Sepsis‑induced myopathy (SIM) is a common complication in intensive care units, which is often associated with adverse outcomes, primarily manifested as skeletal muscle weakness and atrophy. Currently, the management of SIM focuses on prevention strategies, as effective therapeutic options remain elusive. Glucagon‑like peptide‑1 (GLP‑1) receptor agonists (GLP‑1RAs) have garnered attention as hypoglycemic and weight‑loss agents, with an increasing body of research focusing on the extrapancreatic effects of GLP‑1. In preclinical settings, GLP‑1RAs exert protective effects against sepsis‑related multiple organ dysfunction through anti‑inflammatory and antioxidant mechanisms. Based on the existing research, we hypothesized that GLP‑1RAs may serve potential protective roles in the repair and regeneration of skeletal muscle affected by sepsis. The present review aimed to explore the relationship between GLP‑1RAs and sepsis, as well as their impact on muscle atrophy‑related myopathy. Furthermore, the potential mechanisms and therapeutic benefits of GLP‑1RAs are discussed in the context of muscle atrophy induced by sepsis.

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed for the treatment of type 2 diabetes mellitus and obesity, they were one of the first drug classes to be examined in individuals with MASLD/MASH. Successful phase 2 randomised clinical trials with these agents have resulted in progression to phase 3 clinical trials (principally testing the long-term efficacy of subcutaneous semaglutide). Over the last few years, in addition to GLP-1RAs, newer agents with glucose-dependent insulinotropic peptide and/or glucagon receptor agonist functions have been tested, with increasing evidence from phase 2 randomised clinical trials of histological improvements in MASLD/MASH, as well as benefits on MASLD-related extrahepatic complications. Based on this background of evidence, single, dual or triple incretin receptor agonists are becoming an attractive and promising treatment option for MASLD or MASH, particularly in individuals with coexisting obesity or type 2 diabetes mellitus. In this narrative review, we examine the rapidly expanding body of clinical evidence supporting a role of incretin-based pharmacotherapies in delaying or reversing MASH progression. We also discuss the biology of incretins and the putative hepatoprotective mechanisms of incretin-based pharmacotherapies for managing MASLD or MASH.

Incretin receptor agonists (IRAs), primarily composed of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs), work by mimicking the actions of the endogenous incretin hormones in the body. GLP-1RAs have been approved for use as monotherapy and in combination with GIPRAs for the management of type 2 diabetes mellitus (T2DM). In addition to their role in glucose regulation, IRAs have demonstrated various benefits such as cardiovascular protection, obesity management, and regulation of bone turnover. Some studies have suggested that IRAs not only aid in glycemic control but also exhibit anti-atherosclerotic effects. These agents have been shown to modulate lipid abnormalities, reduce blood pressure, and preserve the structural and functional integrity of the endothelium. Furthermore, IRAs have the ability to mitigate inflammation by inhibiting macrophage activation and promoting M2 polarization. Research has also indicated that IRAs can decrease macrophage foam cell formation and prevent vascular smooth muscle cell (VSMC) phenotype switching, which are pivotal in atheromatous plaque formation and stability. This review offers a comprehensive overview of the protective effects of IRAs in atherosclerotic disease, with a focus on their impact on atherogenesis.

Liraglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Despite its benefits, including improved glycemic control and weight loss, the common metabolic changes induced by liraglutide and correlations between those in rodents and humans remain unknown. Here, we used advanced machine learning techniques to analyze the plasma metabolomic data in diet-induced obese (DIO) mice and patients with T2DM treated with liraglutide. Among the machine learning models, Support Vector Machine was the most suitable for DIO mice, and Gradient Boosting was the most suitable for patients with T2DM. Through the cross-evaluation of machine learning models, we found that liraglutide promotes metabolic shifts and interspecies correlations in these shifts between DIO mice and patients with T2DM. Our comparative analysis helped identify metabolic correlations influenced by liraglutide between humans and rodents and may guide future therapeutic strategies for T2DM and obesity.

Diabetes leads to a significantly accelerated incidence of various related macrovascular complications, including peripheral vascular disease and cardiovascular disease (the most common cause of mortality in diabetes), as well as microvascular complications such as kidney disease and retinopathy. Endothelial dysfunction is the main pathogenic event of diabetes-related vascular disease at the earliest stage of vascular injury. Understanding the molecular processes involved in the development of diabetes and its debilitating vascular complications might bring up more effective and specific clinical therapies. Long-acting glucagon-like peptide (GLP)-1 analogs are currently available in treating diabetes with widely established safety and extensively evaluated efficacy. In recent years, autophagy, as a critical lysosome-dependent self-degradative process to maintain homeostasis, has been shown to be involved in the vascular endothelium damage in diabetes. In this review, the GLP-1/GLP-1R system implicated in diabetic endothelial dysfunction and related autophagy mechanism underlying the pathogenesis of diabetic vascular complications are briefly presented. This review also highlights a possible crosstalk between autophagy and the GLP-1/GLP-1R axis in the treatment of diabetic angiopathy.

