The molecular mechanism of GLP-1RA is intricate ( Figure 1 ). GLP-1RA and GLP-1R can be recognized and combined to play diverse physiological regulatory roles in different signaling pathways. First, GLP-1RA can activate the first messenger adenylate cyclase (AC) after binding to the receptor, which stimulates an increase in the secretion level of the intracellular second messenger cyclic adenosine phosphate (cAMP) and subsequently activates the intracellular secondary messenger protein kinase A (PKA) (48). PKA, in turn, inhibits the opening of adenosine triphosphate (ATP)-sensitive potassium channels (KATP) on the cell membrane (49), inhibits potassium efflux and promotes the opening of L-type voltage-dependent calcium channels (VDCs) (50), facilitating the release of calcium ions. Second, activated cAMP can also promote the activation of rap guanine nucleotide exchange Factor 4 (RAPGEF4). Thus, the activation of Ras protein 1 and phospholipase C, as well as the activation of the IP3 and diacylglycerol (DAG) pathways (15), induces calcium ion inflow, triggers the exocytosis of insulin particles, and results in insulin secretion (15, 51). Moreover, cAMP, the first discovered secondary messenger, can regulate gene expression, protein activity and cell function by altering the level of cAMP, thereby influencing the processes of cell growth, metabolism, differentiation and apoptosis (52).

For example, after GLP-1RA stimulates the activation of AC (14), intracellular cAMP secretion increases, inhibits the signaling of the AKT and ERK1/2 pathways, and induces the apoptosis of tumor cells. Furthermore, GLP-1RA can activate GLP-1R and inhibit the PI3K/AKT pathway (13), thereby inhibiting the proliferation and metastasis of cancer cells. In addition, GLP-1RA can also directly act on hypothalamic neurons or indirectly act on the AMPK signaling pathway (53–55) to promote learning and memory; play a neuroprotective role (56); affect white−brown fat metabolism and other mechanisms (55, 57); reduce visceral, subcutaneous and liver fat contents; and regulate blood lipid metabolism (56).

GLP-1RA has been widely acknowledged at home and abroad for its hypoglycemic effects, safe use and beneficial effect on human metabolism. Its clinical application is no longer confined to hypoglycemic reduction, and the types of GLP-1RA used in clinical applications are also increasingly more diverse. There are eight types of GLP-1RAs commonly used in the domestic market in China, including three short-acting GLP-1RAs, exenatide, lisenatide, and benarutide, and a long-acting GLP-1RA, liraglutide. In addition, it also contains four ultralong-acting GLP-1RAs, namely, semaglutide, dulaglutide, polyethylene glycol losenatide, and exenatide microspheres.

Short-acting and long-acting preparations of GLP-1RA have distinct effects on controlling blood sugar (58). The short-acting preparation of GLP-1RA mainly reduces postprandial blood glucose by delaying gastric emptying and increasing insulin secretion (28, 59). Long-acting GLP-1RA reduces blood sugar by stimulating and activating GLP-1R for a prolonged period, promoting the secretion of insulin and inhibiting the secretion of glucagon, and it has a limited effect on postprandial blood sugar fluctuations. Although the pharmacological mechanism of different preparations is the same, they have different clinical benefits. The cause of this disparity lies in the dissimilar structure and potency of drugs. The 2023 ADA Guidelines suggest that the hypoglycemic efficacy of the ultralong-acting GLP-1RA dulaglutide is highly favorable, and tha the same ultralong-acting GLP-1RA semaglutide not only has a significant hypoglycemic effect but also has a marked effect on weight loss. Additionally, long-acting liraglutide and ultralong-acting semaglutide can mitigate the risk of adverse cardiovascular events in T2DM patients, whereas exenatide has no substantial effect on the incidence of adverse cardiovascular events (60). Due to variations in drug structure and potency, different preparations may have distinct clinical benefits.

