Diabetes mellitus, a chronic metabolic disorder, has been recognized as a major global public health burden (1). According to the World Health Organization, an estimated 422 million people were living with diabetes worldwide in 2014, a figure that is projected to rise to about 642 million people by 2040 accompanied by a paralleled increase in its associated complications (2, 3). One of the associated complications of diabetes is diabetic nephropathy (DN) – a microvascular complication characterized by albuminuria and progressive loss of kidney function (4) and is also considered to be the leading cause of end-stage renal disease (ESRD) in the United States (5) and across the globe (6, 7).

Individuals with excess body weight, an indication of excess fat mass may suffer from several cardiometabolic disorders (8). Indeed, a number of studies have reported a positive relationship between renal disease and being overweight among individuals with or without diabetes (9–13). However, some studies have reported conflicting results. For example, in one prospective observational study, the authors found higher levels of body mass index (BMI), a measure of obesity, to be protective against renal function decline in patients with type 2 diabetes mellitus (14). Other studies have also reported U-shaped relationship between obesity measures and microvascular diabetic complications, suggesting that both low and high levels of obesity indexes may act as potential risk factors for renal dysfunction (15, 16).

Body composition varies between men and women, and so is the incidence and health outcomes associated with these sex-specific differences (17). However, most of these studies did not assess the association between obesity indexes and renal outcome stratified by sex. As an indicator of upper body adipose tissue distribution and abdominal obesity, waist circumference (WC) and waist-to-height ratio (WHtR) are considered a potential anthropometric measure of obesity (18). Thus, in the present study, we sought to assess the association between obesity (defined by WC, WHtR, and BMI) and diabetic nephropathy (DN) separately among men and women with T2DM.

In this context, we sought to concurrently investigate the association of WC, WHtR, and BMI with incident DN using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which was a randomized, multicenter, double 2 × 2 factorial trial in 10,251 patients with T2DM (18).

Among the 8,887 participants with T2DM, 5,489 (61.8%) were men and 3,398 (38.2%) were women. Table 1 summarizes the baseline characteristics stratified by subjects who subsequently developed DN and those who did not. Compared with those without DN, those who developed DN were more likely to be men, white, belonged to the lipid treatment arm of ACCORD, had higher levels of WC, WHtR, BMI, HbA1c, SBP, UACR, but lower HDL, LDL, and serum creatinine levels. We also presented the baseline characteristics of the study participants by quartiles of WC, WHtR, BMI categories ( Supplementary Tables 3 and 5 ). Patients with a larger WC, WHtR, and BMI were more likely to be younger, white, and have higher diastolic BP. Higher WHtR and BMI were more likely to be associated with being female, whereas higher levels of WC were associated with being a male.

Over 24,302 person-years of follow-up, 5,296 participants (3,345 men and 1,951 women) developed the DN composite outcome (2.3 per 10 person-years in men; 2.1 per 10 person-years in women). Among men, higher levels of WC, WHtR, and BMI in the unadjusted models were associated with an increased risk of incident DN, but all lost significance in the full models although the 3^rd quartile of WHtR showed marginally significant results (P = 0.052). Compared with the lowest quartile, the fully adjusted hazard ratio (HR) and 95% confidence interval (CI) for the 3rd quartile of WHtR was 1.10 (95% CI 1.00-1.21) among men ( Table 2 ). On the contrary, among women, higher levels of WC, WHtR, and BMI were all associated with incident DN in the full models. The fully-adjusted HR (95% CIs) for WC among women was 1.35 (1.15-1.57) for the highest group (≥ 88cm), compared with the lower group (P-trend <0.001); the fully-adjusted HR (95% CIs) for WHtR among women were 1.09 (0.96-1.25), 1.12 (0.98-1.28), and 1.14 (1.00-1.30) for the 2^nd to the 4^th quartile compared with the 1st, respectively (P-trend = 0.047); also, the fully-adjusted HR (95% CIs) for BMI among women were 1.28 (1.04-1.58), 1.36 (1.10 – 1.67), 1.43 (1.16-1.78) and 1.32 (1.05 – 1.66) for the overweight category to Class III obese category, compared with the normal weight category, respectively (P-trend = 0.035) ( Table 3 ). Similar results were obtained in examining the association between each 1 SD increase in WC, WHtR, and BMI with incident DN among men and women. The results for men showed no significant association between each SD increase in WC, WHtR, and BMI with incident DN whereas among women, each SD increase in WC, WHtR, and BMI were associated with a significantly increased risk of DN ( Tables 2 and 3 ).

Analysis of each DN diagnostic event that comprised the composite outcome [(1) doubling of SCr or >20 mL/min/1.73m² decrease in eGFR; (2) macroalbuminuria; and (3) renal failure or ESRD (dialysis) or SCr >3.3mg/dL in absence of an acute reversible cause] showed that among men, WC ≥ 102 cm was associated with reduced risk of macroalbuminuria ( Supplementary Table 7 ). All other analyses for the relationship of WC, WHtR, and BMI with other DN diagnostic outcomes were null for the full models among men ( Supplementary Tables 6–8 ). Among women, however, higher levels of WC, WHtR, and BMI were all associated with an increased risk of doubling of SCr or > 20 mL/min/1.73m² decrease in eGFR ( Supplementary Tables 9 ). The results for the relationship between WC, WHtR, and BMI with other DN outcomes were null for women ( Supplementary Tables 10 and 11 )

