What are the latest recommendations for using Glucagon-like peptide-1 (GLP-1) analogs, such as liraglutide (Victoza) (liraglutide), semaglutide (Ozempic) (semaglutide), or dulaglutide (Trulicity) (dulaglutide), in the treatment of type 2 diabetes?

Latest Recommendations for GLP-1 Receptor Agonists in Type 2 Diabetes Management

GLP-1 receptor agonists (GLP-1 RAs) with demonstrated cardiovascular benefit, including semaglutide, liraglutide, and dulaglutide, are strongly recommended as part of the glucose-lowering regimen for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD) or are at high risk for ASCVD. 1

Cardiovascular Benefits

• GLP-1 RAs have shown significant cardiovascular benefits in patients with type 2 diabetes, with several agents demonstrating reduction in major adverse cardiovascular events (MACE) 1
• Liraglutide demonstrated a 13% reduction in the primary composite outcome (MI, stroke, or cardiovascular death) compared to placebo (HR 0.87; 95% CI 0.78-0.97) and a 22% reduction in cardiovascular death (HR 0.78; 95% CI 0.66-0.93) 1
• Semaglutide showed a 26% reduction in MACE in the SUSTAIN-6 trial (HR 0.74; 95% CI 0.58-0.95) 2, 1
• Dulaglutide has also demonstrated cardiovascular benefit and is recommended for patients with type 2 diabetes and established cardiovascular disease 1

Specific Agent Recommendations

• For patients with established ASCVD or at high risk for ASCVD, the European Society of Cardiology specifically recommends liraglutide, semaglutide, or dulaglutide to reduce cardiovascular events 1
• Liraglutide is specifically recommended to reduce the risk of death in patients with type 2 diabetes and CVD or at very high/high CV risk 1
• Semaglutide (both injectable and oral formulations) has shown strong efficacy for both glycemic control and weight reduction 3, 4

Dosing and Administration

• GLP-1 RAs are available in different administration schedules:
  • Once-daily: liraglutide, lixisenatide 3
  • Once-weekly: semaglutide, dulaglutide, exenatide extended-release 3
  • Oral: semaglutide (first oral GLP-1 RA) 5
• Initiate at the lowest dose and follow labeling instructions for dose titration to minimize gastrointestinal side effects 1
• For semaglutide, start at 0.25 mg SC weekly and titrate to 0.5 mg or 1 mg weekly as tolerated 1
• For liraglutide, start at 0.6 mg SC daily and titrate to 1.8 mg daily or maximally tolerated dose 1

Contraindications and Cautions

• Contraindications for GLP-1 RAs include:

  • Personal or family history of medullary thyroid carcinoma 1
  • Multiple endocrine neoplasia syndrome type 2 (MEN2) 1
  • History of serious hypersensitivity reaction to the drug 1
  • Pregnancy or breastfeeding 1

• Cautions for use include:

  • History of pancreatitis (use liraglutide with caution) 1
  • Severe renal impairment (use liraglutide and semaglutide with caution) 1
  • Increased risk of hypoglycemia when used with insulin or insulin secretagogues (dose adjustment of these agents may be required) 1
  • Semaglutide has been associated with diabetic retinopathy complications, particularly with rapid glucose reduction 1

Adverse Effects

• Most common adverse effects are gastrointestinal, including nausea, vomiting, and diarrhea 2, 3
• Gastrointestinal side effects typically decrease over time 6
• Slow titration is recommended to improve gastrointestinal tolerability 2
• Recent data suggests potential differences in gallstone and acute cholecystitis risk between agents, with dulaglutide showing lower risk compared to semaglutide 7

Comparative Effectiveness

• Recent comparative effectiveness studies in veterans with type 2 diabetes found similar risks for kidney and cardiovascular outcomes among liraglutide, semaglutide, and dulaglutide initiators 7
• Semaglutide appears to have greater efficacy for both glycemic control and weight reduction compared to other GLP-1 RAs 3, 4
• All three agents (liraglutide, semaglutide, dulaglutide) have demonstrated cardiovascular benefits, though with some differences in specific outcomes 1

Algorithm for GLP-1 RA Selection

1. For patients with established ASCVD or at high risk:

   • First choice: Semaglutide (strongest glycemic and weight effects) 3, 4
   • Alternative if CV mortality reduction is priority: Liraglutide 1

2. For patients with renal impairment:

   • Both semaglutide and dulaglutide can be used without dose adjustment in chronic kidney disease 2
   • Avoid exenatide and lixisenatide in severe renal impairment 1

3. For patients with concerns about injection frequency:

   • Once-weekly options: semaglutide, dulaglutide, exenatide extended-release 3
   • Oral option: oral semaglutide 5, 4

4. For patients with history of retinopathy:

   • Consider agents other than semaglutide or use with careful monitoring 1