The multifaceted effects of semaglutide: exploring its broad therapeutic applications

Abstract

Semaglutide, a GLP-1 receptor agonist, is FDA-approved for managing type 2 diabetes (T2D) and reducing cardiovascular risk. Its off-label use in weight management and other conditions has grown, prompting a review of its benefits and risks. This review evaluates evidence on semaglutide’s effects, highlighting its therapeutic potential beyond approved indications. Studies from 2021–2024 were reviewed via PubMed, ScienceDirect, and Google Scholar. Semaglutide showed promise in managing PCOS-related obesity, insulin resistance, and demonstrated renoprotective effects in diabetics and chronic kidney disease (CKD). Additionally, it improves liver enzyme levels, steatosis, and stiffness, aiding in managing Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in non-fibrotic patients. The FDA has approved it for reducing major adverse cardiovascular events, heart failure symptoms, and physical limitations in diabetic and non-diabetics. Preclinical studies suggest benefits in cognitive disorders associated with insulin resistance, including Alzheimer’s disease, Parkinson’s disease, and vascular dementia in animals. Although rare cases of thyroid cancer have been reported, no causal relationship has been established, emphasizing the need of caution in high-risk populations. GLP-1 therapy has also exerted protective effects against the risk of various types of cancer. However, ongoing human studies are essential to validate these findings and clarify semaglutide’s association with cancer.

PLAIN LANGUAGE SUMMARY

• Semaglutide is a medicine that helps people with type 2 diabetes and can also lower the risk of heart problems. It might also help people with PCOS by making insulin work better and helping them lose weight. It may also protect the kidneys and make the liver healthier.

• Doctors use semaglutide to help people with heart problems even if they do not have diabetes. In some studies with animals, it has also helped with memory and thinking problems like in Alzheimer’s disease.

• There is no proof that semaglutide causes thyroid cancer, but doctors are careful with people at high risk. It might even lower cancer risk in people with diabetes but more research is needed. Scientists are still studying its safety and long-term effects.

ARTICLE HIGHLIGHTS

• Weight loss and Its Ripple Effects on Hormonal Regulation

  • Weight Loss: Semaglutide promotes weight loss, improves metabolic health

  • Polycystic Ovary Syndrome (PCOS): Benefits PCOS by enhancing insulin sensitivity and hormonal balance.

• Semaglutide’s Integrated Effects on Key Body Systems

  • Renal Health: Semaglutide protect kidney functions by reducing eGFR, albuminuria, and kidney- related risks, with rare but manageable side effects.

  • Liver Health: As well as improving liver conditions and potentially preventing fibrosis progression.

  • Cardiovascular Health: It shows promise for HFpEF and cardiovascular protection, reducing inflammation, and improving heart and vascular health.

  • Cognitive and Mental Disorders: It shows neuroprotective potential by improving brain insulin sensitivity, reducing oxidation stress, and promoting neuronal survival.

• Smoking Cessation and Cancer Risk through Metabolic Regulation.

  • Smoking Cessation: It shows potential in smoking cessation by reducing cravings and modulating dopamine pathways

  • Cancer Risk: No proven link to increase cancer risk.

1. Introduction

With the rapid increase in the incidence of type 2 diabetes mellitus, the demand for new therapeutic medications is increasing [1]. Many classes of antidiabetic drugs have been introduced in the last decade, and one of the most effective is semaglutide, a new generation subcutaneously injectable glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) [2]. It was approved by the Food and Drug Administration (FDA) in 2017 under three major brand names, Ozempic, Wegovy, and Rybelsus, primarily as a glucose-lowering agent for type 2 diabetes, to reduce cardiovascular risk and provide cardiovascular protection [3]. An oral form was recently approved in 2019 as a non-injection alternative for glycemic control [4].

Semaglutide mimics the GLP-1 hormone, an incretin, with 94% structural similarity to endogenous GLP-1, with modifications extending its half-life to 155–184 h by reducing metabolic degradation, enhancing receptor affinity in organs such as the pancreas and hypothalamus, and increasing albumin binding. Consequently, a single weekly dose of 0.5 or 1.0 mg, starting with 0.25 mg for the first 4 weeks, is effective [5,6]. Upon receptor binding, it stimulates insulin secretion from pancreatic beta cells and inhibits glucagon secretion from alpha cells, thereby reducing blood glucose levels.

Semaglutide exerts a wide range of effects on many physiological systems within the body because of the varied expression of the GLP-1 receptor, which is not limited to the pancreas. Therefore, its effects extend beyond the pancreas and include slowing gastric emptying, appetite suppression, weight loss, and cardiovascular protection. Moreover, it has the potential to exert neuroprotective as well as renoprotective effects. It may contribute to menstrual regulation, hormonal rebalance, and increased fertility owing to factors associated with weight loss [7]. Consequently, they have been used in various clinical scenarios.

Most systematic reviews of semaglutide focus on glycemic control and weight loss benefits, highlighting a gap in exploring other medical applications [8,9]. Demand for semaglutide is rising for both FDA-approved and off-label use [3]. Owing to its broader application, the FDA advises patients to consider potential metabolic and adverse effects [3]. This study investigated the application of semaglutide in diverse clinical settings to enhance the understanding of its therapeutic and metabolic impacts. It also discusses future prospects and contributes to existing reviews by emphasizing safety, efficiency, and necessary caution in diverse contexts.

2. Methods

To evaluate the therapeutic impact and safety of semaglutide under various conditions, we conducted a comprehensive literature review. Databases, including PubMed, ScienceDirect, and Google Scholar, were searched for relevant studies published between 2021 and 2024. The selection criteria were RCTs, systematic reviews, meta-analyses, and observational studies that discussed the effects of semaglutide in clinical and preclinical settings. Data extraction prioritized recent findings on the efficacy, dosing, side effects, and broader applications of semaglutide beyond diabetes management.

