Supplementary Material

Journal: Clinical Drug Investigation

Safety of Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs): A
Real-World Study Based on FDA Adverse Event Reporting System
(FAERS) Database
† †
Tingxi Wu1, , Yang Zhang2,3, ,, Yanfeng Shi4, Kefu Yu1, Mei Zhao5, Shangyi Liu6, Zhigang Zhao1,
1
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
2
Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
3
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key
Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing, China
4
Center of excellence for Omics Research, National Clinical Research Center for Neurological Diseases,
Beijing Tiantan Hospital, Capital Medical University, Beijing, China
5
Department of Pharmacy, Peking University People’s Hospital, Beijing, China
6
School of Chinese Materia Medical, Tianjin University of Traditional Chinses Medicine, Tianjin,
China

†Tingxi Wu and Yang Zhang contributed equally to this work.

*
Address correspondence to
Yang Zhang, Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95
Yongan Road, Xicheng District, Beijing 100050, China; e-mail: [email protected].
Zhigang Zhao, Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119
Nansihuan West Road, Fengtai District, Beijing 100070, China; e-mail: [email protected]
Table S1. Generic names and brand names of GLP-1RAs
Generic name Brand name
Albiglutide TANZEUM®
Dulaglutide Trulicity®
Exenatide Byetta®; Bydureon®; BYDUREON BCise®
Liraglutide Victoza®; Saxenda®
Lixisenatide Adlyxin®
Semaglutide Ozempic®; Rybelsus®; Wegovy®

Table S2. The narrow expression of acute pancreatitis (SMQ 20,000,022)

Narrow_SMQ Broad_SMQ
Cullen's Sign Amylase Abnormal
Grey Turner's Sign Amylase Creatinine Clearance Ratio Abnormal
Haemorrhagic Necrotic Pancreatitis Amylase Increased
Hereditary Pancreatitis Bilirubin Conjugated Abnormal
Immune-Mediated Pancreatitis Blood Bilirubin Increased
Ischaemic Pancreatitis Blood Trypsin Increased
Oedematous Pancreatitis Computerised Tomogram Pancreas Abnormal
Pancreatic Abscess Hyperamylasaemia
Pancreatic Cyst Drainage Hyperbilirubinaemia
Pancreatic Haemorrhage Hyperlipasaemia
Pancreatic Necrosis Lipase Abnormal
Pancreatic Phlegmon Lipase Increased
Pancreatic Pseudoaneurysm Lipase Urine Increased
Pancreatic Pseudocyst Pancreatic Enzyme Abnormality
Pancreatic Pseudocyst Drainage Pancreatic Enzymes Abnormal
Pancreatic Pseudocyst Haemorrhage Pancreatic Enzymes Increased
Pancreatic Pseudocyst Rupture Ultrasound Pancreas Abnormal
Pancreatitis Abdominal Compartment Syndrome
Pancreatitis Acute Abdominal Distension
Pancreatitis Haemorrhagic Abdominal Pain
Pancreatitis Necrotising Abdominal Pain Upper
Pancreatitis Relapsing Abdominal Rebound Tenderness
Pancreatorenal Syndrome Abdominal Rigidity
 Abdominal Tenderness
Abdominal Wall Oedema
Acute Abdomen
Ascites
Fat Necrosis
Gastrointestinal Pain
Gastrointestinal Sounds Abnormal
Haemorrhagic Ascites
Ileus Paralytic
Intestinal Atony
Intra-Abdominal Pressure Increased
Jaundice
Nausea
Pancreatic Duct Rupture
Peripancreatic Fluid Collection
Vomiting
Vomiting Projectile

Table S3. Two-by-two contingency table for the disproportionality analysis*

Interested AEs Other AEs
Interested drugs a b
Other drugs c d
*In Table S3, AEs: adverse events; a is the number of records of interested drug-interested AE pairs, b is the number of
records of interested drug-non-interested AE pairs, c is the number of records of non-interested drug-interested AE pairs,
d is the number of records of non-interested drug-non-interested AE pairs. In FAERS, all AEs are coded as Preferred
Terms (PTs) according to MedDRA. We matched all PTs with the corresponding primary system organ classes (SOCs)
and subsequently performed disproportionality analysis from the level of SOCs. At SOC level, a is the number of records
of interested drug-SOC pairs, b is the number of reports with all other SOCs of the intersted drugs; c is the number of
reports with the interested SOCs of all other drugs; d is the number of reports with all other SOCs of all other drugs.
