What is the best GLP-1 (Glucagon-like peptide-1) receptor agonist?

Best GLP-1 Receptor Agonist for Clinical Use

Semaglutide is the most effective GLP-1 receptor agonist, demonstrating superior glycemic control, weight reduction, and cardiovascular benefits compared to other agents in its class. 1, 2

Efficacy Comparison of GLP-1 Receptor Agonists

• Semaglutide shows the greatest glucose-lowering efficacy among GLP-1 receptor agonists, followed by dulaglutide and liraglutide, then exenatide once weekly, and finally exenatide twice daily and lixisenatide 1
• Semaglutide produces substantially greater weight loss (14.9% reduction from baseline in non-diabetic patients) compared to other GLP-1 receptor agonists, with weight loss effects previously only seen with bariatric surgery 1
• Tirzepatide, a dual GIP/GLP-1 receptor agonist, shows even greater weight reduction (up to 20.9% at higher doses), though it has a slightly different mechanism of action 1

Cardiovascular Benefits

• Dulaglutide, liraglutide, and semaglutide have all demonstrated cardiovascular benefits in large cardiovascular outcome trials 1
• The SUSTAIN 6 trial showed semaglutide reduced the risk of major adverse cardiovascular events (cardiovascular death, non-fatal MI, or stroke) by 26% compared to placebo (6.6% vs 8.9%, HR 0.74) 1
• The LEADER trial demonstrated liraglutide reduced the primary composite cardiovascular outcome by 13% compared to placebo 1
• Cardiovascular benefits appear more pronounced in patients with reduced renal function (eGFR <60 ml/min/1.73 m²) 1

Renal Benefits

• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline, as demonstrated in cardiovascular outcome trials 1
• Dulaglutide has been shown to produce similar glycemic control to insulin glargine but with significantly slower GFR decline in patients with moderate-to-severe CKD 1
• GLP-1 receptor agonists retain glucose-lowering potency across the range of eGFR, including in dialysis patients 1, 3
• These agents can be used with eGFR as low as 15 ml/min/1.73 m² 1

Administration Options

• Semaglutide is the only GLP-1 receptor agonist available in both subcutaneous and oral formulations 2, 4
• Dulaglutide, exenatide extended-release, and semaglutide are administered once weekly, while liraglutide and lixisenatide require daily administration 1
• Oral semaglutide uses a novel SNAC technology that prevents destruction in the stomach and enables absorption through the gastric membrane 4

Safety Considerations

• Common adverse effects include nausea, vomiting, and diarrhea (occurring in 15-20% of patients), which are typically dose-dependent, more frequent with short-acting formulations, and usually abate over time 1
• GLP-1 receptor agonists have minimal risk for hypoglycemia when used as monotherapy 1, 2
• These agents are not recommended for patients at risk for thyroid C-cell tumors, pancreatic cancer, or pancreatitis 1
• Semaglutide may increase the risk of biliary disease (cholelithiasis) 2
• Due to its potent glucose-lowering effect, patients with existing diabetic retinopathy should be carefully monitored if treated with semaglutide, particularly if also on insulin therapy 2

Algorithm for GLP-1 RA Selection

1. For patients requiring maximum glycemic control and weight loss: Choose semaglutide (oral or injectable based on patient preference) 1, 2, 5
2. For patients with established cardiovascular disease: Choose semaglutide, liraglutide, or dulaglutide 1
3. For patients with CKD: Any GLP-1 RA with proven cardiovascular benefit is recommended, with preference for those showing renal benefits (semaglutide, liraglutide, dulaglutide) 1
4. For patients with severe gastrointestinal intolerance: Consider dulaglutide which may have a more favorable GI side effect profile compared to semaglutide 6
5. For patients requiring an oral option: Oral semaglutide is the only available choice 4

Practical Considerations

• Start GLP-1 receptor agonists at a low dose and titrate upward slowly to improve gastrointestinal tolerability 1
• When used with insulin or insulin secretagogues, doses of these drugs may need to be reduced to avoid hypoglycemia 1
• In moderate-to-severe CKD, rates of hypoglycemia are reduced by half even with concurrent insulin therapy 1
• Avoid use in patients with gastroparesis and use with caution in those with a history of pancreatitis 1