Chapter 14 - Glucagon-like peptide-1 receptor agonists: role in the prevention and treatment of diabetes-related cardiovascular complications

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

Mimetics and analogs that extend the half-life of native glucagon-like peptide-1 (GLP-1), i.e., glucagon-like peptide-1 receptor agonists (GLP-1 RAs), at therapeutic doses, are indicated as adjuncts to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In patients with T2DM, GLP-1 RAs not only affect improvements in impaired beta cell and alpha cell function, suppress appetite, and induce weight loss but also possess multiple cardiovascular protective properties that potentially have a beneficial impact on atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. Required to demonstrate CV safety, compared to standard-of-care antidiabetic therapies, GLP-1 RAs have revealed statistically significant non-inferiority (p < 0.001), among CV outcome trials (CVOTs) thus far completed. Once-daily liraglutide and once-weekly semaglutide demonstrated significant superiority (p = 0.01 and p = 0.02, respectively), reducing 3-point composite major adverse cardiovascular events (MACE) in extreme risk secondary prevention adults with T2DM. Once-weekly exenatide demonstrated only a non-significant (p = 0.06) favorable trend for CV superiority, possibly due to in-trial mishaps, including placebo drop-ins with other CV protective medications. The short half-life lixisenatide was neutral (p = 0.81) in reducing MACE, most likely due to ineffective once-daily dosing. Structural differences among GLP-1 mimetics and analogs may explain potency differences in both A1C reduction and weight loss that may parallel important cardiovascular protective properties of the GLP-1 RA class. Significant superiority in reducing 3-point composite MACE in adults with T2DM with GLP-1 RAs has been limited to liraglutide and semaglutide. Careful attention to within-trial drop-in of cardioprotective antidiabetic agents assuring equipoise between placebo and investigational product groups might demonstrate significant MACE risk reduction with once-weekly exenatide. Maintenance of 24-h circulating levels, by an alternative administration method, may resurrect lixisenatide as a cardioprotective agent. Before a GLP-1 RA bioequivalence "class effect" claim for composite MACE risk reduction superiority can be fully discussed, we are obliged to wait for the pending results of CVOTs with other GLP-1 RAs, particularly albiglutide and dulaglutide, where steric hindrance may potentially inhibit full mimicry of pharmacologic GLP-1.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.

Glutamatergic neurons represent 40% of neurons in the human central nervous system. Glutamate accounts for approximately 90% of all excitatory neurotransmitters. Previous research reports the presence of glucagon-like peptide-1 (GLP-1) receptors on neurons that produce glutamate. Herein, we aim to evaluate whether GLP-1 receptor agonists' (GLP-1 RAs) modulate glutamatergic signaling and whether GLP-1 RAs' anti-obesity effects are mediated through the glutamatergic system. We conducted a systematic review of extant literature published on PubMed, Ovid and Scopus databases from inception to March, 2025. Identified studies were screened independently by two reviewers (S.W. and G.H.L.) using the Covidence platform. We sought to include in vitro, in vivo, and human clinical studies. A total of 31 studies were identified as meeting eligibility for an inclusion in this review. No human studies were identified. Across the included preclinical and pharmacologic studies, GLP-1 RAs were associated with increased glutamate release, NMDA/AMPA receptor activation and increased release of neurotrophic factors associated with neurogenesis, neurodifferentiation, and synaptic plasticity. In addition, GLP-1 RA-induced suppression of food intake was reported to be dependent on AMPA, but not NMDA, receptor signaling. The effect of GLP-1 RAs on feeding behavior is mediated via central glutamatergic signaling. A comprehensive mechanistic framework mediating GLP-1 RA activity implicates crosstalk between GLP-1 and ionotropic glutamate receptors. The aforementioned trends instantiate a need to evaluate the therapeutic efficacy of GLP-1 RAs for disparate neuropsychiatric disorders. Conducting target engagement studies of GLP-1 RAs with the glutamatergic system in humans is a future research vista.

