GLP-1 medications have been getting a lot of attention in recent years–and for good reason. These medications can help, but they must be part of a larger care strategy. Some patients also report mood changes or symptoms of depression. Additionally, the study assessed weight and metabolic responses, finding that efinopegdutide’s tolerability was similar to that of semaglutide, although certain gastrointestinal side effects were more common. A 2023 study published in the “Journal of Hepatology” reported on a Phase IIa trial aimed at evaluating the efficacy and safety of efinopegdutide in patients with NAFLD, comparing it to semaglutide.144 Efinopegdutide is a dual agonist for GLP-1R and GIPR.144 The study used a randomized, open-label design and employed magnetic resonance imaging technology (MRI-PDFF) to measure liver fat content (LFC) after 24 weeks of treatment. NASH is a liver disease primarily caused by fat accumulation, which can progress to liver fibrosis, cirrhosis, or even liver cancer.494,495,496,497,498 The role of GLP-1 in NASH has garnered attention due to its potential in regulating metabolism, improving insulin sensitivity, and exerting anti-inflammatory effects.17,499,500,501,502,503 Insulin resistance, a common occurrence in NASH patients, is a key driver of the disease’s progression.504,505,506 GLP-1 enhances the insulin signaling pathway in the liver by activating the GLP-1R, especially through the phosphorylation of insulin receptor substrates and the activation of the PI3K/Akt signaling pathway, thereby increasing hepatic insulin sensitivity, facilitating glucose uptake and utilization, and reducing hepatic gluconeogenesis.3,507 However, the exogenous administration of GLP-1RAs can mitigate sympathetic excitability by suppressing the peripheral chemoreflex originating from the carotid body.467 Under hyperglycemic conditions, GLP-1RAs regulate hypertension by inhibiting carotid body function.468 Specifically, these agents can attenuate the excitability of carotid body cells and diminish sympathetic activation, ultimately leading to a reduction in sympathetic responses.465 This modulatory effect holds promise for ameliorating sympathetic activity in individuals with hypertension, as these agents lower blood pressure levels.469 Importantly, the “GLP-1-carotid body pathway” may represent a novel therapeutic target for managing cardiovascular metabolism and treating patients with diabetes and hypertension who exhibit heightened sympathetic activity.465 (Fig. 6). GLP-1 RAs can support reversing unhealthy metabolism and maintaining a normal weight. Therefore, it’s important to implement dietary and lifestyle changes that promote health and manage weight lifelong. GLP-1 agonists can lower blood lipids, including LDL, VLDL, total cholesterol, and triglycerides. However, consult your doctor if you experience any side effects. Similar articles Several population-based studies have demonstrated an association between Body Mass Index (BMI), MFI, and subfecundity, defined as time to pregnancy or lack of conception after ≥12 months of unprotected intercourse . Furthermore, it has been correlated to significant clinical, psychosocial, and economic burdens as a result of increased morbidity and mortality 2,6,7. Obesity is a pervasive and complex disease that has become an epidemic affecting more than 650 million adults 1,2. Overall, the EXSCEL study also had slightly shorter duration and lower HgA1c, although given the incidence of cardiovascular events was similar to other studies, this should not have affected the outcome. The EXSCEL study also found no significant difference in cardiovascular outcomes with once-weekly exenatide20; however, it should be noted that the EXSCEL study had no run-in period to improve adherence to the medication regimen, and therefore the discontinuation rate was higher, which could have attenuated the significance. Of these, all have shown non-inferiority, and liraglutide, subcutaneous semaglutide, albigultide and dulaglutide have shown significant reductions in composite cardiovascular outcomes. Of these patients, 84.7% had established cardiovascular disease or chronic kidney disease, and average baseline HgA1c was 8.2%. Moreover, a similar trend has been observed in the post-hoc analysis of clinical trials for SGLT2is. On the other hand, the risks of HHF (HR 0.93, 95% CI 0.83–1.04 with GLP-1RAs and HR 0.69, 95% CI 0.61–0.79 with SGLT2is) and composite kidney outcomes excluding macroalbuminuria (HR 0.92, 95% CI 0.80–1.06 with GLP-1RAs and HR 0.55, 95% CI 0.48–0.64 with SGLT2is) significantly reduced with SGLT2is only. The risk of MACE was reduced by 12% (HR 0.88, 95% CI 0.84–0.94) with GLP-1RAs and by 11% (HR 0.89, 95% CI 0.83–0.96) with SGLT2is compared with that in placebo groups, suggesting that GLP-1RAs and SGLT2is reduce the risk of MACE to a similar extent. Preclinical studies suggested that GLP-1RAs reduced immune cell activity and oxidative stress in kidney and led to decrease in fibrosis 15, 45. Also in kidney, localization of GLP-1 receptor is under investigation, but it is thought to be expressed in vascular smooth muscle cells and immune cells in kidney . GLP-1 RAs and Obesity Interestingly, a clinical study published in “Nature Metabolism” in 2023 investigated the restorative effects of liraglutide on impaired associative learning in individuals with obesity. In addition to its effects on metabolic regulation, GLP-1, when synthesized within the brain, exhibits neuroprotective properties.397,427,431 A clinical trial titled “Liraglutide in Early Parkinson’s Disease” was published in the New England Journal of Medicine, exploring the effects of liraglutide on patients with early-stage PD diagnosed within the last three years.432 The research was a 14-month Phase II double-blind randomized controlled trial. It was found that semaglutide, a long-acting GLP-1RA, could improve symptoms caused by sepsis, reduce body temperature, and decrease the bacterial load in multiple organs, along with the levels of inflammatory factors in plasma and lungs.423 These findings further confirmed the central role of the CNS in regulating the anti-inflammatory effects of GLP-1RAs, highlighting the potential application of GLP-1RAs in anti-inflammatory treatment. By modulating inflammatory responses, GLP-1RAs can help prevent the degeneration of dopamine-producing cells.413 GLP-1RAs play a neuroprotective role in neurons by facilitating neuronal survival and promoting neuronal growth, thereby preserving the structural and functional integrity of synapses.6,14 Furthermore, GLP-1 signaling indirectly enhances and restores the insulin signaling pathway in neurons, leading to a reduction in the phosphorylation of insulin receptor substrates and the burden caused by monomeric α-synuclein.414 Together, these effects contribute to the protection of dopaminergic neurons (source). Thus, maintaining genomic function and integrity is an emerging issue in studying the pathology of diseases. In this review, we discuss the protective effects of GLP-1R that correlate with the BER pathway in cerebral ischemic strokes, brain trauma, and chronic neurodegenerative diseases, and emphasize potential therapeutic strategies utilizing DNA repair mechanisms. In our recent study, we reported that stimulation of GLP-1R enhanced APE1 expression and BER activity; moreover, administration of Exendin-4 (EX-4), a GLP-1R agonist, substantially reduced ischemia-induced nuclear DNA damage in brain cells . Supplements To Regulate