Objective
T1D is a lifelong condition that goes beyond insulin deficiency, affecting various metabolic pathways. Despite advances in insulin therapy, many challenges remain, including the need for treatments that address insulin resistance, glucagon dysregulation, and the risk of severe hypoglycemia. The TIRTLE2 study aims to explore how the novel drug TZP, which mimics two natural hormones (GLP-1 and GIP), could offer solutions to these unmet needs.
The objective of TIRTLE2 is to assess the effect of TZP on metabolism in T1D. The main aim (primary objective) is to find out if TZP, given as a once-a-week injection as an add-on to usual insulin treatment, can improve insulin sensitivity in T1D. We have chosen to study insulin sensitivity, because impaired insulin sensitivity (insulin resistance) is associated with increased cardiovascular risk and contributes to difficulties in managing blood sugars and weight.
Our other aims (secondary objectives) are to test the effect of TZP on meal-time glucagon and glucose levels, and metabolism overnight (overnight growth hormone and fat metabolism). We will also test the effect of TZP on hormonal response to low-blood glucose episodes. We predict that with TZP treatment in T1D, glucagon levels will be boosted in response to a low-blood glucose event and may help to recover from a low glucose level faster, and needing less glucose to correct a low glucose level.
We will also test the effect of TZP on insulin dose, time in target glucose range measured by continuous glucose monitoring, effect on blood vessel stiffness, energy expenditure, alongside other measures.
Background Rationale
T1D is an autoimmune condition where the body’s immune system destroys insulin-producing cells in the pancreas, leading to lifelong insulin dependency. But T1D is not just about insulin deficiency; it also involves complex metabolic issues, including insulin resistance and excessive production of the hormone glucagon, which raises blood sugar levels. These challenges worsen with obesity and other health complications, driving the need for better treatments beyond insulin.
While insulin therapy is essential for T1D, it is far from perfect. Injected insulin does not replicate the natural delivery system of the pancreas, leading to imbalances such underexposure of the liver to insulin, and over exposure of other tissues in the body. These imbalances can disrupt metabolism, and people with T1D are more likely to experience insulin resistance, excessive glucagon production after meals, and at nighttime can have excessive growth hormone levels. Addressing these issues could improve health outcomes for people with T1D.
One promising new approach is TZP, a medication currently approved for T2D and obesity. TZP is unique because it mimics two natural hormones, GLP-1 and GIP, which help regulate blood sugar, appetite, and fat metabolism. GLP-1 helps lower blood sugar by suppressing glucagon. Meanwhile, GIP promotes glucose uptake in fat tissue, enhances overall insulin sensitivity. TZP acts on both hormones, potentially offering more comprehensive metabolic benefits, than therapies that target one hormone only. The effect of TZP on metabolism has not been tested before in T1D.
Description of Project
Medications used in type 2 diabetes (T2D) to improve diabetes management, weight and metabolism have great potential address these same issues in type 1 diabetes (T1D). In T1D, there are numerous factors that contribute to difficulties in blood sugar management, overweight and obesity and increased heart disease risk. Many of these factors appear unique to T1D and include insulin resistance, excess glucagon hormone levels after eating food, yet inadequate glucagon levels needed to respond to low blood glucose levels, and excess overnight growth hormone levels that affect glucose regulation during sleep.
This project will determine if tirzepatide (TZP), given as a simple once a week injection to the skin can improve insulin resistance and metabolic health in T1D. Adults with T1D and excess weight will be treated with tirzepatide or placebo injections in addition to their usual insulin therapy for 6 weeks. The main outcome we will study will be improvement in the insulin sensitivity. We will also test mealtime and overnight hormone responses, and test if tirzepatide can quicken the way the body reacts to a low blood glucose level. TIRTLE2 will test if this treatment can be used in T1D to improve metabolism and help insulin work better.
Anticipated Outcome
TIRTLE2 offers several outcomes including:
1. A deeper understanding of metabolism in T1D: T1D involves unique metabolic disturbances that TZP's dual action on GLP-1 and GIP receptors could address. While GLP-1 helps lower blood sugar by increasing insulin and reducing glucagon, GIP supports fat metabolism and insulin sensitivity. Understanding how these hormones work together in T1D is crucial, especially since they can sometimes have competing effects. This study will use advanced techniques, including the "gold standard" hyperinsulinemic-euglycemic clamp, to assess how TZP influences blood sugar and fat metabolism in T1D. By measuring changes in insulin sensitivity, glucagon regulation, and growth hormone levels, researchers hope to identify specific pathways that TZP may effectively target. These findings will shed light on how the drug might provide benefits beyond weight loss, such as improving glucose regulation and reducing the need for insulin.
By examining their impact on various metabolic axes, this study will provide a comprehensive view of TZP’s biological effects, paving the way for more effective treatments.
2. Addressing safety and broadening potential: One of the key questions TIRTLE2 will tackle is whether TZP maintains a protective response to hypoglycemia—a common and dangerous complication of T1D. This could significantly expand TZP’s therapeutic potential, ensuring it not only improves metabolic outcomes but also enhances safety for individuals with T1D.
3. New treatments for T1D: The findings from TIRTLE2 could have wide-reaching implications, from encouraging investment in new T1D therapies to refining existing ones. By providing proof-of-concept data, the study aims to guide future trials and the development of tailored treatments. Beyond its immediate goals, TIRTLE2 will lay the groundwork for future research. Insights into how TZP affects pathways such as glucagon regulation and insulin sensitivity could inform the development of new drugs. By establishing a robust framework for studying adjunctive therapies in T1D, the study sets a precedent for future trials aimed at addressing the complex needs of this condition.
4. Off-label use of TZP in T1D is already happening, driven by community interest, but there’s a lack of robust clinical evidence. TIRTLE2 seeks to address this by providing much-needed data on the drug’s efficacy, safety, and mechanisms of action. This will not only inform clinical guidelines but also give individuals with T1D and their healthcare providers confidence in its use.
Relevance to T1D
Treatment options for T1D remain confined to insulin. However, non-insulin therapies, widely used in conditions like T2D and obesity, offer considerable potential to address metabolic challenges and hormonal imbalances associated with T1D. Research in T2D has demonstrated that these treatments can provide extensive benefits, including protection against heart and kidney diseases. Recognizing this potential, many individuals with T1D have started using these therapies off-label.
One such promising therapy is TZP. Preliminary findings, including data from the TIRTLE1 study and real-world observations capturing off-label use, suggest that TZP can reduce weight, decrease insulin requirements, and improve blood glucose control in T1D. The next critical step is understanding the mechanisms through which TZP achieves these effects, which will pave the way for its safe integration into T1D management. TIRTLE2 aims to generate essential knowledge that will guide clinicians in prescribing TZP with greater confidence and support future research to optimize non-insulin therapies for T1D to unlock better glucose control and health in T1D.
Ultimately, TIRTLE2 seeks to transform the care landscape for T1D. By defining the underlying issues with metabolism in T1D and testing the effect of TZP on these metabolic processes, this study will take a significant step toward personalized and effective treatments, with the potential to greatly improve health outcomes and quality of life for people living with T1D.