Endogenous Incretin Secretagogue Compositions as a Mechanistic Class Versus Pharmacological Incretin Receptor Agonists for Weight Reduction in Overweight Adults: A Real-World Observational Cohort Analysis of a Nutraceutical Composition (Trimsulin) and Comparison with Published Outcomes for Semaglutide and Tirzepatide

Endogenous Incretin Secretagogue Compositions as a Mechanistic Class Versus Pharmacological Incretin Receptor Agonists for Weight Reduction in Overweight Adults: A Real-World Observational Cohort Analysis of a Nutraceutical Composition (Trimsulin) and Comparison with Published Outcomes for Semaglutide and Tirzepatide | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endogenous Incretin Secretagogue Compositions as a Mechanistic Class Versus Pharmacological Incretin Receptor Agonists for Weight Reduction in Overweight Adults: A Real-World Observational Cohort Analysis of a Nutraceutical Composition (Trimsulin) and Comparison with Published Outcomes for Semaglutide and Tirzepatide Richard Clark Kaufman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9657897/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Pharmacological glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists such as tirzepatide produce clinically meaningful weight reduction in adults with overweight or obesity. However, gastrointestinal and serious adverse events affect a substantial proportion of treated patients, contributing to discontinuation and limiting long-term adherence. Nutraceutical compositions designed to stimulate endogenous GLP-1 and GIP secretion may offer a tolerability advantage. Objective: To describe weight change and adverse event rates in a real-world cohort of overweight adults using a nutraceutical endogenous incretin secretagogue composition (Trimsulin Weight Loss Program) and to compare these outcomes with publicly available outcome data for semaglutide and tirzepatide. Methods: Observational cohort analysis of 503 overweight adults enrolled in the Trimsulin Weight Loss Program, comprising two nutraceutical products (Control, a powdered drink mix; Thermo, a capsule formulation) taken twice daily before meals, plus a structured dietary protocol and a moderate-exercise recommendation. Body weight, BMI, and participant-reported adverse events were tracked at 12 weeks and 24 weeks. Comparative weight-loss outcomes for semaglutide and tirzepatide were drawn from the on-treatment estimand of the published Truveta-derived real-world cohort analysis by Rodriguez et al. (n = 18,386; mean baseline BMI 39.0). Comparative adverse event rates were drawn from a separate body of clinical trial and pharmacovigilance evidence. Outcomes are reported descriptively; no inferential statistical testing was performed between cohorts. Results: Of more than 1,000 enrolled program participants, 503 completed six months of program participation with protocol-conformant follow-up measurements and constitute the analysis cohort. Mean baseline weight was 201.2 lb (range 130–360); mean BMI was 27.5 (range 20.0–50.1). At 3 months, mean weight reduction was 7.3% in the Trimsulin cohort, compared with 3.6% (semaglutide) and 5.9% (tirzepatide) reported in published comparator data. At 6 months, mean reductions were 14.1%, 5.8%, and 10.1%, respectively. Any adverse event was reported by 4.8% of Trimsulin participants, compared with 89.7% (semaglutide) and 81.0% (tirzepatide) in published trial cohorts. No serious adverse events were reported in the Trimsulin cohort, compared with approximately 3.0% for semaglutide and 5–7% for tirzepatide. These hypothesis-generating findings support further controlled investigation of endogenous incretin secretagogue compositions as a class. The present cohort study evaluated one licensed implementation of the BSM platform framework. Future research directions of highest priority include prospective randomized controlled trials of BSM-framework compositions — including next-generation formulations incorporating more advanced ingredient systems and delivery architectures — compared against placebo and against active pharmacological incretin comparators. Secondary endpoints of particular mechanistic value include changes in plasma active GLP-1 and GIP concentrations, DPP-4 activity, fasting and post-prandial glycemic response, UCP-1 induction, and patient-reported tolerability. A factorial design apportioning the contribution of the BSM supplement components versus the dietary and behavioral program elements would clarify the mechanistic contribution of each. Adjunctive use of BSM-framework compositions in patients who discontinue pharmacological incretin therapy due to intolerance represents a clinically meaningful research direction, given the established real-world discontinuation burden of pharmacological GLP-1 receptor agonists. [11–14] Beyond supplement formats, investigation of BSM-framework ingredient systems in functional food and food-additive delivery formats represents a translational research direction of broader public health relevance, given the potential for population-scale access that food-category routes offer relative to pharmaceutical channels. Endocrinology & Metabolism obesity weight loss GLP-1 GIP incretin nutraceutical secretagogue semaglutide tirzepatide observational cohort real-world evidence 1. Introduction Overweight and obesity are highly prevalent conditions associated with increased morbidity, cardiovascular mortality, and metabolic disease burden. [1–3] Pharmacological treatments — particularly GLP-1 receptor agonists (GLP-1RAs) such as semaglutide and dual GIP/GLP-1 receptor agonists such as tirzepatide — have demonstrated clinically significant weight reduction and metabolic benefit in randomized controlled trials. [4–7] Despite these efficacy findings, real-world adoption is constrained by adverse event burden, discontinuation, cost, and the need for chronic injectable administration. Real-world discontinuation of pharmacological GLP-1RA therapy reaches approximately 50% within one year and approximately 70% within two years of initiation, with primary reasons including gastrointestinal intolerance, preference for oral over injectable administration, and out-of-pocket cost; approximately 13% of discontinuations cite cost as the principal driver. The combination of these access barriers — clinical, behavioral, and financial — leaves a substantial population of overweight and obese adults without an effective, tolerable, accessible option for incretin-based weight management. GLP-1RAs mimic the actions of the endogenous incretin hormone GLP-1, which is secreted from intestinal enteroendocrine L-cells and from neurons in the nucleus tractus solitarius. GIP is a second incretin hormone secreted from intestinal K-cells. Pharmacological GLP-1RAs are engineered to resist degradation by dipeptidyl peptidase-4 (DPP-4), which prolongs systemic exposure relative to native GLP-1. Increasing evidence suggests that pharmacological GLP-1RAs and endogenous incretin signaling diverge mechanistically even where their downstream clinical effects overlap. [6,8] In preclinical models, endogenous GLP-1 secretagogues combined with DPP-4 inhibition have been shown to elevate active endogenous GLP-1 to concentrations approaching those produced by exogenous pharmacological agonists. [7] Endogenous GLP-1 and GIP releasers include nutritional fibers, phytochemicals, botanical extracts, fatty acids, resistant starches, flavonoids, alkaloids, peptides, and selected probiotic and prebiotic compounds — many of which carry generally recognized as safe (GRAS) regulatory status. Flavonoid compounds with documented in-vitro DPP-4 inhibitory activity may contribute to extended active incretin half-life when administered in combination with secretagogues. Trimsulin is a nutraceutical composition designed to (a) stimulate endogenous GLP-1 and GIP release, (b) inhibit DPP-4-mediated degradation of active incretins, (c) activate uncoupling protein 1 (UCP-1)-mediated thermogenesis and white-to-brown adipocyte conversion, and (d) activate hormone-sensitive lipase to support lipid mobilization. The licensed formulation comprises two products taken in combination — Trimsulin Control (a powdered drink mix) and Trimsulin Thermo (a capsule formulation) — and is delivered to consumers as part of an integrated weight-management program that includes a structured dietary protocol and moderate-exercise recommendation (see Section 2.3). Current pharmacological incretin therapies achieve substantial weight reduction, but adverse events affect more than 80% of treated patients in published trial populations. [11–14] This study reports outcomes from a real-world observational cohort of 503 overweight adults who used the Trimsulin Weight Loss Program and compares these outcomes descriptively with published outcomes for semaglutide and tirzepatide. The primary aim is hypothesis-generating: to characterize the weight-reduction and adverse-event profile of an endogenous incretin secretagogue composition under real-world conditions and to inform subsequent randomized controlled investigations. 1.1 Prior Evidence on Endogenous Incretin Secretagogues The mechanistic premise underlying the present study draws on a growing preclinical and small-trial literature characterizing individual endogenous incretin secretagogue compounds. Berberine, an isoquinoline alkaloid present in the Control composition evaluated here, has demonstrated AMPK activation, hepatic gluconeogenesis suppression, and modulation of incretin axis activity in both rodent and human studies. Soluble dietary fibers, including inulin, support intestinal L-cell density and postprandial GLP-1 secretion through fermentation-derived short-chain fatty acid signaling at FFAR2 and FFAR3 receptors. Quercetin and myricetin — flavonoids present in the Control composition — have demonstrated in-vitro DPP-4 inhibitory activity at micromolar concentrations, although the in-vivo clinical magnitude relative to pharmacological inhibitors remains under investigation. Mulberry leaf extract demonstrates α-glucosidase inhibitory activity that attenuates postprandial glycemic excursion through delayed carbohydrate hydrolysis. Allulose, a rare sugar with a very low metabolizable carbohydrate load, has demonstrated independent attenuation of postprandial glycemic response in randomized human studies. What has not previously been reported in the published literature is a real-world cohort outcome assessment of a coordinated multi-compound endogenous incretin secretagogue composition formulated to simultaneously stimulate dual GLP-1 and GIP release, inhibit DPP-4-mediated incretin degradation, and engage downstream metabolic regulatory pathways. The present analysis addresses this gap. The work is positioned as the first published real-world cohort evaluation in a class of nutraceutical compositions defined mechanistically — endogenous incretin secretagogues with adjunctive DPP-4 inhibition and downstream pathway coordination — rather than as a single-product evaluation. 2. Methods 2.1 Study Design This was a retrospective observational cohort analysis of de-identified outcome data from adult participants enrolled in the Trimsulin Weight Loss Program, a commercially available wellness program. The methodological framework was modeled on the outcome assessment protocols used in published GLP-1RA and dual GIP/GLP-1RA trials [4–7] to support cross-cohort comparability. The study was not a randomized, placebo-controlled clinical trial. 2.2 Setting and Participants Participants were drawn from a Trimsulin Weight Loss Program population of more than 1,000 enrolled adults. Of this larger program population, 503 participants provided complete six-month outcome data and were included in the analysis cohort. Inclusion in the analysis cohort required (a) baseline body weight at program enrollment, (b) program participation through six months, and (c) protocol-conformant follow-up measurements at the 12-week and 24-week timepoints. Participants who enrolled but did not complete six months of program participation, or who did not provide follow-up measurements at both protocol timepoints, were not included in the analysis cohort. The implications of this selection process for the interpretation of cohort outcomes are addressed in Section 4.4 (Limitations). Demographic data, racial background, height, waist circumference, baseline weight, BMI, monthly weight changes, and participant-reported adverse events were captured for all 503 analyzed participants. Data Collection Protocol Outcome data were collected through a structured online reporting framework developed by the principal investigator and modeled on the data-collection protocols used in the pivotal pharmacological GLP-1 receptor agonist clinical trials [4–7] referenced as comparators in this analysis. Specific protocol elements included: (a) baseline weight measurement and confirmation at program enrollment; (b) standardized self-measurement instructions, including consistent time of day for weighing, consistent scale, consistent clothing/state-of-fasting conditions, and instructions to record measurements immediately rather than from recall; (c) incremental monthly reporting rather than retrospective reporting at study endpoints, to reduce recall bias and improve temporal resolution of weight trajectories; and (d) structured prompted adverse-event reporting at each follow-up timepoint, including specific prompted categories (gastrointestinal, neurologic, cardiovascular, musculoskeletal, sleep, and "other") rather than open-ended self-disclosure alone. Modeling the data-collection framework on published pharmaceutical trial protocols was a deliberate methodological choice intended to improve cross-cohort comparability with the comparator data sources used in this analysis. The protocol is available from the corresponding author. 