3. Discussion

3.1. Weight loss and its ripple effects on hormonal regulation

3.1.1. Weight loss

Semaglutide is primarily utilized for weight reduction, as both once-daily oral and once-weekly subcutaneous administration [10] have been evaluated in several long-term trials, including the SELECT trial involving 17,604 patients with preexisting cardiovascular disease. After 208 weeks, the semaglutide group exhibited a statistically significant decrease in weight (−10.2%) and waist-to-hip ratio (−6.9%) compared to the control group. These outcomes were consistent among both sexes, races, and body sizes [11].

A meta-analysis of 13 randomized controlled trials involving 5838 patients demonstrated significant absolute weight reduction in the semaglutide group [12]. Bioinformatic analysis of mice treated with intraperitoneal semaglutide identified 640 differentially expressed proteins that are integral to lipid transport and metabolism. These alterations contribute to decreased visceral fat, improved blood lipid profiles, and enhanced glucose tolerance [13]. Additionally, studies have identified downregulated genes that play crucial roles in fatty acid and triglyceride synthesis [14]. Semaglutide also enhanced satiety, as evidenced by a 38.9% reduction in calorie intake following a fat-rich breakfast in subjects taking oral semaglutide, although no significant differences were observed with a standard breakfast [15].

Semaglutide also offers significant benefits to type 2 diabetes patients by effectively reducing blood LDL and cholesterol levels, thereby contributing to weight loss. By activating GLP-1 receptors, semaglutide promotes neogenesis and proliferation of pancreatic β-cells and decreases their apoptosis [10,14]. Additionally, it inhibits glucagon release from pancreatic α-cells and reduces hepatic glucose production [14].

3.1.2. Polycystic ovary syndrome (PCOS)

Weight loss positively influences PCOS pathophysiology by reducing insulin resistance and hyperandrogenism. In addition to diet and exercise, GLP-1 analogs show promise for weight loss and improving metabolic and androgenic parameters in obese women with PCOS [16].

Metformin is commonly used as a first-line treatment for PCOS. Combining other antidiabetic drugs with metformin can enhance glycemic control in women with PCOS. GLP-1RAs have demonstrated potential benefits in treating PCOS [17], with long-acting GLP-1RAs showing superior hypoglycemic effects compared with dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) [17].

Most trials on semaglutide have focused on T2DM patients, revealing significant improvements in glycemic parameters, substantial weight loss, and decreased cardiometabolic risks. These findings suggest that semaglutide may benefit PCOS management [18].

In a 16-week randomized single-blind pilot study with 25 participants, semaglutide (1.0 mg) was more effective than a placebo in reducing body weight in obese women with PCOS [19]. Semaglutide participants experienced significant reductions in tongue fat tissue and fat proportion, which correlated with changes in body weight, BMI, and waist circumference. The semaglutide group lost an average of 5.2 kg, compared to 1.9 kg in the placebo group [19].

In a study on the effects of low dose semaglutide (0.5 mg weekly) in obese PCOS patients, 27 participants showed notable improvements, including an average weight decrease of 7.6 kg and a body mass index (BMI reduction of 3.1 after three months [20]. Improvements in insulin sensitivity and fasting glucose levels were observed, along with normalization of menstrual cycles in most patients. Semaglutide is well-tolerated, with minor side effects such as morning nausea and occasional vomiting [20].

In a 12-week single-blind, placebo-controlled trial involving 20 obese women with PCOS, participants were randomized to subcutaneous semaglutide 1.0 mg weekly or placebo to evaluate its effect on gastric emptying (GE) using scintigraphy. Semaglutide significantly delayed GE compared with placebo, likely promoting weight loss by prolonging satiety [21]. Additionally, semaglutide significantly reduced androstenedione and free testosterone levels while increasing sex hormone-binding globulin (SHBG) levels, potentially improving hyperandrogenism. It is well tolerated, with mild and self-resolving symptoms and no treatment discontinuation [21]. Table 1 summarizes studies discussing the effect of semaglutide on PCOS.

Table 1.

Clinical studies that highlighted semaglutide’s effect on PCOS.

