How To Switch From Ozempic To Mounjaro
Clin Diabetes. 2020 Oct; 38(4): 390–402.
Switching Between Glucagon-Similar Peptide-1 Receptor Agonists: Rationale and Practical Guidance
Jaime P. Almandoz
iUT Southwestern Medical Center, Dallas, TX
Ildiko Lingvay
oneUT Southwestern Medical Middle, Dallas, TX
Javier Morales
2Hofstra/Northwell University, New York, NY
Carlos Campos
threeUniversity of Texas Health Scientific discipline Center, San Antonio, TX
Glucagon-similar peptide-1 (GLP-i) receptor agonists are a class of incretin-based therapies for the direction of hyperglycemia and, in some cases, cardiovascular chance in people with type 2 diabetes. These agents act on multiple physiological pathways involved in type 2 diabetes with the effect of increasing insulin secretion and decreasing glucagon to control glucose levels (one,2). They also transiently slow gastric emptying, reduce appetite, and facilitate weight loss and other metabolic improvements (3).
Consensus recommendations from the American Diabetes Association (ADA)/European Clan for the Study of Diabetes (EASD) and American Clan of Clinical Endocrinologists/American College of Endocrinology advocate that GLP-1 receptor agonists, among other therapies, should exist considered every bit a second-line treatment option in people with type 2 diabetes when glucose levels are not well controlled on metformin (four–6). Additionally, in patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease, a GLP-1 receptor agonist or sodium–glucose cotransporter 2 (SGLT2) inhibitor with proven cardiovascular benefit is recommended as a first-line therapy for the reduction of cardiovascular risk (four–vi). GLP-1 receptor agonists may likewise be used every bit a first-line treatment in those who cannot utilize metformin or when reduced renal function precludes metformin use (homo-based GLP-ane receptor agonists just) (4–half dozen). In particular, the recommendations favor GLP-1 receptor agonists and SGLT2 inhibitors because they have a low risk of hypoglycemia and promote weight loss (five).
Several GLP-1 receptor agonists are available in the The states and worldwide, some of which are analogs of human GLP-one (dulaglutide, liraglutide, and semaglutide), whereas others are exendin-based (exenatide and lixisenatide) (7–13). The GLP-1 receptor agonist albiglutide was as well approved, just has been withdrawn for commercial reasons. Until recently, all GLP-1 receptor agonists were administered by subcutaneous injection, although a once-daily oral conception of semaglutide has now been approved for use in the The states (7). Among the subcutaneous GLP-ane receptor agonists, some are dosed once daily (liraglutide and lixisenatide) or twice daily (exenatide), whereas others are given one time weekly (dulaglutide, semaglutide, and exenatide extended release) (eight–thirteen).
Several studies and reviews have explored the comparative efficacy and condom profiles of the dissimilar GLP-i receptor agonists (14–19). Chemist's data suggest that upwardly to ane-4th of patients switch from their initial GLP-i receptor agonist to another glucose-lowering agent later the first year of treatment (xx,21). Some of these patients may be switching to a dissimilar GLP-ane receptor agonist, which may occur for several reasons, merely practical guidance on how to safely and effectively manage such a transition is scarce. This article summarizes reasons why health care providers (HCPs) may consider switching their patients between different GLP-one receptor agonists and provides real-world guidance on achieving a smooth transition. We supplement the bachelor data with our clinical feel to provide practical suggestions for switching.
Literature Search Methods
The PubMed database was searched using the terms: 1) GLP-1 AND (switch OR switching OR switched); and 2) GLP-ane AND (once-daily OR "once daily") AND (in one case-weekly OR "once weekly"). These searches yielded 161 and 97 results, respectively. Abstracts of the retrieved publications were manually reviewed to identify relevant manufactures that included whatever information related to switching betwixt different GLP-1 receptor agonists.
Characteristics of Available Injectable GLP-1 Receptor Agonists
Although they belong to a single medication class, the approved GLP-1 receptor agonists differ in many ways, including in structure, molecular size, pharmacology, efficacy, and safety (Table 1) (7–13). Native GLP-1 remains in the bloodstream for just a few minutes, so alterations to the molecule (amino acid changes or side concatenation additions) are required to brand it resistant to the result of dipeptidyl peptidase-iv (one,2). Even then, almost of the older GLP-ane receptor agonists require frequent administration (Table 1) (8–10). Newer GLP-1 receptor agonists that permit in one case-weekly dosing take been achieved either by attaching heavy chain fragments that slow their degradation (dulaglutide and subcutaneous semaglutide) (11,12) or formulating an extended-release preparation in the case of exenatide (Table 1) (thirteen).
