From the Guidelines
GLP-1 receptor agonists are synthetic medications designed to mimic the action of the natural hormone glucagon-like peptide-1 (GLP-1), but they are not natural mimics. These medications, including semaglutide and liraglutide, are engineered to resist breakdown by the enzyme DPP-4, which normally degrades natural GLP-1 within minutes 1. This modification gives these medications a much longer half-life, allowing them to work for hours or even days after administration.
Key Points
- GLP-1 receptor agonists, such as semaglutide and liraglutide, have been shown to be effective in weight loss and improving weight-related comorbidities in adults with obesity without diabetes 1.
- The STEP trials examined the efficacy of semaglutide and found that mean weight loss at 68 weeks was 14.9% and 16.0% in the STEP 1 and STEP 3 trials, respectively, compared to 2.4% and 5.7% with placebo 1.
- Long-term use of GLP-1 receptor agonists is necessary to maintain weight loss, as significant weight regain was observed after cessation of treatment 1.
- GLP-1 receptor agonists have also been shown to decrease the risk of cardiovascular events in adults with overweight or obesity without diabetes 1.
Medication Details
- Semaglutide is dosed once weekly and was FDA approved to treat obesity in 2021 1.
- Liraglutide is dosed daily and was FDA approved to treat obesity in 2014 1.
- Both medications have been shown to be effective in reducing weight and improving weight-related comorbidities, but semaglutide has been found to be more effective in some studies 1.
From the FDA Drug Label
Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1 Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells.
GLP-1 receptor agonists are designed to mimic the action of the natural hormone GLP-1.
- They have a similar amino acid sequence to the endogenous human GLP-1.
- They activate the GLP-1 receptor, leading to insulin release and glucagon secretion in a glucose-dependent manner.
- The mechanism of blood glucose lowering also involves a delay in gastric emptying. Therefore, GLP-1 receptor agonists, such as liraglutide, can be considered as natural mimics of the GLP-1 hormone 2.
From the Research
GLP-1 Receptor Agonists as Natural Mimickees
- GLP-1 receptor agonists are a class of drugs that mimic the action of the naturally occurring hormone glucagon-like peptide-1 (GLP-1) 3.
- GLP-1 is a multifaceted hormone with broad pharmacological potential, including glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, and inhibition of food intake 3.
- GLP-1 receptor agonists have been developed to overcome the short half-life of native GLP-1 and are used to treat type 2 diabetes and obesity 4, 5.
Mechanisms of Action
- GLP-1 receptor agonists share common mechanisms of action, including augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and reduction in calorie intake and body weight 4.
- Long-acting GLP-1 receptor agonists have more profound effects on overnight and fasting plasma glucose and HbA1c, while short-acting agents have reduced effectiveness on these parameters 4.
Therapeutic Implications
- GLP-1 receptor agonists are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, due to their effectiveness in reducing HbA1c and body weight, and low risk of hypoglycemic episodes 4.
- GLP-1 receptor agonists have also been shown to have cardiovascular benefits, including reducing the risk of acute myocardial infarction, stroke, and associated mortality 4, 5.
- The use of GLP-1 receptor agonists has been associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders, and several respiratory conditions, but an increased risk of gastrointestinal disorders and other adverse effects 6.