Although good glycemic control in patients with type 2 diabetes (T2D) can prevent cardiovascular complications, many diabetic patients still have poor optimal control. A new class of antidiabetic drugs (e.g., glucagon-like peptide-1-GLP-1 receptor agonists, sodium-glucose co-transporters-SGLT2 inhibitors), in addition to the low hypoglycemic effect, exert multiple beneficial effects at a metabolic and cardiovascular level, through mechanisms other than antihyperglycemic agents. This review aims to discuss the effects of these new antidiabetic drugs, highlighting cardiovascular and metabolic benefits, through the description of their action mechanisms as well as available data by preclinical and clinical studies. Moreover, new innovative tools in the T2D field will be described which may help to advance towards a better targeted T2D personalized care in future.

Background and Objectives: The rise in global diabetes cases, reaching a staggering 529 million in 2021 from 108 million in 1980, underscores the urgency of addressing its complications, notably macrovascular ones like coronary artery, cerebrovascular, and peripheral artery diseases, which contribute to over 50% of diabetes mortality. Atherosclerosis, linked to hyperglycemia-induced endothelial dysfunction, is pivotal in cardiovascular disease development. Cytokines, including pentraxin 3 (PTX3), copeptin, lipoprotein(a) [Lp(a)], and matrix metalloproteinase-9 (MMP-9), influence atherosclerosis progression and plaque vulnerability. Inhibiting atherosclerosis progression is crucial, especially in diabetic individuals. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), increasingly used for type 2 diabetes, show promise in reducing the cardiovascular risk, sparking interest in their effects on atherogenesis. This study sought to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on biomarkers that indicate the instability of atherosclerotic plaques. These biomarkers include pentraxin 3 (PTX3), copeptin (CPC), matrix metalloproteinase-9 (MMP-9), and lipoprotein(a) [Lp(a)]. Materials and Methods: A total of 34 participants, ranging in age from 41 to 81 years (with an average age of 61), who had been diagnosed with type 2 diabetes mellitus (with a median HbA1c level of 8.8%), dyslipidemia, and verified atherosclerosis using B-mode ultrasonography, were included in the study. All subjects were eligible to initiate treatment with a GLP-1 RA-dulaglutide. Results: Significant reductions in anthropometric parameters, blood pressure, fasting glucose levels, and HbA1c levels were observed posttreatment. Moreover, a notable decrease in biochemical markers associated with atherosclerotic plaque instability, particularly PTX3 and MMP-9 (p < 0.001), as well as Lp(a) (p < 0.05), was evident following the GLP-1 RA intervention. Conclusions: These findings underscore the potential of GLP-1 RAs in mitigating atherosclerosis progression and plaque vulnerability, thus enhancing cardiovascular outcomes in individuals with type 2 diabetes mellitus.

Cardiovascular disease (CVD) remains a major global health concern, and obesity and diabetes mellitus have been found to be important risk factors. Tirzepatide a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) receptor agonist has been shown to have cardioprotective effects. Noteworthy benefits of Tirzepatide include decreased cardiovascular risk factors in people with Type 2 diabetes mellitus (T2DM). In the SURPASS-4 trial, tirzepatide significant decreased blood pressure, body weight, and HbA1c. Furthermore, the SURMOUNT-1 trial demonstrated the effectiveness of tirzepatide in reducing cardiometabolic risk factors in people with obesity without T2DM. Together, the dual receptor agonism improves lipid profiles, increases insulin secretion, reduces inflammation, and promotes endothelial integrity. Tirzepatide shows promise as a comprehensive therapeutic option for managing cardiovascular risk factors in patients with T2DM and obesity. While further studies are needed to assess the long-term cardiovascular benefits, current evidence supports tirzepatide's potential impact on cardiovascular health beyond its antidiabetic properties.

Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.

Metabolic syndrome (MetS) represents an important factor that increases the risk of myocardial infarction, and more severe complications. Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs) exhibit cardioprotective potential, but their efficacy in MetS-related myocardial dysfunction has not been fully explored. Therefore, we aimed to assess the effects of exenatide and dulaglutide on heart function and redox balance in MetS-induced rats. Twenty-four Wistar albino rats with induced MetS were divided into three groups: MetS, exenatide-treated (5 µg/kg), dulaglutide-treated (0.6 mg/kg). After 6 weeks of treatment, in vivo heart function was assessed via echocardiography, while ex vivo function was evaluated using a Langendorff apparatus to simulate ischemia-reperfusion injury. Heart tissue samples were analyzed histologically, and oxidative stress biomarkers were measured spectrophotometrically from the coronary venous effluent. Both exenatide and dulaglutide significantly improved the ejection fraction by 3% and 7%, respectively, compared to the MetS group. Histological analyses corroborated these findings, revealing a reduction in the cross-sectional area of cardiomyocytes by 11% in the exenatide and 18% in the dulaglutide group, indicating reduced myocardial damage in GLP-1RA-treated rats. Our findings suggest strong cardioprotective potential of GLP-1RAs in MetS, with dulaglutide showing a slight advantage. Thus, both exenatide and dulaglutide are potentially promising targets for cardioprotection and reducing mortality in MetS patients.

Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT).

PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients.

The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = -0.123, 95% CI (-0.170, -0.076), P < 0.0001, I2 = 98% and MD = -0.048, 95% CI (-0.092, -0.004), P = 0.031, I2 = 95%, respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment.

Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i.

Ischaemic cardiovascular diseases, including peripheral and coronary artery disease, myocardial infarction, and stroke, remain major comorbidities for individuals with type 2 diabetes (T2D) and obesity. During cardiometabolic chronic disease (CMCD), hyperglycaemia and excess adiposity elevate oxidative stress and promote endothelial damage, alongside an imbalance in circulating pro-vascular progenitor cells that mediate vascular repair. Individuals with CMCD demonstrate pro-vascular 'regenerative cell exhaustion' (RCE) characterized by excess pro-inflammatory granulocyte precursor mobilization into the circulation, monocyte polarization towards pro-inflammatory vs. anti-inflammatory phenotype, and decreased pro-vascular progenitor cell content, impairing the capacity for vessel repair. Remarkably, targeted treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in subjects with T2D and coronary artery disease, and gastric bypass surgery in subjects with severe obesity, has been shown to partially reverse these RCE phenotypes. SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the management of individuals with T2D and comorbid obesity. In addition to glucose-lowering action, both drug classes have been shown to induce weight loss and reduce mortality and adverse cardiovascular outcomes in landmark clinical trials. Furthermore, both drug families also act to reduce systemic oxidative stress through altered activity of overlapping oxidase and antioxidant pathways, providing a putative mechanism to augment circulating pro-vascular progenitor cell content. As SGLT2i and GLP-1RA combination therapies are emerging as a novel therapeutic opportunity for individuals with poorly controlled hyperglycaemia, potential additive effects in the reduction of oxidative stress may also enhance vascular repair and further reduce the ischaemic cardiovascular comorbidities associated with T2D and obesity.

Type 2 diabetes mellitus (T2DM) is a relevant risk factor for severe forms of COVID-19 (SARS coronavrus 2 [SARS-CoV-2] disease 2019), and calls for caution because of the high prevalence of T2DM worldwide and the high mortality rates observed in patients with T2DM who are infected with SARS-CoV-2. People with T2DM often take dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1ras), or sodium-glucose co-transporter-2 inhibitors (SGLT-2is), all of which have clear anti-inflammatory effects. The study aimed to compare (i) the severity and duration of hospital stay between patients with T2DM categorized by pre-hospitalization drug class utilization and (ii) the COVID-19-related death rates of those three groups.

We designed an observational, retrospective, multi-center, population-based study and extracted the hospital admission data from the health care records of 1916 T2DM patients over 18 years old who were previously on GLP-1ra, SGLT-2i, or DPP-4i monotherapy and were hospitalized for COVID-19 (diagnosis based on ICD.9/10 codes) between January 2020 and December 2021 in 14 hospitals throughout Italy. We analyzed general data, pre-admission treatment schedules, date of admission or transfer to the intensive care unit (ICU) (i.e., the index date; taken as a marker of increased COVID-19 disease severity), and death (if it had occurred). Statistics analyzed the impact of drug classes on in-hospital mortality using propensity score logistic regressions for (i) those admitted to intensive care and (ii) those not admitted to intensive care, with a random match procedure used to generate a 1:1 comparison without diabetes cohort replacement for each drug therapy group by applying the nearest neighbor method. After propensity score matching, we checked the balance achieved across selected variables if a balance was ever achieved. We then used propensity score matching between the three drug classes to assemble a sample in which each patient receiving an SGLT-2i was matched to one on a GLP-1ra, and each patient on a DPP-4i was matched to one on a GLP-1ra, adjusting for covariates. We finally used GLP-1ras as references in the logistic regression.

The overall mortality rate (MR) of the patients was 14.29%. The MR in patients with COVID was 53.62%, and it was as high as 42.42% in the case of associated T2DM, regardless of any glucose-lowering therapy. In those on DPP-4is, there was excess mortality; in those treated with GLP-1ras and SGLT-2is, the death rate was significantly lower, i.e., almost a quarter of the overall mortality observed in COVID-19 patients with T2DM. Indeed, the odds ratio (OR) in the logistic regression resulted in an extremely high risk of in-hospital death in individuals previously treated with DPP-4is [incidence rate (IR) 4.02, 95% confidence interval (CI) 2.2-5.7) and only a slight, nonsignificantly higher risk in those previously treated with SGLT-2is (IR 1.42, 95% CI 0.6-2.1) compared to those on GLP-1ras. Moreover, the longer the stay, the higher the death rate, which ranged from 22.3% for ≤ 3-day stays to 40.3% for 4- to 14-day stays (p < 0.01 vs. the former) and 77.4% for over-14-day stays (p < 0.001 vs. both the others).

Our data do not support a protective role of DPP-4is; indeed, this role has already been questioned due to previous observations. However, the data do show a strong protective effect of SGLT-2is and GLP-1ras. Beyond lowering circulating glucose levels, those two drug classes were found to exert marked anti-phlogistic effects: SGLT-2is increased adiponectin and reduced urate, leptin, and insulin concentrations, thus positively affecting overall low-grade inflammation, and GLP-1ras may also greatly help at the lung tissue level, meaning that their extra-glycemic effects extend well beyond those acknowledged in the cardiovascular and renal fields.

