GLP-1RA-Associated Side Effects and Potential Concerns: Comparison
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Amidst the obesity and type II diabetes mellitus (T2DM) epidemics, glucagon-like peptide-1 receptor agonists (GLP-1RAs) stand out as a promising therapeutic ally, achieving notable success in glycemic control and weight management. While GLP-1RAs’ positive clinical outcomes are commendable, they introduce significant gastrointestinal (GI) challenges, emphasizing the pivotal role of gastroenterologists in understanding and managing these implications. Physicians should be vigilant of potential complications if endoscopy is indicated and considered.

  • GLP-1RA
  • T2DM
  • side effects
  • gastrointestinal
  • pancreatic
  • thyroid neoplasms
  • dermatological
  • renal
  • facial

1. Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are synthetic hormones significant in managing T2DM and obesity, offering marked reductions in blood sugar and body weight with a minimal risk of hypoglycemia. As these drugs gain popularity in the U.S. for their “shortcut to fitness” appeal, gastroenterologists must grasp their gastrointestinal effects and broader implications. Prescribing physicians must be well informed about their use, action, dosing, side effects, and management of complications to safely guide patients who are attracted to this weight loss trend. Moreover, given the wide-reaching effects of GLP-1-RAs due to the prevalence of receptors on various organs, they can contribute to weight reduction and increased insulin sensitivity. Still, they may also cause unintended side effects, including nausea and potential undetermined cancer risks.

2. Gastrointestinal Impact of GLP-1 Receptor Agonists

Clinical investigations into GLP-1RAs ubiquitously report gastrointestinal disturbances as a principal side effect, significantly embodying nausea and diarrhea and, to a lesser extent, vomiting, constipation, abdominal pain, and dyspepsia [41,42,43,44][1][2][3][4]. The onset of such side effects predominantly emerges conspicuously during the initiation and up-titration of treatment, demonstrating a potential dose- and class-effect dependency, with nausea disturbing up to 50% of patients [45,46,47][5][6][7]. The delay in gastric emptying and peaks of the GLP-1 effect with short-acting formulations have been hypothesized as causative agents for the pervasiveness of nausea [48,49][8][9]. Notably, gastrointestinal side effects, particularly constipation, may linger despite a general attenuation over time and are seemingly less frequent with long-acting GLP-1RAs [6,47][7][10]. Gastrointestinal (GI) disturbances are common adverse effects associated with semaglutide. In phase 3 trials, subcutaneous semaglutide induced nausea in 11.4 to 20%, vomiting in 4 to 11.5%, and diarrhea in 4.5 to 11.3% of patients [50,51,52,53][11][12][13][14]. The incidence of GI disturbances was higher in the SUSTAIN 6 trial, which included older patients with comorbid conditions [53][14]. For oral semaglutide, the occurrence rates were 5.1 to 23.2% for nausea, 2.9 to 9.9% for vomiting, and 5.1 to 15% for diarrhea during the on-treatment period [54,55,56][15][16][17]. In a phase 2 trial, the total amount of GI disturbances was similar for oral and subcutaneous semaglutide (56% vs. 54%), with nausea occurring in 34% vs. 32%, vomiting in 16% vs. 9%, and diarrhea in 20% vs. 14% [57][18]. Higher doses of semaglutide are associated with more frequent GI adverse effects, which has led to the recommendation of a dose escalation scheme starting with a low dose [57][18]. GI complaints are the primary adverse-event-related cause of drug discontinuation in phase 3 trials, with rates up to 12%. Approximately 10% of patients will discontinue semaglutide because of GI complaints, which may be slightly higher than other GLP-1 analogs [58][19]. The analysis of GLP-1 dose groups revealed a significant increase in the likelihood of experiencing nausea, vomiting, and diarrhea compared to placebo and conventional treatment (CT). Exenatide 10 μg twice daily (EX10BID) exhibited the highest odds ratio (OR) and incidence for nausea (OR 2.89–6.10, 37.13%) and vomiting (13.13%), significantly surpassing placebo (nausea 9.36%; vomiting 2.01%). A dose–response relationship was observed for nausea and vomiting, with EX10BID posing the highest risk. The risk of both nausea and vomiting decreased for 26 weeks. For diarrhea, all GLP-1 dose groups had a significantly worse impact than placebo and CT, with the highest incidences observed in liraglutide 1.8 mg once daily (LIR1.8, 12.52%), exenatide 2 mg once weekly (EX2QW, 12.09%), and liraglutide 1.2 mg once daily (LIR1.2, 11.94%) [59][20]. In a study of 1842 patients with T2DM (T2D), participants were divided into three groups to receive different doses of dulaglutide: 1.5 mg, 3.0 mg, and 4.5 mg [60][21]. The 3.0 mg and 4.5 mg doses were more effective in lowering HbA1c than the 1.5 mg dose. Gastrointestinal (GI)-related symptoms like nausea, diarrhea, and vomiting were the most common treatment-emergent adverse events (TEAEs) [60][21]. The highest incidence of new-onset GI symptoms occurred within the first two weeks of initiating the 0.75 mg dose, declining by over 50% afterward. Most GI TEAEs were mild, with less than 1% of participants experiencing severe events. Few patients discontinued the study drug due to GI adverse events (1.4% for nausea, 0.7% for vomiting, and 0.7% for diarrhea). Significant interactions were observed between female and male subgroups concerning nausea and diarrhea, with females experiencing higher incidences of nausea across all dose groups and males demonstrating higher incidences of nausea and diarrhea in the 3.0 mg and 4.5 mg groups compared to the 1.5 mg group [61][22]. Patients experiencing GI disturbances can be counseled to eat slowly with reduced portions per meal, avoid high-fat foods, and consider anti-emetic therapy. However, long-term data are unavailable for the latter [62][23]. The mechanisms behind nausea/vomiting and diarrhea induced by GLP-1RAs are incompletely understood but may include effects on gastric emptying, the central nervous system, nutrient absorption, and intestinal motility [63,64,65,66,67,68,69][24][25][26][27][28][29][30]. Furthermore, nausea induced by GLP-1RAs is linked to weight loss in some studies, although the relationship is not consistent across all trials [67,68,69][28][29][30].

