Diabetes mellitus (DM) prevalence is rising quickly not only globally (by the year 2045 it is expected to become 9.9% with a total number of 629 Million), but also in Saudi Arabia (KSA) with its great impacts on both morbidity and mortality  .
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) provide effective glycemic control, weight reduction, low risk of hypoglycaemia and CV risk reduction. Both the American Diabetes Association (ADA) guidelines and the ADA/European Association for the Study of Diabetes (EASD) consensus report, recommended their usage for type 2 DM (T2DM), particularly when hypoglycemia or weight gain should be considered. In addition, they recommended their usage whenever a failure of initial therapy with metformin and comprehensive lifestyle modifications    .
Among the several GLP-1RAs developed, exenatide, liraglutide, semaglutide, and dulaglutide are available in the Saudi market. They have some differences in terms of their kinetics and dynamics  - . Exenatide, liraglutide, lixisenatide, oral semaglutide are used on a daily base, either once or twice as in the case of exenatide. However, dulaglutide, exenatide extended-release and semaglutide are used once per week  .
Of all GLP-1RAs currently available, dulaglutide, liraglutide and once weekly semaglutide have demonstrated CV benefits, based on the results of several trials   . Therefore, their usage for patients with established atherosclerotic CV disease was recommended by the ADA. Also, other guidelines recommended their usage for those patients irrespective of glycemic control   .
There are many recent updates in the treatment paradigm of T2DM in the light of new evidence available. There are many types of GLP-1RAs, with a knowledge gap regarding how to switch between the different types. Switching from one GLP-1RA to another may be beneficial and may delay the need to intensify therapy, thus avoiding an increase in the treatment burden. That may enable the reduction of the dose of concomitant oral anti-hyperglycemic drugs and/or insulin; therefore, improving the adherence to treatment .
We, a Saudi task force, gathered to develop an explicit, evidence-based consensus for switching between GLP-1RAs, when, why and how? This article has the recommendations of this expert panel.
2. Insights from Available Literature
The task force searched the medical literature for any manuscript about switching from one GLP-1RA to another. In addition to the available randomized controlled trials and real-world studies, the task force found two eminent review articles; one review by Almandoz et al. provided advice on switching between GLP-1RAs in clinical practice; and also did another recent review was about switching between GLP-1RAs by Jain et al.  .
1) GLP-1RAs have a good impact on glycemic control as well as weight reduction
Glucose-lowering efficacy differs between GLP-1RAs. That has been observed in both clinical trials and analyses of real-world data of GLP-1RA-naïve patients  - . The differences in HbA1c and weight reduction in GLP1-RA-naïve patients are shown in Table 1.
In addition, switching from one GLP1-RA to another led to improved glycemic control and weight reduction in both randomized controlled trials and retrospective observational studies (Table 2)  - .
These studies, therefore, demonstrate that switching between GLP-1RAs can provide additional benefits in terms of glycemic control and further weight loss.
2) GLP1-RAs have cardioprotective benefits
Some GLP1-RAs have proven cardio protective benefits like OW semaglutide, liraglutide, dulaglutide. Therefore, their indications for use have been expanded in some countries to reduce the risk of major adverse CV events in adults with T2DM and established CVD      . On the other hand, others have not proven cardioprotective benefits like lixisenatide and exenatide ER  .
Why do we need to switch from one GLP1-RA to another?
There are many drives to switch from one GLP1-RA to another. First is the need for further glycemic control and further weight reduction. The second drive to switch is the need for cardioprotection. Other motives to switch are more safety and tolerability, patients’ preferences and adherence issues, and more convenient devices .
One of the reasons behind the reduced efficacy of GLP1-RAs is the development of increasing antibody titer as seen in an analysis of exenatide clinical trials .
The available GLP1-RAs have variable safety profiles. Short-acting GLP1-RAs are more likely to cause nausea and/or vomiting. Long-acting GLP1-RAs are more likely to cause diarrhea  . Therefore, switching from one GLP1-RA to another may help alleviate these adverse effects .
Poor adherence reduces the effectiveness of therapy. Improved glycemic control was observed for GLP1-RAs in patients with good adherence compared with poor adherence   . First, adherence is affected by the frequency of dosing. Several studies demonstrated that as the frequency decreases, the adherence to GLP1-RA is increased   . More adherences were observed with OW GLP1-RAs than the daily-based GLP1-RAs    .
Table 1. HbA1c and weight reduction in GLP1-RA-naïve patients.
