3.1 Basic characteristics of obese and non-obese participants in this study
In the NHANES cycles of 2007-2010 and 2017-2018, a total of 17,833 participants were enrolled in the survey. Initially, individuals lacking essential demographic characteristics such as marital status, drinking status, PIR, etc., were excluded. Subsequently, participants without information on flavonoid intake, anthropometric measurements (BMI, waist circumference, and blood pressure), and laboratory biochemical data were also excluded. Please refer to Figure 1 for a detailed screening process. Ultimately, our study sample comprised 5,477 participants.
In a cohort of 5,477 eligible participants, the mean age was 47.23 years, with 49.2% being male, and the average BMI was 28.74 (Table 1). Obesity was prevalent among 36.19% of the cohort, with a diabetes prevalence of 15.1%, hypertension in 37.1%, CVD in 8.3%, NAFLD in 26.4%, and CKD in 5.7%. Over a median follow-up period of 9.92 years (interquartile range (IQR) 5.54–14.29 years), a total of 639 participants experienced mortality, with weight all-cause mortality rate of 8%.
Obese participants had lower dietary intake of anthocyanidins, flavonols, and flavones compared to their non-obese counterparts. Obesity was associated with a higher prevalence of comorbidities, and the survival time during the follow-up period was shorter among obese individuals compared to the non-obese group. In various biochemical and physical measurements, obese participants exhibited lower high-density lipoprotein, higher triglycerides, fasting blood glucose, insulin resistance index, HbA1c%, and larger waist circumference, systolic and diastolic blood pressure compared to non-obese participants.
3.2 Participants with different health statuses were grouped into tertiles of flavonoid intake, and the weighted comorbidity prevalence was assessed.
Figure 2 displays the weighted comorbidity prevalence in non-obese participants grouped by tertiles of flavonoid intake. The results reveal that, except for participants with NAFLD, the group with the highest tertile of flavonoid intake (top quartile) exhibited a lower comorbidity prevalence. Similarly, Figure 3 illustrates the weighted comorbidity prevalence in obese participants grouped by tertiles of flavonoid intake. The results indicate that, except for participants with NAFLD, the group with the highest tertile of flavonoid intake (top quartile) showed a lower comorbidity prevalence. Furthermore, the prevalence of comorbidities is significantly higher among individuals with obesity compared to non-obese participants.
3.3. Relationship between dietary flavonoid intake and BMI as well as Obesity
Table 2 displays the linear correlation between tertiles of total flavonoid intake and BMI. After adjusting for covariates, compared to lower tertile flavonoid intake, both the second tertile (β: -0.72, 95% CI: -1.29, -0.16) and the third tertile (β: -0.78, 95% CI: -1.36, -0.20) showed a significant negative correlation with BMI. Table 3 illustrates the inverse correlation between tertiles of flavonoid intake and the risk of obesity. Compared to lower flavonoid intake tertiles, the second tertile (OR: 0.68, 95% CI: 0.57 - 0.80) and the third tertile (OR: 0.73, 95% CI: 0.57 - 0.93) reduced the risk of disease by 32% and 27%, respectively.
3.4 Relationship between dietary flavonoid intake and all-cause mortality in non-obese participants
In exploring the contribution of flavonoid intake among non-obese individuals (Table S2), after adjusting for relevant covariates, a significant association between the second quartile of flavonoid intake and reduced mortality risk was observed among non-obese participants with CKD (HR: 0.60, 95% CI: 0.36 - 0.99). However, controlling for covariates, no significant positive effects were observed in the non-obese healthy group, non-obese individuals with diabetes, non-obese individuals with NAFLD, and non-obese individuals with CVD (p > 0.05).
3.5 Relationship between dietary flavonoid intake and all-cause mortality in individuals with obesity
Table 4 investigates the influence of flavonoid consumption on individuals with obesity and various associated health conditions. COX regression models, with adjustments for relevant covariates, did not detect statistically significant effects (p >0.05) among all participants with obesity, those with metabolically abnormal obesity, or individuals with obesity combined with NAFLD. However, in the case of metabolically healthy obese participants, a notable association with a reduced risk of mortality was observed for the second quartile of flavonoid intake (HR: 0.23, 95% CI: 0.10-0.53) and the third quartile (HR: 0.15, 95% CI: 0.07-0.35). Similar trends were also apparent among individuals with obesity and coexisting diabetes (HR: 0.51, 95% CI: 0.29-0.88), obesity with concurrent CVD (HR: 0.37, 95% CI: 0.17-0.83), and obesity with accompanying CKD (HR: 0.22, 95% CI: 0.11-0.44), suggesting potential health benefits.
