(M-011) Quantitative Systems Pharmacology (QSP) Modeling of efficacy and nausea of GLP-1 mono and dual (GLP-1/GIP) receptor agonists (RA) to support weight management and glycemic control in obese patients

Shivaani E – Vantage Research LLC; Neelima Patnaikuni – Vantage Research LLC; Arjun Kolappurth Madathil – Vantage Research LLC; Narmada BC – Vantage Research LLC; Kannan Thiagarajan – Vantage Research LLC; Narendra Dixit – Bioengineering – Indian Institute of Science; Rukmini Kumar – Vantage Research LLC

Background: Glucagon-like-peptide-1 (GLP-1) is peptide secreted by intestinal mucosal cells, pancreatic islet cells and neurons in the nucleus of the solitary tract. GLP-1 receptor agonists (GLP-1RA) mimics the action of endogenous GLP-1 activating GLP-1R, thereby enhancing insulin secretion, inhibiting glucagon release, delaying gastric emptying and reducing food intake through satiety/appetite suppression. Potential applications of GLP-1RA in treating various disorders are being explored by the scientific community (1). Gastrointestinal (GI)-related adverse events, especially nausea is a key safety concern which leads to poor adherence and early discontinuation from treatment. This warrants a deep understanding of their mechanism of action, which involves receptor occupancy and target engagement in both target (e.g., pancreas, gut) and non-target tissues which leads to GI adverse events.
Scientific objective: Several mono GLP RA, as well as Tirzepatide have been approved for treating T2DM and subsequently for chronic weight management in adults. Insights derived from such mechanistic models can inform dose optimization and design of dosing regimens that improve compliance and patient adherence, which is crucial in more effective long-term weight management therapies.

Methods: We have utilized the published works of (2) that demonstrates the short long-term effects of caloric intake on body weight, and (3), glycemia model’s effects of caloric intake on glycemic control. Our model further integrated the elements from both models with the introduction of GLP-1RA/GIP RA dose to capture the glucose-insulin dynamics, weight loss, reduction in HbA1C. A simple 2-compartment model of semaglutide and tirzepatide was developed to capture the drug PK and PD effects consistent with what was reported in the public domain (4)-(11). These primary effects further result in the key efficacy outcome of reduction in HbA1c and body weight loss which was calibrated to fit clinical data at various doses. We implemented a safety module to capture incidence rate of nausea at population level as reported in clinical trial data (8, 10, 11) where plasma drug concentrations drive probability of GI adverse events in a given patient population.

Results: Our model thus well integrates the drug PK to the weight and glycemic control & safety and connects receptor occupancy predictions to PD, and downstream effects on clinical readouts such as weight loss, HbA1c for semaglutide and Tirzepatide. The model is robust and can capture PK-PD-safety including the differences in mechanism of action and magnitude of impact between these two drugs in obese populations.

Conclusions: A platform QSP model incorporating energy expenditure and glucose-insulin dynamics has been built and calibrated to the observed efficacy of GLP-1R mono agonist Semaglutide and dual agonist Tirzepatide reported in the clinical literature. A major limitation of the current work is the lack of target engagement at multiple sites to address the growing use of GLP-1 RA based therapeutic strategy to treat diseases other than diabetes and weight-loss, which is being actively explored in the future versions of the model.

Citations: 1. Thiara D. GLP-1 Receptor Agonists—From Breakthroughs in Cardiometabolic Treatment to Emerging Neuroprotective Potential. JAMA Neurol. Published online April 07, 2025. doi:10.1001/jamaneurol.2025.0237
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9. Gummesson A, Nyman E, Knutsson M, Karpefors M. Effect of weight reduction on glycated haemoglobin in weight loss trials in patients with type 2 diabetes. Diabetes Obes Metab. 2017 Sep;19(9):1295-1305. doi: 10.1111/dom.12971. Epub 2017 May 22. PMID: 28417575.
10. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10. PMID: 33567185. doi: 10.1056/NEJMoa2032183
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Keywords: GLP-1RA, QSP, GIP, Weight loss, Glycemic control