Real-World EHR Signals from a Cohort of Blinded Incretin Trial Participants Motivate Novel Indication Opportunities

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Abstract

Understanding organ-specific effects of multi-agonist metabolic therapies beyond weight loss remains challenging, particularly while randomized clinical trials are ongoing and treatment allocation remains blinded. Here, we evaluated whether real-world longitudinal biomarker trajectories can provide early hypothesis-generating signals associated with masked trial-medication exposure. Using propensity-matched, de-identified electronic health records from a large federated health network, we compared changes in laboratory and physiologic biomarkers across receptor-defined metabolic therapies. Semaglutide, tirzepatide, and pramlintide served as reference therapies representing GLP-1 receptor, dual GIPR-GLP1R, and amylin-pathway pharmacology, respectively. Individuals with documented participation in a blinded CagriSema/placebo clinical trial were analyzed as a single masked exposure group because active treatment assignment could not be determined from routine-care records. Twenty-five CagriSema/placebo participants were propensity matched 1:5 to tirzepatide (n=125) and empagliflozin (n=125). At 6 months, the masked CagriSema/placebo cohort showed similar changes in weight and HbA1c compared with matched tirzepatide-treated patients (weight, -7.7% vs -10.2%, P=0.27; HbA1c, -2.8% vs -5.1%, P=0.69), but larger increases in estimated glomerular filtration rate (+26.4% vs +6.5%, BH P=0.028). Compared with matched empagliflozin-treated patients, the masked cohort demonstrated larger reductions in weight (-7.7% vs -3.5%, P=0.048), mean arterial pressure (-12.0% vs -1.0%, BH P<0.001), creatinine (-17.4% vs -2.4%, BH P=0.020), and greater increases in eGFR (+26.4% vs +6.4%, BH P=0.030). To provide pharmacologic context, patients with type 2 diabetes receiving basal insulin who initiated pramlintide were independently matched to tirzepatide (652 pairs) and semaglutide (761 pairs). Tirzepatide and semaglutide were associated with larger HbA1c reductions than pramlintide at 6 months (-9.0% vs -3.0%, BH P<0.001; -10.1% vs -3.5%, BH P<0.001). However, after normalization for weight loss, pramlintide demonstrated greater blood pressure reduction per kilogram of weight lost than tirzepatide for both systolic (-4.9 vs -3.4% per kg, BH P=0.046) and diastolic blood pressure (-5.7 vs -3.4% per kg, BH P=0.029), whereas tirzepatide and semaglutide showed similar weight-normalized laboratory responses. Medication-transition analyses did not support co-intervention confounding, and single-cell transcriptomic analyses demonstrated substantially broader expression of amylin receptor components (CALCR, RAMP1/2/3) than GIPR or GLP1R in the kidney (9.8-14.7-fold). These findings illustrate how real-world longitudinal biomarker analyses can complement ongoing blinded clinical trials by identifying early, hypothesis-generating physiologic signals associated with masked trial-medication exposure. The observed renal and blood-pressure patterns, together with receptor-expression analyses, motivate prospective evaluation after trial unblinding to determine whether they reflect amylin-pathway biology or other treatment-associated effects.

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