What are the treatment options for Glucagon-like peptide-1 (GLP-1)?

From the Guidelines

GLP-1 receptor agonists, such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), are the most effective options for weight loss and diabetes management, with semaglutide and tirzepatide showing the greatest weight loss potential of up to 20% of body weight. The main options for GLP-1 receptor agonists include semaglutide, tirzepatide, liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), and exenatide (Byetta, Bydureon) 1. For weight loss, semaglutide (Wegovy) at 2.4mg weekly or tirzepatide (Zepbound) at 5-15mg weekly are most effective, with tirzepatide showing the greatest weight loss potential of up to 20% of body weight. For diabetes, starting doses are typically lower: semaglutide 0.25mg weekly (increasing to 0.5-1mg), tirzepatide 2.5mg weekly (increasing to 5-15mg), or liraglutide 0.6mg daily (increasing to 1.2-1.8mg) 1.

Key Considerations

• These medications work by mimicking GLP-1, a hormone that regulates blood sugar and appetite, and have been shown to reduce albuminuria and slow eGFR decline in patients with chronic kidney disease 1.
• Side effects commonly include nausea, vomiting, and diarrhea, which typically improve over time, and patients should start at low doses and gradually increase to minimize these effects 1.
• The medications require injection, with frequency ranging from daily to weekly depending on the specific drug, and have been shown to be effective in reducing the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes 1.
• GLP-1 receptor agonists do not cause hypoglycemia per se, but when used with insulin or insulin secretagogues, doses of these drugs may be reduced to avoid hypoglycemia 1.

Patient Selection

• For patients with BMI >35 kg/m2, GLP-1 receptor agonists constitute the second-line drug of choice, with the greatest potential for weight loss 1.
• For patients with BMI <30 kg/m2, DPP-4 inhibitors and SGLT2 inhibitors are considered equally preferable second-line treatment options 1.
• GLP-1 receptor agonists are also preferred agents for patients with cardiovascular disease, as they have been shown to reduce the risk of MACE 1.

Treatment Approach

• The treatment approach should prioritize the use of GLP-1 receptor agonists, such as semaglutide and tirzepatide, as first-line or second-line therapy, depending on the patient's individual characteristics and medical history.
• Patients should be started on low doses and gradually increased to minimize side effects, and the treatment approach should be individualized based on the patient's response to therapy and medical history 1.

From the FDA Drug Label

INDICATIONS AND USAGE OZEMPIC is a glucagon-like peptide 1 (GLP-1) receptor agonist indicated as: INDICATIONS AND USAGE TRULICITY® is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated Two GLP-1 options are:

• Semaglutide (SQ), referenced as 2
• Dulaglutide (SQ), referenced as 3

From the Research

GLP-1 Options

• GLP-1 receptor agonists (GLP-1 RAs) are a class of injectable glucose-lowering agents that lower A1C with added benefits of weight loss and improved cardiovascular risk markers 4, 5.
• GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide) 4.
• A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved 4.
• All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight 4.

Types of GLP-1 RAs

• Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment 4.
• Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin 4.
• More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight 4.

Clinical Considerations

• GLP-1 RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment 4.
• GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations 4.
• The selection of the most appropriate treatment for individual patients is important, considering factors such as patient preference, efficacy, and safety profiles 5, 6.
• Real-world evidence suggests that GLP-1 RAs are often less effective than in clinical trial conditions, due to factors such as non-adherence and lower dosing 7.