Cortisol: How to Lower Stress, Increase Energy, and Support Adrenal Health In this process, several medications within the GLP-1 RA class have not only shown non-inferiority but have also shown superiority in terms of their cardiovascular outcomes, which we will present here. All have found non-inferiority for cardiovascular outcomes, with many finding superiority of these drugs. Third, significant heterogeneity was present among several of the outcomes we analyzed, particularly among the cardiovascular risk factors. The relationship between GLP-1 and the risk of bone fractures has not been fully elucidated. This result implied that exenatide, in comparison with insulin, may promote BMD while facilitating weight reduction. The specific processes and related molecular mechanisms of the effects of GLP-1 on bone metabolism need to be further explored and clarified. Some of the more commonly experienced side effects include nausea, vomiting, and diarrhea . While there are several advantages to the medication, it is not without its side effects. Current research suggests that GLP-1 receptors are present throughout the body; hence, its effect extends beyond glycemic control . However, synthetically produced GLP-1 agonists are able to evade the effect of DPP-4 (as they are administered with a DPP-4 inhibitor), thereby increasing insulin production and lowering blood glucose levels over longer periods of time . While many have popularized both Wegovy® and Ozempic®, fewer have discussed Rybelsus® and other GLP-1 agonists. Glucagon-like peptide-1 (GLP-1) receptor agonists are a novel and promising class of drugs for T2DM, which may also have clinical applications in bone tissue disorders. This is because these GLP-1 agonists have weight loss effects. So far, some studies show that these medications can help lower A1C and help with weight loss in people with T1D. GLP-1 agonists are medications that help lower blood sugar levels and promote weight loss. The study also confirmed past research findings detailing the drugs’ potential to lower the risk of heart attack, stroke and other cardiovascular concerns. In the following years long acting, once weekly injected GLP-1 receptor agonists were approved (once-weekly exenatide, dulaglutide, albiglutide, semaglutide). GLP-1 exerts physiological effects by binding to the GLP-1 receptor (GLP-1R) on target cells. One class of drugs that has gained significant attention in this context is the glucagon-like peptide-1 (GLP-1) receptor agonists. To address this critical issue, the past decade has witnessed a surge in cardiovascular outcome trials (CVOTs) focused on evaluating the cardiovascular safety and efficacy of various antidiabetic drugs. Participants were at least 50 years of age with T2D and either previous cardiovascular events or cardiovascular risk factors. In SUSTAIN-6, the increased retinopathy events was hypothesised to be related to relatively rapid reductions in HgA1c values, but this study did not look at retinopathy outcomes. This trial was the shortest duration trial given its high-risk population and relatively high baseline HgA1c compared with other CVOTs (table 2). The primary composite outcome (table 2) occurred in 11.4% of patients in the exenatide group compared with 12.2% in the placebo group which did not reach significance for superiority. Among patients with type 2 diabetes (T2D), the risk of CVD is substantially elevated (1). Despite major advance in treatment, cardiovascular diseases are still one of the leading causes of mortality and morbidity in the world. Studies have shown their positive impact on kidney outcomes in patients with T2D compared to placebo. GLP-1RAs, initially developed for glycemic control and weight loss, have evolved into cornerstone therapies for cardiometabolic diseases, marking a paradigm shift in modern healthcare. Preclinical studies have highlighted potential signaling pathways, but have revealed species-specific differences in receptor distribution, raising concerns about direct extrapolation to humans. Don’t try to lose weight faster by eating too little, as this can cause muscle loss and nutritional deficiencies. Currently, there are no proven natural supplements that effectively replace GLP-1 medications. However, these foods supplement rather than replace prescription medications. While no foods replicate Ozempic’s effects, certain foods can support similar processes. Additional metabolic effects include fatty acid oxidation, gluconeogenesis, and energy expenditure. The PI3K/Akt pathway enhances glucose sensitivity in β cells, promoting insulin secretion. In β cells, GLP-1(9–36) activates the GLP-1R, which increases cAMP levels, subsequently activating PKA and CREB, leading to the promotion of insulin secretion. This may be due to altered α-cell function in diabetic patients, which impairs the efficacy of GLP-1(9–36).241 In vivo experiments have shown that high concentrations of exogenous GLP-1(9–36) can lower circulating glucagon levels during insulin-induced hypoglycemia. Recent studies have shown that GLP-1(9–36) is particularly effective at low glucose concentrations, with its inhibitory effect being similar to that of GLP-1(7-36).241 GLP-1(9–36) retains its ability to inhibit glucagon secretion even after GLP-1R inactivation, suggesting that its mechanism of action may not be entirely dependent on the GLP-1R.241 GLP-1(9–36) promotes the undocking of secretory granules (SG) by inhibiting the entry of Ca2+ through voltage-gated Ca2+ channels. Extended data Do not use GLP-1 medications during pregnancy or when nursing. However, they are not entirely free of side effects. Using these medications is a way to biohack your metabolism to control high glucose levels by promoting better insulin management. GLP-1 stimulates insulin release by β cells and inhibits glucagon release by pancreatic α cells, resulting in less glucose production in the liver. These comparisons inform shared decision-making discussions when considering GLP1RAs alongside other anti-hyperglycemic medications for patients with T2D. For example, sulfonylureas and insulin are known to cause weight gain, and therefore, reductions in weight were more pronounced when GLP1RAs were compared to sulfonylureas (−5.37 kg), TZDs (−4.85 kg), and insulin (−4.13 kg), than with DPP4Is (−2.13 kg). Therefore, small sample size, high attrition, and serious imprecision limited our assessment of microvascular and macrovascular outcomes for comparisons of GLP1RAs to other anti-hyperglycemic medications. In clinical practice, the major clinical decision is often not whether to initiate a diabetes medication but rather which diabetes medication to select. Furthermore, we did not find sufficient data allowing conclusions on how GLP1RAs compare to other anti-hyperglycemic medications for microvascular outcomes or macrovascular outcomes. GLP-1R is expressed not only on β-cells and α-cells but also on δ-cells in the pancreatic islets.242 δ-cells primarily secrete somatostatin, which is an important regulatory hormone.242 The expression of GLP-1R on δ-cells helps to inhibit the secretion of glucagon.242 When GLP-1 binds to GLP-1R on δ-cells, it activates these cells and promotes the secretion of somatostatin.243 Somatostatin is a potent inhibitory hormone that affects the surrounding α-cells and β-cells.The European Society of Cardiology has even updated their 2019 guidelines to suggest GLP-1 RA or SGLT-2 inhibitors be considered as first-line therapy for T2D patients with known cardiovascular disease