TABLE 1
Key Features of Currently Available GLP-1 Receptor Agonists (7–13)
| Generic Name | Derivation | Molecular Weight, kDa | Half-Life | Route of Administration | Dose | Frequency | Dosing Atmospheric condition |
|---|---|---|---|---|---|---|---|
| Lixisenatide | Animal | 4.86 | ∼3 hours | Subcutaneous | Adults: 10 µg for 14 days, then 20 µg from day 15 | Once daily | At the same time each day, ≤1 hour before the outset meal of the day |
| Exenatide | Animal | iv.19 | 2.four hours | Subcutaneous | Adults: 5 µg per dose; increment to x µg subsequently 1 calendar month based on clinical response | Twice daily | ≤1 hour before morning and evening meals (or the two main meals of the day, ≥six hours apart) |
| Exenatide extended release | Animal | four.19 | vii–14 days | Subcutaneous | Adults: ii mg | Once weekly | Can exist taken at any time of solar day with or without nutrient |
| Liraglutide | Human | 3.75 | ∼13 hours | Subcutaneous | Adults: 0.6 mg for ane week, then i.2 mg; if required, increase dose to 1.8 mg after a farther week | Once daily | Tin can be taken at whatever fourth dimension of day |
| Children ≥10 years: 0.6 mg for ≥one calendar week; only increase the dose to 1.2 mg or 1.8 mg if required | |||||||
| Dulaglutide | Human | ∼63 | ∼five days | Subcutaneous | Adults: 0.75 mg, increased to one.5 mg, if needed | Once weekly | Tin exist taken at whatsoever time of day with or without food |
| Semaglutide | Man | 4.11 | ∼seven days | Subcutaneous | Adults: 0.25 mg, increasing to 0.5 mg after 4 weeks. If required, increase to i mg later a further four weeks | Once weekly | Tin be taken at any time of day with or without food |
| Oral semaglutide | Human | 4.eleven | ∼seven days* | Oral | Adults: 3 mg for 30 days, then 7 mg, escalated to 14 mg after a farther 30 days, if required | Once daily | Must be taken on an empty stomach with no more iv fl oz (120 mL) of plain water and at least thirty minutes earlier the outset food, beverage, or other oral medication of the day |
There are other differences among the various injectable GLP-1 receptor agonists that may influence treatment choice (Tabular array ane) (seven–xiii). One time-daily liraglutide and the once-weekly agents can be taken at whatsoever time of day, whereas twice-daily exenatide and once-daily lixisenatide must exist taken within 1 hour before eating (7–xiii). Liraglutide is the only GLP-1 receptor agonist indicated for apply in children (≥10 years of age) with blazon 2 diabetes (10). Lixisenatide is available as a stock-still-ratio combination with insulin glargine 100 units/mL (22); liraglutide iii.half dozen mg/mL plus insulin degludec 100 units/mL tin can likewise be given as a single injection (23). These combinations can be used in patients who demand intensification of glucose-lowering therapies and are already on either a basal insulin or a GLP-one receptor agonist alone (4–six).
In randomized phase 3 trials, GLP-1 receptor agonists have shown better or similar efficacy for glycemic command and weight loss in patients with type 2 diabetes when compared with placebo and other classes of antidiabetic medications (Table ii). Several GLP-1 receptor agonists accept also demonstrated cardiovascular benefits in patients at high risk, although this is non a universal finding, as described later (24–thirty). The master adverse events associated with GLP-1 receptor agonists are gastrointestinal (GI) in nature, primarily nausea, vomiting, and diarrhea (Table 2). GI side effects ordinarily occur early in the course of treatment. In the clinical experience of the authors, such furnishings tend to exist variable in terms of severity and usually resolve with continuous use. These observations are supported by trial information. Lowering the dose of GLP-one receptor agonist or using a slower titration regimen may help to mitigate these effects.
