Type 1 Diabetes Mellitus Treatment Options: is there more than just insulin?

Type 1 Diabetes Mellitus Treatment Options: is there more than just insulin?
Kaylin Maddy, PharmD, Park Nicollet Health Services

Background: Treatment of type 1 diabetes mellitus (T1DM) is mostly dependent on the use of insulin. Less than 30% of patients with T1DM meet glycemic targets, largely limited by wide fluctuations in glucose levels and inability to further escalate insulin doses due to hypoglycemic episodes. 

Additionally, obesity rates are greater than 50% in those with T1DM, in many cases due to long-term insulin use. Glucagon-like peptide 1 receptor agonists (GLP-1 RA) have been a highly valued addition to the treatment of type 2 diabetes mellitus (T2DM), without the weight gain or hypoglycemia common to insulin. Interestingly, GLP-1 RA’s also address a gap in the current available treatment options for T1DM by targeting alpha cell dysfunction and potentially disease progression.  

Evidence: It is thought that GLP-1 RA work in T1DM by suppressing glucagon secretion from alpha cells, increasing satiety, and having insulinotropic effects. Of the GLP-1 RA’s, considerable data only exists for exenatide and liraglutide in T1DM. Exenatide evidence is limited, with only three studies looking at the immediate release formulation and one small study looking at extended release. The first immediate release exenatide study was a one day study looking at eight adolescent patients, which found significant reductions in postprandial hyperglycemia and delayed gastric emptying. The second study looked at 20 individuals with longstanding T1DM and found a significant decrease in weight and total daily insulin needs, but no significant findings for A1C or endogenous insulin production. They hypothesized the insignificant findings could be attributed to the fact that exenatide did not have insulinotropic effects in those with longstanding disease and complete insulin deficiency. The final study looked at 18 patients with newly diagnosed T1DM and detectable C-peptide. They found a significant decrease in insulin requirements and weight, and a non-significant increase in C-peptide levels. 

For extended-release exenatide, a retrospective study looked at 11 individuals. While they did find significant reductions in weight, insulin needs and A1c, they noted 45% of patients discontinued therapy by 6 months due to intolerance of injection site nodule formation or gastrointestinal intolerance. Liraglutide has more comprehensive evidence to support its use in T1DM, with nine studies in total. 

Overall, the studies showed no increase in C-peptide levels in both patients with detectable and undetectable levels at baseline. They found a mean A1C reduction of 0.23% for 1.2 mg daily dose and 0.8% for 1.8 mg daily dose. The overall weight decrease was 4 to 5.9 kg from baseline on maximum dose liraglutide. Weight and A1C effects were both more prominent in patients with detectable C-peptide levels. Observed rates of hypoglycemia with liraglutide in T1DM were similar to the use of liraglutide used in combination with sulfonylureas in T2DM, however this was with a 25-50% empiric insulin dose reduction. 

Discussion: Overall for exenatide, the most encouraging findings are for the use of the immediate release formulation in patients with newly diagnosed T1DM. However due to small sample sizes in the few available studies, further research is recommended before implementing its use in clinical practice. Liraglutide has a greater amount of available evidence to support its use, however clear recommendations for its use in T1DM are still unknown. GLP-1 RA’s, specifically exenatide and liraglutide, may be a future new tool for add-on therapy in patients with T1DM seeking a reduction in insulin doses, weight loss, or modest improvements in A1C. The beneficial effects are more pronounced when C-peptide is detectable, potentially due to lack of insulinotropic effects when undetectable. The modest improvements in A1C should be noted, however, it should be recognized that the addition of GLP-1 RA occurred in combination with significant insulin dose reductions likely contributing to this modest finding. There does not appear to be a significant increased risk of hypoglycemia, though empiric insulin dose reductions should be followed. Further research is needed to evaluate the use of dulaglutide and semaglutide for patients with T1DM. Additionally, the effects on microvascular and macrovascular complications need to be further explored.

Clinical Impact: The use of GLP-1 RA’s may be an exciting future tool for individuals with T1DM, more likely to benefit those with detectable C-peptide, weight above goal, or struggling with hypoglycemia on insulin therapy. However, there is not currently enough conclusive evidence to support their use in practice.

Reference:

  1. Guyton, J., Jeon, M., & Brooks, A. (2019). Glucagon-like peptide 1 receptor agonists in type 1 diabetes mellitus. American Journal Of Health-System Pharmacy, 76(21), 1739-1748.