or those at high risk, even before the use of metformin.25The influence of GLP-1 receptor agonists on heart failure with reduced ejection fraction has been investigated so far only by two small clinical trials, the FIGHT and the LIVE trial.However, semaglutide did not improve histologic outcomes in patients with MASH who had progressed to cirrhosis .There are several other types of diabetes medications, like oral (taken by mouth) medications.Previous studies have demonstrated that menadione is capable of inducing oxidative DNA damage, as well as triggering apoptosis in neurons 27,153.Additionally, a thriving interest in GLP-1 agonists research within cardiovascular medicine was observed, with a notable surge in publications from 2016 onwards.Physicians and patients should be aware of the unique aspects of existing treatment options, the impacts of off-label prescribing, and the effects of these medications. The diagram illustrates downstream signaling pathways and cellular functions after activation of the GLP-1 receptor. The actions of GLP-1 or its analogues are mediated by the GLP-1 receptor (GLP-1R), a seven-transmembrane spanning G protein-coupled receptor. GLP-1 also exerts trophic effects, such as triggering islet β cell proliferation, differentiation, inhibiting apoptosis, and enhancing cell survival 88,89. These restrictions and warnings demonstrate the FDA’s stringent consideration of patient safety in the drug approval process.108 In March 2015, the FDA required a black box warning on Tanzeum due to the observed risk of thyroid C-cell tumors in animals, although it is unclear if this effect also occurs in humans.108 Later, the FDA added a warning about the risk of anaphylactic shock to the medication’s label. As a GLP-1RA,102 albiglutide works by stimulating insulin release and reducing glucagon production, leading to improved blood sugar control in patients with T2DM.102,103 Albiglutide is a long-acting GLP-1RA injected subcutaneously once a week. Lixisenatide was developed by Sanofi to treat T2DM.64,93 Structurally, lixisenatide is based on the exenatide structure but lacks proline at position 38, and six lysines are linked after serine at position 39.94 The six lysine residues increase the rigidity of the molecule’s structure, thus allowing its drug properties to be improved.78 These changes stabilize its structure, prevent protein degradation of the molecule in the circulation, and increase the circulation time enough to ensure once-daily injection (compared with exenatide, which is injected two or three times daily). The results caused further investigation and debate on the usage of these drugs to lower cardiovascular risks.Next it was demonstrated by Nauck et al. , that intravenous GLP1 infusion normalised plasma glucose in individuals with longstanding type 2 diabetes.Tirzepatide targets GLP-1 receptors by attaching to them and activating the release of insulin.The Mayo Clinic Diet now supports your journey with a special Companion program for weight-loss medication.To date, a comprehensive review of longer-term benefits and harms of GLP1RAs vs. placebo and other anti-hyperglycemic medications has not been published.The effect of 2.4 mg once-weekly injected semaglutide in patients with HFpEF, obesity and T2D is currently investigated in an ongoing trial STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes) (64, 65).The use of prazosin, an α1-adrenergic receptor blocker, showed that the ability of GLP-1RAs to reduce TNF-α in plasma was disrupted, signifying the vital role of α1-adrenergic receptors in the anti-inflammatory action of GLP-1RAs.The results showed that in high risk patients with T2D liraglutide reduced the risk of MACE by 13% (primary endpoint included cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke) (37). Hormonal imbalances stemming from alterations in the hypothalamic–pituitary–gonadal axis play a crucial role in how excess weight adversely affects semen parameters. The results of this trial demonstrated that tirzepatide led to a mean weight reduction of −20.9% in the group receiving 15 mg weekly . In a Phase 3a component of the SCALE trial, liraglutide was investigated in obese individuals without diabetes. These findings provide evidence that the regulatory influence of endogenous GLP-1R signaling on bone resorption is likely mediated through pathways that involve calcitonin.362 Considering the expression of the GLP-1R in thyroid C cells and the ability of GLP-1 to stimulate calcitonin secretion through a cAMP-mediated mechanism in vitro, it is plausible that calcitonin plays a role in the alterations in bone metabolism observed in GLP-1R-treated animals.369,370 Later, quantitative real-time PCR analysis demonstrated that the administration of exendin-4, a GLP-1RA, resulted in significant upregulation of thyroid calcitonin mRNA levels in wild-type mice.362 Additionally, treatment with GLP-1RA and exendin-4 increased the expression of the calcitonin gene in the thyroids of normal (wild-type) mice. Since GLP-1R is expressed in thyroid C cells and GLP-1 directly stimulates the secretion of calcitonin, which is a potent inhibitor of bone resorption in osteoclasts, GLP-1 may contribute to the nutrient-mediated reduction in bone resorption.369,370 Genetic disruption of GLP-1R signaling leads to cortical osteopenia and heightened bone fragility, primarily caused by increased bone resorption by osteoclasts. These findings provide further evidence for the impact of GLP-1RAs on osteoclastic bone resorption.367 A study involving 12-week-old ovariectomized mice revealed that administering liraglutide for 4 weeks effectively prevented the loss of trabecular bone. When we changed the search term to “Huntington’s disease”, 143 studies were found but none of these cases related to GLP-1 or its analogues. These results suggest that EX-4 can protect neurons against metabolic and oxidative insults, and provide preclinical support for the therapeutic potential of EX-4 in the treatment of PD. Lixisenatide, another GLP-1R agonist, developed to treat type 2 diabetes, has been shown to have neuroprotective effects similar to liraglutide, including improved working memory, increased LTP, decreased Aβ deposition, and reduced inflammatory responses in an AD mouse model . GLP-1 prevented murine hippocampal HT22 cells from cell death by treatment with H2O2-, Aβ1–42, and other toxic agents through AKT- and ERK1/2-mediated signaling pathways . Additionally, GLP-1RAs facilitate the maintenance of endothelial barrier integrity, thus playing a crucial role in preventing vascular leakage.452 Endothelial cells exhibit enhanced NO production and concurrent suppression of endothelin formation, resulting in vascular smooth muscle relaxation and vasodilation mediated by the endothelium (e.g., GLP-1, exenatide, and liraglutide).453 Indeed, GLP-1RAs, including exenatide, liraglutide, and semaglutide, have been linked to the diminished expression of matrix metalloproteinases (MMPs).454,455,456 MMPs are a class of enzymes that play a crucial role in the breakdown of extracellular matrix components.For the investigation, a team led by Al-Aly sifted through the records of nearly 2 million people with diabetes who were treated by the Veterans Health Administration for an average of almost four years between October 2017 and the end of December 2023.The majority of reviews have examined only one or two categories of clinically important outcomes (either cardiovascular risk factors,8–14 microvascular outcomes,15 