Part of the GLP-1RA (Liraglutide, Semiglutide) has been verified to be efficacious in the treatment of fatty liver and is employed in the management of T2DM complicated with nonalcoholic fatty liver disease, primarily by ameliorating metabolic dysfunction, insulin resistance, and lipotoxicity of the organs related to its pathogenesis (61), decelerating the fibrosis process and reducing the liver fat content. It can also lower blood sugar, blood lipids, weight, and cardiovascular risk (62). GLP-1RA can also be utilized to treat polycystic ovarian syndrome (PCOS) by increasing hyperandrogenaemia and associated metabolic parameters. Furthermore, the combination of the short-acting formulation exenatide and the long-acting formulation lilaplutide can significantly increase the number of natural pregnancies in PCOS patients (63), the frequency of menstruation, the regularity of the menstrual cycle (64), and the pregnancy rate associated with in vitro fertilization (IVF) (65). The renoprotective effect of GLP-1RA can be achieved by reducing urinary protein levels and the glomerular filtration rate (66, 67). GLP-1RA has an outstanding hypoglycemic effect. It can not only influence the fasting blood glucose of patients but also decrease the postprandial blood glucose of patients and have an impact on the glycosylated hemoglobin (HbA1c) of patients (68). It has also been discovered that GLP-1RA has the potential risk of inducing hypoglycemia, but it only occurs when it is combined with other hypoglycemic drugs (such as sulfonylureas and insulin). When used independently, hypoglycemia rarely occurs and hypersensitivity is infrequent (69). In addition to the aforementioned adverse reactions, GLP-1RA was also shown to increase the risk of triggering pancreatitis and adverse thyroid events. However, due to the small sample size and restricted scope of the study, it remains unclear whether this phenomenon is induced by the drug itself, which requires further verification. There was no significant disparity in adverse reactions among the different preparations of GLP-1RA, among which the most common were gastrointestinal reactions, which mainly manifested as nausea, vomiting, and diarrhea; however these adverse reactions were tolerable and mostly temporary. Currently, the United States has sanctioned the application of GLP-1RA in therapeutic fields beyond type 2 diabetes, but China has not yet fully expanded its therapeutic scope.

In addition to the aforementioned hypoglycemic, cardiovascular system protection, kidney protection, weight loss, and other effects, it was also found to have antitumor effects. Thus, the correlation between GLP-1RAs and tumors has also become a focus of attention in recent years. Currently, both domestic and international studies have investigated the correlations between GLP-1RAs and medullary thyroid cancer, pancreatic cancer, colorectal cancer, prostate cancer, breast cancer, reproductive system tumors, and other oncological disorders. These findings confirmed that GLP-1RA had a certain influence on the occurrence and development of tumors. Based on a comprehensive analysis of the relevant literature, due to the extensive distribution of GLP-1R, its expression has been detected on the surface of related endocrine glands such as the pancreas and digestive glands. The possible mechanism affecting the development of tumors is the excessive activation or inhibition of GLP-1R expression. Currently, the relationship between GLP-1RAs and tumors unclear. Some scholars believe that GLP-1RAs can promote the occurrence and development of tumors, mainly by facilitating tumor proliferation and inhibiting apoptosis, whereas others hold opposing viewpoints. Additionally, another comprehensive analysis of GLP-1RAs and the risk of malignant tumors in T2DM patients demonstrated that there was no significant difference in the risk of malignant tumors between the experimental and control groups (70). Therefore, some scholars have adopted a neutral stance and believe that GLP-1RAs have no significant correlation with the occurrence or development of tumors. The differences in the effects of GLP-1RA on tumors may be related to differences in experimental subjects, differences in inclusion and exclusion criteria, differences in experimental methods, groups, and instruments; and the lack of uniform outcomes, and it is still necessary to conduct in-depth studies with large sample sizes and unified standards to further classify and explore its role and mechanism.

