Glucagon-like Peptide-1 Receptor Agonists: Are They as Good as They Seem? A Systematic Review of Severe Adverse Effects

Abstract

As obesity evolves as a global pandemic, the use of drugs to treat it is booming. The latest among these are Glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Along with their use, the incidence of adverse events has become more common. Although severe effects have been mentioned, details and associations are unclear regarding some of them. We performed a systematic review of studies related to GLP-1 RA drugs. Drugs that have been the subject of at least three studies meeting all our criteria were included. Analysis of GLP-1 RA therapies across eight studies, involving 4422 subjects, indicated varying rates of Serious Adverse Events (SAEs). Semaglutide demonstrated an SAE incidence of 8.9%, compared to 6.2% for Liraglutide. These results were not statistically significant. For both drugs, no clear association with pancreatitis or neoplasm was established. Discontinuation rates due to adverse effects were 10.3% for Semaglutide and 8.3% for Liraglutide. Severe adverse effects with GLP-1 RA use are not uncommon, and warrant further close monitoring when patients are started on treatment. Further studies are required to analyze the difference between the adverse effect profiles of each drug and to assess whether or not each of these severe adverse effects is dose dependent.

1. Background

The American Diabetes Association has recommended Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as a first line of treatment for patients with type 2 diabetes mellitus and those who are at high risk for development of atherosclerotic cardiovascular disease (ASVD) [1]. This class of medications inhibits Glucagon secretion, decreasing gastric emptying, which leads to an indirect benefit of significant weight loss in patients using this medication. As a result, the use of GLP-1 agonists has dramatically increased, despite a lack of research regarding their long-term safety and tolerability. Previous systematic reviews have reported significant adverse effects of this medication class affecting various organ systems [2].

The first FDA approval of a GLP-1 RA was in 2005, for the drug Exenatide. Since then, this drug class has undergone substantial transformation, both in its usage and recognition. The most famous in this class is Semaglutide, commonly known as Ozempic. Its phase 2 trials started in 2008 [3], phase 3 in 2016, and it was FDA approved in 2017. The recognition of this drug and its prescription has since experienced a parabolic trajectory. As the drug is relatively new, the general population and healthcare providers remain oblivious to the side-effect profile of medications in this class.

In the past few decades, the world has witnessed a growing pandemic of diabetes, cardiovascular disease, and obesity. Modern lifestyles and facilities render themselves to excessive weight gain, with persistent pressure for weight loss and improving physique [4]. GLP-1 RAs have become the new opium for the masses. Initially introduced as anti-diabetic drugs, there has been a significant increase in their popularity among patients with cardiac issues and obesity. These drugs have proven to have numerous benefits. They result in improved glycemic control, metabolic parameters, cardiovascular mortality, and composite outcomes in patients with kidney disease [5]. These benefits seem to exceed superficial parameters and reach more basic pathophysiologic parameters, like improvement in endothelial dysfunction, inflammatory markers, subclinical atherosclerosis, and even genetic expressions, among others [6,7,8]. As the use of these drugs increases across a wide patient population, we expect to see an increasing number of side effects as well. We aimed to complete a comprehensive review of myriad studies undertaken with different medications in this class, throughout the world, and prepare a more compressive database to better understand their side effects and the incidents thereof.

2. Materials and Methods

Our systematic review adhered to PRISMA guidelines. This systematic review was also registered on PROSPERO [9].

2.1. Study Design

This was a systematic review and meta-analysis of studies related to GLP-1 RA drugs. Details about these studies are listed below. Drugs that were the subject of at least three studies meeting all our criteria were included.

A pre-print version of this paper is available at SSRN pre-prints [10].

2.2. Search Strategy

A comprehensive systematic literature search was performed on PubMed. The initial search was performed using the terms “GLP-1 agonist”, “Glucagon-like peptide-1 receptor agonist”, “Semaglutide”, “Liraglutide”, “Dulaglutide”, “side effects”, “adverse effects”, “adverse reactions”, “randomized controlled trial”, and “clinical trial”. Studies published in the last 15 years were included.

