Wegovy: A Breakthrough in Weight Loss?

Introduction
Mechanism of action
Safety and side effects
Future prospects 
References
Further reading

Wegovy, or semaglutide, is the newest weight loss medication to receive regulatory approval. Wegovy was recently approved, on 4 June 2021, by the US Food and Drug Administration (FDA) for the management of adult obesity or overweight with one or more related medical conditions.

Introduction

The mechanisms of action, safety, and remarkable clinical efficacy of Wegovy have led to much interest in its applications for weight management. Multiple trials have taken place and are ongoing to test the safety and clinical efficacy of Wegovy in obese people.

Obesity is a chronic metabolic challenge associated with multiple health issues, including hypertension, type 2 diabetes mellitus, dyslipidemia, cardiovascular disease (CVD), renal disease, osteoarthritis, and several cancers. It also worsens the outcomes of other conditions, such as coronavirus disease 2019 (COVID-19).  

The global prevalence of obesity has gone up threefold since 1975, to about 13% among adults, based on the body mass index (BMI). In the USA, 42% of American adults were obese in 2017-18, with almost $200 billion spent on treating obesity-linked conditions.

Most of these issues are mitigated by the loss of 5-10% of body weight. However, most people who lose weight cannot keep it off with lifestyle interventions alone. Hence, the search for more durable adjunctive interventions.

Bariatric surgery is the gold standard for weight management, with long-term weight loss of at least 20% persisting at ten years. This reduces deaths from CVD and cancer by 30% and 23%, respectively. Its complexity, risks, and expense make it impractical as a large-scale option.  

Scientists are still searching for the ideal anti-obesity medication (AOM). This “should correct excess weight while reducing the risk of CVD and other comorbidities, devoid of the potential for abuse, tachyphylaxis and other adverse effects.”

So far, approved weight loss medications help lose only 3-8% of body weight beyond that associated with lifestyle modification. Safety concerns also limit their use to 3-6 months.

Many AOMs were enthusiastically received at first, such as amphetamines, thyroid hormones, and “rainbow pills” or drug cocktails. But they were soon withdrawn because of their serious adverse effects or poor efficacy. Most of them have been spectacular failures.  

Various weight loss medications act by reducing fat absorption from the gut, increasing satiety, inducing heat production, and affecting energy uptake and utilization. Some, like leptins, trigger the adiposity signaling pathway to reduce energy intake but rapidly cause desensitization.

The use of AOMs affecting central metabolic pathways is potentially dangerous as these disrupt essential survival mechanisms in the brain concerned with nutrition and energy balance. “Striking a balance in striving for efficacy that promotes metabolic health and is psychologically meaningful to a patient, but of suitable chronic tolerability and safety, constitutes the medicinal challenge.”

In this context, Wegovy for weight management was studied intensively in trials such as the multi-centric international phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program. The long-term administration of semaglutide for 68 weeks has been safe, well-tolerated, and exceptionally effective in achieving up to 20% weight loss.

Mechanism of action

Wegovy is the newest glucagon-like peptide-1 receptor agonist (GLP-1RA) to be approved for clinical use. Glucagon-like peptide-1 (GLP-1) is an incretin, a metabolic hormone secreted from the L-cells of the small intestine and colon and specialized cells in the brainstem within a few minutes of eating.

Natural GLP-1 is rapidly broken down in the body. Semaglutide is a GLP-1 analog with a longer duration of action. 

GLP-1 acts on multiple tissues, including the brain, cardiovascular system, kidneys, lungs, and the gut, via its receptors. By preventing glucose production and promoting glucose uptake by muscle and fat tissue, depending on the blood glucose levels, it reduces energy intake without causing hypoglycemia. It also produces a feeling of fullness while eating, keeps the stomach full for longer, and reduces appetite.

Among obese or overweight adults who were simultaneously encouraged to eat appropriately and be physically active, two years of Wegovy treatment led to an average of >15% weight loss vs. <3% with placebo, and exceeding short-course results as well.

