Objective
This project aims to advance fully automated insulin delivery systems, considering tirzepatide as an adjunctive therapy for the overweight and obese Type 1 diabetes population. The following two objectives are defined:
Objective 1. To study the effect of tirzepatide on gastric emptying at escalating doses using the “gold standard” gastric emptying scintigraphy test (FAITH-T1D/1 study). A multicentric clinical study will be conducted at Hospital Universitario Ramón y Cajal (Madrid) and Hospital Universitari i Politècnic La Fe (València), with a total cohort of 12 adults with T1D and overweight/obesity.
Objective 2. To develop and validate a new control algorithm for fully automated insulin delivery, incorporating tirzepatide as an adjunctive therapy. The FLEX-AP algorithm, developed by the Universitat Politècnica de València, will be enhanced to account for the effects of tirzepatide. This addition is expected to significantly impact key biomarkers over time, including time in the target glucose range, body weight, insulin sensitivity, and meal responses, in a dose-dependent manner. Adaptation techniques will be incorporated into the control algorithm to efficiently compensate for such changes. We aim to demonstrate, in silico, the superior performance of the fully automated system with tirzepatide compared to fully automated and hybrid insulin-only configurations. As a previous step, the pharmacokinetic and pharmacodynamic mathematical models describing tirzepatide’s influence on gastric emptying and its downstream effects on postprandial glucose control will be developed from the data generated in the FAITH-T1D/1 study. A new simulation platform will be developed for in-silico validation of the new algorithm, as there is currently no such computational tool available.
Background Rationale
Achieving optimal glycemic control in individuals with type 1 diabetes (T1D) remains a major clinical challenge, despite the availability of modern insulin analogs, the improving accuracy of continuous glucose monitoring, the widening use of intensive insulin therapy, and the advent of Automated Insulin Delivery (AID) systems. These latter are rapidly becoming the standard of care for T1D. However, all AID systems currently available in the market are hybrid: they require the patient’s intervention to manage meals. Patients must still count carbs and announce them to the system, which remains a high burden for most patients. Carb counting is prone to significant estimation errors, leading to inadequate insulin dosing at meals. Numerous strategies have been proposed to eliminate meal announcement in pursuit of fully automated insulin delivery systems; however, achieving this without compromising glycemic control relative to a hybrid system remains challenging. Inherent limitations of subcutaneous insulin delivery have led to the investigation of new ways to soften glucose rises after meals, such as the use of additional drugs together with an AID system (adjunctive therapies). Various drugs are under investigation, which slow the absorption of meal carbohydrates or reduce glucose levels in an insulin-independent manner.
Incretin analogs have gained considerable traction over the last few years for the management of type 2 diabetes and obesity, given the potential to control hyperglycemic excursions, promote weight loss, and cardiovascular and renal protective benefits. Even though not yet cleared for T1D, positive results with these drugs have motivated interest in their use in T1D. Glycemic control in T1D is highly variable, with postprandial hyperglycemia among the most significant and recurring challenges. Also, T1D may contribute to a propensity for overweight or obesity problems. Indeed, the prevalence of overweight or obesity in people with T1D has increased significantly.
In combination with insulin, incretin analogs have been shown to improve glycemic control, reducing insulin needs and weight in patients with T1D. However, when used alongside an AID system, the settings must be adjusted at the start of treatment to reduce the risk of hypoglycemia. Also, due to the uncertainty surrounding drug tolerance, prescribing practices, and reimbursement, healthcare providers should carefully consider factors such as up-titration, down-titration, intermittent dosing, and discontinuation, which would require new re-configurations. Considering that current AID systems already depend on the patient’s intervention, adding an extra configuration layer defeats the purpose of calling them “automatic”. There is a need for further investigation to adapt AID control algorithms for their optimal use with incretin analogs and to get the most benefit out of this combined therapy, with the achievement of elimination of meal announcement without loss of glycemic control.
Description of Project
Glycemic control in type 1 diabetes (T1D) remains a challenge, despite the availability of modern insulin analogs, the improving accuracy of continuous glucose monitoring, the widening use of intensive insulin therapy, and the advent of Automated Insulin Delivery (AID) systems. Although AID systems are becoming the standard of care for T1D, all currently available systems are hybrid: they require user intervention during meals to minimize post-meal glucose peaks. In this regard, people with T1D must still count carbohydrates and report them to the system, which remains a significant burden for most. Carb counting can lead to substantial estimation errors, resulting in inadequate insulin dosing during meals. Various strategies have been proposed to eliminate meal announcements in the pursuit of fully automated insulin delivery systems. However, preliminary results show that it is still hard to achieve without affecting blood sugar control, especially compared to a hybrid system. Inherent limitations of subcutaneous insulin delivery have led to the investigation of new approaches to address postprandial glucose elevations, such as the use of additional drugs (adjunctive therapies) in combination with insulin (through AID systems). Various drugs are under investigation, which slow the absorption of meal carbohydrates and/or help reduce glucose levels in an insulin-independent manner.
