From the Guidelines
Long-term side effects of GLP-1 agonists are generally mild and tolerable, with the most common side effects being nausea, vomiting, and diarrhea, occurring in 15%–20% of patients, which usually abate over several weeks to months with dose titration 1.
Common Side Effects
- Gastrointestinal symptoms: nausea, vomiting, and diarrhea are the most common side effects, but they are usually mild and temporary.
- Injection site reactions: rare, occurring in less than 1% of patients.
- Increased heart rate: typically an increase of ~5 bpm, but not associated with higher blood pressure or other adverse events.
Serious but Rare Side Effects
- Theoretical risks: of thyroid C-cell tumors, pancreatic cancer, or pancreatitis, although the evidence is based on preclinical models and not confirmed in human studies.
- No increased risk: of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, or serious adverse events compared to placebo, as shown in several large randomized controlled trials 2, 3, 4, 5.
Cardiovascular Benefits
- Reduced risk: of major adverse cardiovascular events, including heart attack, stroke, and cardiovascular death, in adults with type 2 diabetes and established cardiovascular disease, as demonstrated by several large randomized controlled trials, including the LEADER trial with liraglutide 4 and the REWIND trial with dulaglutide 3.
From the Research
Long-term Side Effects of GLP-1 Agonists
The long-term side effects of Glucagon-Like Peptide-1 (GLP-1) agonists have been studied in various research papers. Some of the potential long-term side effects include:
- Pancreatitis: Studies have shown that GLP-1 agonists may be associated with an increased risk of pancreatitis, with a study published in 2024 finding a subdistributional hazard ratio (sHR) of 2.01 for pancreatitis in patients taking GLP-1 agonists compared to those taking metformin-only 6.
- Thyroid cancer: The same study found an increased risk of thyroid cancer in patients taking GLP-1 agonists, with an sHR of 2.25 compared to metformin-only users 6.
- Kidney failure: GLP-1 agonists may also be associated with an increased risk of kidney failure, with an sHR of 3.73 compared to metformin-only users 6.
- Acute nephritis: The study published in 2024 also found an increased risk of acute nephritis in patients taking GLP-1 agonists, with an sHR of 3.20 compared to metformin-only users 6.
- Gastrointestinal symptoms: GLP-1 agonists are commonly associated with gastrointestinal symptoms such as nausea, vomiting, and diarrhea, although these symptoms are often transient and less common with long-acting drugs 7, 8.
Comparison of GLP-1 Agonists
Different GLP-1 agonists may have varying side effect profiles. For example:
- Exenatide has been linked to an increased risk of acute kidney injury, primarily due to hemodynamic derangement caused by nausea, vomiting, and diarrhea 7.
- Liraglutide and other long-acting GLP-1 agonists may have a lower risk of gastrointestinal symptoms compared to short-acting agents 9, 8.
- Semaglutide has been shown to have a greater efficacy in lowering plasma glucose and body weight compared to other GLP-1 agonists, but may also have a higher risk of adverse effects such as nausea and vomiting 9.
Safety Profile
Despite the potential long-term side effects, GLP-1 agonists are generally considered to have a favorable safety profile. A study published in 2014 found that GLP-1 agonists do not have a negative effect on cardiovascular risk in patients with type 2 diabetes 7. Another study published in 2015 found that the safety concerns associated with GLP-1 agonists, such as pancreatitis and thyroid cancer, are not supported by clinical trials and post-marketing analyses 10. However, ongoing trials are necessary to further assess the long-term safety of GLP-1 agonists 7, 6.