Semaglutide | Reviews, Clinical Data, and Benefits
Semaglutide is an approved treatment of both diabetes and obesity, with a host of potential research applications. Inside, researchers will find what they must know about semaglutide, including results from clinical trials.
Compound Overview
Class of Compound:
Peptide
Mechanism of Action:
Semaglutide is a synthetic version of glucagon-like peptide-1 (GLP-1) and thus mimics the action of this human incretin. Unlike other GLP-1 agonists, semaglutide resists degradation linked to the dipeptidyl peptidase-IV enzyme. Thanks to a mechanism that stimulates insulin and reduces glucagon secretions in a glucose-dependent manner, semaglutide has been shown to reduce fasting and postprandial blood glucose levels.
Notable Studies:
- Once-Weekly Semaglutide for Weight Management: A Clinical Review
- Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes
- Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials
Also Known As:
Ozempic, Rybelsus, Wegovy, A10BJ06
Research Applications:
- Anti-obesity and weight loss
- Glycemic control
- Cardiovascular health
- Neuroprotection
Risks:
- Gastrointestinal upset and related reactions
- Link to thyroid C-cell tumors in rodent studies
- Contraindicated in Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- Risk of acute and chronic pancreatitis
- FDA approval only for T2D and overweight/obese subjects
Chemical Structure
What is Semaglutide?
Semaglutide is a synthetic 31-amino-acid polypeptide analog of the endogenous glucagon-like peptide-1 (GLP-1), belonging to the class of drugs labeled glucagon-like peptide-1 receptor agonists (GLP-1 RAs).
Within this category, semaglutide is the only drug to hold FDA approval in both oral and injectable formulations. An approved antidiabetic treatment due to its hypoglycemic effects, it is of further clinical interest as an appetite suppressant and weight loss agent, indicated for chronic weight management in non-diabetic obese and overweight patients. It has also been shown to reduce cardiovascular risk in type 2 diabetes patients [1, 2].
Naturally occurring GLP-1 is an incretin hormone that is secreted within the gastrointestinal tract upon food ingestion. It is vital to proper metabolic function, stimulating the GLP-1 receptors to affect glycemic control while regulating appetite. Semaglutide is 94% homologous to endogenous GLP-1 and maintains its physiological function. However, it is modified for increased stability and extended duration of action, boosting its therapeutic potential in a range of contexts [3, 4].
Semaglutide has a favorable safety profile when used as prescribed. Ongoing studies suggest further therapeutic benefits beyond its approved uses.
Read on to learn how this cutting-edge peptide works, as well as its safety, proper handling, and dosage recommendations.
How Semaglutide Works
Here, we will explore semaglutide’s physiological effects with special attention to its weight management and blood sugar control outcomes.
Mechanism of Action
A GLP-1 analog, semaglutide stimulates the body’s GLP-1 receptors to boost pancreatic insulin secretion in a glucose-dependent manner and reduce glucagon levels, thereby improving glycemic control.
Endogenous incretin hormones such as GLP-1 are naturally released within the intestines upon food ingestion with direct action upon the hypothalamus, lowering blood sugar levels and slowing gastric motility to reduce appetite and caloric intake. The administration of exogenous GLP-1 analogs is demonstrated to promote long-term weight loss in obese patients [4, 5].
Semaglutide and other GLP-1-RA’s are also shown to improve cardiovascular health and impart anti-inflammatory benefits in multiple organ systems. More stable than endogenous GLP-1 due to its albumin-binding abilities, semaglutide has an extended duration of action and is thus suitable for once-weekly administration [4, 5].
Effects on Blood Sugar and Insulin Levels
Semgalutide’s hypoglycemic effects have been clinically demonstrated in subjects with type 2 diabetes, attributed largely to its stimulation of insulin secretion. However, its glucose homeostasis is in part achieved through its glucagon suppression and slowing of gastric emptying rate.
These actions combine to reduce appetite, which further reduces blood sugar levels. Extensive phase 3 trials on semaglutide use in T2D patients showed significant reductions in blood HbA1c and fasting plasma glucose (FPG) levels within just 12 weeks of once-weekly, subcutaneously [5].
Role in Promoting Weight Loss
Studies indicate the effectiveness of semaglutide as a weight loss agent in both diabetic and non-diabetic populations. It is currently approved as an adjunct to lifestyle adjustments for weight management in obese and overweight patients with a weight-related comorbidity, such as dyslipidemia and hypertension [6].
