How does semaglutide work to lose weight?

Understanding semaglutide
How semaglutide helps with weight loss
Beyond weight loss
Safety and side effects
Semaglutide and weight management
References
Read more

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Semaglutide, commonly known as Ozempic, is a glucagon-like peptide-1 (GLP-1) agonist used for glycemic control and obesity management in type 2 diabetes (T2D). It is an effective weight loss drug that works by mimicking satiety hormones, reducing appetite and slowing gastric emptying. This sustained action helps users feel fuller for longer and, when combined with diet and exercise, can reduce weight loss.

Semaglutide is a drug that is attracting attention for the following reasons: Effectiveness in weight loss management.¹ As a GLP-1 agonist, it mimics the physiological effects of natural GLP-1 released in the body.¹

In response to glucose ingestion, PPG neurons in the central nervous system (CNS) and L cells in the intestine produce and secrete the inhibitory gastrointestinal hormone GLP-1.¹

Once released, GLP-1 activates the receptor GLP-1R in pancreatic islet beta cells, leading to a myriad of metabolic changes characterized by insulin secretion and appetite suppression.¹

This insulin secretion causes an overall drop in blood sugar levels and reduces glucagon production. This prevents the release of glucose stores from the liver, induces a satiety response, increases insulin sensitivity, and causes weight loss.¹

This drug works by relying on glucose to stimulate insulin secretion, which reduces the risk of hypoglycemia.¹ Moreover, they have long-term positive effects on β-cell survival, proliferation, and neogenesis.¹

Semaglutide has been studied to mimic the effects of GLP-1, which is primarily released from the gut rather than the brain.² This is because most of the brain's GLP-1 receptors are beyond the reach of these systemically administered drugs.² Semaglutide is highly effective in reducing food intake and weight, despite its limited direct action on GLP-1 receptors in the brain.²

This appears to be achieved by activating a network of neurons throughout the CNS, many of which are secondary targets that do not directly express GLP-1 receptors.² The commercial version of semaglutide approved in 2024 will be Ozempic.^3-4Libersus^3,5and Wegovy injection^3,6developed by Novo Nordisk.

Semaglutide has profound effects on CNS processes such as satiety, thermogenesis, blood pressure regulation, neurogenesis, and inflammation reduction.⁷

Semaglutide has a long half-life, which prolongs CNS effects and modulates appetite and metabolic processes.⁷ It reduces food intake, slows gastric emptying, and stimulates the secretion of hormones such as leptin and peptide YY, which are important for satiety.⁷

In pancreatic β cells, GLP-1R activation by semaglutide promotes glucose catabolism and insulin secretion through the mTOR-dependent HIF-1α pathway, promoting glycolysis and insulin release.⁷

Under normal conditions, this release occurs rapidly, peaking approximately 10 minutes after the initial glucose stimulus.⁷ 90-95% of the insulin granules are then released for a long time and can last up to 60 minutes.⁷

This is due in part to its antagonism to the GLP-1 inhibitor DPP-4, which prolongs GLP-1R signaling and maintains insulin secretion.⁷ Semaglutide also activates the AMPK pathway and promotes GLUT4 translocation to the cell membrane, increasing glucose uptake and homeostasis.⁷

Semaglutide has received significant attention for its positive effects in the management of type 2 diabetes (T2D), obesity, and cardiovascular risk reduction.¹

T2D is characterized by elevated blood sugar levels caused by insufficient production of insulin or improper insulin function (also called insulin resistance).⁸ Over time, elevated blood sugar levels can lead to a variety of health complications that affect multiple organ systems, including the heart, kidneys, feet, and retina.⁸

In T2D patients, semaglutide is effective in lowering blood sugar levels and promoting weight loss.⁹ In clinical trials, it has been demonstrated to reduce HbA1c levels when added to metformin, with patients experiencing an average weight loss of more than 15%.⁹

Additionally, it has been shown to reduce the risk of developing T2D by 60%, regardless of whether the patient is prediabetic or has normal blood sugar levels.¹⁰ This diabetes risk reduction is critical, as T2D is associated with an increased risk of heart disease and other cardiometabolic complications.¹⁰

Semaglutide has shown significant cardiovascular benefits, particularly in reducing the risk of serious adverse cardiovascular events such as heart attack and stroke.¹¹ The SELECT trial showed a 20% reduced risk of these events in adults with obesity and cardiovascular disease but no history of diabetes.¹¹

