Can Glucagon-like peptide-1 (GLP-1) receptor agonists be used as first-line treatment for diabetes if a patient is intolerant to Metformin (Biguanide)?

From the Guidelines

GLP-1 receptor agonists (GLP-1 RAs) can be considered as a first-line treatment for type 2 diabetes in patients who are intolerant to metformin, despite being of low value compared to metformin as initial therapy. According to the most recent and highest quality study, a systematic review of cost-effectiveness studies for the American College of Physicians published in the Annals of Internal Medicine in 2024 1, GLP-1a and SGLT2i are of low value as first-line therapy but may be of intermediate value when added to metformin or other background therapy compared to adding nothing.

Key Points to Consider

• GLP-1 RAs, including semaglutide, dulaglutide, liraglutide, and tirzepatide, are effective alternatives to metformin for patients who are intolerant to it.
• When starting a GLP-1 RA, it's typically initiated at a low dose and gradually increased to minimize gastrointestinal side effects, such as nausea, vomiting, and diarrhea.
• These medications offer additional benefits beyond glucose control, including weight loss and cardiovascular protection in some cases, as noted in the study by Guzauskas et al, 2021, which compared GLP-1a (oral semaglutide) vs. nothing added to metformin with or without sulfonylurea 1.
• Patients should be monitored for potential rare side effects such as pancreatitis and advised about proper injection technique if using injectable formulations.

Clinical Decision Making

In clinical practice, the decision to use GLP-1 RAs as first-line treatment for type 2 diabetes in patients intolerant to metformin should be based on individual patient factors, including the presence of cardiovascular disease, kidney disease, and other comorbidities, as well as the patient's preferences and values. The study by Choi et al, 2022, which compared SGLT2i vs. metformin as first-line pharmacologic therapy, found that SGLT2i are of low value compared with metformin as a first-line treatment 1. However, GLP-1 RAs may be a viable alternative for patients who cannot tolerate metformin.

Treatment Initiation and Monitoring

When initiating GLP-1 RA therapy, it's essential to start with a low dose and gradually increase as needed and tolerated, to minimize gastrointestinal side effects. For example, injectable semaglutide starts at 0.25mg weekly for 4 weeks, then increases to 0.5mg weekly, with potential further increases to 1mg or 2mg weekly as needed for glycemic control. Regular monitoring of blood glucose levels, kidney function, and potential side effects is crucial to ensure the safe and effective use of GLP-1 RAs.

From the FDA Drug Label

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 FDA drug label does not answer the question about using GOP (Glucagon-like peptide-1 receptor agonist, e.g. semaglutide) as a first-line treatment for diabetes in patients intolerant to metformin. The label indicates that semaglutide is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, but it does not provide information on its use as a first-line treatment in patients intolerant to metformin 2.

From the Research

GLP-1 Receptor Agonists as First-Line Treatment for Diabetes

• GLP-1 receptor agonists (GLP-1 RAs) are a class of medications that have been shown to be effective in the treatment of type 2 diabetes 3, 4, 5.
• They work by augmenting hyperglycemia-induced insulin secretion, suppressing glucagon secretion, and decelerating gastric emptying, which helps to reduce post-meal glycemic increments 3, 4.
• GLP-1 RAs have been compared to other existing therapies, including metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas, and have been shown to have a similar or superior effectiveness in reducing HbA1c levels 4, 6, 7.

Use of GLP-1 RAs in Patients Intolerant to Metformin

• For patients who are intolerant to metformin, GLP-1 RAs may be considered as a first-line treatment option 4, 5.
• The choice of a specific GLP-1 RA will depend on patient preferences, potential adverse effects, and cost 3, 7.
• GLP-1 RAs have been shown to have a low risk of hypoglycemia and can help with weight loss, which may be beneficial for patients with type 2 diabetes 4, 5.

Clinical Experience and Guidelines

• Clinical trials and real-world studies have demonstrated the efficacy and safety of GLP-1 RAs in the treatment of type 2 diabetes 4, 5.
• Guidelines recommend GLP-1 RAs as a therapeutic option in various settings, including in patients who have not achieved HbA1c targets after first-line metformin and lifestyle modifications 5.
• GLP-1 RAs have also been shown to have cardiovascular benefits, particularly in patients with established cardiovascular disease or at high cardiovascular risk 4, 5.