Table ii
Summary of Safe and Efficacy Results From Global Phase 3 Head-to-Head Studies of GLP-1 Receptor Agonists Approved for Use in the United States*
| Trial Name | Active Comparators | Background Regimen | Fourth dimension Point for Primary Efficacy Analysis, weeks | Relative A1C Reduction, % (ETD [95% CI], P) | Relative Weight Loss, kg (ETD [95% CI], P) | Safety and Tolerability Observations† |
|---|---|---|---|---|---|---|
| Once daily vs. once/twice daily | ||||||
| PIONEER 4 (64) | Oral semaglutide 14 mg once daily vs. liraglutide 1.8 mg one time daily | Metformin ± SGLT2 inhibitor | 26 | Similar (–0.ane [−0.three to 0.0], <0.0001 for noninferiority‡) | Significantly greater with oral semaglutide than liraglutide (−ane.ii [−ane.9 to −0.6], 0.0003‡) | Nausea: 20 vs. xviii% |
| Diarrhea: xv vs. 11% | ||||||
| Vomiting: 9 vs. v% | ||||||
| LIRA-LIXI (65) | Liraglutide 1.8 mg in one case daily vs. lixisenatide 20 µg once daily | Metformin | 26 | Significantly greater with liraglutide than lixisenatide (–0.6 [–0.8 to –0.4], <0.0001) | Similar (–0.half-dozen kg [–i.vi to 0.four], 0.23) | Nausea: 22 vs. 22% |
| Diarrhea: 12 vs. 10% | ||||||
| Vomiting: 7 vs. 9% | ||||||
| LEAD-6 (66) | Liraglutide 1.eight mg once daily vs. exenatide 10 µg twice daily | Metformin, SU, or both | 26 | Significantly greater with liraglutide than exenatide (–0.33 [–0.47 to –0.18], <0.0001) | Like (–0.38 [–0.99 to 0.23], 0.2235) | Nausea: 26 vs. 28% |
| Diarrhea: 12 vs. 12% | ||||||
| Vomiting: 6 vs. 10% | ||||||
| GetGoal-Ten (67) | Lixisenatide 20 µg once daily vs. exenatide x µg twice daily | Metformin | 24 | Similar based on noninferiority margin of 0.4% for upper CI (0.17 [0.03–0.30], North/R) | Significantly less with lixisenatide than exenatide (one.02 [0.46–one.58], N/R) | Nausea: 25 vs. 35% |
| Diarrhea: ten vs. 13% | ||||||
| Vomiting: 10 vs. xiii% | ||||||
| In one case weekly vs. once/twice daily | ||||||
| SUSTAIN-10 (34) | Subcutaneous semaglutide one.0 mg once weekly vs. liraglutide 1.2 mg once daily | Metformin, SU, or SGLT2 inhibitor, or whatsoever combination thereof | 30 | Significantly greater with semaglutide than liraglutide (–0.69 [–0.82 to –0.56], <0.0001) | Significantly greater with semaglutide than liraglutide (–3.83 [–iv.57 to –three.09], <0.0001) | Nausea: 22 vs. sixteen% |
| Diarrhea: 16 vs. 12% | ||||||
| Vomiting: 10 vs. eight% | ||||||
| AWARD-6 (37) | Dulaglutide 1.5 mg once weekly vs. liraglutide i.viii mg once daily | Metformin | 26 | Similar (–0.06 [–0.nineteen to 0.07], <0.0001 for noninferiority) | Significantly less with dulaglutide than liraglutide (0.71 [0.17–ane.26], 0.011) | Nausea: 20 vs. eighteen% |
| Diarrhea: 12 vs. 12% | ||||||
| Vomiting: vii vs. eight% | ||||||
| Honor-1 (68) | Dulaglutide 0.75/ 1.v mg once weekly vs. exenatide x µg twice daily | Metformin + pioglitazone | 26 | Significantly greater with dulaglutide than exenatide (one.5 mg: –0.52 [–0.66 to –0.39], <0.001; 0.75 mg: –0.31 [–0.44 to –0.eighteen], <0.001) | Similar for dulaglutide 1.5 mg and exenatide (–0.24 [N/R], 0.474) | Nausea: 29/17%(1.v mg/0.75 mg) vs. 28% |
| Significantly less with dulaglutide 0.75 mg than exenatide (one.27 [N/R], <0.001) | Diarrhea: xiii/ix% vs. 8% | |||||
| Airsickness: 17/half dozen% vs. 12% | ||||||
| Elapsing-vi (38) | Exenatide ii mg one time weekly vs. liraglutide one.8 mg once daily | Metformin and/or SU, or metformin ± pioglitazone | 26 | Significantly less with exenatide than liraglutide (0.21 [0.08–0.33], 0.0018) | Significantly less with exenatide than liraglutide (0.90 [0.39–1.40, 0.0005) | Nausea: 9 vs. 21% |
| Diarrhea: 6 vs. xiii% | ||||||
| Airsickness: 4 vs. 11% | ||||||
| Elapsing-five (69) | Exenatide two mg in one case weekly vs. exenatide ten µg twice daily | Metformin, SU, and TZD, alone or in combination | 24 | Significantly greater with exenatide once weekly than exenatide twice daily (–0.seven [–0.9 to –0.4], <0.0001) | Similar (–0.95 [–1.9 to 0.01], <0.05) | Nausea: 14 vs. 35% |
| Diarrhea: 9 vs. 4% | ||||||
| Vomiting: 5 vs. 9% | ||||||
| DURATION-1 (70) | Exenatide ii mg one time weekly vs. exenatide 10 µg twice daily | Metformin, SU, TZD, or a combination of 2 | 30 | Significantly greater with exenatide once weekly than exenatide twice daily (–0.33 [–0.54 to –0.12], 0.0023) | Similar (N/R [–1.three to 1.1], 0.89) | Nausea: 26 vs. 34% |
| Diarrhea: 14 vs. 13% | ||||||
| Vomiting: 11 vs. 19% | ||||||
| Once weekly vs. once weekly | ||||||
