Before we dive into how GLP1 agonists can help manage obesity, let’s first discuss the condition's pathophysiology.
While it is generally accepted that weight gain results from an imbalance between caloric intake and caloric expenditure, the risk of being obese are linked to both environmental and genetic factors. More than 140 genetic chromosomal areas linked to obesity have been discovered using data from the genome project. Aside from some conditions like Cushing's disease and hypothyroidism, using certain medications like corticosteroids and antidepressants is also linked to weight gain. It has been discovered through GI system research that a changed microbiota may potentially contribute to the emergence of obesity.
The pancreas, GI system, central nervous system, heart, lungs, kidneys, blood vessels, and peripheral nervous system are among the organs where GLP-1 receptors are most abundant. The latest agents to fight obesity target GLP 1 receptors in these areas.
Incretin hormones are gastrointestinal peptides, or GI peptides, released after eating and when blood sugar levels rise. Observing the incretin impact led to the development of the focus on incretin hormones as an obesity treatment. This effect describes the greater insulin stimulation from the pancreas after oral glucose intake than intravenously. When oral glucose is consumed, the specialized cells in the gut secrete glucose-dependent insulinotropic polypeptide GIP and GLP-1, two hormones influenced by blood sugar levels. In the duodenum and upper jejunum, K-cells make GIP, while L-cells make GLP-1 in the lower GI system. In healthy adults, the combined effects of GIP and GLP-1 cause increased insulin secretion and delayed stomach emptying. This incretin impact, however, is diminished or nonexistent in persons with type 2 diabetes.
The hypothalamus absorbs glucagon-like peptide-1, which decreases desire and food intake while increasing satiety. The alpha cells of the pancreas release glucagon, while the beta cells release insulin. GIP and GLP-1 receptors are present on the membranes of both types of cells. The presence of GLP-1 slows intestinal transit while delaying stomach emptying and acid output. The liver's uptake of GLP-1 reduces lipogenesis, boosts glycogen storage, and reduces gluconeogenesis.
Glucagon-like peptide-1 receptor agonists improve glycemic control by increasing insulin secretion from the beta-pancreatic cells and decreasing glucagon release from the alpha-pancreatic cells. Additionally, the agonists decrease stomach emptying, boost satiety, and suppress appetite, contributing to weight loss. Endogenous GLP-1 has a short half-life of 2 minutes due to quick degradation by dipeptidyl peptidase IV (DPP4). GLP-1 agonists are classified as short-acting and long-acting glucagon-like peptide-1 receptor agonists depending on their half-life. Short-acting agonists circulate for a few hours, followed by intervals of GLP-1 inactivity. A long-lasting drug concentration is produced by long-acting agonists, with slight variations in drug levels. Long-acting GLP-1 agonists lower glucose levels by slowing gastric emptying, increasing insulin production, and suppressing glucagon, as opposed to short-acting GLP-1 agonists, which do so by decreasing gastric emptying. Semaglutide and liraglutide are both long-acting medications; short-acting medications are not yet authorized for use in weight loss.
Both liraglutide and semaglutide, which are now approved for the treatment of type 2 diabetes, are produced by the same company, Novo Nordisk. Both drugs, sold under the trade names Saxenda and Wegovy, are also approved as supplements to calorie restriction and increased physical activity to manage chronic weight.
Liraglutide (3 mg) was the first GLP-1 agonist approved by the Food and Drug Administration in 2015 for the chronic control of weight in individuals with obesity and overweight. The FDA authorized an amended label for liraglutide's use in treating teenage obesity in December 2020. (12-17 years). The target dose is 3 mg once daily, and the starting dose is 0.6 mg once daily for one week. 11 Liraglutide has a half-life of 12.6 to 14.3 hours, is long-acting, and is given as a daily subcutaneous injection.
The FDA authorized semaglutide in June 2021 for the chronic management of weight in persons who are obese and overweight. The once-weekly subcutaneous injection should start at 0.25 mg and escalate to 2.4 mg over four weeks. Semaglutide can be administered once a week because of its prolonged half-life of roughly one week.
The most frequent side effects of GLP-1 agonists are vomiting, diarrhea, constipation, abdominal pain, headaches, fatigue, dyspepsia, dizziness, abdominal distension/pain, injection site reactions with liraglutide, increased lipase with liraglutide, pyrexia with liraglutide, eructation with semaglutide, flatulence with semaglutide, hypoglycemia in patients of diabetes type 2 and gastroesophageal reflux (semaglutide).
Most reported adverse events are mild, while serious ones are uncommon. Only a small number of patients discontinue their prescriptions due to drug-related side effects, and those who cite GI-related events.
Semaglutide and liraglutide are examples of GLP-1 receptor agonists used to treat patients who have developed acute pancreatitis and gallbladder disease. The usage of GLP-1 agonists has been linked to an increased risk of getting upper respiratory infections. Although the higher risk is mentioned as an adverse response in some package inserts of this class, it is not a warning or precaution and is not a reason to avoid using the product.
Glucagon-like peptide-1 receptor agonists gain access to particular brain regions crucial for controlling hunger, causing weight loss. These pathways might explain why GLP-1 agonist therapy lowered hunger and food cravings while improving eating control. Liraglutide and semaglutide are GLP-1 agonists that are successful in helping patients with obesity who do not have diabetes lose weight, with semaglutide data showing a more significant weight loss in clinical trials. GLP-1 agonists have minor negative effects, although the advantages in terms of weight loss may exceed these.
As shown in the treatment of type 2 diabetes with GLP-1 receptor agonists and other chronic diseases, once-weekly delivery may increase patient compliance and quality of life compared to a once-daily dose.