Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of anti-diabetic medications used primarily for the treatment of type 2 diabetes. They mimic the effects of endogenous GLP-1, a hormone produced in the gut, which plays a key role in blood glucose regulation. GLP-1 receptor agonists work by stimulating insulin secretion in a glucose-dependent manner and reducing glucagon secretion. They also delay gastric emptying and promote satiety. In this article, we explore the mechanism of action, approved drugs, efficacy, safety and future prospects of this important class of anti-diabetic agents.
Mechanism of Action
GLP-1 is a gut hormone released after meals. It acts on GLP-1 receptors present in the pancreas, stomach, brain and other tissues. In the pancreas, binding of GLP-1 to its receptor on beta cells stimulates insulin secretion in a glucose-dependent manner. Insulin secretion increases only when blood glucose levels are high after a meal and decreases during periods of low blood glucose like between meals and overnight. This helps avoid hypoglycemia. GLP-1 also suppresses glucagon secretion from alpha cells of the pancreas in a glucose-dependent way. Glucagon is a hormone that triggers hepatic glucose production, thus its reduction helps in lowering blood glucose. In the stomach, GLP-1 slows gastric emptying, which delays glucose absorption into the bloodstream. It also promotes satiety in the brain leading to decreased food intake and weight loss. GLP-1 receptor agonists mimic these effects of endogenous GLP-1.
Approved GLP-1 Receptor Agonists
Exenatide was the first GLP-1 receptor agonist to be approved for diabetes treatment in 2005. It is administered through twice daily subcutaneous injections. Exenatide improves glycemic control by lowering both fasting and post-prandial blood glucose levels. It also leads to modest weight loss. Common side effects include nausea, diarrhea and vomiting.
Liraglutide is a once daily GLP-1 receptor agonist approved in 2010 for type 2 diabetes. With its longer half-life, liraglutide provides more effective A1C and weight lowering than exenatide. It also comes with an auto-injector pen device for ease of administration. Adverse reactions are similar to exenatide. Rare cases of acute pancreatitis have also been reported with liraglutide and other GLP-1 receptor agonists.
This weekly GLP-1 receptor agonist gained FDA approval in 2014. Dulaglutide further improved compliance compared to daily drugs. Clinical trials indicate efficacy and safety comparable to other drugs of this class. It provides reductions in both A1C and body weight.
Semaglutide (Ozempic, Rybelsus):
Semaglutide is available both as once weekly Ozempic injection and daily Rybelsus oral pill. The former was approved in 2017 for diabetes while the latter oral formulation was approved in 2020. Semaglutide leads to superior glycemic control and weight loss than other GLP-1 receptor agonists, with effects lasting beyond the dosing period. Gastrointestinal side effects are reported less frequently with semaglutide than other drugs of this class.
Efficacy of GLP-1 Receptor Agonists
GLP-1 receptor agonists are highly effective for glycemic control as monotherapy or add-on therapy. They lower A1C levels by 0.5% to 1.5% on an average. The magnitude of A1C reduction depends on the drug, starting A1C level and individual response. Most patients achieve target A1C levels of below 7%. In clinical trials, GLP-1 receptor agonists also led to significant reductions in fasting and post-prandial glucose levels. Many are weight neutral or promote weight loss of 3-5% over placebo. This makes them valuable drugs for obese diabetic population. The glucose lowering effect is seen within 2 weeks and persists for the duration of treatment.
Safety Profile of GLP-1 Receptor Agonists
Overall, GLP-1 Receptor Agonist have a good safety profile. The most common adverse effects include gastrointestinal symptoms like nausea, vomiting and diarrhea which are usually mild-moderate in intensity and tend to diminish over time. Hypoglycemia risk is low due to glucose-dependent insulin secretion stimulated by these drugs. Reports of acute pancreatitis are extremely rare. Cardiovascular safety studies indicate a potential benefit in reducing risk of major cardiovascular events in high-risk patients with type 2 diabetes. GLP-1 receptor agonists are usually well tolerated in patients with mild-moderate kidney or liver disease, though caution is warranted in advanced organ dysfunction. Post-marketing cases of thyroid C-cell tumors have led to a boxed warning on labeling. However, the clinical significance of this risk remains unclear given the rarity of these tumors.
1. Source: Coherent Market Insights, Public sources, Desk research
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