MACE,16–19 mortality,17 or adverse events9,11,12,20).Participants in the dulaglutide group took the study drug 82.2% of the time from randomisation to either the primary outcome event or final follow-up.Additionally, the study uncovered a noteworthy disparity in sperm telomere length, with obese men exhibiting shorter telomeres compared to the normal BMI group .Several strategies are proposed to restore neurological function or to ameliorate neuronal injury, especially for neurodegenerative diseases.All have found non-inferiority for cardiovascular outcomes, with many finding superiority of these drugs.This study ultimately demonstrated the presence of GLP-1 RA’s in Sertoli cells and identified their role in testicular energy homeostasis.How can you control the short-term side effects, such as gastrointestinal symptoms and muscle loss (“Ozempic face”), and what are the long-term risks of taking these drugs? The potential impact of GLP-1RAs on colorectal cancer (CRC) treatment is achieved through the modulation of Bone Morphogenetic Protein 4 (BMP4).519 In T2DM and CRC, the regulation of BMP4 is abnormal, which is a key focus of the research.519 Specifically, high blood glucose-induced insulin resistance in CRC cells leads to increased BMP4 expression, which activates the BMP4-Smad1/5/8 signaling pathway.519 The activation of this pathway enhances cell proliferation and metastatic capabilities by promoting epithelial-mesenchymal transition (EMT), thereby increasing the invasiveness and metastatic potential of tumors. Results showed that efinopegdutide was more effective in reducing LFC compared to semaglutide. When dietary nutrients are ingested, endogenous incretins (GIP and GLP-1) activate K and L cells in the gut, which then secrete GIP and GLP-1.488,489,490 In the pancreas, this stimulates the secretion of insulin and inhibits the secretion of glucagon.491 In the brain, it reduces appetite and improves satiety.130,133 In the gastrointestinal tract, it lowers the synthesis and secretion of triglycerides.491 By regulating appetite, insulin secretion, and lipid metabolism, GLP-1RAs have potential benefits in the treatment of NAFLD, NASH, and T2DM.130,492,493 Commenting on the study, Professor Sir Stephen O'Rahilly, who is director of the Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories at the University of Cambridge in the UK, said that it is encouraging that the already-demonstrated benefits of GLP-1RAs on heart disease, stroke, and other cardiovascular and kidney diseases are apparent in the new study. While observational studies are hard to interpret and generally don't influence clinical practice or public health policy – and this one was skewed towards a population of older, white males – the associations they reveal can be useful in guiding prospective studies to explore potential benefits or risks. "The study's results provide insights into some known and previously unrecognised benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas. Data from 81 selected studies were extracted and analyzed, focusing on mental health outcomes and reported adverse effects. Those are the findings of an observational study that claims to be the largest ever conducted on the drug class – based on 2.4 million people in the US Department of Veterans Affairs health record databases, including a cohort of 215,000 treated with GLP-1RAs – and has been published in the journal Nature Medicine.Once results are in, your provider will follow up to discuss your options, including GLP-1 medications if appropriate.Moreover, in a meta-analysis of eight trials, GLP-1RAs reduced MACE by 14% (HR 0.86, 95% CI 0.79–0.94), cardiovascular death by 13% (HR 0.87, 95% CI 0.78–0.96), and stroke by 16% (HR 0.84, 95% CI 0.76–0.94) (Table 2).Among the 60 participants treated with GSBR-1290, only one (2.8%, from the T2DM group) discontinued the study due to drug-related adverse events (AEs).The cluster analysis conducted within the research domain of GLP-1 agonists and their impact on cardiovascular diseases has led to a significant classification, identifying 12 distinct clusters.Results failed to show the benefit of GLP-1 receptor agonists in reducing the risk of heart failure; in the LEADER, REWIND, EXSCEL, ELIXA and SUSTAIN-6 trials were no significant difference in HF hospitalization between GLP-1 receptor agonist and placebo group (37–44, 66).Third, significant heterogeneity was present among several of the outcomes we analyzed, particularly among the cardiovascular risk factors.Due to inconsistencies in how cardiovascular death was defined across trials, we did not analyze cardiovascular death as an outcome.Therefore, intrinsic cardiac load and capacity do not improve in patients with heart failure with reduced ejection fraction, and patients HFpEF benefit only from the treatment of abnormal metabolism and inflammation.475,480,481 Summary of baseline characteristics and primary composite cardiovascular outcomes of the completed CVOTs for GLP-1 RA EGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; QW, every week; GLP-1 RA, glucagon-like peptide 1 receptor agonist. The primary endpoint in these trials was the first occurrence of a three-point or four-point cardiovascular composite outcome that slightly differs based on the trial. Exenatide For instance, semaglutide has been approved and is being researched for indications including obesity, T2DM, reducing cardiovascular risk, chronic kidney disease, NAFLD, and AD, indicating that the development of new indications could provide new growth opportunities for GLP-1 drugs. Therefore, BMP4 becomes a potential therapeutic target in CRC, especially in a diabetic context where high blood glucose significantly affects cancer progression through the BMP4 pathway.519 Ultimately, GLP-1RA, by regulating BMP4 and its effects on cell proliferation and metastasis, provides a promising treatment approach.519 This not only demonstrates the role of GLP-1RA in diabetes management but also offers potential for integrating diabetes and cancer treatment.520 This finding emphasizes the importance of considering metabolic status in cancer treatment and the necessity for further research in this area.519 While early models have shown promising results, the application of GLP-1RAs in cancer treatment has not yet been established and requires further clinical trials.527 AS is characterized by the formation of fibrofatty plaques within arterial walls and is one of the foremost global causes of mortality.5 GLP-1RAs, as exemplified by liraglutide and semaglutide, exhibit pronounced cardiovascular protective effects.43 Liraglutide and semaglutide have been demonstrated to be effective at reducing lipid and blood pressure levels through numerous scientific investigations, thereby contributing to the mitigation of AS and cardiovascular ailments.442 Preclinical studies have documented the inhibitory effects of GLP-1RAs on the development of AS in animal models.443 These agents exert their anti-atherosclerotic effects through various mechanisms, including by improving blood lipid profiles,444 preserving endothelial integrity and regulating endothelial function,445 as well as modulating inflammatory processes.70 Overall, this bibliometric analysis provided insights into the current state and future directions of research on GLP-1 agonists and their impact on cardiovascular health, guiding future research endeavors, and informing clinical practice.CStudies required (1) pre-existing CVD; (2) pre-existing CVD or older age and high