Back-to-back studies show the long-term effectiveness of semaglutide as an obesity treatment. While the weight loss outcomes of semaglutide and other GLP-1-RA drugs are widely documented, the underlying mechanism is not fully understood. Researchers believe that its appetite regulation is achieved through hypothalamic stimulation as well as slowed gastric emptying [7].
In the PIONEER clinical trials, orally administered semaglutide led to significant weight loss in a dose-dependent manner over 26 weeks, outperforming other GLP-1-RA drugs. Decreased waist circumference and BMI were also observed. The STEP clinical trial program on semaglutide for weight management in both diabetic and non-diabetic subjects showed similar findings [7].
Semaglutide Benefits
Wide clinical research has demonstrated the therapeutic benefits of semaglutide in a range of contexts.
Here, we will explore the most notable and well-documented advantages to date:
Semaglutide as a Type 2 Diabetes Treatment
Semaglutide is currently approved as a type 2 diabetes (T2D) treatment. In combination with exercise and diet, it is proven to lower blood sugar levels and improve glycemic control. This is achieved through its twofold mechanism of increased insulin secretion and glucagon suppression. In contrast to other antidiabetic medications, semaglutide has demonstrated a relatively reduced risk of hypoglycemic events. It is available in both injectable and oral formulations [2].
Semaglutide and Cardiovascular Risk
Clinical findings support the role of semaglutide in reducing cardiovascular risk in patients with type 2 diabetes and cardiovascular disease. Studies on its cardiovascular effects in at-risk populations pointed to a lowered incidence of major adverse cardiovascular events (MACE), such as stroke and heart attack. The underlying mechanisms for semgalutide’s cardioprotective benefits include its systemic anti-inflammatory effects, as well as its inhibition of visceral and epicardial fat storage [5, 8].
Under the brand name Ozempic, semaglutide is currently approved for reducing cardiovascular risk in type 2 diabetes patients with at least one diagnosed cardiovascular comorbidity [9].
Semaglutide and Weight Loss
Also approved as a weight management treatment, semaglutide has demonstrated anti-obesity effects attributed to its appetite suppression. This is achieved through its ability to increase feelings of satiety, leading to reduced caloric intake.
Clinical trials have shown its long-term effectiveness and safety as a weight reduction aid in both injectable and oral formulations. In this capacity, it is prescribed for chronic weight management in obese or overweight adults with weight-related diagnoses including but not limited to type 2 diabetes. In early 2023, semaglutide also gained FDA approval to treat obesity in pediatric patients aged 12 years and older [6, 7].
Semaglutide is shown to be a superior weight loss agent in comparison to other GLP-1-RA drugs, such as liraglutide. This will be discussed further in the following sections [6].
Other Potential Benefits of Semaglutide
Emerging studies suggest further potential benefits in semaglutide therapy. These include the treatment of nonalcoholic steatohepatitis (NASH) in T2D patients due to the peptide’s effects on lipid metabolism, inflammatory response, and body composition [10, 11].
Semaglutide is also shown to have potential kidney benefits in T2D patients driven in part by its hypoglycemic and cardioprotective effects [12].
Additional studies in rat models suggest semaglutide’s neuroprotective benefits in the context of Parkinson's disease, attributed to its attenuation of inflammatory response and inhibition of neural apoptosis [13].
Clinical developments are sure to add to this impressive list of benefits. Researchers are encouraged to stay abreast of current findings.
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Semaglutide for Weight Loss in Non-Diabetics
Although initially developed as a T2D treatment, semaglutide has been shown to aid weight management in non-diabetic subjects, as well.
The clinical trial program known as Semaglutide Treatment Effect in People with Obesity (STEP) examined the weight loss effects of both oral and injectable semaglutide beyond the scope of T2D treatment. Over 20 weeks, semaglutide prompted clinically significant weight loss with once-weekly administration in combination with diet and exercise [6, 7].
Its effectiveness as a weight loss drug is attributed to its appetite suppression through hypothalamic stimulation, increasing feelings of satiety. The resultant regulation of caloric intake leads to weight reduction. Meanwhile, its regulation of blood sugar levels and metabolism is linked with a reduction in both visceral and cardiac fat storage, resulting in improved body composition [6, 7].
Clinical findings suggest the long-term effectiveness and safety of semaglutide as a weight loss agent in non-diabetics, with sustained weight loss over a two-year period and few hypoglycemic events noted. In clinical trials, semaglutide has consistently outperformed other marketed anti-obesity and weight loss drugs in terms of both effectiveness and safety. Under the brand name Wegovy, it is indicated for weight management in non-diabetic populations with weight-related comorbidities [6, 7].
