Perspective
`Clinical Recommendations to Manage Gastrointestinal Adverse
`Events in Patients Treated with Glp-1 Receptor Agonists:
`A Multidisciplinary Expert Consensus
`, Almudena Castro 4,
`Juan J. Gorgojo-Martínez 1,†, Pedro Mezquita-Raya 2,†, Juana Carretero-Gómez 3
`Ana Cebrián-Cuenca 5
`, Alejandra de Torres-Sánchez 2, María Dolores García-de-Lucas 6, Julio Núñez 7
`Juan Carlos Obaya 8, María José Soler 9, José Luis Górriz 10,*
`and Miguel Ángel Rubio-Herrera 11
`
`,
`
`1 Department of Endocrinology and Nutrition, Hospital Universitario Fundación Alcorcón,
`28922 Madrid, Spain
`2 Department of Endocrinology and Nutrition, Hospital Universitario Torrecárdenas, 04009 Almería, Spain
`3 Department of Internal Medicine, University Hospital of Badajoz, 06080 Badajoz, Spain
`4 Department of Cardiology, University Hospital la Paz, IdiPAZ, Biomedical Research
`Center-Cardiovascular Diseases (CIBERCV-ISCIII), 28046 Madrid, Spain
`5 Health Centre Casco Antiguo Cartagena, Primary Care Research Group, Biomedical Research Institute of
`Murcia (IMIB), 30201 Cartagena, Spain
`6 Department of Internal Medicine, Costa del Sol Hospital, 29603 Marbella, Spain
`7 Department of Cardiology, Valencia Clinic University Hospital, Instituto de Investigación
`Sanitaria (INCLIVA), 46010 Valencia, Spain
`8 Health Centre la Chopera, 28100 Madrid, Spain
`9 Nephrology and Kidney Transplantation Research Group, Nephrology Department, Vall d’Hebron Institut de
`Recerca (VHIR), Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain
`10 Nephrology Department, Valencia Clinic University Hospital, Instituto de Investigación Sanitaria (INCLIVA),
`Universitat de València, 46010 Valencia, Spain
`11 Department of Endocrinology and Nutrition, San Carlos Clinical Hospital, Health Research Institute of the
`San Carlos Clinical Hospital (IDISSC), 28040 Madrid, Spain
`* Correspondence: jlgorriz@uv.es; Tel.: +34-961973811; Fax: +34-961970977
`† These authors contributed equally to this work.
`
`Abstract: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated in type 2 diabetes and
`obesity for their high efficacy in controlling glycaemia and inducing body weight loss, respectively.
`Patients may develop gastrointestinal adverse events (GI AEs), namely nausea, vomiting, diarrhoea
`and/or constipation. To minimize their severity and duration, healthcare providers (HCPs) and
`patients must be aware of appropriate measures to follow while undergoing treatment. An expert
`panel comprising endocrinologists, nephrologists, primary care physicians, cardiologists, internists
`and diabetes nurse educators convened across virtual meetings to reach a consensus regarding
`these compelling recommendations. Firstly, specific guidelines are provided about how to reach
`the maintenance dose and how to proceed if GI AEs develop during dose-escalation. Secondly,
`specific directions are set about how to avoid/minimize nausea, vomiting, diarrhoea and constipation
`symptoms. Clinical scenarios representing common situations in daily practice, and infographics
`useful to guide both HCPs and patients, are included. These recommendations may prevent people
`with T2D and/or obesity from withdrawing from GLP-1 RAs treatment, thus benefitting from their
`superior effect on glycaemic control and weight loss.