| SUSTAIN-iii (35) | Subcutaneous semaglutide ane mg in one case weekly vs. exenatide two mg one time weekly | one–2 OADs (metformin, SU, TZD) | 56 | Significantly greater with semaglutide than exenatide (–0.62 [–0.80 to –0.44], <0.0001) | Significantly greater with semaglutide than exenatide (–3.78 [–4.58 to –2.98], <0.0001) | Nausea: 22 vs. 12% |
| Diarrhea: 11 vs. 8% | ||||||
| Vomiting: 7 vs. vi% | ||||||
| SUSTAIN-vii (36) | Subcutaneous semaglutide 0.5/1 mg one time weekly vs. dulaglutide 0.75/1.5 mg one time weekly | Metformin | 40 | Significantly greater with semaglutide than dulaglutide (0.5 vs. 0.75 mg: –0.40 [–0.55 to –0.25]; one vs. 1.five mg: –0.41 [–0.57 to –0.25]; < 0.0001 for both) | Significantly greater with semaglutide than dulaglutide (0.5 vs. 0.75 mg: –two.26 [–3.02 to –1.51]; 1 vs. 1.5 mg: –3.55 [–iv.32 to –two.78], <0.0001 for both) | Nausea: 23/21 (0.5/1.0 mg) vs. thirteen/xx% (0.75/1.5 mg) |
| Diarrhea: 14/14 vs. 8/18% | ||||||
| Vomiting: 10/10 vs. iv/10% | ||||||
Why Switch Between GLP-one Receptor Agonists?
In clinical practice, unique factors often bulldoze therapeutic decisions that are fabricated by patients, HCPs, or both. The post-obit are potential reasons for switching between GLP-1 receptor agonists.
Need for Improved Glycemic or Weight Control
Several caput-to-caput studies have compared the clinical efficacy of various GLP-one receptor agonists and have identified differences in dominance for glycemic control and weight loss betwixt agents (Table ii). It should be noted that merely liraglutide currently has an indication for weight loss (at a higher dose of iii mg one time daily) (31). These differences may be a factor in clinical decisions for both the initial selection of a GLP-ane receptor agonist and potential switching between GLP-i receptor agonists.
In general, data suggest that long-acting GLP-i receptor agonists have greater effects on A1C, fasting plasma glucose, and body weight than those that are short-interim (32,33). Although many analyses practise not however integrate data with semaglutide, several head-to-head clinical trials report that subcutaneous semaglutide 1.0 mg once weekly provided superior A1C and weight reductions compared with liraglutide i.2 mg once daily (34), also as both exenatide 2 mg once weekly (35) and dulaglutide 1.five mg once weekly (Table 2) (36). On the other hand, liraglutide 1.eight mg once daily was similar to dulaglutide 1.v mg once weekly (37) and better than exenatide ii mg once weekly (38) in terms of A1C and weight reduction; this finding suggests that dosing frequency is not the but gene that determines glycemic efficacy (Table 2). It is important to note that these head-to-head studies varied in many ways, including in the dosages studied and in the prior and background therapies permitted.
Requirement for Cardioprotection
For patients with elevated cardiovascular take a chance, in that location is an bear witness-based rationale for switching to a GLP-one receptor agonist with proven cardiovascular do good, regardless of the patient's A1C, and for continuing a GLP-one receptor agonist in patients who are already receiving one but may require boosted medications for glycemic control (5).
Liraglutide once daily, dulaglutide one time weekly, and subcutaneous semaglutide in one case weekly take all demonstrated superior cardiovascular outcomes compared with placebo when added to standard-of-care treatment in patients with type two diabetes who had a history of cardiovascular illness or are at high cardiovascular risk (24–26). Albiglutide one time weekly also showed a cardiovascular do good only is no longer marketed, equally mentioned previously (27). In contrast, no significant improvements in cardiovascular outcomes were observed with lixisenatide once daily in patients who had had a recent acute coronary event (28) or with exenatide once weekly among patients with or without established cardiovascular affliction (29). Oral semaglutide has proven to be noninferior to placebo in loftier-run a risk patients in a pre-approving report (30), and a larger trial to evaluate the long-term cardiovascular do good of oral semaglutide is ongoing ({"blazon":"clinical-trial","attrs":{"text":"NCT03914326","term_id":"NCT03914326"}}NCT03914326). The differences in cardiovascular outcomes observed between trials of GLP-ane receptor agonists may relate to variations in the blueprint and populations of the trials, merely could as well exist the result of the dissimilar characteristics of the GLP-ane receptor agonists themselves (39,xl).