TABLE S4. All AEs with significant disproportionality induced by GLP-1RA monotherapy based on all other drugs as "non-case". *

Albiglutide Dulaglutide Exenatide Liraglutide Semaglutide

SOC pt
a IC025 a IC025 a IC025 a IC025 a IC025
Blood and lymphatic system disorders Red blood cell abnormality 5 1.63
Coronary artery occlusion 37 1.52 2
Angina unstable 1 7 31 1.25
Cardiac disorders Myocardial ischaemia 26 0.12 4
Coronary artery stenosis 1 16 0.41 5 -1.77
Electromechanical dissociation 5 0.66
Goitre 21 1.53 39 2.73 1
Thyroid mass 4 7 0.72 34 3.77 9 3.50
Thyroiditis 2 8 0.47 1
Endocrine disorders
Adrenal mass 1 7 1.68 1
Hyperparathyroidism 6 0.06 1
Thyroid cyst 1 1 5 1.95
Vision blurred 16 -0.84 48 -0.96 28 -1.75 46 1.24
Diabetic retinopathy 1 1 11 1.37 15 2.07 17 4.45
Retinopathy 3 6 -0.50 1 34 5.03
Eye disorders Papilloedema 1 15 1.03
Macular oedema 1 5 -1.58 2 5 0.70
Vitreous haemorrhage 2 3 3 5 1.39
Macular degeneration 11 0.03
Pancreatitis 2 124 3.15 1996 5.34 1735 5.26 173 3.91
Nausea 26 0.71 495 1.95 1619 1.69 1306 1.49 483 2.15
Gastrointestinal disorders Vomiting 20 0.81 203 1.15 808 1.21 726 1.18 374 2.32
Diarrhoea 10 -0.86 178 0.56 502 0.12 554 0.39 224 1.16
Pancreatitis acute 8 2.79 25 1.43 612 4.51 610 4.63 18 1.08
Abdominal pain 6 -0.63 73 0.40 377 0.94 423 1.24 103 1.20
Abdominal pain upper 4 143 2.30 214 0.90 242 1.21 43 0.59
Constipation 1 43 0.02 179 0.29 203 0.60 91 1.49
Abdominal discomfort 3 45 0.80 97 0.02 140 0.72 47 1.11
Abdominal distension 3 30 0.63 156 1.30 96 0.65 38 1.27
Dyspepsia 1 25 0.51 119 1.07 115 1.14 30 1.07
Eructation 2 15 2.71 71 3.36 113 4.23 28 4.07
Gastrooesophageal reflux disease 4 23 0.24 68 0.04 83 0.49 25 0.62
Gastrointestinal disorder 1 27 0.65 51 -0.31 60 0.09 61 2.27
Flatulence 15 0.59 58 0.90 72 1.38 27 1.88
Gastritis 3 68 1.07 51 0.72 11 0.15
Pancreatitis chronic 1 100 5.28 28 3.29 2
Impaired gastric emptying 1 11 2.19 66 3.30 43 2.71 9 2.04
Pancreatitis necrotising 5 1.92 63 4.56 18 2.53 4
Ileus 12 0.77 33 0.55 24 0.12 5 -0.77
Lip swelling 4 33 0.09 20 -0.67 2
Gastric ulcer 1 28 0.07 13 -1.19 5 -0.96
Pancreatic mass 1 20 3.70 22 3.99 2
Pancreatic pseudocyst 1 23 4.05 15 3.40 1
Retching 1 20 0.39 12 -0.42 5 -0.04
Colitis ischaemic 19 0.56 12 -0.17 4
Pancreatitis haemorrhagic 33 5.37 1
Pancreatic disorder 3 19 2.26 8 0.74 2
Pancreatitis relapsing 29 4.65 3
Pancreatic cyst 10 1.81 17 2.93 1
Vomiting projectile 4 12 2.30 6 1.05 2
Gastrointestinal pain 5 0.64 4 12 0.49 2
Stomach discomfort 23 2.63
Paraesthesia oral 2 13 -0.34 3 5 0.02
Duodenitis 7 -0.37 11 0.65 3
Obstructive pancreatitis 2 7 3.08 12 6.30
Ileus paralytic 2 2 12 0.32 4
Bowel movement irregularity 3 13 1.16 2
Abdominal tenderness 10 0.06 4 1
Abdominal hernia 11 0.68 3
Breath odour 5 0.15 7 0.98 2