3.6 Relationship between dietary flavonoid intake quantity and risk of mortality analyzed by Kaplan-Meier survival curves and RCS analysis in individuals with different health status
Figure S1 presents the Kaplan-Meier survival curves and RCS analysis results for non-obese participants categorized by different health conditions. Apart from participants with normal weight and concurrent chronic kidney disease (as shown in Figure S1(6)), those who consumed higher levels of total flavonoids, categorized by tertiles of intake, did not exhibit a significantly higher survival probability (log-rank p > 0.05). RCS analysis revealed no nonlinear relationship (all p for nonlinearity > 0.05) between total flavonoid intake levels and the risk of death in populations with normal weight, regardless of the presence of any specific diseases.
Figure S2 presents Kaplan-Meier survival curves and RCS analysis findings for participants with obesity categorized by different health statuses. Participants with higher flavonoid intake demonstrated greater survival probabilities in cases of obesity combined with diabetes, obesity combined with CVD, and obesity combined with CKD (log-rank p < 0.05). Figure 4 illustrates a U-shaped association between total flavonoid intake and mortality risk in obese participants, with an inflection point identified at 371.876 mg/day, indicating the optimal intake level. U-shaped associations between flavonoid intake and overall mortality risk were observed in participants with MHO-type obesity, obesity combined with diabetes, obesity combined with NAFLD, and obesity combined with CKD (p non-linear < 0.05). Following adjustments for potential confounding factors, the inflection point for the lowest risk of mortality among participants, as estimated through RCS curve fitting for flavonoid intake, ranged from 319.4978 to 448.6907 mg/day.
3.7. Subgroup analysis based on six major components of flavonoids.
Table S3 (1-6) displays the COX regression analysis results for participants without obesity and specific comorbidities, including those without obesity but with diabetes, without obesity but with NAFLD, without obesity but with CVD, and without obesity but with CKD, considering the six flavonoid components. The COX regression results indicate that, after adjusting for covariates, higher intake levels of anthocyanidins, flavonols, flavan-3-ols, and isoflavones are associated with a lower risk of mortality in participants without obesity and with diabetes. After multiple adjustments, the HR range of the Cox model was from 0.06 for higher flavonol levels to 0.59 for higher anthocyanidin levels.
Table S4 (1-7) shows the results of COX regression analyses for participants with obesity and the six flavonoid components. In all participants with obesity and those with MAO, higher intake levels of anthocyanidins and isoflavones are associated with a reduced risk of mortality [Table S4(1-2)]. Among MHO participants [Table S4(3)], the intake level of flavonols is related to a decreased risk of mortality (HR: 0.06, 95% CI: 0.01-0.28). Higher intake levels of flavan-3-ols are associated with a reduced risk of mortality in participants with obesity and diabetes (HR: 0.58, 95% CI: 0.34-0.98), [Table S4(4)]. Higher intake levels of flavan-3-ols (HR: 0.19, 95% CI: 0.08-0.46), and flavonols (HR: 0.40, 95% CI: 0.19-0.83) are related to a decreased risk of mortality in participants with obesity and kidney disease [Table S4(7)].
3.8. Sensitivity analysis
Expanding the sample size to include all obese and overweight individuals in the sensitivity analysis, besides observing a reduced mortality risk associated with higher total flavonoid intake in all participants (HR: 0.74, 95% CI: 0.56 - 0.96), no significant differences in survival were observed in the remaining subgroups of health statuses, Table S5(1). Table S5(2) presents the results of COX regression analyses for the six flavonoid components in all study participants. We found that, after controlling for covariates, only the intake level of the third tertile of isoflavones was associated with a reduced risk of mortality in the participants (HR: 0.71, 95% CI: 0.57-0.90). This implies heterogeneity in the response to flavonoids among populations with different health statuses, further confirming the survival benefits of flavonoid intake for obese participants.