Association between high-density lipoprotein cholesterol and reversion to normoglycemia from prediabetes: an analysis based on data from a retrospective cohort study

The available evidence on the connection between high-density lipoprotein cholesterol (HDL-C) levels and the reversion from prediabetes (Pre-DM) to normoglycemia is currently limited. The present research sought to examine the connection between HDL-C levels and the regression from Pre-DM to normoglycemia in a population of Chinese adults. This historical cohort study collected 15,420 Pre-DM patients in China who underwent health screening between 2010 and 2016. The present research used the Cox proportional hazards regression model to investigate the connection between HDL-C levels and reversion from Pre-DM to normoglycemia. The Cox proportional hazards regression model with cubic spline functions and smooth curve fitting was employed to ascertain the nonlinear association between HDL-C and reversion from Pre-DM to normoglycemia. Furthermore, a set of sensitivity analyses and subgroup analyses were employed. Following the adjustment of covariates, the findings revealed a positive connection between HDL-C levels and the likelihood of reversion from Pre-DM to normoglycemia (HR 1.898, 95% CI 1.758–2.048, P < 0.001). Furthermore, there was a non-linear relationship between HDL-C and the reversion from Pre-DM to normoglycemia in both genders, and the inflection point of HDL-C was 1.540 mmol/L in males and 1.620 mmol/L in females. We found a strong positive correlation between HDL-C and the reversion from Pre-DM to normoglycemia on the left of the inflection point (Male: HR 2.783, 95% CI 2.373–3.263; Female: HR 2.217, 95% CI 1.802–2.727). Our sensitivity analysis confirmed the robustness of these findings. Subgroup analyses indicated that patients with SBP < 140 mmHg and ever smoker exhibited a more pronounced correlation between HDL-C levels and the reversion from Pre-DM to normoglycemia. In contrast, a less robust correlation was observed among patients with SBP ≥ 140 mmHg, current and never smokers. This study provides evidence of a positive and nonlinear association between HDL-C levels and the reversion from Pre-DM to normoglycemia in Chinese patients. Implementing intensified intervention measures to control the HDL-C levels of patients with Pre-DM around the inflection point may substantially enhance the likelihood of regression to normoglycemia.


Study population
The Rich Healthcare Group Review Board authorized the initial research 22 .This secondary analysis does not require ethical approval.The present research followed the Declaration of Helsinki.All procedures, including the Declarations section declarations, followed relevant laws and conventions.
The initial research included 685,277 individuals aged 20 and above from the Rich Healthcare Group in China who had undergone at least two health examinations.A total of 473,444 subjects were excluded from the research due to not meeting the specified exclusion criteria.The exclusion criteria for this research were as follows: (1) individuals with follow-up intervals < 2 years; (2) individuals with extreme body mass index (BMI) values (< 15 kg/m 2 or > 55 kg/m 2 ); (3) individuals lacking information on fasting plasma glucose (FPG), weight, sex, and height at baseline; (4) individuals with DM at the time of inclusion; and (5) individuals with unknown DM status during follow-up.Finally, the initial research involved 211,833 individuals 22 .A total of 26,018 subjects with Pre-DM were entered into the present research.We excluded individuals with missing FPG information at follow-up (n = 12) and HDL-C information at baseline (n = 10,586).Ultimately, the current research included a total of 15,420 participants.The selection process for participants is depicted in Fig. 1.

Data collection
In the initial study, researchers of professional standing employed standardized questionnaires to collect baseline data pertaining to alcohol consumption, tobacco usage, and familial predisposition to diabetes.Trained personnel conducted measurements of subjects' blood pressure, height, and weight.BMI is obtained by dividing weight (kg) by the square of height (m).At each visit, venous blood samples were obtained following a minimum 10-h fasting period.The FPG and total cholesterol (TC), aspartate aminotransferase (AST), low-density lipoprotein cholesterol (LDL-C), blood urea nitrogen (BUN), alanine aminotransferase (ALT), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and serum creatinine (Scr) were quantified using a Beckman 5800 autoanalyzer.The definition of prediabetes was impaired fasting glucose levels (FPG: 5.6-6.9mmol/L).According to the American Diabetes Association (ADA) criteria, the definition of Pre-DM is characterized by impaired fasting glucose levels falling within the range of 5.6 to 6.9 mmol/L for FPG 23 .HDL-C measured at baseline is the independent variable.The dependent variable is the reversion to normoglycemia from Pre-DM discovered during the follow-up.Participants' return dates for one or more physical exams were used to determine when normoglycemia would return.

