ICAM-1 Associates Glycemic Variability with Persistent Systemic Inflammation after Intensive LDL-Cholesterol Reduction in Type 1 Diabetes

Introduction and Objective: Intercellular adhesion molecule-1 (ICAM-1) reflects endothelial activation and contributes to cardiovascular disease risk in type 1 diabetes (T1D). Whether systemic inflammation persists after intensive LDL-cholesterol (LDL-c) reduction and how it relates to glycemic variability (GV) in T1D remains unclear. We examined plasma ICAM-1 responses to intensive LDL-c reduction and its relationship with GV. Methods: Adults with T1D and LDL-c ≥100 mg/dL underwent intensive lipid lowering with a PCSK9 inhibitor plus atorvastatin or ezetimibe for 30 days. Plasma ICAM-1 and inflammatory markers were measured before and after LDL-c reduction. GV indices were derived from 30-day continuous glucose monitoring. Associations among ICAM-1, GV, HbA1c, and body mass index (BMI) were evaluated. Results: Analysis were conducted among 72 participants with available biomarker and CGM data. Participants were 37.6±12.3 years of age; 63% female, and HbA1c was 6.9±1.1%. Intensive therapy achieved an LDL-c reduction (−83.5±30.3 mg/dL). Despite marked LDL-c lowering, ICAM-1 concentrations did not change and remained associated with HbA1c (p=0.01) and CGM-derived GV indices including continuous overall net glycemic action (p<0.05). Those with HbA1c of ≥8 had more post-treatment ICAM-1 concentrations when compared to individuals with HbA1c of ≤6.5% (p=0.03). After LDL-c reduction, BMI was associated with GV and elevated hsCRP concentrations, indicating residual systemic inflammation. Conclusion: ICAM-1 identifies persistent systemic inflammation after intensive LDL-c reduction in T1D. Dysglycemia and adiposity remain key drivers of residual cardiovascular risk. These findings underscore that ICAM-1 is a biomarker that connects CGM-derived dysglycemia to endothelial inflammation, and suggest targeting GV and obesity mitigates systemic and potentially endothelial inflammation beyond lipid lowering alone. Disclosure: B. Dorcely: None. L. Huggins: None. B. Russell: None. M.P. Komack: None. C.N. Calistru: None. A. Akinlonu: None. C. Bredefeld: None. L. Golden: None. C. Levy: Research Support; Current; Tandem Diabetes Care, Inc., Novo Nordisk, Abbott Diabetes, MannKind Corporation. Consultant; Current; MannKind Corporation, Tandem Diabetes Care, Inc. Research Support; Current; Deka/Sequel, Dexcom, Inc., Genti Bio. Consultant; Current; Deka/Sequel. J. Berger: None. I.J. Goldberg: Advisory Panel; Current; arrowhead. Funding: National Institutes of Health (5R01HL164949-04)