Gastrointestinal necrosis 4 9 0.38
Pancreatic duct stenosis 12 5.35
Hyperchlorhydria 2 4 6 1.08 1
Haemorrhoidal haemorrhage 10 0.52 1 1
Barrett's oesophagus 9 0.87 2
Colonic polyp 9 0.01 2
Gastritis haemorrhagic 7 0.96 3
Bezoar 1 3 5 0.90
Oedematous pancreatitis 5 1.72 4
Erosive oesophagitis 8 0.92
Gastric dilatation 5 1.00 3
Pancreatic insufficiency 7 2.69
Sigmoiditis 2 6 3.02
Abdominal rigidity 5 0.14 1
Mallory-weiss syndrome 1 -3.91 6 0.70
Pancreatolithiasis 1 5 2.77 1
Polyp colorectal 6 2.71 1
Gastric ileus 5 5.09 1
Oesophagitis ulcerative 5 1.00 1
Injection site pain 1 219 2.68 298 1.11 80 -0.83 14 -1.69
 Injection site erythema 11 1.83 66 1.49 200 1.21 194 1.29 3
Injection site pruritus 9 2.42 55 2.16 205 2.23 133 1.67 2
Injection site nodule 8 1.77 351 6.14 13 0.80 1
Injection site rash 6 2.84 32 2.49 115 2.56 148 3.09 6 -0.42
Injection site haemorrhage 2 46 2.53 202 2.88 20 -0.82 6 -0.99
Injection site mass 49 3.17 191 3.32 21 -0.20 1
Injection site reaction 5 0.91 31 0.89 77 0.38 144 1.50 2
Injection site urticaria 1 17 1.80 126 3.13 107 3.00
Injection site bruising 6 1.74 36 1.60 165 2.04 26 -0.88 2
Injection site swelling 1 33 1.10 131 1.32 47 -0.22 1
Feeling abnormal 2 16 -1.35 138 0.24 33 -1.99 9 -2.21
Injection site extravasation 162 4.23 2 5 0.32
Drug effect decreased 115 1.38 3
General disorders and administration Nodule 3 92 3.05 17 0.30
site conditions Injection site haematoma 4 41 2.01 56 2.66
Drug intolerance 26 0.13 23 -2.12 19 -2.34 22 0.07
Injection site irritation 4 63 3.49 19 1.56 1
Feeling jittery 4 50 2.27 8 -0.92 5 0.25
Early satiety 2 52 5.49
Therapeutic response unexpected 2 44 1.30 6 -2.27
Injection site induration 6 0.07 32 1.18 11 -0.63 1
Hunger 36 3.06 8 0.42 3
Injection site warmth 2 2 32 0.52 10 -1.48
Injection site discolouration 1 4 26 1.19 10 -0.45 3
Injury associated with device 1 25 3.34 12 -0.04 3 1
Sudden death 2 2 13 -1.03 23 0.13 1
Feeling cold 2 26 0.25 4 1
Mass 2 28 0.92 4 1
 Non-cardiac chest pain 23 1.78 9 0.15 2
Injection site inflammation 2 22 2.15 8 0.37
Injection site discomfort 6 1.00 16 0.88 3
Injection site hypersensitivity 1 10 1.81 9 1.73 3
Accidental needle stick 22 5.62
Injection site vesicles 2 5 -0.54 7 0.29 5 1.73
Thirst 1 11 -0.64 3 5 0.04
Injection site injury 7 3.57 9 2.04 1 1
Systemic inflammatory response syndrome 14 0.63 3
Sudden cardiac death 11 0.58 2
Energy increased 1 10 1.20 1
Injection site paraesthesia 3 5 3.49 2
Injection site scar 9 1.92 3
Illness 5 0.21 6 0.83
Injection site cyst 1 7 4.04 2
Injection site coldness 2 5 3.03
Injection site indentation 7 3.17
Difficulty in walking 6 0.39
Pitting oedema 5 1.20
Cholelithiasis 4 17 0.40 270 2.93 185 2.46 55 2.67
Cholecystitis 5 2.65 4 52 1.48 55 1.69 48 3.62
Cholecystitis acute 8 1.10 26 1.26 63 2.88 38 4.19