Subgroup analyses of the HRs of DN for each SD increase in the WC, WHtR, and BMI are shown in Supplementary Tables 12–14 . Generally, there were no significant interactions between various subgroups among men. However, among women, we found that allocation to BP/lipid treatment group significantly modified the relation between each 1SD increase in the WC, WHtR and BMI and the risk of incident DN (P _interaction = 0.044, 0.028 and 0.026 respectively). The links between WC, WHtR and BMI, and incident DN were stronger among participants assigned to the BP treatment group than those assigned to the lipid treatment group ( Supplementary Tables 12–14 ). Also, we found significant modified effect between duration of diabetes and each 1SD increase in BMI among women (P _interaction = 0.023). The link between BMI and incident DN was stronger among participants with < 9years of diabetes duration than in those in ≥ 9years ( Supplementary Table 14 ). The results were not materially changed after excluding those who had serious adverse events in the first 2 years of follow-up except for the quartiles of WHtR which lost significance among women, whereas the 3rd quartile of WHtR became fully significant among men ( Supplementary Tables 15 and 16 ).

In this post-hoc study, using data from 8,887 patients with T2DM, we examined the association of anthropometric measures with the risk of DN. The results from the present study suggest that obesity, as defined by WC, WHtR, and BMI, may be associated with an increased risk of DN in women but not in men after adjustment for potential-related confounders.

Mixed results have been reported by previous studies assessing the association between central obesity and general obesity with renal diseases in participants with or without T2DM. The results of the present study are consistent with some studies that found detrimental associations between obesity indices and renal function in women but not in men. In a study to assess the sex difference in the association between anthropometric measures and albuminuria in a sample of 3,841Korean adults, the researchers found both WC and BMI were associated with albuminuria in women but not men (25). Lin et al. in a study of 2,350 middle-aged Chinese participants also found central obesity indicators to be associated with the development of albuminuria in women but not men (26). A similar finding was observed in a sample of 569 T2DM patients (27). However, these studies are either cross-sectional studies or smaller sample sizes.

Using a sample of nearly 9,000 participants with T2DM from a randomized clinical trial, we provided important data supporting evidence of higher levels of WC, WHtR, and BMI as a risk factor for DN in women. The pathological mechanisms underlying these associations of obesity and renal function decline are not entirely clear. However, adipose tissues have been implicated in the release of inflammatory mediators such as interleukin-6 and tumor necrosis factor α, and also linked to the cause of insulin resistance (28). The combination of these factors may lead to structural changes in the kidneys and eventually result in obesity-related glomerulopathy (29). Furthermore, excess visceral adipose tissue may also provoke hemodynamic changes in the kidneys which subsequently cause elevated glomerular capillary pressure leading to possible renal damage (28).

It must be noted that other studies found obesity markers to be associated with increased risk of renal function decline in men but not in women (30–33). The reason for the insignificant relationship between anthropometric measures and the renal outcomes in men with T2DM in our study is unclear. This may suggest that some other factors such as sex hormones may play important role in the pathological mechanism between men and women. Another possibility is that men generally have higher levels of lean body mass which have been associated with better health outcomes (34, 35); and may account for the null associations observed in the relationship between the obesity indexes and incident DN among men (25, 36). Further studies will be necessary to elucidate the sex-specific association of anthropometric measures in women with T2DM and the lack thereof among men.

Our findings suggest that both central and general obesity indicators may be an important measure to assess among women with T2DM. These central adiposity indexes like the general obesity indices, not only come at relatively low cost, easy to assess, and easily carried out in any clinical setting, but have an added advantage of having a high correlation with visceral adiposity than the general obesity indicator of BMI (37). Clinicians might want to consider efforts to increase awareness and prevention of both central and general obesity to reduce DN risk as the prevalence of diabetes is projected to increase globally (37).

The strengths of our study include the relatively large sample size, comprehensive clinical and biological characterization of participants, and prospective data collection. There was also a special nephropathic examination at baseline and at subsequent visits, which permitted the accurate assessment of the effect of anthropometric measures on the risk of DN. The attrition of participants in this study was also very minimal. However, our study has some limitations. Firstly, our study lacks the ability to determine causality because of its observational study design. Secondly, due to the limited number of participants in the underweight category in this sample, we could not establish any relationship for individuals who are underweight. Thirdly, the generalization of these findings to other populations may be limited since all study participants were from northern America and there may be variability in body composition across different populations.

In conclusion, among participants with T2DM, higher levels of both central and general obesity measures were associated with DN risk among women but not in men. Women with T2DM should maintain a healthy weight targeted at reducing both abdominal fat and general obesity to enhance nephroprotection.

Publicly available datasets were analyzed in this study. This data can be found here: https://biolincc.nhlbi.nih.gov/studies/accord/(Repository: Biologic Specimen and Data Repository).

The studies involving human participants were reviewed and approved by ACCORD Protocol Review Committee appointed by National Heart, Lung, and Blood Institute (NHLBI) & Local institutional review boards of participating clinical sites. The patients/participants provided their written informed consent to participate in this study.

DH and F-RL conceived, analyzed the data and wrote the manuscript. RZ, J-ZZ, X-XW, and X-BW contributed to the discussion and reviewed/edited the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by Open Project of Guangdong Provincial Key Laboratory of Tropical Disease Research and Guangdong Basic and Applied Basic Research Foundation.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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