GLP-1 receptor agonists for type 2 diabetes currently available in the U.S.

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1 GLP-1 receptor agonists for type 2 diabetes currently available in the U.S. GLP-1 agonists are a class of antidiabetic agents that mimic the actions of the glucagon-like peptide. GLP-1 is one of several naturally occurring incretin compounds that affect the body after they are released from the gut during digestion. By binding and activate GLP-1 receptors, GLP-1 agonists, and endogenous GLP-1 are capable to reduce blood glucose levels helping T2DM patients to reach a glycemic control. These antidiabetic agents increase the glucose-dependent secretion of insulin from functioning beta cells, decrease glucagon release after meals, decrease hepatic glucose production, delayed gastric emptying, suppress the appetite and promotes beta cell proliferation. After the launched of exenatide (Byetta) in 2005 newer formulations have been released with the allowing for longer half life s and better side effect profiles. The newest GLP-1 agonist, Ozempic (semaglutide) is not yet FDA approved but the launch is expected at any time soon. On the other hand, Soliqua and Xultophy are two combination pen devices that deliver a GLP-1 RA and basal insulin simultaneously allowing a robust reduction of HbA1c when compare to insulin alone. Below you will find a list with the different GLP-1 receptor agonist available in the U.S. and some of their featured characteristics. Drug Name Dulaglutide (Trulicity) ~ 5 days ~$675 (0.75 mg and 1.5 mg doses) ~1.5% Start with 0.75 mg SQ QW, regardless of meals. Increase to 1.5 mg QW if inadequate glycemic response If 3 days until the next scheduled dose, administer as soon as possible. If <3 days until next scheduled dose, omit the missed dose and Single-dose pens and prefilled syringes: 0.75 mg and 1.5 mg ~2.5 kg Nausea: 0.75 mg: ~12.4% 1.5 mg: ~ 21.1% reactions: 0.5% Sinus Tachycardia: 3% to 6% No dosage changes necessary in patients with renal impairment. Monitor renal function in patients with significant GI adverse effects. dysfunction is not expected to affect drug concentrations. Trial: REWIND CV death, MI, or stroke Ongoing Trial Last update posted on January 16, 2018

2 resume administration at the next regularly scheduled weekly dose. Exenatide (Byetta) 2-4 hours ~$710 (5 mcg and 10 mcg doses) ~1% Start with 5 mcg SQ BID within 60 minutes prior to morning and evening meals. After 1 month, may be increased to 10 mcg BID for better glycemic control. Missed dose: If you miss one dose, skip it and continue with your normal schedule. Do not double the dose. Multi-dose pens (60 doses per pen): 5 and 10 mcg/dose ~2.0 kg Nausea: Monotherapy: 8% to 11% Add-on therapy: 44% reactions: >10% Use is not recommended in CrCl. <30 ml/minute. dysfunction is not expected to affect drug concentrations. Trial: ITCA exenatide in DUROS CV death, UA, MI, or stroke results not yet available. Trial end date July 2018 Exenatide Extended- Release (Bydureon, Bydureon BCise) 2 mg once weekly at any time of day, regardless of food. 1. Bydureon Single-dose vial Nausea 4 to 11% Use is not recommended in CrCl. <30 ml/minute. Trial: EXSCEL CV death, MI, or stroke

3 > 1 week ~$660 HbA1c: ~1.5% (Bydureon) ~1.4% (Bydureon BCise) If 3 days until the next scheduled dose, give as soon as possible. If <3 days until next scheduled dose, skip and give at next regularly scheduled dose. 2 mg (prefilled diluent syringe, vial connector, and 23 g needle.) Single-dose dual pen 2 mg (One chamber with medication and one with diluent, comes with 23 g needle.) ~2.5 kg 2. Bydureon BCise reactions > 17% nodule: 11% dysfunction is not expected to affect drug concentrations. Among patients with T2DM with or without previous CVD, the incidence of major CV events did not differ significantly between patients who received exenatide vs. placebo Single-dose autoinjector ~1.4 kg Liraglutide (Victoza, Saxenda) hours ~$ mg daily ~$ mg daily ~1.5% Start with 0.6 mg Qdaily for 1 week; then increase to 1.2 mg Qdaily. If glycemic control is not achieved, increase to 1.8 mg Qdaily. Administer at any time of day, regardless of food. Give the missed dose as Multi-dose pens (6 mg/ml, 3 ml): Each pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg ~2.5 kg Saxenda is indicated for chronic weight management Nausea: 18% to 20% reactions: 2% Headaches: 11% Upper respiratory tract infection: 7% No renal or hepatic dosage adjustment is necessary. Trial: LEADER CV death, MI, or stroke Rate of the first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke among patients with

