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Interchanging GLP-1 RAs:
A Roadmap for Pharmacists (Module #3)

Interchanging GLP1-RAs: A Roadmap for Pharmacists

Interchanging a glucagon-like peptide-1 receptor agonist (GLP-1 RA) for another in the class may be necessary or desirable. Rationale for the interchange may include greater efficacy, improved tolerability, lower cost, or for an alternative dosing route, frequency, or device for administration.1,2 During these times, pharmacists are uniquely poised to facilitate the interchange with clear communication to optimize outcomes.

Case Scenario: Part 1

Three years ago, HC, a 34-year-old man, was diagnosed with type 2 diabetes (T2D). His diabetes pharmacotherapy includes metformin 1000 mg twice daily. His current A1C is 8.2% and body mass index is 37 kg/m2 . He is interested in starting once weekly semaglutide to help him lower his A1C and lose weight. After using weekly semaglutide 0.25 mg subcutaneously for a month, he complains of gastrointestinal (GI) discomfort. He and his provider decide to continue with the same dose for another month to see if his GI adverse effects improve. Another month later his nausea resolves, and he is ready to increase to 0.5 mg weekly. However, 3 weeks later he reports severe nausea with vomiting. Although delighted with some mild weight loss and convenience of the once-weekly GLP-1 RA therapy, he asks if he can switch to another product.

Rationale for Interchanging GLP-1 RAs

Interchanging for enhanced efficacy: Although part of the same pharmacologic class, these agents vary in multiple aspects.3 Glycemic reduction, weight loss, and cardiovascular benefits are prime reasons why a GLP-1 RA interchange might occur3 (Table 1). The shorter-acting GLP-1 RAs, exenatide and lixisenatide, profoundly blunt the postprandial blood glucose (PPG) rise, but minimally affect fasting blood glucose.4 Short-acting GLP-1 RAs produce an average A1C decline of 0.55%.5 The longer-acting GLP-1 RAs, liraglutide, exenatide XR, dulaglutide, and both oral and injected semaglutide, are more balanced on impacting the postprandial and fasting indices of the glycemic curve and, therefore, result in more robust A1C improvements (on average around 1.01%).5

Table 1. Clinical Comparison of GLP-1 RAs*
  Generic name Primary glucose profile target Within-class comparability of A1C-lowering efficacy Within-class comparability of effect on weight Within-class comparability of GI adverse effects Demonstrated CV benefit
Short-acting Exenatide PPG Low Low Highest Not studied
Lixisenatide PPG Low Low Intermediate Safety
Long-acting Dulaglutide FPG and PPG High Intermediate Intermediate/high Benefit
Exenatide XR FPG and PPG Intermediate Low Low Safety
Liraglutide FPG and PPG High High Intermediate Benefit
Semaglutide FPG and PPG Highest Highest High Benefit
Semaglutide (oral) FPG and PPG High/highest Highest Intermediate/high Safety
*Based on studies of direct head-to-head comparisons.
A1C, glycated hemoglobin; CV, cardiovascular; FPG, fasting plasma glucose; GI, gastrointestinal; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; PPG, postprandial glucose

Likewise, while all products in the class are known to promote weight loss, the amount varies among the products from -0.48 kg to -3.4 kg.5 The shorter-acting GLP-1 RAs, exenatide and lixisenatide, have a smaller impact on weight (2.8-2.96 kg) compared to the longer-acting products, with the once-weekly GLP-1 RAs ranging up to 3.24 kg to 6.5 kg.6 Additionally, the once-weekly injected semaglutide recently received FDA approval specifically for weight loss when dosed at the maximum of 2.4 mg weekly.7 Injectable semaglutide treatment for weight loss resulted in a 17.4% mean change in body weight,8 which will be discussed in greater detail in Module 4. Thus, switching to a more robust GLP-RA may facilitate greater A1C decline or weight loss. Similarly, while all cardiovascular outcome trials for GLP-1 RAs have demonstrated cardiovascular safety, some have uniquely demonstrated cardiovascular risk reduction. Specifically, the subcutaneously injected liraglutide, semaglutide, and dulaglutide hold expanded FDA indications for reducing the risk of major adverse cardiovascular events (MACE) in persons with T2D and clinical ASCVD.9-11 Dulaglutide is further FDA-indicated to reduce the risk of MACE in people with T2D and multiple cardiovascular risk factors.9 Thus, a GLP-1 RA interchange to a product with proven cardiovascular benefit may be desirable specifically in those with pre-existing cardiovascular disease.

