Credit: CC0 Public Domain

Overview

Semaglutide (Wegovy) is a glucagon-like peptide (GLP), which is released in the gastrointestinal tract after eating. Semaglutide improves the efficiency of incretin function by activating GLP-1 receptors. It acts by numerous mechanisms including augmented insulin secretion (glucose-dependent), inhibition of glucagon release and suppressed hepatic gluconeogenesis; thereby reducing both fasting and postprandial glucose.

At the recent 2024 European Congress on Obesity (ECO), Novo Nordisk presented groundbreaking research findings for its weight loss therapy, semaglutide. The data indicated that the substantial weight loss achieved with semaglutide can be sustained for up to four years and that cardiovascular health improvements are possible regardless of the amount of weight loss.

The newly announced studies are derived from the SELECT Phase 3 clinical trial results. This trial enrolled 17,604 adults who were either overweight or obese, from 41 different countries. Participants received a weekly subcutaneous injection of 2.4 mg of semaglutide or a placebo. These individuals had a history of heart disease, stroke, and/or peripheral arterial disease but did not have type 1 or type 2 diabetes at the time of enrollment in the study.

First Study

The latest research indicates that the treatment with Wegovy can result in consistent weight reduction in overweight or obese adults without diabetes for a period exceeding 65 weeks and can be sustained for up to four years. After 208 weeks, the use of semaglutide was linked to an average decrease in weight by 10.2%, a reduction in waist circumference by 7.7 cm, and a decrease in the waist-to-height ratio by 6.9% compared to the placebo, which showed reductions of 1.5%, 1.3 cm, and 1.0%, respectively (P < 0.0001 for all comparisons against placebo). Significant weight loss was observed across both genders, various races, different body sizes, and geographic regions.

The long-term weight loss efficacy results of Wegovy were simultaneously published in the Nature Medicine.

After two years of treatment, a significant outcome was observed in patients using Wegovy, with over half (52%) experiencing a reduction in their BMI category, as opposed to just 16% in the placebo group. For instance, the percentage of obese patients (BMI ≥ 30 kg/m²) within the Wegovy-treated group dropped from 71% to 43%. In contrast, the placebo group saw a marginal decrease from 72% to 68%. Furthermore, 12% of those on Wegovy achieved a healthy weight (BMI ≤ 25 kg/m²), while merely 1.2% of the placebo group reached this milestone.

Wegovy treatment can lead to sustained weight loss for more than 65 weeks and can be maintained for up to 4 years.

Credit: Nat Med (2024). DOI:10.1038/s41591-024-02996-7

Regarding safety, no unexpected safety concerns emerged with Wegovy's use. The rate of serious adverse events (SAEs) was lower in the Wegovy group compared to the placebo group, with percentages at 33% and 36%, respectively. A higher number of patients on Wegovy discontinued the trial due to gastrointestinal issues, such as nausea and diarrhea, mostly occurring during the 20-week dose escalation period. Furthermore, when examining all BMI categories (<30, 30 to <35, 35 to <40, and ≥40 kg/m²), the incidence rates of serious adverse events were consistently lower for Wegovy compared to the placebo (43.23, 43.54, 51.07, and 47.06 for Wegovy vs. 50.48, 49.66, 52.73, and 60.85 for placebo). While Wegovy did not lead to an increased occurrence of pancreatitis among patients, there was a higher frequency of gallstones noted in those receiving Wegovy treatment.

The proportion of patients experiencing different degrees of weight loss with Wegovy compared to placebo treatment.

Credit:Nat Med (2024). DOI:10.1038/s41591-024-02996-7

"Our extensive evaluation of Wegovy demonstrates that substantial weight loss can be sustained for up to 4 years in a large and diverse group of overweight and obese adults who do not have diabetes. The observation of this level of weight reduction in such a varied population suggests that Wegovy could potentially alleviate the public health challenges posed by numerous obesity-related conditions. While our study primarily concentrated on cardiovascular incidents, effective weight management may also positively influence a range of other chronic illnesses, including various cancers, osteoarthritis, as well as mental health issues like anxiety and depression," stated Professor Donna Ryan from the Pennington Biomedical Research Centre in New Orleans, USA, who spearheaded the research on Wegovy's long-term weight loss benefits.

The BMI category of patients decreased after 104 weeks of Wegovy treatment.