The cardiovascular benefits of semaglutide are thought to be due to several mechanisms other than weight loss.¹¹ These include lowering blood pressure, blood lipids, and inflammation, as well as direct effects on the heart muscle and blood vessels.^7,11

GLP-1 agonists help regulate chronic inflammation associated with obesity by suppressing proinflammatory cytokines such as TNF-α, IL-6, and IL-1β and improving endothelial function.⁷

Semaglutide is beneficial for managing type 2 diabetes and weight loss, but it is not without side effects.¹² Commonly, patients may experience gastrointestinal disturbances such as nausea, vomiting, diarrhea, and constipation.¹²

Although less common, more serious effects such as pancreatitis and allergic reactions can occur.¹² Because of these potential side effects, medical supervision is essential when starting and maintaining treatment with semaglutide.

Healthcare providers can help manage and reduce side effects by considering a patient's medical history and potential drug interactions to ensure the benefits outweigh the risks for each individual.^12-13

When using semaglutide for weight loss, it is important to incorporate lifestyle factors such as diet and exercise.^14-15 Although semaglutide is an effective treatment, it is not a substitute for a healthy diet and regular physical activity.^14-15

Long-term changes in diet and activity are essential to maintain weight loss and prevent weight regain after medication discontinuation.^14-15 It is important to note that obesity is a chronic disease and discontinuation of semaglutide may result in weight regain due to a decrease in lean body mass and basal metabolic rate (BMR).^14-15

Therefore, sustainable weight management requires a holistic approach that includes lifestyle modifications and medical supervision.

1. Marzouk, A., Thomas, A., and Jones, B. (2021). Interaction of glucagon-like peptide-1 receptor trafficking and signaling in pancreatic beta cells. Frontiers of endocrinology12. https://doi.org/10.3389/fendo.2021.678055
2. Trapp, S., Brierley, D. I. (2021). Brain GLP-1 and the regulation of food intake: the action of GLP-1 in the brain and its impact on GLP-1 receptor agonists in obesity treatment. British Journal of Pharmacology179(4), 557–570. https://doi.org/10.1111/bph.15638
3. Pharmaceutical Evaluation Research Center (n.d.) Drugs containing semaglutide, US Food and Drug Administration. [Online] https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss.
4. Ozempic® (semaglutide) injection for type 2 diabetes. (n.d.). [Online] https://www.ozempic.com/
5. Type 2 Diabetes Medications | RYBELSUS® (Semaglutide) Tablets. (n.d.). [Online] https://www.rybelsus.com/
6. Prescription drugs for weight loss | Wegovy® (semaglutide) injection 2.4 mg. (n.d.). [Online] https://www.wegovy.com/
7. Tamayo-Trujillo, R., et al. (2024). Molecular mechanisms of semaglutide and liraglutide as treatment options for obesity. Frontiers of nutrition11. https://doi.org/10.3389/fnut.2024.1398059
8. Type 2 diabetes. (n.d.). Diabetes UK. [Online] https://www.diabetes.org.uk/diabetes-the-basics/types-of-diabetes/type-2
9. Chamberlin, S., Dabbs, W. (2019). Semaglutide (Ozempic) for type 2 diabetes. AAFP. [Online] https://www.aafp.org/pubs/afp/issues/2019/0715/p116.html
10. Pope, A. (2022). 'Transformative' semaglutide could cut type 2 diabetes risk by more than half – News. UAB News. [Online] https://www.uab.edu/news/research/item/13156-transformational-semaglutide-can-cut-type-2-diabetes-risk-by-more-than-half
11. Semaglutide reduces cardiovascular risk regardless of blood sugar levels. (2024). [Online] https://www.utsouthwestern.edu/newsroom/articles/year-2024/june-cardiovascular-risk-blood-sugar.html
12. GoodRx – (n.d.). [Online] https://www.goodrx.com/ozempic/semaglutide-side-Effects
13. Ozempic Drug Interaction Checker (n.d.) drug.com. [Online] https://www.drugs.com/drug-interactions/semaglutide,ozempic-index.html
14. Taylor. (2024). Pros and Cons of Semaglutide for Weight Loss – Dr. Taylor. Southwest Family Medical. [Online] https://swfamilymedical.com/pros-cons-semaglutide-for-weight-loss
15. N.S. (2023). Ozempic rebound: Why most people gain weight back when they stop semaglutide. health line. [Online] https://www.healthline.com/health-news/weight-regain-after-stopping-ozempic