What are the effects of long-term use of Glucagon-like peptide-1 (GLP-1) analogs, such as liraglutide (Victoza) or semaglutide (Ozempic), on patients?

Long-term Effects of GLP-1 Analogs

Long-term use of GLP-1 analogs is associated with significant weight loss, cardiovascular benefits, and potential renal protection, but requires monitoring for gastrointestinal side effects, pancreatitis, gallbladder disease, and diabetic retinopathy complications.

Beneficial Effects of Long-term GLP-1 Analog Use

Weight Loss

• Significant and sustained weight loss is a major benefit:
  • Liraglutide: 5.8-6.0% reduction from baseline 1
  • Semaglutide: 7.0-9.6% reduction from baseline (at 1.0-2.4mg weekly doses) 1
  • Tirzepatide (dual GIP/GLP-1 agonist): 12.8-14.7% reduction from baseline 1

Cardiovascular Benefits

• Several GLP-1 analogs demonstrate cardiovascular protection in patients with type 2 diabetes and established cardiovascular disease 1:
  • Liraglutide: 13% reduction in major adverse cardiovascular events (MACE)
  • Semaglutide: 26% reduction in MACE
  • Mechanisms include reduced blood pressure (1-6 mmHg), improved lipid profiles, and potential direct effects on the myocardium and vasculature 1

Renal Protection

• Evidence suggests renal benefits with long-term use:
  • Liraglutide: 20% reduction in composite renal outcomes
  • Semaglutide: 36% reduction in persistent macroalbuminuria
  • Particularly beneficial in patients with diabetic kidney disease and proteinuria 2

Adverse Effects and Safety Concerns

Gastrointestinal Effects

• Most common adverse effects (dose-dependent and typically transient) 1, 3, 4:
  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Abdominal pain
  • These effects are usually mild-to-moderate and diminish over time, especially with longer-acting formulations

Pancreatic Safety

• Pancreatitis risk:

  • FDA labels include warnings about acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis 3
  • However, recent large-scale analysis found no increased risk of pancreatitis with GLP-1 RAs in comorbidity-free patients with T2DM 5
  • Patients should be monitored for signs of pancreatitis (persistent severe abdominal pain)

• Pancreatic cancer:

  • Early concerns were raised 6, but more recent systematic reviews show no increased risk with semaglutide 7, 8
  • Animal studies with liraglutide showed no increased risk 9

Thyroid Safety

• Black box warning: Risk of thyroid C-cell tumors in rodents; human relevance not determined 1, 3
• Contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 1, 3
• Recent systematic review found no significant increase in thyroid cancer risk with semaglutide 7

Gallbladder Disease

• Increased risk of cholelithiasis and acute cholecystitis 1, 3, 8
• In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients treated with semaglutide 0.5mg and 1mg, respectively 3

Diabetic Retinopathy Complications

• Semaglutide was associated with increased risk of diabetic retinopathy complications in SUSTAIN-6 trial 1, 3
• Risk is higher in patients with pre-existing retinopathy and may be related to rapid glucose reduction 3
• Regular eye examinations are recommended, especially in patients with history of retinopathy 3

Renal Effects

• Potential risk of acute kidney injury due to volume depletion from gastrointestinal side effects 3, 4
• Caution needed in patients with severe renal impairment:
  • Exenatide and lixisenatide are contraindicated in severe renal impairment
  • Liraglutide and semaglutide should be used with caution 1, 2

Hypoglycemia

• Low risk when used as monotherapy
• Increased risk when combined with insulin or insulin secretagogues (e.g., sulfonylureas) 1, 3
• May require dose reduction of insulin or sulfonylureas when adding GLP-1 analog

Monitoring Recommendations for Long-term Use

1. Baseline assessment:

   • Renal function (eGFR)
   • Comprehensive eye examination if not done within past 12 months
   • Gallbladder assessment if symptomatic

2. Ongoing monitoring:

   • Regular assessment of gastrointestinal symptoms
   • Monitor for signs of pancreatitis (persistent severe abdominal pain)
   • Regular eye examinations, especially in those with pre-existing retinopathy
   • Renal function monitoring, particularly after dose increases
   • Blood glucose monitoring if combined with insulin or sulfonylureas

Practical Considerations for Long-term Management

• Dose titration: Start with lower doses and titrate slowly to minimize gastrointestinal side effects 2
• Hydration: Ensure adequate hydration to reduce risk of acute kidney injury 2
• Medication adjustments: Consider reducing doses of concomitant medications that increase hypoglycemia risk 1
• Patient education: Inform about potential side effects and when to seek medical attention

Common Pitfalls to Avoid

• Failure to monitor for diabetic retinopathy progression in high-risk patients
• Overlooking volume status in patients with gastrointestinal side effects
• Not adjusting doses of concomitant medications (especially insulin and sulfonylureas)
• Ignoring signs of potential pancreatitis or gallbladder disease
• Prescribing to patients with personal or family history of MTC or MEN2