2.3. Eligibility Criteria

We included studies with subjects aged 18 years and older. Studies that included details regarding adverse effects were included in the initial screening. Subsequently, published studies that involved subjects on different oral antihyperglycemics and/or insulin were excluded.

2.4. Study Selection

All 275 studies from the search were exported to Rayyan online software (https://www.rayyan.ai/, accessed on 31 March 2024). We searched for duplicate studies, and none were found. These 275 studies were divided among four reviewers. Reviewers were divided into groups of two, and two reviewers screened each study to determine its eligibility. Conflicts regarding a study’s inclusion were resolved with a detailed review by a third reviewer. Initially, titles and abstracts were screened. Subsequently, full texts of studies were reviewed. Each study was reviewed at least twice. Initially, 110 studies were selected. Further, studies that included multiple oral hypoglycemics were excluded. Thereafter, studies in which there were no exportable data regarding side effects of medications were excluded. In order to perform a systematic review and data analysis, drugs that were the subject of less than three studies with a placebo arm were excluded. Finally, eight studies were selected for systematic review (Figure 1).

2.5. Data Extraction

Full texts of studies, including supplements, were reviewed.

2.6. Statistical Analysis

Statistical analysis was performed using RevMan 5.4.1 software. Dichotomous outcomes are presented as odds ratios and continuous outcomes as mean differences with 95% confidence intervals. A p value < 0.05 was considered statistically significant.

3. Results

3.1. Outcomes

A total of 4422 subjects were included in the GLP-1 RA group, while 1906 were in the placebo group, including all eight studies. Serious Adverse Events (SAEs) related to therapy were analyzed. The incidence of SAEs of medications was about 8.9% for Semaglutide and 6.2% for Liraglutide (excluding those who discontinued a study due to AEs). The demographics of the study population are mentioned below (Table 1).

3.2. Analysis of SAEs of Semaglutide

In total, 1757 participants from four studies were included in the systematic review and meta-analysis. Of these, 1245 subjects received Semaglutide, while 512 received a placebo. The mean duration of trials was about 388 days. Among participants treated with Semaglutide, the risk of having an SAE was found to be higher, with an odds ratio (OR) = 1.27, but it did not have statistical significance (95% CI 0.84–1.91, p = 0.26, I² = 63%) (Figure 2). In a sensitivity analysis, after removing the study of Garvey et al. [11], which carried a significant weight in the original analysis (39.8%), results indicated further increased risk of SAEs in groups treated with Semaglutide, which did not reach statistical significance, with an OR = 1.68 (95% CI 1.0–2.8; p = 0.05, I² = 56%) (Figure 3).

Discontinuation Rate: It was also noted that 129 (10.3%) participants using Semaglutide had to discontinue treatment due to adverse effects, as opposed to 16 (3.1%) participants taking a placebo (Table 2). As it was not clear if these incidents were included or excluded in each study under SAEs, or if they were in fact SAEs, they were excluded from the statistical analysis.

3.3. Analysis of SAEs of Liraglutide

In total, 3132 subjects received Liraglutide and 1478 were in placebo groups. Patients in Liraglutide groups had an increased risk of SAEs, with an OR of 1.19 (95% CI 0.91–1.55, I² = 40%). This result was not significant (p = 0.21) (Figure 4). A sensitivity analysis was performed after removing the study by Pi-Sunyer et al. [12], which carried about 77% weightage on initial analysis, in which the risk of SAEs was not different, with an OR of 0.95 (95% CI 0.53–1.71, p = 0.86, I² = 54%) (Figure 5).

Upon detailed evaluation of included studies, it was noted that these SAEs were mainly related to the gastrointestinal (GI) system. In addition to nausea and vomiting, cholelithiasis was the major AE of this medication. The incidence of SAEs was at least 5%, and ranged up to 20% in these studies.