A systematic review in effects of glucagon-like peptide-1 (GLP-1) mono-agonists on functional connectivity: Target engagement and rationale for the development in mental disorders

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) effectively manage type 2 diabetes mellitus (T2DM) but may impair gastrointestinal motility, increasing the risk of small intestinal bacterial overgrowth (SIBO). Diagnostic evaluation of SIBO commonly involves breath testing and clinical assessment. This study aimed to assess the association between GLP-1 RAs or dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RAs are associated with incident SIBO. Methods: We conducted a retrospective cohort study using the TriNetX global database, identifying adult T2DM patients initiating GLP-1 RA or dual GLP-1/GIP RA therapy versus other second-line T2DM agents (OSLT2DM) from 1 January 2006 to 2 December 2024. Patients with major abdominal surgery, connective tissue disorders, gastroparesis, or other high-risk conditions for SIBO were excluded. 1:1 Propensity score matching was applied. Short-term (<1 year) and long-term (up to 5 years) risks were evaluated with Kaplan–Meier curves and univariable Cox models. Results: After matching, 216,173 patients per cohort were analyzed. Short-term analysis demonstrated a higher incidence of diagnostically confirmed SIBO in patients treated with GLP-1 RA/GIP (0.177 per 1000 patient-years) compared to OSLT2DM (0.083 per 1000 patient-years; HR 2.14, 95% CI 1.13–4.07; p = 0.0491). Long-term analysis indicated a non-significant trend toward increased risk in the GLP-1 RA/GIP group (HR 2.02, 95% CI 0.98–4.12), though Kaplan–Meier analysis revealed a sustained divergence (p = 0.017). Conclusions: GLP-1 RA and dual GLP-1/GIP RA therapy are associated with increased short-term SIBO risk. Symptom-driven SIBO breath-test evaluation may be warranted in patients initiating these agents.

IntroductionOnce-weekly semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is currently available as 1.0 mg and 0.5 mg dose for the treatment of type 2 diabetes (T2D). Currently, no head-to-head trial investigating once-weekly semaglutide as an add-on to basal insulin vs other GLP-1 receptor agonists (GLP-1 RAs) is available. The aim of this study was to conduct a network meta-analysis (NMA) to assess the efficacy and safety of once-weekly semaglutide vs other GLP-1 RAs in patients with T2D inadequately controlled on basal insulin.MethodsA systematic literature review was performed to identify all trials of GLP-1 RAs as an add-on to basal insulin in patients with T2D. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in an NMA), including the change from baseline in glycated hemoglobin (HbA1c), body weight, and systolic blood pressure, and the incidence of nausea, vomiting, and diarrhea. Data were synthesized using a NMA and a Bayesian framework.ResultsIn total, eight studies were included across the base-case analyses. The results demonstrate that once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c (− 0.88% to − 1.39% vs comparators) and weight (− 1.49 to − 4.69 kg vs comparators) and similar odds of experiencing nausea, vomiting, or diarrhea vs all GLP-1 RA comparators. Once-weekly semaglutide 1.0 mg was also equally effective at reducing systolic blood pressure compared with liraglutide 1.8 mg. Once-weekly semaglutide 0.5 mg significantly reduced HbA1c vs the majority of other GLP-1 RAs, except liraglutide 1.8 mg QD. The odds of experiencing nausea were significantly lower with once-weekly semaglutide 0.5 mg compared with all GLP-1 RA comparators.ConclusionOnce-weekly semaglutide 1.0 mg as an add-on to basal insulin is likely to be the most efficacious GLP-1 RA for reducing HbA1c and weight from baseline after 6 months of treatment. The efficacy of once-weekly semaglutide is not associated with a significant increase in the incidence of gastrointestinal side-effects vs other GLP-1 RAs.FundingNovo Nordisk.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0428-y) contains supplementary material, which is available to authorized users.

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) administration has been associated with neuroproliferative effects and modulatory effects in neuronal pathways. Herein, we conducted a comprehensive synthesis of the effects of GLP-1 and GLP-1 RAs on neurogenesis. We examined studies that investigate changes in neurogenesis mediated by GLP-1 and GLP-1 RA administration in both human and animal populations. Relevant articles were retrieved through OVID (MedLine, Embase, AMED, PsychINFO, JBI EBP Database), PubMed, and Web of Science from database inception to July 2nd. Primary studies investigating the role of GLP-1 and GLP-1 RAs on neurogenesis were included for analysis. GLP-1 and GLP-1 RAs (i.e. exenatide, geniposide, liraglutide, lixisenatide, and semaglutide), increased neurogenesis within the dentate gyrus, hippocampus, olfactory bulb, and the medial striatum in animal models. Additionally, GLP-1 and GLP-1 RAs were associated with modulating changes in multiple apoptotic pathways and upregulating survival pathways. GLP-1 and GLP-1 RAs are positively associated with neurogenesis. This effect may have translational implications insofar as disparate mental disorders that are characterised by neurogenesis defects (e.g. depressive disorders and neurocognitive disorders) may be benefitted by these agents.