Reference	Study design	Study population	Patient characteristics	Duration	Intervention	Outcome	Conclusion	Gaps and limitations
[71]	Randomized single-blind, pilot study.	35	Obese women with PCOS (33.7 ± 5.3 years, body mass index (BMI) 36.1 ± 3.9 kg/m2, mean ± SD)	16 weeks	1.0 mg Semaglutide versus placebo weekly for 16 weeks	Semaglutide significantly reduced tongue fat and fat proportion compared to placebo, with correlations to reductions in body weight, BMI, and waist circumference in obese women with PCOS.	This study is the first to confirm Semaglutide’s beneficial effects on tongue structure in obese women with PCOS, highlighting the need for further research to determine the clinical significance of these findings.
[72]	Preclinical, randomized	24 mice	Female C57BL/6J mice with DHEA-induced PCOS	4 weeks	Mice were divided into four groups: control, PCOS, PCOS treated with liraglutide (0.3 mg daily), and PCOS treated with Semaglutide (0.1 mg three times weekly). Both treatments were administered interperitoneally for 4 weeks.	Both GLP-1RAs improved metabolic and reproductive disorders in PCOS, modulating gut microbiota and showing efficacy in weight loss with Semaglutide increasing Helicobacter.	Semaglutide shows potential to improve conditions associated with PCOS.	Future studies should be conducted on a larger scale with clinical patients to further explore the mechanisms of bacteria identified during the trial.
[73]	Single-blind, Randomized, placebo-controlled trial	20	Women with PCOS and obesity, without diabetes and other comorbidities	8 weeks	Randomized Semaglutide 1.0 mg was subcutaneously injected once weekly vs placebo, while assessing gastric emptying of a solid meal with 99mTC colloid after injection by scintigraphy.	Semaglutide showed higher remaining activity of 99mTC colloid and slower gastric emptying compared to placebo, indicating a prolonged digestion process.	Weekly 1.0 mg Semaglutide injections significantly delayed gastric emptying and suppressed appetite compared to placebo, leading to weight loss and improvements in metabolic markers such as HbA1c and androgen levels.	The study’s small population and short duration highlight the need for extended research on larger groups to assess the long-term effects and safety of Semaglutide.
[73]	Preclinical, randomized	24 mice	Female prepubertal C57B/6 mice (3 weeks old, 10–12 g)	7 weeks	Mice were divided into four groups: control, DHEA-induced PCOS, DHEA+ liraglutide (0.3 mg daily), and DHEA+ semaglutide (0.1 mg three times weekly), both administered interperitoneally for 4 weeks. Normal saline was used for control and DHEA-only groups.	Semaglutide and liraglutide normalized fasting insulin levels, reduced HOMA-IR, affected ovarian morphology, reduced testosterone and inflammatory markers, and induced “browning” of white adipose tissue.	GLP-1 agonists improved metabolic disorders in PCOS mice, primarily through anti-inflammatory effects, promoting the browning of white adipose tissue, and impacting ovarian tissue pathology. Semaglutide also suggested improved glucose tolerance, indicating its potential to enhance PCOS treatment.	There’s a need for additional clinical trials to confirm these findings. Further research is also necessary to investigate the link between the browning of white adipose tissue (WAT) and inflammatory responses, and the potential impact of other inflammatory signaling pathways on GLP-1 therapy effects.
[74]	Observational study (prospective cohort)	25	Women with obesity and PCOS, aged (33.7 ± 5.3 years)	2 years	Participants received 1.0 mg of Semaglutide alongside 200 mg/d of metformin for 16 weeks, followed by a continuation of only metformin for 2 years.	Initial weight and testosterone reductions during Semaglutide treatment reverted toward baseline two years post-treatment, although some weight loss and cardiometabolic improvements remained significant.	Although women with PCOS on metformin regained a third of their weight loss after discontinuing Semaglutide, 84% maintained a lower body weight compared to baseline after two years	The study’s main limitations include a small sample size and the absence of a control group. Future studies should utilize randomized controlled trials, particularly in populations with insulin resistance.
[20]	Prospective Cohort	27	Obese patients (BMI kg/m2, ≥30) with phenotype A PCOS, who were unresponsive to lifestyle modifications.	3 months + 3 months in responsive patients	Participants received 1.0 mg of Semaglutide alongside 200 mg/d of metformin for 16 weeks, followed by a continuation of only metformin for 2 years.	Three months of Semaglutide treatment significantly reduced weight, BMI, and improved fasting glucose and insulin sensitivity.	Semaglutide effectively reduced weight in 80% of obese patients with PCOS and improved menstrual cycles and fasting glucose levels with minimal side effects.	The small sample size and lack of a control group are recurrent limitations across multiple aspects of the study.
[75]	Single-blind, placebo-controlled, randomized, prospective.	30	Obese women with PCOS (age 33.7 ± 6.1 years, BMI 36.4 ± 4.4 kg/m2, mean ± SD)	16 weeks	Patients received 1.0 mg of Semaglutide injection subcutaneously versus placebo in a controlled trial.	Semaglutide altered the expression of over a thousand genes in the tongue, enhanced taste sensitivity, reduced emotional eating, and modulated brain activation in response to food stimuli.	Semaglutide altered the transcriptomic profile and brain response to food, enhanced taste satisfaction, and reduced cravings for high-calorie food, further supporting its beneficial impact on obese PCOS patients.	The short duration of the study is a repeated concern, underscoring the need for prolonged investigation periods.

3.2. Semaglutide integrated effects on key body systems

3.2.1. Renal health

Semaglutide has a protective effect on the kidneys of patients with type 2 diabetes and chronic kidney disease (CKD), mitigating severe outcomes such as significant declines in estimated glomerular filtration rate (eGFR) and kidney function loss [22]. Although the precise mechanism of its renoprotective effect is unclear, recent studies have suggested that it may involve glycemic control, weight loss, and improvements in blood pressure and lipid profiles. Additionally, as GLP-1 receptors are present in various parts of the kidney, GLP-1RAs may directly inhibit pathogenic mechanisms such as inflammation, oxidative stress, and endothelial dysfunction [23,24].

Recent research on patients with type 2 diabetes and CKD indicates that semaglutide effectively reduces the risk of primary outcomes, defined as major kidney disease events, including a sustained >50% decline in eGFR, incident end-stage kidney disease (ESKD), onset of kidney failure, and kidney-related death [22,25]. Moreover, treatment with semaglutide significantly decreased the mean annual decline rates of eGFR and the urinary albumin-to-creatinine ratio (UACR) compared with placebo, suggesting its efficacy in reducing albuminuria, a key indicator of glomerular damage, and better preservation of kidney function [25].

A randomized flow trial across 28 countries examined the effects of weekly 1.0 mg subcutaneous semaglutide on T2DM and CKD patients (n = 3534, mean age 66.6 years) using an 8-week dose escalation regimen (0.25–0.5 mg/week for four weeks, followed by 1.0 mg/week for another four weeks). The trial ended in November 2023 because of the significant efficacy shown in a pre-specified interim analysis [25]. A follow-up trial in July 2024 (median follow-up = 3.4 years) confirmed these results, showing a 24% reduction in the primary outcome risk in the semaglutide group compared to the placebo group. The confirmatory secondary outcomes also showed improvement, with a mean annual eGFR slope of 1.16 ml/min/1.73 m² in the semaglutide group. The risk of death from any cause was 20% lower and fewer serious adverse events were reported in the semaglutide group than in the placebo group (49.6% vs. 53.8%) [22,23].