Hepatic steatosis 1 6 -0.83 82 1.85 32 0.40 1
Hepatobiliary disorders Gallbladder disorder 2 39 0.97 32 0.76 4
Hepatitis 2 23 -0.90 40 0.18 1
Bile duct stone 1 9 0.28 22 2.07 25 4.45
Cholecystitis chronic 23 0.83 15 0.18 9 1.35
Drug-induced liver injury 4 2 8 -2.57 10 0.02
 Biliary colic 5 -0.44 13 1.61 1
Bile duct obstruction 4 10 1.20 1
Hepatitis acute 14 0.09
Cholangitis acute 2 4 7 4.00
Bile duct stenosis 1 5 0.30 1 1
Biliary dyskinesia 10 1.29
Hepatitis toxic 9 0.34 1
Gallbladder polyp 6 1.51 2 1
Biliary tract disorder 6 0.86 1
Hepatic vein thrombosis 6 2.81
Immune system disorders Anaphylactic reaction 1 3 75 0.29 24 -1.51 4
Gastroenteritis 1 2 38 0.60 33 0.48 9 0.26
Diverticulitis 3 43 0.45 23 -0.51 4
Injection site abscess 1 28 2.97 3
Gastroenteritis viral 2 20 0.18 5 -2.41
Injection site cellulitis 2 1 17 2.70 2
Cholecystitis infective 1 8 1.03 5 0.17 2
Helicobacter gastritis 4 9 1.55
Infections and infestations
Injection site infection 10 1.19 3
Acute sinusitis 8 0.44
Pancreas infection 7 3.56 2
Pneumonia staphylococcal 9 0.87
Abdominal wall abscess 1 5 1.37
Incision site infection 6 1.18
Injection site pustule 5 3.13
Off label use 2 21 -2.79 495 0.28 162 -1.32 115 0.29
Injury, poisoning and procedural
Incorrect dose administered 1 100 2.52 170 1.32 25 -1.71 17 -0.25
complications
Drug dose omission 22 2.42 38 -0.12 126 -0.20 16 -3.56
Underdose 16 3.89 53 2.48 80 1.12 1 1
Inappropriate schedule of product administration 111 3.81 3 36 2.20
Accidental overdose 76 3.48 41 0.42 16 -1.11 5 -1.26
Medication error 2 111 1.49 2
Overdose 50 0.53 37 -2.02 13 -3.76 8 -2.55
Device use error 97 8.20 1 3 1
Contusion 4 71 0.02 11 -3.13
Accidental underdose 1 80 7.65
Inappropriate schedule of drug administration 40 1.47 15 -2.30 8 -3.39 15 -0.03
Drug prescribing error 4 57 1.47 6 -2.53 3
Extra dose administered 55 4.76 1 6 -1.22 4
Incorrect dose administered by device 1 48 2.46 7 -0.93 4
Product dose omission 33 1.02 20 -1.90 3 1
Wrong technique in product usage process 10 1.55 9 -2.15 18 -2.88 8 -4.30 9 -1.92
Road traffic accident 3 36 0.02 7 -2.89 1
Accidental exposure to product 29 4.48 12 -0.61 1 2
Circumstance or information capable of leading to medication error 42 1.84 1
Wrong technique in device usage process 39 2.93 2
Drug administration error 2 35 0.40 2
Drug dispensing error 3 25 0.55 3
Product dispensing error 2 5 -2.05 1 21 3.02
Product dose omission issue 19 0.95 7 -3.00 2
Product prescribing error 11 1.37 1 12 1.77
Product storage error 15 0.83 1 2 2
Ankle fracture 1 17 0.04 1
Product administered at inappropriate site 19 4.67
Product preparation error 17 6.05 2
Drug dose titration not performed 12 3.17 5 3.55
 Intentional device misuse 15 4.22 1
Drug titration error 9 2.23 6 3.56
