Association between pcsk9 levels and diabetes risk: a community-based nested case-control study

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as both a promising therapeutic target and a risk factor for cardiovascular disease (CVD)(1). Evidence suggests that elevated PCSK9 levels are associated with an increased risk of CVD, while the widespread use of PCSK9 inhibitors has demonstrated significant protective effects against cardiometabolic disorders(2, 3). Meanwhile, diabetes mellitus (DM) remains a major chronic disease and a well-established cardiovascular risk factor. However, the relationship between PCSK9 and DM remains uncertain(4). Given the growing interest in targeting PCSK9 as a therapeutic strategy for cardiometabolic disorders, it is crucial to assess the association between PCSK9 levels and the risk of new-onset diabetes mellitus (NODM). Purpose To explore the association between circulating PCSK9 level and NODM in general population Methods This nested case-control study included NODM cases and controls matched by age and sex, all free from DM, stroke, and coronary heart disease at baseline. Participants were derived from a community-based cohort focusing on cardiovascular risk factors, followed from 2012 to 2018. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals, while restricted cubic spline analyses examined the nonlinear association. Results From 3,347 eligible participants, this study identified 336 NODM cases and 336 matched controls. A nonlinear association between PCSK9 levels and NODM was observed after multivariable adjustment (P = 0.045), with a cut-off value of 197.29 ng/ml (Figure 1A). A negative association was found in individuals with PCSK9 levels below this threshold (OR 0.352, 95% CI: 0.127–0.973 for a 100 ng/ml increase). Conditional logistic regression revealed that the highest quartile of PCSK9 levels was associated with a significantly higher risk of NODM compared to the second quartile (OR 1.830, 95% CI: 1.076–3.111) (Figure 2). This association was consistent in females (Figure 1C, P = 0.004) and the prediabetic population (Figure 1B, P = 0.041), but no significant association was observed in males (Figure 1D). Subgroup analyses showed significant interactions by sex (P for interaction = 0.025) and menopause status (P for interaction = 0.048). Conclusions We observed a U-shaped association between PCSK9 levels NODM, indicating increased diabetic risk at both high and low PCSK9 levels. This relationship remained consistent in females but not in males. Given PCSK9’s critical role in cardiovascular disease treatment, monitoring PCSK9 levels may be important for assessing diabetes risk, warranting further investigation.Nonlinear association with NODM Table for associations with NODM