GIP GLP-1 dual agonist

GLP - 1 & Dual GLP - 1/GIP Receptor Agonists

Glucagon-like-peptide-1 (GLP-1) agonists are formulated as either injectables or tablets that mimic the action of gut hormones called incretins. Dual GLP-1/GIP Receptor Agonists are injectable. They assist in glycemic management via these mechanisms:

• Increasing insulin secretion from the pancreas in response to eating
• Decreasing glucagon secretion from the pancreas after a meal and thus reducing the release of glucose from the liver
• Slowing stomach emptying and thus the meal-derived glucose appearance in the blood
• Reducing appetite and promoting satiety via receptors in the brain

Topics

• Therapeutic Considerations
• Dosing Consideration
• Brand Considerations
  • Dulaglutide - Trulicity®
  • Liraglutide - Victoza®
  • Liraglutide + Insulin Degludec - Xultophy®
  • Lixisenatide - Adlyxine®
  • Lixisenatide + Insulin Glargine - Soliqua®
  • Semaglutide - Ozempic®
  • Semaglutide - Rybelsus®
  • Tirzepatide - Mounjaro® (GLP1-ra + GIP)
• Related
  • Diabetes Canada Patient Handout:GLP-1 & Dual GLP-1/GIP Receptor Agonists
  • Complete Medication Table:GLP-1 & Dual GLP-1/GIP Receptor Agonists

Therapeutic Considerations with GLP-1 & Dual GLP-1/GIP Receptor Agonists

All information from medication product monographs unless referenced below.

Dosing Considerations with GLP-1 & Dual GLP-1/GIP Receptor Agonists

• Refer to Renal Impairment considerations, Diabetes Canada. Includes recommendations for all GLP-1 agonists except semaglutide (Ozempic).
• Semaglutide (Ozempic): No dose adjustment for decreased renal function is required. There is limited clinical experience in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2), and caution should be used in this patient population. Semaglutide is not recommended for use in patients with end-stage renal disease.
• General recommendation is to decrease basal insulin (if applicable) by 20% when starting GLP-1 & Dual GLP-1/GIP Receptor Agonists.

Brand Considerations

Dulaglutide - Trulicity®

• See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
• Side effects in addition to those listed in table above: fatigue.
• Each pen contains only 1 dose and is disposed of after one use. Each pen has a needle already attached. The pen clicks when the green dosing button is pressed and should be held until a second click sounds within 5-10 seconds. The dose was delivered the right way if the gray plunger is visible.
• Each single-use, prefilled syringe and single-use prefilled pen contains 0.5 mL of solution. Each 0.5 mL of TRULICITY solution contains 0.75 mg or 1.5 mg of dulaglutide.
• PDF for Trulicity (dulaglutide) pen.
• Video for Trulicity (dulaglutide) Pen.

Cardiovascular Outcome Trial for dulaglutide: REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes).

• Participants: This study included patients ≥ 50 years of age with type 2 diabetes. Participants had previous cardiovascular disease or over age 60 with CV risk factors (smoking, dyslipidemia, hypertension or abdominal obesity). 31.5% of participants had previous cardiovascular disease. Follow-up median of 5.4 years.
• Outcome: Fewer patients on dulaglutide had a major adverse cardiovascular event (12% vs. 13.4% on placebo). This is in a patient group with lower previous cardiovascular disease (31.5%) implying it may be beneficial to those with CVD as well as those with CVD risk factors.
• Adverse Events: Higher percentage of patients on dulaglutide had GI side effects (47.4%) compared to placebo (34.1%).

Exenatide - Byetta®

• See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
• Side effects in addition to those listed in table above: feeling 'jittery', dizziness, headache.
• 5 mcg twice a day to be injected at any time within the 60 minute period before morning and evening meals (or before the two main meals of the day, at least 6 hours or more apart). BYETTA should not be injected after a meal. The dose of BYETTA may be increased to 10 mcg twice daily after a month if required to improve blood sugar control. Maximum is 10 mcg twice daily.
• If dose of BYETTA is missed, do not take an extra dose or increase the amount of next dose. Take next dose at the next prescribed time.
• Oral contraceptives and antibiotics should be taken at least one hour prior to administering Byetta.