Device misuse 13 3.43 1
Excoriation 10 0.58
Product communication issue 1 2 7 4.71
Joint sprain 9 1.35
Expired drug administered 6 0.34 2
Incorrect route of product administration 6 0.80 2 -1.52
Subcutaneous haematoma 7 0.86
Incorrect storage of drug 1 6 1.27
Neck injury 1 6 0.36
Post procedural bile leak 5 2.24
Weight decreased 8 0.10 64 0.33 1821 3.45 426 1.39 91 1.14
Blood glucose increased 8 1.46 147 3.03 1363 4.38 278 2.10 32 0.77
Blood glucose decreased 4 13 0.98 368 4.48 78 2.16 9 0.51
Lipase increased 4 20 2.39 142 3.62 300 4.91 20 2.63
Weight increased 3 15 -1.60 194 0.64 94 -0.38 15 -1.37
Glycosylated haemoglobin increased 1 50 3.85 171 3.79 77 2.64 15 1.98
Blood glucose abnormal 2 25 3.37 122 3.96 21 1.14 4
Blood creatinine increased 1 5 -3.24 92 0.01 43 -1.12 9 -1.79
Investigations
Blood triglycerides increased 9 0.33 85 2.24 19 -0.18 4 -1.14
Liver function test abnormal 77 0.71 38 -0.34
Blood amylase increased 67 3.92 43 3.31
Blood glucose fluctuation 6 1.35 86 4.11 9 0.26 1
Amylase increased 14 3.00 11 0.50 71 3.89 6 1.56
Blood urea increased 1 2 38 0.21 10 -2.08 2
Glomerular filtration rate decreased 1 5 -0.36 20 0.31 22 0.61 5 -0.12
Pancreatic enzymes increased 2 21 3.20 27 3.77 1
 Glycosylated haemoglobin decreased 2 8 2.72 19 4.48 5 4.02
Blood calcium increased 2 14 0.45 15 0.70
Blood calcitonin increased 1 3 20 6.81
Liver function test increased 1 3 1 6 -2.55 8 0.19
Catheterisation cardiac 10 0.61 7 0.02
Renal function test abnormal 10 0.81 2 1
High density lipoprotein decreased 1 8 0.24 1
Lipids increased 3 6 0.53 1
Blood thyroid stimulating hormone decreased 7 0.09 1
Creatinine renal clearance increased 5 1.27 1
Decreased appetite 3 61 0.37 466 1.53 263 0.78 71 0.86
Dehydration 1 41 0.05 274 1.05 191 0.62 66 1.07
Hypoglycaemia 1 24 0.37 226 2.01 93 0.73 13 -0.51
Diabetic ketoacidosis 13 0.51 73 1.46 95 2.01 24 1.86
Hyperglycaemia 5 -2.10 135 1.76 43 0.02 8 -0.89
Diabetes mellitus inadequate control 1 12 1.23 82 2.52 51 1.87 6 0.08
Anorexia 80 2.19
Increased appetite 1 6 0.46 37 1.82 29 1.52 3
Hypertriglyceridaemia 2 36 1.88 3
Metabolism and nutrition disorders
Ketoacidosis 1 3 21 1.24 9 -0.22 3
Feeding disorder 11 1.66 2 7 -1.15 6 0.68
Weight loss poor 25 4.35 2
Obesity 2 21 0.49 3
Weight fluctuation 25 2.07 1
Hypovolaemia 2 15 0.30 5 -1.77 1
Hyperlipasaemia 1 18 4.17
Oral intake reduced 14 1.23
Food craving 9 1.89 3 1
 Fluid intake reduced 10 0.64 2 1
Food aversion 1 8 2.40 2 2
Hyperamylasaemia 4 8 2.17
Ketosis 2 5 1.45 2
Overweight 1 8 0.50
Appetite disorder 7 0.11 1
Diabetic complication 2 5 0.53
Insulin resistance 1 5 0.92
Neck mass 1 2 -2.25 9 1.25 2
Musculoskeletal and connective tissue Polymyalgia rheumatica 7 0.36 6 0.16
disorders Periarthritis 7 0.67 1
Costochondritis 5 0.24