3. Pancreatic Concerns

GLP-1RAs have insinuated concerns regarding pancreatic integrity. Animal studies and clinical evaluations illustrating elevated pancreatic enzymes have spotlighted potential inflammatory responses and pancreatitis [70,71,72,73,74,75][31][32][33][34][35][36]. Despite these apprehensions, numerous studies and meta-analyses have contested establishing a direct causative relationship between GLP-1RAs and pancreatitis, presenting a nuanced perspective on its pancreatic safety [76,77,78][37][38][39]. Concerns about the possible association between GLP-1-RAs and neoplasm emergence have prompted investigators to research the incidence of thyroid and pancreatic neoplasms amongst patients being treated with GLP-1-RAs. A 2011 analysis of FDA databases from 2004 to 2009 found that while both the FDA and EMA assert that concerns of a causal association between incretin-based drugs and pancreatic cancer are inconsistent with current data, thyroid and pancreatic cancer were reported more frequently in patients treated with exenatide than with rosiglitazone [79][40]. A real-world study by Yang et al. (2022) [4][41] utilized data from the FDA Adverse Event Reporting System (FAERS) between 2004 and 2021 and found that the proportional reporting ratios (PRRs) for malignant pancreatic neoplasms related to GLP-1-RA therapy were greater than 2. The PRR compares the ratio of neoplasms formed under therapy with GLP-1-RAs with those formed under comparator therapy; PRRs equal to one signify that GLP-1RA-associated neoplasms were reported as frequently as comparator-associated neoplasms. The study found that in cases with malignant pancreatic neoplasms, about half of these cases were associated with the combination use of GLP-1-RAs with DPP-4 inhibitors; the PRR tended to increase when this combination therapy was utilized. It is proposed that using DPP-4 inhibitors significantly prolongs the half-life of GLP-1-RAs, allowing enhanced β-cell proliferation, inhibiting apoptosis, and increasing the risk of tumor formation.

4. Concern for Thyroid Neoplasms

While studying the incidence of pancreatic neoplasms, Yang et al. (2022) found that the PRRs for benign and malignant thyroid neoplasms associated with GLP-1-RAs were greater than three and five, respectively. Proposed explanations for this apparent increase in PRR for thyroid neoplasms obfuscate the strength of the association between GLP-1-RA therapy and neoplasm formation. Amongst patients with thyroid neoplasms, Synthroid was the second most common combined drug identified, suggesting that these patients were being treated for hypothyroidism. A 2020 meta-analysis reported that hypothyroidism was associated with a higher risk of thyroid cancer within the first 10 years of follow-up. In addition, the International Agency for Research on Cancer (IARC) found that increased screening for thyroid cancer has directly resulted in an increased incidence of thyroid cancer across 25 countries. This is further compounded by the FDA’s issue of a warning that GLP-1-RA use may increase the risk of medullary thyroid cancer, causing reporters to attribute more thyroid cancers to GLP-1-RA use and patients undergoing GLP-1-RA treatment to proactively seek thyroid ultrasounds, resulting in increased detection of thyroid neoplasms [4][41]. Meanwhile, the PRR for other neoplasms, including respiratory and mediastinal, breast, most male and female reproductive, bone and skin soft tissue, nervous system, ocular, and hematologic, was less than 1 [4][41].

