Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus
Abstract
:1. Introduction
2. Methods
3. AEs Most Frequently Associated with GLP-1 RAs
4. Practical Guide to Follow When Initiating Treatment with GLP-1 RAs
4.1. Patient Education Prior to GLP-1 RA Start
4.2. Overall Procedures
- 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]:
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- Extend the dose escalation phase duration (2–4 more weeks with the previous dose or temporary suspension).
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- Avoid dose escalation while GI AEs persist.
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- 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.
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- 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.
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- Withhold treatment temporarily until the resolution of AEs and then resume treatment.
- Start a differential diagnosis procedure to rule out underlying conditions causing the symptoms or their exacerbation [35].
- 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
- ○
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- 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
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- Maintaining hydration is particularly important.
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- Small amounts of food should be taken in more frequent meals.
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- Consider anti-emetic and/or prokinetic medications. Domperidone should be used rather than metoclopramide, as explained above [47].
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- 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.
4.3.3. Diarrhoea
4.3.4. Constipation
5. Uncommon AEs
6. Myths or Reality?
6.1. Impact of GI AEs on Weight Loss
6.2. Patient Profiles Falsely Considered Unfit
6.2.1. Patients with Eating Disorders
6.2.2. Patients aged 75 Years Old or Older
6.2.3. Patients with Upper Gastrointestinal Disease
7. Clinical Scenarios of Interest
8. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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GLP-1 RA | Program | Refs | Patient Profile | Dose | Method of Administration | Nausea | Vomiting | Diarrhoea | Constipation |
---|---|---|---|---|---|---|---|---|---|
Semaglutide | SUSTAIN | 9 | T2D | 1 mg | s.c. once weekly | 15–24 | 7–15 | 7–19 | 4–7 |
Semaglutide | STEP | 10 | Obesity * | 2.4 mg | s.c. once weekly | 14–58 | 22–27 | 10–36 | 12–37 |
Semaglutide | PIONEER | 11 | T2D | 14 mg | p.o. SID | 8–23 | 6–12 | 5–15 | 7–12 |
Liraglutide | LEAD | 12 | T2D | 1.8 mg | s.c. SID | 10–40 | 4–17 | 8–19 | 11 |
Liraglutide | SCALE | 13 | Obesity * | 3 mg | s.c. SID | 27–48 | 7–23 | 16–26 | 12–30 |
Dulaglutide | AWARD | 14 | T2D | 1.5 mg | s.c. once weekly | 15–29 | 7–17 | 11–17 | n.r. |
Exenatide | DURATION | 15 | T2D | 2 mg | s.c. once weekly | 5–14 | <1–6 | 5–11 | 1–8 |
Exenatide | — | 16 | T2D | 10 µg | s.c. BID | 35–59 | 9–14 | 4–9 | 5 |
Lixisenatide | GETGOAL | 17 | T2D | 20 µg | s.c. SID | 16–40 | 7–18 | 4–12 | 5† |
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 |
GLP-1 RA | Program | Refs | Target Patient | Dose | Administration | Cholelithiasis | AP |
---|---|---|---|---|---|---|---|
Semaglutide | SUSTAIN | 9 | T2D | 1 mg | s.c. once weekly | 0–2 | 0-<1 |
Semaglutide | STEP | 10 | Obesity * | 2.4 mg | s.c. once weekly | <1–3 | 0-<1 |
Semaglutide | PIONEER | 11 | T2D | 14 mg | p.o. QD | 0-<1 | 0-<1 |
Liraglutide | LEAD | 12 | T2D | 1.8 mg | s.c. QD | 0 | 0-<1 |
Liraglutide | SCALE | 13 | Obesity * | 3 mg | s.c. QD | <1–1 | 0-<1 |
Dulaglutide | AWARD | 14 | T2D | 1.5 mg | s.c. once weekly | 0 | <1 |
Exenatide | DURATION | 15 | T2D | 2 mg | s.c. once weekly | 0-<1 | 0-<1 |
Exenatide | — | 16 | T2D | 10 µg | s.c. BID | 0 | 0 |
Lixisenatide | GETGOAL | 17 | T2D | 20 µg | s.c. QD | 0 | 0 |
Scenario 1. Persistent Nausea in Middle-Aged Patients |
---|
Female patient, 52 y.o., T2D, 6 years’ duration on metformin treatment. The patient starts oral semaglutide 3 mg OD without having received guidelines to prevent GI AEs. Four weeks later, the dose is increased to 7 mg OD, and 4 weeks later, to 14 mg OD. Since then, occasional intense episodes of nausea associated with eating large meals that include fatty foods occur. The dose is maintained at 14 mg OD for 2 months, at the end of which HbA1c improves from 7.8% to 7.3% and weight decreases by 3.7 kg (BMI 29.7 kg/m2), but nausea episodes persist. |
Recommended clinical decision |
|
Follow-up |
The patient begins to apply the diet and lifestyle recommendations and starts taking domperidone before main meals. After 4 days, domperidone is not required anymore. Three months afterward, the patient reports decreased appetite without nausea. Additional decreases in HbA1c (6.8%) and weight (7% of the initial one, BMI 28.9 kg/m2), are achieved. |
Comment |
Before starting treatment with GLP-1 RA, the patient has to receive information on dietary recommendations to prevent GI AEs. If, even after applying these measures, the patient experiences nausea, temporary anti-emetic and/or prokinetic medications may be useful. |
Scenario 2. Heartburn after GLP1-RA up-titration |