2.3 Intervention The Trimsulin Weight Loss Program, as evaluated in this analysis, comprised two licensed nutraceutical products taken together daily, accompanied by a structured dietary protocol and a moderate-exercise recommendation. The two products are commercially distributed by FirstFitness Nutrition (FFN) under the Trimsulin® trademark and are described below using FFN's published product information. Trimsulin Control. A sugar-free, mango-flavored powdered drink mix. Active components and mechanistic rationale by ingredient: allulose — a rare low-metabolizable sugar with documented attenuation of postprandial glycemic excursion and endogenous GLP-1 secretagogue activity; inulin (chicory-derived) — a prebiotic soluble fiber supporting intestinal L-cell density and GLP-1 secretion through FFAR2/FFAR3 short-chain fatty acid signaling; resistant starch — a non-digestible carbohydrate with prebiotic fermentation-mediated GLP-1 and GIP secretagogue activity; myricetin — a flavonoid with documented in-vitro DPP-4 inhibitory activity and GLP-1 secretagogue properties; mulberry leaf polyphenols — α-glucosidase inhibitory activity attenuating postprandial carbohydrate absorption and supporting downstream incretin signaling; mangosteen extract — botanical extract with documented GLP-1 secretagogue activity and anti-inflammatory properties; resveratrol — stilbenoid polyphenol with documented DPP-4 inhibitory activity and sirtuin1-AMPK pathway activation; pterostilbene — a methylated resveratrol analog with enhanced bioavailability, insulin-resistance improvement, and AMPK activation; quercetin — flavonoid with documented in-vitro DPP-4 inhibitory activity; alpha-lipoic acid — a mitochondrial cofactor with documented insulin-sensitizing and antioxidant activity; chromium picolinate — a trace mineral cofactor supporting insulin receptor signaling and glucose disposal; turmeric root (a source of curcuminoids) — with documented DPP-4 inhibitory activity and anti-inflammatory pathway modulation. The coordinated multi-compound formulation constitutes the inventive composition underlying the pending patent estate (see Regulatory positioning, below); individual compounds are not novel in isolation. Administration: one 7-gram level scoop dissolved in 4–6 fl oz of cold water, taken twice daily 30–60 minutes before breakfast and before dinner. Trimsulin Thermo. A capsule formulation. Active components and mechanistic rationale by ingredient: caffeine — methylxanthine with sympathomimetic and phosphodiesterase-inhibitory thermogenic activity; green coffee bean extract (standardized to 50% chlorogenic acid / 20% caffeine) — source of chlorogenic acid, a GIP secretagogue and α-glucosidase inhibitor, combined with adjunctive caffeine thermogenesis; synephrine HCl — selective β3-adrenergic receptor agonist supporting adipose lipolysis and thermogenesis with a reduced cardiovascular activation profile relative to ephedrine-class compounds; yohimbine HCl — α2-adrenergic receptor antagonist supporting catecholamine-mediated lipolysis from regional adipose depots resistant to β-adrenergic stimulation; forskolin (30% standardized extract) — diterpene adenylyl cyclase activator elevating intracellular cAMP and supporting hormone-sensitive lipase-mediated fat mobilization; capsinoids/capsaicin — TRPV1-receptor-mediated thermogenic activation, UCP-1 upregulation, and lipid oxidation; fucoxanthin (10% standardized algal extract) — marine carotenoid with documented UCP-1-mediated thermogenesis, AMPK activation, and white-to-brown adipocyte conversion activity in preclinical models; berberine HCl — isoquinoline alkaloid with AMPK activation, hepatic gluconeogenesis suppression, and GLP-1 secretagogue properties (also present in Control). Administration: one capsule taken twice daily 30–60 minutes before breakfast and before dinner. The combination of caffeine, synephrine HCl, and yohimbine HCl constitutes a documented sympathomimetic stack; the cardiovascular safety profile of this combination is described in the supplement-pharmacology literature and warrants attention in cardiovascular-risk subgroups (addressed in Section 4.4). Dietary protocol and physical activity. Program participants were provided the Trimsulin Healthy Eating Menu Guide, a structured 30-day dietary protocol emphasizing lean protein, vegetables, smart carbohydrates, fruits, and healthy fats, and were instructed to engage in moderate physical activity in accordance with FFN's program guidance. The cohort outcomes reported in this analysis, therefore, reflect the integrated Trimsulin Weight Loss Program (Control + Thermo + Menu Guide + moderate exercise) rather than the supplements in isolation. The contribution of each program component to the overall outcomes cannot be apportioned within this observational design and is addressed in Section 4.4 (Limitations). Regulatory positioning. Both Trimsulin Control and Trimsulin Thermo are composed of ingredients with generally recognized as safe (GRAS) regulatory status and are marketed by FFN as dietary supplements. FFN's published product information explicitly states that Trimsulin does not contain GLP-1 and is not a GLP-1 receptor agonist medication. The mechanistic rationale for the present study is therefore that of endogenous incretin secretagogue activity — stimulating the body's own release of GLP-1 and GIP and reducing their enzymatic degradation — rather than exogenous incretin receptor agonism. The compositional architecture of the Trimsulin formulation is the subject of pending United States patent applications filed by the author, currently under examination by the United States Patent and Trademark Office. Patent examination constitutes a form of independent technical review by examiners with specialized scientific training and no commercial interest in the outcome, encompassing prior-art search, novelty review, non-obviousness assessment, and enablement evaluation. While patent examination is not equivalent to peer scientific review, it represents a recognized form of external technical scrutiny that most nutraceutical compositions have not undergone, and is offered here as one element of the broader scientific basis for the present analysis. 2.4 Comparator Data Sources Comparative weight-loss outcomes for semaglutide and tirzepatide were derived from the published real-world cohort analysis by Rodriguez and colleagues [9], which evaluated 18,386 propensity-score-matched adults with overweight or obesity who initiated treatment between May 2022 and September 2023 using the Truveta integrated electronic health record dataset. The Rodriguez study population received semaglutide or tirzepatide formulations labeled for type 2 diabetes (Ozempic, Mounjaro), with a mean baseline weight of 110 kg (242 lbs), a mean baseline BMI of 39.0, and a 52.0% prevalence of type 2 diabetes. Comparator weight-loss values reported in this manuscript correspond to the on-treatment estimand from Rodriguez (Figure 4 of that paper), in which patients are censored at the time of treatment discontinuation, medication switching, or loss to follow-up. Rodriguez also reported a modified intention-to-treat (ITT) sensitivity analysis that included post-discontinuation weights and demonstrated numerically smaller weight reductions: 3.3% / 5.0% for semaglutide and 5.3% / 8.2% for tirzepatide at 3 and 6 months, respectively. The on-treatment estimand was selected for the present comparison because it is the primary analysis reported by the source study and represents the comparator therapies under conditions of sustained adherence. Comparative adverse event rates were drawn from a separate body of evidence — published clinical trials and pharmacovigilance studies of semaglutide and tirzepatide [11–14] — sourced through systematic searches of PubMed, Embase, CINAHL, Scopus, and Web of Science. The Rodriguez analysis was not used as the comparator source for adverse events. Rodriguez deliberately captured only moderate-to-severe gastrointestinal events (bowel obstruction, cholecystitis, cholelithiasis, gastroenteritis, gastroparesis, pancreatitis) due to expected under-capture of mild events in EHR data and reported similar rates of these moderate-to-severe events between semaglutide and tirzepatide. The adverse event comparator data sources cited here [11–14] use protocolized, prompted ascertainment of mild-through-severe events, which is appropriate for the present comparison. Cohort outcome data from all sources were normalized into a common data model through syntactic and semantic normalization to support cross-cohort descriptive comparison. 2.5 Outcome Measures Primary outcomes were: Percent change in body weight from baseline at week 12 and week 24. Cumulative incidence of any participant-reported adverse event during program participation. Cumulative incidence of gastrointestinal adverse events (nausea, vomiting, diarrhea, gastritis), headache, insomnia, and serious adverse events. Outcomes were assessed descriptively against the corresponding semaglutide and tirzepatide rates reported in the comparator data sources. 2.6 Statistical Analysis Outcomes are reported as means with ranges for continuous variables and as percentages for categorical variables. Given the observational, single-cohort design and reliance on published comparator data drawn from heterogeneous study populations and adverse event collection methods, no inferential statistical comparisons were performed between cohorts. All comparative findings are descriptive and hypothesis-generating. Trimsulin cohort outcomes at 3 and 6 months are reported for the at-risk subpopulation at each time point — that is, all enrolled participants with available follow-up weight measurement at the corresponding window. The cohort was not subject to on-treatment censoring; participants who reduced or discontinued program use during the follow-up window were retained in the analysis where weight measurements were available. This reporting framework is methodologically distinct from the on-treatment estimand reported by Rodriguez et al. [9], which censors patients at discontinuation, medication switching, or loss to follow-up. The implication is that the comparator weight-loss values cited in this manuscript represent semaglutide and tirzepatide under conditions of sustained adherence (the most favorable interpretation of comparator efficacy), whereas the Trimsulin cohort values reflect outcomes across all 503 analyzed participants — all of whom provided complete data through six months. If the Rodriguez modified ITT estimand were used as a comparator instead, the relative magnitude of the Trimsulin cohort advantage would be larger. Of the 503 analyzed participants, weight measurements were available for the full cohort at both the 12-week and 24-week timepoints by inclusion criterion. 2.7 Ethics This was a retrospective analysis of de-identified outcome data collected as part of standard program enrollment. Per common research ethics guidance for retrospective analyses of de-identified program data, formal Institutional Review Board (IRB) review was not required. All program participants consented to outcome tracking as part of program enrollment. The analysis was conducted in accordance with the principles of the Declaration of Helsinki. 3. Results 3.1 Baseline Characteristics and Cohort Disposition The Trimsulin Weight Loss Program enrolled more than 1,000 adults during the analysis period. A total of 503 participants completed six months of program participation with protocol-conformant follow-up measurements at both 12-week and 24-week timepoints and constitute the analysis cohort. All 503 analyzed participants had weight measurements available at both timepoints. Participants enrolled but not meeting completion and protocol-conformant reporting criteria were not included in the analysis cohort (see Sections 2.2 and 4.4). Within the analyzed cohort (n = 503), mean baseline body weight was 201.2 lb (range 130–360 lb). Mean baseline BMI was 27.5 (range 20.0–50.1). Duration of program participation in the analyzed cohort ranged from 3 to 10 months, with a mean of 5.4 months. 3.2 Weight Loss Outcomes Mean percent weight reduction in the Trimsulin cohort was 7.3% at 3 months and 14.1% at 6 months. In the comparator cohort, mean percent weight reduction was 3.6% (semaglutide) and 5.9% (tirzepatide) at 3 months, and 5.8% (semaglutide) and 10.1% (tirzepatide) at 6 months. [9] Outcomes are summarized in Table 1. Table 1. Mean percent weight reduction at 3 and 6 months (Trimsulin cohort vs. published comparator data). Duration Trimsulin Semaglutide Tirzepatide 3 Months 7.3% 3.6% 5.9% 6 Months 14.1% 5.8% 10.1% 3.3 Adverse Events in the Trimsulin Cohort Of 503 participants, 4.8% reported any adverse event during program participation. The most commonly reported events were insomnia (4.3%), gastrointestinal disorders (2.9%), loose stools (2.5%), nausea (2.1%), and gastritis (1.0%). No serious adverse events, vomiting, or headache were reported. Adverse event rates within the Trimsulin cohort are summarized in Table 2. Table 2. Participant-reported adverse event rates in the Trimsulin cohort (n = 503). Adverse Event Percentage (%) Any adverse effect 4.8% Gastrointestinal disorder 2.9% Nausea 2.1% Loose stools 2.5% Gastritis 1.0% Insomnia 4.3% 3.4 Comparative Adverse Event Rates Adverse event rates in the Trimsulin cohort were substantially lower than the rates reported for semaglutide and tirzepatide in published clinical trial cohorts. Any adverse event was reported by 4.8% of Trimsulin participants, compared with 89.7% (semaglutide) and 81.0% (tirzepatide). [11–14] Gastrointestinal adverse events were reported by 2.9% of Trimsulin participants, compared with 59.7% (semaglutide) and 46.0% (tirzepatide). No serious adverse events were reported in the Trimsulin cohort, compared with approximately 3.0% (semaglutide) and 5–7% (tirzepatide). Comparative adverse event rates are summarized in Table 3. Table 3. Comparative adverse event rates: Trimsulin cohort versus published clinical trial data for semaglutide and tirzepatide. Adverse Event Trimsulin (%) Semaglutide (%) [11–14] Tirzepatide (%) [11–14] Any adverse effect 4.8% 89.7% 81.0% Gastrointestinal disorder 2.9% 59.7% 46.0% Nausea 2.1% 44.2% 35.5% Vomiting 0.0% 24.8% 16.4% Diarrhea 2.5% 29.7% 21.1% Headache 0.0% 22.7% 21.4% Serious adverse effect 0.0% 3.0% 5–7% Note: Adverse event data for semaglutide and tirzepatide are derived from published clinical trials and meta-analyses, which typically capture adverse events more comprehensively and with more standardized prompting than observational, participant-reported cohort data. This methodological asymmetry should be considered when interpreting comparative adverse event rates (see Limitations). 4. Discussion 4.1 Summary of Findings In this real-world observational cohort of 503 overweight adults, mean percent weight reduction with the Trimsulin Weight Loss Program was 7.3% at 3 months and 14.1% at 6 months. These outcomes were quantitatively greater than published mean weight reduction outcomes reported for semaglutide and tirzepatide over the same time intervals in a comparable real-world cohort. [9] Reported adverse event rates in the Trimsulin cohort were substantially lower than the rates reported for pharmacological incretin therapies in published clinical trials [11–14], with no serious adverse events reported. 4.2 Comparison with Published Literature Pharmacological GLP-1RAs and dual GIP/GLP-1RAs have demonstrated robust weight reduction in randomized controlled trials. STEP 1 (semaglutide) reported a mean weight reduction of approximately 14.9% at 68 weeks. [4] STEP 2 reported 9.6% at 68 weeks in adults with type 2 diabetes. [5] STEP 5 reported 15.2% at 104 weeks. [6] SURMOUNT-1 (tirzepatide) reported up to 20.9% at 72 weeks. [7] However, real-world outcome data report substantially lower mean weight reduction than randomized trial outcomes, reflecting differences in adherence, dose titration, and discontinuation. The comparator data used in this analysis are drawn from a real-world Truveta-derived cohort and are therefore methodologically more comparable to the present cohort than randomized controlled trial outcomes. [9] The adverse event burden of pharmacological incretin therapy is well documented. Gastrointestinal adverse events occur in 40–60% of treated patients in published trials and are the dominant driver of treatment discontinuation. [11,12] Reported serious adverse events include pancreatitis, gallbladder disease, intestinal obstruction, kidney injury, psychiatric events, and cardiovascular events. [12,13] A material population characteristic differs between the present cohort and the Rodriguez comparator. The Rodriguez cohort had a mean baseline BMI of 39.0 (class 2/3 obesity), a mean baseline weight of 110 kg (242 lbs.), and a 52.0% prevalence of type 2 diabetes; participants received formulations labeled for diabetes management (Ozempic, Mounjaro). The Trimsulin cohort had a mean baseline BMI of 27.5 (overweight at threshold), a mean baseline weight of 91 kg (201 lbs.), and was not specifically characterized by type 2 diabetes status. Patients with higher baseline BMI generally exhibit larger absolute weight reductions on incretin-based therapy, and percentage weight reduction has been observed to scale modestly with available adipose mass; randomized trial data demonstrate consistently larger percentage reductions in higher-BMI strata. [4–7] Despite this population asymmetry — which would be expected to favor the higher-BMI Rodriguez cohort on percentage outcomes — the lower-BMI Trimsulin cohort posted larger numerical percentage reductions at both 3 and 6 months. Two interpretations are possible. First, the Trimsulin composition may produce meaningful weight reduction that does not depend on the high baseline adiposity required for percentage outcomes with pharmacological GLP-1 receptor agonists. Second, the difference may reflect program-selection effects intrinsic to a paid commercial wellness program — including higher motivation, behavioral engagement, and possible co-occurring lifestyle modification. Both interpretations warrant prospective controlled investigation; neither can be resolved by observational data alone. 