Table 2. HbA1c and weight reduction after switching to another GLP1-RA.
Moreover, patient preference studies indicated that the injection frequency is highly considered by both injection-naïve and -experienced patients when selecting a GLP1-RA     .
Therefore, switching from one GLP1-RA that is dosed either once or twice daily to another OW agent may improve adherence and outcomes in some patients. Despite both being OW GLP1-RAs, adherence to dulaglutide was significantly higher than exenatide ER. That indicates factors other than the frequency of dosing are also critical when considering adherence .
Technology-related issues are other factors affecting the decision to switch due to convenience. GLP1-RAs devices are variable. The delivery device and needle size are essential when selecting between GLP-1RAs . The needle size varies between GLP1-RAs devices from large diameter (23-gauge in exenatide OW , 29 - 31 gauge for exenatide twice daily, and 29-gauge for dulaglutide) and a smaller diameter (32-gauge in OW semaglutide)   . A decision to switch, based on the delivery device, should only be made if a patient indicates that they have had difficulty using the injection device of their current GLP1-RA. Also, another factor is the ability to allow micro-titration (i.e., titration to intermediary doses); allowing slower up-titration may help manage GI adverse effects is a significant factor  . In addition, the degree to which the dose can be selected varies between GLP1-RA injection devices.
In the summary difference in potency, dosage frequency and adherence, duration of action see table. In general, data suggest that long-acting GLP1-RAs have greater effects on HbA1c, fasting plasma glucose, and body weight than those that are short-acting .
3. When to Switch from One GLP1-RA to Another?
There are several medical causes for switching. They are poor glycemic control, more weight reduction is needed, CV risk increased, or the presence of more advanced chronic kidney disease (CKD), and adverse effects. Non-medical causes are patient preference, cost, better technology, and insurance decrees  . The following table illustrates these reasons and what to do in each (Table 3).
4. How to Switch from One GLP1-RA to Another?
An individualized approach should be considered   once the decision has been made to switch from one GLP1-RA to another. Many factors should be considered; one of them is the reimbursement requirements, if any.
Consider any contraindications
Any contraindications or warnings should be considered when switching (Table 4).
Selecting the dose to initiate
If the patient has a history of GI adverse effects with his GLP1-RA, switch to one that enables gradual up-titration (Figure 1). Initiate it at the lowest dose. For example, 0.25 mg in OW semaglutide and 0.75 mg in dulaglutide. If the patient had no or minimal GI AEs with his GLP1-RA, start OW semaglutide 0.5 mg. Adjust the duration before up-titrating the new GLP-1RA according to the
Table 3. Drivers for switching and what to do in each.
Figure 1. Switching plan to a new GLP-1RA. BID, twice daily; GI, gastrointestinal; GLP1-RA, glucagon-like peptide-1 receptor agonist; OW, once weekly; QD, once daily.
Table 4. Contraindications for switching.
presence and severity of GI AEs with the previous GLP-1RA. If GI AEs were absent or minor, then up-titrate (every two weeks). If substantial GI AEs are there, then up-titrate more slowly (every four weeks). If a patient was on the current GLP1-RA for less than one month, consider him a GLP-1RA-naïve patient. If he was on it for more than one month, consider the current GLP1-RA dose when calculating the dose of the new one    .
Timing of the first dose of the new GLP1-RA
The first dose of the new GLP1-RA should be at the time of the next dose of the previous GLP1-RA  .
Consider concomitant therapy when initiating the new GLP1-RA
The dose of sulphonylurea or insulin may need adjustment when switching to reduce the risk of AEs. Sulphonylurea dose should be reduced by 50%, insulin by 20%, and close monitoring for hypoglycemia  . Dipeptidyl peptidase-4 inhibitors should be stopped when initiating a GLP1-RA .
Deal with barriers to switch:
Patients may feel that they are doing well and do not need to change. In addition, they have concerns about GI AEs. Moreover, the change of devices may be a barrier for some patients. Finally, the increased cost or reimbursement issues may be present. Discuss with the patient about the benefits obtained, and reassure that GI AEs are transient. Also, emphasize that the treatment cost and burden will not be increased  .
In conclusion, switching from one GLP1-RA to another has several benefits as an alternative to intensifying therapy. These include improving glycemic control, more weight reduction, more adherence, and drugs with proven CV benefits. Also, switching needs to be individualized upon many discussed factors like the dose of the previous GLP1-RA and GI AEs. Discussion with patients about the why and how to switch is critical.
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