The aforedescribed observational clinical data relating to a population of Italian inpatients with T2DM suggest that GLP-1ras and SGLT-2is can be considered antidiabetic drugs of choice against COVID-19, and might even prove beneficial in the event of any upcoming pandemic that has life-threatening effects on the pulmonary and cardiovascular systems.

(1) Background: Oral semaglutide represents the first oral GLP-1 RA approved for the treatment of type 2 diabetes mellitus (T2DM). This real-world retrospective study aimed at evaluating its effectiveness and tolerability in the treatment of patients with T2DM when patients switched from a glucose-lowering agent to it and when it was added to the usual therapy. (2) Methods: Adult patients with T2DM taking oral semaglutide and followed in the ASUGI Diabetes Center were identified with the use of electronic medical records between October 2022 and May 2023. (3) Results: A total of 129 patients were recruited. The median follow-up was 6 months. Be it as a switchover or as an add-on therapy, oral semaglutide significantly reduced HbA1c and BMI. Switching from DPPIV inhibitors to oral semaglutide was associated with a significant reduction in HbA1c and BMI, switching from SGLT2 inhibitors was associated with a significant reduction in HbA1c, and switching from sulphonylureas was associated with a significant reduction in BMI. The median HbA1c change was associated with baseline HbA1c. SBP significantly decreased in the add-on group. Oral semaglutide was well tolerated. (4) Conclusions: This study shows that in the real-world setting, oral semaglutide is effective and safe as a switchover or as an add-on therapy for the treatment of T2DM.

Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays a central role in maintaining vascular integrity and homeostasis and is in direct contact with the blood flow. Research over the past century has shown that mechanical perturbations of the vascular wall contribute to the formation and progression of atherosclerosis. While the straight part of the artery is exposed to sustained laminar flow and physiological high shear stress, flow near branch points or in curved vessels can exhibit 'disturbed' flow. Clinical studies as well as carefully controlled in vitro analyses have confirmed that these regions of disturbed flow, which can include low shear stress, recirculation, oscillation, or lateral flow, are preferential sites of atherosclerotic lesion formation. Because of their critical role in blood flow homeostasis, vascular endothelial cells (ECs) have mechanosensory mechanisms that allow them to react rapidly to changes in mechanical forces, and to execute context-specific adaptive responses to modulate EC functions. This review summarizes the current understanding of endothelial mechanobiology, which can guide the identification of new therapeutic targets to slow or reverse the progression of atherosclerosis.

Glucagon-like peptide-1 receptor agonist liraglutide may have beneficial effects on atherosclerosis development in impaired glucose tolerance (IGT). To the best of our knowledge, however, little conclusive evidence from clinical trials has been presented. The present study aimed to investigate the effect of liraglutide on atherosclerosis progression in patients with IGT. The present study was a double-blind, randomized controlled clinical trial. A total of 39 of patients aged 20-75 years who were overweight or obese (BMI, 27-40 kg/m²) and presented IGT were randomized to receive liraglutide (n=17) or lifestyle interventions (n=22) for 6 months. Serum glucose and insulin (INS) levels, lipid profile, inflammatory biomarkers and carotid intima-media thickness (CIMT) were assessed at the start and end of each treatment. Side effects were also recorded. Liraglutide treatment was found to significantly improve glycaemia, including glycosylated hemoglobin, fasting and postprandial glucose as well as INS levels (all P<0.001). Liraglutide also significantly decreased serum total cholesterol and low-density lipoprotein levels (all P<0.001). Furthermore, serum levels of inflammatory biomarkers, as well as CIMT, were decreased following liraglutide treatment compared with those in the lifestyle intervention group (all P<0.001). Kaplan-Meier analysis showed that the risk of vasculopathy in the liraglutide group was lower than that in the lifestyle intervention group (log-rank test; P=0.041). The monitoring of drug-associated side effects indicated that the dose of liraglutide (0.6 to 1.2 mg/QD via subcutaneous injection) was safe and well-tolerated. The present study suggested that liraglutide may slow atherosclerosis development and improve inflammatory status as well as intimal function in patients with IGT with few side effects. The trial was registered through the Chinese Clinical Trial Registry (ChiCTR; trial registration no. ChiCTR2200063693; retrospectively registered) on Sep 14, 2022.

