A 2021 review provides guidance for switching from one glucagon-like peptide-1 receptor agonist (GLP-1RA) to another. However, this guidance is also based on the authors’ clinical experience and lacks supporting clinical data. Initially, it is important to consider any contraindications or warnings for the GLP-1RA being switched to that could lead to patient harm. For example, the majority of available GLP-1RAs are not recommended for use in patients with end-stage renal disease. Exceptions to this contraindication are once-weekly semaglutide and dulaglutide. When selecting the dose to initiate, the patient’s history of gastrointestinal (GI) adverse events (AEs) with previous GLP-1RAs should be considered. If there is a history, then it is recommended to switch to a GLP-1RA that allows for slow up-titration, and it should be initiated at the lowest dose, such as 0.25 mg for once-weekly semaglutide and 0.75 mg for dulaglutide. Exenatide extended-release is only available as a single dose and thus cannot be initiated at a lower dose. [1]
When initiating the new GLP-1RA, if the patient has no or minimal GI AEs and/or expresses a preference to initiate at a higher dose, then the authors recommend starting once weekly semaglutide at 0.5 mg, despite incompliant with FDA-approved labeling. Initiating once weekly semaglutide at 1.0 mg is not recommended for the majority of patients due to the increased risk of AEs. The length of time before up-titrating the new GLP-1RA may also be adjusted depending on the presence and/or severity of GI AEs with the initial GLP-1RA. If GI AEs were previously absent/minor, the frequency of up-titration may be increased (e.g., every 2 weeks instead of every 4 weeks), whereas if patients previously experienced substantial GI AEs, waiting longer than 4 weeks before increasing the dose is suggested. [1]
When initiating a new GLP-1RA treatment, details of the current or previous GLP-1RA treatment should also be considered (e.g., how long the patient has been on it, the dose, time of the next dose), which will help guide the dose of the GLP-1RA being switched to. If a lower than maximum dose is being used, the new GLP-1RA should be initiated at the lowest available dose, but if a maximum dose of the initial GLP-1RA is being used, then in the authors’ opinion, initiating at a higher dose can be considered. However, if a patient has only been receiving the initial GLP-1RA for a short duration (<1 month), then the approach to switching to a new GLP-1RA should be the same as the approach taken when initiating that therapy in GLP-1RA naive patients. In patients receiving the initial GLP-1RA for > 1 month, then the dose of the current GLP-1RA should be considered. In general, the first dose of the new GLP-1RA should be given at the time when the next dose of the previous GLP-1RA would have been given. [1]
Doses of concomitant therapies may need adjustment when switching in order to reduce the risk of AEs. For example, in patients who are receiving a sulfonylurea or insulin, the dose may need to be adjusted to reduce the risk of hypoglycemia. An initial 50% dose reduction of sulfonylurea and a 20% reduction of insulin is feasible for most patients based on the authors’ clinical experiences and clinical protocols. In both instances, reductions of doses should be based on baseline HbA1c. All patients should regularly self-monitor blood glucose in the short-term following initiation of the new GLP-1RA to monitor for hypoglycemia and inform any decisions concerning subsequent dose changes. Additionally, dipeptidyl peptidase-4 inhibitors should be discontinued when initiating GLP-1RAs, as the mechanism of action of these two drug classes is not synergistic. [1]
Once a patient is initiated on a new GLP-1RA, they should be monitored for GI AEs with subsequent dose up-titrations to achieve greater effectiveness if needed. In the absence of GI AEs, the authors believe up-titration may be performed rapidly (i.e., increasing to the next dose after 2-4 weeks), regardless of recommendations from prescribing information. If GI AEs are present, a more cautious approach with slower-up titration (i.e., every 4 to 8 weeks) should be taken. If GI AEs are intolerable to the patient after several weeks following up-titration, the patient could be moved back to a lower dose. Antiemetics may be prescribed for short periods if GI AEs are severe and the patient wishes to remain on a GLP-1RA. However, if GI AEs have not reduced after a course of antiemetics is complete, the patient may need to be switched from the GLP-1RA to an alternative glucose-lowering therapy. [1]
A 2020 review proposed a practical algorithm for switching between once-daily and once-weekly GLP-1RA therapies, but the algorithm is primarily based on the authors’ clinical experience and is not supported by clinical data. When the decision to switch GLP-1RAs is made, the current GLP-1RA should be discontinued, and the patient should be counseled on the differences between the two agents. It is suggested that patients can generally be switched from once daily, twice daily, or once weekly GLP-1RAs to any other GLP-1RA (i.e., once daily, twice daily, or once weekly). If a patient is being switched from a once daily or twice daily GLP-1RA, the first dose of the new GLP-1RA should be administered the following day after discontinuation. In cases when patients are switching from a once-weekly GLP-1RA, the first dose of the new GLP-1RA should be administered 7 days after discontinuation. [2]
When initiating the switch, the new agent should be initiated after waiting for symptoms to resolve if the switch was prompted by GI side effects. The new agent is recommended to be started at the lowest available dose, and slower titration to the maximum dose should be considered. A lower maintenance dose can be considered if needed due to GI AEs. If the switch was prompted by other reasons and not GI intolerance, it is the opinion of the authors that the new agent should be started with an equivalent (or lower) dose (see Table 1) and titrated according to prescribing information. The assessment of equivalent dose is noted to be entirely based on the authors’ opinion, which is said to be based on head-to-head clinical trials when available and/or clinical experience. The patient should be re-evaluated every 2 to 3 months for side effects, adequate titration, and glycemic response. Authors noted that switching from injectable GLP-1RA to an oral agent could be remarkably different from switching between injectable formulations, and additional clinical experiences are still needed to inform appropriate transition. [2]
A 2022 Saudi guideline provides a consensus for switching between GLP-1 RAs based on available randomized controlled trials and two review articles. The guideline recommends an individualized approach and several considerations such as adverse effects with the current GLP-1RA, duration of current GLP-1RA therapy, glycemic control needed, and patients’ preferences. A summary of changes in HbA1c and weight reduction observed in clinical studies after switching GLP-1RAs can be found in Table 3. [3]
A 2018 study utilizing a pharmacokinetic simulation model and observational data from four phase 3 semaglutide trials evaluated the impact of switching treatment from another GLP-1RA to semaglutide. A 26-week simulated treatment with liraglutide 1.2 or 1.8 mg, dulaglutide 0.75 or 1.5 mg, or exenatide extended-release 2.0 mg was followed by a simulated semaglutide treatment 1 day after the last once-daily dose of liraglutide and 1 week after the last once-weekly doses of dulaglutide or exenatide extended-release. The dose of semaglutide was gradually increased from 0.25 mg to 0.5 mg and eventually to 1 mg. At week 52, decreases in HbA1c ranged from ~0.3% to ~0.8%-points and reduction in body weight from ~2% to ~4% with semiglutide 1.0 mg. A summary of effects on HbA1c during the transition from other GLP-1RA to semaglutide 0.25 or 0.5 mg is presented in Table 2. Of note, this exposure-response modeling only reflects mean outcomes and is not adjusted for variations among individual patients. Additionally, other clinical outcomes besides weight loss cannot be extrapolated from the study findings. [4]