4.3 The Bioactive Signaling Molecule Framework The mechanistic interpretation of the cohort outcomes proposed here is grounded in a coordinated multi-pathway construct termed the Bioactive Signaling Molecule (BSM) framework. The BSM framework, described in the patent estate underlying the Trimsulin composition [2,3] organizes the mechanistic basis of nutraceutical incretin-axis modulation around three coordinated functional layers rather than around individual compounds. The first layer is dual incretin secretagogue activity — coordinated stimulation of endogenous GLP-1 release from intestinal L-cells and GIP release from intestinal K-cells. The second layer is DPP-4 inhibition with compounds that have documented active-site inhibition, extending the half-life of active endogenous incretins. The third layer is downstream metabolic regulatory pathway coordination, in which the same multi-compound composition engages a network of intracellular signaling pathways that are downstream of, parallel to, and synergistic with incretin signaling itself. The therapeutic premise of the BSM framework is that the cumulative metabolic effect of coordinated multi-pathway modulation exceeds what would be predicted from incretin signaling alone, while the indirect physiological character of the modulation produces a more favorable tolerability profile than direct receptor agonism. The lower reported adverse event rates observed in the Trimsulin cohort may be attributable to several mechanistic features consistent with this framework. First, stimulating endogenous GLP-1 and GIP release produces incretin signaling that follows physiological release patterns rather than the sustained supraphysiological exposure produced by long-acting injectable agonists. Second, oral daily administration may avoid the peak-trough pharmacokinetics characteristic of weekly injectable depot formulations, which have been associated with peak-related gastrointestinal symptoms. [11] Third, the multi-pathway character of the BSM mechanism distributes the metabolic effect across multiple regulatory nodes, potentially reducing the magnitude of perturbation at any single pathway and the associated adverse event load. Published evidence implicates multiple cellular signaling pathways in obesity and weight regulation [17], of which the following are activated or modulated by compound classes present in the Trimsulin BSM composition: Insulin / Insulin Receptor Substrate (IRS) signaling — central to glucose metabolism, insulin sensitivity, and lipid storage. Adipokine signaling — adipose-derived hormones modulating inflammation and metabolism. Sirtuin1–AMPK signaling — regulating cellular energy metabolism and lipid oxidation; engaged by berberine and fucoxanthin. AMPK / mTOR signaling — central to energy balance and cellular growth under conditions of energy availability or restriction. PI3K-AKT signaling — insulin sensitivity, glucose uptake, and downstream metabolic regulation. MAPK / p38 signaling — cellular stress and energy regulation. Inflammatory pathways and PPAR signaling — modulating chronic obesity-associated inflammation and regulating lipid storage and glucose metabolism. PKG signaling and gut hormone regulation — supporting energy balance and modulating GLP-1 and GIP release. β3-adrenergic signaling — regulating adipose tissue lipolysis and energy expenditure; engaged by synephrine and capsaicin/capsiate. α2-adrenergic antagonism — supporting lipolysis from regional adipose depots otherwise resistant to catecholamine-mediated mobilization; engaged by yohimbine. Ob-R / JAK2 signaling — leptin-mediated regulation of energy intake and adipose function. TRPV1 receptor signaling — thermogenic activation; engaged by capsaicin and capsiate. FFAR2 / FFAR3 (free fatty acid receptor) signaling — short-chain fatty acid sensing and L-cell incretin release; engaged by inulin-derived fermentation products. Phytochemicals, botanical extracts, mineral cofactors, flavonoids, fibers, prebiotics, peptides, amino acids, and intense sweeteners present in the Trimsulin composition demonstrate documented activity at one or more of these regulatory nodes. The proposed mechanistic basis of the BSM framework — that coordinated modulation across this network produces metabolic effects exceeding those of incretin signaling alone — is hypothesized rather than demonstrated by the present observational analysis. Direct measurement of plasma active GLP-1 and GIP concentrations, DPP-4 activity, UCP-1 expression, and downstream pathway activation under Trimsulin administration is required to confirm the framework and represents a high-priority direction for subsequent mechanistic research. The individual compounds that comprise the BSM framework have established GRAS regulatory status and a documented history of use across food, supplement, and food additive categories. If the weight-reduction and tolerability outcomes observed in this cohort are validated in prospective controlled studies, the findings would suggest that coordinated multi-pathway incretin secretagogue activity is achievable through compositions embedded in the food supply—a public health inference worth investigating, given the cost and access constraints of pharmacological incretin therapy discussed in Section 4.6. Whether that inference holds across different delivery formats and populations is an empirical question that the present data cannot answer. 4.4 Limitations Several limitations must be considered when interpreting these findings. Study design. This was a single-arm observational cohort analysis without randomization, blinding, placebo control, or concurrent comparator. Comparative outcomes are drawn from published external datasets and are therefore subject to selection bias, residual confounding, and unmeasured population differences. Selection-related attrition. The 503 participants analyzed represent the subset of a Trimsulin Weight Loss Program population of more than 1,000 adults who provided complete six-month follow-up data. Participants who enrolled but did not complete six months of program participation, or who did not provide protocol-conformant follow-up measurements at both timepoints, were not included in the analysis cohort. The reasons for non-completion or non-reporting were not systematically captured and may include treatment dissatisfaction, weight-related discouragement, lifestyle change unrelated to the program, or routine non-response. Outcomes among non-reporting program participants may differ from outcomes in the analyzed cohort, and the present analysis cannot quantify that difference. The reported cohort outcomes, therefore, reflect the experience of program completers with sustained six-month engagement and may overstate the average outcome that would be observed in a randomized intent-to-treat analysis of the full enrolled program population. This limitation is structurally similar to the on-treatment estimand reported by Rodriguez et al. for the comparator drugs [9], in which patients censored at discontinuation are excluded from the analyzed denominator. Adverse event capture asymmetry. Adverse events in the Trimsulin cohort were captured through participant-reported observational data using a structured online reporting framework with prompted adverse-event categories modeled on the protocols used in the pivotal pharmacological GLP-1 receptor agonist trials [4–7] (see Section 2.2, Data Collection Protocol). Comparator adverse event rates are drawn from clinical trials and pharmacovigilance studies, which use clinician-confirmed and systematically prompted ascertainment in controlled clinical settings. Despite the deliberate methodological alignment, residual under-ascertainment in the participant-reported observational cohort relative to clinician-confirmed trial cohorts is likely. The magnitude of the observed difference in adverse-event rates (4.8% vs. 81–90%), however, is unlikely to be fully explained by ascertainment differences alone; even substantial under-ascertainment in the observational cohort would leave a clinically meaningful residual gap. Comparator heterogeneity. Published comparator data span different study designs, populations, durations of follow-up, and dose-titration schedules. The Rodriguez weight-loss comparator cohort differed materially from the Trimsulin cohort in baseline BMI (39.0 vs. 27.5), baseline weight (110 kg vs. 91 kg), prevalence of type 2 diabetes (52.0% vs. uncharacterized), and use of T2D-labeled rather than weight-loss-labeled drug formulations. Adverse event comparator data were drawn from a different evidence base (clinical trials and pharmacovigilance registries [11–14]) that uses protocolized, prompted ascertainment, which is methodologically more sensitive than EHR-derived or observational adverse event capture. Direct numerical comparison of mean outcomes across heterogeneous cohorts must be interpreted as descriptive rather than causal. No inferential testing. No between-cohort statistical hypothesis testing was performed. The findings are descriptive and hypothesis-generating only. Generalizability. Participants enrolled in a commercial wellness program may differ from clinical trial populations in motivation, adherence, and behavioral engagement. The mean baseline BMI of 27.5 places the cohort at the lower end of the BMI range studied in pivotal pharmacological incretin trials, and the upper-BMI subset of the present cohort was not analyzed separately. Multimodal intervention. The Trimsulin Weight Loss Program comprises Control + Thermo, a structured dietary protocol (the Trimsulin Healthy Eating Menu Guide), and a moderate exercise recommendation. The cohort outcomes reported here reflect the integrated program, not the supplement components in isolation. Within an observational, single-arm design, the contribution of supplement-mediated incretin secretagogue activity, dietary protocol, and exercise cannot be separately apportioned. Caloric restriction and increased physical activity each independently produce weight reduction, and a portion of the observed effect is therefore attributable to the program's dietary and behavioral components. Future randomized controlled trials with appropriate factorial or active-control arms (supplement + diet + exercise vs. diet + exercise alone vs. supplement alone) are needed to apportion the mechanism. The same caveat applies to the comparator data: pharmacological GLP-1 RA trials and real-world cohorts also typically include lifestyle counseling, so the comparison is between two integrated weight-management approaches rather than between isolated agents. Cardiovascular safety profile of Thermo. Trimsulin Thermo contains caffeine, synephrine, and yohimbine — a sympathomimetic combination with a documented cardiovascular activity profile in the supplement-pharmacology literature. Although no serious cardiovascular adverse events were reported in the present cohort and overall adverse-event rates were low, the population studied here had a mean baseline BMI of 27.5 and was not specifically characterized by cardiovascular risk status. Caution is warranted in interpreting the cohort safety profile as generalizable to populations with established cardiovascular disease, uncontrolled hypertension, arrhythmia, or concurrent stimulant use. Future studies should specifically capture cardiovascular-risk-stratified safety data, including blood pressure and heart rate monitoring across the dosing window. Conflict of interest. The author is the inventor of the Trimsulin formulation and the founder of NutraGLP Biosciences. While the analysis was conducted in good faith and uses published external comparator data, the potential for unconscious bias in cohort framing and outcome interpretation must be acknowledged. 4.5 Comparison with Recent Real-World Cohort Studies In addition to the Rodriguez et al. analysis [9], two further real-world cohort studies of pharmacological incretin therapy have been published recently and provide additional context for the present analysis. The SHAPE study evaluated 9,916 adults with overweight or obesity without type 2 diabetes who initiated semaglutide 2.4 mg or tirzepatide labeled for weight management, drawn from the Komodo Health database between June 2021 and December 2023, with one year of follow-up. [18] A separate retrospective analysis of 339 participants in a 12-month remote weight management program combining medication, app-based behavioral support, and dietitian coaching reported mean 12-month weight reductions of 22.1% (tirzepatide) and 17.1% (semaglutide). [19] These published 12-month outcomes — drawn from real-world cohorts that, like the present analysis, combine pharmacological incretin therapy with structured behavioral and dietary support — provide a useful methodological reference point for the integrated multimodal weight-management framework discussed in Section 2.3 and Section 4.4. The 14.1% six-month outcome observed in the present Trimsulin cohort is consistent in magnitude with the trajectory of these recent real-world programs and is achieved without exposure to injectable pharmacological agents. 4.6 Cost and Access Considerations Real-world weight management is increasingly defined by cost and access constraints in addition to efficacy. Pharmacological GLP-1 receptor agonists labeled for weight management currently retail at approximately $1,000–1,300 per month at the standard dose in the United States; insurance coverage for weight-management indications remains inconsistent, and high out-of-pocket cost is a documented driver of treatment discontinuation in the published real-world literature. [9] The Trimsulin Weight Loss Program is currently retailed by FirstFitness Nutrition at approximately $175 per 30-day program, including supplements and the structured eating guide. While direct cost-effectiveness comparison is beyond the scope of the present hypothesis-generating analysis and would require formal incremental cost-effectiveness evaluation, the order-of-magnitude difference in monthly cost is a structurally relevant element of any comparative evaluation between the two approaches and is acknowledged here as a factor in real-world treatment selection. 4.7 Strengths The present analysis has several methodological strengths that should be considered alongside the limitations described in Section 4.4. The analysis cohort of 503 participants with complete six-month follow-up is materially larger than the typical pilot or feasibility cohort reported for nutraceutical weight-management compositions, and the six-month follow-up duration exceeds that of many published nutraceutical efficacy studies. The data collection framework was deliberately modeled on the protocols used in the pivotal pharmacological GLP-1 receptor agonist clinical trials [4–7], supporting cross-cohort comparability with the comparator data sources. The selection of the Rodriguez et al. real-world cohort [9] as the primary weight-loss comparator — rather than randomized controlled trial outcomes — reduces the comparator-population artifact in which clinical trial outcomes overstate real-world drug effectiveness. The multimodal nature of the intervention is explicitly disclosed, and the comparator data are appropriately framed as also reflecting integrated multimodal care rather than isolated pharmacological agents. The conflict of interest borne by the principal investigator is disclosed candidly, and the analysis was conducted using published external comparator data that the author did not generate. The compositional architecture evaluated is the subject of pending patent applications currently under examination by the United States Patent and Trademark Office, as referenced in Section 2.3. 