4 soon as possible. If >3 days have passed since the last dose restart the regimen with 0.6 mg Qdaily and then go up weekly. T2DM was lower with liraglutide vs. placebo. Lixisenatide (Adlyxin) ~3 hours ~$590 for the 20 mcg daily dose ~1% 10 mcg SQ daily for 14 days, then increase to 20mcg daily. Administer within one hour prior to the first meal of the day. Give the dose within one hour of next meal. Multi-dose pens (14 doses per pen): 10 mcg and 20 mcg ~2.0 kg Nausea: 25% reactions: 4% Headache: 9% Use with caution mild to moderate renal impairment. Not recommended ESRD. dysfunction is not expected to affect drug concentrations. Trial: ELIXA CV death, UA, MI, or stroke In patients with ACS and T2DM, the inclusion of lixisenatide to the current therapy did not significantly change the rate of major CV events or other serious adverse events.

5 Insulin degludec/ liraglutide (Xultophy100/3.6) ~ 25 hours ~$990 for max daily dose Start with 16 units Q daily and titrate up or down every 3 to 4 days in 2 units range. Maximum daily dose is 50 units/day Multi-dose pens (3mL) Each pen delivers doses from 10 units to 50 units with each injection Nausea: 8% reactions: 3% Headaches: 9% No renal or hepatic dosage adjustment is necessary. No clinical trials evaluating CV outcomes in combination therapy. ~1% more than insulin degludec alone. Administer missed dose as soon as possible. If >3 days have been passed since last dose, reinitiate with 16 units. Do not double dose. ~2.5 kg when compare to insulin degludec. Insulin glargine/ lixisenatide (Soliqua100/33) ~3 hours ~$815 for max daily dose HbA1c ~ 0.5% more than insulin glargine alone Poor glycemic control on <30 units of basal insulin or lixisenatide: Start with 15 units (15 units insulin glargine/5 mcg lixisenatide) SQ once daily. Poor glycemic control on 30 to 60 units of basal insulin: Start with 30 units (30 units insulin glargine/10 mcg Multi-dose pens 3 ml Insulin glargine (100 units/ml) and lixisenatide (33 mcg/ml). Each pen delivers doses from 15 to 60 units per injection. ~1.4 kg when compare to insulin glargine. Nausea: 10% reactions: 2.0% Hypoglycemia: 26% to 40% Dose adjustments may be necessary renal or hepatic impairment. No clinical trials evaluating CV outcomes in combination therapy.

6 lixisenatide) SQ once daily. Adjust dose by 2 units Maximum daily dose: 60 units insulin glargine/ 20-mcg lixisenatide per day. Should be taken within the hour before the first meal every day. Administer missed dose as soon as possible. Do not double dose. Semaglutide (Ozempic) ~ 1 week ~$675 (0.5 mg and 1 mg doses) ~1.5% Start with 0.25 mg SQ QW at any time of day regardless of food. Increase to 0.5 mg once weekly after four weeks. Multi-dose pens (1.34 mg/ml, 1.5 ml): 1 pen box mg and 0.5 mg doses. 2 pens box - 1 mg doses. Nausea: 16% to 20% reactions: <1.0% No renal or hepatic dosage adjustment is necessary. Trial: SUSTAIN-6 CV death, MI, or stroke

7 Max. Dose 1.0 mg QW. If 5 days until the next scheduled dose, administer as soon as possible. If <5 days until next scheduled dose, skip the missed dose and administer at the next weekly dose. ~4 kg In patients with T2DM at high CV risk, the rate of CV death, nonfatal MI, or nonfatal stroke was significantly lower with semaglutide vs. placebo for noninferiority. Abbreviations: Qdaily = once daily; QW = once weekly; BID = twice daily; ESRD = end-stage renal disease; SQ = subcutaneously; CV = cardiovascular; CVD = cardiovascular disease; MI = myocardial infarction; T2DM = type 2 diabetes mellitus: UA = unstable angina; ACS = acute coronary syndrome. Practice Pearls: GLP-1 agonist has multiple physiological effects that make it a great therapy option to help improve glycemic control in type 2 diabetes patients. This drug class of antidiabetic agents carries a warning of a risk of worsening renal function, acute pancreatitis, and a possible association with thyroid cancer in animals. For most patients, GLP-1 agonists should be reserved for those who require two or more antidiabetic agents in order to reach and maintain the goal HbA1c. References: Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist s Letter/Prescriber s Letter. January 2017.

8 Schnell, Oliver et al. Updates on Outcome Trials in Diabetes. Diabetology 16 (2017): 128. PMC. Web. 17 June Diabetes In Control Kennen Munoz Munoz, Pharm. D. Candidate 2019, LECOM School of Pharmacy