Pancreatic carcinoma 22 2.51 172 3.87 274 4.72 23 2.82
Pancreatic carcinoma metastatic 1 4 53 3.82 59 4.12 5 1.70
Thyroid cancer 3 35 2.36 64 3.49 3
Metastases to liver 4 38 0.66 26 0.13 4
Thyroid neoplasm 20 2.02 50 3.72
Pancreatic neoplasm 1 1 27 3.99 37 4.66 2
Adenocarcinoma pancreas 1 30 3.84 35 4.23
Papillary thyroid cancer 8 1.17 35 4.00 4
Neoplasms benign, malignant
Medullary thyroid cancer 1 3 2 17 5.76 5 5.49
Gastric cancer 9 -0.61 14 0.36 3
Renal cell carcinoma 1 14 0.48 11 0.15
Bile duct cancer 12 2.21 10 1.98
Hepatic neoplasm malignant 19 1.48 3
Benign neoplasm of thyroid gland 1 7 2.50 7 2.62 2
Pancreatic carcinoma stage iv 1 2 14 3.84
Pancreatic neuroendocrine tumour 1 11 3.35 4
 Lipoma 12 1.47 2
Adenocarcinoma 5 -0.48 7 0.35 1
Thyroid adenoma 2 11 4.54
Intraductal papillary mucinous neoplasm 2 1 9 4.37
Lung adenocarcinoma 1 10 0.52
Adenoma benign 6 1.27 4
Cholangiocarcinoma 1 8 1.76 1
Adenocarcinoma of colon 1 7 0.61
Colon adenoma 3 5 0.03
Gallbladder cancer 8 2.34
Endometrial cancer stage iii 5 4.77 2
Parathyroid tumour benign 1 6 1.72
Myeloproliferative disorder 1 5 1.96
Angiomyolipoma 5 2.64
Hypergammaglobulinaemia benign monoclonal 5 1.64
Marrow hyperplasia 5 1.00
Dizziness 7 -0.94 42 -1.14 323 0.08 167 -0.82 56 -0.42
Loss of consciousness 12 -1.89 133 0.18 42 -1.57 5 -3.42
Dysgeusia 1 6 -1.90 69 0.50 58 0.33 12 -0.28
Hypoglycaemic unconsciousness 2 24 3.71 13 2.72
Diabetic neuropathy 1 12 0.99 3
Nervous system disorders Parosmia 3 8 0.05 1
Viith nerve paralysis 3 9 0.03
Metabolic encephalopathy 1 1 9 0.54
Hypoaesthesia facial 7 0.79 3
Hypoglycaemic seizure 9 2.55 1
Taste disorder 1 8 1.98
Product issues Product quality issue 13 2.33 114 0.51 31 -1.52 3
 Device malfunction 83 1.23 29 -0.40 14 0.44
Device leakage 22 5.99 92 2.86 2
Device issue 1 73 0.93 1 2
Needle issue 39 1.32 3
Pharmaceutical product complaint 36 0.95
Device failure 1 21 0.44 7 -1.52
Device defective 11 1.19
Device delivery system issue 10 1.80
Product packaging quantity issue 7 0.01
Stress 4 45 0.03 4
Psychiatric disorders
Post-traumatic stress disorder 1 8 0.42
Renal failure acute 277 1.71 120 0.52
Renal failure 3 10 -2.43 225 0.81 96 -0.41 14 -1.55
Acute kidney injury 5 -0.42 26 -0.74 14 -3.89 36 -2.09 48 0.55
Nephrolithiasis 1 3 70 0.99 30 -0.31 2
Renal failure chronic 49 1.61 10 -1.10
Renal injury 50 2.26 1 1
Renal cyst 26 1.02 7 -1.32
Renal and urinary disorders Renal tubular necrosis 2 23 0.50 8 -1.36 1
Renal pain 12 0.47 2 4
Renal mass 8 1.26 2 1
Calculus ureteric 8 1.29 1
Diabetic nephropathy 5 0.09 3
Calculus urinary 7 0.86
Ureteric obstruction 7 0.90
Kidney fibrosis 6 0.59
Reproductive system and breast Benign prostatic hyperplasia 10 0.11 1
disorders Postmenopausal haemorrhage 1 5 0.13 2
 Dysfunctional uterine bleeding 5 0.93