A new class of medication known as incretin analogs has gained considerable attention over the last few years for the management of type 2 diabetes and obesity, given their efficacy in controlling hyperglycemic excursions, promoting weight loss, and providing cardiovascular and renal protective benefits. These positive results have sparked interest among scientists due to their potential to help people with T1D, associated with a greater prevalence of overweight and obesity than in the general population. However, studies with this medication in T1D have only started.
In combination with insulin, incretin analogs have been shown to improve glycemic control, reducing insulin needs and weight in people with T1D. However, the use of these medications also presents challenges. First, when using an AID system, it is essential to adjust settings at the start of treatment to reduce the risk of hypoglycemia. Second, due to the uncertainty surrounding drug tolerance, prescribing practices, and reimbursement, healthcare providers should carefully consider factors such as up-titration, down-titration, intermittent dosing, and discontinuation. To make this treatment viable for T1D, it is essential to avoid imposing additional burdens on patients, caregivers, and healthcare professionals. Therefore, further investigation is warranted to adapt AID systems for their orchestrated use with incretin analogs optimally and ultimately get the most benefit out of this combined therapy, with the achievement of elimination of meal announcement without loss of glycemic control.
This project aims to advance fully automated insulin delivery systems, considering tirzepatide as an adjunctive therapy for overweight/obese T1D. Tirzepatide is a once-weekly dual-action incretin medication that has shown superior efficacy compared with single-action analogs such as semaglutide or dulaglutide in terms of glucose control and body weight reduction. We have proposed a clinical study that will assess the dose-dependent effect of tirzepatide on gastric emptying using scintigraphy as the gold standard. Then, a new fully-automated control algorithm accounting for the adjunctive use of tirzepatide will be developed from the gained knowledge, and validated in silico. To this end, mathematical models describing tirzepatide’s influence on gastric emptying and its downstream effects on glucose control will be developed from data generated in the project. A new simulation platform will be produced integrating these models and allowing in silico validation of the new algorithm.
Anticipated Outcome
The project will produce both clinical and engineering outcomes. The clinical study FAITH-T1D/1 will generate valuable data for the understanding of the dose response of tirzepatide on gastric emptying delay by means of the gold standard test of gastric emptying scintigraphy. This data will be key for the development of next-generation fully-automated AID systems incorporating mechanisms to adapt to the metabolic changes induced by the concomitant use of tirzepatide, such as weight loss and increased insulin sensitivity besides delayed meal dynamics.
From the engineering point of view, new pharmacokinetic and pharmacodynamic models of the above tirzepatide effects will be produced, as well as new simulation tools incorporating tirzepatide as adjunctive therapy, necessary for in silico validation of new control algorithms. Currently, no such computational tool is available. Finally, a new control algorithm, evolved from the fully-automated AID system FLEX-AP by UPV, will be designed and validated in silico. It is expected to demonstrate in silico superior performance of this new fully-automated system with tirzepatide, compared to fully-automated and hybrid insulin-only configurations, generating supporting data for a future clinical validation.
Relevance to T1D
The adjunctive use of incretin-based therapies, particularly tirzepatide, represents a promising advancement in the management of T1D, especially when integrated with AID systems. Recent trials and real-world studies have demonstrated that incretin treatments significantly improve glycemic control, reduce daily insulin dose (especially the prandial one), and promote substantial weight loss in individuals with T1D and overweight or obesity. These effects are particularly relevant in the context of AID systems, where optimizing insulin delivery algorithms is critical to achieving tight glucose regulation. Tirzepatide’s ability to delay gastric emptying introduces a novel physiological variable that, if accurately modeled, could enhance postprandial glucose control and reduce the mismatch between insulin action and nutrient absorption—a persistent challenge in closed-loop systems. Indeed, one of the most burdensome aspects of AID system use remains the requirement for patients to manually announce meals, which demands accurate carbohydrate estimation and timely input. The integration of tirzepatide may reduce or even eliminate this need by attenuating postprandial glucose excursions through slowed gastric emptying and enhanced insulin sensitivity. This could allow AID systems to function more autonomously, improving patient adherence and quality of life. The primary objective of our study is to develop and validate insulin infusion algorithms that incorporate the pharmacodynamic effects of tirzepatide, particularly its impact on gastric emptying. By modeling this effect, we aim to refine insulin delivery timing and dosing within AID systems, thereby enhancing their responsiveness and safety. This approach not only has the potential to improve glycemic outcomes but also to reduce the cognitive and emotional burden associated with diabetes self-management. As incretin therapies continue to evolve, their integration into T1D technology-assisted care may redefine therapeutic standards and offer new pathways toward fully automated, patient-friendly diabetes management.