4.8 Implications for Future Research These hypothesis-generating findings support further controlled investigation of endogenous incretin secretagogue compositions as a class. The present cohort study evaluated one implementation of the BSM platform framework. Future research directions of highest priority include prospective randomized controlled trials of BSM-framework compositions — including next-generation formulations incorporating more advanced ingredient systems and delivery architectures — compared against placebo and against active pharmacological incretin comparators. Secondary endpoints of particular mechanistic value include changes in plasma active GLP-1 and GIP concentrations, DPP-4 activity, fasting and post-prandial glycemic response, UCP-1 induction, and patient-reported tolerability. A factorial design apportioning the contribution of the BSM supplement components versus the dietary and behavioral program elements would clarify the mechanistic contribution of each. Adjunctive use of BSM-framework compositions in patients who discontinue pharmacological incretin therapy due to intolerance represents a clinically meaningful research direction, given the established real-world discontinuation burden of pharmacological GLP-1 receptor agonists. [11–14] Beyond supplement formats, investigation of BSM-framework ingredient systems in functional food and food-additive delivery formats represents a translational research direction of broader public health relevance, given the potential for population-scale access that food-category routes offer relative to pharmaceutical channels. 5. Conclusions In this real-world observational cohort of 503 overweight adults, weight-loss outcomes with the Trimsulin Weight Loss Program were quantitatively greater than those reported for pharmacological incretin therapies, and reported adverse event rates were substantially lower. No serious adverse events were reported. While the descriptive nature of the analysis, the asymmetry in adverse event ascertainment, and the author's disclosed conflict of interest all constrain the conclusions that can be drawn, the findings are consistent with the hypothesis that endogenous incretin secretagogue compositions may offer a more tolerable approach to incretin-based weight management. A prospective randomized controlled investigation is warranted. Declarations Funding This study was self-funded by Richard Clark Kaufman, PhD, and FirstFitness Nutrition (FFN). No external grant funding or industry sponsorship was received. Conflict of Interest Richard Clark Kaufman, PhD, is the inventor of the Trimsulin formulations evaluated in this study and the founder and Chief Scientific Officer of NutraGLP Biosciences, the entity holding the intellectual property rights to the formulation. FirstFitness Nutrition is a commercial licensee of a Trimsulin-related product. The author has financial interests that may benefit from positive outcomes reported in this study. The analysis was conducted in good faith using published external comparator data. The reader is encouraged to interpret the findings in the context of this disclosure. Author Contributions RCK conceived the study, designed the analytic framework, developed the data collection protocol, conducted the analysis, and wrote and revised the manuscript. As the sole author of the present submission, RCK is responsible for the integrity of the data and the accuracy of the analysis. The author confirms that all aspects of the work have been reviewed for accuracy and that no portion of the analysis has been generated by undisclosed contributors. Should additional contributors join future iterations of this work — for example, a statistical methodologist for a planned randomized controlled trial follow-up, or co-investigators for mechanistic substudies — author contributions will be specified in accordance with International Committee of Medical Journal Editors (ICMJE) authorship criteria, and ORCID identifiers will be reported for all contributing authors. Acknowledgments The author thanks the participants enrolled in the Trimsulin Weight Loss Program and FirstFitness Nutrition for program operational support. The author also thanks Daniel Kimball, JD (Loza & Loza LLP), for review of intellectual property–related disclosures. Data Availability Statement De-identified aggregate outcome data supporting the findings of this study are available from the corresponding author upon reasonable request. Composition-specific formulation data are protected under issued and pending intellectual property and may be made available under appropriate confidentiality agreements. Ethics Approval Statement This study constituted a retrospective analysis of de-identified outcome data from participants in a commercially available wellness program. Per common research ethics guidance for retrospective analyses of de-identified program data, formal IRB review was not required. All program participants consented to outcome tracking at the point of program enrollment. The study was conducted in accordance with the principles of the Declaration of Helsinki. Regulatory Positioning The formulation evaluated in this study is composed of ingredients with generally recognized as safe (GRAS) regulatory status. The BSM framework underlying this composition is designed for application across multiple non-pharmaceutical product categories, including dietary supplements, functional foods, food additives, and conventional food products — all regulated under food and supplement frameworks rather than pharmaceutical frameworks. The specific composition evaluated here (Trimsulin Control + Thermo) is currently marketed as a dietary supplement. This study is not intended to support or imply drug-level claims, nor to support regulatory classification of the formulation or its derivative compositions as pharmaceutical agents. The findings are presented for scientific, informational, and research purposes only and do not constitute medical advice, diagnosis, or treatment recommendations. Individual results may vary. References Ogden CL, Fakhouri TH, Carroll MD et al (2017) Prevalence of obesity among adults, by household income and education — United States, 2011–2014. MMWR Morb Mortal Wkly Rep 66(50):1369–1373. 10.15585/mmwr.mm6650a1 Raisi-Estabragh Z, Kobo O, Mieres JH et al (2023) Racial disparities in obesity-related cardiovascular mortality in the United States: temporal trends from 1999 to 2020. J Am Heart Assoc 12(18):e028409. 10.1161/JAHA.122.028409 Wing RR, Lang W, Wadden TA, Look AHEAD Research Group et al (2011) Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 34(7):1481–1486. 10.2337/dc10-2415 Wilding JPH, Batterham RL, Calanna S, STEP 1 Study Group et al (2021) Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 384(11):989–1002. 10.1056/NEJMoa2032183 Davies M, Færch L, Jeppesen OK, STEP 2 Study Group et al (2021) Semaglutide 2.4 mg once a week in adults with overweight or obesity and type 2 diabetes (STEP 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 397(10278):971–984. 10.1016/S0140-6736(21)00213-0 Garvey WT, Batterham RL, Bhatta M, STEP 5 Study Group et al (2022) Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 28(10):2083–2091. 10.1038/s41591-022-02026-4 Jastreboff AM, Aronne LJ, Ahmad NN et al (2022) SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 387(3):205–216. 10.1056/NEJMoa2206038 Smits MM, Holst JJ (2023) Endogenous glucagon-like peptide (GLP)-1 as alternative for GLP-1 receptor agonists: could this work and how? Diabetes Metab Res Rev 39(8):e3699. 10.1002/dmrr.3699 Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, Brar R, Baker C, Gluckman TJ, Stucky NL (2024) Semaglutide vs tirzepatide for weight loss in adults with overweight or obesity. JAMA Intern Med 184(9):1056–1064. 10.1001/jamainternmed.2024.2525 Weghuber D, Barrett T, Barrientos-Pérez M et al (2022) STEP TEENS Investigators. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 387(24):2245–2257. 10.1056/NEJMoa2208601 Wharton S, Calanna S, Davies M et al (2022) Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes Metab 24(8):1553–1564. 10.1111/dom.14725 Shu Y, He X, Wu P et al (2022) Gastrointestinal adverse events associated with semaglutide: a pharmacovigilance study based on FDA adverse event reporting system. Front Public Health 10:996179. 10.3389/fpubh.2022.996179 Mishra R, Raj R, Elshimy G et al (2023) Adverse events related to tirzepatide. J Endocr Soc 7(4):bvad016. 10.1210/jendso/bvad016 Garvey WT, Frias JP, Jastreboff AM et al (2023) SURMOUNT-2 investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 402(10402):613–626. 10.1016/S0140-6736(23)01200-X Aronne LJ, Sattar N, Horn DB et al (2024) SURMOUNT-4 Investigators. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 331(1):38–48. 10.1001/jama.2023.24945 Kadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y (2022) Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol 10(9):634–644. 10.1016/S2213-8587(22)00187-5 Wen X, Zhang B, Wu B, Xiao H, Li Z, Li R, Xu X, Li T (2022) Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 7(1):298. 10.1038/s41392-022-01149-x Real-World Weight Loss Observed With (2025) Semaglutide and Tirzepatide in Patients with Overweight or Obesity and Without Type 2 Diabetes (SHAPE). Adv Ther. 10.1007/s12325-025-03340-2. Available from PMC PMC12579654 Additional Declarations The authors declare potential competing interests as follows: Affiliations: NutraGLP Biosciences, Santa Monica, California, USA Financial interests / Competing interests / COI: Richard Clark Kaufman, PhD, is the inventor of the Trimsulin formulation evaluated in this study and the Founder and Chief Scientific Officer of NutraGLP Biosciences. FirstFitness Nutrition is a commercial licensee of a Trimsulin-related product. The author has financial interests that may benefit from positive outcomes reported in this study. The analysis was conducted using published external comparator data that the author did not generate. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9657897","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":637109482,"identity":"5c6d11ca-3d78-4072-b445-931e9f6efb25","order_by":0,"name":"Richard Clark Kaufman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDACZgY2ECkH48swSDA2EKXFGMRiOMDAwENYCwNES2IDQgsB9ebtzM8e/Nxjnb5dIv/Y5w81tTzm0s2NDxhqbKJxaZE5zGZu2PMsPXfnjGTmGQeOHeexnHOw2YDhWFouLudJMPOwSfAcOJy74UYyM8MBtmM8BjcS24DeOYxXi+SfA4fTDcBa/hGpRRpoSwJYy8G2GmK0sJlJyxxIN9xw5rExw9m+AxC/JODzC//hZ5JvDljLGxxPfMxQ8a1Ozly6/eGDDzU2OLWgg8MMBiAqgUjlIFAH0TIKRsEoGAWjAAkAANVpV9qltcILAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0001-5218-3799","institution":"NutraGLP Biosciences","correspondingAuthor":true,"prefix":"","firstName":"Richard","middleName":"Clark","lastName":"Kaufman","suffix":""}],"badges":[],"createdAt":"2026-05-08 20:45:07","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9657897/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9657897/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109125089,"identity":"c897b226-69b0-41fe-a82d-43bff8a4de86","added_by":"auto","created_at":"2026-05-12 18:35:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":289632,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9657897/v1/69cf1a6d-c184-4eee-b420-8fce5ccb3220.pdf"},{"id":109125085,"identity":"e24ff894-179b-46b1-9d99-588d402e78d7","added_by":"auto","created_at":"2026-05-12 18:35:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19957,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9657897/v1/88f6933145fdd89aa6066473.docx"}],"financialInterests":"The authors declare potential competing interests as follows: Affiliations:\nNutraGLP Biosciences, Santa Monica, California, USA\n\nFinancial interests / Competing interests / COI:\nRichard Clark Kaufman, PhD, is the inventor of the Trimsulin formulation evaluated in this study and the Founder and Chief Scientific Officer of NutraGLP Biosciences. FirstFitness Nutrition is a commercial licensee of a Trimsulin-related product. The author has financial interests that may benefit from positive outcomes reported in this study. The analysis was conducted using published external comparator data that the author did not generate.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEndogenous Incretin Secretagogue Compositions as a Mechanistic Class Versus Pharmacological Incretin Receptor Agonists for Weight Reduction in Overweight Adults: A Real-World Observational Cohort Analysis of a Nutraceutical Composition (Trimsulin) and Comparison with Published Outcomes for Semaglutide and Tirzepatide\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOverweight and obesity are highly prevalent conditions associated with increased morbidity, cardiovascular mortality, and metabolic disease burden. [1–3] Pharmacological treatments — particularly GLP-1 receptor agonists (GLP-1RAs) such as semaglutide and dual GIP/GLP-1 receptor agonists such as tirzepatide — have demonstrated clinically significant weight reduction and metabolic benefit in randomized controlled trials. [4–7] Despite these efficacy findings, real-world adoption is constrained by adverse event burden, discontinuation, cost, and the need for chronic injectable administration. Real-world discontinuation of pharmacological GLP-1RA therapy reaches approximately 50% within one year and approximately 70% within two years of initiation, with primary reasons including gastrointestinal intolerance, preference for oral over injectable administration, and out-of-pocket cost; approximately 13% of discontinuations cite cost as the principal driver. The combination of these access barriers — clinical, behavioral, and financial — leaves a substantial population of overweight and obese adults without an effective, tolerable, accessible option for incretin-based weight management.\u003c/p\u003e\n\u003cp\u003eGLP-1RAs mimic the actions of the endogenous incretin hormone GLP-1, which is secreted from intestinal enteroendocrine L-cells and from neurons in the nucleus tractus solitarius. GIP is a second incretin hormone secreted from intestinal K-cells. Pharmacological GLP-1RAs are engineered to resist degradation by dipeptidyl peptidase-4 (DPP-4), which prolongs systemic exposure relative to native GLP-1. Increasing evidence suggests that pharmacological GLP-1RAs and endogenous incretin signaling diverge mechanistically even where their downstream clinical effects overlap. [6,8]\u003c/p\u003e\n\u003cp\u003eIn preclinical models, endogenous GLP-1 secretagogues combined with DPP-4 inhibition have been shown to elevate active endogenous GLP-1 to concentrations approaching those produced by exogenous pharmacological agonists. [7]\u003c/p\u003e\n\u003cp\u003eEndogenous GLP-1 and GIP releasers include nutritional fibers, phytochemicals, botanical extracts, fatty acids, resistant starches, flavonoids, alkaloids, peptides, and selected probiotic and prebiotic compounds — many of which carry generally recognized as safe (GRAS) regulatory status. Flavonoid compounds with documented in-vitro DPP-4 inhibitory activity may contribute to extended active incretin half-life when administered in combination with secretagogues.