CVD risk; (3) enrolled 70% patients with CVDAppropriate drug choice according to the patient clinical situation will lead to the precision medicine in the field of cardiovascular-kidney-metabolic syndrome.In addition to weight control, many patients report an overall improvement in wellness with GLP-1 therapy.The effects of GLP-1 receptor agonists on cardiovascular system extend beyond their primary role in glycemic control.There is a substantial and growing body of research comparing the efficacy of different clinical trials and examining long-term safety.We need individualized nutrition strategies to minimize risks and optimize results.Leading journals and co-cited journals in the field of GLP-1 agonists in cardiovascular disease. GLP-1 receptor agonists and next-generation metabolic hormone therapies in chronic kidney disease The absorption of semaglutide is reduced with excess fluid intake and when taken with food. Novel technology has allowed for semaglutide to now become available as the first oral GLP-1RA medication through its coformulation with sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) . Both semaglutide and dulaglutide were more recently also investigated at higher doses than initially licenced for glucose lowering. Semaglutide was superior to liraglutide 1.2 mg in HbA1c (–1.7% vs. –1.0%) and weight reductions (–5.7 kg vs. –1.9 kg) from a baseline of approximately 97 kg. The encouraging results obtained with semaglutide in patients with heart failure and a preserved ejection fraction may provide a new option for this patient population, in which additional therapy, as well as another upstream therapy for patients with a higher BMI who have indications for this condition, is urgently needed. Therefore, intrinsic cardiac load and capacity do not improve in patients with heart failure with reduced ejection fraction, and patients HFpEF benefit only from the treatment of abnormal metabolism and inflammation.475,480,481 The confirmatory secondary endpoints included the change in the 6-min walking distance, a hierarchical composite of death and heart failure events; the difference between the change in the KCCQ-CSS and the change in the 6-min walking distance; and the change in the C-reactive protein (CRP) level.470 In this trial, semaglutide benefited patients with heart failure and preserved ejection fraction by intervening with upstream metabolic drivers. Moreover, GLP-1R has not yet been identified on human myocardial cells, negating any direct effects of GLP-1RAs on myocardial cells.470 GLP-1 by inhibiting the chemoreception in carotid body cell activity to adjust the new mechanism of sympathetic nerve excitability, and points out that GLP-1 agonists can inhibit the origin of the carotid body around chemical reflection to lighten the sympathetic nerve excitability, which is expected to improve the sympathetic activity of the patients with high blood pressure, reduce blood pressure levels Furthermore, GLP-1 increases OPG expression while decreases receptor activator for nuclear factor-κB ligand (RANKL) expression. GLP-1 might bind to its receptor on osteoblast and its function is possibly mediated by mitogen-activated protein kinase (MAPK) pathways, Wnt pathways, or c-fos transcription promotion. The published animal and human studies on the impact of GLP-1 on bone metabolism are described in Table 1. It is possible that different GLP-1 agents have divergent effects on bone fractures, as shown in another meta-analysis of RCTs that ended in December 2013. However, with the lack of data on bone condition, including BMD, microarchitecture, bone quality, calcium, and phosphorus levels at baseline in this study, the results should not be taken as definitive. It showed that liraglutide treated patients performed significantly better than placebo in temporal lobe and whole cortical magnetic resonance imaging volume and cognitive function . Encouraging results from animal studies have shown that GLP-1RAs improve cognitive performance and synaptic plasticity . Renal specific benefits which have already been tested as primary outcomes for SGLT2 inhibitors require similar testing in GLP-1RAs to validate them. GLP-1RA therapies have demonstrated tantalising renal benefits as secondary outcomes in the CVOTs with a reduction of albuminuria (with variations in definitions of either micro- or macroalbuminuria), new onset of albuminuria and a decline in glomerular filtration rate, being reported. For instance, a study found that more than half of respondents who underwent rhinoplasty did so due to social media “before and after” advertisements .Semaglutide is a long-acting GLP-1RA agent used once weekly to improve glycemic control in patients with T2DM.115 Compared with the structure of human GLP-1(7-37), the amino acid sequence of semaglutide contains diaminoisobutyric acid at position 8, arginine at position 34, and acylated lysine at position 26.31 Semaglutide has a longer aliphatic chain and increased hydrophobicity, but its hydrophilicity is greatly enhanced by PEG modification of the short chain.Liraglutide 1.8 mg once daily, however, was superior to albiglutide as assessed by reductions in HbA1c (ETD 0.21%) and weight loss (–2.2 kg vs. –0.6 kg) from a baseline of approximately 92 kg .Tirzepatide, under the name Mounjaro®, was approved by the FDA on May 14, 2022, for the treatment of type 2 diabetes .The primary composite cardiovascular endpoint (table 2) occurred in 7% of patients in the albiglutide group compared with 9% of patients in the placebo group, which was significant.GLP-1 agonists can lower blood lipids, including LDL, VLDL, total cholesterol, and triglycerides. A new class of weight-loss drugs has received enormous, almost unprecedented attention in the mainstream media and business press. Given the tremendous costs of treating cardiovascular disease and continuing renal replacement therapy, the suspected total benefits obtained from therapy should not be overlooked. In addition, few studies currently support the use of GLP-1RAs in patients with HFrEF. Multifactorial favorable effects on cardiometabolic parameters, including glycemia, body weight, blood pressure, and lipid profiles These agents potentially have complementary effects in cardiovascular and renal protection (Graphical Abstract). The FDA currently approves the use of semaglutide and high-dose liraglutide to help treat obesity. Together, you and your healthcare provider will determine a treatment plan that works best for you. This is because GlP-1 agonists help lower blood sugar levels. A recent study by Lillenes et al. showed that mRNA levels of APE1 were significantly lower in the entorhinal cortex of AD patients than in the same cortical regions of healthy controls . Downregulation of APE1 expression or suppression of its endonuclease activity could modulate vulnerability toward assorted types of cancer or cardiovascular diseases 53,54,55, as well as neurological disorders, including AD 55,56,57,58,59, PD , HD , ALS , traumatic brain injury , and cerebral ischemia . Over the past two decades, extensive study and increasing evidence has revealed that brain tissues are susceptible to oxidative DNA damage which may lead to the pathogenesis of neurodegenerative diseases and is tightly connected to the competence of DNA repair 1,43,44. For example, triple-target agonists like retatrutide are leading multi-target GLP-1 drugs. Conclusively, research on GLP-1R and its agonists marks a promising direction in metabolic disease therapy, extending