Type 2 diabetes (T2DM) management increasingly focuses on cardiometabolic protection. Sodium-glucose co-transporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have complementary mechanisms, making their combination a promising strategy. This systematic review evaluates the cardiometabolic benefits and risks of SGLT2i and GLP-1 RA combination therapy in T2DM. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search of PubMed, Scopus, Embase, and Web of Science was conducted for randomised controlled trials (RCTs) published between 2020 and 2025. Nine RCTs, including cardiovascular outcome trials and mechanistic studies, were included. Data on cardiovascular, renal, glycaemic, and safety outcomes were extracted. The Cochrane RoB 2 tool was used for quality assessment. Combination therapy demonstrated additive cardioprotective effects. Post-hoc analyses showed GLP-1 RAs reduced major adverse cardiovascular events (MACE) and heart failure hospitalisation regardless of background SGLT2i use, and SGLT2i benefits were maintained with concomitant GLP-1 RAs. The combination provided superior glycaemic control (HbA1c reduction), weight loss, and systolic blood pressure reduction compared to monotherapy. The safety profile was consistent with the known effects of each drug class, with no new or unexpected safety signals and manageable gastrointestinal and genital infection risks. The combination of SGLT2is and GLP-1 RAs in T2DM provides synergistic benefits for cardiovascular risk reduction, glycaemic control, weight, and blood pressure, without a significant increase in adverse events. This supports its use as a potent therapeutic strategy for high-risk patients, though definitive evidence from prospective trials designed specifically for combination therapy is still needed.

