GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment
Abstract
:1. Introduction
2. Background
3. Exploring the Multifaceted Impact of GLP-1RAs: Beyond Glycemic Control
3.1. Weight Reduction
3.2. Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis
Year & Study Author | Participants & Condition | Type of Study | Drug & Outcomes |
---|---|---|---|
2009; Jendle et al. [25] | 314 T2DM patients, 18–80 years, BMI ≤ 40 kg/m2 (LEAD-2), ≤45 kg/m2 (LEAD-3), HbA1c 7.0–11.0% | Randomized, double-blind, and parallel-group trials (LEAD-2 and LEAD-3), where the reduction in fat mass and hepatic steatosis was a primary outcome. | Liraglutide 1.8 mg/metformin: Significant increase in liver-to-spleen attenuation ratio, indicating reduced hepatic steatosis. |
2015; Tang et al. [26] | 35 T2DM patients inadequately controlled on metformin monotherapy or combination | Randomized study; insulin vs. liraglutide effects on liver fat were the primary outcome. | Insulin: Improved glycated hemoglobin (7.9% to 7.2%, p = 0.005), decreased liver MRI-PDFF (13.8% to 10.6%, p = 0.005), liver volume, and total liver fat index (304.4 vs. 209.3%·mL, p = 0.01). Liraglutide: Improved glycated hemoglobin (7.6% to 6.7%, p < 0.001), no significant change in liver MRI-PDFF, liver volume, or liver fat index. |
2015; Eguchi et al. [27] | 27 subjects with NASH and glucose intolerance, post lifestyle modification intervention. | Prospective, uncontrolled study; the impact on histological findings in NASH was a primary outcome. | After 24 weeks of liraglutide treatment at 0.9 mg/body per day, 19 subjects showed significant improvements in body mass index, visceral fat accumulation, aminotransferases, and glucose abnormalities. Six subjects who continued liraglutide for 96 weeks showed a decrease in histological inflammation as determined by NASH activity score and stage as determined by Brunt classification without significant adverse events. |
2016; Armstrong et al. [28] | 52 overweight patients with clinical evidence of non-alcoholic steatohepatitis. | Multicentre, double-blinded, randomized, placebo-controlled phase 2 trial; resolution of non-alcoholic steatohepatitis without worsening in fibrosis was a primary outcome. | 1.8 mg daily of liraglutide led to a resolution of definite non-alcoholic steatohepatitis in 39% of patients, compared with 9% in the placebo group (relative risk 4.3 [95% CI 1.0–17.7]; p = 0.019). A total of 2 (9%) of 23 patients in the liraglutide group versus 8 (36%) of 22 patients in the placebo group had fibrosis progression. Adverse events were mostly mild to moderate, with gastrointestinal disorders being more common in the liraglutide group. |
2016; Dutour et al. [29] | 44 obese subjects with T2DM uncontrolled on oral antidiabetic drugs. | Prospective randomized clinical trial; hepatic and epicardial fat reduction was a primary outcome. | Exenatide treatment resulted in significant weight loss (−5.3 ± 0.4 kg; p = 0.001 for the difference between groups) and a decrease in epicardial adipose tissue (EAT) (−8.8 ± 2.1%) and hepatic triglyceride content (HTGC) (−23.8 ± 9.5%), compared with the reference treatment (EAT: +1.2 ± 1.6%; HTGC: +12.5 ± 9.6%; p = 0.003 and p = 0.007, respectively). No significant change in myocardial triglyceride content (MTGC) was observed. |
2016; Armstrong et al. [21] | 14 NASH patients | Double-blind, randomized, placebo-controlled trial; the effect on insulin sensitivity, hepatic lipid handling, and adipose dysfunction was a primary outcome. | Liraglutide treatment led to a reduction in BMI (−1.9 vs. +0.04 kg/m2; p < 0.001), HbA1c (−0.3 vs. +0.3%; p < 0.01), LDL cholesterol (−0.7 vs. +0.05 mmol/L; p < 0.01), and ALT (−54 vs. −4.0 U/L; p < 0.01). It also increased hepatic insulin sensitivity and decreased endogenous glucose production (p < 0.05), increased adipose tissue insulin sensitivity (p < 0.05), and inhibited lipolysis and de novo lipogenesis (both p < 0.05) in vivo and in primary human hepatocytes. |
2017; Seko et al. [30] | 15 biopsy-proven NAFLD patients with T2DM refractory to diet intervention. | Retrospective study; the effectiveness of dulaglutide in NAFLD patients with T2DM was the main focus, implying it was a primary outcome. | Dulaglutide (0.75 mg for 12 weeks) significantly reduced body weight, hemoglobin A1c, transaminase activities, total body fat mass, and liver stiffness. |
