie restriction (the DSE group) (25). Both insulin resistance (26,27) and reduced muscle function (28) are associated with a higher risk of CKD. Additionally, compared with the DSE group, the ILI group was prescribed a reduced-energy, low-fat diet and partial meal replacement (29). Improved diet quality may be another potential reason for the kidney health benefits in the ILI group. These findings highlight the importance of incorporating a healthy diet and exercise training into any weight loss program to maximize the health benefits of lifestyle therapies.

The Look AHEAD trial found that weight loss through caloric restriction, improved diet quality, and physical activity is feasible and beneficial for the health of participants with overweight/obesity and T2DM. Furthermore, there is growing evidence that pharmacological treatments and bariatric surgery also have substantial health benefits for individuals with obesity (30–32). These obesity management measures complement each other. A comprehensive intervention strategy that combines intensive lifestyle interventions with weight-loss treatments with different mechanisms may be more effective and have fewer side effects than monotherapy. Our study further emphasizes the importance of maintaining a high TTR during a weight loss program for health, providing a new important indicator for effective weight control.

Our study has some limitations. First, this was a post hoc analysis of data from a subset of participants in the Look AHEAD trial. Although the included (n = 3,601) and excluded (n = 1,300) populations had similar population characteristics and a series of covariates were adjusted in our analysis, there may still be selection bias and residual confounding. Second, in the Look AHEAD trail, participants’ body weight was measured annually, and body weight TTR was calculated on the basis of at least three body weight measurements during the first 4 years, which may not fully reflect the actual time spent within the target weight range. However, weight change may be a gradual process, and previous studies assessing the impact of weight change on study outcomes have also been based on annual weight data (33,34). Furthermore, given the novelty of the body weight TTR concept, our findings were just hypothesis-generating and should be interpreted with greater caution. Third, the small study sample size and small composite kidney outcome numbers substantially limit the power of the analyses.

In summary, our study showed that in participants with overweight/obesity and T2DM, a higher body weight TTR, with a weight loss target of ≥7% of initial weight induced by calorie restriction plus exercise training, was associated with a lower risk of composite kidney outcome, independent of the mean body weight, body weight variability, and the percentage of body weight loss. If further confirmed, body weight TTR may add incremental value to current, widely used body weight control indicators, and has important clinical importance for the optimal management of people with overweight/obesity and T2DM in real-life clinical practice. Efforts to reduce the risk of kidney outcomes among individuals with overweight/obesity and T2DM should be undertaken in usual care or via self-monitoring by attaining a high TTR through a weight loss program that incorporates a healthy diet and physical exercise.

Acknowledgments. The authors thank the Look AHEAD study participants, staff, and investigators.

Funding. This study was supported by the National Key Research and Development Program (grants 2022YFC2009600 and 2022YFC2009605 to X.Q.); the National Natural Science Foundation of China and its Key Program (respectively, grant 81973133 to X.Q. and grant 82030022 to F.F.H.); the Program of Introducing Talents of Discipline to Universities, 111 Plan (grant D18005 to F.F.H.); Guangdong Provincial Clinical Research Center for Kidney Disease (grant 2020B1111170013 to F.F.H.), and Key Technologies R&D Program of Guangdong Province (grant 2023B1111030004 to F.F.H.). Look AHEAD was conducted by the Look AHEAD Research Group and supported by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the U.S. National Heart, Lung, and Blood Institute (NHLBI), the U.S. National Institute of Nursing Research, the U.S. National Institute of Minority Health and Health Disparities, the Office of Research on Women’s Health, and the U.S. Centers for Disease Control and Prevention. The data from Look AHEAD were supplied by NIDDK Central Repository.

The manuscript was not prepared under the auspices of Look AHEAD and does not represent analyses or conclusions of the Look AHEAD Research Group, NIDDK Central Repository, or the U.S. National Institutes of Health. The funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. C.Z. and X.Q. designed and conducted the research and wrote the manuscript; C.Z., M.L., and X.Q. conducted the data management and statistical analyses; all authors read and approved the final manuscript. X.Q. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.