Using Glucagon-like Peptide 1 Receptor Agonists In Type 1 Diabetes

Examining the effects of GLP-1RAs exenatide and liraglutide on weight and insulin dosage for type 1 diabetes patients. 

Hyperglycemia in type 1 diabetes is due to autoimmune destruction of the pancreas’s beta cells and alpha cell dysfunction. This alpha cell dysfunction leads to hyperglucagonemia, followed by gluconeogenesis, which contributes to further hyperglycemia. Insulin is the typical treatment for hyperglycemia, but this does not target disease progression or alpha cell dysfunction. Treatment with insulin can be confusing, often requiring multiple daily injections. Insulin can cause weight gain and hypoglycemia. Therapy intensification may be avoided due to fear of hypoglycemia, resulting in failure to meet glycemic goals. Pramlintide is an adjunctive therapy for type 1 diabetes, decreasing glucagon secretion, improving satiety, and delaying gastric emptying. Pramlintide requires multiple daily injections, reduces HbA1c moderately, and may cause weight loss. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) suppress glucagon secretion from alpha cells, improve satiety, and have insulinotropic effects if residual beta cells function. GLP1-RAs target hyperglucagonemia, which is essential in type 1 diabetes.   

Of the 6 GLP-1RAs approved in the U.S., only exenatide and liraglutide have been studied in type 1 diabetes. This review found 13 original studies that focused on patients with type 1 diabetes. Exenatide has been shown to significantly reduce HbA1c and weight, with minimal risk of hypoglycemia in patients with type 2 diabetes. Only four studies have looked at the glycemic effects when exenatide is used in patients with type 1 diabetes. One study examined its use in long-standing type 1 diabetes, which led to a second focused on patients with newly diagnosed type 1 diabetes to see if it would be more useful in patients with residual beta–cell function. Six studies looked at liraglutide in patients with type 1 diabetes.  

Exenatide was found to reduce postprandial hyperglycemia (P < 0.0001) and significantly delay gastric emptying (P < 0.004). One study that looked at patients with long-standing type 1 diabetes saw a mean weight loss of 4.1 ± 2.9 kg (P < 0.0003) and a relative insulin dose decrease of 0.07 ± 13 units/kg/day (P = 0.0062) after six months. Mean HbA1c and glycemic control did not change. A third study looked at patients recently diagnosed with type 1 diabetes to see if the residual beta–cell function would increase benefit from exenatide. The fourth study was a retrospective, observational study that evaluated the use of extended-release exenatide over six months. It found significant reductions in HbA1c, body weight, and total daily insulin dose at three months. Of the 11 patients started on exenatide in this study, five discontinued use before six months – 4 for injection-site nodule formation and 1 for gastrointestinal intolerance.   

The first liraglutide study saw a significant decrease in daily insulin dose and weight but no substantial glycemic control improvement. The group assigned insulin with liraglutide had significantly less hypoglycemia than those on insulin therapy alone, with no significant differences in HbA1c between groups. ADJUNCT ONE, a year-long study of close to 1,400 patients with type 1 diabetes, found significant decreases in weight, daily insulin dose, and HbA1c, with substantial increases in hypoglycemia rates when liraglutide was added. The group receiving 1.8 mg/day also experienced hyperglycemia, including ketosis, at a more frequent rate. Similar results were seen in the ADJUNCT TWO trial, a 26-week study of 835 patients with type 1 diabetes, given a placebo or liraglutide combined with insulin. HbA1c was found to have been reduced in patients that received liraglutide, with reductions of 0.23% and 0.8% for 1.2mg and 1.8mg doses, respectively. The most significant change was seen between weeks 12 and 20, with a slight rebound afterward. Statistically effective rates of achieving HbA1c of <7% were seen only in patients who received the 1.2 or 1.8mg doses. Insulin doses were most commonly reduced by 25-29% of the total daily dose when liraglutide was started, with a further 10% reduction in dose with each liraglutide dose increase. 56-78% of patients who received liraglutide experienced nausea, compared with 10-17% receiving a placebo or insulin alone. These effects were found to be largely dose-dependent, with higher doses resulting in more common nausea. Several studies found no discontinuation of liraglutide due to adverse effects, meaning that treatment is generally well tolerated. Ketosis was seen in patients receiving liraglutide at a significantly higher rate only when receiving the 1.8 mg dose, which is why the authors of this review recommend against its use in patients with type 1 diabetes.   

The data for the use of GLP-1RAs in patients with type1 diabetes is limited to liraglutide and exenatide. Both medications have shown significant decreases in insulin doses, weight loss, and modest glycemic improvement. The benefits of GLP-1RAs were more pronounced in patients newly diagnosed with type 1 diabetes.    

Practice Pearls:  

• While still being studied, both exenatide and liraglutide have shown promise in treating patients with type 1 diabetes. 
• The most significant decreases in HbA1c were seen between weeks 12 and 20.   
• Ketosis was higher in patients that received a dose of 1.8 mg/day of liraglutide.  

Guyton, Justinne, et al. “Glucagon-like Peptide 1 Receptor Agonists in Type 1 Diabetes Mellitus.“ OUP Academic, Oxford University Press,  

George McConnell, PharmD. Candidate, LECOM School of Pharmacy