The side effects of semaglutide primarily include acute kidney injury (AKI), such as acute interstitial nephritis, particularly in immunocompromised patients, those with preexisting renal impairment, or those suffering from severe dehydration and volume depletion due to gastrointestinal side effects [24,26]. Although semaglutide-associated AKI is rare, it can lead to severe outcomes, requiring temporary hemodialysis and discontinuation of GLP-1 therapy [27]. Most studies indicate that GLP-1 agonist-associated AKI is prerenal, caused by GI symptoms and reduced oral intake, and is often associated with other risk factors for renal disease, such as hypertension, cardiac disease, or nephrotoxic medications, such as ACE inhibitors [27].

3.2.2. Cardiovascular health

Semaglutide is a novel therapeutic agent for heart failure with a preserved ejection fraction (HFpEF) [28]. Enhancing the functional status of patients with HFpEF is crucial, highlighting the need for innovative treatments, particularly for obesity-related HFpEF [29]. The Semaglutide Treatment Effect in People with obesity and HFpEF (STEP-HFpEF) program showed that weekly semaglutide significantly improved HF symptoms, physical limitations, and exercise capacity and reduced inflammation and congestion biomarkers [29]. It also lowered systolic blood pressure by 2–6 mmHg in hypertensive individuals and caused a modest increase in heart rate (2–4 beats/min), regardless of hypertension [30]. Semaglutide also reduced NT-proBNP and high-sensitivity CRP levels, indicating direct cardiovascular benefits [31]. Compared with other glucose-lowering drugs, semaglutide has been linked to lower CRP levels [32,33] and potential plaque stabilization [33]. The cardiovascular benefits of semaglutide are independent of its glucose-lowering effects [33] and have been observed in obese patients with high cardiovascular risk without diabetes at high doses [32].

The cardiovascular benefits of semaglutide are attributed to direct cardiac effects (protection against myocardial ischemia, reduction of epicardial adipose tissue, and improved cardiac contractility) and vascular effects (vasodilation and enhanced endothelial function) [32]. Its actions on the heart and endothelial cells prevent atherosclerosis progression by increasing nitric oxide and decreasing endothelin-1, reactive oxygen species, and inflammatory cytokines [34]. Thus, cardiovascular benefits are expected in normoglycemic patients with ASCVD and those without HbA1c improvement [35].

Semaglutide activates GLP-1 receptors, improving metabolic status and stabilizing blood glucose levels. It also lowers blood pressure and enhances the lipid profile. Its ability to promote endothelial and vascular health is crucial for CV outcomes, as it improves blood flow, reduces vascular resistance, and enhances. Semaglutide’s direct CV benefits stem from its anti-inflammatory properties, as it reduces systematic inflammation, lowers CV damage, and slows the progression of CVD [36]. Additionally, anti-atherosclerosis properties prevent the formation if plaques and related risks, such as hypertension. By decreasing appetite, reducing calories, and promoting weight loss, semaglutide further improves lipid metabolism by lowering LDL cholesterol and potentially raising HDL levels. It helps prevent harmful structural changes in the heart by reducing myocardial fibrosis, as indicated by lower fibrosis biomarker [36]. This supports improved heart function and reduces the risk of heart failure. Furthermore, semaglutide stimulated neurohormonal pathways and sympathetic activity, leading to reduced cardiac workload, which lowers the likelihood of arrhythmias and heart failure.

A meta-analysis showed that semaglutide significantly reduced the occurrence of AF [37]. Serious adverse events such as cardiac disorders, atrial fibrillation, and cardiac failure were more common in the placebo group than in the semaglutide group, indicating beneficial hemodynamic effects [38]. Semaglutide, found in the hindbrain, enhances protein synthesis by prolactin-releasing peptide (PrRP) and tyrosine hydroxylase [39]. PrRP is a neuropeptide with cardioprotective properties, including lowering blood pressure and prevention of heart damage. Tyrosine hydroxylase, an enzyme involved in dopamine production, regulates the heart rate and blood pressure. By boosting these proteins, semaglutide may improve heart function and protect against cardiovascular disease [39].

The SUSTAIN-6 trial indicated that subcutaneous semaglutide significantly reduced three-point MACEs, although individual MACEs did not show significant differences compared with placebos [40]. Subcutaneous Semaglutide also lowered the risk of nonfatal stroke, whereas oral semaglutide did not [41]. The PIONEER-6 trial found no significant differences between stroke and myocardial infarction with oral semaglutide [40]. According to a 2024 retrospective study, the number of fatal events was higher in the semaglutide group than in the placebo group. The long-term effects of semaglutide treatment beyond one year remain uncertain [38]. Previous studies noted significant weight regain and worsening of cardiometabolic risk markers after semaglutide withdrawal [42].

In a SELECT trial involving 17,604 patients with a BMI of 27 or higher and preexisting cardiovascular disease, but without diabetes, weekly subcutaneous semaglutide reduced the risk of composite death by cardiovascular events by 20% [43]. However, a contradicting study revealed that patients with a BMI below 35 experienced a significant reduction in cardiovascular events, whereas those with a BMI of 35 or higher did not, indicating a potential correlation. Further analysis and clinical trials are required to explore this possibility [44].

3.2.3. Liver health

Among the GLP1 agonists, semaglutide exhibits the highest efficacy in glycemic control and weight reduction. It is also effective in treating Metabolic Dysfunction-Associated Steatotic Liver Disease (MATLD) owing to its beneficial impact on metabolic syndrome parameters [45]. MATLD is closely linked to insulin resistance and type 2 diabetes mellitus and can progress to Nonalcoholic Steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma [45]. Semaglutide is a promising treatment for NASH [46], with resmetirom being the only FDA-approved drug specifically for NASH with fibrosis [47]. Clinical trials have shown that semaglutide can reduce and even resolve NASH without cirrhosis, improving histological hepatic conditions, lobular inflammation, and hepatocellular ballooning [48]. Numerous studies have indicated significant improvements in hepatic steatosis with semaglutide treatment [49]. Semaglutide also moderately decreased ALT and AST levels, aiding in fibrosis regression and slowing MATLD progression. Daily Semaglutide appears to improve ALT levels more effectively than weekly doses [28], whereas weekly doses effectively reduce transaminitis characterized by elevated ACT and ALT levels [49]. The impact of semaglutide on liver stiffness in MATLD and NASH remains debated, and an analysis of five RCTs found no significant change in two studies. In contrast, three reported a significant reduction in liver stiffness [50].

