What are the side effects of Glucagon-like peptide-1 (GLP-1) agonists?

From the Guidelines

GLP-1 agonists commonly cause gastrointestinal side effects, including nausea, vomiting, diarrhea, and constipation, which can be managed by following the prescribed titration schedule and reporting persistent symptoms to a healthcare provider 1.

Common Side Effects

The most frequent issues associated with GLP-1 agonists include:

• Nausea and vomiting, which can be avoided in patients with gastroparesis by avoiding the use of these medications 1
• Dyspepsia, which can be managed by starting the medication at a low dose and titrating upward slowly 1
• Diarrhea, which can be reduced by decreasing meal size 1
• Gastrointestinal reflux, which can be limited by avoiding alcohol and carbonated drinks 1
• Constipation, which can be avoided by not consuming a high-fat diet 1

Serious Side Effects

More serious but less common side effects of GLP-1 agonists include:

• Pancreatitis, which has been reported in clinical trials, although causality has not been established 1
• Gallbladder problems, including cholelithiasis and gallstone-related complications 1
• Kidney issues, including the potential risk of acute kidney injury, particularly in patients with pre-existing kidney disease 1
• Potential thyroid tumors, based on animal studies, with a black box warning for this risk 1

Management of Side Effects

To minimize side effects, patients should:

• Follow the prescribed titration schedule, starting with lower doses and gradually increasing 1
• Stay well-hydrated and eat smaller meals to reduce gastrointestinal side effects 1
• Report persistent or severe symptoms to their healthcare provider immediately 1

Cardiovascular Benefits

GLP-1 agonists have been shown to have cardiovascular benefits, including a reduced risk of cardiovascular death, non-fatal myocardial infarction, and stroke 1. The LEADER trial demonstrated a benefit in cardiovascular outcomes with liraglutide, with a 13% reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke 1. Similarly, the SUSTAIN 6 trial showed a reduced risk of cardiovascular events with semaglutide, with a 26% reduction in the primary outcome of cardiovascular death, non-fatal myocardial infarction, or stroke 1.

From the FDA Drug Label

The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5. 1)] • Pancreatitis [see Warnings and Precautions (5.2)] • Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.5)] • Acute Kidney Injury [see Warnings and Precautions (5.6)] • Hypersensitivity [see Warnings and Precautions (5.7)]

5.4 Hypoglycemia Adult patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.

1. 5 Acute Kidney Injury Liraglutide injection has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in liraglutide injection-treated patients

5.6 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide injection

1. 7 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing.

Gastrointestinal: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus

The side effects of GLP-1 agonists include:

• Pancreatitis: confirmed by adjudication in 7 semaglutide-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years) 2
• Diabetic Retinopathy Complications: more events of diabetic retinopathy complications occurred in patients treated with semaglutide (3.0%) compared to placebo (1.8%) 2
• Hypoglycemia: increased risk when used in combination with insulin secretagogues or insulin 2 3
• Acute Kidney Injury: postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis 2 3
• Hypersensitivity: serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported 2 3
• Acute Gallbladder Disease: acute events of gallbladder disease, such as cholelithiasis or cholecystitis, have been reported in GLP-1 receptor agonist trials and postmarketing 3 3

From the Research

Side Effects of GLP-1 Agonists

The side effects of Glucagon-like peptide-1 (GLP-1) agonists include:

• Gastrointestinal side effects such as nausea, vomiting, diarrhea, eructation, and gastroesophageal reflux 4, 5
• More severe side effects including pancreatitis, allergic reactions, renal function disorders, and possibly an increased risk of thyroid cancer 4, 6
• Other potential side effects may include obstipation 5

Specific Side Effects of Individual GLP-1 Agonists

• Semaglutide: gastrointestinal side effects such as nausea, vomiting, diarrhea, and gastroesophageal reflux 4, 5
• Exenatide: increased odds ratio for reported pancreatitis and pancreatic cancer 6
• Liraglutide: gastrointestinal side effects such as nausea, vomiting, diarrhea, and gastroesophageal reflux 4, 5
• Tirzepatide: gastrointestinal side effects such as nausea, vomiting, diarrhea, and gastroesophageal reflux 5

Mitigating Side Effects

• Slow up-titration of GLP-1-based therapies can help mitigate gastrointestinal side effects 5