`
`Keywords: type 2 diabetes; obesity; glucagon-like peptide-1 receptor agonists; gastrointestinal
`adverse events; guidelines
`
`1. Introduction
`Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have represented a paradigm
`shift in the treatment of type 2 diabetes (T2D) and obesity. The incretin effect induced
`
`Citation: Gorgojo-Martínez, J.J.;
`Mezquita-Raya, P.; Carretero-Gómez,
`J.; Castro, A.; Cebrián-Cuenca, A.; de
`Torres-Sánchez, A.; García-de-Lucas,
`M.D.; Núñez, J.; Obaya, J.C.; Soler,
`M.J.; et al. Clinical Recommendations
`to Manage Gastrointestinal Adverse
`Events in Patients Treated with Glp-1
`Receptor Agonists: A Multidisciplinary
`Expert Consensus. J. Clin. Med. 2023,
`12, 145. https://doi.org/10.3390/
`jcm12010145
`
`Academic Editor: Alejandro
`Gugliucci
`
`Received: 25 November 2022
`Revised: 21 December 2022
`Accepted: 23 December 2022
`Published: 24 December 2022
`
`Copyright: © 2022 by the authors.
`Licensee MDPI, Basel, Switzerland.
`This article is an open access article
`distributed under
`the terms and
`conditions of the Creative Commons
`Attribution (CC BY) license (https://
`creativecommons.org/licenses/by/
`4.0/).
`
`J. Clin. Med. 2023, 12, 145. https://doi.org/10.3390/jcm12010145
`
`https://www.mdpi.com/journal/jcm
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`Journal of
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`by GLP-1 RAs allows for glycaemic control in a glucose-dependent manner more effi-
`ciently than other therapeutic classes without increasing the risk of hypoglycaemia [1].
`Interestingly, some of them are able to cross the blood–brain barrier and act on the brain
`to stimulate satiety [2], which leads to food intake reduction and, consequently, body
`weight loss, which occurs at the expense of fat mass. As a result, the risk of progression to
`T2D decreases, and improvements in lipid profile, blood pressure or sleep apnoea have
`been observed [3]. GLP-1 RAs also exert pleiotropic actions with metabolic, hepatic, renal
`and cardiovascular beneficial effects [4–7]. Of note, a recent meta-analysis encompassing
`those clinical trials focused on the cardiovascular safety of GLP-1 RAs found significant
`reductions in MACE3 (a composite of cardiovascular death, non-fatal myocardial infarction,
`and non-fatal stroke), hospitalization for heart failure and progression of chronic kidney
`disease [8]. The currently commercialized GLP-1 RAs with indications for T2D or obesity
`are summarized in Supplementary Table S1.
`Ample clinical evidence arising from trials and real-world scenarios highlights that the
`most frequent adverse events (AEs) associated with GLP-1 RA are those of a gastrointestinal
`(GI) nature, namely nausea, vomiting, diarrhoea and constipation. According to the
`literature addressing clinical trials, GI AEs usually develop in 40–70% of treated patients,
`although they have sometimes been reported in up to 85% [9–17].
`GI AEs arise irrespective of the half-life (long/short action) or route of administration
`(subcutaneous/oral) of the chosen GLP-1 RA. They are usually transient, typically starting
`during the dose-escalation period and generally resolving shortly after the maintenance
`dose is reached, and, in most cases, they are mild to moderate in severity. A recent report
`summarizing the results of several trials reported that the majority (99.5%) of documented
`GI AEs in people with obesity on GLP-1 RA treatment were non-serious [18]. A meaningful
`body of evidence in real-world settings roughly replicates these observations [19–22].
`Nevertheless, it is essential that patients and healthcare professionals (HCPs) are aware of
`the right procedures to follow to prevent GI AEs from arising or, if they occur, to mitigate
`their effects and improve adherence and persistence to the treatment.
`GI AEs may lead to the temporary or permanent discontinuation of GLP-1 RA treat-
`ment. Although interruption has been reported to occur in up to 12% of GLP-1 RA-treated
`patients (vs. ~2% in those treated with placebo) [9–18], permanent discontinuations range
`between 1.6–6% of treated patients (vs. <1% with placebo), according to clinical trial pro-
`grams [9,15,18]. In the real-world setting, persistence with GLP-1 RA therapy has been
`found to range between 40% and 60% and between 34% and 67% at 180 and 360 days,
`respectively [23–25]. The results seem to be better with once-weekly administered GLP-1
`RAs compared to those requiring once-daily injections [26–28]. The adequate management
`of GI AEs would potentially improve a patient’s experience while undergoing treatment
`with GLP-1 RA, preventing discontinuations secondary to GI AEs.
