GLP-1 Agonists (Incretin Mimetics)

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

 All information from medication product monographs unless referenced below. 

2. 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.

3. 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)⁷

• 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)⁸

• 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 addtion 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^2-4: 
  • 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  for: cost/month; Blue Cross coverage; available strengths;  dosing frequency; Health Canada indications.
• See comments above for adlyxine and the points below from the product monograph.
• Use alternative products if patients require basal insulin <15 units or > 60 units.
• One pre-filled pen contains 3 mL equivalent to 300 units insulin glargine and 100 mcg lixisenatide.
• Opened (in-use) pens up to 28 days at room temperature (25 °C).
• SOLIQUA should be administered daily within 1 hour prior to the first meal.
  If a dose of SOLIQUA is missed, it should be injected within the hour prior to the next meal. An extra dose should not be taken to make up for the missed dose.
• In patients inadequately controlled on less than 30 units of basal insulin, the
  recommended starting dosage of SOLIQUA is 15 units.
• In patients inadequately controlled on 30 to 60 units of basal insulin, the recommended
  starting dosage of SOLIQUA is 30 units.
• Increase by two to four units every week, based on self-monitored fasting plasma glucose results, patient’s metabolic needs and until the target fasting plasma glucose is achieved
• To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed with changes in physical activity, meal patterns or renal or hepatic function; during acute illness; or when used with other medications

Semaglutide - Ozempic®

• 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: gallstones, dizziness, fatigue. The SUSTAIN-6 trial also showed an increased progression of retinopathy in treatment group (50%) - this has been identified as area for further investigation. 
• Disposable multi-use pens package in cartons with 1 pen (doses 0.25 mg or 0.5 mg) or 2 pens (doses of 1 mg). Storage at room temperature (< 30 °C) for up to 8 weeks.
• Cost: Please be aware to save money, some patients may be using (off-label) 1 mg pens and dialing halfway to receive 0.5 mg doses (eg. "half of the audible clicks for the 1 mg dose). Dosage accuracy for this practice has not been confirmed.
• No interaction with absorption of oral contraceptives or statins.
• Presence of anti-drug-antibodies (1% or less of users) did not correlate with reduced efficacy as measured by HbA1c.
• Titration is 0.25 mg weekly for 4 weeks, then 0.5 mg for 4 weeks. Dose can be maintained at the 0.5 mg or be increased to max dose 1 mg/week.
• Maximum effect 1-3 days post first dose. Reaches steady state after 4-5 weeks.
• Dose is taken same day once a week. If patient forgets, they can take up to 5 days later (need more than 2 days between doses).
• The SUSTAIN-6⁵ trial showed a significant 26% lower risk of the primary composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) driven mostly by a 39% decrease in the rate of nonfatal stroke and a nonsignificant 26% decrease in nonfatal MI.
• The SUSTAIN-7⁶ trial (40 weeks) showed a mean percentage A1c reduction of 1.5% with the 0.5 mg dose and 1.8% with the 1.0 mg dose as well as a  mean weight reduction of 4.6 kg with the 0.5 mg dose and 6.5 kg with the 1.0 mg dose.

Semaglutide (tablets) Rybelsus®

• See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths;  dosing frequency; Health Canada indications
• WATER intake with tablet: The semaglutide is paired with an absorption enhancer that is referred to as SNAC. SNAC helps the semaglutide absorb by increasing the pH of a small area within the stomach. When the semaglutide is taken with too much water or food, SNAC is “overwhelmed” and little (or no) semaglutide is absorbed. However, the 120 mL or ½ cup of water is the ideal amount to get the medication down the esophagus, but not affect absorption. Hence, the instructions to take on an empty stomach, at least 30 minutes before eating with no more than 120 mL or ½ cup water. 

 References: 

1. Inzucchi SE, Bergenstal RM, Buse JB, det al. Management of hyperglycemia in type 2 diabetes: a patient-centred approach. Diabetes Care 2012; 35: 1364-79.   http://care.diabetesjournals.org/content/35/6/1364  (Accessed Feb 26, 2018). 

2. Kapitza C, Forst H, Poitiers F et al. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on Metformin. Diabetes, Obesity and Metabolism 2013; 15:642-649.

3. Lorenz M, Pfeffer C, Steinstraesser A et al. Effects of lixisenatide once daily on gastric emptying in type 2 diabetes- Relationship to postprandial glycemia. Regulatory Peptides 2013; 185: 1-8.

4. Becker R, Stechl J, Steinstraesser A et al. Lixisenatide reduces postprandial hyperglycemia via gastrostatic and insulinotropic effects. Diabetes/Metabolism Research and Reviews 2015; 31: 610-618.

5. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.DOI: 10.1056/NEJMoa1607141 

6.  Pratley R.E., Aroda V.R., Lingvay I., Ludemann J., Andreassen C., Navarria A., Viljoen A.Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. The Lancet Diabetes and Endocrinology, 2018; 6(4):275-286. DOI https://doi.org/10.1016/S2213-8587(18)30024-X 

7. Gerstein HC, Colhoun HM, Dagenais GK, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet 2019: 394: 121-30. Published Online June 10, 2019 http://dx.doi.org/10.1016/ S0140-6736(19)31149-3 

8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22.