GLP-1 agonists are an effective medication in treating type 2 diabetes mellitus.  GLP-1 agonists are a synthetic version of the body’s naturally occurring GLP-1. However, synthetic GLP-1 has the advantage of being resistant to DPP4 degradation.  GLP-1 agonists have many actions in the body that make them effective at lowering A1C as well as providing weight loss. This class of medication works by promoting satiety, reducing appetite, and decreasing postprandial glucagon secretion. There are many different medications in this class with varying dosing schedules. These variations can cause some confusion so let’s review the titration of GLP-1 agonists (See table below for a quick overview).

Exenatide comes in both a short-acting form which must be dosed twice daily (Byetta) as well as a long-acting form which may be dosed once-weekly (Bydureon). Byetta’s initial dose is 5 mcg twice daily subcutaneously. This dose may be increased to 10 mcg twice daily subcutaneously after one month if additional glycemic control is needed. One clinically significant challenge for patients is that doses should be taken 60 minutes prior to morning and evening meals. Bydureon is dosed 2 mg once weekly, without regard to mealtime. If a dose is missed it should be taken as soon as possible if it is >/=3 days until the next dose and then normal dosing should resume. If it is <3 days till the next scheduled dose, the missed dose should be omitted and dosing should resume at the next scheduled weekly dose.

Liraglutide (Victoza) is dosed once daily independent of meals and has a recommended titration schedule. The initial dose is 0.6mg subcutaneous daily for one week which is then increased to 1.2 mg daily subcutaneously. 1.2 mg daily subcutaneously is a therapeutic dose but if additional glycemic control is desired it may be further increased to 1.8 mg daily subcutaneously after a week at the 1.2 mg dose. Starting at a lower, but non-therapeutic dose is intended to reduce GI symptoms and promote better adherence to the medication. 

Dulaglutide (Trulicity) is dosed once weekly. The initial dose is 0.75 mg SubQ, once weekly. If additional glycemic control is needed the dose may be increased to 1.5 mg once weekly after 4 weeks. If a dose is missed it should be taken as soon as possible if it is >/=3 days until the next dose and then normal dosing should resume. If it is <3 days until the next scheduled dose, the missed dose should be omitted and dosing should resume at the next scheduled weekly dose.

Lixisenatide (Adlyxin) is dosed once daily 60 minutes prior to a meal and must be titrated. The initial dose is 10 mcg once daily subcutaneously for 14 days, on the 15^th day the dose is increased to 20 mcg once daily subcutaneously. 

Semaglutide is the only GLP-1 available in an oral formulation as well as a subcutaneous form. The subcutaneous form, brand name Ozempic is dosed once weekly and requires titration. The initial dose is 0.25 mg subcutaneously once weekly for 4 weeks, which is then titrated up to a therapeutic dose of 0.5 mg subcutaneously once weekly. If additional glycemic control is needed Ozempic may be further titrated up to 1 mg subcutaneously once weekly after 4 weeks at the 0.5 mg dose. A missed dose should be administered as soon as possible within 5 days of the missed dose. If more than 5 days have elapsed the missed dose should be omitted and administration should be resumed at the next scheduled weekly dose.

Semaglutide is available as an oral tablet under the brand name Rybelsus.  Rybelsus should be taken 30 minutes prior to the first food, beverage, or other oral medication of the day with no more than 4 ounces of plain water only. The initial dose is 3 mg by mouth once daily for 30 days. After 30 days the dose should be increased to 7 mg by mouth daily. If additional glycemic control is needed the dose may be further increased to 14 mg by mouth daily after at least 30 days on the 7 mg dose.

GLP-1 Quick Reference Guide

Generic	Route	Dose/Titration	Administration time relating to food intake
Exenatide (Byetta)	Subcutaneous	5 mcg twice daily subcutaneously, may be increased to 10 mcg twice daily subcutaneously after one month if additional glycemic control is needed	60 minutes prior to morning and evening meal
Exenatide Extended Release (Bydureon)	Subcutaneous	2 mg once weekly subcutaneously	No Relation
Liraglutide (Victoza)	Subcutaneous	0.6mg subcutaneously daily for one week then increased to 1.2 mg daily subcutaneously. If additional glycemic control is desired it may be further increased to 1.8 mg daily subcutaneously after a week at the 1.2 mg dose	No Relation
Dulaglutide (Trulicity)	Subcutaneous	0.75 mg once weekly subcutaneously. If additional glycemic control is needed the dose may be increased to 1.5 mg once weekly subcutaneously after 4 weeks	No Relation
Lixisenatide (Adlyxin)	Subcutaneous	10 mcg once daily subcutaneously for 14 days on the 15th day the dose is increased to 20 mcg once daily subcutaneously	60 minutes prior to the same meal everyday
Semaglutide (Ozempic)	Subcutaneous	0.25 mg subcutaneously once weekly for 4 weeks, it is then titrated up to a therapeutic dose of 0.5 mg subcutaneously once weekly. If additional glycemic control is needed titrate up to 1 mg subcutaneously once weekly after 4 weeks at the 0.5 mg dose	No Relation
Semaglutide (Rybelsus)	By Mouth	3 mg by mouth once daily for 30 days. Then increase to 7 mg by mouth daily. If additional glycemic control is needed increase to 14 mg by mouth daily after at least 30 days on the 7 mg dose	30 minutes prior to first food, beverage, or other oral medication of the day

Did you find this article on the titration of GLP-1 Agonists helpful? You’ll probably like this SGLT-2 comparison table.

Article was written by Rochelle Fabian in collaboration with Eric Christianson, PharmD

References

1. Micromedex Solutions. Retrieved August, 2020, from https://www.micromedexsolutions.com/home/dispatch/ssl/true
2. UptoDate, Retrieved August, 2020, from https://www.uptodate.com/home
3. Hinnen D. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Diabetes spectrum : a publication of the American Diabetes Association. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556578/. Published August 2017. Accessed September 2, 2020.