Hiccups 5 0.61 10 -0.02 17 1.11 7 1.55
Respiratory, thoracic and mediastinal Atelectasis 31 0.62 1
disorders Pharyngeal swelling 1 9 3.06
Oropharyngeal swelling 5 1.47
Rash 2 54 -0.67 187 -0.71 161 -0.82 71 0.02
Urticaria 1 19 -1.16 192 0.64 109 -0.13 30 -0.11
Hyperhidrosis 1 4 114 0.23 39 -1.41 7 -2.42
Angioedema 10 -1.23 57 -0.18 46 -0.41 17 0.01
Rash generalised 3 3 47 0.25 39 0.06 8 -0.68
Rash pruritic 1 1 34 -0.45 12 -2.20 14 0.24
Cold sweat 32 1.00 11 -0.81 1
Dermatitis allergic 2 18 0.18 9 -1.01 1
Skin and subcutaneous tissue disorders
Skin mass 2 19 1.62 2
Panniculitis 5 -0.33 13 1.71
Angioneurotic oedema 12 1.35
Lipodystrophy acquired 8 0.68 2
Dermatomyositis 2 6 0.23
Hair growth abnormal 1 6 0.04 1
Diabetic foot 5 0.19 1
Urticaria generalised 6 1.93
Social circumstances Economic problem 6 0.17
Cholecystectomy 24 1.11 22 1.08 16 2.65
Coronary revascularisation 20 6.00
Percutaneous coronary intervention 9 3.59
Surgical and medical procedures
Gallbladder operation 6 0.36 1
Splenectomy 6 1.23 1
Thromboembolectomy 7 4.67
 Eye operation 6 0.82
Aortic aneurysm 12 0.39 6 -0.86
Vascular disorders
Peripheral ischaemia 13 0.64

*AEs: Adverse Events; SOC: System Organ Class; PT: Preferred Term; IC: information component; IC025: the lower limit of the 95% confidence interval of IC. IC025>0 was deemed
a signal.

TABLE S5. All IMEs with significant disproportionality induced by GLP-1RAs monotherapy based on all other drugs as "non-case". *
Albiglutide Dulaglutide Exenatide Liraglutide Semaglutide
SOC PT
a IC025 a IC025 a IC025 a IC025 a IC025
Coronary artery occlusion 1 3 21 1.24 9 -0.22 3
Angina unstable 1 8 1.76 1
Cardiac disorders
Myocardial ischaemia 9 0.87 2
Coronary artery stenosis 1 5 1.37
Retinopathy 3 6 -0.50 1 34 5.03
Papilloedema 1 1 9 0.54
Eye disorders Macular oedema 1 5 -1.58 2 5 0.70
Vitreous haemorrhage 2 3 3 5 1.39
Macular degeneration 2 2 12 0.32 4
Pancreatitis 33 5.37 1
Pancreatitis acute 12 5.35
Pancreatitis chronic 8 1.17 35 4.00 4
Impaired gastric emptying 3 35 2.36 64 3.49 3
Gastrointestinal disorders Pancreatitis necrotising 9 2.55 1
Ileus 2 7 3.08 12 6.30
Gastric ulcer 5 1.92 63 4.56 18 2.53 4
Colitis ischaemic 1 3 70 0.99 30 -0.31 2
Pancreatitis haemorrhagic 7 0.96 3
 Pancreatitis relapsing 7 0.90
Obstructive pancreatitis 1 7 -1.64 31 1.25
Ileus paralytic 1 15 1.03
Gastrointestinal necrosis 4 9 0.38
Pancreatic duct stenosis 6 0.59
Barrett's oesophagus 2 23 0.50 8 -1.36 1
Gastritis haemorrhagic 23 0.83 15 0.18 9 1.35
Oedematous pancreatitis 5 1.72 4
Erosive oesophagitis 1 14 0.48 11 0.15
Pancreatolithiasis 1 5 2.77 1
Gastric ileus 5 5.09 1
Oesophagitis ulcerative 5 1.00 1
Sudden death 12 2.21 10 1.98
General disorders and administration site
Systemic inflammatory response syndrome 8 0.68 2
