Is it Time to Expand Glucagon-like Peptide-1 Receptor Agonist Use for Weight Loss in Patients Without Diabetes?

The obesity and type 2 diabetes mellitus epidemics demonstrate that simply emphasizing a healthy lifestyle is insufficient. While weight loss medications have historically been considered "cosmetic", glucagon-like peptide-1 receptor agonists (GLP1-RAs) also reduce cardiovascular risk in patients with type 2 diabetes. Therefore, we assessed whether GLP1-RAs warrant use in patients who are overweight (body mass index 27.0-29.9 kg/m) without weight-related comorbidity. We reviewed trials of available GLP1-RAs with a natural GLP1 backbone given their trend toward cardiovascular benefit and excluded trials requiring concurrent antidiabetic agents associated with weight gain. We assessed 20 phase III trials of GLP1-RAs studied in cardiovascular outcome trials. The GLP1-RAs consistently produced weight loss. Hypoglycemia risk with GLP1-RAs was generally low without other precipitating factors, whereas gastrointestinal adverse effects were common. Dulaglutide 1.5 mg weekly did not produce sufficient weight loss to support its use specifically for weight loss, while data supporting dulaglutide 3.0 or 4.5 mg weekly were limited to a single trial. Weight loss was sufficient with liraglutide 1.8 mg daily in one trial and was consistently sufficient with liraglutide 3.0 mg daily. Oral and injectable semaglutide at both doses consistently produced weight loss, though demonstrated a potential increased risk for retinopathy. Overall, we suggest five GLP1-RAs can be used in the treatment of overweight (body mass index 27.0-29.9 kg/m without weight-related comorbidity) with shared decision making to address each medications' key limitation: liraglutide 1.8 mg daily (less demonstrated weight loss), liraglutide 3.0 mg daily (no cardiovascular outcome trial at this dose), and oral and injectable semaglutide at both doses (uncertain retinopathy risk and pending cardiovascular outcome trial of high-dose semaglutide). Use should be limited to patients who fail, refuse, or cannot access lifestyle interventions for weight loss, and should be accompanied by standard restrictions on and monitoring of weight loss medications. We expect additional and earlier use of weight loss therapies to help clinicians curb the obesity and type 2 diabetes epidemics.