Semaglutide: A Multifaceted GLP-1 Agonist Showing Promise in Weight Loss, Cardiovascular Protection, Alcohol Use Disorder, and Erectile Dysfunction

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Divine and Mysterious

Recently, the clinical development of various extended indications for semaglutide has further highlighted its "miracle drug" characteristics. In addition to further data confirming its weight loss efficacy, large-scale retrospective analyses have validated its benefits in alcohol addiction, cardiovascular diseases, and even in improving erectile dysfunction, a male-related condition.

2024-5-14, Results from two studies presented at the European Congress on Obesity in Italy showed that Novo Nordisk's semaglutide (Wegovy) for weight loss can maintain meaningful weight reduction and improve cardiovascular health over a period of up to four years.

The first study was published in the journal *Nature Medicine* on 2024-5-13. The study conducted a 208-week follow-up of patients from Novo Nordisk's SELECT cardiovascular outcomes trial and found that patients receiving Wegovy treatment were able to maintain their initial weight loss during this period.

Wegovy Group Patients' Weight Continuously Decreased Over 65 Weeks, and They Were Able to Maintain Their Weight Without Rebound for 4 Years. On Average, the Wegovy Group Patients' Weight Decreased by 10.2%, While the Placebo Group Only Decreased by 1.5%. The Treatment Difference Between the Two Groups Was 8.7%, Which Was Statistically Significant.

Among them, SELECT is a randomized, double-blind, parallel-group trial, recruiting more than 17,600 overweight or obese patients without a history of diabetes, with Wegovy administered at a dose of 2.4 mg.

In addition to weight loss, the 104-week study results also showed that 52% of patients who received Wegovy treatment had their Body Mass Index (BMI) reduced to a lower level after two years, compared to only 16% in the placebo group. After receiving Wegovy treatment, 12% of patients reached a healthy Body Mass Index, compared to 1.2% in the placebo group.

Study results show that regardless of patients' baseline weight and weight loss, Wegovy treatment provides cardiovascular benefits. This means that even patients with lower levels of obesity or those with minimal weight reduction can see improvements in cardiovascular disease outcomes.

In the fast-breaking news, this upcoming trial is a randomized, double-blind, parallel-group Phase 2 trial, expecting to enroll 240 adult patients with alcohol-related liver disease. These patients have self-reported a history of alcohol consumption for over or equal to 5 years, and their average daily alcohol intake in the last year prior to signing the consent form was over or equal to 50 grams (for men) / 40 grams (for women).

In addition, the patient's Enhanced Liver Fibrosis (ELF) score is greater than or equal to 9.8 units. This 39-week study will examine the effects of these three drugs, used alone or in combination, compared to placebo in patients with alcohol-related liver disease, including measurements of changes in liver fibrosis and alcohol consumption.

Phase II trial will be completed in June 2025. This is the first study to evaluate the effectiveness of a new generation of weight-loss therapy on alcoholic liver disease, which causes more than 30,000 deaths in the United States each year. Semaglutide offers the possibility of treating this disease, for which there are few other options.

This trial may be significant in revealing how GLP-1 drugs alter addictive symptoms in people. GLP-1 was initially found to function in the gut, but numerous studies show that GLP-1 drugs, which are more potent than the natural hormone, can actually enter the brain and modify the neural circuits that drive cravings.

Overall, the impact of GLP-1 drugs is not limited to the healthcare field; it is transforming the landscape of multiple industries.

2024-5-11~2024-5-14, The 26th European Congress of Endocrinology was grandly held in Sweden. Giuseppe Lisco shared his team's latest research at the conference. The study report shows that GLP-1R agonists can enhance erectile function in men with type 2 diabetes (T2D) and erectile dysfunction (ED).

Giuseppe Defeudis noted in "WILEY" that the etiology of erectile dysfunction (ED) is highly complex, potentially involving numerous irreversible and reversible factors that often coexist and typically interact with each other. Common risk factors include age, obesity, hypertension, dyslipidemia, cardiovascular disease, metabolic syndrome (MetS), lack of exercise, and smoking, among others, in addition to diabetes. The incidence of erectile dysfunction in male patients with diabetes is approximately 3.5 times higher than in non-diabetic males.

To better investigate whether GLP-1R drugs can improve male erectile dysfunction, Giuseppe Lisco's team designed a one-year retrospective cohort study.

Giuseppe Lisco used 108 patients with type 2 diabetes as treatment samples. Control group: 45 patients using metformin alone; Experimental group: 63 patients using GLP-1RA as an add-on therapy to metformin. After one year of stable treatment, erectile function was assessed using the 5-item International Index of Erectile Function (IIEF5). Values were compared between the two groups before treatment (T0) and after 12 months of treatment (T12).

All patients in the experiment were confirmed to have erectile dysfunction (IIEF5 score 13 to 19) before treatment. After 12 months of treatment, the results showed that the final experimental group (metformin + GLP-1) had a higher International Index of Erectile Function (IIEF5) score than the control group (metformin) (2.74 ± 0.53, P < 0.0001).

Regardless of the background characteristics and testicular function of T2D patients, "Metformin + GLP-1" is superior to "Metformin" alone in increasing serum testosterone levels and improving erectile dysfunction (ED) in patients with type 2 diabetes and functional hypogonadism.

Conclusion

In Q1 2024, the sales of Ozempic, the injectable diabetes medication containing semaglutide, continued to climb to DKK 27.81 billion, approximately $4.041 billion, with a growth rate of 43%. The sales of the oral diabetes product Rybelsus reached DKK 5.013 billion, approximately $728 million, marking a year-on-year increase of 17%. Meanwhile, the sales of the weight-loss drug Wegovy more than doubled, reaching DKK 9.377 billion, approximately $1.363 billion. The combined revenue of these three products amounted to a staggering DKK 42.2 billion, approximately $6.132 billion, accounting for the majority of the company's total revenue.

In recent years, Semaglutide has gained tremendous popularity in the market. However, faced with an increasingly competitive GLP-1 market, Novo Nordisk continues to explore and expand the boundaries of Semaglutide's indications. Multiple clinical trials have been initiated for various indications such as MASH, AD, HFpEF, DR, and PAD. Now, the indication is being extended to alcohol addiction, striving to create BIC products across various indications. As the trials progress, Semaglutide is expected to bring more surprises. Both academia and industry are watching closely.