Objectives:Glucagon-like-peptide-1 (GLP-1) agonists, also known as GLP-1 receptor agonists (GLP-1 RAs), incretin mimetics, or GLP-1 analogs are a class of medications that have surged in popularity since their approval. Originally developed and indicated for the treatment of type 2 diabetes mellitus, GLP-1 RAs have now also been approved for the treatment of obesity, with more uses currently under investigation. Thus, GLP-1 RA use is only expected to increase. Despite this, little research has been done to assess the possible adverse effects of GLP-1 RA use, especially on surgical complications. In this study, we queried the TriNetX database to investigate the effects of GLP-1 RA therapy on the incidence of several 90-day surgical complications in total shoulder arthroplasty (TSA) patients.Methods:The TriNetX research network was queried to identify all patients undergoing primary anatomic TSA between May 2005 and July 2024 across 66 healthcare organizations. Patients were then sorted into two different cohorts based on preoperative GLP-1 use. Propensity score matching was performed to account for prior differences in demographics, lab values, and comorbidities. Data analysis and risk calculations for the selected 90-day complications were performed using TriNetX’s built-in analysis platform.Results:A total of 59,180 patients underwent TSA, with 1,489 of them using GLP-1 RAs pre-operatively. After propensity score matching, there were 1390 patients in the GLP-1 and no GLP-1 cohorts undergoing TSA. Subsequently, we found no statistically significant differences in the risk of various 90-day complications after TSA between those who used GLP-1 RAs and those who did not. These included readmission, ED utilization, revision surgery, superficial surgical site infection, infection of prosthesis, deep vein thrombosis, pulmonary embolism, acute renal failure, aspiration, and mortality.Conclusions:GLP-1 RA use preoperatively was not associated with any statistically significant change in the risk of complications within 90 days of undergoing TSA. Patients taking GLP-1 RAs experienced similar risks of all examined complications as those who were not prescribed GLP-1 RAs. Thus, our results indicate that GLP-1 RAs are likely safe for patient use prior to TSA and do not increase the risk of 90-day complications described in this study.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are newer medications used to treat type 2 diabetes mellitus (T2DM) and obesity. There is growing evidence of a potential association between the use of GLP-1 RAs and non-arteritic anterior ischemic optic neuropathy (NAION). Here, we report a case of NAION in a young patient with diabetes receiving semaglutide (GLP-1 RA), which showed a complete resolution of symptoms after discontinuing the GLP-1 RA. This case adds to growing concerns, given emerging evidence suggesting an increased incidence of NAION among users of GLP-1 RAs. Further studies are required to clarify causality, identify risk factors, and develop monitoring strategies for patients receiving GLP-1 RAs.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising class of medications for type 2 diabetes (T2D) management. While their glucose-lowering effects are well-established, their long-term impact on cardiovascular outcomes remains a subject of ongoing research and debate. This systematic review aims to assess the long-term cardiovascular effects of GLP-1 RAs in adults with T2D compared to placebo, standard care, or other glucose-lowering medications. We systematically searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) and observational studies published from database inception to April 2024. Two independent reviewers screened the studies and extracted the data. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Secondary outcomes included individual components of MACE, hospitalization for heart failure, and all-cause mortality. We included 15 studies (eight RCTs and seven observational studies) involving over 180,000 participants. GLP-1 RAs were associated with a significant reduction in MACE compared to placebo or standard care (risk ratio: 0.88, 95% CI: 0.82-0.94, p<0.001). GLP-1 RAs also demonstrated superior cardiovascular protection compared to DPP-4 inhibitors and sulfonylureas. The benefits were particularly pronounced in reducing the risk of stroke and MI. Notably, some studies found larger cardiovascular benefits in frail patients. The effects on heart failure outcomes were mixed, with potential attenuated benefits in patients with baseline heart failure. GLP-1 RAs also showed promising effects on renal outcomes and metabolic parameters. The quality of evidence ranged from moderate to high across outcomes. This systematic review provides strong evidence that GLP-1 RAs offer significant cardiovascular benefits in adults with T2D, particularly in reducing MACE, stroke, and MI. The findings support current guidelines recommending GLP-1 RAs as preferred agents in patients with established cardiovascular disease or high cardiovascular risk. However, the variability in effects across different patient subgroups underscores the need for personalized treatment approaches. Future research should focus on head-to-head comparisons between different GLP-1 RAs, long-term follow-up studies, and investigation of combination therapies to further optimize the use of these agents in clinical practice.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently gained widespread use among patients with type 2 diabetes mellitus or obesity, owing to their substantial impact in lowering blood glucose levels and reducing body weight. Apart from this, the FDA Adverse Event Reporting System (FAERS) identified several dermatological side effects, including hair loss, associated with the administration of GLP-1 RAs, prompting further research. This systematic review aimed to provide a comprehensive and up-to-date overview of hair loss related to the use of GLP-1 RAs. The search strategy utilized PubMed, SCOPUS, and Web of Science databases using key terms: (("GLP-1 receptor agonist"[Mesh] OR "GLP1- receptor agonist"[tiab] OR "Glucagon-Like Peptide 1"[tiab] OR "GLP-1 agonist"[tiab] OR semaglutide[tiab] OR liraglutide[tiab] OR tirzepatide[tiab] OR exenatide[tiab] OR dulaglutide[tiab]) AND (hair loss[Mesh] OR alopecia[tiab] OR "telogen effluvium"[tiab] OR "alopecia areata"[tiab] OR hair[tiab]) ). Including all primary English studies, the hair loss outcomes associated with the use of GLP-1 RA in adults were reported without time restriction. A total of five relevant studies were included in this review, encompassing 2,905 adult patients who received subcutaneous trizepatide mainly on a weekly basis. The study yielded conflicting findings, with some indicating significant improvement and hair regrowth, while others reported hair loss as an adverse dermatological event. Further research is recommended to clarify the relationship between GLP-1 RAs and alopecia.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Extant literature indicated that glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may potentially reduce risk of opioid overdose in persons with opioid use disorders (OUDs). Herein, we conducted a comprehensive synthesis of the effects of GLP-1 and GLP-1 RAs on OUDs. We examined preclinical and clinical paradigms examining the effects of GLP-1 and GLP-1 RAs on OUD and OUD-associated behaviours (i.e. opioid self-administration, opioid-seeking behaviour). Relevant articles were retrieved from OVID (MedLine, Embase, AMED, PsychINFO, and JBI EBP Database), PubMed, and Web of Science from database inception to 1 May 2025. Primary studies (n = 10) examining the aforementioned effects associated with GLP-1 and GLP-1 RA administration were retrieved for analysis. GLP-1 RAs (i.e. exenatide, liraglutide) reduced opioid-seeking behaviour (p < 0.05) and self-administration of opioid drugs (p < 0.05) in preclinical paradigms. In addition, results from human studies indicate that GLP-1 administration was associated with reducing the risk of opioid overdose in human studies (aIRR = 0.60, 95% CI [0.43, 0.83]). GLP-1 RAs may affect opioid self-administration as well as the risk for overdose as evidenced by both preclinical and clinical data. There is a need for adequate well-controlled studies to determine whether GLP-1 RAs may provide clinically meaningful improvement and risk reduction in persons living with OUDs.