What is the difference in effectiveness between oral and injectable Glucagon-like peptide-1 (GLP-1) receptor agonists?

From the Guidelines

Injectable GLP-1 receptor agonists, such as semaglutide and liraglutide, are significantly more effective than oral formulations for weight loss and improving weight-related comorbidities, with a mean weight loss of 14.9% to 16.0% compared to 15.1% for oral semaglutide 1. The difference in effectiveness between oral and injectable GLP-1 receptor agonists can be attributed to several factors, including bioavailability and dosing options. Injectable GLP-1s have a higher bioavailability and can be administered once weekly, whereas oral semaglutide requires daily dosing and has a lower bioavailability. Some key points to consider when choosing between oral and injectable GLP-1 receptor agonists include:

• Mean weight loss: Injectable semaglutide has been shown to result in a mean weight loss of 14.9% to 16.0%, while oral semaglutide has been shown to result in a mean weight loss of 15.1% 1.
• Dosing options: Injectable GLP-1s offer more flexible dosing options, including once-weekly formulations, compared to daily oral dosing.
• Bioavailability: Injectable GLP-1s have a higher bioavailability compared to oral formulations, which can result in superior clinical outcomes.
• Convenience: Oral formulations provide convenience and avoid injections, but may have limited real-world effectiveness due to strict administration conditions. Overall, while oral formulations may provide convenience, injectable GLP-1 receptor agonists are significantly more effective for weight loss and improving weight-related comorbidities, and should be considered for patients seeking maximal clinical outcomes 1.

From the FDA Drug Label

INDICATIONS AND USAGE VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (1). • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1).

INDICATIONS AND USAGE OZEMPIC is a glucagon-like peptide 1 (GLP-1) receptor agonist indicated as: • an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1). • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1).

The effectiveness of oral and injectable GLP-1 receptor agonists, such as liraglutide (SQ) 2 and semaglutide (PO) 3, may differ due to their distinct routes of administration and pharmacokinetic profiles. However, the provided drug labels do not directly compare the effectiveness of these two formulations.

• The labels indicate that both liraglutide (SQ) and semaglutide (PO) are effective as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• Both labels also mention the reduction of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease. Since the labels do not provide a direct comparison, no conclusion can be drawn regarding the difference in effectiveness between oral and injectable GLP-1 receptor agonists.

From the Research

Difference in Effectiveness of Oral and Injectable GLP-1

• The effectiveness of oral and injectable GLP-1 receptor agonists (GLP-1 RAs) has been compared in several studies 4, 5, 6, 7.
• Oral semaglutide has been shown to have similar effectiveness to injectable semaglutide in reducing HbA1c levels and body weight in patients with type 2 diabetes 5, 7.
• A systematic review and meta-analysis found that oral semaglutide significantly reduced HbA1c, body weight, and fasting plasma glucose compared to placebo or active comparators 7.
• Injectable GLP-1 RAs, such as liraglutide and dulaglutide, have also been shown to be effective in reducing HbA1c and body weight, but may have different adverse event profiles compared to oral semaglutide 4, 6.
• The choice between oral and injectable GLP-1 RAs may depend on individual patient factors, such as preference for oral or injectable administration, and the presence of certain comorbidities or adverse events 5, 8.

Adverse Events and Safety

• Oral semaglutide has been associated with gastrointestinal adverse events, such as nausea, diarrhea, and vomiting, but did not increase the incidence of hypoglycemia, myocardial infarction, or stroke compared to placebo or active comparators 7.
• Injectable GLP-1 RAs have also been associated with gastrointestinal adverse events, as well as other adverse events such as pancreatitis and thyroid cancer 4, 6.
• The safety and efficacy of oral and injectable GLP-1 RAs are being continuously monitored and evaluated in ongoing clinical trials and real-world studies 5, 8.

Clinical Implications

• The availability of oral and injectable GLP-1 RAs provides clinicians with more treatment options for patients with type 2 diabetes, and may help improve adherence and outcomes in certain patient populations 4, 5.
• The choice of GLP-1 RA should be individualized based on patient factors, such as renal function, hepatic function, and history of adverse events 6, 7.
• Further research is needed to fully understand the long-term effects and potential benefits of oral and injectable GLP-1 RAs in patients with type 2 diabetes and other conditions, such as obesity and cardiovascular disease 8.