Discontinuation Rate: In addition, it was noted that 256 (8.3%) subjects in Liraglutide groups and 50 (3.3%) subjects in placebo groups discontinued study participation due to AEs (Table 2).

The difference in incidence of discontinuation in these studies was significant, but not included in analysis given the ambiguity of data, as subjects may have withdrawn from a study due to a perceived AE, which in reality was not an SAE, but more of an annoyance to the patient, prompting them to opt out of a study.

3.4. Specific Severe Adverse Effects

Incidence of pancreatitis: One patient in the Liraglutide arm of the study by Rubino et al. [13] had subclinical pancreatitis (not requiring treatment). Three incidents were noted in Davies et al.’s [14] study, but were deemed mild-to-moderate in severity. In the study by Astrup et al. [15], one subject developed acute pancreatitis along with cholelithiasis.

In the study by Pi-Sunyer et al. [12], eleven subjects developed acute pancreatitis in the Liraglutide group, compared with one in the placebo group.

Cancer: There was an overall increased incidence of neoplasm in GLP-1 RA groups; however, a clear association and cause–effect relationship are yet to be established. Patients had various cancers noted in GLP-1 RA groups, and no predilection towards a particular neoplasm was noted (Table 3).

In the study by Astrup et al. [15], the extension period compared Liraglutide to Orlistat instead of a placebo. It had several noteworthy AEs: one subject was found to have developed breast cancer and one was found to have metastatic intestinal adenocarcinoma well into the second year of the study. Another three SAEs of special interest were atrial fibrillation, uterine leiomyoma, and prostate cancer.

Hypoglycemia: Hypoglycemia was not commonly noted. Only two incidents were reported in the study by Davies et al. [14].

Table 1. Demographics of study populations.

Study, Year	Drug	Duration of Study (Days)	Age GLP-1 RA	Age Placebo	BMI GLP-1 RA	BMI Placebo
Wadden et al., 2021 [16]	Semaglutide	78	46	46	38.1	37.8
Rubino et al., 2022 [13]	Semaglutide	476	48	51	37	38.8
Garvey et al., 2022 [11]	Semaglutide	728	47.3	37.4	38.6	38.5
Davies et al., 2017 [14]	Semaglutide	217		40		32.6
Larsen et al., 2017 [17]	Liraglutide	112	42.1	43	33.7	33.9
Rubino et al., 2022 [13]	Liraglutide	476	49	N/A	37.2	N/A
Astrup et al., 2012 [15]	Liraglutide	365 (of 730)		45.9		34.9
Pi-Sunyer et al., 2015 [12]	Liraglutide	392	45.2	45	38.3	38.3

Table 1. Demographics of study populations.

Study, Year	Drug	Duration of Study (Days)	Age GLP-1 RA	Age Placebo	BMI GLP-1 RA	BMI Placebo
Wadden et al., 2021 [16]	Semaglutide	78	46	46	38.1	37.8
Rubino et al., 2022 [13]	Semaglutide	476	48	51	37	38.8
Garvey et al., 2022 [11]	Semaglutide	728	47.3	37.4	38.6	38.5
Davies et al., 2017 [14]	Semaglutide	217		40		32.6
Larsen et al., 2017 [17]	Liraglutide	112	42.1	43	33.7	33.9
Rubino et al., 2022 [13]	Liraglutide	476	49	N/A	37.2	N/A
Astrup et al., 2012 [15]	Liraglutide	365 (of 730)		45.9		34.9
Pi-Sunyer et al., 2015 [12]	Liraglutide	392	45.2	45	38.3	38.3

Table 2. Serious Adverse Effects (SAEs) in study populations.

