Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of medications that mimic the effects of naturally occurring GLP-1 hormone in the body. GLP-1 plays an important role in regulating blood sugar levels after eating by stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner. It also slows the emptying of the stomach and promotes feelings of fullness to reduce appetite.
Drug companies have developed GLP-1 receptor agonists that are resistant to breakdown in the body, allowing them to remain active for longer periods of time. These drugs activate the GLP-1 receptor on pancreatic beta cells and other tissues, resulting in lower blood sugar levels with a very low risk of hypoglycemia. In addition to improving blood sugar control, GLP-1 receptor agonists also assist with weight loss by decreasing appetite.
Currently available GLP-1 receptor agonists
The first GLP-1 receptor agonist approved for clinical use was exenatide (Byetta), which was introduced in 2005. Exenatide is injected twice a day and is effective at lowering A1C by around 1% on average. In 2010, a long-acting form of exenatide called exenatide extended release (Bydureon) became available. It needs to be injected only once a week.
Liraglutide (Victoza) was approved in 2010. It has a longer half-life than exenatide and is dosed once daily by injection. On average, liraglutide lowers A1C by around 1.5% and also aids weight loss of approximately 3-4kg over a year. In 2015, the FDA approved albiglutide (Tanzeum), which is injected once a week. It provides A1C reductions of around 1% along with some weight loss. Dulaglutide (Trulicity) was approved in 2014 and acts once weekly like albiglutide but has a greater glucose- and weight-lowering effect.
Introducing Semaglutide - a next generation GLP-1 agonist
Semaglutide (Semaglutide/Rybelsus) is a new option within the GLP-1 receptor agonist class that was developed by Novo Nordisk. It has an extended half-life of approximately 1 week, allowing convenient once-weekly dosing by subcutaneous injection or oral tablet. What sets Semaglutide apart from earlier GLP-1 agonists is its superior glycemic control and weight loss potential.
Semaglutide's potent effects on blood sugar and weight
In pivotal phase 3 trials, once-weekly Semaglutide resulted in remarkable reductions in both A1C and body weight in patients with type 2 diabetes. In SUSTAIN-1, Semaglutide 0.5mg and 1mg lowered A1C by around 1.5% and 1.9% respectively after 30 weeks of treatment. Weight loss was also significant at around 3-4kg.
Similar robust glucose and weight lowering was seen in SUSTAIN-2 and SUSTAIN-6 trials testing higher doses of Semaglutide up to 2.4mg. Remarkably, in SUSTAIN-6, the 2.4mg dose produced an average A1C reduction of 2.1% and average weight loss of 8.4kg after 68 weeks compared to 1.5%/3.6kg with the highest approved dose of injectable GLP-1 agonist.
Semaglutide as a treatment for obesity
Due to its potent effects on weight, Semaglutide has also been tested as a treatment for obesity alone in non-diabetic individuals. Study 2 (STEP 1) explored the use of once-weekly Semaglutide 2.4mg versus placebo over 68 weeks in participants with a BMI of 30 or above. The results were groundbreaking - Semaglutide facilitated average weight loss of 15.2kg compared to just 2.6kg with placebo. 65% of patients on Semaglutide lost at least 10% of their baseline body weight. This demonstrated Semaglutide's potential as a promising new anti-obesity medication.
Tablet formulation of Semaglutide
An oral tablet formulation of Semaglutide was tested in PIONEER 1 trial. This pill version showed it was able to achieve similar reductions in A1C and body weight compared to the injected form. Rybelsus is now approved as the first oral GLP-1 receptor agonist, presenting a non-injectable option for patients. The tablet formulation delivers steady absorption and offers a simpler administration method over injections.
Safety profile of Semaglutide
Clinical trials have found Semaglutide to be safe and well tolerated. The most common side effects include nausea, vomiting, and diarrhea, which are usually mild to moderate in severity and tend to diminish over time. Like other GLP-1 receptor agonists, there is a very low risk of hypoglycemia when used as add-on to other anti-diabetic medications. Semaglutide has not been associated with an increased risk of pancreatitis or cancer based on trial data to date. Long-term safety of this newer GLP-1 agonist still needs to be established through ongoing surveillance.
The impressive results from clinical trials have established Semaglutide as one of the most effective medical treatment options currently available for people with type 2 diabetes and obesity. Its ability to profoundly lower blood sugar as well as promote significant, sustained weight loss makes Semaglutide an attractive therapeutic alternative for many patients. Its once-weekly dosing and new oral tablet form also represent more convenient options versus daily injections. If long-term safety can be confirmed, Semaglutide may reshape how diabetes and obesity are managed.
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