Semaglutide; What It Is and Isn’t


Background Info:

Semaglutide is used to treat type 2 diabetes and has also been approved for treating obesity in adults. It is usually administered once a week by injection under the skin. Semaglutide is marketed under various brand names depending on the indication and country. Here are a few examples:

    1. Ozempic: used for the treatment of type 2 diabetes
    2. Rybelsus: used for the treatment of type 2 diabetes
    3. Wegovy: used for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity

Semaglutide is a medication that belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists. It mimics the action of the GLP-1 hormone, which is naturally produced by the body to stimulate insulin release, reduce glucagon secretion, and decrease appetite. GLP-1 agonists have grown in popularity as a weight loss drug among those without obesity, a concerning trend. It is essential to follow the prescribing information and use Semaglutide only as a healthcare professional directs.


Common side effects include nausea, vomiting, diarrhea, constipation, and abdominal pain. More severe side effects, such as pancreatitis, gallbladder disease, kidney problems, and allergic reactions, can also occur. There is some evidence to suggest that Semaglutide may affect thyroid function

    1. In some clinical trials, an increased incidence of thyroid tumors has been observed in rodents treated with Semaglutide. 
    2. Additionally, in some human clinical trials, a small percentage of participants taking Semaglutide experienced changes in their thyroid function tests, such as decreased thyroid-stimulating hormone (TSH) levels.

Patients taking Semaglutide should be monitored for potential side effects and contact their healthcare provider if they experience any concerning symptoms. The term “Ozempic face” refers to sagging in the skin, which some users claim to experience and may result from weight loss.


For Weight Loss:

Semaglutide is an effective treatment for weight loss (referring to fat AND fat-free mass) in adults who are overweight or obese. The results of a clinical trial called STEP 1 showed that Semaglutide was significantly more effective than a placebo in reducing body weight. 

      1. After 68 weeks of treatment, patients taking Semaglutide lost an average of 15% of their body weight compared to 2.4% for those on the placebo (Wilding et al., 2021).

The effectiveness of Semaglutide in promoting weight loss has been established in other clinical trials, including the STEP 2 and STEP 3 trials (Wilding et al., 2021). The mechanism of action for Semaglutide is thought to involve a reduction in appetite, an increase in feelings of fullness, and a delay in stomach emptying (Astrup et al., 2009).

For Body Composition:

The U.S. Food and Drug Administration’s guidelines for evaluating weight management treatments state that the sole primary efficacy endpoints acceptable for weight loss drug trials are those that directly measure changes in body weight.

    1. This is a problem because we need to consider body composition. All fat loss is not created equal.

Significant lean mass loss in data:

    1. Based on sub-cohort data, there are indications that these drugs may result in a notable loss of lean mass, which is alarming considering the possible health hazards linked to diminished lean mass.
    2. As part of the 2021 STEP 1 trial, which was the first to establish the effectiveness of semaglutide as a therapy for adult obesity, a subgroup of 140 patients underwent DEXA scans to analyze body composition. The results indicated that lean mass constituted around 39% of the total weight loss among these patients, which is significantly higher than the recommended amount (Wilding et al., 2021). 
    3. During a subanalysis of 178 patients from the SUSTAIN 8 trial that assessed the efficacy of semaglutide as a diabetes treatment, it was discovered that the average percentage of lean mass loss was almost the same, at 40%, despite lower doses and less overall weight loss compared to the STEP 1 trial (McCrimmon et al., 2020).
    4. This data suggests that GLP-1 agonists should be used cautiously, especially among healthy-weight individuals.

Why we Care About Muscle Loss:

Losing weight is one thing, but we want to be very careful about losing fat and minimizing the risk of muscle loss. Preserving muscle is critical because losing weight without preserving muscle will change your body composition (we want to increase muscle and lose fat). Losing muscle can lead to decreased physical function, making it harder to perform daily activities and exercise. Moreover, it can become harder to lose weight in the future and easier to regain the weight. There is fundamental research that shows the loss of fat-free mass appears to be predictive of weight gain. Also, refer to weight cycling. In short, we want to try our very best to work on building and preserving muscle. This could be problematic, as it appears that Semaglutide may cause significant lean mass loss.

Weight Cycling:

Weight cycling, also known as yo-yo dieting, is a pattern of losing and regaining weight. Most individuals that are taking Semaglutide for obesity and diabetes are using this long term, whereas short term may lead to gaining weight back after stopping usage. There is also evidence to show that weight cycling leads to increased body fat gain over time, which will make it more challenging to lose fat in the future (lose weight, gain it back, then it will take longer to lose the same amount of weight on the same amount of cals, and so on). Also, see the risk of muscle loss. We must also focus on sustainable lifestyle changes to prevent weight cycling.

Drug Shortage Issues:

When a drug goes viral and becomes very popular among the public, the demand will overburden the healthcare system. As the drug becomes more popular, there may be a shortage and higher costs, making it more difficult for some patients to access it – specifically those who need it to treat their diabetes. Currently, demand has outpaced the supply, leading to shortages and long waiting lists at some pharmacies. Those with serious health issues are having issues obtaining medication. Had healthcare professionals not been willing to prescribe Ozempic to individuals without diabetes, or those who do not have medical need for Semaglutide, this situation would not have occurred.


Individuals with obesity can experience significant health benefits from losing body fat, and semaglutide may be a reasonable intervention. However, healthy-weight individuals may only gain minimal benefits from fat loss when using semaglutide. Furthermore, the potential benefits are not likely to counterbalance the considerable health risks that come with weight cycling and reducing lean mass. 


Aroda, V. R., Bain, S. C., Cariou, B., et al. (2017). Semaglutide for the Treatment of Type 2 Diabetes. New England Journal of Medicine, 377(15), 1452-1462.


Astrup, A., Rössner, S., Van Gaal, L., Rissanen, A., Niskanen, L., Al Hakim, M., … & Sjöström, L. (2009). Effects of liraglutide in treating obesity: a randomised, double-blind, placebo-controlled study. The Lancet, 374(9701), 1606-1616.


FDA approves new treatment for chronic weight management, first since 2014. (2021, June 4). U.S. Food and Drug Administration.


LeBlanc, E. S., O’Connor, E., Whitlock, E. P., et al. (2018). Effectiveness of Primary Care-Relevant Treatments for Obesity in Adults: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Annals of Internal Medicine, 168(5), 317-325.


Marso, S. P., Bain, S. C., Consoli, A., et al. (2016). Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine, 375(19), 1834-1844.


McCrimmon, R. J., Catarig, A.-M., Frias, J. P., Lausvig, N. L., le Roux, C. W., Thielke, D., & Lingvay, I. (2020). Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia, 63(3), 473–485.

Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., Kushner, R. F., & STEP 1 Study Group. (2021). Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine, 384(11), 989–1002.




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