Need for Improved Rubber and Tolerability
All GLP-one receptor agonists have the potential to cause GI adverse furnishings, simply information technology has been suggested that nausea attenuates more than rapidly with long-interim GLP-1 receptor agonists than short-acting agents because of their less pronounced effects on gastric emptying (sixteen). There may be differences between GLP-1 receptor agonists in the nature, onset, and duration of GI adverse events (16), and it should likewise be noted that metformin tin contribute to their occurrence (41). Trial data generally support a lower incidence of GI furnishings with the longer-interim agents (Tabular array 2), and the authors' clinical experience suggests fewer such events when using lower doses.
Injection-site reactions may exist a consideration for switching from ane GLP-1 receptor agonist to another. Injection frequency appears to be a factor; for example, there were fewer injection-site reactions with once-weekly compared with twice-daily exenatide (42). Notwithstanding, formulation may besides play a part; there were fewer injection-site reactions with dulaglutide and subcutaneous semaglutide in one case weekly (35,43), and likewise with liraglutide one time daily (38), compared with exenatide once weekly.
Avoidance of hypoglycemia is also a potential consideration for switching treatments, but at that place are no head-to-head information indicating whatsoever reward of ane GLP-1 receptor agonist over any other in terms of the incidence of hypoglycemia. In full general, the risk of hypoglycemia is low with all GLP-1 receptor agonists (17).
People with type 2 diabetes often have chance factors for acute pancreatitis (e.yard., gallstones or hypertriglyceridemia) (44). Data from clinical trials indicate that GLP-one receptor agonists practise not increase the risk of developing pancreatitis (45). Still, caution should exist exercised in patients with a history of pancreatitis, and GLP-1 receptor agonist therapy should exist discontinued if pancreatitis develops (6–13).
Patient Preference and Adherence Concerns
Patients' perceptions of their current treatment may drive them to asking a change. For example, they may take read or heard about a newer treatment or may take a preference for one commitment device or route over another. It is important to emphasize to patients that glycemic efficacy and weight loss are not necessarily mutually exclusive. Although they may not exist losing weight, their handling may be decision-making their blood glucose levels. However, handling choice should be aligned with the goals of both the HCP and patient.
Across published trials, better adherence to injectable medications was by and large plant to exist associated with improved glycemic command (46). Withal, in a gimmicky, large, real-world report, 39% of patients receiving GLP-1 receptor agonists did not run across efficacy goals; information technology was suggested that lack of adherence (as well every bit a greater number of comorbidities) compared with trial populations may accept contributed (47). Indeed, U.S. claims data indicate that poor adherence accounts for approximately 75% of the departure in A1C reduction observed with GLP-1 receptor agonists in clinical do versus in randomized controlled trials (48). ADA/EASD guidelines recommend that a lack of notable response to whatsoever noninsulin therapies should exist a trigger to review adherence (iv).
Dissatisfaction with treatment frequency may exist a reason for patients non to adhere fully to their prescribed regimen and may be ameliorated by a switch from a once- or twice-daily to a once-weekly GLP-1 receptor agonist. Several patient surveys signal a preference for less frequent dosing with GLP-ane receptor agonists, specifically for one time-weekly over one time-daily dosing, in both injection-naive and injection-experienced patients (49,l). Patient-reported outcomes information from clinical trials in Japanese patients indicated that patients considered less frequent injections more convenient and flexible (51) and that their employ led to an improvement in quality of life, without compromising glycemic control (52).
Retrospective database studies suggest that adherence and persistence rates with once-weekly injectable GLP-1 receptor agonists are amend than those achieved with more frequently dosed treatments (53–56). Existent-world prescription data from Deutschland indicated that, among those switching between GLP-1 receptor agonists (exenatide twice daily, exenatide once weekly, dulaglutide once weekly, or liraglutide one time daily), post-switch persistence rates were greater amidst those receiving dulaglutide one time weekly compared with liraglutide in one case daily and exenatide twice daily (Figure i) (57).
Kaplan-Meier assay of persistence among patients switching from a previous GLP-1 receptor agonist to dulaglutide once weekly, exenatide twice daily or once weekly, or liraglutide in one case daily. Patients were switched from dulaglutide (v.0%), exenatide twice daily (28.1%), exenatide once weekly (17.4%), or liraglutide (49.v%). Information are from a retrospective analysis of a German prescription database using information from one Feb 2014 to 31 March 2017. Reprinted with permission from Otto et al. (57). BID, twice daily; QW, one time weekly.
Dosing frequency is not the sole commuter of adherence and persistence, supporting the need to consider the overall profile of each once-weekly GLP-1 receptor agonist when deliberating a switch. For instance, in the above studies, persistence rates were greater with dulaglutide once weekly compared with exenatide one time weekly and liraglutide one time daily (53–57). When determining an appropriate strategy to increment adherence with injectable therapies, it is also of import to consider the convenience of the dosing device. Ready-to-use formulations and easy-to-use delivery systems such as single-dose prefilled pens and hidden, pre-attached needles may encourage patient acceptance (58).