`The literature addressing the management of GI AEs in clinical practice associated
`with the use of GLP-1 RA from a multidisciplinary perspective is scarce [29]. For this
`reason, we formed a multidisciplinary team consisting of HCPs of several specialties and a
`diabetes nurse educator (DNE) with experience in the management of patients treated with
`GLP-1 RA in their daily practice. The main goal of this document is to reach a consensus
`regarding patient education and procedures to minimize the frequency and intensity of
`GLP-1 RA-associated GI AEs. Hopefully, this multidisciplinary consensus may contribute
`to expanding our knowledge of the practical use of GLP1-RAs, providing useful tools
`for physicians to use when managing people with T2D or overweight/obesity with this
`therapeutic class. More importantly, the better management of GI AEs could potentially
`have a positive impact on the adherence/persistence, effectiveness of treatment and quality
`of life (QoL) among GLP-1 RA-treated patients.
`
`2. Methods
`A multidisciplinary expert panel comprising three endocrinologists, two nephrologists,
`two primary care physicians (PCPs), two cardiologists, two internists and one DNE, all of them
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`with clinical expertise in the management of people with T2D or obesity with GLP-1 RA-based
`therapies, convened across virtual meetings to reach a consensus. The participants performed
`a comprehensive literature search using prespecified keys (Supplementary Table S2). The
`experts agreed that GI AEs should be the main topic to focus on when addressing the optimal
`medical care of patients treated with GLP-1 RA. The proper management of such occurrences
`is of paramount importance since it contributes significantly to treatment adherence and
`persistence and may improve QoL. Hepatobiliopancreatic AEs are also discussed in brief
`because, although they are extremely infrequent, it is important to exercise caution with those
`patients with a history of pancreatic and gallbladder disorders. Finally, widely accepted
`myths and erroneous considerations concerning other AEs and profiles of subjects wrongly
`considered unfit to receive this medication are also reviewed to ensure that as many patients
`as possible can benefit from treatment with GLP-1 RA.
`
`3. AEs Most Frequently Associated with GLP-1 RAs
`As anticipated, the AEs that were most frequently associated with GLP-1 RAs are
`those of a GI nature. Table 1 shows a summary of their frequency of occurrence in phase III
`clinical trials. Among the most common GI side effects, namely nausea, vomiting, diarrhoea
`and constipation, nausea appears systematically as the most frequent event in all clinical
`trials. The prevalence of the other GI AEs is lower. Overall, the onset of GI AEs is slightly
`higher in those trials designed to assess the efficacy and safety of GLP-1 RAs in people
`with obesity, which may be ascribed to the fact that doses are higher than those used in
`clinical trials in people with T2D. It is worth mentioning that long-acting agents have been
`associated with less nausea and vomiting but with more diarrhoea [30], which might be
`explained by a more sustained effect of these compounds on GLP-1 intestinal receptors [31].
`Finally, it is worth mentioning that flatulence may occasionally appear, although studies
`reporting its frequency are lacking.
`
`Table 1. Frequency of GI AEs in clinical trials with GLP-1 RA in people with obesity or T2D.
`
`GLP-1 RA
`
`Program
`
`Refs
`
`Patient
`Profile
`
`Dose
`
`Method of
`Administration
`
`Nausea
`
`Vomiting
`
`Diarrhoea
`
`Constipation
`
`Semaglutide
`Semaglutide
`Semaglutide
`Liraglutide
`Liraglutide
`Dulaglutide
`Exenatide
`Exenatide
`Lixisenatide
`
`SUSTAIN
`STEP
`PIONEER
`LEAD
`SCALE
`AWARD
`DURATION
`—
`GETGOAL
`
`9
`10
`11
`12
`13
`14
`15
`16
`17
`
`4–7
`7–19
`7–15
`15–24
`s.c. once weekly
`1 mg
`T2D
`12–37
`10–36
`22–27
`14–58
`s.c. once weekly
`2.4 mg
`Obesity *
`7–12
`5–15
`6–12
`8–23
`p.o. SID
`14 mg
`T2D
`11
`8–19
`4–17
`10–40
`s.c. SID
`1.8 mg
`T2D
`12–30
`16–26
`7–23
`27–48
`s.c. SID
`3 mg
`Obesity *
`n.r.
