What is the role of GLP1 (Glucagon-like peptide-1) receptor agonists, such as Victoza (liraglutide) or Ozempic (semaglutide), in the treatment of type 2 diabetes?

Role of GLP-1 Receptor Agonists in Type 2 Diabetes Management

GLP-1 receptor agonists are highly effective medications for type 2 diabetes that should be considered as preferred agents after metformin, particularly in patients with established cardiovascular disease, high cardiovascular risk, chronic kidney disease, or obesity. 1

Mechanism of Action and Benefits

GLP-1 receptor agonists work through multiple mechanisms:

• Enhance glucose-dependent insulin secretion
• Inhibit glucagon secretion
• Delay gastric emptying
• Promote satiety and reduce food intake via central appetite suppression
• Reduce body weight (1.5-3.5 kg on average) 1

Glycemic Efficacy

• Reduce HbA1c by approximately 0.5-1.5% 1, 2
• Minimal risk of hypoglycemia when used alone 1
• Different potency within the class, with semaglutide showing greatest efficacy for both glucose lowering and weight reduction 2

Cardiovascular Benefits

GLP-1 receptor agonists with proven cardiovascular benefits include:

• Liraglutide (LEADER trial) - 13% reduction in MACE 1
• Semaglutide (SUSTAIN-6 trial) - 26% reduction in MACE 1
• Dulaglutide (REWIND trial) 1

These agents are particularly recommended for patients with:

• Established atherosclerotic cardiovascular disease
• Multiple cardiovascular risk factors
• Age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%
• Left ventricular hypertrophy
• eGFR <60 mL/min/1.73m² or albuminuria 1

Renal Benefits

• Reduce albuminuria and slow eGFR decline 1
• Particularly beneficial in patients with eGFR <60 mL/min/1.73m² 1
• Dulaglutide has demonstrated significantly slower GFR decline compared to insulin glargine 1

Available Formulations and Administration

GLP-1 receptor agonists are available in different formulations:

1. Once-weekly injections:

   • Semaglutide (Ozempic)
   • Dulaglutide (Trulicity)
   • Exenatide extended-release

2. Once-daily injections:

   • Liraglutide (Victoza)
   • Lixisenatide

3. Oral formulation:

   • Oral semaglutide (Rybelsus) - first oral GLP-1 receptor agonist 3, 4

Placement in Treatment Algorithm

GLP-1 receptor agonists should be considered:

1. After metformin as preferred second-line therapy, especially in patients with:

   • Established cardiovascular disease
   • High cardiovascular risk
   • Chronic kidney disease
   • Obesity 1, 5

2. As first injectable therapy before insulin in most patients with type 2 diabetes 1, 2

3. In combination with insulin when needed, which can reduce insulin requirements 2

Common Side Effects and Contraindications

Side Effects:

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) - most common, typically transient 1
• Injection site reactions (rare, <1%) 1
• Increased heart rate (approximately 5 bpm) 1

Contraindications:

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

Cautions:

• History of pancreatitis (use liraglutide with caution)
• Severe renal impairment (use liraglutide and semaglutide with caution)
• Risk of hypoglycemia increased when combined with insulin or sulfonylureas
• Gastroparesis (shorter-acting agents may worsen symptoms)
• Prior gastric surgery 1
• Diabetic retinopathy complications with semaglutide (related to rapid glucose reduction) 1

Perioperative Considerations

Recent evidence suggests potential concerns about delayed gastric emptying in the perioperative period:

• Increased risk of pulmonary aspiration during anesthesia 1
• American Society of Anesthesiologists recommends stopping once-daily doses the day before procedures and once-weekly doses the week before procedures 1
• However, benefits of continued use include improved perioperative glycemic control and lower postoperative insulin requirements 1

Practical Considerations

• Start with low doses and titrate gradually to minimize gastrointestinal side effects 1
• Consider reducing doses of concomitant insulin or sulfonylureas to prevent hypoglycemia 1
• For patients unable or unwilling to use injectable medications, oral semaglutide provides a viable alternative with similar efficacy 3, 4
• When comparing agents within the class, semaglutide generally shows greater efficacy for both glucose lowering and weight reduction than liraglutide, though both are effective 2, 6

GLP-1 receptor agonists represent a significant advancement in type 2 diabetes management, offering benefits beyond glycemic control including cardiovascular protection, renal benefits, and weight reduction, making them a cornerstone therapy for many patients with type 2 diabetes.