Study, Year	Drug	SAEs GLP	SAEs Placebo	No Withdrawn: GLP	No Withdrawn: Placebo
Wadden et al., 2021 [16]	Semaglutide	23	0	24	6
Rubino et al., 2022 [13]	Semaglutide	10	6	4	3
Garvey et al., 2022 [11]	Semaglutide	12	18	10	7
Davies et al., 2017 [14]	Semaglutide	53	7	91	0
Larsen et al., 2017 [17]	Liraglutide	6	13	3	0
Rubino et al., 2022 [13]	Liraglutide	14	6	6	0
Astrup et al., 2012 [15]	Liraglutide	20	3	5	3
Pi-Sunyer et al., 2015 [12]	Liraglutide	154	62	246	47

Table 2. Serious Adverse Effects (SAEs) in study populations.

Study, Year	Drug	SAEs GLP	SAEs Placebo	No Withdrawn: GLP	No Withdrawn: Placebo
Wadden et al., 2021 [16]	Semaglutide	23	0	24	6
Rubino et al., 2022 [13]	Semaglutide	10	6	4	3
Garvey et al., 2022 [11]	Semaglutide	12	18	10	7
Davies et al., 2017 [14]	Semaglutide	53	7	91	0
Larsen et al., 2017 [17]	Liraglutide	6	13	3	0
Rubino et al., 2022 [13]	Liraglutide	14	6	6	0
Astrup et al., 2012 [15]	Liraglutide	20	3	5	3
Pi-Sunyer et al., 2015 [12]	Liraglutide	154	62	246	47

Table 3. Incidence of cancers.

Study, Year	Drug	Incidence of Cancer: GLP1-RA N (%)	Types of Cancer	Incidence of Cancer: Placebo N (%)	Types of Cancer
Wadden et al., 2021 [16]	Semaglutide	3 (0.7)	Basal cell carcinoma, breast cancer, and papillary thyroid cancer	1 (0.5)	Invasive lobular breast carcinoma
Rubino et al., 2022 [13]	Semaglutide	3 (2.4)	Basal cell carcinoma, clear cell renal cell carcinoma, and invasive ductal breast carcinoma	1 (1.2)	Invasive ductal breast carcinoma
Garvey et al., 2022 [11]	Semaglutide	2 (1.3)	Basal cell carcinoma and Bowen’s disease	4 (2.6)	2 X Invasive ductal breast carcinoma, lung adenocarcinoma, and small cell lung cancer
Davies et al., 2022 [14]	Semaglutide	3	Basal cell carcinoma, GI tract adenoma [benign], and keratoacanthoma [benign])	0	N/A
Larsen et al., 2017 [17]	Liraglutide	N/A	N/A	N/A	N/A
Rubino et al., 2022 [13]	Liraglutide	3 (2.4)	Basal cell carcinoma, invasive ductal breast carcinoma, and invasive lobular breast carcinoma	1 (1.2)	Invasive lobular breast carcinoma
Astrup et al., 2012 [15]	Liraglutide	4 (all noted in the second year of study)	Breast cancer, intestinal adenocarcinoma, uterine leiomyoma, and prostate cancer	0	N/A
Pi-Sunyer et al., 2015 [12]	Liraglutide	9 (1 patient had malignant neoplasm detected X 2)	Breast cancer: 3 pre-malignant and 6 malignant	3	Breast cancer: 1 pre-malignant and 2 malignant

Table 3. Incidence of cancers.