`11–17
`7–17
`15–29
`s.c. once weekly
`1.5 mg
`T2D
`1–8
`5–11
`<1–6
`5–14
`s.c. once weekly
`2 mg
`T2D
`5
`4–9
`9–14
`35–59
`s.c. BID
`10 µg
`T2D
`5†
`4–12
`7–18
`16–40
`s.c. SID
`20 µg
`T2D
`Results are expressed as percentages of patients from the treatment cohort who experienced the AE at least
`once during the period of the study. Values correspond to the minimum and maximum values reported when
`considering all the studies of the program. * One out of 6 studies recruited people with obesity and T2D as well.
`† Data reported in one study only. BID, twice a day; GI AEs, gastrointestinal adverse events; GLP-1 RA, GLP-1
`receptor agonist; n.r., not reported; p.o., oral; Refs, references; s.c., subcutaneous; SID, once a day; T2D, diabetes
`mellitus type 2.
`
`4. Practical Guide to Follow When Initiating Treatment with GLP-1 RAs
`4.1. Patient Education Prior to GLP-1 RA Start
`Patient education in terms of how to take and deal with satiety once GLP-1 RAs
`are started is crucial for ensuring treatment compliance. It is accepted that persistence
`improves when weight is adequately managed and safe, straightforward treatments are
`used [32–34]. GLP-1 RA-based treatments comply with these characteristics. The proper
`education of patients by HCPs on their expectations when initiating treatment, how to
`prevent AEs, and how to treat them if they appear is particularly important. Patients have
`to learn that, although GI AEs may occur, these will be transient and of mild/moderate
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`severity in the majority of cases and that following specific dietary recommendations will
`relieve symptoms (Table 2, Figures 1–3).
`
`Table 2. Guidelines for patients.
`
`Recommendations to Minimize Occurrence/Severity of GI AEs when Starting GLP-1 RA Therapy
`
`General recommendations
`Observe the guidelines of the data sheet regarding posology and method of administration
`Improve eating habits
`Eat slowly
`Eat only if you are really hungry
`Eat smaller portions
`Avoid lying down after having a meal
`Stop eating in case of feeling of fullness
`Increase meal frequency
`Avoid drinking using a straw
`Eat without distractions and enjoy savouring the food
`Try not to be too active after eating
`Avoid eating too close to bedtime
`Adapt food composition to your requirements
`Choose easy-to-digest food, low fat diets (focus on bland foods)
`Use oven, cooking griddle or boiling
`Increase fluid intake, especially clear, fresh drinks (in small sips), but no so much as to make you feel too full
`Healthy food that contain water (soups, liquid yogurt, gelatin, and others)
`Avoid sweet meals
`Avoid dressings, spicy foods, canned food, sauces that are not home-cooked
`Get some fresh air and do some light exercise
`Keep a food diary, as it may be useful to identify foods or meal timings that make it worse
`Additional recommendations for patients with nausea
`Provided that 30 min have passed since the last GLP-1 RA dose, eat foods able to ease the symptoms of nausea, such as
`crackers, apples, mint, ginger root or ginger-based drinks
`Avoid strong smells
`
`Additional recommendations for patients with vomiting
`Be particularly careful with hydration
`Eat smaller amounts of food in more frequent meals
`Additional recommendations for patients with diarrhoea
`Generous hydration, for example with water, lemon and a teaspoon of bicarbonate
`Avoid isotonic drinks intended to be used in the context of sport activities
`Avoid dairy products, laxative juices or meals, coffee, alcoholic drinks, soft drinks, very cold or very hot foods, products
`with sweeteners ending in “ol” (sorbitol, mannitol, xylitol, maltitol), including candy and gum
`Avoid (or temporarily reduce your intake of) foods with high fibre content * such as grain and seed products, such as
`grain cereals, nuts, seeds, rice, barley, whole grain bread or baked goods vegetables such as artichokes, asparagus, beans,
`cabbage, cauliflower, garlic and garlic salts, lentils, mushrooms, onions, sugar snap, snow peas skinned fruits, apples,
`apricots, blackberries, cherries, mango, nectarines, pears, plums
`Eat chicken broth, rice, carrots, very ripe fruit without skin
`Additional recommendations for patients with constipation
`Ensure the amount of fibre in your diet is adequate
`Increase physical activity
`Ensure your diet is healthy and balanced
`Drink generous amounts of water (or other sugar-free liquids)
`Additional recommendations when GLP-1 RA are unusually severe or/and persistent
`In case of persistence of nausea and/or vomiting, avoid drinks during meals, rather have them between 30 and 60 min
`before and/or after meals
`If nausea, vomiting, diarrhoea and/or constipation persist in spite of following all the guidelines depicted above, inform
`HCP as soon as possible
`* Gradually increase the amount of fibre intake once the symptoms improve. HCP, healthcare provider.