\u003c/p\u003e\n\u003cp\u003eTrimsulin is a nutraceutical composition designed to (a) stimulate endogenous GLP-1 and GIP release, (b) inhibit DPP-4-mediated degradation of active incretins, (c) activate uncoupling protein 1 (UCP-1)-mediated thermogenesis and white-to-brown adipocyte conversion, and (d) activate hormone-sensitive lipase to support lipid mobilization. The licensed formulation comprises two products taken in combination — Trimsulin Control (a powdered drink mix) and Trimsulin Thermo (a capsule formulation) — and is delivered to consumers as part of an integrated weight-management program that includes a structured dietary protocol and moderate-exercise recommendation (see Section 2.3). Current pharmacological incretin therapies achieve substantial weight reduction, but adverse events affect more than 80% of treated patients in published trial populations. [11–14]\u003c/p\u003e\n\u003cp\u003eThis study reports outcomes from a real-world observational cohort of 503 overweight adults who used the Trimsulin Weight Loss Program and compares these outcomes descriptively with published outcomes for semaglutide and tirzepatide. The primary aim is hypothesis-generating: to characterize the weight-reduction and adverse-event profile of an endogenous incretin secretagogue composition under real-world conditions and to inform subsequent randomized controlled investigations.\u003c/p\u003e\n\u003ch2\u003e1.1 Prior Evidence on Endogenous Incretin Secretagogues\u003c/h2\u003e\n\u003cp\u003eThe mechanistic premise underlying the present study draws on a growing preclinical and small-trial literature characterizing individual endogenous incretin secretagogue compounds. Berberine, an isoquinoline alkaloid present in the Control composition evaluated here, has demonstrated AMPK activation, hepatic gluconeogenesis suppression, and modulation of incretin axis activity in both rodent and human studies. Soluble dietary fibers, including inulin, support intestinal L-cell density and postprandial GLP-1 secretion through fermentation-derived short-chain fatty acid signaling at FFAR2 and FFAR3 receptors. Quercetin and myricetin — flavonoids present in the Control composition — have demonstrated in-vitro DPP-4 inhibitory activity at micromolar concentrations, although the in-vivo clinical magnitude relative to pharmacological inhibitors remains under investigation. Mulberry leaf extract demonstrates α-glucosidase inhibitory activity that attenuates postprandial glycemic excursion through delayed carbohydrate hydrolysis. Allulose, a rare sugar with a very low metabolizable carbohydrate load, has demonstrated independent attenuation of postprandial glycemic response in randomized human studies.\u003c/p\u003e\n\u003cp\u003eWhat has not previously been reported in the published literature is a real-world cohort outcome assessment of a coordinated multi-compound endogenous incretin secretagogue composition formulated to simultaneously stimulate dual GLP-1 and GIP release, inhibit DPP-4-mediated incretin degradation, and engage downstream metabolic regulatory pathways. The present analysis addresses this gap. The work is positioned as the first published real-world cohort evaluation in a class of nutraceutical compositions defined mechanistically — endogenous incretin secretagogues with adjunctive DPP-4 inhibition and downstream pathway coordination — rather than as a single-product evaluation.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003ch2\u003e2.1 Study Design\u003c/h2\u003e\n\u003cp\u003eThis was a retrospective observational cohort analysis of de-identified outcome data from adult participants enrolled in the Trimsulin Weight Loss Program, a commercially available wellness program. The methodological framework was modeled on the outcome assessment protocols used in published GLP-1RA and dual GIP/GLP-1RA trials [4\u0026ndash;7] to support cross-cohort comparability. The study was not a randomized, placebo-controlled clinical trial.\u003c/p\u003e\n\u003ch2\u003e2.2 Setting and Participants\u003c/h2\u003e\n\u003cp\u003eParticipants were drawn from a Trimsulin Weight Loss Program population of more than 1,000 enrolled adults. Of this larger program population, 503 participants provided complete six-month outcome data and were included in the analysis cohort. Inclusion in the analysis cohort required (a) baseline body weight at program enrollment, (b) program participation through six months, and (c) protocol-conformant follow-up measurements at the 12-week and 24-week timepoints. Participants who enrolled but did not complete six months of program participation, or who did not provide follow-up measurements at both protocol timepoints, were not included in the analysis cohort. The implications of this selection process for the interpretation of cohort outcomes are addressed in Section 4.4 (Limitations).\u003c/p\u003e\n\u003cp\u003eDemographic data, racial background, height, waist circumference, baseline weight, BMI, monthly weight changes, and participant-reported adverse events were captured for all 503 analyzed participants.\u003c/p\u003e\n\u003ch3\u003eData Collection Protocol\u003c/h3\u003e\n\u003cp\u003eOutcome data were collected through a structured online reporting framework developed by the principal investigator and modeled on the data-collection protocols used in the pivotal pharmacological GLP-1 receptor agonist clinical trials [4\u0026ndash;7] referenced as comparators in this analysis. Specific protocol elements included: (a) baseline weight measurement and confirmation at program enrollment; (b) standardized self-measurement instructions, including consistent time of day for weighing, consistent scale, consistent clothing/state-of-fasting conditions, and instructions to record measurements immediately rather than from recall; (c) incremental monthly reporting rather than retrospective reporting at study endpoints, to reduce recall bias and improve temporal resolution of weight trajectories; and (d) structured prompted adverse-event reporting at each follow-up timepoint, including specific prompted categories (gastrointestinal, neurologic, cardiovascular, musculoskeletal, sleep, and \u0026quot;other\u0026quot;) rather than open-ended self-disclosure alone. Modeling the data-collection framework on published pharmaceutical trial protocols was a deliberate methodological choice intended to improve cross-cohort comparability with the comparator data sources used in this analysis. The protocol is available from the corresponding author.\u003c/p\u003e\n\u003ch2\u003e2.3 Intervention\u003c/h2\u003e\n\u003cp\u003eThe Trimsulin Weight Loss Program, as evaluated in this analysis, comprised two licensed nutraceutical products taken together daily, accompanied by a structured dietary protocol and a moderate-exercise recommendation. The two products are commercially distributed by FirstFitness Nutrition (FFN) under the Trimsulin\u0026reg; trademark and are described below using FFN\u0026apos;s published product information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrimsulin Control.\u0026nbsp;\u003c/strong\u003eA sugar-free, mango-flavored powdered drink mix. Active components and mechanistic rationale by ingredient: allulose \u0026mdash; a rare low-metabolizable sugar with documented attenuation of postprandial glycemic excursion and endogenous GLP-1 secretagogue activity; inulin (chicory-derived) \u0026mdash; a prebiotic soluble fiber supporting intestinal L-cell density and GLP-1 secretion through FFAR2/FFAR3 short-chain fatty acid signaling; resistant starch \u0026mdash; a non-digestible carbohydrate with prebiotic fermentation-mediated GLP-1 and GIP secretagogue activity; myricetin \u0026mdash; a flavonoid with documented in-vitro DPP-4 inhibitory activity and GLP-1 secretagogue properties; mulberry leaf polyphenols \u0026mdash; \u0026alpha;-glucosidase inhibitory activity attenuating postprandial carbohydrate absorption and supporting downstream incretin signaling; mangosteen extract \u0026mdash; botanical extract with documented GLP-1 secretagogue activity and anti-inflammatory properties; resveratrol \u0026mdash; stilbenoid polyphenol with documented DPP-4 inhibitory activity and sirtuin1-AMPK pathway activation; pterostilbene \u0026mdash; a methylated resveratrol analog with enhanced bioavailability, insulin-resistance improvement, and AMPK activation; quercetin \u0026mdash; flavonoid with documented in-vitro DPP-4 inhibitory activity; alpha-lipoic acid \u0026mdash; a mitochondrial cofactor with documented insulin-sensitizing and antioxidant activity; chromium picolinate \u0026mdash; a trace mineral cofactor supporting insulin receptor signaling and glucose disposal; turmeric root (a source of curcuminoids) \u0026mdash; with documented DPP-4 inhibitory activity and anti-inflammatory pathway modulation. The coordinated multi-compound formulation constitutes the inventive composition underlying the pending patent estate (see Regulatory positioning, below); individual compounds are not novel in isolation. Administration: one 7-gram level scoop dissolved in 4\u0026ndash;6 fl oz of cold water, taken twice daily 30\u0026ndash;60 minutes before breakfast and before dinner.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrimsulin Thermo.\u0026nbsp;\u003c/strong\u003eA capsule formulation. Active components and mechanistic rationale by ingredient: caffeine \u0026mdash; methylxanthine with sympathomimetic and phosphodiesterase-inhibitory thermogenic activity; green coffee bean extract (standardized to 50% chlorogenic acid / 20% caffeine) \u0026mdash; source of chlorogenic acid, a GIP secretagogue and \u0026alpha;-glucosidase inhibitor, combined with adjunctive caffeine thermogenesis; synephrine HCl \u0026mdash; selective \u0026beta;3-adrenergic receptor agonist supporting adipose lipolysis and thermogenesis with a reduced cardiovascular activation profile relative to ephedrine-class compounds; yohimbine HCl \u0026mdash; \u0026alpha;2-adrenergic receptor antagonist supporting catecholamine-mediated lipolysis from regional adipose depots resistant to \u0026beta;-adrenergic stimulation; forskolin (30% standardized extract) \u0026mdash; diterpene adenylyl cyclase activator elevating intracellular cAMP and supporting hormone-sensitive lipase-mediated fat mobilization; capsinoids/capsaicin \u0026mdash; TRPV1-receptor-mediated thermogenic activation, UCP-1 upregulation, and lipid oxidation; fucoxanthin (10% standardized algal extract) \u0026mdash; marine carotenoid with documented UCP-1-mediated thermogenesis, AMPK activation, and white-to-brown adipocyte conversion activity in preclinical models; berberine HCl \u0026mdash; isoquinoline alkaloid with AMPK activation, hepatic gluconeogenesis suppression, and GLP-1 secretagogue properties (also present in Control). Administration: one capsule taken twice daily 30\u0026ndash;60 minutes before breakfast and before dinner. The combination of caffeine, synephrine HCl, and yohimbine HCl constitutes a documented sympathomimetic stack; the cardiovascular safety profile of this combination is described in the supplement-pharmacology literature and warrants attention in cardiovascular-risk subgroups (addressed in Section 4.4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDietary protocol and physical activity.\u0026nbsp;\u003c/strong\u003eProgram participants were provided the Trimsulin Healthy Eating Menu Guide, a structured 30-day dietary protocol emphasizing lean protein, vegetables, smart carbohydrates, fruits, and healthy fats, and were instructed to engage in moderate physical activity in accordance with FFN\u0026apos;s program guidance. The cohort outcomes reported in this analysis, therefore, reflect the integrated Trimsulin Weight Loss Program (Control + Thermo + Menu Guide + moderate exercise) rather than the supplements in isolation. The contribution of each program component to the overall outcomes cannot be apportioned within this observational design and is addressed in Section 4.4 (Limitations).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegulatory positioning.\u0026nbsp;\u003c/strong\u003eBoth Trimsulin Control and Trimsulin Thermo are composed of ingredients with generally recognized as safe (GRAS) regulatory status and are marketed by FFN as dietary supplements. FFN\u0026apos;s published product information explicitly states that Trimsulin does not contain GLP-1 and is not a GLP-1 receptor agonist medication. The mechanistic rationale for the present study is therefore that of endogenous incretin secretagogue activity \u0026mdash; stimulating the body\u0026apos;s own release of GLP-1 and GIP and reducing their enzymatic degradation \u0026mdash; rather than exogenous incretin receptor agonism. The compositional architecture of the Trimsulin formulation is the subject of pending United States patent applications filed by the author, currently under examination by the United States Patent and Trademark Office. Patent examination constitutes a form of independent technical review by examiners with specialized scientific training and no commercial interest in the outcome, encompassing prior-art search, novelty review, non-obviousness assessment, and enablement evaluation. While patent examination is not equivalent to peer scientific review, it represents a recognized form of external technical scrutiny that most nutraceutical compositions have not undergone, and is offered here as one element of the broader scientific basis for the present analysis.\u003c/p\u003e\n\u003ch2\u003e2.4 Comparator Data Sources\u003c/h2\u003e\n\u003cp\u003eComparative weight-loss outcomes for semaglutide and tirzepatide were derived from the published real-world cohort analysis by Rodriguez and colleagues [9], which evaluated 18,386 propensity-score-matched adults with overweight or obesity who initiated treatment between May 2022 and September 2023 using the Truveta integrated electronic health record dataset. The Rodriguez study population received semaglutide or tirzepatide formulations labeled for type 2 diabetes (Ozempic, Mounjaro), with a mean baseline weight of 110 kg (242 lbs), a mean baseline BMI of 39.0, and a 52.0% prevalence of type 2 diabetes.\u003c/p\u003e\n\u003cp\u003eComparator weight-loss values reported in this manuscript correspond to the on-treatment estimand from Rodriguez (Figure 4 of that paper), in which patients are censored at the time of treatment discontinuation, medication switching, or loss to follow-up. Rodriguez also reported a modified intention-to-treat (ITT) sensitivity analysis that included post-discontinuation weights and demonstrated numerically smaller weight reductions: 3.3% / 5.0% for semaglutide and 5.3% / 8.2% for tirzepatide at 3 and 6 months, respectively. The on-treatment estimand was selected for the present comparison because it is the primary analysis reported by the source study and represents the comparator therapies under conditions of sustained adherence.\u003c/p\u003e\n\u003cp\u003eComparative adverse event rates were drawn from a separate body of evidence \u0026mdash; published clinical trials and pharmacovigilance studies of semaglutide and tirzepatide [11\u0026ndash;14] \u0026mdash; sourced through systematic searches of PubMed, Embase, CINAHL, Scopus, and Web of Science. The Rodriguez analysis was not used as the comparator source for adverse events. Rodriguez deliberately captured only moderate-to-severe gastrointestinal events (bowel obstruction, cholecystitis, cholelithiasis, gastroenteritis, gastroparesis, pancreatitis) due to expected under-capture of mild events in EHR data and reported similar rates of these moderate-to-severe events between semaglutide and tirzepatide. The adverse event comparator data sources cited here [11\u0026ndash;14] use protocolized, prompted ascertainment of mild-through-severe events, which is appropriate for the present comparison.