Male patient, 63 y.o., BMI 34.5 kg/m2, with a history of gastroesophageal reflux subsequent to hiatal hernia treated with alkaline salts and with PPIs (omeprazole) for large meals. The patient comes to consultation to manage obesity. Liraglutide treatment is started following the recommended dose-escalation protocol, with weekly dose increases. When 1.8 mg OD is reached, the patient reports gastrointestinal symptoms after meals, namely postprandial heaviness, frequent eructation and heartburn, especially before bedtime. |
Recommended clinical decision |
|
|
|
Follow-up |
Shortly after following the advised habits and pharmacological treatment, gastroesophageal reflux symptoms notably improved. After 2 weeks of maintaining liraglutide at 1.8 mg OD, dose-escalation is resumed at 2-week intervals, until the maximum effective dose of 3 mg OD is reached. Six months after treatment start, weight loss is 8.2% (BMI 31.7 kg/m2). |
Comment |
Gastroesophageal reflux is common in obesity. GLP-1 RAs have occasionally been described to exacerbate its symptoms, possibly because of the transient delay in gastric emptying subsequent to treatment initiation [78,79]. Suitable diet habits and PPI use are usually enough to relieve symptoms. Furthermore, these improve as weight decreases. Thus, there is no need to keep pharmacological support for a long time. |
Scenario 3. Elderly patients with GI AEs subsequent to GLP-1 RA initiation |
Female patient, 80 y.o., 98 kg, BMI 39.2 kg/m2, T2D with HbA1c 7.2%. The current treatment is metformin 850 mg BID/sitagliptin 100 mg OD. Weight loss is required before knee prosthesis placement. Previous attempts were unsuccessful. Sitagliptin is suspended and s.c. semaglutide is started, escalating doses every 4 weeks. When 0.5 mg/wk is reached, moderate to severe GI AEs appear (persistent nausea, postprandial vomiting several times a week, pronounced hyporexia). Symptoms persist for 2 months. Three months after semaglutide start, weight loss is 14 kg; the patient reports overall weakness and sarcopenia is diagnosed according to chair stand and timed-up-and-go tests, dinamometry and bioelectrical impedance analysis. |
Recommended clinical decision |
|
|
Follow-up |
Semaglutide is maintained at 0.25 mg/wk, and GI AEs are not reported. Sarcopenia tests improve in 2 months. After 6 months, patient weight is 82 kg (BMI 32.8 kg/m2), and HbA1c decreases to 5.9%. Knee surgery is undertaken with no complications. |
Comment |
Obesity is common in the elderly, with GI AE onset being earlier and more severe. The scarce experience with GLP-1 RA in >75 y.o. patients invites us to start low and go slow. Sarcopenia risk must be assessed before and during GLP-1 RA treatment since the sharp weight loss in the elderly may be in part at the expense of lean mass [80,81]. |
Scenario 4. Insulin-treated elderly people with T2D, obesity and CKD |
Male patient, 76 y.o., BMI 32.0 kg/m2, poorly controlled T2D (HbA1c 8.9%), retinopathy and autonomic neuropathy, CKD with eGFR 25 mL/min/1.73 m2 and albumin-to-creatinine ratio 658 mg/g. The treatment consisted of linagliptin, dapagliflozin, atorvastatin and antihypertensive drugs. Baseline s.c. insulin degludec 0.2 U/kg before breakfast is started. Three months later, HbA1c is 7.5%. Linagliptin is suspended and s.c. semaglutide 0.25 mg/wk is started. The dose is increased to 0.5 mg/wk one month later. Two weeks later, the patient presents with 4–5 daily episodes of diarrhoea regardless of food composition. |
Recommended clinical decision |
|
|
|
Follow-up |
Four months after semaglutide dose is set at 0.5 mg/wk, metabolic and CKD parameters improve (HbA1c 6.1%, albumin-to-creatinine ratio 310 mg/g), and BMI decreases to 28.0 kg/m2. No new GI AEs are reported. The patient did not require insulin treatment. |
Comment |
Semaglutide exposure is not influenced by renal impairment [83], and thus it is a suitable choice for T2D patients with CKD and obesity. CKD and autonomic neuropathy cause gastroparesis, thus increasing GI AE risk. CKD increases the risk of GLP-1 RA-associated diarrhoea, with symptoms being more severe with albuminuria [84]. Despite GI AEs may be frequent in the first weeks, attempts to alleviate symptoms are worthwhile: withdrawal risk decreases; thus, patients benefit from cardiorrenal protection and efficient metabolic control, which may allow reducing the intensity of insulin treatment, thus minimizing hypoglycaemia risk [82]. |
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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
Gorgojo-Martínez JJ, Mezquita-Raya P, Carretero-Gómez J, Castro A, Cebrián-Cuenca A, de Torres-Sánchez A, García-de-Lucas MD, Núñez J, Obaya JC, Soler MJ, et al. Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. Journal of Clinical Medicine. 2023; 12(1):145. https://doi.org/10.3390/jcm12010145
Chicago/Turabian StyleGorgojo-Martínez, Juan J., Pedro Mezquita-Raya, Juana Carretero-Gómez, Almudena Castro, Ana Cebrián-Cuenca, Alejandra de Torres-Sánchez, María Dolores García-de-Lucas, Julio Núñez, Juan Carlos Obaya, María José Soler, and et al. 2023. "Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus" Journal of Clinical Medicine 12, no. 1: 145. https://doi.org/10.3390/jcm12010145