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`Figure 1. Minimizing occurrence/severity of GI AEs: patients general guidelines.
`
`Figure 2. Additional specific guidelines for each separate GI AE.
`
`
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`Figure 3. Additional specific guidelines for unusually severe/persistent GI AEs.
`
`4.2. Overall Procedures
`Compliance with the guidelines contained in Table 2 will be useful in avoiding the onset
`of GI AEs and mitigating their intensity in those cases where they develop. Indeed, it is
`important to start low and go slow: the lowest dose of medication should be used to start,
`and HCPs should ensure that patients follow their instructions closely. In those rare cases of
`particularly intense and/or persistent GI AEs, HCPs can apply further measures (Figure 4):
`•
`If GI AEs appear during the dose-escalating phase, HCPs could modify the planned
`schedule by implementing one or several of the following points [35,36]:
`(cid:5)
`Extend the dose escalation phase duration (2–4 more weeks with the previous
`dose or temporary suspension).
`Avoid dose escalation while GI AEs persist.
`If a GI AE is experienced when moving up to a higher dose, go back on the
`lower one and stay on it for a few days. Then, increase the dose gradually, taking
`advantage of the multidose pen-injector when available.
`In the case of persistent tolerability limitations set a dose lower than the maximum
`one recommended by the technical data sheet as a maintenance dose.
`(cid:5) Withhold treatment temporarily until the resolution of AEs and then resume treatment.
`
`(cid:5)
`(cid:5)
`
`(cid:5)
`
`
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`Figure 4. Minimizing occurrence/severity of GI AEs: the role of HCPs.
`
`Appropriate management during the dose-escalation phase could help patients to
`develop tachyphylaxis, i.e., to avoid excessive delay in gastric emptying upon treatment
`with GLP-1 RAs, especially with the long-acting ones [37,38].
`•
`Start a differential diagnosis procedure to rule out underlying conditions causing the
`symptoms or their exacerbation [35].
`• Make sure that the patient understands and complies with the guidelines regarding
`diet habits (Table 2, Figures 1 and 2).
`•
`Start symptomatic treatment focused on the specific GI AE (see below).
`•
`Switching to another GLP-1 RA may be considered. Although reported data from
`trials and real-world series do not show definitive differences between GLP-1 RAs in
`terms of tolerability (Table 1), there are studies claiming that the tolerability profile
`may vary between different compounds [1,33,39]. In fact, the switching strategy has
`already been proposed in the context of the treatment of people with T2D [40,41]. It is
`advisable to start the new GLP-1 RA at its lowest escalation dose. If the patient is on
`treatment with semaglutide, switching the route of administration, i.e., from s.c. to
`oral semaglutide or vice versa, may be an option [42].
