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Abstract Importance Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists have demonstrated what may be considered transformative efficacy in recent randomized clinical trials for the treatment of obesity, yielding substantial weight loss in a majority of participants. However, the extent to which these trial results translate into routine clinical practice particularly within the rapidly expanding direct-to-consumer (DTC) telehealth sector serving self-pay populations remains insufficiently characterized. As access to and affordability of these therapies broaden beyond traditional insurance-based care models, evaluating real-world effectiveness, safety, and patient engagement among individuals shouldering the full financial cost of treatment is essential for informing future models of obesity care delivery. Objective To assess long-term medication specific weight loss outcomes, including gender-specific responses and discrepancies, and explore usage trends in a real-world, self-pay telehealth cohort receiving GLP -1 RA therapy, using an Observational study design (Retrospective data analysis). Setting and Participants Retrospective data of patients enrolled in electronic health records (EHR) from CareValidate, a national US telehealth platform provider for Online TeleHealth companies. The data collected ranged for a total of 703 days from January 12, 2024, to December 15, 2025. The analysis included 572 adults with overweight or obesity diagnosis who initiated treatment with semaglutide or tirzepatide and completed a minimum of 9 months of active follow-up. Patients with insufficient follow-up or those utilizing insurance coverage were excluded to isolate the self-pay phenotype. Exposures Prescription of semaglutide or tirzepatide (injectable or oral formulations) via synchronous or asynchronous telehealth consultations, titrated according to standard clinical protocols adapted for patient tolerance and financial sustainability. Main Outcomes and Measures The primary outcome was percentage total body weight loss (%TBWL) from baseline to the last recorded encounter. Secondary outcomes included categorical responder rates (≥5%, ≥10%, ≥15%, >20% weight loss), weight loss velocity analysis, and telehealth utilization metrics (frequency of encounters and visit intervals) including gender differences in approaching the telehealth program. Results The final analytical cohort included 572 patients (79.2% female; 20.8% male). Overall, 95.8% (548/572) achieved weight loss, while 3.7% experienced weight gain. At 12 months, the mean %TBWL was 13.8% for the semaglutide cohort (n=450) and 12.5% for the tirzepatide cohort (n=122), with no statistically significant difference between the two medications (P >.05), contrary to standard clinical trial data suggesting tirzepatide superiority. A significant gender difference was observed: females were significantly more in number comprising 80% of the cohort and were likely to be “major responders” (>20% weight loss) compared to males (29.8% vs 5.9%; P <.001). Conversely, males demonstrated significantly higher utilisation rates, attending more frequent encounters (mean 13.5 vs 12.7; P =.028) with shorter intervals between visits (35.6 vs 44.1 days; P =.009) compared to females. Weight loss velocity for both medications peaked during months 1 to 3 (∼1.07 lbs/week) and declined substantially by months 12–15, indicating a plateau effect independent of the specific agent used. Conclusions and Relevance Telehealth-managed GLP 1 treatment in a self-pay population demonstrates high efficacy comparable to clinical trials for semaglutide. However, tirzepatide outcomes fell short of trial benchmarks, likely due to economic barriers preventing optimal dose titration and lower sample size. The study identifies a discrepancy where females approach the telehealth based self pay system more but males engage more frequently with the digital platform which could be due to inferior physiological outcomes (less weight loss and more non responders) compared to females.This suggests that while telehealth is a viable model for long-term obesity care, the “one size fits all” approach may be insufficient for underresponders, who may require distinct titration strategies or tailored behavioral interventions to overcome baseline genetic & biological resistance.