The impact of Semaglutide on NASH-related fibrosis has been inconsistent. An RCT involving 50 patients [51] indicated a significant improvement in liver fibrosis, whereas two other RCTs reported non-significant improvements compared with placebo [48]. No worsening of fibrosis has been observed with semaglutide use [48,52], suggesting that it may prevent NASH-associated fibrosis progression. The potential benefits of fibrosis may emerge with extended follow-up [52].

3.2.4. Cognitive and mental disorders

Emerging research highlights the neurological therapeutic potential of GLP-1 RAs, with clinical trials indicating significant prevention of neurological complications, cognitive impairment, and peripheral neuropathy [53,54]. When GLP-1 RA semaglutide binds to brain GLP receptors, it activates intracellular signaling pathways that inhibit apoptosis, reduce oxidative stress, promote neuronal survival, and enhance neurogenesis and cerebral blood flow, thereby exhibiting neuroprotective effects [53,54]. Its impact on diabetes, particularly in improving insulin sensitivity, is crucial because impaired brain insulin signaling heightens the risk of neurodegenerative disorders, thus showing neuroprotective benefits beyond metabolic regulation [55]. The widespread presence of GLP-1 receptors in the brain suggests that GLP-1 signaling is integral to numerous neurophysiological pathways, promoting neurological health and mitigating cognitive dysfunction in conditions such as Parkinson’s disease, Alzheimer’s disease, and vascular dementia [53,56].

The neuroprotective effect of semaglutide is attributed to its inhibition of NLRP3 inflammasome activation, leading to a reduction in inflammatory responses, practically in neurological conditions such as epilepsy. This inhibition decreases the downstream secretion of pro-inflammatory cytokines, including IL-1β and IL-18, thereby excreting a protective effect on neuronal health and cognitive function [57,58]. Semaglutide also reduces hippocampal neuron apoptosis, as evidenced by the reduction of apoptosis-related protein markers. Research further highlights its role in regulating hypothalamic neuronal activity to moderate energy balance, potentially influencing cognitive and behavioral functions through the activation of proopiomelanocortin (POMC) neurons, which amplifies their activity [57,58]. Additionally, hypothalamic regulation may involve anti-inflammatory effects. Semaglutide is also suggested to indirectly inhabit the activity of neuropeptide Y/Agouti-related peptide (NPY/AgRP) contributing to its neuroprotective profile [57,58].

Some studies have proposed that this neuroprotective effect is linked to weight loss in obesity, as reduced neuronal and myelin viability is observed in obese mice [59]. While human studies on semaglutide’s effect on obesity-related cognitive function are lacking, it has shown promise in diabetic animals with neurotransmitter receptor dysregulation and brain GLP-1R, improving spatial learning and memory in obese mice and reducing seizure severity [53,57]. The main limitation to fully understanding its neuronal role is the scarcity of human studies [53,60]. Animal studies and preliminary human trials have suggested potential neuroprotective effects, but further research is necessary to confirm these findings.

Details regarding the neurocognitive effects of semaglutide are shown in Table 2 and studies addressing the mental health aspects of semaglutide are listed in Table 3.

Table 2.

Clinical studies that measured the neurocognitive effects of semaglutide.