`
`4.3. Specific Procedures
`4.3.1. Nausea
`Real-world studies confirm that nausea is the most frequent GI AE that arises upon
`initiation of GLP-1 RA [20,43,44]. The frequency varies among clinical trials, although
`it usually ranges between 15 and 50% (Table 1). Prevalence is higher during the first
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`4–5 weeks of treatment, when gastric emptying is more significantly delayed [45], decreas-
`ing thereafter [9–17]. Symptoms are usually moderate and disappear 8 days or less after
`their onset [18,46]. To alleviate symptomatology, the following measures are advisable [29]:
`
`Figures 1–3).
`
`(cid:35) Comply with recommendations regarding intake habits and food composition (Table 2,
`(cid:35) If symptoms still persist, consider anti-emetic and/or prokinetic medications (Figure 4).
`
`Domperidone (10–20 mg three to four times daily, oral dosage, not in children < 12 years)
`should be used rather than metoclopramide, especially in older patients, to minimize the
`risk of extrapyramidal side effects [47]. Among substituted benzamides, cinitapride may
`be an alternative to metoclopramide [48]. In the event that oral semaglutide is being
`used, a period of 30 min must elapse between the administration of both medications.
`If drugs to mitigate nausea (or other GI AEs) are needed for over a month when the
`maintenance GLP-1 RA dose has been reached, a dose reduction should be considered
`for the patient to tolerate the drug with no need for pharmacological support [35].
`
`4.3.2. Vomiting
`Vomiting occurs at a frequency that usually ranges between 5 and 20%, i.e., lower
`than that reported for nausea (Table 1). Symptoms have been reported to disappear in
`1–8 days [18,46]. Initial measures do not substantially differ from those already reviewed
`(Figure 1). In case of abnormally long persistence or unexpected severity, additional actions
`may be undertaken (Table 2, Figures 2–4) [35]:
`
`rather than metoclopramide, as explained above [47].
`
`(cid:35) Maintaining hydration is particularly important.
`(cid:35) Small amounts of food should be taken in more frequent meals.
`(cid:35) Consider anti-emetic and/or prokinetic medications. Domperidone should be used
`(cid:35) In case of persistence and/or remarkable severity, and where the patient presents with
`
`dizziness, confusion and fatigue, standard procedures to clinically manage severe
`vomiting can be initiated. Although rarely, intravenous rehydration may be necessary.
`If the above measures are not as efficient as expected, either a decrease in GLP-1 RA
`dose or a temporary interruption of the treatment may be considered [35].
`
`4.3.3. Diarrhoea
`The frequency of diarrhoea also varies among trials, usually ranging between 5 and 25%
`(Table 1). Diarrhoea initiates during the first four weeks of treatment, after which the incidence
`notably decreases [15,49]. Symptoms have been reported to last for about three days in people
`with obesity treated with GLP-1 RA [18]. The patients must be encouraged to follow the
`specific recommendations to avoid/mitigate diarrhoea (Table 2, Figures 1–3), which should
`already have been taught to them as part of their education prior to GLP-1 RA initiation. In
`the event of persistence, in spite of compliance with these and the other guidelines, probiotic
`and/or antidiarrheal supplements such as loperamide could be considered [29]. GLP-1
`RA may exacerbate diarrhoea in patients receiving metformin treatment, especially if they
`are also taking omeprazole. In such cases, a reduction in the dose of metformin may be
`advisable (Figure 4).
`
`4.3.4. Constipation
`Constipation generally occurs at frequencies in the range of 4–12%, i.e., lower than
`those documented with other GI AEs. Nevertheless, some trials have reported a prevalence
`of up to 25 and 35% in people with obesity (Table 1). Accordingly, real-world series
`confirmed that constipation occurs more frequently in patients with overweight/obesity
`than with T2D [50]. The onset can be in the first 16 weeks of treatment, particularly during
`the first 28 days [49,51,52]. Constipation symptoms have been reported to last longer than
`those of the other GI AEs. The symptoms persisted for a median duration of 47 days in
`people with obesity on GLP-1 RA therapy [18], which may be ascribed to the more chronic
`nature of the condition [35]. Secondary to the feeling of gastric fullness after receiving the
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`drug, patients tend to reduce water intake, which may predispose them to this AE. Patients
`should be advised to increase their mobility, and intake of water and fibre, as well as to
`consider the use of stool softeners (Figures 1–3). Clinicians should not discard a reduction
`in the GLP-1 RA dose upon a worsening of symptoms (Figure 4) [35].