Over 75% of the Wegovy cohort lost 5% or more of their body weight at two years, confirming its clinical efficacy. These odds were fivefold greater compared to placebo and emphasize the need to treat obesity as a chronic condition.

Waist circumference and blood lipid levels also dropped on Wegovy. Many people successfully reduced or stopped antihypertensive medications. Physical functioning improved, along with a lower BMI and better insulin sensitivity/glucose control.

The resulting decrease in cardiovascular and metabolic disease risk agrees with the observed Wegovy-associated reduction in cardiometabolic risk and mortality in type 2 diabetes mellitus. These findings support long-term treatment with Wegovy over short-course regimens.  

In the STEP 4 clinical trial, 62% of the Wegovy cohort lost at least 10% of body weight. Half of them lost 15% or more, while one-third lost 20%. With liraglutide, another GLP-1 inhibitor, only one in three lost 10% weight with liraglutide, and less than one in seven lost 15% or more. 

It seems that Wegovy could be prescribed for weight management as an adjunct to behavioral/lifestyle therapy. It must be remembered, however, that real-world effectiveness is typically lower due to poor adherence to treatment or drug intolerance.

Safety and side effects

Wegovy has only been in use for just over a year. Most users report transient mild to moderate gastrointestinal disturbances that resolve in about 20 weeks. There was no increased risk for cardiovascular events or renal damage.

Gallstones were reported in about 3% of participants on extended Wegovy. About one in 10 users stop the drug because of serious side effects. Wegovy is contraindicated in specific cases such as acute or chronic pancreatitis, a family history of certain cancers, or renal impairment.

Future prospects

Obesity is a polygenic condition with neurobehavioral, endocrine, and metabolic risk factors. Wegovy users may benefit more if it is prescribed in combination with other medications to target different drug mechanisms.   

Overall, “Subcutaneous semaglutide appears to offer the best A1C and weight reduction but also has higher rates of GI AEs [gastrointestinal adverse effects].” The greatest cardiometabolic risk reduction is observed with long-term Wegovy.  Oral Wegovy could encourage better compliance among patients.

Further research will show if Wegovy can produce comparable or better results than bariatric surgery. Moreover, it is both difficult and important to assess cardiovascular risk reduction and safety outcomes in obese adults without other cardiometabolic risk factors who are on Wegovy.

References

• Rubino, D. et al. (2021). Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA Network Open. doi:10.1001/jama.2021.3224. https://jamanetwork.com/journals/jama/fullarticle/2777886.
• Amaro, A. et al. (2022). Efficacy and safety of semaglutide for weight management: evidence from the STEP program. Postgraduate Medicine. doi: https://doi.org/10.1080/00325481.2022.2147326. https://www.tandfonline.com/doi/full/10.1080/00325481.2022.2147326.
• Trujillo, J. M. et al. (2021). GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism. doi: https://doi.org/10.1177%2F2042018821997320. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953228/.
• Muller, T. D. et al. (2021). Anti-obesity drug discovery: advances and challenges. Nature Reviews Drug Discovery. doi: https://doi.org/10.1038/s41573-021-00337-8. https://www.nature.com/articles/s41573-021-00337-8.
• Wilding, J. P. H. et al. (2021). Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2032183. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183.
• Garvey, W. T. et al. (2022). Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nature Medicine. doi: https://doi.org/10.1038/s41591-022-02026-4. https://www.nature.com/articles/s41591-022-02026-4.
• Singh, G. et al. (2023). Wegovy (semaglutide): a new weight loss drug for chronic weight management. Journal of Investigative Medicine. doi: https://doi.org/10.1136/jim-2021-001952. https://journals.sagepub.com/doi/10.1136/jim-2021-001952.
• Weight loss from bariatric surgery compared to nonsurgical care for people with severe obesity (2021). https://www.niddk.nih.gov/news/archive/2021/weight-loss-from-bariatric-surgery-compared-to-nonsurgical-care-for-people-with-severe-obesity.

Further Reading

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• Circadian Rhythm and Weight Loss

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.