In June 2021, the FDA approved Semaglutide (Wegovy), a GLP-1 receptor agonist developed by Novo Nordisk, for use as a weight loss drug. Due to its excellent weight loss effect and favorable safety profile, semaglutide has become popular all over the world.
In addition to its use in lowering blood sugar and weight loss, some recent studies have shown that semaglutide also has unexpected benefits: restoring natural killer cell (NK cell) function and reducing cancer risk; reducing the risk of cardiovascular disease; and helping to quit smoking and drinking, etc.
Semaglutide Kidney Study Ends Early for Early Efficacy
On October 10, 2023, Novo Nordisk announced the early termination of a Phase 3 clinical trial of semaglutide for the treatment of patients with kidney injury and chronic kidney disease who have type 2 diabetes. The decision to terminate the clinical trial early was based on the recommendation of independent Data Monitoring Committee (DMC), which concluded that the results from an interim analysis met certain pre-specified criteria for stopping the trial early for efficacy .
To protect the integrity of the trial, Novo Nordisk remains blinded to the results until trial completion. Novo Nordisk expects that FLOW will read out during the first half year of 2024.
Initiated in 2019, FLOW is a randomized, double-blind, parallel-group, placebo-controlled trial designed to demonstrate the superiority of injectable semaglutide 1.0 mg when used as an adjunct to standard care in people with type 2 diabetes and chronic kidney disease. 3,534 people are enrolled in the trial which has been conducted in 28 countries at more than 400 investigator sites.
Figure 1. FLOW trial of Semaglutide, source: Novo Nordisk official website
The key objective of the FLOW trial is to demonstrate delay in progression of CKD and to lower the risk of kidney and cardiovascular mortality through the composite primary endpoint consisting of the following five components: compared with baseline: 1) sustained decrease in eGFR1 ≥50%; 2) persistent eGFR1 <15 mL/min/1.73m²; 3) initiation of dialysis or renal transplantation; 4) death from renal disease; and 5) death from cardiovascular disease.
Mechanism of Action and Development of Semaglutide
Semaglutide is a potent and widely used GLP-1 (glucagon-like peptide-1) receptor agonist, primarily employed in the treatment of type 2 diabetes. It mimics the action of the natural hormone GLP-1, stimulating insulin secretion and reducing glucagon release to help regulate blood sugar levels.
In 2017, Novo Nordisk developed semaglutide, an improved version of liraglutide, which beat out dulaglutide in a head-to-head study of glucose-lowering and weight-loss effects to become "the best diabetes drug ever".
In June 2021, the FDA approved Wegovy for chronic weight management for adults with obesity (BMI ≥30kg/m2) or overweight (BMI ≥27kg/m2) and related comorbidities with at least one weight-related comorbidity, to be administered subcutaneously at 2.4mg once weekly. Semaglutide has since become a blockbuster drug, with sales of $10.882 billion in 2022. It has been approved for marketing in more than 50 countries and regions, including the U.S., Europe, Canada, and Japan.
Exploration of Expanded Indications: Semaglutide in HFpEF, NASH, AD, etc.
Multiple pivotal Phase III studies of Semaglutide are ongoing in heart failure with preserved ejection fraction (HFpEF), Alzheimer's disease (AD), diabetic retinopathy (DR), Non-alcohol related steatohepatitis (NASH), and peripheral arterial disease (PAD) in addition to CKD.
Figure 2. Semaglutide in other indications, source: Novo Nordisk official website
Heart failure with preserved ejection fraction (HFpEF)
On August 8, 2023, NovoNordisk announced results from the SELECT clinical phase 3 trial of semaglutide. The analysis showed that the trial reached its primary endpoint with a 20% reduction in the risk of major adverse cardiovascular events in overweight or obese adults (patients without a history of diabetes) with a single weekly subcutaneous injection of 2.4 mg semaglutide. 
On August 25, 2023, Novo Nordisk announced additional results from the Phase 3 clinical trial STEP HFpEF. The results showed that among adult patients with HFpEF associated with obesity, once-weekly injections of semaglutide 2.4 mg substantially reduced heart failure-related symptoms and physical limitations, and improved exercise function, as well as achieving greater weight loss, compared to placebo. 
Based on the results of these two trials, Novo Nordisk expects to deliver data from the SELECT with STEP HFpEF trial in the U.S. and EU this year to expand new indications for the drug. In addition, STEP HFpEF-DM, another trial in obese adults with HFpEF and type 2 diabetes, is expected to be completed in the fourth quarter of this year.
Non-alcohol related steatohepatitis (NASH)
Semaglutide has been granted Breakthrough Therapy Designation by the FDA in the NASH indication and is currently in clinical Phase III.
Positive results have been obtained with semaglutide in Phase II clinics. Compared to placebo, semaglutide monotherapy significantly eliminated histologic symptoms of NASH in patients without exacerbating liver fibrosis.
In the group of patients receiving the highest dose of semaglutide , NASH symptoms were eliminated in 66.7% of patients. In terms of improving liver fibrosis in patients, semaglutide also demonstrated a trend toward providing clinical benefit to patients, with fewer NASH patients experiencing progression of liver fibrosis compared to placebo. Among patients treated with the highest dose of semaglutide, 5.8% of patients experienced progression of liver fibrosis.
Alzheimer's disease (AD)
Semaglutide has also shown potential in the area of neurodegenerative diseases where research and development has faced great difficulties. As reported by Reuters on May 8, 2023, starting in 2021, Novo Nordisk initiated two large Phase 3 trials testing (evoke and evoke+) whether oral semaglutide can alleviate early Alzheimer's disease symptoms. Each of the two trials is expected to enroll 1,840 patients who will be randomly assigned to take oral once-a-day semaglutide (with the dose tapered to 14 mg) or placebo for up to 173 weeks. Preliminary trial results are expected to be generated in September 2025.
Semaglutide has been a blockbuster drug in recent years. In the increasingly competitive GLP-1 market, Novo Nordisk has continued to explore and expand the boundaries of Semaglutide's indications, with multiple clinical launches in NASH, AD, HFpEF, DR, PAD, and other indications. It is believed that Semaglutide will bring more surprises to people as the trial proceeds.
 The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease https://doi.org/10.1093/ndt/gfad009
 Novo Nordisk A/S: Semaglutide 2.4 mg reduces the risk of major adverse cardiovascular events by 20% in adults with overweight or obesity in the SELECT trial https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=166301
 STEP-HFpEF: Semaglutide Improves Symptoms, Physical Limitations, Weight Loss in Patients With HFpEF and Obesity. https://www.acc.org/Latest-in-Cardiology/Articles/2023/08/23/19/16/fri-515am-step-hfpef-esc-2023
 Barritt AS 4th, Marshman E, Noureddin M. Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know. Aliment Pharmacol Ther. 2022 Apr;55(8):944-959. doi: 10.1111/apt.16794. Epub 2022 Mar 9. PMID: 35266164; PMCID: PMC9310586.