Author and date	Country	Study design	Population	Sample size	Methodology	Duration	Key findings	Possible gaps and limitations
De Giorgi et al. [76]	USA	retrospective cohort study	18 years old and above with a diagnosis of T2DM	>100 million	Analyzing 22 neurological and psychiatric outcomes within one year using Cox regression.	12 months	No increase in the 12-month risk of adverse neuropsychiatric outcomes compared to other antidiabetic medications.	Further clinical trials are needed to explore potential benefits for cognitive deficits and nicotine misuse.
Xiaoyi  et al. [20]	China	Preclinical	C57BL/6JC male mice (age: 6 weeks)	32	Mice divided into control, high-fat diet, and subgroups receiving semaglutide, empagliflozin, or saline; assessed for cognitive function and biochemical markers after 12 weeks.	12 weeks	Semaglutide and empagliflozin increased protein serine phosphorylation, influencing neuronal development, synaptic plasticity, and cognitive function.	Need for more evidence to confirm causal relationships.
Wang et al. [77]	China	Preclinical	2-month-old male APP/PS1/Tau transgenic mice and C57B6/129 wild type mice	100	Mice treated with semaglutide or saline, with one group also receiving EX527; behavioral tests conducted over 30 days.	1 month	Enhanced cognition and reduced memory impairment in 3xTg mice; attributed to promotion of glycolysis.	Focus on the CA3 region may enhance understanding of underlying mechanisms.
Chen et al. [78]	China	Preclinical	24SPF-grade C57BL/6J male mice and tissue samples	16	Obese mice are divided into model, semaglutide, and control groups; cognitive function assessed via Morris water maze and hippocampal proteomics analysis.	12 weeks	Significant reduction in serum triglycerides and LDL-C, with a decrease in HDL-C; improved obesity outcomes and possibly reduced dementia risk independently of weight loss.	Unexplored mechanisms of action of semaglutide on hippocampal tissue and cognitive function in diet-induced obese mice.
Sass et al. [79]	Denmark	double-blinded, randomized and placebo-controlled trial	Prediabetics or diabetics aged 18–65 years diagnosed with a schizophrenia spectrum disorder within the last 60 months	104	Patients randomly assigned to receive weekly injections of 1.0 mg semaglutide or a placebo for 26 weeks.	26 weeks	Potential enhancement of overall glycemic control and reduction of metabolic disturbances caused by antipsychotic medications.	Lack of rescue medication and a short trial duration (26 weeks) might affect patient retention and obscure full treatment benefits.
Sadek et al. [80]	Egypt	Preclinical	Adult male Swiss-Albino mice weighing 20–25 g and Sprague–Dawley rats weighing 200–250 g	10	Mice divided into control and experimental autoimmune encephalomyelitis (EAE) groups, treated with saline or semaglutide; analyzed using Shapiro–Wilk and Brown–Forsythe tests.	2 weeks	Protected against cognitive and motor impairments by activating the PI3K/Akt/GSK-3β pathway, enhancing remyelination, and boosting antioxidant and anti-inflammatory effects.	Limited study duration may not capture long-term effects and potential side effects of semaglutide.
Hussein et al. [81]	Saudi Arabia	Preclinical	BTBR mice (age: 6–8 week)	60	Mice are divided into five groups receiving various treatments including saline, semaglutide, and cyclophosphamide.	6 weeks	Non-genotoxic, reduced autism-like behaviors, oxidative stress, and enhanced DNA repair gene expression in BTBR mice.	Use of only BTBR mice may not adequately represent the diversity of autism spectrum disorder in humans.
Koychev et al. [82]	UK	randomized, double-blind and placebo-controlled clinical trails	Individuals aged ≥55 years with brain amyloid positivity	88	Participants undergo brain scans and cognitive tests, focusing on changes in tau PET signal.	1 year	Valuable data linking PET measures of brain changes to early AD biomarkers.	Limited sample size and issues with participant stratification; biomarker efficacy and amyloid levels not correlating with increased psychiatric symptoms.
Chuong et al. [83]	USA	Preclinical	C57BL/6J mice weighed 15–25 g and Wistar rats	77 mice 60 rats	Mice and rats subjected to drinking-in-the-dark procedure to assess changes in spontaneous inhibitory postsynaptic currents.	Approximately 4 weeks	Semaglutide reduced alcohol intake and modulated GABA neurotransmission across drinking behaviors.	Electrophysiology results limited to alcohol intake effects and studies only included male subjects.
Zhang et al. [84]	China	Preclinical	Adult male Sprague-Dawley (SD) rats weighted 220–250 g (age: 3 months)	40	Rats divided into groups receiving saline, 6-OHDA with saline, 6-OHDA with semaglutide, and 6-OHDA with DA5-CH.	31 days	Promising treatment due to protection of dopaminergic neurons and increased tyrosine hydroxylase expression in substantia nigra.	Potential side effects not fully explored, important for evaluating overall safety.
Li et al. [85]	China	prospective cohort	Patients with T2DM aged 18–65 years with a glycated hemoglobin (HbA1c) value of >7.0% who were treated with oral antidiabetic drugs or insulin for at least 3 months	50	Patients treated with a GLP-1 analog, followed by cognitive assessments and brain monitoring using functional near-infrared spectroscopy.	12 weeks	Improvement in cognitive function and activation of brain regions related to cognitive gains, independent of metabolic changes.	Tests can be influenced by subjective judgments; fMRI limited by postural changes and doesn’t provide real-time brain activation data.
Chen et al. [86]	China	Preclinical	C57BL/6J adult mice weighed 22–25 g	–	Assessing effects on neuronal ferroptosis, neuroinflammatory cytokines, and neurological scores in a mouse model.	–	Enhanced SIRT1-induced ferroptosis pathway, offering insights into anti-inflammatory and neuroprotective effects.	Only one dose tested; lacks assessment of long-term effects and specific roles in preventing ferroptosis or the role of SIRT1.
Abdel-Halim et al. [87]	Egypt	Preclinical	Male Sprague Dawley rats (age: 6–8 weeks)	40	Rats on a high-fat diet analyzed after receiving additional treatments with metformin, dapagliflozin, or semaglutide.	14 weeks	GLP1 analogs and SGLT2 inhibitors provided neuroprotective benefits by reducing oxidative stress and boosting protective proteins.	Further studies are needed for full elucidation of the exact mechanisms
Secnik et al. [88]	Sweden	Prospective cohort	T2 diabetics with Alzheimer’s disease or mixed-pathology dementia who had at least one follow-up appointment after their dementia diagnosis	1873	Analysis of medication use and cognitive decline using propensity-score matching.	–	Variations in the impact on MMSE scores; Metformin and incretin-based drugs highlighted.	Need further investigation for potential cognitive benefits.
Davidy et al. [89]	–	Randomized Controlled Trial	Adults >60 with mild cognitive impairment (MOCA 20–27, CDR 0.5)	80	Participants divided into four groups to assess the effects of intranasal insulin (INI) and oral semaglutide on cognitive functions.	3–12 months	Combining insulin with other type 2 diabetes medications may enhance neuroprotection and influence cerebrovascular health more effectively than monotherapy.	Small sample sizes and short follow-up periods may affect the generalizability and statistical power of the study; lacks direct body fat measurements and focuses on long-term cognitive effects.

Table 3.

An overview of studies addressing the mental health aspect of semaglutide.