Outcome measures
Reversion to normoglycemia was determined according to no self-reported diabetic events and FPG less than 5.6 mmol/L at follow-up 23,24 .

Statistical analysis
We used R software 3.6.1 and Empower Stats (R) version 2.2 for data analysis.
The participants were separated into four groups (Q1 ≤ 1.120, 1.120 < Q2 ≤ 1.310, 1.310 < Q3 ≤ 1.510, Q4 > 1.510) based on their HDL-C quartiles.For continuous data with Gaussian distributions, the means and standard deviations were provided; for data with skewed distributions, the medians were supplied; and for categorical data, the frequencies and percentages were reported.To look for differences between various HDL-C groups, we employed the Kruskal-Wallis H test (data with skewed distribution), χ 2 (categorical data), or the One-Way ANOVA test (data with normal distribution).We expressed the incidence rates in terms of cumulative incidence and person-years.Using the Kaplan-Meier approach, survival and cumulative event rate comparisons were made.Additionally, using the log-rank test, we analyzed the Kaplan-Meier hazard ratios (HR) of adverse events.
After conducting collinearity screening, we employed univariate and multivariate Cox proportional hazards regression models to investigate the association between HDL-C and the reversion from Pre-DM to normoglycemia.This analysis included three models: Model 1, which did not involve any adjusted covariates; Model 2, which adjusted for minimal covariates (adjusted family history of diabetes, DBP, age, sex, drinking status, SBP, BMI, and smoking status); and Model 3, which incorporated full covariate adjustments (adjusted DBP, smoking status, SBP, BMI, gender, age, drinking status, FPG, AST, BUN, ALT, LDL-C, Scr, TG, and family history of diabetes).The study recorded effect sizes (HR) and their corresponding 95% confidence intervals (CI).According to the findings of univariate analysis, literature reports, and clinical experience, adjustments were made to account for potential confounding factors.Furthermore, the final multivariate Cox proportional hazards regression equation excluded TC due to its collinearity with other variables (Table S1).
In order to ascertain the dependability of the results, a sequence of sensitivity analyses was conducted.Prior research has indicated a significant association between BMI and age with the reversion from Pre-DM to normoglycemia 21,27  www.nature.com/scientificreports/another sensitivity analysis was performed by excluding subjects with age ≥ 60 years.To validate the reliability of the findings, the continuity covariate was also integrated into the equation as a curve utilizing a generalized additive model (GAM).In addition, we conducted E-value calculations to assess the potential influence of unmeasured confounding on the connection between HDL-C levels and the reversion from Pre-DM to normoglycemia 28 .Additionally, we employed a Cox proportional hazards regression model with cubic spline functions and smooth curve fitting to address the non-linear association between HDL-C levels and the reversion to normoglycemia from Pre-DM.Moreover, a two-piecewise Cox proportional hazards regression model was utilized to   29 .In addition to accounting for the stratification factor, adjustments were made for various covariates, including DBP, age, sex, SBP, BMI, FPG, AST, BUN, ALT, LDL-c, Scr, TG, family history of diabetes, drinking status, and smoking status.The presence of interaction terms in models with and without such terms was then determined using the likelihood ratio test.The STROBE statement was adhered to for reporting all findings 30 .Statistical significance was determined using a two-tailed test with a threshold of P < 0.05.

Ethics approval and consent to participate
The original study followed guidelines outlined by the Helsinki Declaration and was approved by the Rich Healthcare Group Review Board.In addition, the Rich Healthcare Group Review Board has waived informed consent for the current retrospective study.All methods were performed in accordance with the relevant the Declaration of Helsinki.2).Significantly more participants with higher HDL-C levels had a reversal rate than those with lower HDL-C levels (P < 0.001 for trend).

