Semaglutide, developed by Novo Nordisk, has been approved for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. Surprisingly, however, recent studies have found that, in addition to improving metabolic disorder, semaglutide may have the potential to protect against cardiovascular disease, treat NAFLD, fight cancer, alleviate neurodegenerative diseases and reduce addictive behaviors, etc.
Semaglutide: Mechanism of Action
Semaglutide is a long-acting Glucagon-like peptide 1 receptor agonist (GLP-1 RA). GLP-1, an incretin hormone secreted by intestinal L-cells in response to glucose and other ingested nutrients, induces insulin secretion via the GLP-1R in a glucose-regulated manner. Semaglutide improves blood glucose levels dramatically in patients with type 2 diabetes. It also acts to delay gastric emptying and suppress appetite, inducing weight loss by decreasing appetite and reducing food intake.
Figure 1. Semaglutide mechanism of action (source: Edgar181, Public domain, via Wikimedia Commons)
Like other GLP 1RAs, semaglutide acts primarily through the GLP 1 receptor. There is growing evidence that GLP 1 receptors are commonly expressed in the pancreas (α, β and δ cells), lung, heart, kidney, stomach, intestine, pituitary gland, skin, vagal ganglia, and multiple regions of the central nervous system (including brainstem, hypothalamus, hippocampus and cortex), determining the diversity of GLP 1 physiological actions. However, semaglutide also has its own unique mechanism to affect the brain, altering the food/reward pathway, with the ability to control individuals to increase food intake and change food preferences, resulting in the presence of lower preferences for high-fat foods.
Figure 2. GLP 1RAs treatment, source: reference 
Semaglutide Reduces Cardiovascular Disease Risk
As obesity is an important risk factor for cardiovascular disease, weight loss should theoretically reduce the risk of cardiovascular disease in participants, however, this speculation has not been validated by clinical trials.
New research by Mayo Clinic presented at this year's European Congress on Obesity (ECO2023, Dublin, 17-20 May) shows that after a year of taking semaglutide, the risk of a heart attack or a stroke over the next ten years dropped to 6.3% from 7.6% in a multicenter, 1-year-long real-world study. Since there was no control group in this study, the researchers said they could not confirm whether the reduction in cardiovascular disease risk was definitely due to the use of semaglutide. However, they did observe improvements in blood pressure, blood glucose levels, liver function, and a reduction in other medication use in the participants.
Novo Nordisk is conducting a large 5-year Phase 3 clinical trial (NCT03574597) to see if semaglutide may reduce the risk of having cardiovascular events in patients with overweight or obesity and with prior cardiovascular disease. The results of this trial are expected this summer, and Dr. Andres Acosta, a professor at Mayo Clinic, said the results of this real-world study bode well for the potential success of Novo Nordisk's large clinical trial as well.
Semaglutide For Neurodegenerative Disease
Neurodegenerative diseases include a group of progressive and complex conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc. Current treatments for neurological disorders include hormone replacement therapy and antioxidants, which primarily slow disease progression, lack the ability to reverse the disease, and have limited efficacy.
In addition to being the natural incretin hormone that regulates blood sugar, GLP-1 is also a recognized neurotransmitter whose receptors are expressed in many regions of the brain. Animal studies have shown that the administration of liraglutide, a GLP-1 receptor agonist, improves memory and learning, increases neuronal numbers, reduces amyloid beta (Aβ), and prevents tau protein accumulation. Modulation of GLP-1 activity also increased dopamine levels in a mouse model of Parkinson's disease.
A retrospective analysis of tens of thousands of patients with type 2 diabetes (including pooled data from three randomized, double-blind trials), published in the journal Alzheimer's & Dementia in 2022, showed that the incidence of dementia was significantly lower in those with diabetes who had used GLP-1 receptor agonists than in controls (HR: 0.47, 95% CI: 0.25-0.86). Dr. Suzanne Craft, professor of geriatrics at Wake Forest University School of Medicine, noted at a medical conference last year that it is urgent to examine the role of diabetes class I drugs in slowing the progression of Alzheimer's disease.
Novo Nordisk has initiated two large Phase 3 trials since 2021 to examine whether semaglutide can relieve symptoms in patients with early stage Alzheimer's disease. The two trials are each expected to enroll 1,840 patients who will be randomly assigned to receive either once-a-day oral semaglutide (tapered to 14 mg) or placebo for 173 weeks. Preliminary trial results are expected by September 2025. According to Reuters, a number of smaller companies, including Neuraly and Kariya Pharmaceuticals, have said they are evaluating the effects of needles of their experimental GLP-1 drugs in Parkinson's disease and are considering expanding the study area to Alzheimer's disease after results from the Novo Nordisk trial.