Study, Year	Drug	Incidence of Cancer: GLP1-RA N (%)	Types of Cancer	Incidence of Cancer: Placebo N (%)	Types of Cancer
Wadden et al., 2021 [16]	Semaglutide	3 (0.7)	Basal cell carcinoma, breast cancer, and papillary thyroid cancer	1 (0.5)	Invasive lobular breast carcinoma
Rubino et al., 2022 [13]	Semaglutide	3 (2.4)	Basal cell carcinoma, clear cell renal cell carcinoma, and invasive ductal breast carcinoma	1 (1.2)	Invasive ductal breast carcinoma
Garvey et al., 2022 [11]	Semaglutide	2 (1.3)	Basal cell carcinoma and Bowen’s disease	4 (2.6)	2 X Invasive ductal breast carcinoma, lung adenocarcinoma, and small cell lung cancer
Davies et al., 2022 [14]	Semaglutide	3	Basal cell carcinoma, GI tract adenoma [benign], and keratoacanthoma [benign])	0	N/A
Larsen et al., 2017 [17]	Liraglutide	N/A	N/A	N/A	N/A
Rubino et al., 2022 [13]	Liraglutide	3 (2.4)	Basal cell carcinoma, invasive ductal breast carcinoma, and invasive lobular breast carcinoma	1 (1.2)	Invasive lobular breast carcinoma
Astrup et al., 2012 [15]	Liraglutide	4 (all noted in the second year of study)	Breast cancer, intestinal adenocarcinoma, uterine leiomyoma, and prostate cancer	0	N/A
Pi-Sunyer et al., 2015 [12]	Liraglutide	9 (1 patient had malignant neoplasm detected X 2)	Breast cancer: 3 pre-malignant and 6 malignant	3	Breast cancer: 1 pre-malignant and 2 malignant

Figure 2. Pooled analysis of Severe Adverse Effects of Semaglutide vs. placebo [11,13,14,16].

Figure 2. Pooled analysis of Severe Adverse Effects of Semaglutide vs. placebo [11,13,14,16].

Figure 3. Pooled analysis of Severe Adverse Effects of Semaglutide vs. placebo, sensitivity analysis [11,13,14,16].

Figure 3. Pooled analysis of Severe Adverse Effects of Semaglutide vs. placebo, sensitivity analysis [11,13,14,16].

Figure 4. Pooled analysis of Severe Adverse Effects of Liraglutide vs. placebo [12,13,15,17].

Figure 4. Pooled analysis of Severe Adverse Effects of Liraglutide vs. placebo [12,13,15,17].

Figure 5. Pooled analysis of Severe Adverse Effects of Liraglutide vs. placebo, sensitivity analysis [12,13,15,17].

Figure 5. Pooled analysis of Severe Adverse Effects of Liraglutide vs. placebo, sensitivity analysis [12,13,15,17].

4. Discussion

In our systematic review, we had a robust pool of more than 6300 subjects. It was found, upon analysis, that there was an increased risk of SAEs associated with GLP-1 RAs (for both Semaglutide and Liraglutide), but it was not statistically significant. Also, the rate of discontinuation of medications was significantly higher in GLP-1 RA groups compared to placebo groups. Given the size of the subject pool, we believe our systematic review had enough exposure to examine severe adverse effects of the medications, which may potentially be missed in a small group of patients. This systematic review is also, we believe, the first of its kind with respect to the specific evaluation of severe adverse effects from this class of drugs.

Although an increased incidence of thyroid cell tumors has not been established, based on animal data demonstrating thyroid cell hyperplasia, there is significant concern regarding this neoplasm. A study published by Guiseppe et al. concluded that there was no concern regarding this neoplasm with short-term exposure to a GLP-1 RA, but that there is a need for further studies to evaluate and verify the association with long-term exposure [18]. In our review, however, no incidence of this particular neoplasm was reported. This drug class currently remains contraindicated in patients who have multiple endocrine neoplasia (MEN) type 2 syndrome or a family history of medullary carcinoma of the thyroid.

As expected, a review of the literature suggested that nausea is the most common AE noted for most GLP-1 RAs [2]. A significant number of subjects had to discontinue medication because of SAEs. It has been postulated that an increased incidence of nausea and vomiting, a common AE of these medications, might be a contributing factor for weight loss [19]. An additional mechanism of action is via stimulation of GLP-1 receptors in the hypothalamus, thereby reducing appetite [20]. European guidelines for obesity management in adults recommend discontinuing these drugs if the subject does not lose at least 5% of their weight within 12 weeks of therapy [21].