Factors influencing reversion from Pre-DM to normoglycemia
Univariate analyses revealed significant negative correlations between reversion from Pre-DM to normoglycemia and factors including AST, age, TG, DBP, SBP, ALT, LDL-C, BMI, BUN, TC, and family history of diabetes.Conversely, a positive relationship was observed between reversion from Pre-DM to normoglycemia and factors including never drinking, HDL-C, and never smoking, as shown in Table 3.
Figure 2 illustrates the Kaplan-Meier curves depicting the likelihood of the reversion from Pre-DM to normoglycemia, categorized by quartiles of HDL-C.The probability of transitioning back to normoglycemia from Pre-DM significantly differed across the HDL-C groups (log-rank test, P < 0.001).Moreover, the probability of reversion from Pre-DM to normoglycemia gradually increased with increasing levels of HDL-C.This implies that individuals with the highest HDL-C levels possessed the greatest likelihood of reversion from Pre-DM to normoglycemia.

The connection between HDL-C levels and reversion from Pre-DM to normoglycemia
We employed the multivariate Cox proportional hazards regression model to construct three models to examine the connection between HDL-C levels and the reversion from Pre-DM to normoglycemia.In Model 1, a 1 mmol/L rise in HDL-C levels was associated with a 92.0%increase in the likelihood of the reversion from Pre-DM to normoglycemia (HR 1.920, 95% CI 1.798-2.050,P < 0.001).In Model 2, after adjusting for family history of diabetes, DBP, age, sex, drinking status, SBP, BMI, and smoking status, each 1 mmol/L increase in HDL-C levels was related to an 88.3% higher probability of reverting to normoglycemia (HR 1.883, 95% CI 1.752-2.023,P < 0.001).In Model 3, after adjusting for various factors, including DBP, smoking status, SBP, BMI, gender, age, drinking status, FPG, AST, BUN, ALT, LDL-C, Scr, TG, and family history of diabetes, the HR between HDL-C levels and reversion to normoglycemia from Pre-DM was found to be 1.898 (95% CI: 1.758-2.048,P < 0.001).The confidence intervals in Table 4 indicate that the connection between HDL-C levels and reversion from Pre-DM to normoglycemia, as determined by the model, is statistically reliable.
Furthermore, we discretized the HDL-C levels from a continuous variable to a categorical variable and subsequently reintegrated the categorically transformed HDL-C levels into the model.In model 3, the HR was 1.198 (95% CI 1.115-1.288)for the Q2 group, 1.470 (95% CI 1.368-1.580)for the Q3 group, and 1.733 (95% CI 1.609-1.866)for the Q4 group compared with subjects in the Q1 group.

Sensitivity analysis
A series of sensitivity analyses were conducted to ensure the robustness of our findings.Initially, we incorporated the continuity covariate as a curve into the equation using a GAM.As indicated in Table 4, the results of Model 4 were consistent with the fully adjusted model (Model 3).Specifically, subjects in the group with the highest HDL-C levels (Q4) were 76.7% more likely to return to normoglycemia from Pre-DM compared to those in the group with the lowest HDL-C levels (Q1) (HR 1.767, 95% CI 1.637-1.908,P < 0.001).
Additionally, a sensitivity analysis was conducted on participants with a BMI less than 25 kg/m 2 .Following the adjustment for various confounding variables, such as DBP, age, sex, SBP, BMI, FPG, AST, BUN, ALT, LDL-C, Scr, TG, family history of diabetes, drinking status, and smoking status, the findings revealed a positive correlation   www.nature.com/scientificreports/ between HDL-C levels and the reversion to normoglycemia from Pre-DM (HR 1.831, 95% CI 1.665-2.012,P < 0.001).Furthermore, patients aged 60 years or older were excluded from the analysis.After accounting for confounding variables, the results continued to demonstrate a positive association between HDL-C levels and the reversion to normoglycemia (HR 1.997, 95% CI: 1.840-2.167,P < 0.001) (Table 5).Based on the comprehensive sensitivity analyses conducted, it becomes apparent that our findings possess a high degree of robustness.Furthermore, in order to assess the susceptibility to unmeasured confounding, we employed the calculation of an E-value.The results indicate that the influence of unknown or unmeasured variables on the correlation between HDL-C levels and the transition from Pre-DM to normoglycemia is minimal, as the E-value (2.49) surpasses the relative risk associated with HDL-C levels and unmeasured confounders (1.87).