Exenatide ER (extended release)- Bydureon®

• See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
• Side effects in addition to those listed in table above: lump at injection site, dizziness, headache, joint/muscle pain, "common cold", cough.
• Astra Zeneca has decided to not actively promote Bydureon® in Canada at this time. Bydureon will still be sold in Canada. Representatives will not be actively promoting the medication when talking with doctors and other healthcare providers, but will still provide information if asked.
• Video for Bydureon pen.

Liraglutide - Victoza®

• See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
• Side effects in addition to those listed in table above: headache, infection of upper airways, gallstones, acute gallbladder disease.
• Liraglutide can be taken at any time of the day. It does not matter when taken in relation to meals. The usual starting dose is 0.6 mg once a day for at least one week. Dose then increased to 1.2 mg once a day. If blood glucose is not controlled with a dose of 1.2 mg, dose may be increased to 1.8 mg once a day.
• If a dose of liraglutide is missed, dose next day to be taken as usual. Extra dose or increased dose on the following day is not to be taken to make up for the missed dose.

Cardiovascular Outcome Trial for liraglutide: LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results).

• Participants: Longstanding type 2 diabetes (median 12.8 years) with majority (80%) having CVD. Follow-up median of 3.8 years.
• Outcome: Fewer patients on liraglutide had a major adverse cardiovascular event (13.0% vs 14.9% on placebo). As most patients in this trial had CVD this trial is mostly applicable to those with type 2 with CVD.

Liraglutide + Insulin Degludec - Xultophy®

• See Combination Medications on the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
• Start with 16 units and titrate by 2 units up/down every 3-4 days.
• Prefilled pen contains 3 mL of clear, colorless solution equivalent to 300 units of insulin degludec and 10.8 mg of liraglutide. Delivers doses from 1 to 50 units.
• Use alternative antihyperglycemic products if patients require basal insulin dosing below 16 units or over 50 units.

Lixisenatide - Adlyxine®

• See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
• Side effects in addition to those listed in table above: Upper respiratory infection, urinary tract infection, back pain, headache, dizziness.
• ADLYXINE (lixisenatide injection) is supplied in a disposable pen in two doses. The green starter pen delivers 14 doses of 10 mcg, and the burgundy maintenance pen delivers 14 doses of 20 mcg.
• The starting dose is 10 mcg once daily for 14 days. Increase dose to the maintenance dose of 20 mcg once daily starting on day 15.
• To be administered within one hour before any meal of the day- preferably before the same meal every day (see additional notes on pharmacodynamics below).
• Patients taking oral contraceptives should be advised to take them at least 1 hour before ADLYXINE administration or at least 11 hours after the dose of ADLYXINE.
• Safe to use in individuals that have underlying cardiovascular disease but not shown to reduce cardiovascular risk (ELIXA Trial).
• Immunogenicity: Patients may develop antibodies to lixisenatide following treatment with ADLYXINE.
  • A higher incidence of allergic reactions and injection site reactions occurred in antibody positive patients. In the subset of patients with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed.
  • If a patient receiving ADLYXINE displays worsening glycemic control or failure to achieve targeted glycemic control, or if significant injection site reactions or allergic reactions occur, alternative antidiabetic therapy should be considered.
• Overview of pharmacodynamics:
  • Lixisenatide is a ‘shorter acting’ GLP-1 agonist compared to the other available once daily GLP-1, liraglutide.
  • When given before breakfast, its therapeutic effects (ie: delayed gastric emptying) are highest after the breakfast meal. So a greater post-prandial glucose lowering is seen after the breakfast meal than after the subsequent meals of the day.
  • It is has better post-prandial glucose lowering as compared to liraglutide.

Lixisenatide + Insulin Gargine - Soliqua®

• See Combination Medications on the Complete Diabetes Medication Table.