\u003c/p\u003e\n\u003cp\u003eCohort outcome data from all sources were normalized into a common data model through syntactic and semantic normalization to support cross-cohort descriptive comparison.\u003c/p\u003e\n\u003ch2\u003e2.5 Outcome Measures\u003c/h2\u003e\n\u003cp\u003ePrimary outcomes were:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePercent change in body weight from baseline at week 12 and week 24.\u003c/li\u003e\n \u003cli\u003eCumulative incidence of any participant-reported adverse event during program participation.\u003c/li\u003e\n \u003cli\u003eCumulative incidence of gastrointestinal adverse events (nausea, vomiting, diarrhea, gastritis), headache, insomnia, and serious adverse events.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eOutcomes were assessed descriptively against the corresponding semaglutide and tirzepatide rates reported in the comparator data sources.\u003c/p\u003e\n\u003ch2\u003e2.6 Statistical Analysis\u003c/h2\u003e\n\u003cp\u003eOutcomes are reported as means with ranges for continuous variables and as percentages for categorical variables. Given the observational, single-cohort design and reliance on published comparator data drawn from heterogeneous study populations and adverse event collection methods, no inferential statistical comparisons were performed between cohorts. All comparative findings are descriptive and hypothesis-generating.\u003c/p\u003e\n\u003cp\u003eTrimsulin cohort outcomes at 3 and 6 months are reported for the at-risk subpopulation at each time point \u0026mdash; that is, all enrolled participants with available follow-up weight measurement at the corresponding window. The cohort was not subject to on-treatment censoring; participants who reduced or discontinued program use during the follow-up window were retained in the analysis where weight measurements were available. This reporting framework is methodologically distinct from the on-treatment estimand reported by Rodriguez et al. [9], which censors patients at discontinuation, medication switching, or loss to follow-up. The implication is that the comparator weight-loss values cited in this manuscript represent semaglutide and tirzepatide under conditions of sustained adherence (the most favorable interpretation of comparator efficacy), whereas the Trimsulin cohort values reflect outcomes across all 503 analyzed participants \u0026mdash; all of whom provided complete data through six months. If the Rodriguez modified ITT estimand were used as a comparator instead, the relative magnitude of the Trimsulin cohort advantage would be larger. Of the 503 analyzed participants, weight measurements were available for the full cohort at both the 12-week and 24-week timepoints by inclusion criterion.\u003c/p\u003e\n\u003ch2\u003e2.7 Ethics\u003c/h2\u003e\n\u003cp\u003eThis was a retrospective analysis of de-identified outcome data collected as part of standard program enrollment. Per common research ethics guidance for retrospective analyses of de-identified program data, formal Institutional Review Board (IRB) review was not required. All program participants consented to outcome tracking as part of program enrollment. The analysis was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e"},{"header":"3. Results","content":"\u003ch2\u003e3.1 Baseline Characteristics and Cohort Disposition\u003c/h2\u003e\n\u003cp\u003eThe Trimsulin Weight Loss Program enrolled more than 1,000 adults during the analysis period. A total of 503 participants completed six months of program participation with protocol-conformant follow-up measurements at both 12-week and 24-week timepoints and constitute the analysis cohort. All 503 analyzed participants had weight measurements available at both timepoints. Participants enrolled but not meeting completion and protocol-conformant reporting criteria were not included in the analysis cohort (see Sections 2.2 and 4.4).\u003c/p\u003e\n\u003cp\u003eWithin the analyzed cohort (n = 503), mean baseline body weight was 201.2 lb (range 130\u0026ndash;360 lb). Mean baseline BMI was 27.5 (range 20.0\u0026ndash;50.1). Duration of program participation in the analyzed cohort ranged from 3 to 10 months, with a mean of 5.4 months.\u003c/p\u003e\n\u003ch2\u003e3.2 Weight Loss Outcomes\u003c/h2\u003e\n\u003cp\u003eMean percent weight reduction in the Trimsulin cohort was 7.3% at 3 months and 14.1% at 6 months. In the comparator cohort, mean percent weight reduction was 3.6% (semaglutide) and 5.9% (tirzepatide) at 3 months, and 5.8% (semaglutide) and 10.1% (tirzepatide) at 6 months. [9] Outcomes are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Mean percent weight reduction at 3 and 6 months (Trimsulin cohort vs. published comparator data).\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrimsulin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSemaglutide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTirzepatide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e3 Months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e7.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e3.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e5.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e6 Months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e14.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e5.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 156px;\"\u003e\n \u003cp\u003e10.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e3.3 Adverse Events in the Trimsulin Cohort\u003c/h2\u003e\n\u003cp\u003eOf 503 participants, 4.8% reported any adverse event during program participation. The most commonly reported events were insomnia (4.3%), gastrointestinal disorders (2.9%), loose stools (2.5%), nausea (2.1%), and gastritis (1.0%). No serious adverse events, vomiting, or headache were reported. Adverse event rates within the Trimsulin cohort are summarized in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Participant-reported adverse event rates in the Trimsulin cohort (n = 503).\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse Event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePercentage (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003eAny adverse effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e4.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003eGastrointestinal disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e2.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e2.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003eLoose stools\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e2.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003eGastritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e1.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 360px;\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 264px;\"\u003e\n \u003cp\u003e4.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e3.4 Comparative Adverse Event Rates\u003c/h2\u003e\n\u003cp\u003eAdverse event rates in the Trimsulin cohort were substantially lower than the rates reported for semaglutide and tirzepatide in published clinical trial cohorts. Any adverse event was reported by 4.8% of Trimsulin participants, compared with 89.7% (semaglutide) and 81.0% (tirzepatide). [11\u0026ndash;14] Gastrointestinal adverse events were reported by 2.9% of Trimsulin participants, compared with 59.7% (semaglutide) and 46.0% (tirzepatide). No serious adverse events were reported in the Trimsulin cohort, compared with approximately 3.0% (semaglutide) and 5\u0026ndash;7% (tirzepatide). Comparative adverse event rates are summarized in Table 3.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Comparative adverse event rates: Trimsulin cohort versus published clinical trial data for semaglutide and tirzepatide.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse Event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrimsulin (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSemaglutide (%) [11\u0026ndash;14]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTirzepatide (%) [11\u0026ndash;14]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eAny adverse effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e4.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e89.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e81.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eGastrointestinal disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e2.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e59.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e46.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e2.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e44.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e35.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e24.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e16.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e2.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e29.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e21.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e22.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e21.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eSerious adverse effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e3.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e5\u0026ndash;7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNote:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eAdverse event data for semaglutide and tirzepatide are derived from published clinical trials and meta-analyses, which typically capture adverse events more comprehensively and with more standardized prompting than observational, participant-reported cohort data. This methodological asymmetry should be considered when interpreting comparative adverse event rates (see Limitations).\u003c/em\u003e\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003ch2\u003e4.1 Summary of Findings\u003c/h2\u003e\n\u003cp\u003eIn this real-world observational cohort of 503 overweight adults, mean percent weight reduction with the Trimsulin Weight Loss Program was 7.3% at 3 months and 14.1% at 6 months. These outcomes were quantitatively greater than published mean weight reduction outcomes reported for semaglutide and tirzepatide over the same time intervals in a comparable real-world cohort. [9] Reported adverse event rates in the Trimsulin cohort were substantially lower than the rates reported for pharmacological incretin therapies in published clinical trials [11\u0026ndash;14], with no serious adverse events reported.\u003c/p\u003e\n\u003ch2\u003e4.2 Comparison with Published Literature\u003c/h2\u003e\n\u003cp\u003ePharmacological GLP-1RAs and dual GIP/GLP-1RAs have demonstrated robust weight reduction in randomized controlled trials. STEP 1 (semaglutide) reported a mean weight reduction of approximately 14.9% at 68 weeks. [4] STEP 2 reported 9.6% at 68 weeks in adults with type 2 diabetes. [5] STEP 5 reported 15.2% at 104 weeks. [6] SURMOUNT-1 (tirzepatide) reported up to 20.9% at 72 weeks. [7] However, real-world outcome data report substantially lower mean weight reduction than randomized trial outcomes, reflecting differences in adherence, dose titration, and discontinuation. The comparator data used in this analysis are drawn from a real-world Truveta-derived cohort and are therefore methodologically more comparable to the present cohort than randomized controlled trial outcomes. [9]\u003c/p\u003e\n\u003cp\u003eThe adverse event burden of pharmacological incretin therapy is well documented. Gastrointestinal adverse events occur in 40\u0026ndash;60% of treated patients in published trials and are the dominant driver of treatment discontinuation. [11,12] Reported serious adverse events include pancreatitis, gallbladder disease, intestinal obstruction, kidney injury, psychiatric events, and cardiovascular events. [12,13]\u003c/p\u003e\n\u003cp\u003eA material population characteristic differs between the present cohort and the Rodriguez comparator. The Rodriguez cohort had a mean baseline BMI of 39.0 (class 2/3 obesity), a mean baseline weight of 110 kg (242 lbs.), and a 52.0% prevalence of type 2 diabetes; participants received formulations labeled for diabetes management (Ozempic, Mounjaro). The Trimsulin cohort had a mean baseline BMI of 27.5 (overweight at threshold), a mean baseline weight of 91 kg (201 lbs.), and was not specifically characterized by type 2 diabetes status. Patients with higher baseline BMI generally exhibit larger absolute weight reductions on incretin-based therapy, and percentage weight reduction has been observed to scale modestly with available adipose mass; randomized trial data demonstrate consistently larger percentage reductions in higher-BMI strata. [4\u0026ndash;7] Despite this population asymmetry \u0026mdash; which would be expected to favor the higher-BMI Rodriguez cohort on percentage outcomes \u0026mdash; the lower-BMI Trimsulin cohort posted larger numerical percentage reductions at both 3 and 6 months. Two interpretations are possible. First, the Trimsulin composition may produce meaningful weight reduction that does not depend on the high baseline adiposity required for percentage outcomes with pharmacological GLP-1 receptor agonists. Second, the difference may reflect program-selection effects intrinsic to a paid commercial wellness program \u0026mdash; including higher motivation, behavioral engagement, and possible co-occurring lifestyle modification. Both interpretations warrant prospective controlled investigation; neither can be resolved by observational data alone.\u003c/p\u003e\n\u003ch2\u003e4.3 The Bioactive Signaling Molecule Framework\u003c/h2\u003e\n\u003cp\u003eThe mechanistic interpretation of the cohort outcomes proposed here is grounded in a coordinated multi-pathway construct termed the Bioactive Signaling Molecule (BSM) framework. The BSM framework, described in the patent estate underlying the Trimsulin composition [2,3] organizes the mechanistic basis of nutraceutical incretin-axis modulation around three coordinated functional layers rather than around individual compounds. The first layer is dual incretin secretagogue activity \u0026mdash; coordinated stimulation of endogenous GLP-1 release from intestinal L-cells and GIP release from intestinal K-cells. The second layer is DPP-4 inhibition with compounds that have documented active-site inhibition, extending the half-life of active endogenous incretins. The third layer is downstream metabolic regulatory pathway coordination, in which the same multi-compound composition engages a network of intracellular signaling pathways that are downstream of, parallel to, and synergistic with incretin signaling itself. The therapeutic premise of the BSM framework is that the cumulative metabolic effect of coordinated multi-pathway modulation exceeds what would be predicted from incretin signaling alone, while the indirect physiological character of the modulation produces a more favorable tolerability profile than direct receptor agonism.\u003c/p\u003e\n\u003cp\u003eThe lower reported adverse event rates observed in the Trimsulin cohort may be attributable to several mechanistic features consistent with this framework. First, stimulating endogenous GLP-1 and GIP release produces incretin signaling that follows physiological release patterns rather than the sustained supraphysiological exposure produced by long-acting injectable agonists. Second, oral daily administration may avoid the peak-trough pharmacokinetics characteristic of weekly injectable depot formulations, which have been associated with peak-related gastrointestinal symptoms. [11] Third, the multi-pathway character of the BSM mechanism distributes the metabolic effect across multiple regulatory nodes, potentially reducing the magnitude of perturbation at any single pathway and the associated adverse event load.