The analyses of non-linear relationship between HDL-C levels and reversion from Pre-DM to normoglycemia
Utilizing a Cox proportional hazards regression model with cubic spline functions and smooth curve fitting, our analysis revealed a nonlinear association between HDL-C levels and the likelihood of reverting to normoglycemia in individuals with Pre-DM stratified by gender (Fig. 3A and Fig. 3B).Furthermore, employing a standard binary two-piecewise Cox proportional-hazards regression model to assess the data, we employed the log-likelihood ratio test to determine the most suitable model fit (Table 6).Employing the recursive technique, we identified the HDL-C inflection point as 1.540 mmol/L in males and 1.620 mmol/L in females.There was a strong positive correlation between HDL-C and the reversion from Pre-DM to normoglycemia on the left of the inflection point (Male: HR 2.783, 95% CI 2.373-3.263;Female: HR 2.217, 95% CI 1.802-2.727).However, on the right side of the inflection point, the relationship between HDL-C and the reversion from Pre-DM to normoglycemia was not significant (Male: HR 0.926, 95% CI 0.666-1.288;Female: HR 1.266, 95% CI 0.906-1.770)(Table 6).

The results of subgroup analyses
In all predetermined or exploratory subgroups analyzed (Table 7), the association between HDL-C levels and reversion to normoglycemia from Pre-DM was not influenced by age, sex, DBP, drinking status, or family history of diabetes (P > 0.05 for interaction).However, among patients with SBP < 140 mmHg and those who were ever