Other Considerations
Generally, interactions with other medications are not a major concern when switching between GLP-1 receptor agonists. Withal, increased bleeding risk has been noted when exenatide was co-administered with warfarin (8,13). All GLP-1 receptor agonists delay gastric emptying, which may affect the absorption of other oral medications (7–13). Although this is not considered clinically relevant in nearly cases, caution should be exercised when co-administering medications with narrow therapeutic windows (such equally levothyroxine and warfarin) (7–13).
Cost is likewise a potential consideration for HCPs and patients. In situations in which patients cover the cost of treatment, or when insurance coverage is bachelor but for select therapies, financial considerations may influence the selection of GLP-ane receptor agonist therapy or trigger the need for a switch. In a meta-assay of 34 published trials, higher diabetes-related pharmacy and full health intendance costs for patients who were more adherent and persistent were offset by lower diabetes-related and all-cause medical costs (45). In a U.S. database study, diabetes-related full costs were non significantly dissimilar betwixt dulaglutide in one case weekly and liraglutide once daily, but dulaglutide once weekly was associated with higher costs than exenatide once weekly (59).
Because cardiovascular events are a major driver of health care costs in patients with diabetes, previously mentioned reductions in the incidence of major cardiovascular events associated with several GLP-1 receptor agonists have the potential to translate into health economic benefits (39). Withal, the financial impact of the reported subtract in cardiovascular events has not yet been established (39).
All manufacturers of GLP-i receptor agonists offer eligible patients copay cards and take patient assistance programs. The details of such incentives depend on the manufacturer, region, and other factors. Practitioners should try to become knowledgeable nearly formulary coverage and the relevant pre-authorization processes in their expanse to ensure that patients who need these medications can obtain them as office of their wellness insurance benefits.
Practical Advice on Switching Between GLP-i Receptor Agonists
The recommendations discussed here are largely based on the clinical feel of the authors and are summarized in Effigy 2.
Applied algorithm for switching between in one case-daily and once-weekly GLP-1 receptor agonist therapies. *Kickoff dose of 7 or fourteen mg to be administered 1–vii days subsequently last injection (based on express advice in the prescribing information, which specifies but when switching from semaglutide 0.5 mg subcutaneous). †Cess of equivalent dose is entirely based on authors' opinion, which in turn is based on head-to-head clinical trials when bachelor and/or clinical experience. Other reasons for switching could include patient preference, business organization virtually drug interactions, and toll/insurance issues. Exenatide in one case weekly is non bachelor at a lower dose but could be tried if this is an insurance-preferred GLP-ane receptor agonist. BID, twice daily; GLP-1RA, GLP-ane receptor agonist; QD, once daily; QW, once weekly.
Considerations for Switching Between Once-Daily and Once-Weekly GLP-1 Receptor Agonists
When switching a patient betwixt two GLP-i receptor agonists, it is of import to ensure that the patient remains a suitable candidate for GLP-1 receptor agonist therapy, with no relevant comorbidities or contraindications either for the grade as a whole or for the agent selected. This procedure includes checking for a personal or family history of multiple endocrine neoplasia syndrome type 2 or medullary thyroid carcinoma.
We recommend assessing patients for GI symptoms attributable to GLP-i receptor agonists, such equally nausea, vomiting, dyspepsia, or changes in bowel habit. Other medications used for diabetes management (east.thousand., metformin or acarbose) may exacerbate these symptoms and intolerance for GLP-1 receptor agonists (60). For patients who have experienced GI agin events, consider withholding medications in a stepwise manner to decide the causative agent or facilitate tolerance of the GLP-i receptor agonist. Earlier switching considering of GI intolerance, nosotros recommend ensuring that all reasonable mitigating actions have been implemented, including: 1) verifying that the patient is taking the prescribed dose of the electric current GLP-1 receptor agonist because dose reduction can frequently minimize or resolve GI symptoms; 2) ensuring adherence to the provided dietary recommendations (consuming smaller portions and avoiding high-fat foods can decrease symptoms); and three) trying other mitigating measures without success (e.m., use of natural antinausea supplements such every bit ginger or peppermint, implementation of a brusque-course liquid diet, or temporarily holding metformin if appropriate). The authors do not recommend pharmacotherapy to convalesce nausea.
When switching from one GLP-1 receptor agonist to another, the authors would typically suggest adherence to the recommended posology described within the label for each amanuensis, including the need for gradual dose titration, when applicable. For the once-weekly GLP-one receptor agonists subcutaneous semaglutide and dulaglutide, gradual escalation to the recommended therapeutic dose is recommended (xi,12). Patients irresolute from a in one case-daily GLP-1 receptor agonist because of GI adverse effects may be better suited to a in one case-weekly medication with adjustable doses so they can showtime at a lower dose increment, given that GI adverse effects are frequently dose-dependent. Whereas dulaglutide is initiated at 0.75 mg and increased to ane.v mg if needed, subcutaneous semaglutide can be started at a "quarter dose" of 0.25 mg; this is increased to 0.5 mg once weekly after iv weeks and, if needed, to 1 mg after a further four weeks (11,12). Slower up-titration might be helpful to further minimize the risk of GI symptoms.
