Introduction and Objective: Hypercortisolism is present in almost 1 in 4 patients with difficult-to-control type 2 diabetes (T2D) per the CATALYST study, yet often goes undetected as current diagnostics rely on single-timepoint assessments. These patients undergo escalation of medication for glycemic control without assessing underlying metabolic contributors. Continuous cortisol monitoring (CCM), analogous to continuous glucose monitoring (CGM), could enable detection of occult hypercortisolism. We report first-in-human results from a multiplexed wearable CCM device measuring free cortisol in dermal interstitial fluid (ISF) using molecular switches. Methods: The CCM device employs a 16-channel multiplexed sensor array (8 cortisol-specific aptamer-based molecular switches, 8 controls) to measure free cortisol in dermal ISF. Sensitivity was established in artificial ISF. In-human testing included: (1) exogenous cortisol challenge (n=3) with 20 mg oral hydrocortisone, venous blood sampled every 30 min and analyzed by equilibrium dialysis/LC-MS/MS as reference; (2) overnight diurnal monitoring (n=3) to capture endogenous circadian dynamics. Results: The device achieved high sensitivity in artificial ISF (LOD 1 nM) with inter-sensor CV of ~5% across the array. During exogenous challenge, the device tracked free cortisol rise and fall post-hydrocortisone with good concordance to the reference method. In diurnal monitoring, the device captured circadian patterns including nocturnal nadir and cortisol awakening response consistent with known physiology. Conclusion: To our knowledge, this is the first multiplexed continuous free cortisol measurement in human dermal ISF. Just as CGM transformed diabetes care, CCM may enable a new paradigm for detecting hypercortisolism-driven dysglycemia in T2D. This platform extends beyond cortisol, with the potential to unlock continuous monitoring of metabolic biomarkers that have never been measured in real-time. Further clinical validation is underway. Disclosure N.A. Emmons: None. I. Thompson: Employee; Current; Adaptyx Biosciences. D. Grossman: Employee; Current; Adaptyx Biosciences, Inc. E.A. Christofides: Consultant; Current; Abbott. Research Support; Current; Abbott Diabetes, Amgen Inc. Speaker's Bureau; Current; Ascendis Pharma A/S, Chiesi USA, Inc., Eli Lilly and Company. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Madrigal Pharmaceuticals, Inc. Research Support; Current; Novo Nordisk A/S. Speaker's Bureau; Current; Recordati S.p.A, Xeris Pharmaceuticals, Inc. Advisory Panel; Current; Xeris Pharmaceuticals, Inc. Research Support; Current; Corcept Therapeutics. Speaker's Bureau; Current; Corcept Therapeutics. A. Yoshikawa: Employee; Current; Adaptyx Biosciences. Board Member; Current; Adaptyx Biosciences.
Emmons et al. (Fri,) studied this question.