Author & date	Country	Study design	Population	Sample size	Intervention	Duration	Key findings	Possible gaps and limitations
de Paiva et al. [90]	Brazil	Preclinical	Male C57BL/6 young adults (8–10 weeks) weighing 20 g	60	Mice with type 2 diabetes induced by a high-fat diet were treated weekly with 0.05 mg/kg of Semaglutide intraperitoneally to assess its impact on depressive and anxiety-like behaviors, cognitive function, and neuroinflammation.	18 weeks	Semaglutide demonstrated potential as a treatment for depression and anxiety, primarily by reducing neuroinflammation in the hippocampus and enhancing neurogenesis.	The study utilized only male mice models, necessitating clinical trials to confirm efficacy in diabetic patients with depression and anxiety.
Wang et al. [91]	USA	Retrospective cohort	Patients with overweight or obesity prescribed semaglutide or other anti-obesity medications were included if they had a recent diagnosis, no prior suicidal ideation, and no prior GLP1R agonist use.	1,572,885	Outcomes were compared between patients prescribed Semaglutide and those on non-GLP1R agonist anti-diabetes medications. Kaplan-Meier analysis estimated time-to-event rates, and hazard ratios were calculated for various subgroups based on sex, age, and ethnicity.	≈ 6 months	In patients with overweight, obesity, and type 2 diabetes, Semaglutide was associated with a lower risk of suicidal ideation compared to non-GLP1R agonist medications, with no evidence suggesting an increase in the risk of suicidal thoughts.	The retrospective design of the study may introduce potential biases, and the short follow-up period along with incomplete data call for further research with longer follow-up durations.
Tagliapietra et al. [92]	USA	Retrospective cohort	Veterans newly prescribed GLP-1RA, DPP-4i, or SGLT-2i medications with no prior prescriptions in the past year and no recent antidepressant use or depression diagnoses.	95,276	Depression rates were compared between veterans on GLP-1RA and those on DPP-4i medications using regression analysis. Sensitivity analyses and alternative comparison groups were considered, and time to depression was examined using Cox regression.	1 year	Incident depression rates were slightly higher for patients on GLP-1RA (7.7%) compared to those on DPP-4i (6.3%). However, the relative risk of depression with GLP-1RA versus DPP-4i was 1.02, indicating no significant increase in depression risk.	The presence of confounding factors, reduced generalizability from the study population, and the inability to assess critical outcomes like suicidal ideation or external care data highlight significant limitations.

3.3. Smoking cessation and cancer risk through metabolic regulation

3.3.1. Smoking cessation

Recent studies have suggested that semaglutide may also have the potential to treat various substance use disorders, including smoking cessation. A retrospective cohort study found that semaglutide use was associated with a 44% reduced risk of incident cannabis use disorder (CUD) in patients with no prior history (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.42–0.75) and a 38% reduction in recurrent CUD diagnosis (HR: 0.62, 95% CI: 0.46–0.84) among patients with a prior history, compared to non-GLP-1RA medications [61].

These findings suggest the potential broader applicability of semaglutide in smoking cessation, mainly due to its influence on reducing cravings and modulating dopamine pathways, which are also implicated in nicotine addiction. Furthermore, a study on the cardiovascular effects of semaglutide in people without diabetes but with obesity found that high dose semaglutide (2.4 mg weekly) led to a significant reduction in body weight by 9.4% over 104 weeks compared to a 0.9% reduction in the placebo group [62]. This weight loss and metabolic improvement may indirectly support smoking cessation, as better health outcomes can decrease the desire for nicotine. Although direct evidence linking semaglutide to smoking cessation is still lacking, these studies highlight its potential to reduce addictive behaviors and provide a basis for more targeted clinical trials exploring its effectiveness in treating nicotine dependence.

3.3.2. Cancer risk

Concerns have arisen about the potential cancer risk from GLP-1 agonist therapy, but no evidence has linked the use of semaglutide to increased cancer risk. Although rare cases of thyroid cancer have been reported, no causal link between semaglutide and thyroid cancer has been established [63]. A nested case-control study of T2DM patients using GLP-1 therapy as second-line treatment found a moderate increase in thyroid and medullary cancer risk among those using GLP-1 agonists for one–three years. However, this study was biased due to the omission of critical thyroid cancer risk factors such as BMI and family history. The reported case timeframe also suggests detection bias rather than causation, necessitating further long-term studies to evaluate this risk [64]. High-risk populations should be carefully monitored. Recent global studies have found no significant risk of thyroid cancer associated with Semaglutide [63,65]. Although the risk of rare cancers, such as thyroid cancer, cannot be entirely ruled out, it is minimal. Physicians should balance the benefits and potential risks of semaglutide in their clinical decisions [63].

GLP-1 therapy in patients with type 2 diabetes potentially decreases the risk of multiple cancers, including hepatocellular carcinoma [66], pancreatic cancer [67], and specific types of OACs, compared with insulin or metformin [68], highlighting its potential benefit in mitigating these risks. However, prostate cancer reports remain inconclusive and require further research [69]. A cohort study found no association between semaglutide use and the risk of melanoma or non-melanoma skin cancer, which was supported by secondary and sensitivity analyses. However, dermatological symptoms should be reported as precautionary measures [70]. A review of the studies discussing the association between semgalutide and cancer is presented in Table 4.

Table 4.

A review of the studies discussing the association between semgalutide and cancer.