For patients who are tolerating the maximal therapeutic dose of a one time-daily or twice-daily GLP-one receptor agonist (exenatide ten µg twice daily, liraglutide i.8 mg once daily, or lixisenatide xx mg once daily) but who are changing to a once-weekly GLP-ane receptor agonist, we recommend starting dulaglutide once weekly or exenatide in one case weekly at the maximal therapeutic dose (dulaglutide 1.5 mg, exenatide two mg). For subcutaneous semaglutide, we suggest starting at the intermediary 0.five mg once-weekly dose for 4 weeks earlier transitioning to the maximal therapeutic dose of 1 mg one time weekly to assistance avoid adverse GI effects (Effigy 2).
Switching from a curt-acting to a long-acting GLP-1 receptor agonist could pb to small transient increases in FPG, equally shown in the DURATION-1 trial (61). Additional published clinical testify for this is lacking. However, an exposure-response modeling analysis suggested that an initial deterioration in A1C may be seen when switching from dulaglutide 1.5 mg once weekly or liraglutide 1.2/1.viii mg once daily to the initial recommended 0.25 mg in one case-weekly dose of subcutaneous semaglutide (62). All the same, after this initial rebound, switching to subcutaneous semaglutide would exist expected to result in boosted reductions in A1C and weight compared with the other GLP-one receptor agonists (sixty). In our experience, transient increases in glucose levels seen with changing from a one time-daily to a once-weekly GLP-1 receptor agonist are not clinically significant. Still, the starting dose of the new GLP-1 receptor agonist can exist adjusted to minimize the potential for such increases (Effigy 2). Patients, specially those who actively self-monitor their glucose levels, should be made aware of this possibility and so they can inform their intendance team equally necessary. If glucose levels rise above patient-specific goals, consideration can be given to temporarily adjusting existing diabetes medications or calculation in other medications if needed. Explaining this to patients also serves as an educational opportunity to highlight the relationship between dietary patterns and blood glucose levels.
Information technology is important to consider the timing of a switch between treatments. Patients tolerating once-daily GLP-1 receptor agonist therapy at the maximal therapeutic dose should commencement a once-weekly GLP-i receptor agonist the day after their last dose of once-daily medication. Those who are not tolerating the maximal dose, or are switching to a once-weekly GLP-1 receptor agonist because of GI adverse effects, should stop the in one case-daily medication and wait until their symptoms have resolved earlier starting the lowest dose of the chosen weekly GLP-one receptor agonist.
Before, during, and afterwards switching treatments, patient communication and reinforcement of educational messages are vital to ensure a smooth transition. Given that dissimilar GLP-1 receptor agonists accept different dosing recommendations (Table 1), it is important that patients switching between such agents are counseled on any applicable changes to their previous regimen. The usual recommendations and guidance that would exist given for initiation of a once-weekly GLP-1 receptor agonist should be provided (eastward.g., management to accept the medication one time weekly, data on how to manage missed doses, device-specific instructions, mealtime considerations, appropriate timing for oral medications, storage instructions, and availability of programs supporting adherence) (63).
Patients should exist advised of the potential for experiencing GI adverse effects later on switching to a different GLP-1 receptor agonist and that (as with the initiation of the prior GLP-1 receptor agonist) they should expect these effects to improve over time. They should seek medical advice if such agin effects are severe, or occur for an extended period, so that their provider may consider dose aligning (when applicable), discontinuation, or culling therapies (63).
More mostly, patients should be reminded that it might take several weeks for the full efficacy of a GLP-1 receptor agonist to emerge. Providers should employ the opportunity of GLP-i receptor agonist switching to re-educate patients about the mechanisms of action and set patient expectations, particularly with respect to the effects of delayed gastric emptying. This data may decrease the take chances of discontinuation considering of nausea and may help patients to use the medication as a tool for weight loss by eating less.
In keeping with current guidelines, it is recommended that patients are reassessed inside 2–3 months of switching to appraise the adequacy of dose titration, side effects, need for adjustment of other medications, and accomplishment of therapeutic goals (4). Information technology should be noted that it may accept three months to titrate subcutaneous semaglutide to a 1-mg dose, and therefore the maximum glycemic benefit of that agent may not be evident for up to 6 months after the switch. In our feel, weight loss usually continues for 9–12 months. Because of differences in medication adherence and persistence, patients may achieve significant improvements in blood glucose levels that require adjustment of other diabetes medications, such as insulin. Changes in body weight may also require adjustment of antihypertensive medications, thyroid hormone replacement, and other medications.