Discussion
HDL-C levels and the reversion to normoglycemia from Pre-DM.Our findings indicate a significant positive connection between the increase in HDL-C levels and the probability of regression from Pre-DM to normoglycemia.Furthermore, a threshold effect curve was observed, revealing the distinct connection between HDL-C levels and the reversion to normoglycemia from Pre-DM on either side of the inflection point.Additionally, our study identified that individuals with SBP < 140 mmHg and ever smoker exhibited a stronger correlation between HDL-C levels and the reversion to normoglycemia from Pre-DM.A prospective cohort investigation involving 491 subjects showed that 22.6% of those with Pre-DM experienced a return to normoglycemia over a median follow-up period of 2.5 years 31 .In addition, the findings of www.nature.com/scientificreports/another study after 1 year of follow-up showed that 54% of subjects with Pre-DM returned to normal blood glucose, while 6% developed DM 15 .Furthermore, a cohort study in China, encompassing 14,231 Chinese adults, revealed that 44.9% of patients with Pre-DM reverted to normoglycemia within two years 32 .Our investigation revealed that 6,627 patients with Pre-DM achieved normoglycemia after a median follow-up duration of 2 years.Differences in the rate of reversion to normoglycemia from Pre-DM across various studies can be ascribed to variations in participants' age, duration of follow-up, and ethnic background.It is crucial to acknowledge that all studies have consistently confirmed a significant proportion of individuals with Pre-DM experiencing a return to normoglycemia.Consequently, identifying the factors that contribute to this reversion is of utmost importance in diabetes prevention and the mitigation of associated complications.www.nature.com/scientificreports/Numerous previous studies have indicated a correlation between diminished HDL-C levels and elevated susceptibility to diabetes 33,34 .Furthermore, HDL-C levels in prediabetic subjects were negatively connected to the likelihood of developing diabetes 17,18 .Moreover, lower HDL-C levels have been linked to a substantial risk factor for Pre-DM 35,36 .Consequently, we postulate that a decline in HDL-C levels might be linked to an augmented probability of transitioning from prediabetes to normoglycemia.Regrettably, there is a lack of literature exploring the interrelation between them.In a longitudinal study comprising 1329 individuals diagnosed with prediabetes, the findings of a Cox proportional hazards multivariate model indicated that a 1 mmol/L elevation in HDL-C levels was linked to a 70% increase in the likelihood of achieving normoglycemia among subjects with Pre-DM (HR: 1.70, 95% CI: 1.23-2.34) 21.Another investigation involving 817 individuals diagnosed with prediabetes from Germany has demonstrated that for every 10 mg/dL increase in HDL-C levels, there was a 17% higher probability of attaining normoglycemia in patients with prediabetes after controlling for residential traffic intensity, mental distress, age, lifestyle factors, educational level, anthropometric markers, and sex (HR 1.17, 95% CI 1.02-1.35) 20.Our study served as a valuable addition to the current body of literature, as it provided further support for the hypothesis that a decrease in HDL-C levels is linked to a diminished likelihood of the reversion from Pre-DM to normoglycemia.In contrast to previous studies, our research employed both categorical and continuous variables of HDL-C levels as independent variables, enabling a more comprehensive exploration of their relationship with the reversion from prediabetes to normoglycemia.This approach minimized the loss of pertinent information and facilitated the quantification of their association.Furthermore, our study employed distinct covariates for adjustment compared to previous studies.We accounted for more parameters: ALT, smoking status, Scr, LDL-C, AST, FPG, drinking status, and BUN [37][38][39][40][41] .Extensive evidence has demonstrated the association between these parameters and the onset of diabetes.Additionally, our sensitivity analysis revealed that this association persists among individuals with a BMI < 25 kg/m 2 and age < 60 years.The results have substantiated the enduring correlation between HDL-C levels and the reversion from Pre-DM to normoglycemia.This discovery offers a valuable point of reference for clinical interventions targeting HDL-C levels to augment the likelihood of the reversion from Pre-DM to normoglycemia.Notably, this study, which investigates nonlinearity, represents a significant advancement compared to prior research endeavors.
The precise mechanism for connecting HDL-C levels and the reversion from Pre-DM to normoglycemia is not yet fully understood.The following mechanisms may explain the ability of HDL-C to contribute to reversion from Pre-DM to normoglycemia.Prior research has demonstrated that HDL-C possesses antioxidant and antiinflammatory properties 42 .By preventing the apoptosis that is triggered by inflammatory cytokines or oxidized low-density lipoprotein, such as tumor necrosis factor-alpha, HDL-C can directly increase the viability of islet cells 43 .Additionally, by triggering the Adenosine 5'-monophosphate-activated protein kinase pathway, HDL-C increases skeletal muscle cells' sensitivity to insulin and glucose absorption 44 .Furthermore, HDL-C promotes insulin secretion by encouraging the outflow of cholesterol from pancreatic β cells 45 .These mechanisms might logically explain the elevation in HDL-C associated with a greater chance of the reversion from Pre-DM to normoglycemia.
Moreover, the present study employed a two-piecewise Cox proportional hazards regression model to elucidate the nonlinear relationships.The results revealed a nonlinear association and a threshold effect between HDL-C levels and the reversion from Pre-DM to normoglycemia.After accounting for confounding factors, the inflection point of HDL-C levels was determined to be 1.540 mmol/L in males and 1.620 mmol/L in females.Notably, no significant correlation was observed between elevated HDL-C levels and the reversion to normoglycemia from Pre-DM when HDL-C levels exceeded the inflection point.However, when the HDL-C levels were below the inflection point, the likelihood of returning to normoglycemia increased significantly by 1.783-fold in males and 1.217-fold in females for every 1 mmol/L increase in HDL-C levels.This suggests that the probability of the reversion from Pre-DM to normoglycemia gradually rises with increasing HDL-C levels in individuals with Pre-DM.However, once the HDL-C level reaches an inflection point, the probability of reversion