What is the role of GLP-1 (Glucagon-Like Peptide-1) agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), in managing type 2 diabetes?

GLP-1 Receptor Agonists in Type 2 Diabetes Management

Primary Recommendation

GLP-1 receptor agonists, particularly semaglutide and liraglutide, should be prioritized as first-line injectable therapy for type 2 diabetes, especially in patients with established atherosclerotic cardiovascular disease, due to their proven mortality reduction and cardiovascular benefits. 1, 2

Mechanism and Glycemic Efficacy

• GLP-1 receptor agonists stimulate glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and promote satiety through central appetite suppression 3, 4
• Semaglutide demonstrates the greatest glucose-lowering efficacy among GLP-1 receptor agonists, reducing HbA1c by 1.2-1.5% 4, 5
• Long-acting agents (semaglutide, liraglutide, dulaglutide) provide superior HbA1c reduction and fasting glucose control compared to short-acting formulations 4
• The hypoglycemia risk is minimal when used as monotherapy due to glucose-dependent mechanisms, but increases when combined with insulin or sulfonylureas—dose reduction of these agents is required 3, 4

Cardiovascular and Mortality Benefits

The cardiovascular benefits represent the most compelling reason to use GLP-1 receptor agonists in appropriate patients:

• Liraglutide reduced cardiovascular death by 22% and the composite of MI, stroke, or cardiovascular death by 13% in the LEADER trial 2
• Semaglutide reduced cardiovascular events by 26% in the SUSTAIN-6 trial 2
• In patients with peripheral arterial disease and type 2 diabetes, liraglutide showed a beneficial trend for major adverse cardiovascular events (HR 0.77,95% CI 0.58-1.01), though not statistically significant due to limited power 1
• Patients with established atherosclerotic cardiovascular disease should receive GLP-1 receptor agonists as first-line therapy based on proven mortality benefits 2

Weight Loss Benefits

• Non-diabetic patients achieve 6.1-17.4% weight loss, while diabetic patients achieve 4-6.2% weight loss 2
• Semaglutide 2.4 mg weekly produces mean body weight reduction of 14.9% in non-diabetic overweight/obese patients 2
• Oral semaglutide 14 mg produces superior weight loss (-4.4 kg) compared to subcutaneous liraglutide (-3.1 kg) and placebo (-0.5 kg) at 26 weeks 5

Renal Benefits

• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline without increasing heart failure hospitalization risk 3
• These agents are recommended for patients with type 2 diabetes and chronic kidney disease who do not meet glycemic targets with metformin and/or SGLT2 inhibitors 4
• Exenatide and lixisenatide are contraindicated in severe renal impairment; liraglutide and semaglutide should be used with caution 3

Available Formulations and Dosing

Semaglutide (Ozempic): 6

• Start at 0.25 mg subcutaneously once weekly for 4 weeks
• Increase to 0.5 mg once weekly; if additional glycemic control needed after at least 4 weeks, increase to 1 mg once weekly
• Administer at any time of day, with or without meals
• Oral formulation also available 3

Liraglutide (Victoza): 7

• Once-daily subcutaneous injection
• Approved for adults and pediatric patients aged 10 years and older with type 2 diabetes
• Indicated to reduce major adverse cardiovascular events in adults with established cardiovascular disease

Safety Profile and Contraindications

Absolute Contraindications: 3, 6

• Personal or family history of medullary thyroid carcinoma
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
• Known hypersensitivity to the drug

Common Adverse Effects: 3

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur during initial treatment and typically diminish over time
• These effects are dose-dependent and more pronounced with semaglutide 3
• Nausea is minimized with gradual dose titration 8

Serious Adverse Events Requiring Monitoring: 3, 6

• Pancreatitis—discontinue promptly if suspected; do not restart if confirmed
• Diabetic retinopathy complications—monitor patients with history of diabetic retinopathy, especially with rapid glucose reduction
• Acute kidney injury—monitor renal function in patients with renal impairment experiencing severe gastrointestinal reactions
• Delayed gastric emptying may slow absorption of other oral medications 3

Special Clinical Situations

Peripheral Arterial Disease: 1

• Tight glycemic control with GLP-1 receptor agonists is recommended, preferably adding metformin and other agents as necessary
• Target HbA1c <53 mmol/mol (7%) to avoid hypoglycemia; consider higher threshold (<69 mmol/mol [8.5%]) for limited life expectancy

Non-Alcoholic Fatty Liver Disease: 3

• GLP-1 receptor agonists may decrease hepatic steatosis
• Semaglutide 0.4 mg daily achieved NASH resolution without worsening fibrosis in 59% versus 17% on placebo 2

Perioperative Management: 2

• Preoperative liraglutide treatment improves glycemic control in the perioperative period in patients with and without diabetes
• Tachyphylaxis to gastric emptying effects develops with continuous exposure 2

Pregnancy Planning: 6

• Discontinue semaglutide at least 2 months before planned pregnancy due to long washout period

Clinical Positioning Algorithm

For patients with type 2 diabetes and established atherosclerotic cardiovascular disease:

• Use semaglutide or liraglutide as first-line injectable therapy 1, 2

For patients requiring weight loss:

• Prioritize semaglutide (greatest weight loss efficacy) or liraglutide 4, 2

For patients with chronic kidney disease:

• Use GLP-1 receptor agonists with proven cardiovascular benefit if not meeting targets with metformin/SGLT2 inhibitors 4
• Avoid exenatide and lixisenatide in severe renal impairment 3

For patients at risk of hypoglycemia:

• GLP-1 receptor agonists are safe choices due to glucose-dependent mechanism 4, 8
• Reduce insulin or sulfonylurea doses when initiating to prevent hypoglycemia 3, 2

For patients preferring oral therapy:

• Oral semaglutide is non-inferior to subcutaneous semaglutide for HbA1c reduction 5, 9