2017; Khoo et al. [23] | Non-diabetic Asian adults with NAFLD; BMI ≥ 30 kg/m2, mean weight 96.0 ± 16.3 kg | Randomized study; comparing liraglutide and lifestyle intervention on NAFLD was a primary outcome. | Both the liraglutide group (3 mg daily) and the diet/exercise group saw similar and significant weight reductions (−3.5 ± 3.3 kg vs. −3.5 ± 2.1 kg, respectively, p = 0.72) and liver fat fraction decreases (−8.9 ± 13.4% vs. −7.2% ± 7.1%, p = 0.70). Changes in serum alanine aminotransferase (−42 ± 46 vs. −34 ± 27 U/L, p = 0.52) and aspartate aminotransferase (−23 ± 24 vs. −18 ± 15 U/L, p = 0.53) were not statistically significant. |
2019; Newsome et al. [31] | Subjects with obesity and/or T2DM at risk of NAFLD. | Data from a 104-week cardiovascular outcomes trial and a 52-week weight management trial; effect on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) as primary outcomes. | In the weight management trial of patients with elevated baseline ALT, semaglutide led to end-of-treatment ALT reductions of 6–21% (p < 0.05 for doses ≥0.2 mg/day) and hsCRP reductions of 25–43% vs. placebo (p < 0.05 for 0.2 and 0.4 mg/day). Normalization of elevated baseline ALT occurred in 25–46% of weight management trial subjects vs. 18% on placebo. In the cardiovascular outcomes trial, no significant ALT reduction was noted at 0.5 mg/week. A reduction was observed at this dose at week 30 but was not sustained to week 56, while a 9% reduction vs. placebo was seen at 1.0 mg/week (p = 0.0024). |
2020; Teshome et al. [32] | 590 participants with non-alcoholic fatty liver disease (NAFLD). | Systematic review; the study compiled data from randomized controlled trials, single-arm trials, and cohorts. | GLP-1 analogs led to decreased serum transaminases, improved liver histology and insulin resistance, reduced body weight, and normalized liver enzymes. Specifically, ALT, AST, and GGT decreased by 5.5%, 59.5%, 52.8%, and 44.8%, respectively, and there was a reduction in proinflammatory cytokines and an enhancement of protective adipokines noted in some studies. |
3.3. Neurodegenerative Applications of GLP-1RAs
3.4. Cardiovascular Implications of GLP-1RAs
4. GLP-1RA-Associated Side Effects and Potential Concerns
4.1. Gastrointestinal Impact of GLP-1 Receptor Agonists
4.2. Pancreatic Concerns
4.3. Concern for Thyroid Neoplasms
4.4. Cardiovascular Implications
4.5. Endocrinological and Glycemic Considerations
4.6. Allergenic and Immune Responses
4.7. Musculoskeletal Implications
4.8. Dermatological Implications
4.9. Renal Concerns
4.10. Facial Implications
4.11. Implications of Overdose
5. Management of Gastrointestinal Adverse Events: “The Three E’s”
6. Safety and Tolerability of GLP-1RAs
Official Statements Regarding Endoscopic Procedure Precautions
7. Alternative Non-GLP-1-RA Approaches to Weight Loss
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug Name | Approval Date & Use(s) | Dosing and Administration | Key Precautions and Side Effects | Clinical and Post-Marketing | Use in Populations and Conclusion |
---|---|---|---|---|---|
Albiglutide (Tanzeum/Eperzan) [7,8] |
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|
|
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Dulaglutide (Trulicity) [9] |
|
|
|
|
|
Exenatide (Byetta/Bydureon) [10] |
|
|
|
|
|
Liraglutide (Victoza, Saxenda) [11,12] |
|
|
|
|
|
|
|
|
|
| |
Lixisenatide (Adlyxin) [13,14] |
|
|
|
|
|
Semaglutide (Ozempic/Rybelsus/Wegovy) [14] |
|
|
|
|
|
|
|
|
|
|
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© 2024 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/).
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Wan, J.; Ferrari, C.; Tadros, M. GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment. Gastroenterol. Insights 2024, 15, 191-212. https://doi.org/10.3390/gastroent15010014
Wan J, Ferrari C, Tadros M. GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment. Gastroenterology Insights. 2024; 15(1):191-212. https://doi.org/10.3390/gastroent15010014
Chicago/Turabian StyleWan, Justin, Caesar Ferrari, and Micheal Tadros. 2024. "GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment" Gastroenterology Insights 15, no. 1: 191-212. https://doi.org/10.3390/gastroent15010014