their potential beyond glucose regulation and offering hope for more comprehensive approaches in addressing metabolic diseases. These pathways play a crucial role in its wide-ranging therapeutic effects, extending the benefits of GLP-1RAs beyond metabolic diseases. It explored the mechanisms of action of GLP-1RAs and their therapeutic potential in a wide array of diseases, such as diabetes mellitus, providing new insights into metabolic disease management. The change in body weight from baseline was − 13.3% and − 2.6% in the semaglutide and placebo groups, respectively. The mean LVEF was 33.7% and 35.4% in the liraglutide and placebo groups, respectively, and 60% of patients had ischaemic heart disease. In LIVE, 241 clinically stable patients with HFrEF were randomized to receive liraglutide at 1.8 mg per day or placebo . Thus, unlike for MACE, the effect of GLP-1RAs in reducing the risk of HHF has not yet been consistently demonstrated in individual trials. GLP-1RA glucagon-like peptide-1 receptor agonist, HHF heart failure hospitalization, MACE major adverse cardiovascular events, MI myocardial infarction It is notable that in a study performed by Bernardo, some human GLP-1 could bind to a functional receptor in rat MC3T3-E1 cells with a dependence on time and temperature, but independent of the type of cAMP-linked G protein receptor. In summary, current research is inadequate to explain the effects of GLP-1 and related drugs on bone fracture risk. Second, exenatide tends to cause more weight loss and lower glucose control than liraglutide, which may result in a higher risk of bone fractures (11). Only patients in the former group experienced significant lowering of body weight and had maintained BMD levels, after 44 weeks of treatment (14). After those were introduced, studies began to suggest they, too, had benefits which extended beyond their use in preventing heart attacks and strokes, such as lowering the risk of some types of cancer and perhaps protecting the brain from dementia. Al-Aly said he was inspired to do the study by the story of statin drugs, like Lipitor, which are prescribed to treat high cholesterol. As some people have already noticed, the drugs appear to cut the risk for some substance use disorders, including addictions to opioids, alcohol, stimulants and sedatives. GLP-1 drugs also seemed to reduce a person’s risk for seizures and bleeding strokes. There have been some studies suggesting that GLP-1 medications reduce symptoms of schizophrenia in animals. Although the incidence of worsening kidney function outcome based predominantly on eGFR change was nominally reduced after removal of ELIXA (0.82, HR 95% CI 0.69–0.98), composite outcomes excluding macroalbuminuria, mainly declining eGFR and doubling creatinine, were not significant (HR 0.86, 95% CI 0.72–1.02) . In contrast, the effect on cardiovascular death did not reach at the statistical significance (HR 0.82, 95% CI 0.57–1.16), possibly due to lower event rate. On the other hand, it is becoming clear that obesity and diabetes themselves affect the pathogenesis, progression, and prognosis of heart failure with preserved ejection fraction (HFpEF). One factor that may have contributed to such a result in patients with HFrEF is the increased heart rate caused by GLP-1RAs . Thus, no evidence currently indicates that patients with HFrEF benefit from the administration of GLP-1RAs, but rather, the increased arrhythmias and death are concerning. This discrepancy between results in animal models and clinical studies may partly be due to myocardial insulin resistance in severely failing hearts and the use of beta-blockers . Nevertheless, in vitro studies on blood vessels have shown that GLP-1RAs inhibit vascular smooth muscle cell proliferation, reduce reactive oxygen species, and increase nitric oxide in vascular endothelial cells . Furthermore, information on GLP-1 receptor expression in the heart is still lacking, and whether GLP-1RAs act directly or indirectly on the cardiovascular system remains inconclusive. GLP-1 receptors are thought to be expressed on atrial and ventricular cardiomyocytes, endothelial cells in the human heart, and endothelial and smooth muscle cells in blood vessels . Therefore, most of renoprotective effects of GLP-1RAs were likely to be due to the inhibition of progression to macroalbuminuria , and the effects on other clinically important renal endpoints, including eGFR decline, initiation of renal replacement therapy and renal death, was unclear . Women experienced greater weight loss than men, while participants who self-identified as Asian experienced smaller reductions, possibly due to differences in BMI classification . Interestingly, the proteomic changes induced by semaglutide in participants of the STEP trial were linked to a broad spectrum of biological processes, including body weight regulation, glycemic control, lipid metabolism, and inflammatory pathways . Liraglutide was the first GLP-1RA approved for the treatment of obesity in 2014, followed by semaglutide and tirzepatide in 2023 . The effects of GLP-1 receptor agonists on cardiovascular system extend beyond their primary role in glycemic control. Meta-analysis of 35 clinical trials demonstrated a modest reduction in LDL cholesterol, total cholesterol, and triglycerides in patients treated with GLP-1 RAs compared to controls (4). Weight reduction has many positive effects, from improving insulin sensitivity to reducing the risk of cardiovascular diseases (40, 56, 57). Maintaining stable blood glucose levels through lifestyle modifications and medications can mitigate the adverse effects of hyperglycemia on blood vessels, thereby contributing to CVD risk reduction in diabetic patients (48, 49). Tight glucose management, as demonstrated in landmark clinical trials such as the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), has been related to reduced risk of cardiovascular events. Similar results were seen in the pivotal STEP 1 trial, where semaglutide resulted in an average weight reduction of 14.9% compared to 2.4% in the placebo group . After 56 weeks, those receiving the higher dose achieved 6% weight loss compared to 4.7% in the lower dose group and 2% in the placebo group . In recent years, there have been several clinical trials investigating the use of GLP-1 RAs in chronic weight management. These side effects are likely due to direct GI effects such a delay in gastric emptying or central activation of GLP1 receptors in the brainstem, such as the area postrema.Many have voiced concerns about the availability and continuity of care interruptions inevitable for individuals with diabetes as Ozempic® continues to see growing demand.Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes.VA data are made freely available to researchers behind the VA firewall with an approved VA study protocol.Given the high costs of GLP1RAs, the lack of long-term evidence comparing GLP1RAs to other anti-hyperglycemic medications has significant policy and clinical practice implications.And everyone in the study had diabetes, so no one was taking these medications solely for weight loss.Most people find it difficult to overeat on these medications because they feel full very quickly. This non-systematic literature review predominantly concentrates on both pre-clinical and clinical studies pertaining to GLP-1 RAs, specifically exploring their impact on male reproductive hormones and sperm parameters. In addition to weight control, many patients report an overall improvement in wellness with GLP-1 therapy. The era of GLP-1 prescriptions for weight loss is just beginning. The average time patients received the intended liraglutide during the trial was 84%. The primary outcome was the first occurrence of a composite cardiovascular outcome consisting of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. This trial also used a run-in period of injecting a placebo to increase compliance, and once this run-in period of 2 weeks was completed, patients were randomly assigned to 1.8 mg liraglutide (or maximum tolerated dose) or volume-matched placebo injection. Additionally, compliance with the medication was lower than most other trials for unknown reasons. An in vitro study also showed that administration of EX-4 rescued rat cortical neurons from oxygen/glucose deprivation (OGD) through the PKA pathway . Two studies in the cerebral ischemic rat model reported that EX-4 exerted neuroprotective functions through AKT-eNOS and cAMP-PKA-CREB, respectively 113,114. Long-lasting or DPP-4 resistant GLP-1 analogues and DPP-4 inhibitors are widely studied to test their effect on cerebral ischemic conditions but fewer studies explore the signaling mechanisms that are involved in their neuroprotective functions. Exploring the neuroprotective function of GLP-1 and agonists of the GLP-1R has been a fast growing area of research in the last decade. The brain cells of the infarct area suffer depletion of oxygen and glucose which leads to cell death and irreversible brain injury, approximately three hours after stroke occurrence. GLP-1 receptor agonists (GLP-1RAs) are a novel class of drugs for T2DM (2); they stimulate insulin secretion, increase β cell mass, and suppress glucagon secretion (3–5). Researchers are currently studying the safety and effectiveness of GLP-1 agonists for people with Type 1 diabetes (T1D). These combined effects often result in weight loss. Healthcare providers must make sure to consider the unique history, needs, and goals of their patients before prescribing a GLP-1 agonist. Furthermore, off-label medication could interact with other medications and worsen other health conditions and may not have rigorous data to support its safety and effectiveness short or long term in different patient populations. Some concerns include that there has been limited research finalized on the effective, safe use of these medications in children . There is also growing evidence for off-label antiobesity medications such as metformin and topiramate . For instance, a study found that more than half of respondents who underwent rhinoplasty did so due to social media “before and after” advertisements . Continued high levels of blood sugar cause harm to the microvasculature, resulting in complications like retinopathy, neuropathy, and nephropathy in patients with T2DM. In our analysis, we identified a total of 4624 keywords across the included studies. Out of 1686 included studies, 116 were cited at least 100 times by other scholars, as shown in Figure 10B. This mapping highlights the interdisciplinary character of scientific research and its dissemination by highlighting the relationships between and effects of several domains on one another. These findings have stimulated further investigation into whether higher doses of GLP-1RAs could achieve greater weight loss in individuals with obesity, even in the absence of T2D 10, 23. In contrast, trials such as ELIXA , EXSCEL , and FREEDOM , which evaluated lixisenatide and exenatide in patients with T2D and CVD, reported neutral results for three-point MACE. This highlights the importance of designing future trials with well-defined inclusion and exclusion criteria, particularly to account for variations in comorbidities such as hypertension, coronary artery disease, and heart failure (HF). In this context, a post-hoc analysis of the SURPASS clinical trial program showed that treatment with tirzepatide resulted in a clinically meaningful reduction in the prevalence of metabolic syndrome, emphasizing its potential to address broader cardiometabolic health . In fact, GLP-1 receptor agonists have been linked to improved cardiac function (i.e., decreased blood pressure and lower risk of stroke or heart attack) and kidney function . In the same way, GLP-1 agonists bind to GLP-1 receptor sites and trigger the same effects even in the absence of intrinsic GLP-1 molecules. Glucagon-like peptide 1 (GLP-1) agonists belong to a class of type-2 diabetes medications that mimic the function of the GLP-1 hormone secreted by the pancreas . Thus, current studies are interested in the differential efficacy, benefits, and side effects of these different forms of semaglutide. Furthermore, there are very tangible side effects including hypoglycemia, gastrointestinal effects, cardiovascular risks, and drug interactions . Only two of these trials required pre-existing ASCVD (eTable 7). Flow diagram of study selection process. Two trials had comparisons with both placebo and another anti-hyperglycemic medication. For comparisons of GLP1RAs vs. other anti-hyperglycemic medications, subgroup analyses by other anti-hyperglycemic medications class were also conducted. “It’s hard to make a blanket recommendation, because the side effects are real,” Al-Aly said. Some of the biggest risk reductions were for shock, aspiration pneumonia, liver failure, lung failure and cardiac arrest. These risks primarily involved the digestive system and included nausea and vomiting, stomach pain, heartburn and gastroparesis, or stomach paralysis. In mammalian cells, several predominant DNA repair mechanisms are well studied, including direct repair, base excision repair (BER), nucleotide excision repair (NER), mismatch repair, homologous recombination repair (HR), and non-homologous end-joining repair (NHEJ) 5,6.The publications concerning GLP-1 agonists in CVDs were gathered from the Web of Science Core Collection, and visualizations were created utilizing Excel 2019, Cite Space, and VOS viewer software.In LIVE, 241 clinically stable patients with HFrEF were randomized to receive liraglutide at 1.8 mg per day or placebo .Together, you and your healthcare provider will determine a treatment plan that works best for you.Similarly, in the SURPASS-2 trial, tirzepatide was shown to be both non-inferior and superior to semaglutide in reducing glycated hemoglobin (HbA1c) levels at 40 weeks . 