Hypertension is a significant risk factor of cardiovascular diseases (CVDs) with high prevalence worldwide, the current treatment has multiple adverse effects and requires continuous administration. The glucagon-like peptide-1 receptor (GLP-1R) agonists have shown great potential in treating diabetes mellitus, neurodegenerative diseases, obesity and hypertension. Butyric acid is a potential target in treating hypertension. Yet, the application of GLP-1 analogue and butyric acid in reducing blood pressure and reversing ventricular hypertrophy remains untapped. In this study, we combined the therapeutic capability of GLP-1 and butyric acid by transforming Clostridium butyricum (CB) with recombinant plasmid pMTL007 encoded with hGLP gene to construct the engineered probiotics Clostridium butyricum-pMTL007-GLP-1 (CB-GLP-1). We used spontaneous hypertensive rat (SHR) models to evaluate the positive effect of this strain in treating hypertension. The results revealed that the intragastric administration of CB-GLP-1 had markedly reduced blood pressure and improved cardiac marker ACE2, AT2R, AT1R, ANP, BNP, β-MHC, α-SMA and activating AMPK/mTOR/p70S6K/4EBP1 signalling pathway. The high-throughput sequencing further demonstrated that CB-GLP-1 treatments significantly improved the dysbiosis in the SHR rats via downregulating the relative abundance of Porphyromonadaceae at the family level and upregulating Lactobacillus at the genus level. Hence, we concluded that the CB-GLP-1 greatly improves blood pressure and cardiomegaly by restoring the gut microbiome and reducing ventricular hypertrophy in rat models. This is the first time using engineered CB in treating hypertension, which provides a new idea for the clinical treatment of hypertension.

The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.

Liraglutide (LG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve white adipose tissue mitochondrial metabolism in mice but not in human adipocytes. Therefore, we explored whether LG has therapeutic efficacy in mitochondrial dysfunction in human adipocytes in vitro.

We tested the effects of short-term (ST-LG: 24 h) and long-term (LT-LG: D0-15 days) treatments in human SGBS adipocytes on mitochondrial respiration, mRNA and protein expression. GLP-1R inhibition was investigated by the co-treatment of GLP-1R inhibitor, exendin 9-39 (Ex9-39) and ST-LG treatment. We also explored the ability of ST-LG to alleviate mitochondrial dysfunction induced by tumor necrosis factor-alpha (TNFα).

LT-LG treatment induced the formation of smaller lipid droplets and increased the expression of genes related to lipolysis. Both ST-LG and LT-LG treatments promoted mitochondrial respiration. Additionally, LT-LG treatment increased the expression of a brown adipocyte marker, uncoupling protein 1 (UCP-1), and the markers of mitochondrial biogenesis. Interestingly, ST-LG rescued TNFα-induced defects in mitochondrial energy metabolism and inflammation in SGBS adipocytes.

LG stimulates mitochondrial respiration and biogenesis in human adipocytes, potentially via UCP-1-mediated adipocyte browning. Importantly, our study demonstrates for the first time that LG has a therapeutic potential on mitochondrial activity in human adipocytes.

Chronic low-grade inflammation has been identified as a major contributor in the development of atherosclerosis. Nuclear Factor-κappa B (NF-κB) is a critical transcription factors family of the inflammatory pathway. As a major catalytic subunit of the IKK complex, IκB kinase β (IKKβ) drives canonical activation of NF-κB and is implicated in the link between inflammation and atherosclerosis, making it a promising therapeutic target. Various natural product derivatives, extracts, and synthetic, show anti-atherogenic potential by inhibiting IKKβ-mediated inflammation. This review focuses on the latest knowledge and current research landscape surrounding anti-atherosclerotic drugs that inhibit IKKβ. There will be more opportunities to fully understand the complex functions of IKKβ in atherogenesis and develop new effective therapies in the future.

Beyond improving hemoglobin A1c (HbA1c) in adults with type 2 diabetes, glucagon-like peptide 1 receptor agonists (GLP-1RA) have been approved for reducing risk of major adverse cardiovascular events (MACE) with established cardiovascular disease (CVD) or multiple CV risk factors. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also reduced the risk for the primary composite CV outcome in patients with type 2 diabetes at high risk for CV events. In the American Diabetes Association (ADA) and European Association of Study in Diabetes (EASD) consensus report 2022, there is the description "In people with established atherosclerotic CVD (ASCVD) or with a high risk for ASCVD, GLP-1RA were prioritized over SGLT2i"; however, the evidence supporting such statement is limited. Therefore, we studied the superiority of GLP-1RA over SGLT2i for prevention of ASCVD from various viewpoints. We could not find a meaningful difference in the risk reduction in three-point MACE (3P-MACE), mortality due to any cause, mortality due to CV cause and nonfatal myocardial infarction between GLP-1RA and SGLT2i trials. The risk of nonfatal stroke decreased in all five GLP-1RA trials; however, two of three SGLT2i trials showed an increase in risk of nonfatal stroke. The risk of hospitalization for heart failure (HHF) decreased in all three SGLT2i trials, and one GLP-1RA trial showed an increase in risk of HHF. The risk reduction of HHF in SGLT2i trials was greater than that in GLP-1RA trials. These findings were consistent with current systematic reviews and meta-analyses. The risk reduction of 3P-MACE was significantly and negatively correlated with changes in HbA1c (R = -0.861, P = 0.006) and body weight (R = -0.895, P = 0.003) in GLP-1RA and SGLT2i trials. The studies using SGLT2i failed to reduce carotid intima media thickness (cIMT), the surrogate marker for atherosclerosis; however, several studies using GLP-1RA successfully reduced cIMT in patients with type 2 diabetes. Compared with SGLT2i, GLP-1RA had a higher probability of decreasing serum triglyceride. GLP-1RA have multiple vascular biological anti-atherogenic properties.