to normoglycemia from Pre-DM stabilizes rather than continues to increase.The nonlinear relationship between HDL-C and the reversion to normoglycemia from prediabetes might be due to the influence of other covariates at baseline.Compared to those on the left side of the inflection point, participants on the right side tend to be older, with higher TC, LDL-C, and BUN levels and a higher proportion of current drinkers (Table S2A and Table S2B).Previous studies have indicated that these covariates inhibit the reversion of normoglycemia from prediabetes 18,21,46 .Therefore, we speculate that once HDL-C exceeds the inflection point, its role in promoting the reversion to normoglycemia from prediabetes might be weakened due to the influence of age, TC, LDL-C, BUN, and alcohol consumption.This discovery of a curvilinear association between HDL-C and the reversion to normoglycemia from Pre-DM holds significant clinical value, as it benefits clinical advice and provides a useful reference for decision-making processes to optimize preventive DM strategies.Individuals with pre-DM are not only at risk for the development of T2DM but also for the onset of all-cause mortality and cardiovascular disease 47,48 .Prior studies have indicated that even a brief restoration to normoglycemia is linked to a substantially reduced risk of T2DM development in individuals with Pre-DM 12 .Consequently, the treatment of Pre-DM should prioritize achieving a return to normoglycemia rather than focusing solely on mitigating the potential consequences of Pre-DM and reducing the possibility of developing T2DM.Our work established an HDL-C threshold for the return to normoglycemia in Chinese people with pre-DM.In other words, keeping HDL-C levels near the inflection point in patients with prediabetes may greatly increase the likelihood of reversion from pre-DM to normoglycemia.
Based on previous studies, there are methods to increase HDL-C levels.Lifestyle modifications, including regular physical activity, weight management, smoking cessation, and dietary changes, are fundamental in the augmentation of HDL-C concentrations 49,50 and can also increase the likelihood of reversion from pre-DM to normoglycemia 9,51 .In addition, some drugs also increased HDL-C levels, but they remained controversial for improving insulin resistance and glucose metabolism.Niacin has been used to increase HDL-C levels and improve lipid profiles significantly, but it may also worsen insulin resistance 52 .Statins, while primarily used to lower LDL-C, can have a modest effect on raising HDL-C levels.Some studies suggest that statins may increase insulin resistance 53,54 .Cholesteryl ester transfer protein inhibitors are of interest to researchers because they not only have the potential to increase HDL-C levels but also have been associated with a reduction in the incidence of diabetes and an improvement in glucose metabolism 55 .
Subgroup analyses showed that individuals with SBP < 140 mmHg and ever-smokers exhibited a stronger correlation between HDL-C levels and the reversion to normoglycemia from Pre-DM.We observed that participants with SBP < 140 mmHg exhibited a lower BMI (Table S3A).Previous studies have suggested that lower SBP and a reduced BMI may indicate diminished insulin resistance 56,57 .In contrast, ever-smokers exhibited higher BMI (Table S3B).A review of the existing literature indicated that an increase typically followed the cessation of smoking in body weight 58 .Although smoking cessation might lead to weight gain, it also improves HDL-C, total high-density lipoprotein, and the size of high-density lipoprotein particles, with these positive changes in HDL-C mitigating the negative impact of weight gain 58 .Moreover, smoking cessation has enhanced high-density lipoprotein functionality, boosting cholesterol efflux capacity and reducing inflammation without altering HDL-C levels or high-density lipoprotein subtypes 59 .We postulated that HDL-C levels and the reversion to normoglycemia from prediabetes were more pronounced in participants with SBP < 140 mmHg and ever-smokers due to the above reasons.
This research possesses several noteworthy strengths.Firstly, it uncovers the non-linear relationship between HDL-C and the reversion from Pre-DM to normoglycemia and identifies crucial inflection points.Secondly, a multiple imputation approach was employed to address the issue of missing data, enabling the attainment of optimal statistical power while mitigating bias arising from absent covariate information.Lastly, a set of sensitivity analyses were performed to ascertain the results' dependability.
The study has several potential limitations that should be acknowledged.Firstly, the homogeneity of the participant sample, consisting solely of individuals of Chinese descent, necessitates further investigation to establish the relationship between HDL-C and return to normoglycemia in individuals with Pre-DM from diverse genetic backgrounds.Secondly, it is important to note that relying solely on FPG measurements may not fully capture the complexity of prediabetes.However, these additional assessments were not feasible due to logistical challenges associated with measuring HbA1c levels and 2-h oral glucose tolerance tests within a large study cohort.Future research endeavors will address this limitation by conducting our own study or collaborating with other researchers to gather data on 2-h oral glucose tolerance tests and HbA1c levels.Furthermore, it should be noted that this study relies on a secondary analysis of previously published data, which limits our ability to control for variables that were not originally included in the dataset, such as insulin concentration and the use of lipidlowering medications.Nevertheless, we employed the E-value to quantify the potential influence of unmeasured confounders and determined that these confounders are unlikely to account for the observed outcomes.Additionally, this is a secondary retrospective study, and the data was downloaded from the DATADRYAD database.Only baseline HDL-C was measured in the previous original study, and the original research did not involve changes in HDL-C over time.Because our study was observational, we cannot determine a causal relationship between HDL-C and the reversion from prediabetes to normoglycemia.In the future, we can consider designing our studies to collect as many variables as possible, including information on the evolution of HDL-C during follow-up.Therefore, we can observe the changes in HDL-C and further explore the effect of changes in HDL-C on the reversion from pre-DM to normoglycemia in the future through a generalized additive mixed model.