Side Effects and Safety
As an FDA-approved drug, semaglutide has been subject to full safety screenings that provide a wealth of data on its potential side effects and necessary precautions. Although it has an overall favorable safety profile when properly administered under supervision, handlers should keep a few things in mind.
Common semaglutide side effects
Most semaglutide side effects are mild and transient, subsiding within several weeks as subjects adjust to the course of treatment. These include gastrointestinal complaints such as the following, observed in both oral and parenteral administration [9, 14]:
- Constipation
- Diarrhea
- Indigestion
- Abdominal pain
- Nausea
- Vomiting
Adverse GI effects are time- and dose-dependent. Researchers and clinicians do not fully understand the mechanisms behind these disturbances; however, they are likely linked to the drug’s alterations in intestinal nutrient uptake and gastric motility. Gastrointestinal side effects appear to be more pronounced in oral formulations, while injectable administration can cause injection site irritation [14].
Serious semaglutide side effects
Although rare, serious side effects have been observed. If such reactions occur, discontinue use and seek medical attention. These include [9, 14]:
- Hypoglycemia
Due to its reduction in blood glucose levels, semaglutide and other GLP-1-RA’s can sometimes lead to hypoglycemic events. However, this is uncommon and linked with concomitant antidiabetic medication administration.
- Pancreatic inflammation and cancer
Although definitive evidence is lacking, GLP-1-RA’s have been linked with pancreatitis as well as pancreatic cancer. This is attributed to their effects on pancreatic enzyme levels. Patients with a history of pancreatitis are cautioned against the use of semaglutide due to the increased risk of pancreatic cancer.
- Thyroid cancer
Although only observed in animal studies, GLP-1-RA’s can lead to thyroid C-cell hyperplasia and malignancies. Semaglutide is therefore contraindicated in at-risk subjects.
- Diabetic retinopathy
Retinal complications such as blindness and vitreous hemorrhage have been reported in rare cases and are linked with insulin co-administration.
- Gallbladder disease
The risk of gallbladder issues such as cholelithiasis may increase. Symptoms include jaundice and fever.
- Kidney injury
Renal impairment and dehydration can occur, causing severe GI upset.
- Hypersensitivity reactions
Severe allergic reactions have been reported in rare cases. These include anaphylaxis, angioedema, rash, and urticaria.
Safety Considerations
Because it slows gastric motility, semaglutide may affect the metabolism of orally administered medications. Handlers should consult all available literature to determine possible drug interactions as well as safe timing and dosages [9].
While semaglutide is considered to have an overall excellent safety profile, subjects with increased risk of the previously mentioned severe side effects are advised to exercise caution. These include patients with histories or predisposal towards renal failure, biliary disease, thyroid cancer, diabetic retinopathy, and pancreatitis. Additionally, co-administration of semaglutide with other diabetic therapies must be performed under close medical supervision due to the increased risk of hyperglycemia [9].
Precautions and Warnings
Semaglutide is not recommended for use in certain populations. Although data on semaglutide administration in pregnant women is sparse, there is some concern that it may cause fetal harm.
Animal studies on semaglutide use during early pregnancy have been linked to severe fetal developmental abnormalities as well as embryo-fetal death. However, the benefits of diabetes management during pregnancy may outweigh the risks. Assessment should be made on a case-by-case basis with a medical professional. Lactating women are similarly encouraged to exercise caution due to potential adverse effects [9].
The use of semaglutide is not yet approved in children under 12 years of age, and geriatric use in sensitive populations is relatively lacking in safety data [9].
This is not an exhaustive review of safety findings on semaglutide. Handlers must consult drug prescribing information and thoroughly adhere to relevant guidelines under medical supervision.
Semaglutide Dosage and Administration
Semaglutide is marketed in both subcutaneous and oral forms. Dosage and administration guidelines vary based on the prescribed use. Subcutaneous semaglutide is more common than oral tablets.
Bearing in mind that exact dosage and administration protocols are to be determined by the presiding researchers, let’s explore the broad clinical findings on semaglutide dosage and common indications.
Semaglutide Dosage for T2D
The guidelines for subcutaneously semaglutide in the treatment of type 2 diabetes are detailed in the Ozempic brand drug labeling as follows [9]:
- The starting dose is 0.25mg; once a week for 4 weeks.