Interchanging to improve tolerability: The most common adverse event associated with the GLP-1 RA class is GI in nature, occurring in a dose-dependent fashion, although the intensity of nausea, vomiting, and diarrhea is typically mild to moderate and transient with continued use.12 Despite initiating therapy with the lowest dose and titrating slowly to improve tolerability, some patients are still unable to endure these side effects. At these times, switching to a GLP-1 RA with a lower GI event risk is reasonable. In general, the shorter-acting GLP-1 RAs have the highest event profile for nausea and vomiting, compared to the longer-acting products. Among the long-acting GLP-1 RAs, exenatide XR has the lowest GI event rate.13

  • Interchanging due to other rationale: Interchanging one GLP-1 RA for another is not limited for the purpose of improving efficacy or tolerability. Products in the class also vary by dosing frequency and route of administration. The short-acting exenatide is injected subcutaneously twice daily within 60 minutes prior to the morning and evening meals and lixisenatide, although dosed once only once daily, still must thoughtfully be administered within 60 minutes before breakfast.14,15 Thus, some patients may prefer a product that is dosed without regard to mealtime, such as long-acting once-daily injected liraglutide. Others may prefer an even less frequently administered product such as dulaglutide, exenatide XR, and semaglutide, which are injected subcutaneously once weekly. Lastly, the newest available product in the class appeals to patients who prefer noninjectable options. Oral semaglutide is taken once daily in the morning 30 minutes before any food or beverage with no more than 4 oz of water and separated from administration of other oral medications.16

Another aspect that may be considered is the device used for injection.4,17 Each subcutaneously injected GLP-1 RA is dispensed for use in a uniquely designed device. Exenatide XR and dulaglutide are available in single-use pens for weekly administration, whereas the others come in multi-use devices. Dulaglutide is uniquely packaged with an encased and ready-to-use needle, which may benefit those with dexterity issues. Other devices are not supplied with pen needle attached or require a separate pen needle purchased, which can add to the overall cost. Of course, cost or insurance itself may influence the need for a GLP-1 RA interchange, along with other factors such as development of subcutaneous nodules at the injection site, which occurs with exenatide XR,18,19 typical injection site reactions, or patient preference in general.

Practical Approaches to Interchanging GLP-1 RAs

Regardless, of the rationale for the interchange, a practical approach is needed for transitioning the patient from one GLP-1 RA to another. The method for transitioning among GLP-1 RA products is based on the rationale for the interchange. If GI intolerance drives the need for the product switch, discontinue the first GLP-1 RA without initiating the second GLP-1 RA until the adverse event resolves. Once subsided, initiate a GLP-1 RA, with a lower risk of GI disturbances, at the lowest available dose.2 While GLP-1 RAs are typically dose escalated at monthly intervals in patients with past GI events to a previously used GLP-1 RA, dose titration may occur at a slower pace.1 On the other hand, if the interchange is desired for another reason, including improved efficacy, less frequent injections, oral formulation preferred, or cost, discontinue the first GLP-1 RA and initiate the new product at an equivalent dose based on glycemic efficacy and titrate as recommended (Table 2). Administer the first dose of the new GLP-1 RA when the next dose of the discontinued GLP-1 RA would otherwise be given.1,2 Lastly, advise patients to regularly self-monitor blood glucose through the transition, especially in the short term.

Table 2. Equivalent Doses Among GLP-1 RAs
GLP-1 RA Dosing route & frequency Equivalent dose
Exenatide SC twice daily 5 ug 10 ug
Lixisenatide SC daily 10 ug 20 ug
Liraglutide SC weekly 0.6 mg 1.2 mg 1.8 mg
Exenatide XR SC weekly 2 mg
Dulaglutide SC weekly 0.75 mg 1.5 mg 4.5 mg*
Semaglutide SC weekly 0.25 mg 0.5 mg 1 mg
Semaglutide PO daily 3 mg 7 mg 14 mg
GLP-1 RAs, glucagon-like peptide-1 receptor agonists; PO, by mouth; SC, subcutaneous.
*Based on clinical evidence from Frias JP, et al. Diabetes. 2020;69(suppl 1). doi.org/10.2337/db20-357-OR.

Needed Patient Education During GLP-1 RA Interchange

The importance of shared decision making and patient education cannot be over emphasized when transitioning from one GLP-1 RA to another. Achievement of mutual understanding between the patient and healthcare provider is necessary to ensure the newly selected GLP-1 RA meets the desires of both parties. Secondly, product-specific training must be given to effectively on-board the patient and prevent dosing or administration errors (Table 3). Review differences in storage, administration timing and frequency, and multi-use vs single-use devices.

Table 3. Availability, Dosing, and Administration Requirements of GLP-1 RAs
Drug Availability, storage, and preparation Dosing Missed dose recommendations Use in renal impairment
Exenatide

· Multidose pens (5 mcg/dose and 10 mcg/dose; 60 doses per pen)

· Pen needles not supplied with pen; 29-, 30-, or 31-gauge required

· Keep refrigerated

· After first use, store at room temperature; discard 30 days after first use

· No reconstitution required

· Start with 5 mcg twice daily

· Increase to 10 mcg twice daily after 1 month, if needed for additional A1C lowering

· Inject within 60 minutes prior to morning and evening meals (or before the 2 main meals of the day; administer ≥ 6 hours apart)

· Skip the dose and resume next dose at the prescribed time

 Not recommended with severe renal impairment (eGFR or CrCl < 30 mL/min)
Lixisenatide

· Multidose pens (10 mcg/dose and 20 mcg/dose; 14 doses per pen)