Obesity is an ever-increasing phenomenon, with 42% of Americans being considered obese (BMI ≥ 30) and 9.2% being considered morbidly obese (BMI ≥ 40) as of 2016. With obesity being characterized by an abundance of adipose tissue expansion, abnormal tissue remodeling is a typical consequence. Importantly, this pathological tissue expansion is associated with many alterations in the cellular populations and phenotypes within the tissue, lending to cellular, paracrine, mechanical, and metabolic alterations that have local and systemic effects, including diabetes and cardiovascular disease. In particular, vascular dynamics shift during the progression of obesity, providing signaling cues that drive metabolic dysfunction. In this review, paracrine-, autocrine-, and matrix-dependent signaling between adipocytes and endothelial cells is discussed in the context of the development and progression of obesity and its consequential diseases, including adipose fibrosis, diabetes, and cardiovascular disease.

Vascular inflammation can be detected in the pericoronary adipose tissue (PCAT) by coronary computed tomography angiography (CCTA) attenuation. Treatment with liraglutide is associated with anti-inflammatory effects and reduces cardiovascular risk in diabetic patients. This study is aimed at examining the effect of clinically indicated liraglutide on PCAT attenuation. Asymptomatic patients with type 2 diabetes mellitus (T2DM) and without known ischemic heart disease underwent clinical examination, blood analysis, and CCTA. The main coronary arteries were outlined and PCAT attenuation was measured on the proximal 40 mm. Patients treated with liraglutide on a clinical indication were compared to patients not receiving liraglutide. The study included 190 patients; 53 (28%) received liraglutide (Lira+) and 137 (72%) did not (Lira-). There were no significant differences in PCAT attenuation between the two groups in either artery. However, PCAT attenuation measured around the left anterior descending artery (LAD) was lower in the Lira+ group after adjustment for age, sex, body mass index, and T2DM duration (b coefficient -2.4, p = 0.029). In a population of cardiac asymptomatic T2DM patients, treatment with clinically indicated liraglutide was not associated with differences in PCAT attenuation compared to nonliraglutide treatment in the unadjusted model. An association was seen in the adjusted model for the left anterior descending artery, possibly indicating an anti-inflammatory effect.

Pathological destruction of insulin signaling molecules such as insulin receptor substrate, especially due to the increase in suppressors of cytokine signaling molecules, has been demonstrated in experimental diabetes. The contribution of suppressors of cytokine signaling proteins to the development of insulin resistance and the effects of antidiabetic drugs and exercise on suppressors of cytokine signaling proteins are not clearly known.

A total of 48 Wistar albino adult male rats were divided into six groups: control group, obese group with diabetes, obese diabetic rats treated with metformin, obese diabetic rats treated with pioglitazone, obese diabetic rats treated with exenatide, and obese diabetic rats with applied exercise program. Immunohistochemical staining was performed in both the liver and adipose tissue.

There was a statistically significant decrease in suppressors of cytokine signaling-1, a decrease in suppressors of cytokine signaling-3, an increase in insulin receptor substrate-1, and a decrease in immunohistochemical staining in the obese group treated with metformin and exenatide compared to the obese group without treatment in the liver tissue (p<0.05). A statistically significant decrease in immunohistochemical staining of suppressors of cytokine signaling-1 and suppressors of cytokine signaling-3 was found in the obese group receiving exercise therapy compared to the obese group without treatment in visceral adipose tissue (p<0.05). Likewise, no significant immunohistochemistry staining was seen in diabetic obese groups.

Metformin or exenatide treatment could prevent the degradation of insulin receptor substrate-1 protein by reducing the effect of suppressors of cytokine signaling-1 and suppressors of cytokine signaling-3 proteins, especially in the liver tissue. In addition, exercise can play a role as a complementary therapy by reducing suppressors of cytokine signaling-1 and suppressors of cytokine signaling-3 proteins in visceral adipose tissue.

In the past few decades, non-alcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) have become the most common chronic liver disease and the main form of heart failure (HF), respectively. NAFLD is closely associated with HFpEF by sharing common risk factors and/or by boosting systemic inflammation, releasing other secretory factors, and having an expansion of epicardial adipose tissue (EAT). Therefore, the treatments of NAFLD may also affect the development and prognosis of HFpEF. However, no specific drugs for NAFLD have been approved by the Food and Drug Administration (FDA) and some non-specific treatments for NAFLD are applied in the clinic. Currently, the treatments of NAFLD can be divided into non-pharmacological and pharmacological treatments. Non-pharmacological treatments mainly include dietary intervention, weight loss by exercise, caloric restriction, and bariatric surgery. Pharmacological treatments mainly include administering statins, thiazolidinediones, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and metformin. This review will mainly focus on analyzing how these treatments may affect the development and prognosis of HFpEF.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Atherosclerosis is still considered a disease burden with long-term damaging processes towards the cardiovascular system. Evaluation of atherosclerotic stages requires the use of independent markers such as those already considered traditional, that remain the main therapeutic target for patients with atherosclerosis, together with emerging biomarkers. The challenge is finding models of predictive markers that are particularly tailored to detect and evaluate the evolution of incipient vascular lesions. Important advances have been made in this field, resulting in a more comprehensible and stronger linkage between the lipidic profile and the continuous inflammatory process. In this paper, we analysed the most recent data from the literature studying the molecular mechanisms of biomarkers and their involvement in the cascade of events that occur in the pathophysiology of atherosclerosis.

