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

Long-Term Side Effects of GLP-1 Receptor Agonists

GLP-1 receptor agonists have a generally favorable long-term safety profile, with the most significant concerns being gastrointestinal effects, potential pancreatitis risk, and emerging evidence of delayed gastric emptying that persists long-term, increasing perioperative aspiration risk. 1

Cardiovascular and Metabolic Effects

Heart Rate and Blood Pressure

• GLP-1 receptor agonists consistently increase heart rate by 3-10 beats per minute, which persists with long-term use 2
• Systolic blood pressure decreases by 2-3 mm Hg, likely due to improved endothelium-dependent vasodilation 2
• In patients with established heart failure with reduced ejection fraction (HFrEF) and recent decompensation, liraglutide showed a trend toward increased heart failure readmission (41% vs 34%; HR 1.30) and more serious cardiac events 2

Diabetic Retinopathy

• In patients with pre-existing diabetic retinopathy, GLP-1 receptor agonists increased retinopathy complications (8.2% vs 5.2% placebo) over 2 years 1
• Among patients without known retinopathy history, the risk was lower (0.7% vs 0.4% placebo) 1
• This appears related to rapid glucose improvement causing temporary worsening of retinopathy 1

Gastrointestinal Effects

Common GI Side Effects

• Nausea, vomiting, and diarrhea are the most common adverse effects, resulting from delayed gastric emptying 2, 3
• Nausea occurs in up to 44% of patients, diarrhea in 13-18%, and constipation in 10-30% 4
• These effects are typically transient and less common with long-acting formulations 5

Delayed Gastric Emptying - Critical Long-Term Concern

• Short-acting GLP-1 receptor agonists maintain their effect on gastric emptying during long-term treatment, while long-acting agents show tachyphylaxis over time 6
• However, emerging evidence shows that delayed gastric emptying can persist even after prolonged fasting periods, creating significant perioperative risk 2
• Multiple case reports document regurgitation and pulmonary aspiration during anesthesia despite fasting for 18-20 hours 2
• Current recommendations suggest holding GLP-1 receptor agonists for at least three half-lives before elective procedures 2, 3

Cholelithiasis and Cholecystitis

• Increased risk of gallstone formation and cholecystitis has been reported 2, 7
• In liraglutide trials, cholelithiasis occurred in 0.3% of both treated and placebo patients, with cholecystitis in 0.2% of both groups 7

Pancreatic Effects

Pancreatitis Risk

• Acute pancreatitis rates in clinical trials: 0.27-0.3 cases per 100 patient-years with GLP-1 receptor agonists vs 0.2-0.33 with placebo/comparator 1
• The FDA label requires discontinuation if pancreatitis is suspected and permanent discontinuation if confirmed 1
• Meta-analyses have not confirmed a definitive causal relationship between GLP-1 receptor agonists and pancreatitis 8
• Monitor for persistent severe abdominal pain, especially radiating to the back 1

Pancreatic Cancer Concerns

• Animal studies and database analyses suggested associations, but multiple meta-analyses failed to confirm a cause-effect relationship 8
• Lipase increased by 33% and amylase by 15% in renal impairment patients on liraglutide 7

Thyroid Effects

Medullary Thyroid Carcinoma (MTC)

• Absolute contraindication: personal or family history of MTC or Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 4, 1
• Based on rodent studies showing thyroid C-cell tumors; relevance to humans uncertain 1
• Routine calcitonin monitoring is of uncertain value and may lead to unnecessary procedures 1
• If calcitonin is measured and >50 ng/L, further evaluation is required 1

Renal Effects

Acute Kidney Injury

• Postmarketing reports of acute kidney injury and worsening chronic renal failure, sometimes requiring hemodialysis 1
• Majority of cases occurred in patients with severe GI symptoms causing dehydration 1, 8
• Monitor renal function when initiating or escalating doses, especially in patients with severe GI reactions 1

Beneficial Renal Effects

• GLP-1 receptor agonists can enhance natriuresis and reduce albuminuria 2, 3
• May slow eGFR decline, particularly beneficial in patients at risk for renal complications 3

Hepatobiliary Effects

• Postmarketing reports include elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, and hepatitis 7
• Mildly elevated bilirubin (up to 2x upper limit) occurred in 4.0% of liraglutide-treated patients vs 2.1% placebo, without other liver test abnormalities 7

Hypersensitivity Reactions

• Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists 1
• Use caution in patients with history of angioedema or anaphylaxis to another GLP-1 receptor agonist 1
• Allergic reactions including rash and pruritus reported postmarketing 7

Long-Term Efficacy and Treatment Failure

• HbA1c improvement peaks in the first year (-1.2%) and is maintained at 4 years (-1.4%) in only one-third of patients 9
• Treatment failure occurred in 51% of patients after mean duration of 50 months 9
• Predictive factors for failure: baseline HbA1c >9.0% and male gender 9
• BMI reduction is sustained: -0.9 kg/m² at 1 year, -1.9 kg/m² at 4 years 9

Special Populations and Precautions

Heart Failure Patients

• Use with caution in patients with established HFrEF and recent decompensation given trend toward worse outcomes 2
• Safe to use but not beneficial for preventing heart failure in at-risk patients 2

Perioperative Management

• Hold for at least three half-lives before elective procedures (for weight loss indication) 2, 3
• For diabetes patients, consult endocrinology regarding risks/benefits of holding 2, 3
• Consider gastric ultrasound to assess residual gastric contents 2
• Consider rapid-sequence intubation in high-risk patients 2

Hypoglycemia Risk

• Minimal intrinsic hypoglycemia risk, but increases risk when combined with insulin secretagogues or insulin 1
• Dose reduction of sulfonylureas or insulin required when initiating GLP-1 receptor agonists 1

Common Pitfalls to Avoid

1. Do not assume standard fasting times are adequate before procedures - delayed gastric emptying can persist despite prolonged fasting 2
2. Do not overlook diabetic retinopathy screening in patients with pre-existing retinopathy before initiating therapy 1
3. Do not continue therapy if pancreatitis is confirmed - permanent discontinuation required 1
4. Do not use in patients with personal/family history of MTC or MEN2 - absolute contraindication 4, 1
5. Do not ignore severe GI symptoms - can lead to dehydration and acute kidney injury 1, 8