SAT-249 Hydroxychloroquine Modifies Lipoprotein Metabolism in Adults with Insulin Resistance

Abstract Disclosure: T.B. Mendes: None. R.G. Miller: None. F.G. Toledo: None. Background: Hydroxychloroquine (HCQ) is widely used to treat rheumatologic diseases. In addition to immunomodulatory effects, HCQ improves glucose metabolism and dyslipidemia, but its impact on specific lipoprotein subclasses remains unexplored. Methods: Lipoproteins subclasses were measured by NMR spectroscopy in blood samples from participants of a mechanistic trial that investigated the effects of HCQ on insulin resistance. Key inclusion criteria were BMI>25 kg/m2 and 1+ markers of insulin resistance, and key exclusion criteria were diabetes, autoimmune disease, and corticosteroid use. Participants were assigned to either HCQ 400 mg/day (n=17) or placebo (n=15) (randomized, double-blinded) for 13 ± 1 weeks. Within-treatment change and between-treatment difference were analyzed by mixed-effects linear regression models to obtain maximum likelihood-based estimates of change. Outcomes are reported as placebo-adjusted changes from baseline. Results: 75% of participants were female and 84% had a family history of diabetes. Mean age was 44.9 ± 16.8 and 50.1 ± 14.5 years in the placebo and HCQ group, respectively. BMI was 35.9 ± 6.2 Kg/m2 in the placebo and 34.1 ± 7.2 Kg/m2 in the HCQ group.Treatment with HCQ affected several lipid fractions. Triglycerides decreased by 36 mg/dL, a 27.2% placebo-adjusted reduction from baseline (p=0.04). Total cholesterol decreased by 19 mg/dL, equivalent to a 10.1% reduction (p=0.003). The LDL fraction decreased by 14 mg/dL, a 11.9% reduction (p<0.001) but HDL cholesterol was unaffected (+2.5 mg/dL, 4.56%, p=0.15). Non-HDL cholesterol decreased by 22 mg/dL, or 15.7% (p<0.001).Although HCQ lowered triglycerides, it did not change VLDL particle concentration (-17.2%, p=0.18). In contrast, HCQ lowered LDL particles by 15.6% (p=0.02) and apo B-100 by 10.1% (p=0.009). HCQ did not change total HDL particle concentration (-3.57%, p=0.23), but increased large HDL particle concentrations by 13.8% (p =0.02), and decreased small HDL concentrations by 18.5% (p =0.04). Apo A1 concentration decreased by 4%, but without statistical significance (p=0.06). In sensitivity analyses, adjustment for sex, age, and BMI yielded similar findings. Conclusion: HCQ lowers cholesterol levels by decreasing circulating LDL particle concentrations. In contrast, HCQ lowers triglycerides without affecting VLDL particles concentrations, implying that it reduces the triglyceride content of VLDL particles. While HCQ treatment did not impact HDL cholesterol levels or total particle concentrations in this study, it affected the relative distribution between small and large HDL particles. HCQ changes lipoprotein metabolism in individuals with insulin resistance, promoting a less atherosclerotic profile. These findings suggest potential therapeutic cardiovascular benefits that warrant further investigation. Presentation: Saturday, July 12, 2025