Semaglutide For Nonalcoholic Fatty Liver Disease (NAFLD)
Studies have shown that various GLP 1RAs such as liraglutide, dulaglutide, and semaglutide significantly improve Nonalcoholic steatohepatitis (NASH). Among them, semaglutide also significantly reduces the activity of alanine aminotransferase in a dose-dependent manner, decreases hypersensitive C-reactive protein levels, and reduces hepatic steatosis by stimulating GLP 1 receptors and reducing inflammation. Therefore, many trials have been investigating the effectiveness of semaglutide in the management of NASH/NAFLD.
A phase II clinical trial (NCT02970942) evaluated the efficacy and safety of semaglutide in 320 patients with biopsy-confirmed NAFLD over 72 weeks and showed that semaglutide resulted in significant improvement in up to 59% of patients with NASH compared to 17% in the placebo group, with no significant improvement in fibrosis, but also no worsening.
A placebo-controlled phase II clinical trial (NCT03987451) is evaluating the effect of semaglutide compared to placebo in patients with NAFLD and cirrhosis. This study includes 65 subjects treated with semaglutide 2.4 mg (1 time/week) for 48 weeks with liver MRI scans to measure pre- and post-cirrhosis, fibrosis, liver stiffness, liver fat content changes, and also to assess changes in NAFLD activity scores.
There is also a 5-year Phase III clinical trial (NCT04822181) underway to investigate the efficacy and safety of semaglutide monotherapy in patients with NASH without cirrhosis, assessing the primary endpoints of progression of cirrhosis, regression of steatohepatitis, inflammation, and histological changes in balloon-like hepatocytes.
Semaglutide for Cancer
Recently, a study published in the journal Obesity attracted a lot of attention. In this small trial of 20 obese patients, researchers found that obese patients had significantly lower levels of NK cells and production of cytokines (such as interferon IFN-γ) that mediate the toxic-killing effect compared to non-obese controls in the trial. However, after the obese patients were treated with semaglutide once a week for 6 months, in addition to the expected positive effects of weight loss and glycemic control, the scientists found that the patients' metabolic function of NK cells was restored and their levels of IFN-γ and granzyme B production (which induces apoptosis) were significantly increased. When the researchers tested the ability of the NK cells isolated from the patients to fight cancer cells in the laboratory, they found that they were twice as effective in killing cancer cells as they were before the patients were treated with semaglutide.
Notably, the researchers found that the changes in IFN-γ and granzyme B levels induced by semaglutide did not significantly correlate with the percentage of weight loss in patients. That is, the restoration of the anti-tumor capacity of NK cells may not be directly correlated with the weight loss effect produced by the drug. Although this study suggests that GLP-1 therapies like semaglutide may be useful in the fight against cancer, the number of participants in this study was small, so a large randomized controlled trial is needed to further validate the role of such therapies in the fight against cancer.
Effects of Semaglutide on Addictive Behavior
In animal studies, scientists have found that GLP-1 analogs can reduce the animals' need for a variety of addictive drugs, such as alcohol and cocaine. Most of these studies have used the first-generation GLP-1 drugs liraglutide and exenatide, though researchers expect more positive findings using semaglutide to be published soon.
While GLP-1 analogs have shown a reduction in addictive behavior in a variety of animal models, there is still less experimental evidence in humans. In a clinical trial published in 2022, scientists evaluated the effects of the GLP-1 analog exenatide on alcohol consumption. Using functional magnetic resonance imaging (fMRI), they found that participants treated with exenatide no longer had increased activity in the brain's "reward center" when they saw pictures of alcohol. Although the overall participants in this study did not have a significant decrease in drinking levels, the researchers observed a decrease in alcohol use and days of heavy drinking in obese patients with a body mass index (BMI) of more than 30. Scientists at the University of North Carolina are conducting clinical trials to evaluate the effects of semaglutide on smoking cessation and nicotine intake.
These positive results of studies on semaglutide in different disease areas undoubtedly make this clinically proven safe therapy a new hope for the treatment of a wide range of patients.
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 De Barra, Conor et al. “Glucagon-like peptide-1 therapy in people with obesity restores natural killer cell metabolism and effector function.” Obesity (Silver Spring, Md.), 10.1002/oby.23772. 9 May. 2023, doi:10.1002/oby.23772
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