In our study, we included SAEs of multiple drugs, providing a more comprehensive review of SAEs associated with this class of drugs. Although AEs like nausea and diarrhea are sometimes easier to deal with using mitigation tools and strategies [22], SAEs like hypoglycemia can be associated with an increased risk of morbidity and mortality.

An increased risk of acute cholecystitis is another risk factor associated with the use of GLP-1 RAs [23]. This was also noted in our study, along with an increased incidence of pancreatitis. Although the numbers were small, this remains a potential concern nonetheless [24].

Limitations of this study included comorbidities and the exclusion of studies using various oral antihyperglycemics and insulin. This excluded significant populations that were prescribed these medications. Details regarding SAEs were lacking. More comprehensive and detailed descriptions of SAEs and subjects’ reasons for discontinuing studies may have been useful. Further, we did not include studies that included subjects on multiple hypoglycemic agents. Studies involving various oral antihyperglycemic agents may indicate a different safety profile and concerns, like a higher incidence of hypoglycemia [25]. This is especially important given that diabetics have an increased tendency for gastroparesis, which can be an important independent causative factor for nausea and vomiting. Also, SAEs were not divided based on the dose of GLP-1 RAs or the route of administration (subcutaneous vs. oral). It has been noted in various studies, like STEP 2 trials and other STEP 1–5 trials, that AEs can be dose-based, and sometimes a lower dose increases tolerability [26]. Also, the degree of adverse effects might be related to the degree of weight loss. We could not find data related to this in order to establish this relationship.

In our analysis, subjects receiving Semaglutide had a discontinuation rate > 10% compared to about 3% of those receiving a placebo, whereas Wilding et al. [25] showed discontinuation rates of 7% vs. 3.1%, respectively, owing majorly to GI AEs. The incidence of SAEs reported from our analysis was about 8.9% with Semaglutide; it was about 9.8% in the study by Wilding et al. [25]. This slight difference could be secondary to different doses and durations of various studies. The effect of dose and duration on SAEs is yet to be established.

There has been some concern regarding the development of acute kidney injury (AKI) among patients being prescribed Semaglutide. Although no direct toxicity or mechanism of injury to the kidney has been established, the reported incidence is thought to be due to volume depletion secondary to nausea and vomiting [27].

There is also an increased concern about adverse psychiatric effects from this group of medications. A recent article published by Mansour et al. [28] identified that the majority of adverse psychiatric effects of GLP-1 RAs are related to depression. Suicidal ideation consisted of about 19.6% of adverse psychiatric events. The study reported nine deaths (eight men) from successful suicides.

There is a silent pandemic of obesity, DM and ASVD (including cardiovascular disease) ongoing, and only worsening, in developing nations [29,30]. This increases the importance of the development of new drugs to help treat these conditions [31]. GLP-1 RAs are drugs that treat all three conditions in combination or independent of each other. This is likely the reason for the meteoric rise in their usage. To date, most drugs developed for weight loss have GI adverse effects, and a brief overview is provided in the image below (Figure 6) [21].

5. Conclusions

The incidence of severe adverse effects was about 8.9% for Semaglutide and 6.2% for Liraglutide (excluding those who discontinued studies due to AEs). Given that minor AEs can lead to other AEs like AKI and, in rare instances, to the development of SAEs, close monitoring for these effects is recommended.

Furthermore, detailed data collection from patients who suffer from serious AEs, like thyroid or other cancers, AKI, etc., should be a priority in order to better understand risk factors and identify the high-risk population for these AEs. Other potential complications, like acute pancreatitis, need to be kept in mind, and further studies excluding other drugs that can cause potential bias need to be conducted.

Further studies are required to assess if some adverse effects, like neoplasm, are associated with long-term GLP-1 RAs exposure, high-dose exposure, or both, or not associated with either. This will help physicians identify potential candidates who need close monitoring for the development of these adverse effects or who are not suitable candidates for GLP-1 RAs therapy.