\u003c/p\u003e\n\u003cp\u003ePublished evidence implicates multiple cellular signaling pathways in obesity and weight regulation [17], of which the following are activated or modulated by compound classes present in the Trimsulin BSM composition:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eInsulin / Insulin Receptor Substrate (IRS) signaling \u0026mdash; central to glucose metabolism, insulin sensitivity, and lipid storage.\u003c/li\u003e\n \u003cli\u003eAdipokine signaling \u0026mdash; adipose-derived hormones modulating inflammation and metabolism.\u003c/li\u003e\n \u003cli\u003eSirtuin1\u0026ndash;AMPK signaling \u0026mdash; regulating cellular energy metabolism and lipid oxidation; engaged by berberine and fucoxanthin.\u003c/li\u003e\n \u003cli\u003eAMPK / mTOR signaling \u0026mdash; central to energy balance and cellular growth under conditions of energy availability or restriction.\u003c/li\u003e\n \u003cli\u003ePI3K-AKT signaling \u0026mdash; insulin sensitivity, glucose uptake, and downstream metabolic regulation.\u003c/li\u003e\n \u003cli\u003eMAPK / p38 signaling \u0026mdash; cellular stress and energy regulation.\u003c/li\u003e\n \u003cli\u003eInflammatory pathways and PPAR signaling \u0026mdash; modulating chronic obesity-associated inflammation and regulating lipid storage and glucose metabolism.\u003c/li\u003e\n \u003cli\u003ePKG signaling and gut hormone regulation \u0026mdash; supporting energy balance and modulating GLP-1 and GIP release.\u003c/li\u003e\n \u003cli\u003e\u0026beta;3-adrenergic signaling \u0026mdash; regulating adipose tissue lipolysis and energy expenditure; engaged by synephrine and capsaicin/capsiate.\u003c/li\u003e\n \u003cli\u003e\u0026alpha;2-adrenergic antagonism \u0026mdash; supporting lipolysis from regional adipose depots otherwise resistant to catecholamine-mediated mobilization; engaged by yohimbine.\u003c/li\u003e\n \u003cli\u003eOb-R / JAK2 signaling \u0026mdash; leptin-mediated regulation of energy intake and adipose function.\u003c/li\u003e\n \u003cli\u003eTRPV1 receptor signaling \u0026mdash; thermogenic activation; engaged by capsaicin and capsiate.\u003c/li\u003e\n \u003cli\u003eFFAR2 / FFAR3 (free fatty acid receptor) signaling \u0026mdash; short-chain fatty acid sensing and L-cell incretin release; engaged by inulin-derived fermentation products.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003ePhytochemicals, botanical extracts, mineral cofactors, flavonoids, fibers, prebiotics, peptides, amino acids, and intense sweeteners present in the Trimsulin composition demonstrate documented activity at one or more of these regulatory nodes. The proposed mechanistic basis of the BSM framework \u0026mdash; that coordinated modulation across this network produces metabolic effects exceeding those of incretin signaling alone \u0026mdash; is hypothesized rather than demonstrated by the present observational analysis. Direct measurement of plasma active GLP-1 and GIP concentrations, DPP-4 activity, UCP-1 expression, and downstream pathway activation under Trimsulin administration is required to confirm the framework and represents a high-priority direction for subsequent mechanistic research.\u003c/p\u003e\n\u003cp\u003eThe individual compounds that comprise the BSM framework have established GRAS regulatory status and a documented history of use across food, supplement, and food additive categories. If the weight-reduction and tolerability outcomes observed in this cohort are validated in prospective controlled studies, the findings would suggest that coordinated multi-pathway incretin secretagogue activity is achievable through compositions embedded in the food supply\u0026mdash;a public health inference worth investigating, given the cost and access constraints of pharmacological incretin therapy discussed in Section 4.6. Whether that inference holds across different delivery formats and populations is an empirical question that the present data cannot answer.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e4.4 Limitations\u003c/h2\u003e\n\u003cp\u003eSeveral limitations must be considered when interpreting these findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design.\u0026nbsp;\u003c/strong\u003eThis was a single-arm observational cohort analysis without randomization, blinding, placebo control, or concurrent comparator. Comparative outcomes are drawn from published external datasets and are therefore subject to selection bias, residual confounding, and unmeasured population differences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection-related attrition.\u0026nbsp;\u003c/strong\u003eThe 503 participants analyzed represent the subset of a Trimsulin Weight Loss Program population of more than 1,000 adults who provided complete six-month follow-up data. Participants who enrolled but did not complete six months of program participation, or who did not provide protocol-conformant follow-up measurements at both timepoints, were not included in the analysis cohort. The reasons for non-completion or non-reporting were not systematically captured and may include treatment dissatisfaction, weight-related discouragement, lifestyle change unrelated to the program, or routine non-response. Outcomes among non-reporting program participants may differ from outcomes in the analyzed cohort, and the present analysis cannot quantify that difference. The reported cohort outcomes, therefore, reflect the experience of program completers with sustained six-month engagement and may overstate the average outcome that would be observed in a randomized intent-to-treat analysis of the full enrolled program population. This limitation is structurally similar to the on-treatment estimand reported by Rodriguez et al. for the comparator drugs [9], in which patients censored at discontinuation are excluded from the analyzed denominator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event capture asymmetry.\u0026nbsp;\u003c/strong\u003eAdverse events in the Trimsulin cohort were captured through participant-reported observational data using a structured online reporting framework with prompted adverse-event categories modeled on the protocols used in the pivotal pharmacological GLP-1 receptor agonist trials [4\u0026ndash;7] (see Section 2.2, Data Collection Protocol). Comparator adverse event rates are drawn from clinical trials and pharmacovigilance studies, which use clinician-confirmed and systematically prompted ascertainment in controlled clinical settings. Despite the deliberate methodological alignment, residual under-ascertainment in the participant-reported observational cohort relative to clinician-confirmed trial cohorts is likely. The magnitude of the observed difference in adverse-event rates (4.8% vs. 81\u0026ndash;90%), however, is unlikely to be fully explained by ascertainment differences alone; even substantial under-ascertainment in the observational cohort would leave a clinically meaningful residual gap.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparator heterogeneity.\u0026nbsp;\u003c/strong\u003ePublished comparator data span different study designs, populations, durations of follow-up, and dose-titration schedules. The Rodriguez weight-loss comparator cohort differed materially from the Trimsulin cohort in baseline BMI (39.0 vs. 27.5), baseline weight (110 kg vs. 91 kg), prevalence of type 2 diabetes (52.0% vs. uncharacterized), and use of T2D-labeled rather than weight-loss-labeled drug formulations. Adverse event comparator data were drawn from a different evidence base (clinical trials and pharmacovigilance registries [11\u0026ndash;14]) that uses protocolized, prompted ascertainment, which is methodologically more sensitive than EHR-derived or observational adverse event capture. Direct numerical comparison of mean outcomes across heterogeneous cohorts must be interpreted as descriptive rather than causal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNo inferential testing.\u0026nbsp;\u003c/strong\u003eNo between-cohort statistical hypothesis testing was performed. The findings are descriptive and hypothesis-generating only.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneralizability.\u0026nbsp;\u003c/strong\u003eParticipants enrolled in a commercial wellness program may differ from clinical trial populations in motivation, adherence, and behavioral engagement. The mean baseline BMI of 27.5 places the cohort at the lower end of the BMI range studied in pivotal pharmacological incretin trials, and the upper-BMI subset of the present cohort was not analyzed separately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultimodal intervention.\u0026nbsp;\u003c/strong\u003eThe Trimsulin Weight Loss Program comprises Control + Thermo, a structured dietary protocol (the Trimsulin Healthy Eating Menu Guide), and a moderate exercise recommendation. The cohort outcomes reported here reflect the integrated program, not the supplement components in isolation. Within an observational, single-arm design, the contribution of supplement-mediated incretin secretagogue activity, dietary protocol, and exercise cannot be separately apportioned. Caloric restriction and increased physical activity each independently produce weight reduction, and a portion of the observed effect is therefore attributable to the program\u0026apos;s dietary and behavioral components. Future randomized controlled trials with appropriate factorial or active-control arms (supplement + diet + exercise vs. diet + exercise alone vs. supplement alone) are needed to apportion the mechanism. The same caveat applies to the comparator data: pharmacological GLP-1 RA trials and real-world cohorts also typically include lifestyle counseling, so the comparison is between two integrated weight-management approaches rather than between isolated agents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCardiovascular safety profile of Thermo.\u0026nbsp;\u003c/strong\u003eTrimsulin Thermo contains caffeine, synephrine, and yohimbine \u0026mdash; a sympathomimetic combination with a documented cardiovascular activity profile in the supplement-pharmacology literature. Although no serious cardiovascular adverse events were reported in the present cohort and overall adverse-event rates were low, the population studied here had a mean baseline BMI of 27.5 and was not specifically characterized by cardiovascular risk status. Caution is warranted in interpreting the cohort safety profile as generalizable to populations with established cardiovascular disease, uncontrolled hypertension, arrhythmia, or concurrent stimulant use. Future studies should specifically capture cardiovascular-risk-stratified safety data, including blood pressure and heart rate monitoring across the dosing window.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest.\u0026nbsp;\u003c/strong\u003eThe author is the inventor of the Trimsulin formulation and the founder of NutraGLP Biosciences. While the analysis was conducted in good faith and uses published external comparator data, the potential for unconscious bias in cohort framing and outcome interpretation must be acknowledged.\u003c/p\u003e\n\u003ch2\u003e4.5 Comparison with Recent Real-World Cohort Studies\u003c/h2\u003e\n\u003cp\u003eIn addition to the Rodriguez et al. analysis [9], two further real-world cohort studies of pharmacological incretin therapy have been published recently and provide additional context for the present analysis. The SHAPE study evaluated 9,916 adults with overweight or obesity without type 2 diabetes who initiated semaglutide 2.4 mg or tirzepatide labeled for weight management, drawn from the Komodo Health database between June 2021 and December 2023, with one year of follow-up. [18] A separate retrospective analysis of 339 participants in a 12-month remote weight management program combining medication, app-based behavioral support, and dietitian coaching reported mean 12-month weight reductions of 22.1% (tirzepatide) and 17.1% (semaglutide). [19] These published 12-month outcomes \u0026mdash; drawn from real-world cohorts that, like the present analysis, combine pharmacological incretin therapy with structured behavioral and dietary support \u0026mdash; provide a useful methodological reference point for the integrated multimodal weight-management framework discussed in Section 2.3 and Section 4.4. The 14.1% six-month outcome observed in the present Trimsulin cohort is consistent in magnitude with the trajectory of these recent real-world programs and is achieved without exposure to injectable pharmacological agents.\u003c/p\u003e\n\u003ch2\u003e4.6 Cost and Access Considerations\u003c/h2\u003e\n\u003cp\u003eReal-world weight management is increasingly defined by cost and access constraints in addition to efficacy. Pharmacological GLP-1 receptor agonists labeled for weight management currently retail at approximately $1,000\u0026ndash;1,300 per month at the standard dose in the United States; insurance coverage for weight-management indications remains inconsistent, and high out-of-pocket cost is a documented driver of treatment discontinuation in the published real-world literature. [9] The Trimsulin Weight Loss Program is currently retailed by FirstFitness Nutrition at approximately $175 per 30-day program, including supplements and the structured eating guide. While direct cost-effectiveness comparison is beyond the scope of the present hypothesis-generating analysis and would require formal incremental cost-effectiveness evaluation, the order-of-magnitude difference in monthly cost is a structurally relevant element of any comparative evaluation between the two approaches and is acknowledged here as a factor in real-world treatment selection.\u003c/p\u003e\n\u003ch2\u003e4.7 Strengths\u003c/h2\u003e\n\u003cp\u003eThe present analysis has several methodological strengths that should be considered alongside the limitations described in Section 4.4. The analysis cohort of 503 participants with complete six-month follow-up is materially larger than the typical pilot or feasibility cohort reported for nutraceutical weight-management compositions, and the six-month follow-up duration exceeds that of many published nutraceutical efficacy studies. The data collection framework was deliberately modeled on the protocols used in the pivotal pharmacological GLP-1 receptor agonist clinical trials [4\u0026ndash;7], supporting cross-cohort comparability with the comparator data sources. The selection of the Rodriguez et al. real-world cohort [9] as the primary weight-loss comparator \u0026mdash; rather than randomized controlled trial outcomes \u0026mdash; reduces the comparator-population artifact in which clinical trial outcomes overstate real-world drug effectiveness. The multimodal nature of the intervention is explicitly disclosed, and the comparator data are appropriately framed as also reflecting integrated multimodal care rather than isolated pharmacological agents. The conflict of interest borne by the principal investigator is disclosed candidly, and the analysis was conducted using published external comparator data that the author did not generate. The compositional architecture evaluated is the subject of pending patent applications currently under examination by the United States Patent and Trademark Office, as referenced in Section 2.3.