The life history theory assumes that all organisms are under selective pressure to harvest external resources and allocate them to maximise fitness: only organisms making the best use of energy obtain the greatest fitness benefits. The trade-off of energy spans four functions: maintenance, growth, reproduction, and defence against pathogens. The innovative antihyperglycaemic agents glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease bodyweight and have the potential to counter low-grade inflammation. These key activities could rewire two components of the life history theory operative in adulthood-ie, maintenance and defence. In this Personal View, we postulate that the benefits of these medications on the cardiovascular system, beyond their glucose-lowering effects, could be mediated by the reduction of the maintenance cost driven by obesity and efforts spent on blunting low-grade inflammation.

Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.

The incidence of type 2 diabetes (T2DM) has been increasing worldwide and remains one of the leading causes of atherosclerotic disease. Several antidiabetic agents have been introduced in trying to regulate glucose control levels with different mechanisms of action. These agents, and sodium-glucose cotransporter-2 inhibitors in particular, have been endorsed by contemporary guidelines in patients with or without T2DM. Their widespread usage during the last three decades has raised awareness in the scientific community concerning their pleiotropic mechanisms of action, including their putative anti-inflammatory effect. In this review, we delve into the anti-inflammatory role and mechanism of the existing antidiabetic agents in the cardiovascular system and their potential use in other chronic sterile inflammatory conditions.

Oxidative stress is characterized by excessive production of reactive oxygen species together with exhausted antioxidant defenses. This constitutes a main pathophysiologic process that is implicated in cardiovascular and renal diseases. In particular, enhanced oxidative stress may lead to low-density lipoprotein accumulation and oxidation, endothelial cell activation, adhesion molecule overexpression, macrophage activation, and foam cell formation, promoting the development and progression of atherosclerosis. The deleterious kidney effects of oxidative stress are numerous, including podocytopathy, mesangial enlargement, renal hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The prominent role of oxidative mechanisms in cardiorenal diseases may be counteracted by recently developed pharmacotherapies such as novel antidiabetic agents and finerenone. These agents have demonstrated significant antioxidant activity in preclinical and clinical studies. Moreover, the use of melatonin as a treatment in this field has been experimentally investigated, with large-scale clinical studies being awaited. Finally, clinical implications and future directions in this field are presented.

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Ischemic heart disease (IHD) is the leading cause of disability and mortality worldwide. Reactive oxygen species (ROS) have been shown to play key roles in the progression of diabetes, hypertension, and hypercholesterolemia, which are independent risk factors that lead to atherosclerosis and the development of IHD. Engineered biomaterial-based nanomedicines are under extensive investigation and exploration, serving as smart and multifunctional nanocarriers for synergistic therapeutic effect. Capitalizing on cell/molecule-targeting drug delivery, nanomedicines present enhanced specificity and safety with favorable pharmacokinetics and pharmacodynamics. Herein, the roles of ROS in both IHD and its risk factors are discussed, highlighting cardiovascular medications that have antioxidant properties, and summarizing the advantages, properties, and recent achievements of nanomedicines that have ROS scavenging capacity for the treatment of diabetes, hypertension, hypercholesterolemia, atherosclerosis, ischemia/reperfusion, and myocardial infarction. Finally, the current challenges of nanomedicines for ROS-scavenging treatment of IHD and possible future directions are discussed from a clinical perspective.

Diabetes mellitus can result in severe complications, such as neurodegenerative diseases including cognitive impairment and dementia. The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, is a novel antidiabetic drug with neuroprotective effects against neurodegenerative diseases. In this study, we explored the protective effect of liraglutide on SH-SY5Y cells exposed to methylglyoxal (MG), a byproduct of glucose metabolism that plays a key role in the development of diabetic encephalopathy. We found that liraglutide reduced the MG-induced oxidative stress, increased the activity of superoxide dismutase (SOD) and expression levels of P22phox, Gp91phox, and Xdh genes, and reduced reactive oxygen species (ROS) content. Metabolomics analysis based on ¹H nuclear magnetic resonance showed that liraglutide induced alterations in metabolites involved in energy metabolism，including promotion of gluconeogenesis. Moreover, we found that liraglutide promoted oxidative phosphorylation and inhibited glycolysis in SH-SY5Y cells. This study revealed that liraglutide improved diabetes-related neuropathy damage by reducing the level of oxidative stress and maintaining the balance of energy metabolism, thus offering new insights into the potential mechanism of liraglutide in neuronal protection.

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells-leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19.