Author & date	Country	Study design	Population	Sample size	Study objective	Key findings	Possible gaps and limitations
Fischbach et al. [93]	USA	Retrospective cohort	Patients with stage I-III breast cancer	7149	Weight Loss with Semaglutide and Tirzepatide - Analysis of patient data for associations.	Average weight loss of 3.03 kg and BMI reduction of 1.1 kg/m². Maximal weight loss observed was 8.89 kg with a BMI reduction of 3.2 kg/m². Breast cancer recurrence rates similar between treated and untreated groups.	Need more research on long-term safety and weight maintenance of these drugs in breast cancer survivors.
Yang et al. [94]	China	Retrospective cohort	Neoplasm cases	8718	Cancer Risk and GLP-1RA - Disproportionality analysis of tumor cases from FAERS data (2004-2020).	Linked to thyroid, pancreatic, bile duct, and breast neoplasms.	Issues with verification and lack of detailed patient data affecting accuracy. Tumor analysis sensitivity and precision varied by the level of terms used.
Liu et al. [95]	China	Preclinical	Obese mice	16	Semaglutide Impact in High-Fat Diet Mice - Protein analysis via mass spectrometry and bioinformatics.	Proteins ITGAV, LAMC1, FABP5, and LPL play roles in ECM and PPAR signaling pathways. Semaglutide slows liver cancer progression by affecting these proteins.	Concerns about human relevance and the small sample sizes in studies.
Hansen et al. [96]	Denmark	Preclinical	Male C57BL/6 J mice (5–6 weeks old)	46	Semaglutide and Lanifibranor in NASH-HCC Mice - Assessment of disease progression and tumor characteristics.	Reduces tumor burden in mice with severe liver fibrosis. Effective mouse model for testing NASH-HCC treatments.	Semaglutide and Lanifibranor in HCC: Future research should compare their effects on HCC burden in mice.
Chen & Hibler [97]	USA	Retrospective cohort	Cancer survivors	67,591	GLP-1RAs in Cancer Recurrence and Mortality - Outcome comparison using Cox models.	Significantly lowers all-cause mortality in cancer survivors. Does not significantly affect cancer recurrence or mortality in the general population.	Further exploration needed on the use of GLP-1RAs in cancer survivors.
Leslie et al. [98]	USA	Preclinical	Patient-derived organoid models of endometrial cancer	6	Organoid Treatment with Hormones and Semaglutide - Effects studied using combined and single treatments.	Decreased cell viability and increased expression of GLP-1 and progesterone receptors. Indicates a potential synergistic anti-cancer effect.	Studies needed for patients with atypical endometrial hyperplasia or low-grade endometrial cancers.
Dankner et al. [67]	–	Retrospective cohort	Patients aged 21-89 years with type 2 diabetes	543,595	Pancreatic Cancer Rates in GLP-1RA and Insulin Users - Incidence comparison using Cox models.	Hazard ratios for pancreatic cancer not significantly elevated compared to basal insulin use.	Recommendation for continued monitoring beyond 7 years.
Pasternak et al. [65]	Denmark, Norway, and Sweden	Retrospective cohort	Patients aged 18–84 were included if they were new users of GLP-1 receptor agonists or DPP-4 inhibitors	145,410	Thyroid Cancer Subtypes and GLP-1RAs - Hazard ratio estimation for various subtypes.	No significant increase over a 3.9-year follow-up. Maximum relative risk increase compared to DPP-4 inhibitors was 31%.	Mean follow-up of 3.9 years may be insufficient for detecting long-term cancer risks. Small event numbers limit the ability to perform subgroup analyses.
Wang et al. [68]	USA	Retrospective cohort	Type 2 diabetics prescribed GLP-1 receptor agonists with no history of obesity-associated cancer	1,651,452	Tracking Diseases Over 15 Years - Long-term monitoring using Cox and Kaplan-Meier methods.	Lower risk of 10 out of 13 cancers compared to insulin users.	Further research needed on the cancer-preventative effects of GLP-1RAs, newer antidiabetic agents, and their roles in managing obesity and diabetes during cancer therapy.

3.4. Future research and limitations

The extensive clinical use of semaglutide is summarized in Figure 1, highlighting its potential beyond current FDA-approved indications. As we expand our understanding of the clinical utility of semaglutide, it is crucial to address the limitations noted in the current research landscape. Figure 2 illustrates the key areas where further studies are necessary to confirm and extend the findings. These studies will be essential for overcoming the existing gaps in our knowledge and enhancing the therapeutic applications of semaglutide.

Figure 1.

Summary of semaglutide clinical use.

Figure 2.

Semaglutide future research and limitations.

The landscape of semaglutide research and application is poised for a signification evolution in the coming years. Beyond its established role in managing T2DM and cardiovascular risks, its multifaceted benefits are likely to drive a shift in therapeutic approaches of various metabolic and systemic diseases. Emerging evidence highlights its potential in addressing a variety of conditions. Further research will likely focus on the molecular mechanisms behind these benefits, optimizing dosages for diverse patient population, and extending its use to nondiabetic cohorts with complex metabolic and inflammatory disorders. Semaglutide use offers a new era in disease management, as it redefines therapeutic possibilities. However, addressing emerging challenges and navigating ethical considerations will be crucial as its applications expand.

4. Conclusion

Our review of the clinical applications of semaglutide revealed its extensive impact beyond glycemic control in type 2 diabetes. As a potent GLP-1 receptor agonist, semaglutide significantly aids in weight management, resulting in notable weight loss and improved metabolic parameters in long-term trials. It improves metabolic and androgenic parameters in PCOS, offers renal protection for patients with type 2 diabetes and chronic kidney disease, and enhances cardiovascular health by potentially reducing symptoms of heart failure and systemic inflammation. Semaglutide also shows promise as a treatment for MATLD, supports smoking cessation by modulating addictive behaviors, and exhibits neuroprotective effects that may prevent cognitive decline and neurological disorders. Despite concerns about the potential increased risk of thyroid cancer, semaglutide’s overall cancer risk profile is favorable, with benefits generally outweighing risks. This highlights the significance of semaglutide in modern medical practice, emphasizing the necessity for ongoing research into its diverse benefits and vigilant monitoring of potential adverse effects.

Funding Statement

This paper was not funded.

Ethics statement

As this study represents a literature review, not formal ethics approval was required.

Authors contributions

Mesk Alkhatib: contributed to conception, design, drafted and critically revised the manuscript and gave final approval. Noor Almasri: contributed to the conception, design, drafted and critically revised the manuscript and gave final approval. Sakhr Alshwayyat: contributed to the conception, design, drafted and critically revised the manuscript and gave final approval. Hebah Almahariq: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. Bara M. Hammadeh: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. Zaid Taimeh: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. Lean Alkhatib: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. Anas Alshwayat: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. Nesreen A Saadeh: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. Mohammed Al-mahdi Al-kurdi: contributed to design, interpretation, drafted and critically revised the manuscript and gave final approval. All authors gave their final approval and agree to be accountable for all aspects of the work.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.