Temporal relationship between atherogenic dyslipidemia and inflammation and their joint cumulative effect on type 2 diabetes onset: a longitudinal cohort study

Abstract

Background: Concurrent atherogenic dyslipidemia and elevated inflammation are commonly observed in overt hyperglycemia and have long been proposed to contribute to diabetogenesis. However, the temporal relationship between them and the effect of their cumulative co-exposure on future incident type 2 diabetes (T2D) remains unclear.

Methods: Longitudinal analysis of data on 52,224 participants from a real-world, prospective cohort study (Kailuan Study) was performed to address the temporal relationship between high-sensitivity C-reactive protein (hsCRP) and the atherogenic index of plasma (AIP, calculated as triglyceride/high-density lipoprotein) in an approximately 4-year exposure period (2006/2007 to 2010/2011). After excluding 8824 participants with known diabetes, 43,360 nondiabetic participants were included for further analysis of the T2D outcome. Cox regression models were used to examine the adjusted hazard ratios (aHRs) upon the cumulative hsCRP (CumCRP) and AIP (CumAIP) in the exposure period.

Results: In temporal analysis, the adjusted standardized correlation coefficient (β1) of hsCRP_2006/2007 and AIP_2010/2011 was 0.0740 (95% CI, 0.0659 to 0.0820; P < 0.001), whereas the standardized correlation coefficient (β2) of AIP_2006/2007 and hsCRP_2010/2011 was - 0.0293 (95% CI, - 0.0385 to - 0.0201; P < 0.001), which was significantly less than β1 (P < 0.001). During a median follow-up of 7.9 years, 5,118 T2D cases occurred. Isolated exposure to CumAIP or CumCRP was dose-dependently associated with T2D risks, independent of traditional risk factors. Significant interactions were observed between the median CumAIP (- 0.0701) and CumCRP thresholds (1, 3 mg/L) (P = 0.0308). Compared to CumAIP < - 0.0701 and CumCRP < 1 mg/L, those in the same CumAIP stratum but with increasing CumCRP levels had an approximately 1.5-fold higher T2D risk; those in higher CumAIP stratum had significantly higher aHRs (95% CIs): 1.64 (1.45-1.86), 1.87 (1.68-2.09), and 2.04 (1.81-2.30), respectively, in the CumCRP < 1, 1 ≤ CumCRP < 3, CumCRP ≥ 3 mg/L strata. Additionally, the T2D risks in the co-exposure were more prominent in nonhypertensive, nondyslipidemic, nonprediabetic, or female participants.

Conclusions: These findings suggest a stronger association between elevated hsCRP and future AIP changes than vice versa and highlight the urgent need for combined assessment and management of chronic inflammation and atherogenic dyslipidemia in primary prevention, particularly for those with subclinical risks of T2D.

Keywords: Dyslipidemia; Inflammation; Temporal relationship Longitudinal study; Type 2 diabetes.

Fig. 1

Flowchart of the study participants

Fig. 2

Strategies and design of the current study. The health examinations in the Kailuan Study were provided around every 2 years, except for the current last visit, with a time span of approximately 3 years owing to the influence of the COVID-19 pandemic. For the current study, the path analysis addressing the temporal relationship between AIP and hsCRP was based on data measured in 2006/2007 and 2010/2011. For the survival analysis of T2DM outcome, the cumulative exposure period was from 2006/2007 to 2010/2011. At the end of Visit_2010/2011, the nondiabetic participants were followed up biannually through December 31, 2020. Baseline characteristics were based on the information in Visit_2010/2011

Fig. 3

Cross-lagged standard regression coefficient of hsCRP and AIP (n = 52,225). *P < 0.001. The cross-lagged model was adjusted for age, sex, education, smoking status, drinking status, physical activities, family history of diabetes, BMI, FBG, SBP, TC, eGFR (categorical), antihypertensives, lipid-lowering drugs measured in 2006/2007, and time intervals. Abbreviations: AIP, atherogenic index of plasma; BMI, body mass index; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; HsCRP, high-sensitivity C-reactive protein; SBP, systolic blood pressure; TC, total cholesterol

Fig. 4

Kaplan–Meier curves of the cumulative incidence of T2D over a mean of 7.9 years follow-up across CumAIP-CumCRP subgroups. G1: CumAIP < − 0.0701 and CumCRP < 1 mg/L; G2: CumAIP < − 0.0701 and 1 ≤ CumCRP < 3 mg/L; G3: CumAIP < − 0.0701 and CumCRP ≥ 3 mg/L; G4: CumAIP ≥ − 0.0701 and CumCRP < 1 mg/L; G5: CumAIP ≥ − 0.0701 and 1 ≤ CumCRP < 3 mg/L; G6: CumAIP ≥ − 0.0701 and CumCRP ≥ 3 mg/L. G1 was used as the reference group