Papillary carcinoma, medullary carcinoma, follicular adenocarcinoma and undifferentiated carcinoma are the four common pathological types of thyroid carcinoma. Papillary thyroid cancer is the most common type of cancer. He Liang (71) compared the expression of GLP-1R in papillary thyroid cancer tissues and cells before and after GLP-1RA intervention and reported that GLP-1RA had no significant effect on the proliferation of papillary thyroid cancer cells and did not activate the PI3K/AKT or MAPK/ERK signaling pathway. Studies have shown that GLP-1RA has different effects on the growth and proliferation of different pathological types of thyroid cancer. Intervention with GLP-1RAs in medullary thyroid cancer has been studied in rodents (16), and it was found that GLP-1RAs can continuously activate GLP-1R signaling, thus stimulating the proliferation of thyroid C cells and increasing the release of calcitonin into the blood. Eventually it increase the risk of medullary thyroid cancer. In addition, different species can also cause differences in performance, which may be related to differences in the expression levels of GLP-1R (72, 73). Studies of the same species also varied, with a follow-up of patients treated with GLP-1RAs (74) showing no significant difference in calcitonin concentrations between liraglutide and placebo and no change in the risk of thyroid C-cell tumors. The reasons for these differences may be related to the small sample size and the difference in drug intervention dose. Although there is no consensus regarding whether GLP-1RA can increase the risk of thyroid cancer, some countries have relevant regulations to prohibit the use of GLP-1RA in people at high risk of medullary thyroid cancer and those who have already had medullary thyroid cancer. China has also begun to pay attention to the risk of thyroid cancer induced by GLP-1RA, and this warning has been added to the drug instructions of some GLP-1RAs. Whether the use of GLP-1RA increases the risk of thyroid cancer in humans still requires more long-term, controlled, prospective clinical studies for further confirmation.

GLP-1RA is a novel hypoglycemic agent for the treatment of type 2 diabetes. It acts on pancreatic beta cells, promoting proliferation and inhibiting apoptosis (75, 76). Both T2DM and hypoglycemic drugs are among the risk factors for acute pancreatitis (77). The pancreatic-associated risk of GLP-1RA may be related to its continued proproliferative effect. Marco (78) et al. reported that GLP-1RAs can promote the overactivation of GLP-1R in pancreatic cells, which not only increases susceptibility to pancreatic inflammation but also increases the risk of pancreatic cancer. Elashoff (79) also suggested that, compared with other common hypoglycemic drugs, GLP-1RA may increase the risk of chronic pancreatitis and then change the levels of cellular inflammatory factors and reactive oxygen species, thus increasing the risk of pancreatic cancer. Moreover, in vitro cell culture experiments have confirmed that the correlation between GLP-1RA and pancreatic cancer may be related to its ability to induce phenotypic transformation of pancreatic exocrine cells into pancreatic endocrine cells (80, 81). Some foreign scholars compared the number of pancreatic cancer patients treated with exenatide and those treated with other hypoglycemic drugs, and the results revealed that the number of pancreatic cancer patients treated with exenatide was 2.9 times greater than that of patients treated with other hypoglycemic drugs (82).

However, whether GLP-1RA induces pancreatitis or pancreatic cancer by affecting the expression level of related genes in the pancreas or by regulating the secretion of pancreatic enzymes is still inconclusive. Some studies have shown that differences in the expression of GLP-1R on the surface of different pancreatic cells may affact the development of pancreatic cancer. Studies have shown (13) that GLP-1R is expressed in normal pancreatic islet, acinar and duct cells, and Waser (83) reported that GLP-1R is highly expressed in normal pancreatic secretory cells, expressed at low level in pancreatic acinar cells, not expressed in pancreatic duct cells, and expressed at low or no levels in human pancreatic cancer tissues. Nonexpression of GLP-1R is common in advanced pancreatic tumors with lymphatic metastasis and is associated with poor prognosis, suggesting that GLP-1R may inhibit tumorigenesis and metastasis of human pancreatic cancer cells both in vitro and in vivo. In this context, there are also different opinions. Molin (78) quantified GLP-1R in human pancreatic tissues via RNA in situ hybridization and reported that all types of pancreatic cells expressed GLP-1R and that there was no significant difference in the expression of GLP-1R between normal pancreatic tissues and pancreatic tumors. Based on these results, it is not possible to link the difference in GLP-1R expression with the development of pancreatic cancer. Other studies have suggested that there is no significant difference in the risk of acute pancreatitis or pancreatic cancer between the two groups when GLP-1RA is used (84, 85). Knapen (86) also reported through follow-up studies that the pancreatic tumor risk in patients treated with GLP-1RA for a long period of time was not significantly different.

