Objective
We aim to evaluate efficacy, safety and cardiovascular protection effects of Mazdutide as an add-on therapy in adults with type 1 diabetes who are inadequately controlled and/or with high cardiovascular risk.
Background Rationale
Mazdutide, a synthetic peptide analogue of mammalian oxyntomodulin, is a once-weekly glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonist being developed for the treatment of obesity and type 2 diabetes. Mazdutide has been proved to induce significant weight reduction in patients with obesity and contributed to improved glycemic control in patients with type 2 diabetes. However, as a GCGR agonist, Mazdutide is expected to persistently activate the glucagon receptor, which might increase the blood glucose level. The glucose increasing effect of GCGR agonism is offseted or balanced by GLP-1R agonism when Mazdutide is applied in type 2 diabetes due to the stronger effect GLP-1R agonism. Whether the combination of insulin and Mazdutide would lead to an improved glycemic control due to the weak effect of GLP-1R agnoism remains to be determined. Meanwhile, whether the chronic activation of glucagon receptor could produce similar effect of acute administration of glucagon, which may help maintain a critical counterregulatory response to hypoglycemia, also requires clarification.
Meanwhile, individuals with T1D face a substantially elevated risk of mortality, and cardiovascular disease (CVD) is a major contributor, accounting for 30-44% of all deaths in this population. Treatments proven to improve cardiorenal outcomes in type 2 diabetes (T2D) have not been sufficiently validated for efficacy and applicability in T1D. Given the significant pathophysiological differences in CVD between T1D and T2D, directly extrapolating T2D-effective strategies to T1D is uncertain. There is an urgent need for innovative therapies with demonstrated cardiorenal protective effects specifically for T1D. As coagonist of GCGR/GLP-1R, Mazdutide may offers a new therapeutic approach for cardioprotection in T1D through its synergistic mechanisms. In addition to classical benefits via GLP-1 pathway, including glucose-lowering, weight reduction, anti-inflammatory effects, endothelial function improvement, and potential direct cardioprotection, GCG receptor activation might more effectively address the root causes by reducing ectopic fat deposition (in liver, vascular wall) and systemic inflammation, thereby stabilizing vulnerable plaques at their origin.
Description of Project
Patients with type 1 diabetes (T1D) face a lifelong challenge of managing blood glucose levels. Despite advances, many still struggle to achieve optimal glucose control without increasing the risk of dangerous hypoglycemic episodes. Furthermore, T1D significantly elevates the long-term risk of serious cardiovascular complications, creating a dual burden that existing therapies often fail to address comprehensively.
This clinical trial aims to evaluate a promising new therapeutic strategy named Mazdutide, a dual agonist of glucagon receptor and glucagon-like peptide 1 receptor, for patients with T1D who have inadequate glucose control and/or high cardiovascular risk. The core objective is to determine whether Mazdutide can simultaneously improve two critical health outcomes: achieving safer and more stable glucose levels and directly protecting heart health.
Unlike conventional approaches that treat these aspects separately, our innovative two-phase trial design efficiently integrates both evaluations. Success in this study could provide a transformative treatment option that not only simplifies daily diabetes management by reducing glucose fluctuations but also targets the underlying cardiovascular risks. This has the potential to improve overall quality of life and reduce the future burden of diabetes-related complications for patients with T1D.
Anticipated Outcome
For TIMES-EFFICACY, we anticipate that 16-week treatment with Mazdutide will improve the glycemic control and reduce the hypoglycemia in T1D. It will validate the efficacy and safety of Mazdutide as adjunctive therapy for T1D, which is also the basis to conduct the subsequent TIMES-CV study.
For TIMES-CV, we anticipate that 52-week treatment with Mazdutide will demonstrate a statistically significant and clinically meaningful reduction in coronary non-calcified plaque volume compared to placebo.
Relevance to T1D
TIMES-EFFICACY will be the first study to validate the efficacy and safety of Mazdutide in patients with T1D, helping to explore the role of CGCR activation in improving glycemic control and preventing hypoglycemia inT1D. This will provide new therapeutic options and evidence-based medical support for non‑insulin adjunctive treatments for T1D.
TIMES-CV will provide unique insights into heart disease development in T1D and how Mazdutide works. It directly tests if activating the GCG receptor—which boosts fat burning—can stabilize dangerous heart plaque in T1D, a new concept. By measuring liver fat, inflammation, blood vessel health, and plaque changes together, we will learn how the drug might work. Correlating the changes together with plaque regression will provide critical mechanistic insights into whether Mazdutide's benefit is mediated through reduced ectopic fat, attenuated inflammation, and direct pleiotropic effects on the endothelium and arterial wall.