Conclusion
This study demonstrated an independent connection between HDL-C and regression to normoglycemia in Chinese adults with Pre-DM, revealing a specific non-linear relationship and threshold effect.A significant positive connection was observed between HDL-C levels and the regression from Pre-DM to normoglycemia to normoglycemia, particularly when HDL-C levels were below the inflection point.Consequently, keeping HDL-C levels near the inflection point in patients with prediabetes may greatly increase the likelihood of reversion from pre-DM to normoglycemia.

Figure 3 .
Figure 3. (A)The relationship between HDL-C levels and the reversion to normoglycemia from Pre-DM stratified by gender.A non-linear relationship between HDL-C levels and reversion to normoglycemia from Pre-DM was detected in males after adjustment for DBP, SBP, BMI, age, drinking status, family history of diabetes, smoking status, FPG, AST, BUN, ALT, LDL-C, Scr, and TG.(B) The relationship between HDL-C levels and the reversion to normoglycemia from Pre-DM stratified by gender.A non-linear relationship between HDL-C levels and reversion to normoglycemia from Pre-DM was detected in females after adjustment for DBP, SBP, BMI, age, drinking status, family history of diabetes, smoking status, FPG, AST, BUN, ALT, LDL-C, Scr, and TG.

Table 1
presented the medical characteristics and demographic of the research participants.The mean age was 50.921 ± 13.437 years, with 5414 (35.110%) female participants.The median follow-up time was 2.883 years, and 6627 (42.977%) participants experienced a final reversion to normoglycemia from Pre-DM.The mean ± SD

Table 1 .
The baseline characteristics of participants.Values are n (%) or mean ± SD or median (quartile).HDL-C high-density lipoprotein cholesterol, SBP systolic blood pressures, DBP diastolic blood pressures, BMI body mass index, AST aspartate aminotransferase, ALT alanine aminotransferase, LDL-C low-density lipoprotein cholesterol, TC total cholesterol, TG triglycerides, Scr serum creatinine, BUN blood urea nitrogen, FPG fasting plasma glucose.

Table 2 .
The rate of reversion from Pre-DM to normoglycemia.HDL-C high-density lipoprotein cholesterol, CI confidence interval.

Table 4 .
Relationship HR hazard ratios, CI confidence interval, Ref reference, GAM generalized additive mode, HDL-C high-density lipoprotein cholesterol.

Table 6 .
The result of the two-piecewise Cox proportional hazards regression model.Note 1: In all participants, we adjusted DBP, SBP, BMI, gender, age, drinking status, family history of diabetes, smoking status, FPG, AST, BUN, ALT, LDL-C, Scr, and TG.Note 2: For Male and Female subgroups, we adjusted for DBP, SBP, BMI, age, drinking status, family history of diabetes, smoking status, FPG, AST, BUN, ALT, LDL-C, Scr, and TG.HR hazard ratios, CI confidence, HDL-C high-density lipoprotein cholesterol.

Table 7 .
Effect size of HDL-C levels and reversion to normoglycemia from Pre-DM in prespecified and exploratory subgroups.Note 1: Above model was adjusted for DBP, SBP, BMI, gender, age, drinking status, family history of diabetes, smoking status, FPG, AST, BUN, ALT, LDL-C, Scr, and TG.Note 2: The model is not adjusted for the stratification variable in each case.