- After 4 weeks, the weekly dose is increased to 0.50mg.
- The dosage may be increased to up to 2mg per week if additional glycemic control is needed.
- Injections should be performed on the same day each week.
- Missed doses should be administered within 5 days with the following dose delivered according to schedule.
Semaglutide Dosage for Weight Loss
When used for chronic weight management, semaglutide is be dosed according to the following Wegovy brand prescribing information [15]:
- The starting dose of 0.25mg; once weekly should be maintained for 4 weeks.
- Following the initial four weeks, the weekly dose should be increased based on the following schedule: 500mcg/weekly at weeks 5-8; 1mg/weekly at weeks 9-12; 1.7mg/weekly at weeks 13-16; 2.4mg/weekly at weeks 17 and onward.
- Missed doses must be delivered within 5 days.
- If the subject cannot tolerate a minimum dose of 1.7mg a week, discontinuation of treatment is advised.
Administration of Semaglutide Oral Tablets
Semaglutide has most recently been approved in oral tablet form to treat type 2 diabetes in combination with diet and exercise. It is available under the brand name Rybelsus, administered as follows [16]:
- The starting dose is a 3mg tablet taken once daily for 30 days.
- After 30 days, the dose is to be increased to 7mg a day.
- If additional glycemic control is needed after 30 days, the dose may be increased to 14mg a day.
- Semaglutide ablets should be swallowed whole with minimal water at least 30 minutes before food and drink for proper absorption.
Missed doses are to be skipped.
Consult product literature for guidelines on transitioning between subcutaneous and oral semaglutide. There is no dose equivalency between formats.
Semaglutide vs. Liraglutide | Which is Superior?
Researchers interested in GLP-1-based therapies may be familiar with liraglutide, classed along with semaglutide as a long-acting GLP-1RA hypoglycemic agent and approved for the treatment of type 2 diabetes and chronic weight management [17].
Here, we will compare and contrast these two popular peptides:
Mechanism of Action
Semaglutide and liraglutide are both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) approved for the treatment of type 2 diabetes due to their hypoglycemic outcomes. Both mimic the activity of endogenous GLP-1, regulating blood glucose levels by increasing insulin secretion, inhibiting glucagon secretion, delaying gastric motility, and increasing feelings of satiety. Their outcomes further overlap to include cardiovascular and hepatic benefits [17, 18].
While liraglutide has slightly higher GLP-1R affinity, semaglutide has an extended half-life due to its albumin-binding abilities. This lends semaglutide greater efficacy overall as a weight loss and anti-diabetic agent with a lower therapeutic dose requirement. While liraglutide must be injected daily, semaglutide is suitable for once-weekly injections. Semaglutide is now uniquely available in an oral formulation for greater convenience [17, 18].
Effects on Blood Sugar and Weight Loss
Clinical trials have shown semaglutide to be a more effective hypoglycemic and insulinogenic agent than liraglutide in most cases. It demonstrates greater reductions in both postprandial and fasting blood glucose levels and greater increases in insulin sensitivity.
Unsurprisingly, semaglutide is also proven to be a superior weight loss intervention due to its more pronounced metabolic effects and longer duration of action for sustained appetite reduction.
Semaglutide is further shown to have more targeted effects on the hypothalamus, resulting in feelings of satiety for a more dramatic reduction of caloric intake. Overall, clinicians regard semaglutide as the more efficient and longer-acting drug [17, 18].
Although clinical research indicates the greater overall benefits of semaglutide, the choice between the two may be influenced by factors such as researcher health and cost.
Where to Buy Semaglutide Online? | 2024 Edition
Semaglutide is available under prescription as an antidiabetic and anti-obesity drug in several different formulations and brand names. Its price and availability are subject to wide variation based on format, indication, and region.
Although GLP-1 RAs tend to be priced higher than other anti-diabetic drugs, cost-utility reviews point to the overall cost-effectiveness of semaglutide due to its proven long-term benefits.
One study conducted in the United States comparing the value of semaglutide with that of a similar drug called dulaglutide identified the former as the better option [19].
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FAQ
Semaglutide | Review
This concludes our definitive review on semaglutide, one of the most exciting recent advances in the treatment of type 2 diabetes and obesity. While leading clinicians celebrate this pleiotropic peptide for its well-documented safety and efficacy as a hypoglycemic agent and weight management tool, emerging studies suggest untapped therapeutic potential.