The risk of cardiovascular diseases is closely related to diabetes. Macrovascular disease is the main cause of death and disability in patients with type 2 diabetes. In recent years, the glucagon-like peptide-1 receptor agonist (GLP-1RA), a new type of hypoglycemic drug, has been shown to regulate blood sugar levels, improve myocardial ischemia, regulate lipid metabolism, improve endothelial function, and exert a protective role in the cardiovascular system. This study reviewed the protective effects of GLP-1RA on the cardiovascular system.

Understanding the pathogenesis and risk factors to control the coronavirus disease 2019 (COVID-19) is necessary. Due to the importance of the inflammatory pathways in the pathogenesis of COVID-19 patients, evaluating the effects of anti-inflammatory medications is important. Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is awell-known glucose-lowering agent with anti-inflammatory effects.

Resources were extracted from the PubMed database, using keywords such as glucagon-like peptide-1, GLP-1 RA, SARS-CoV-2, COVID-19, inflammation, in April2021. In this review, the effects of GLP-1RA in reducing inflammation and modifying risk factors of COVID-19 severe complications are discussed. However, GLP-1 is degraded by DPP-4 with aplasma half-life of about 2-5 minutes, which makes it difficult to measure GLP-1 plasma level in clinical settings.

Since no definitive treatment is available for COVID-19 so far, determining promising targets to design and/or repurpose effective medications is necessary.

To evaluate the effect of liraglutide, a glucagon-like peptide 1 receptor agonist, on pulmonary function and serum levels of surfactant protein D (SP-D) in type 2 diabetes. A double-blind, randomized, crossover, placebo-controlled clinical trial comprising 76 patients with a baseline forced expiratory volume in 1 s <90% of that predicted. Liraglutide was administered for 7 weeks (2 weeks of titration plus 5 weeks at 1.8 mg daily). This short duration was intentional to minimize weight loss as a potential confounding factor. Serum level of SP-D was used as a biomarker of alveolar-capillary barrier integrity. Liraglutide exerted a positive impact on forced vital capacity (FVC) in comparison with placebo (ΔFVC 5.2% of predicted [from 0.8 to 9.6]; P = 0.009). No differences in the other pulmonary variables were observed. Participants under liraglutide treatment also experienced a decrease in serum SP-D (P = 0.038). The absolute change in FVC correlated with final serum SP-D in participants receiving liraglutide (r = -0.313, P = 0.036). Stepwise multivariate regression analysis showed that final serum SP-D independently predicted changes in FVC. In conclusion, liraglutide increased FVC in patients with type 2 diabetes. This effect was associated with a significant decrease of circulating SP-D, thus pointing to a beneficial effect in the alveolar-capillary function.

Glucagon-like peptide-1 alleviates the deleterious effects of advanced glycation end products (AGEs), but the underlying mechanisms are not fully understood. In this study, we investigated the protective mechanism using liraglutide, a glucagon-like peptide-1 receptor agonist, in cultured human aortic endothelial cells (HAECs).

Following liraglutide treatment in HAECs, the receptor for AGEs (RAGE) was measured in both cell lysate and culture supernatant, the cytosolic free Ca²⁺ level was monitored using Fluo-4 AM, the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was analyzed, and immunofluorescence staining was used to visualize a disintegrin and metalloprotease 10 (ADAM10) on the cell surface.

Liraglutide (100 nM) induced ectodomain shedding of RAGE within 30 min and inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) induced by AGEs of bovine serum albumin (AGE-BSA). Further experiments revealed that liraglutide rapidly increased extracellular Ca²⁺ influx through L-type calcium channels and activated AMPK, resulting in translocation of ADAM10 to the cell surface, whereas siRNA-mediated ADAM10 depletion prevented liraglutide-induced ectodomain shedding of RAGE and eliminated liraglutide's inhibitory effect on AGE-BSA-induced ICAM-1 expression. Moreover, compound C-mediated AMPK inhibition and siRNA-mediated AMPK depletion both prevented ADAM10 translocation to the cell surface and ADAM10-mediated ectodomain shedding of RAGE.

Liraglutide reduces the number of intact RAGE on the cell surface by inducing ADAM10-mediated ectodomain shedding, which decreases the inflammatory effects of AGEs. AMPK activated by extracellular Ca²⁺ influx is critically involved in the translocation of ADAM10 to the cell surface, where it cleaves RAGE.

COVID-19 has and still is sweeping away the national health systems worldwide. In this review, we sought to determine the evidence base proofs on the antidiabetic treatment capable to reduce the risk of COVID-19-related mortality.

We have performed a systematic search of published articles using PubMed, and EMBASE from March 2020 to March 31st, 2021. We excluded editorials, commentary, letters to the editor, reviews, and studies that did not have mortality as an outcome. For metformin and insulin only, we performed a meta-analysis using Cochrane RevMan 5.2.

Among antidiabetic drugs, metformin was the only drug associated with a reduced risk of mortality. Conversely, insulin appears associated with an increased risk. The other classes of drugs were neutral.

The totality of articles reports retrospective data strongly affected by "channeling bias" so that most of the existing results on each class of drugs are driven by the phenotype of patients likely to receive that specific drug by prescription.