\u003c/p\u003e\n\u003ch2\u003e4.8 Implications for Future Research\u003c/h2\u003e\n\u003cp\u003eThese hypothesis-generating findings support further controlled investigation of endogenous incretin secretagogue compositions as a class. The present cohort study evaluated one implementation of the BSM platform framework. Future research directions of highest priority include prospective randomized controlled trials of BSM-framework compositions \u0026mdash; including next-generation formulations incorporating more advanced ingredient systems and delivery architectures \u0026mdash; compared against placebo and against active pharmacological incretin comparators. Secondary endpoints of particular mechanistic value include changes in plasma active GLP-1 and GIP concentrations, DPP-4 activity, fasting and post-prandial glycemic response, UCP-1 induction, and patient-reported tolerability. A factorial design apportioning the contribution of the BSM supplement components versus the dietary and behavioral program elements would clarify the mechanistic contribution of each. Adjunctive use of BSM-framework compositions in patients who discontinue pharmacological incretin therapy due to intolerance represents a clinically meaningful research direction, given the established real-world discontinuation burden of pharmacological GLP-1 receptor agonists. [11\u0026ndash;14] Beyond supplement formats, investigation of BSM-framework ingredient systems in functional food and food-additive delivery formats represents a translational research direction of broader public health relevance, given the potential for population-scale access that food-category routes offer relative to pharmaceutical channels.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn this real-world observational cohort of 503 overweight adults, weight-loss outcomes with the Trimsulin Weight Loss Program were quantitatively greater than those reported for pharmacological incretin therapies, and reported adverse event rates were substantially lower. No serious adverse events were reported. While the descriptive nature of the analysis, the asymmetry in adverse event ascertainment, and the author\u0026apos;s disclosed conflict of interest all constrain the conclusions that can be drawn, the findings are consistent with the hypothesis that endogenous incretin secretagogue compositions may offer a more tolerable approach to incretin-based weight management. A prospective randomized controlled investigation is warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was self-funded by Richard Clark Kaufman, PhD, and FirstFitness Nutrition (FFN). No external grant funding or industry sponsorship was received.\u003c/p\u003e\n\u003ch2\u003eConflict of Interest\u003c/h2\u003e\n\u003cp\u003eRichard Clark Kaufman, PhD, is the inventor of the Trimsulin formulations evaluated in this study and the founder and Chief Scientific Officer of NutraGLP Biosciences, the entity holding the intellectual property rights to the formulation. FirstFitness Nutrition is a commercial licensee of a Trimsulin-related product. The author has financial interests that may benefit from positive outcomes reported in this study. The analysis was conducted in good faith using published external comparator data. The reader is encouraged to interpret the findings in the context of this disclosure.\u003c/p\u003e\n\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\n\u003cp\u003eRCK conceived the study, designed the analytic framework, developed the data collection protocol, conducted the analysis, and wrote and revised the manuscript. As the sole author of the present submission, RCK is responsible for the integrity of the data and the accuracy of the analysis. The author confirms that all aspects of the work have been reviewed for accuracy and that no portion of the analysis has been generated by undisclosed contributors. Should additional contributors join future iterations of this work \u0026mdash; for example, a statistical methodologist for a planned randomized controlled trial follow-up, or co-investigators for mechanistic substudies \u0026mdash; author contributions will be specified in accordance with International Committee of Medical Journal Editors (ICMJE) authorship criteria, and ORCID identifiers will be reported for all contributing authors.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe author thanks the participants enrolled in the Trimsulin Weight Loss Program and FirstFitness Nutrition for program operational support. The author also thanks Daniel Kimball, JD (Loza \u0026amp; Loza LLP), for review of intellectual property\u0026ndash;related disclosures.\u003c/p\u003e\n\u003ch2\u003eData Availability Statement\u003c/h2\u003e\n\u003cp\u003eDe-identified aggregate outcome data supporting the findings of this study are available from the corresponding author upon reasonable request. Composition-specific formulation data are protected under issued and pending intellectual property and may be made available under appropriate confidentiality agreements.\u003c/p\u003e\n\u003ch2\u003eEthics Approval Statement\u003c/h2\u003e\n\u003cp\u003eThis study constituted a retrospective analysis of de-identified outcome data from participants in a commercially available wellness program. Per common research ethics guidance for retrospective analyses of de-identified program data, formal IRB review was not required. All program participants consented to outcome tracking at the point of program enrollment. The study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003ch2\u003eRegulatory Positioning\u003c/h2\u003e\n\u003cp\u003eThe formulation evaluated in this study is composed of ingredients with generally recognized as safe (GRAS) regulatory status. The BSM framework underlying this composition is designed for application across multiple non-pharmaceutical product categories, including dietary supplements, functional foods, food additives, and conventional food products \u0026mdash; all regulated under food and supplement frameworks rather than pharmaceutical frameworks. The specific composition evaluated here (Trimsulin Control + Thermo) is currently marketed as a dietary supplement. This study is not intended to support or imply drug-level claims, nor to support regulatory classification of the formulation or its derivative compositions as pharmaceutical agents. The findings are presented for scientific, informational, and research purposes only and do not constitute medical advice, diagnosis, or treatment recommendations. Individual results may vary.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOgden CL, Fakhouri TH, Carroll MD et al (2017) Prevalence of obesity among adults, by household income and education \u0026mdash; United States, 2011\u0026ndash;2014. MMWR Morb Mortal Wkly Rep 66(50):1369\u0026ndash;1373. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.15585/mmwr.mm6650a1\u003c/span\u003e\u003cspan address=\"10.15585/mmwr.mm6650a1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaisi-Estabragh Z, Kobo O, Mieres JH et al (2023) Racial disparities in obesity-related cardiovascular mortality in the United States: temporal trends from 1999 to 2020. 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N Engl J Med 384(11):989\u0026ndash;1002. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2032183\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2032183\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavies M, F\u0026aelig;rch L, Jeppesen OK, STEP 2 Study Group et al (2021) Semaglutide 2.4 mg once a week in adults with overweight or obesity and type 2 diabetes (STEP 2): a randomised, double-blind, placebo-controlled, phase 3 trial. 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N Engl J Med 387(24):2245\u0026ndash;2257. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2208601\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2208601\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWharton S, Calanna S, Davies M et al (2022) Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes Metab 24(8):1553\u0026ndash;1564. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/dom.14725\u003c/span\u003e\u003cspan address=\"10.1111/dom.14725\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShu Y, He X, Wu P et al (2022) Gastrointestinal adverse events associated with semaglutide: a pharmacovigilance study based on FDA adverse event reporting system. Front Public Health 10:996179. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fpubh.2022.996179\u003c/span\u003e\u003cspan address=\"10.3389/fpubh.2022.996179\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMishra R, Raj R, Elshimy G et al (2023) Adverse events related to tirzepatide. J Endocr Soc 7(4):bvad016. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1210/jendso/bvad016\u003c/span\u003e\u003cspan address=\"10.1210/jendso/bvad016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarvey WT, Frias JP, Jastreboff AM et al (2023) SURMOUNT-2 investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 402(10402):613\u0026ndash;626. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(23)01200-X\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(23)01200-X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAronne LJ, Sattar N, Horn DB et al (2024) SURMOUNT-4 Investigators. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 331(1):38\u0026ndash;48. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2023.24945\u003c/span\u003e\u003cspan address=\"10.1001/jama.2023.24945\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y (2022) Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol 10(9):634\u0026ndash;644. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2213-8587(22)00187-5\u003c/span\u003e\u003cspan address=\"10.1016/S2213-8587(22)00187-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWen X, Zhang B, Wu B, Xiao H, Li Z, Li R, Xu X, Li T (2022) Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 7(1):298. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41392-022-01149-x\u003c/span\u003e\u003cspan address=\"10.1038/s41392-022-01149-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReal-World Weight Loss Observed With (2025) Semaglutide and Tirzepatide in Patients with Overweight or Obesity and Without Type 2 Diabetes (SHAPE). Adv Ther. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12325-025-03340-2.\u003c/span\u003e\u003cspan address=\"10.1007/s12325-025-03340-2.\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Available from PMC PMC12579654\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"obesity, weight loss, GLP-1, GIP, incretin, nutraceutical, secretagogue, semaglutide, tirzepatide, observational cohort, real-world evidence","lastPublishedDoi":"10.21203/rs.3.rs-9657897/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9657897/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePharmacological glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists such as tirzepatide produce clinically meaningful weight reduction in adults with overweight or obesity. However, gastrointestinal and serious adverse events affect a substantial proportion of treated patients, contributing to discontinuation and limiting long-term adherence. Nutraceutical compositions designed to stimulate endogenous GLP-1 and GIP secretion may offer a tolerability advantage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo describe weight change and adverse event rates in a real-world cohort of overweight adults using a nutraceutical endogenous incretin secretagogue composition (Trimsulin Weight Loss Program) and to compare these outcomes with publicly available outcome data for semaglutide and tirzepatide.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eObservational cohort analysis of 503 overweight adults enrolled in the Trimsulin Weight Loss Program, comprising two nutraceutical products (Control, a powdered drink mix; Thermo, a capsule formulation) taken twice daily before meals, plus a structured dietary protocol and a moderate-exercise recommendation. Body weight, BMI, and participant-reported adverse events were tracked at 12 weeks and 24 weeks. Comparative weight-loss outcomes for semaglutide and tirzepatide were drawn from the on-treatment estimand of the published Truveta-derived real-world cohort analysis by Rodriguez et al. (n = 18,386; mean baseline BMI 39.0). Comparative adverse event rates were drawn from a separate body of clinical trial and pharmacovigilance evidence. Outcomes are reported descriptively; no inferential statistical testing was performed between cohorts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOf more than 1,000 enrolled program participants, 503 completed six months of program participation with protocol-conformant follow-up measurements and constitute the analysis cohort. Mean baseline weight was 201.2 lb (range 130–360); mean BMI was 27.5 (range 20.0–50.1). At 3 months, mean weight reduction was 7.3% in the Trimsulin cohort, compared with 3.6% (semaglutide) and 5.9% (tirzepatide) reported in published comparator data. At 6 months, mean reductions were 14.1%, 5.8%, and 10.1%, respectively. Any adverse event was reported by 4.8% of Trimsulin participants, compared with 89.7% (semaglutide) and 81.0% (tirzepatide) in published trial cohorts. No serious adverse events were reported in the Trimsulin cohort, compared with approximately 3.0% for semaglutide and 5–7% for tirzepatide.\u003c/p\u003e\n\u003cp\u003eThese hypothesis-generating findings support further controlled investigation of endogenous incretin secretagogue compositions as a class. The present cohort study evaluated one licensed implementation of the BSM platform framework. Future research directions of highest priority include prospective randomized controlled trials of BSM-framework compositions — including next-generation formulations incorporating more advanced ingredient systems and delivery architectures — compared against placebo and against active pharmacological incretin comparators. Secondary endpoints of particular mechanistic value include changes in plasma active GLP-1 and GIP concentrations, DPP-4 activity, fasting and post-prandial glycemic response, UCP-1 induction, and patient-reported tolerability. A factorial design apportioning the contribution of the BSM supplement components versus the dietary and behavioral program elements would clarify the mechanistic contribution of each. Adjunctive use of BSM-framework compositions in patients who discontinue pharmacological incretin therapy due to intolerance represents a clinically meaningful research direction, given the established real-world discontinuation burden of pharmacological GLP-1 receptor agonists. [11–14] Beyond supplement formats, investigation of BSM-framework ingredient systems in functional food and food-additive delivery formats represents a translational research direction of broader public health relevance, given the potential for population-scale access that food-category routes offer relative to pharmaceutical channels.\u003c/p\u003e","manuscriptTitle":"Endogenous Incretin Secretagogue Compositions as a Mechanistic Class Versus Pharmacological Incretin Receptor Agonists for Weight Reduction in Overweight Adults: A Real-World Observational Cohort Analysis of a Nutraceutical Composition (Trimsulin) and Comparison with Published Outcomes for Semaglutide and Tirzepatide","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 18:35:34","doi":"10.21203/rs.3.rs-9657897/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"33083efd-59e6-4310-a6bc-4070d9f743d9","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67817351,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2026-05-12T18:35:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 18:35:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9657897","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9657897","identity":"rs-9657897","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}