This review published in Diabetologia focuses on the exploration of GLP-1RAs' use in type 1 diabetes, a field that has gained significant attention in recent years. The landscape of type 1 diabetes treatment has evolved considerably, with the introduction of insulin analogues, advanced insulin administration systems, and continuous glucose monitoring (CGM). These innovations, coupled with patient education and support, have allowed many individuals with type 1 diabetes to achieve better glycemic control and an enhanced quality of life. However, challenges persist, with some individuals struggling to meet glycemic targets over the long term, often at the cost of hypoglycemia and unexpected weight gain.

The non-physiological replacement of insulin, the inability of current insulins to adapt to varying insulin needs due to factors like exercise and stress, and a relaxation in dietary restrictions to enhance the quality of life have collectively contributed to the growing problem of undesired weight gain in individuals with type 1 diabetes. This issue is prevalent in various regions worldwide, highlighting the need for novel therapeutic approaches to address this concern.

Clinicians have naturally explored therapies from the type 2 diabetes arsenal to improve glycemic control, reduce insulin requirements, and prevent weight gain in people with type 1 diabetes. Two such treatments, metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i), have been tested with varying degrees of success. Metformin, while offering minimal reductions in HbA1c levels, has shown some promise in reducing insulin doses and exerting a modest effect on weight. On the other hand, SGLT2i, particularly low-dose dapagliflozin and sotagliflozin, demonstrated improved glucose control, weight reduction, and insulin-sparing effects. However, their use in type 1 diabetes is marred by the risk of diabetic ketoacidosis (DKA), even with stringent patient selection and education.

The Role of GLP-1 Receptor Agonists in Type 1 Diabetes

GLP-1 receptor agonists have also been tested as adjunct therapies in type 1 diabetes. These agents have the potential to improve glycemic control by stimulating insulin secretion in individuals with remaining beta cells and by suppressing counteracting glucagon, enhancing postprandial glucose control. Additionally, GLP-1 receptor agonists have a positive effect on appetite and weight control, which is particularly beneficial for individuals with type 1 diabetes struggling with weight gain and obesity. Moreover, they are expected to have direct benefits for organ protection.

Studies exploring the use of GLP-1 receptor agonists in type 1 diabetes have generated varied results. Some studies show improvements in glycemic control, insulin dose reductions, and a lower risk of hypoglycemia, particularly for mealtime insulin doses. However, the effect on HbA1c should be evaluated while considering insulin dose adjustments in the background. Some studies reported an insulin-dose-sparing effect, mainly for mealtime insulin doses.

The weight reduction induced by GLP-1 receptor agonists is a consistent observation across these studies. The magnitude of weight loss is dose-dependent, with the most significant reduction occurring around six months after initiation of the treatment. This weight loss is comparable to what has been observed with GLP-1 receptor agonists in individuals with type 2 diabetes, when adjusted for baseline weight. Studies also suggest a selective loss of fat tissue compared to muscle.

Managing Side Effects and Challenges

Like in type 2 diabetes, GLP-1 receptor agonists in type 1 diabetes can lead to side effects, primarily gastrointestinal complaints, including nausea, dyspepsia, diarrhea, and vomiting. However, side effects tend to be more pronounced in type 1 diabetes studies and may appear at lower doses.

Notably, the potential anti-inflammatory effect of liraglutide has been explored in some studies. Liraglutide has shown to lower IL-6 levels, suggesting a possible role in reducing inflammation. Additionally, GLP-1 receptor agonists have demonstrated a direct effect on beta cell function and health.

Exploring the Potential in Other Forms of Diabetes

While type 1 diabetes has been the primary focus of GLP-1 receptor agonist studies, there is growing interest in exploring their potential benefits in other forms of diabetes. These include post-transplant diabetes, corticosteroid-induced diabetes, and monogenic diabetes. Preliminary evidence suggests that GLP-1 receptor agonists may also be effective in these categories, but larger, well-designed trials are needed to confirm their utility.

Latest Research

A qualitative literature review was conducted to identify articles related to the effects of GLP-1RAs on type 1 diabetes and MODY or monogenic diabetes in the PubMed database, covering studies from 2005 onwards.

Two independent reviewers conducted article screening and retrieval. Ultimately, 16 articles were included for this review, 15 of which were randomized controlled trials (RCTs) focusing on type 1 diabetes, and one being a randomized crossover study in MODY. The majority of these studies involved individuals with long-standing type 1 diabetes, often characterized by overweight or obesity, receiving intensive insulin therapy. Some studies examined participants using multiple daily injections (MDI), while others focused on those using continuous subcutaneous insulin infusion (CSII).

Results

The outcomes of the reviewed studies are diverse, reflecting variations in study durations, doses, and insulin titration protocols. For example, exenatide LAR exhibited a notable effect on reducing HbA1c levels, with a 0.3% difference versus placebo at 12 weeks, diminishing by 24 weeks. Interestingly, this effect was most pronounced in individuals with measurable C-peptide levels. These glycemic benefits were achieved with reduced insulin requirements. Weight briefly decreased at 12 and 24 weeks, but these changes were not sustained post-therapy discontinuation. Hypoglycemia rates did not increase, although participants reported more gastrointestinal side effects.

The effects of liraglutide studies varied but consistently showed dose-dependent reductions in HbA1c levels and increased time in the desired glycemic range, especially in shorter-duration studies. The ADJUNCT ONE study, extending to 52 weeks, demonstrated dose-dependent reductions in HbA1c levels, reduced insulin requirements, and weight loss. Moreover, composite endpoints revealed a significant proportion of participants achieving substantial HbA1c reductions without experiencing severe hypoglycemia. Insulin dose reductions, primarily related to mealtime insulin, were also dose-dependent but diminished over time. Weight loss, likewise, was liraglutide-dose-dependent, with the most pronounced effects occurring around 24 weeks. Notably, none of the reviewed studies reported an increased risk of diabetic ketoacidosis (DKA).

Conclusion

In conclusion, GLP-1RAs hold promise as adjunct therapies in type 1 diabetes management. While there is no one-size-fits-all solution, the studies reviewed here showcase their potential benefits in improving glycemic control, reducing insulin doses, and addressing weight-related challenges. The findings underscore the importance of individualized treatment plans and close monitoring for potential side effects. Further research and long-term studies are warranted to fully understand the implications of incorporating GLP-1RAs into type 1 diabetes care, especially concerning cardiovascular and renal outcomes.

Reference Article

Mathieu, C., Ahmadzai, I. Incretins beyond type 2 diabetes. Diabetologia 66, 1809–1819 (2023). https://doi.org/10.1007/s00125-023-05980-x

Related

https://healthnewstrend.com/insulin-treatment-for-type-2-diabetes-understanding-how-it-works-and-its-impact

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