What are the indications, benefits, and risks of using Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), in patients with type 2 diabetes or obesity?

GLP-1 Receptor Agonists: Indications, Benefits, and Risks

GLP-1 receptor agonists are strongly recommended for patients with type 2 diabetes who have established cardiovascular disease, are at high cardiovascular risk, or have chronic kidney disease, as they provide significant benefits beyond glucose control including cardiovascular and renal protection. 1

Indications

Type 2 Diabetes

• First-line therapy (with or without metformin) for patients with:
  • Established atherosclerotic cardiovascular disease (ASCVD) 1
  • High cardiovascular risk 1
  • Heart failure, particularly with reduced ejection fraction 1
  • Chronic kidney disease 1
• Add-on therapy when oral medications alone are insufficient to meet HbA1c goals 2

Obesity Management

• Indicated for adults with:
  • BMI ≥30 kg/m² or
  • BMI ≥27 kg/m² with at least one weight-related comorbidity 3
• Must be used as an adjunct to reduced-calorie diet and increased physical activity 3

Benefits

Glycemic Control

• High glucose-lowering efficacy with minimal risk of hypoglycemia when used as monotherapy 1
• Efficacy varies within the class, with semaglutide showing the greatest effect, followed by dulaglutide and liraglutide 1

Cardiovascular Benefits

• Reduce major adverse cardiovascular events (MACE) in patients with established cardiovascular disease 1
• Liraglutide, semaglutide, and dulaglutide are specifically recommended to reduce cardiovascular events 1
• Liraglutide specifically reduces risk of death in patients with T2DM and cardiovascular disease 1

Renal Protection

• Help prevent progression of chronic kidney disease 1
• Beneficial for patients with eGFR 30-60 mL/min/1.73m² or urinary albumin-to-creatinine ratio >30 mg/g 1

Weight Management

• Promote significant weight loss:
  • Injectable semaglutide 2.4 mg weekly achieves mean weight loss of 14.9-17.4% at 68 weeks 3
  • 64.9% of patients achieve ≥10% weight loss and 46.1% achieve ≥15% weight loss with semaglutide 3

Risks and Adverse Effects

Gastrointestinal Effects

• Most common adverse effects: nausea, vomiting, diarrhea, and constipation 3, 4
• GI side effects are typically dose-dependent and often improve with time 3

Serious Concerns

• Risk of thyroid C-cell tumors (contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2) 4
• Rare reports of pancreatitis (GLP-1 RAs should be avoided in patients with history of pancreatitis) 4
• Gallbladder disease (cholelithiasis, cholecystitis) 3
• Rare reports of suicidal ideation 3

Perioperative Considerations

• May increase risk of delayed gastric emptying and pulmonary aspiration in the perioperative period 1
• For elective surgery:
  • In patients with diabetes: individualized approach with endocrinology consultation due to concerns about glycemic control if discontinued 1
  • For weight management only: withhold for at least three half-lives before surgery 1

Administration and Dosing

Injectable GLP-1 RAs

• Semaglutide (Ozempic):

  • Start with 0.25 mg weekly for 4 weeks (initiation dose)
  • Increase to 0.5 mg weekly
  • May increase to 1 mg weekly if needed after at least 4 weeks 4
  • For weight management: can titrate up to 2.4 mg weekly 3

• Liraglutide (Saxenda for weight management):

  • Start with 0.6 mg daily for 7 days
  • Increase by 0.6 mg increments weekly to target dose of 3.0 mg daily 3

Administration Tips

• Can be administered at any time of day, with or without meals 4
• Inject subcutaneously in abdomen, thigh, or upper arm 4
• Rotate injection sites 4

Important Clinical Considerations

Patient Selection

• BMI should not affect decision to use GLP-1 RAs for cardiovascular or renal protection 5
• Benefits appear consistent across BMI categories for cardiovascular and renal outcomes 5

Long-term Use

• Long-term use is necessary to maintain weight loss
• Significant weight regain (11.6% of lost weight) occurs after discontinuation 3
• Plan for maintenance strategy if discontinuation is needed 3

Monitoring

• Regular assessment of weight response
• Screen for malnutrition in patients with significant weight loss
• Monitor for gallbladder disease and pancreatitis 3
• For patients with diabetes, monitor glycemic control

Practical Management of Side Effects

• Start at low dose and titrate slowly
• Reduce meal size
• Avoid high-fat diet, alcohol, and carbonated drinks
• Avoid use in patients with gastroparesis 3

GLP-1 receptor agonists represent a significant advancement in the treatment of type 2 diabetes and obesity, offering benefits beyond glycemic control including cardiovascular and renal protection, while promoting weight loss. However, careful patient selection and monitoring are essential to maximize benefits and minimize risks.