Credit:Nat Med (2024). DOI:10.1038/s41591-024-02996-7

Second Study

The subsequent study focused on exploring the connection between initial weight measurements of patients, their weight variations throughout the study, and cardiovascular consequences. This includes the duration until the first instance of significant adverse cardiovascular incidents (MACE) and heart failure. MACE encompasses death due to cardiovascular causes, non-fatal heart attacks, or non-fatal strokes.

The findings indicated that treatment with Wegovy offers cardiovascular advantages irrespective of the initial weight of the patients and the extent of their weight loss. That is, even individuals with less severe obesity or those who did not shed much weight could still experience better cardiovascular results.

The results of this study have important implications for clinical practice. In my experience, approximately 50% of patients with cardiovascular diseases exhibit weights comparable to those included in the SELECT trial, and they are likely to benefit from Wegovy treatment," explained Professor John Deanfield from University College London, who spearheaded the research. "Our data indicate that the extent of the treatment's effectiveness is not solely dependent on the amount of weight loss, suggesting that the drug employs additional mechanisms to lower cardiovascular risk aside from merely reducing excess body fat. These other mechanisms might involve improvements in blood sugar levels, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels, or potentially a combination of several of these factors."

The recently reported encouraging outcomes offer compelling proof of Wegovy's sustained weight loss impact and its potential advantages in averting cardiovascular conditions. Nevertheless, scientists advise that SELECT was not structured as a primary prevention study, hence the findings cannot be generalized to all overweight and obese individuals for the prevention of major adverse cardiovascular events (MACE). Furthermore, while the study encompassed a significant and varied participant pool, it lacked sufficient representation from various racial demographics, which complicates the ability to determine the drug's effectiveness among different racial groups.

Wegovy is a medication that acts as a GLP-1 receptor agonist, which helps boost insulin production, curtail glucagon secretion, and lower both appetite and food consumption. In June 2021, the FDA granted approval for its use in treating general obesity, marking it as the first new medication sanctioned by the FDA for managing general obesity or overweight conditions since 2014. Additionally, the drug gained approval from the European Union for obesity treatment later that same year. More recently, in March of this year, the FDA extended Wegovy's approval to include reducing the risk of cardiovascular death, heart attacks, and strokes in adults who are obese or overweight with cardiovascular disease.

Outlook

In the past month, Novo Nordisk revealed the findings from the Phase 3 trial STEP HFpEF DM at the 2024 ACC conference. The study indicated that compared to a placebo, a weekly subcutaneous injection of Wegovy significantly alleviated symptoms related to heart failure and physical limitations, and it enhanced exercise performance in obese patients who have heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2DM). These results were also published concurrently in the New England Journal of Medicine.

Semaglutide Beneficial in HFpEF Patients With Diabetes published in the NEJM.

At the beginning of this year, Novo Nordisk presented the findings from this trial, in conjunction with data from an earlier Phase 3 study on Wegovy's effectiveness for HFpEF patients, to the FDA. They are seeking regulatory approval to broaden the use of this medication to include treatment for HFpEF.

In summary, semaglutide injection is a beneficial therapy for obesity and type 2 diabetes. It is used together with diet and exercise to help reduce your body weight and diabetic blood glucose. This medicine is also used to lower the risk of heart attack, stroke, or death in patients with type 2 diabetes, obesity, and cardiac or vascular disease.

References

1. Ryan, D.H., Lingvay, I., Deanfield, J. et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-02996-7

2. Semaglutide can produce clinically meaningful weight loss and reduce waist size for at least 4 years in adults with overweight or obesity who don’t have diabetes, and delivers cardiovascular benefits irrespective of weight lost. Retrieved May 14, 2024 from https://www.eurekalert.org/news-releases/1044398

3. Novo Nordisk’s Wegovy Sustains Weight Loss for Four Years in Two Studies. Retrieved May 14, 2024 from https://www.biospace.com/article/novo-nordisk-s-wegovy-sustains-weight-loss-for-at-least-four-years-in-two-studies/

4. Novo Nordisk's Wegovy helps keep weight off over four years, new analysis shows. Retrieved May 14, 2024 from https://endpts.com/novo-nordisk-reports-four-year-weight-loss-data-on-wegovy/

5. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024;390(15):1394-1407. doi:10.1056/NEJMoa2313917