conditions
Sudden cardiac death 11 0.58 2
Cholecystitis 8 2.79 25 1.43 612 4.51 610 4.63 18 1.08
Cholecystitis acute 1 4 53 3.82 59 4.12 5 1.70
Hepatitis 2 24 3.71 13 2.72
Bile duct stone 1 11 2.19 66 3.30 43 2.71 9 2.04
Cholecystitis chronic 1 9 0.28 22 2.07 25 4.45
Hepatobiliary disorders Drug-induced liver injury 4 2 8 -2.57 10 0.02
Hepatitis acute 9 -0.61 14 0.36 3
Cholangitis acute 2 4 7 4.00
Bile duct stenosis 1 5 0.30 1 1
Hepatitis toxic 3 43 0.45 23 -0.51 4
Hepatic vein thrombosis 1 28 0.07 13 -1.19 5 -0.96
Immune system disorders Anaphylactic reaction 1 11 3.35 4
Infections and infestations Diverticulitis 8 1.10 26 1.26 63 2.88 38 4.19
 Cholecystitis infective 1 10 0.52
Pancreas infection 9 0.34 1
Pneumonia staphylococcal 1 3 75 0.29 24 -1.51 4
Abdominal wall abscess 14 0.09
Diabetic ketoacidosis 29 4.65 3
Metabolism and nutrition disorders Diabetes mellitus inadequate control 1 30 3.84 35 4.23
Ketoacidosis 1 6 1.72
Musculoskeletal and connective tissue disorders Polymyalgia rheumatica 19 0.56 12 -0.17 4
Pancreatic carcinoma 1 3 2 17 5.76 5 5.49
Pancreatic carcinoma metastatic 7 3.56 2
Thyroid cancer 6 2.81
Metastases to liver 8 2.34
Adenocarcinoma pancreas 50 2.26 1 1
Papillary thyroid cancer 13 0.51 73 1.46 95 2.01 24 1.86
Medullary thyroid cancer 5 -0.33 13 1.71
Gastric cancer 5 2.65 4 52 1.48 55 1.69 48 3.62
Renal cell carcinoma 9 0.87
Neoplasms benign, malignant
Bile duct cancer 3 10 -2.43 225 0.81 96 -0.41 14 -1.55
Pancreatic neuroendocrine tumour 14 0.63 3
Adenocarcinoma 5 -0.48 7 0.35 1
Lung adenocarcinoma 2 6 0.23
Cholangiocarcinoma 1 8 1.03 5 0.17 2
Adenocarcinoma of colon 2 2 13 -1.03 23 0.13 1
Gallbladder cancer 12 -1.89 133 0.18 42 -1.57 5 -3.42
Parathyroid tumour benign 12 0.77 33 0.55 24 0.12 5 -0.77
Angiomyolipoma 5 2.64
Loss of consciousness 22 2.51 172 3.87 274 4.72 23 2.82
Nervous system disorders
Hypoglycaemic unconsciousness 1 12 1.23 82 2.52 51 1.87 6 0.08
 Metabolic encephalopathy 2 23 -0.90 40 0.18 1
Hypoglycaemic seizure 1 16 0.41 5 -1.77
Renal failure 2 124 3.15 1996 5.34 1735 5.26 173 3.91
Acute kidney injury 5 -0.42 26 -0.74 14 -3.89 36 -2.09 48 0.55
Nephrolithiasis 1 100 5.28 28 3.29 2
Renal and urinary disorders Renal injury 37 1.52 2
Renal tubular necrosis 8 0.92
Ureteric obstruction 26 0.12 4
Kidney fibrosis 11 0.03
Reproductive system and breast disorders Postmenopausal haemorrhage 1 5 0.13 2
Angioedema 10 -1.23 57 -0.18 46 -0.41 17 0.01
Panniculitis 1 7 0.61
Skin and subcutaneous tissue disorders
Lipodystrophy acquired 7 0.36 6 0.16
Dermatomyositis 4 38 0.66 26 0.13 4

*IMEs: Important Medical Events; SOC: System Organ Class; PT: Preferred Term; IC: information component; IC025: the lower limit of the 95% confidence interval of IC. IC025>0
was deemed a signal.