3. Biochemical and Metabolic Mechanism These antiinflammatory and antiatherogenic effects of GLP-1 RAs reduce formation of atherosclerotic lesions and progression (59, 60). In addition to above mentioned properties, GLP-1 RAs have an antiinflammatory effect; in comparison with other antidiabetic treatments GLP-1 RAs have significantly reduced inflammatory biomarkers (58). Additionally, GLP-1 agonists may modulate the renin-angiotensin-aldosterone system (RAAS), further influencing vascular tone and blood pressure regulation (54). Many studies have demonstrated that EX-4 has a neuroprotective function to minimize mTBI impairment, prevent cell death, and improve cognitive function 124,125,126. Another study showed that delayed administration of liraglutide, starting one day after MCAO, still improves metabolic and functional recovery of neurons, astrocytes, and endothelia after cerebral ischemia in rats . It also improved mitochondrial function by activating AKT and ERK pathways and inhibiting phosphorylation of c-Jun-NH2-terminal kinase (JNK) and p38 in neurons in both OGD in vitro and middle cerebral artery occlusion (MCAO) in vivo studies . The mounting evidence supporting the weight-reducing effects of GLP-1RA has sparked interest in exploring their potential impact on male factor infertility (MFI). The SCALE trial focused on patients with type 2 diabetes, treating them with either 1.8 mg or 3.0 mg of liraglutide. Across the SCALE, STEP 1, and STEP 8 clinical trials, the incidence of acute pancreatitis was below 1% 30,31,32,33. Short-acting agonists impact fasting blood glucose levels, postprandial hyperglycemia, insulin secretion, glucagon secretion, and gastric emptying, while long-acting agonists exhibit stronger effects on these parameters 26,27. Current interventions for weight loss include lifestyle modifications and surgical interventions. Particularly, GLP-1RAs have greater hypoglycaemic and weight-loss effects and are attracting attention as a means of intervening in obesity, which is the key basis of type 2 diabetes pathogenesis. Lowering blood glucose levels is the basis of diabetes treatment, not only in terms of preventing microvascular complications, including CKD, but also in preventing cardiovascular events. Effect of glycaemic control itself on preventing CKD is relatively small, compared with multifactorial therapy in patients with diabetes 7, 8. There’s a low risk of mild low blood sugar (hypoglycemia) episodes if you take a GLP-1 agonist. GLP-1 agonists aren’t safe to take during pregnancy. Some people form antibodies to GLP-1 agonists, particularly with exenatide. Existing GLP-1 receptor agonist therapies typically require subcutaneous administration which may be inconvenient for or not preferred by some patients, resulting in reduced adherence . Danuglipron is currently not FDA-approved as it has not passed phase three of clinical trials. Unlike other GLP-1 agonists, tirzepatide also targets glucose-dependent insulinotropic polypeptide (GIP) receptors, which help maintain homeostasis by addressing carbohydrate, lipid, and protein metabolic pathways . Tirzepatide, under the name Mounjaro®, was approved by the FDA on May 14, 2022, for the treatment of type 2 diabetes . During the 24-week observation, liraglutide did not improve LVEF but rather caused more death, ventricular arrhythmia, and atrial fibrillation, compared with the placebo. In addition, the results were similar for subgroup analysis by diabetes status. At 180 days follow-up, death (HR 1.10, 95% CI 0.57–2.14) and heart failure rehospitalization (HR 1.30, 95% CI 0.89–1.88) did not differ compared with those in the placebo group. Three hundred patients with HFrEF hospitalized for acute heart failure within 14 days and taking diuretics equivalent to at least 40 mg furosemide were randomized to receive 1.8 mg per day of liraglutide or placebo in FIGHT . Lean proteins, fiber-rich vegetables, and complex carbs support weight loss while preventing uncomfortable side effects. Highly processed foods and certain beverages can interfere with your weight loss goals and worsen side effects. Poor food choices can make side effects worse and work against your weight loss goals. Ask a clinical question and tap into Healio AI's knowledge base. The data used to support the findings of this study are cited within the study and available from the corresponding author upon reasonable request. Future research should explore the differential impacts of GLP-1 agonists in different populations, in individuals with different lifestyle habits, and long-term efficacy data to develop precision medicine recommendations. Subcutaneous, SGLT2i sodium-glucose cotransporter 2 inhibitor, T2DM type 2 diabetes mellitus Although the reasons for the variation are still unclear, this might be due to several differences in the individual study design and patient characteristics rather than drug effect . Their effects on the individual components of MACE, myocardial infarction (reduced in LEADER and Harmony Outcomes), and stroke (reduced in SUSTAIN-6 and REWIND), varied in each trial (Table 1). Comorbidities of diabetes (i.e., hypertension, dyslipidemia, obesity) also have crucial roles in pathophysiology of CKD in diabetes. The exploration of GLP-1 agonists in CKD patients may offer valuable insights into their potential to slow the progression of renal decline and mitigate cardiovascular risk93–96. These outcomes suggest that Tirzepatide holds considerable potential in aiding individuals who are either metabolically healthy obese or overweight, reducing their risk of adverse cardiovascular events and preventing the shift towards a metabolically unhealthy status89. These are all critical studies investigating the impact of GLP-1 agonists on cardiovascular outcomes. This experiment showed that semaglutide recipients had a significantly lower rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke than the placebo group in individuals with type 2 diabetes who were at high cardiovascular risk66. Innovative clinical trials highlighting the cardiovascular benefits of GLP-1 agonists were reported in 2016. Also published in 2016 was liraglutide and cardiovascular outcomes in T2D (LEADER).18 Participants had T2D and were either 50 years of age and older with at least one cardiovascular condition or 60 years of age and older with at least one cardiovascular risk factor. Compared with other studies, this study had a short follow-up period of 2 years and also the highest percentage of participants on statin therapy which provides further cardiovascular benefit (table 2). The primary endpoint (table 2) occurred in 13.4% of patients in the treatment group compared with 13.2% of patients in the placebo group, which was not significant. Brain microphysiological systems are reshaping in vitro neurotoxicity testing through functional validation and advanced disease modeling.Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology.While identifying treatment gaps within this patient demographic, it becomes apparent that obese men, characterized by hypogonadism who wish to preserve fertility, could represent an ideal group for potential intervention with GLP-1 RAs.Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for managing metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity.How and why the drugs have such wide-ranging health benefits is subject to further research, and the GLP-1 drugs were found to increase risks of some conditions, including kidney stones and low blood pressure.Though semaglutides like Ozempic and Wegovy dominate the market in the U.S., Al-Aly and his team included all GLP-1 drugs in the study.Adverse events leading to discontinuation of treatment (majority being gastrointestinal side effects) occurred in 11.5% of those receiving 0.5 mg semaglutide and 14.5% receiving 1.0 mg semaglutide, compared with 5.7% of those receiving 0.5 mg placebo and 7.6% of those receiving 1.0 mg placebo. PD is a chronic neurodegenerative disorder that affects the CNS and is the second most prevalent neurodegenerative disease worldwide.14 GLP-1RAs are promising pharmacological agents for treating PD due to their potential to preserve the integrity and function of dopaminergic neurons. For instance, when peripheral tissues become inflamed, the related signals might be transmitted to the brain through these receptors on the neurons, and the brain could then respond to these signals via neural pathways, thus regulating the level of peripheral inflammation.423 This receptor co-expression on neurons in specific brain regions may enable the brain to finely regulate the body’s response to inflammation.