Additional Considerations When Switching Between Once-Weekly Treatments
In the instance of switching between ii once-weekly GLP-ane receptor agonists, a practical approach is to terminate the current GLP-1 receptor agonist and and then begin the new GLP-ane receptor agonist one week later, on the same day of the week. Patients tolerating a once-weekly GLP-1 receptor agonist at the maximal therapeutic dose should beginning the alternative one time-weekly agent 1 calendar week afterwards the last dose of the electric current treatment. The maximal dose of exenatide two mg once weekly or dulaglutide 1.five mg once weekly may exist started if switching to one of these agents. For subcutaneous semaglutide, nosotros recommend starting 0.v mg one time weekly for 4 weeks before advancing to 1 mg once weekly, depending on tolerability and clinical necessity. In our experience, transitioning directly to subcutaneous semaglutide 1 mg once weekly from another GLP-1 receptor agonist tin exist associated with nausea or GI disturbance.
Patients who are not tolerating the maximal dose of a once-weekly GLP-1 receptor agonist, or those who are switching once-weekly GLP-one receptor agonists due to GI adverse furnishings, should delay the initiation of the new GLP-1 receptor agonist therapy until symptoms have resolved. They should then start the lowest dose of the alternative once-weekly GLP-1 receptor agonist and consider a lower maintenance dose.
Once-daily GLP-one receptor agonist therapies are as well available in fixed-ratio combination formulations with long-acting insulins (insulin glargine with lixisenatide [22] and insulin degludec with liraglutide [23]). When switching patients from a once-daily fixed-ratio combination to a once-weekly GLP-one receptor agonist and split up long-acting insulin, dose equivalency (Figure 2) and insulin dose adjustment must be considered.
Future Perspectives and Conclusion
Until recently, GLP-1 receptor agonists have only been available as subcutaneous injections. Notwithstanding, oral semaglutide in one case daily provided like glycemic control, produced greater weight loss, and had like tolerability to liraglutide once daily (64) (Table 2). Oral semaglutide has now been approved in the United States for use in patients with type two diabetes whose A1C is insufficiently controlled with diet, exercise, and metformin (7).
Switching from an injectable GLP-1 receptor agonist to an oral formulation is a distinctly different proposition from switching between injectable formulations, and additional practical guidance will be required on this topic once sufficient clinical experience has been gained. However, the production label contains some relevant information based on the protocols used in clinical trials. If a patient receiving subcutaneous semaglutide 0.5 mg one time weekly is to be switched to in one case-daily oral semaglutide, they should initiate a 7-mg or xiv-mg dose up to 1–7 days after their last injection (seven). In reverse, patients receiving oral semaglutide xiv mg in one case daily can transition to subcutaneous semaglutide 0.5 mg once weekly the day later on their last oral dose (7).
Switching between GLP-1 receptor agonists can be considered in many clinical scenarios, as explored above, and may be increasingly mutual given the availability of newer agents in the form. Although numerous studies have compared the available GLP-i receptor agonists, few have directly explored the furnishings of switching between these agents, highlighting a demand for further research. Herein, nosotros have aimed to provide practical advice for HCPs because a switch between GLP-1 receptor agonists, based on our clinical feel. Overall, we favor the apply of longer-acting over shorter-acting GLP-i receptor agonists, only the option should accept into business relationship individual clinical factors, patient preferences, risks, and benefits. The availability of an oral agent in this grade provides further options.
Commodity Information
Acknowledgments
The authors give thanks Stephen Purver (Spirit Medical Communications Grouping Ltd.) for assist with medical writing and editorial support. Alisa Schiffman of Novo Nordisk was also provided with the opportunity to perform a medical accuracy review.
Funding
The evolution of and medical writing and editorial support for this article was funded by Novo Nordisk.
Duality of Interest
I.L. received research funding and/or consulting fees, travel, or editorial support from AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, Lilly, Mannkind, Merck, Mylan, Novo Nordisk, Novartis, Pfizer, Sanofi, and Valeritas. J.Yard. is on the speakers' bureaus of and has served equally a consultant for, received honoraria as a promotional speaker from, or participated in advisory boards for Abbott Laboratories, AstraZeneca, Bayer Laboratories, Boehringer Ingelheim, Lilly, Janssen Pharmaceuticals, Mylan Pharmaceuticals, and Novo Nordisk. C.C. is a speaker/consultant for Boehringer Ingelheim, Janssen, Lilly, Mannkind, and Novo Nordisk. No other potential conflicts of involvement relevant to this article were reported.
Author Contributions
All authors contributed equally to the evolution of this review article. Medical writing assistance, undertaken at the direction of the authors, comprised literature searches, drafting of the manuscript, editing of the manuscript, preparation of figures and tables, and contributions to the estimation of the literature in the discussion. All authors are joint guarantors of this work and, equally such, had full access to all of the literature search results and references cited and have responsibility for the integrity of the data cited and the accurateness of the analyses provided.
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