The possible reasons for the different effects of GLP-1RA on the occurrence of pancreatic cancer reported by different scholars are the differences in study groups, small sample sizes, insufficient follow-up times, and low incidence rates of events. After adjusting for the factors that cause the difference, experimental methods can be developed, and conclusions can be drawn from further studies.

He Wenjing (75) reported that GLP-1R expression was lacking in human colon cancer tissues and colon cancer cell lines. However, after the addition of GLP-1RA to colon cancer cells, GLP-1RA had no statistically significant effect on the proliferation or migration of colon cancer cell lines. Another comprehensive analysis of GLP-1RAs and the risk of malignant tumors in T2DM patients also revealed that GLP-1RA intervention had no significant effect on the risk of malignant tumors (70). Koehler (47) reported that GLP-1RAs may induce apoptosis by altering cell morphology in vitro, possibly by activating cAMP expression and inhibiting the activities of the signaling kinases glycogen synthase kinase 3 and ERK1/2, thereby inducing apoptosis and inhibiting the growth and survival of colon cancer cells. There are few studies on GLP-1RAs and colorectal tumors at home or abroad. Accordingly, whether GLP-1RA can improve the prognosis of patients with colon cancer still needs to be further confirmed.

By studying the expression of GLP-1R in human breast cancer tissues and the breast cancer cell lines MCF-7, MDA-MB-231 and KPL-1 (87), Iwaya’s study revealed that decreased levels of GLP-1 may constitute a novel connection between GLP-1 and breast cancer. The activation GLP-1R by GLP-1RA can restrain the activation of NF-κB, thereby facilitating the apoptosis of breast cancer cells and inhibiting their proliferation. Ligumsky (88) also discovered through animal experiments that GLP-1RA could suppress the proliferation of mouse breast cancer cells by triggering the expression of cAMP and CREB. Tanaka (89) reported through clinical studies that GLP-1RA in combination with metformin could inhibit the proliferation and induce the apoptosis of breast cancer cells. The above three experiments were investigated at the cellular, animal, and clinical levels, and it is believed that GLP-1RA has an inhibitory effect on breast cancer. Nevertheless, another scholar has also conducted cell experiments, but the results are quite contrary to these results. Liu Zhaozhao (90) reported that liraglutide can activate GLP-1Rs, and that liraglutide can promote the proliferation of breast cancer cells by activating GLP-1Rs. Thus, the expression of downstream NOX4/ROS/VEGF signaling pathway-related proteins is activated and the proliferation of breast cancer cells is increased, whereas the proliferation of breast cancer cells is inhibited in the control group with the addition of inhibitors. The disparities in the above conclusions may be associated with the variations in the characteristics of breast cancer cell lines, and the effects of GLP-1RA on different breast cancer cell subtypes are distinct. Therefore, further clinical studies are necessary to confirm whether GLP-1RA can be employed as an alternative therapy to inhibit the progression of breast cancer.

Endometrial cancer is one of the most common malignant tumors of the female reproductive system. Diabetes is a high risk factor for endometrial cancer, but the same pathological basis is insulin resistance. As a new hypoglycemic agent, GLP-1RA enhances insulin sensitivity, reduces body weight and protects the cardiovascular system (62). Therefore, we can speculate that GLP-1RA can inhibit the proliferation and migration of endometrial cancer cells. To this end, some scholars have used different concentrations of liraglupeptide to interfere with endometrial cancer cells. These results show that GLP-1RA can induce phosphorylated AMPK expression (91), inhibit the expression and phosphorylation of the mTOR protein (92), promote the apoptosis of endometrial cancer cells, and thus play a potential anticancer role. However, there are too few relevant studies on the association between GLP-1RA and endometrial cancer to confirm that GLP-1RA can inhibit the proliferation of human endometrial cancer cells, so further research is still needed in the future.