`
`5. Uncommon AEs
`Pancreatobiliary complications have been documented, albeit seldom. A compre-
`hensive review encompassing 30 trials focusing on GLP-1 RA safety in people with T2D
`concluded that the risk of gallbladder complications or acute pancreatitis (AP) associated
`with this medication was generally low [53]. In people with obesity, the incidence of
`gallbladder-related events was always <3% [10,54]. Cholelithiasis was reported in 0–<1%
`patients in the majority of cohorts, regardless of having T2D or obesity [9–17]. Its associa-
`tion with GLP-1 RA use, although unusual, has been linked to a combination of factors.
`Among these, the relevant weight loss often experienced by people with obesity may
`promote biliary lithogenicity, such as after bariatric surgery. Other explanations might
`be a direct action of the drug on biliary secretion and/or the modification of gallbladder
`motility [55–58]. On the other hand, cholecystitis episodes were anecdotal [9–17]. Finally,
`although higher circulating levels of lipase and amylase were reported in patients on GLP-1
`RA therapy in many trials, the increases were rarely higher than three or five-fold the upper
`limit of normal (ULN), respectively [9–17], returned to normal levels after medication
`withdrawn, and were poor predictors of AP [54].
`A meta-analysis that included studies lasting for ≥24 months, with more than 9000
`patients treated with GLP-1 RA during such period, did not find an association between
`GLP-1 RA therapy and AP either [59]. Another one covering 55 randomized controlled
`trials and five observational studies with more than 300,000 participants, drew the same
`conclusion [60]. Nevertheless, a recent meta-analysis encompassing up to 76 randomized
`controlled trials concluded that GLP-1 RA treatment was associated with a significant,
`albeit low, increased risk of gallbladder or biliary diseases (relative risk (RR), 1.37; 95%
`confidence interval (CI), 1.23–1.52). When the trials were stratified according to pathology,
`RR was 2.29 (95% CI, 1.64–3.18) in trials focused on people with obesity, near two-fold
`higher than that observed in trials concerning the treatment of T2D or other diseases (1.27;
`95% CI, 1.14–1.43). Higher GLP-1 RA doses and, especially, the duration of treatment
`influenced the risk [61].
`The proportion of patients who developed pancreatobiliary complications such as
`AEs in the course of the more significant clinical trials is summarized in Table 3. AP was
`always experienced by less than 1% of patients treated with GLP-1 RAs. Furthermore,
`many of the cases were reported in subjects with a previous history of pancreatitis or
`gallbladder disease. Thus, caution must be exercised in patients with these antecedents.
`Ursodeoxycholic acid may be administered to patients with a history of cholelithiasis.
`HCPs must be aware of the possibility of these rare side effects to act early and avoid
`the complications related to volume depletion, such as severe renal failure [62,63]. Patient
`education to recognize pancreatitis symptoms is also a recommended practice [29].
`If developed, pancreatobiliary complications should be managed according to the
`guidelines of each centre.
`
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`GLP-1 RA
`Semaglutide
`Semaglutide
`Semaglutide
`Liraglutide
`Liraglutide
`Dulaglutide
`Exenatide
`Exenatide
`Lixisenatide
`
`Program
`SUSTAIN
`STEP
`PIONEER
`LEAD
`SCALE
`AWARD
`DURATION
`—
`GETGOAL
`
`Table 3. Frequency of pancreatobiliary complications in clinical trials with GLP-1 RA in people with
`obesity or T2D.