5. Cardiovascular Implications

In the cardiovascular domain, GLP-1RAs have not denoted an elevation in cardiovascular events; nevertheless, a subtle but potentially clinically pertinent augmentation in heart rate has been associated with their administration [80,81,82,83,84][42][43][44][45][46]. Selected GLP-1RAs, including exenatide, liraglutide, and albiglutide, have not manifested significant alterations in the QTc interval, offering a degree of cardiovascular reassurance [85][47].

6. Endocrinological and Glycemic Considerations

GLP-1RAs, when co-administered with metformin, do not exacerbate clinically relevant hypoglycemic events [86,87,88][48][49][50]. Contrastingly, their combination with sulphonylurea or insulin reveals a noticeable increment in hypoglycemic incidences, attributed to the potential uncoupling of GLP-1’s insulinotropic effect from its glucose dependence [89,90,91][51][52][53]. This underscores the advisability of modulating sulphonylurea or insulin dosages upon GLP-1RA initiation [92][54].

7. Allergenic and Immune Responses

Diverging into the immunogenic milieu, GLP-1RAs and synthetic peptides can engender antibody formation, presenting a spectrum of immunogenicity [93,94,95,96,97][55][56][57][58][59]. Despite the perceivable risk of hypersensitivity, re-exposure to agents such as exenatide did not elevate hypersensitivity occurrences [98][60]. Although rare, severe anaphylactic responses have been documented in post-marketing, stipulating prudent monitoring and management of hypersensitivity phenomena [93,94,95][55][56][57].

8. Musculoskeletal Implications

A notable dichotomy exists between various GLP-1RAs regarding skeletal impacts, where liraglutide demonstrates a risk reduction for bone fractures, whereas exenatide evidences an elevation in such risk [99][61]. Comparatively, studies involving exenatide twice daily and insulin glargine once daily exhibited no substantial modulation in bone mineral density or select serum markers [100][62].

9. Dermatological Implications

GLP-1 receptor agonists (GLP-1RAs) manifest dermatological side effects predominantly at injection sites, with common occurrences of rash, erythema, and itching, particularly with long-acting formulations [93,96,97,100][55][58][59][62]. Exenatide once weekly has been associated with the emergence of small, transient bumps, while isolated reports connect it with panniculitis and other dermatological issues like hyperhidrosis, alopecia, and certain rashes [93,100,101][55][62][63].

10. Renal Concerns

The intersection between GLP-1RAs, notably exenatide, and renal functionality has been scrutinized, with correlations drawn to acute kidney injury, often propelled by side effects like nausea, vomiting, and dehydration [102,103][64][65]. Detailed renal examinations have unearthed ischemic glomeruli and diabetic nephropathy [104][66], with other potential contributors being GLP-1-induced natriuresis and diminished renal perfusion [105][67]. Nevertheless, contrasting analyses have deemed renal issues as seldom and not distinctively divergent from comparators [106,107][68][69]. Practitioners must heed acute renal failure risks, especially in volume contraction scenarios [102][64].

11. Facial Implications

The exploration of GLP-1 receptor agonists, notably Ozempic, reveals an intriguing yet often under-discussed aesthetic concern known as the “Ozempic face.” This phenomenon manifests as a marked, gaunt appearance of the face, resulting from a swift depletion of facial fat, collagen, and elastin, amplifying the visibility of wrinkles and auguring skin sag [108][70]. Not universally documented in clinical trials, this accelerated facial aging confronts plastic surgeons with a unique challenge, necessitating specialized approaches to mitigate these potent aesthetic and potentially psychological changes amidst the enduring popularity of the medication [109][71]. Offering solutions that span from minimally invasive fillers to more substantial surgical interventions, surgeons must also navigate the intricacies of nutritional aspects and their influence on pre- and post-operative recovery [110][72]. Thus, it becomes imperative for facial plastic surgeons to immerse themselves in the particulars of Ozempic and related semaglutide products, considering their aesthetic repercussions and perioperative considerations while transparently communicating potential side effects to those contemplating their use.

12. Implications of Overdose

Overdose with GLP-1RAs, while documented, typically precipitates symptoms like nausea, vomiting, and abdominal pain without hypoglycemia, even in cases of substantial overdose [111,112,113][73][74][75]. Therapeutic intervention in these instances leans predominantly towards supportive care.

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