From the management of cardiovascular and inflammatory disease to addressing a wide spectrum of metabolic disorders, semaglutide is surely among the best in its class. Novel formulations and extensive clinical trials add further appeal to this innovation.
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References
- Smits, M. M., & Van Raalte, D. H. (2021). Safety of Semaglutide. Frontiers in Endocrinology, 12. https://doi.org/10.3389/fendo.2021.645563
- Davies, M., Pieber, T. R., Hartoft-Nielsen, L., H. Hansen, O. K., Jabbour, S., & Rosenstock, J. (2017). Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA, 318(15), 1460-1470. https://doi.org/10.1001/jama.2017.14752
- National Center for Biotechnology Information. PubChem Compound Summary for CID 56843331, Semaglutide. https://pubchem.ncbi.nlm.nih.gov/compound/Semaglutide . Accessed Apr., 2023.
- Michael E Røder. (2019). Clinical potential of treatment with semaglutide in type 2 diabetes patients. Drugs in Context, 8, 1–11. https://doi.org/10.7573/dic.212585
- Senn, J., & Fischli, S. (2023). Medical therapy. Visceral and Ectopic Fat, 353-361. https://doi.org/10.1016/B978-0-12-822186-0.00014-6
- Fornes, A., Huff, J., Pritchard, R. I., & Godfrey, M. (2022). Once-Weekly Semaglutide for Weight Management: A Clinical Review. Journal of Pharmacy Technology, 38(4), 239–246. https://doi.org/10.1177/87551225221092681
- Singh, G., Krauthamer, M., & Bjalme-Evans, M. (2021). Wegovy (semaglutide): a new weight loss drug for chronic weight management. Journal of Investigative Medicine, 70(1), 5–13. https://doi.org/10.1136/jim-2021-001952
- Mansoor Husain, Stephen C. Bain, Anders Gaarsdal Holst, Thomas Mark, Søren Rasmussen, & Ildiko Lingvay. (2020). Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovascular Diabetology, 19(1), 1–11. https://doi.org/10.1186/s12933-020-01106-4
- Indication and important safety information [Internet]. [cited 2023 May]. Available from: https://www.ozempic.com/
- Liava C, Sinakos E. Semaglutide for nonalcoholic steatohepatitis: closer to a solution? Hepatobiliary Surg Nutr. 2021 Aug;10(4):541-544. doi: 10.21037/hbsn-21-231. PMID: 34430539; PMCID: PMC8351017.
- Volpe S, Lisco G, Fanelli M, Racaniello D, Colaianni V, Triggiani D, Donghia R, Crudele L, Rinaldi R, Sabbà C, Triggiani V, De Pergola G, Piazzolla G. Once-Weekly Subcutaneous Semaglutide Improves Fatty Liver Disease in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study. Nutrients. 2022 Nov 4;14(21):4673. doi: 10.3390/nu14214673. PMID: 36364937; PMCID: PMC9657108.
- Mann JFE, Buse JB, Idorn T, Leiter LA, Pratley RE, Rasmussen S, Vilsbøll T, Wolthers B, Perkovic V. Potential kidney protection with liraglutide and semaglutide: Exploratory mediation analysis. Diabetes Obes Metab. 2021 Sep;23(9):2058-2066. doi: 10.1111/dom.14443. Epub 2021 Jun 1. PMID: 34009708; PMCID: PMC8453827.
- Zhang, L., Zhang, L., Li, L., & Hölscher, C. (2018). Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson’s disease mouse model. https://eprints.lancs.ac.uk/id/eprint/126581/
- Smits, M. M., & Van Raalte, D. H. (2021). Safety of Semaglutide. Frontiers in Endocrinology, 12. https://doi.org/10.3389/fendo.2021.645563
- See your potential weight loss [Internet]. [cited 2023 May]. Available from: https://www.wegovy.com/
- What is RYBELSUS®? [Interne t]. [cited 2023 May]. Available from: https://www.rybelsus.com/
- Knudsen, L. B., & Lau, J. (2019). The Discovery and Development of Liraglutide and Semaglutide. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00155
- Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022;327(2):138–150. doi:10.1001/jama.2021.23619
- Wilkinson, L., Hunt, B., Johansen, P. et al. Cost of Achieving HbA1c Treatment Targets and Weight Loss Responses with Once-Weekly Semaglutide Versus Dulaglutide in the United States. Diabetes Ther 9, 951–961 (2018). https://doi.org/10.1007/s13300-018-0402-8