`
`AP
`Cholelithiasis
`Administration
`Dose
`Target Patient
`Refs
`0-<1
`0–2
`s.c. once weekly
`1 mg
`T2D
`9
`0-<1
`<1–3
`s.c. once weekly
`2.4 mg
`Obesity *
`10
`0-<1
`0-<1
`p.o. QD
`14 mg
`T2D
`11
`0-<1
`0
`s.c. QD
`1.8 mg
`T2D
`12
`0-<1
`<1–1
`s.c. QD
`3 mg
`Obesity *
`13
`<1
`0
`s.c. once weekly
`1.5 mg
`T2D
`14
`0-<1
`0-<1
`s.c. once weekly
`2 mg
`T2D
`15
`0
`0
`s.c. BID
`10 µg
`T2D
`16
`0
`0
`s.c. QD
`20 µg
`T2D
`17
`Results are expressed as percentages of patients from the treatment cohort who had the complication at least
`once during the period of the study. Values correspond to the minimum and maximum values reported when
`considering all the studies of the program. * One out of 6 studies recruited people with obesity and T2D as well.
`AP, acute pancreatitis; BID, twice a day; GI AEs, gastrointestinal adverse events; GLP-1 RA, GLP-1 receptor agonist;
`n.r., not reported; p.o., oral; Refs, references; s.c., subcutaneous; QD, once a day; T2D, diabetes mellitus type 2.
`
`6. Myths or Reality?
`When GLP-1 RAs started to be used, the first observations of certain occurrences led
`to misconceptions and erroneous conclusions regarding either the risks associated with the
`use of these drugs or the profiles of patients who would not benefit from these therapies.
`
`6.1. Impact of GI AEs on Weight Loss
`As previously stated, the most common GIs AEs included nausea, vomiting and
`diarrhoea. It has, therefore, been discussed whether the effects of GLP-1 RAs on weight
`loss are linked to these GI AEs. A study performed to assess whether or not there was a
`direct association between GI AEs and the extent of weight loss concluded that weight loss
`was largely independent of GI AEs [47,64].
`
`6.2. Patient Profiles Falsely Considered Unfit
`6.2.1. Patients with Eating Disorders
`Many of these patients can benefit from GLP-1 RA therapy even though their dietary
`habits are poor. For example, patients with binge eating disorder or night-eating syn-
`drome may benefit from GLP-1 RA therapy as long as they also receive proper psycholog-
`ical/psychiatric care. The exception are those patients with anorexia nervosa. GLP-1 RAs
`would also be contraindicated in patients with bulimia and self-induced vomiting until the
`psychiatric disorder was resolved using psychotherapy or pharmacologic means [65–67].
`Indeed, HCPs should take care to provide those patients with eating disorders who are going
`to start GLP-1 RA treatment with educational tips aimed at promoting a healthy lifestyle.
`
`6.2.2. Patients aged 75 Years Old or Older
`The reduced cardiovascular and renal morbimortality associated with the use of GLP-1
`RAs is beneficial for this particularly risky population [68–73]. Caution when using GLP-1
`RAs in older patients, especially those ≥75 years old, has been suggested to prevent the risk of
`sarcopenia. Although, as said above, weight loss induced by GLP-1 RAs comes mainly from
`reductions in fat mass rather than lean mass, nutritional advice and exercise programmes to
`achieve muscle strengthening are recommended to minimize sarcopenic risk [74].
`On the other hand, regarding the concern that GLP-1 RA doses indicated by the
`technical data sheet may be harmful to the elderly, it must be remarked that pivotal trials
`have repeatedly shown that the beneficial effects on weight loss and glycemic control
`can be achieved with no need to reach the recommended maintenance doses [9–17]. An
`intermediate dose may be considered as the maintenance dose in fragile patients, thus
`
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`minimizing risks associated with GI AEs. The Clinical Frailty Scale may sometimes be
`useful to guide dose adjustment [75]. Finally, it must be remarked that GLP-1 RAs may
`be particularly beneficial for older patients receiving insulin treatment. The improved
`glycaemic control achieved with the new medication will probably make it possible to
`reduce insulin doses, which could decrease the risk of hypoglycaemic events and the
`consequences associated with these.
`
`6.2.3. Patients with Upper Gastrointestinal Disease
`A r