· Pen needles not supplied with pen

· Keep refrigerated

· After first use, store at room temperature; discard 14 days after first use

· No reconstitution required

· Start with 10 mcg once daily for 14 days

· Increase to 20 mcg once daily

· Inject within 1 hour prior to first meal of the day

· Skip the dose and resume next dose at the prescribed time

 No dose adjustment recommended; limited experience in severe renal impairment; avoid if eGFR < 15 mL/min
Liraglutide

· Multidose pens (6 mg/mL, 3-mL pen; each pen delivers doses of 0.6, 1.2, or 1.8 mg)

· Pen needles not supplied with pen

· Keep refrigerated

· After first use, store at room temperature; discard 30 days after first use

· No reconstitution required

· Start with 0.6 mg once daily for 1 week

· Increase to 1.2 mg once daily

· Increase to 1.8 mg once daily, if needed for additional A1C lowering

· Inject at any time of day, with or without meals

· Skip the dose and resume next dose at the prescribed time

 No dose adjustment recommended; limited experience in severe renal impairment
Exenatide XR

· Single-dose pen (2 mg): 2 pen options available with different preparation requirements (Bydureon or Bydureon BCise)

· 23-gauge disposable pen needle supplied with pen

· Keep refrigerated

· Store flat in original packaging, protected from light

· May store at room temperature for 4 weeks

· Remove from refrigerator 15 minutes prior to mixing

· Requires reconstitution

· Dose should be administered immediately once reconstituted

· 2 mg once weekly

· Inject at any time of day, with or without meals

· If within 3 days of missed dose, give right away; resume dosing on usual day of administration

· If 3 days have passed, skip dose and resume on usual day of administration

 Not recommended with severe renal impairment (eGFR or CrCl < 30 mL/min)
Dulaglutide

· Single-dose pens (0.75 mg, 1.5 mg, 3 mg, and 4.5 mg)

· Pen needle attached; 29-gauge

· Keep refrigerated

· May store at room temperature for 14 days

· No reconstitution required

· Start with 0.75 mg once weekly

· Increase dose if needed for additional A1C lowering

· Inject at any time of day, with or without meals

· If within 3 days of missed dose, give right away; resume dosing on usual day of administration

· If 3 days have passed, skip dose and resume on usual day of administration

 No dose adjustment recommended; limited experience in severe renal impairment
Semaglutide

· Multidose pens (1.34 mg/mL; 1.5-mL pen; lower- dose pen delivers 0.25-mg or 0.5-mg doses; high-dose pen delivers 1-mg dose)

· Pen needles supplied with pen; 32-gauge

· Keep refrigerated

· After first use, store at room temperature; discard 56 days after first use

· No reconstitution required

· Start with 0.25 mg once weekly

· Increase to 0.5 mg once weekly after 4 weeks

· May increase to 1 mg once weekly after 4 weeks, if needed for additional A1C lowering

· Inject at any time of day, with or without meals

· If within 5 days of missed dose, give right away; resume dosing on usual day of administration

· If 5 days have passed, skip dose and resume on usual day of administration

 No dose adjustment recommended
Semaglutide (oral)

· Oral tablets (3 mg, 7 mg, 14 mg)

· Start with 3 mg once daily for 30 days

· Increase to 7 mg once daily

· May increase to 14 mg once daily after 30 days, if needed for additional A1C lowering

· Take at least 30 minutes before the first food, beverage, or other oral medication of the day with no more than 4 ounces of plain water only

· Swallow tablets whole; do not crush or chew

· Skip the missed dose and resume regular schedule

 No dose adjustment recommended
CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; GLP-1 RAs, glucagon-like peptide-1 receptor agonists.

Case Scenario: Part 2

Despite adequate duration of use, HC is unable to tolerate the GI discomfort from semaglutide. Because an interchange is desired to improve tolerability, the current product should be discontinued, and symptoms should resolve before initiating a new product. In consultation with HC, dulaglutide is selected as the new GLP-1 RA for initiation as he prefers a once-weekly injection to daily use and has greater weight loss compared to once-weekly exenatide. Dulaglutide is started at the lowest dose of 0.75 mg. Education is provided about the single-use device including administration technique and storage. One month later, HC is pleased with his continued weight loss, has tolerated the new GLP-1 RA, and is ready to increase to the next dosing increment.

Conclusion

Interchanging a GLP-1 RA may be needed or desired for a variety for reasons, the majority of which encompass efficacy, tolerability, preference for administration route or frequency, or cost. The healthcare team and patient should work closely, through shared decision making, to select the most appropriate new product based on needs and preferences to ensure a smooth transition from one delivery device to another for optimal management.

REFERENCES

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  2. Almandoz JP, Lingvay I, Morales J, Campos C. Switching between glucagon-like peptide-1 receptor agonists: rationale and practical guidance. Clin Diabetes. 2020;38(4):390-402.
  3. Leiter LA NM. Efficacy and safety of GLP-1 receptor agonists across the spectrum of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2017;125(7):419-435.
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  13. Bettge K, Kahle M, Abd El Aziz MS, Meier JJ, Nauck MA. Occurrence of nausea, vomiting and diarrhea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes Obes Metab. 2017;19(3):336-347.
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