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As obesity evolves as a global pandemic, the use of drugs to treat it is booming. The latest among these are Glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Along with their use, the incidence of adverse events has become more common. Although severe effects have been mentioned, details and associations are unclear regarding some of them. We performed a systematic review of studies related to GLP-1 RA drugs. Drugs that have been the subject of at least three studies meeting all our criteria were included. Analysis of GLP-1 RA therapies across eight studies, involving 4422 subjects, indicated varying rates of Serious Adverse Events (SAEs). Semaglutide demonstrated an SAE incidence of 8.9%, compared to 6.2% for Liraglutide. These results were not statistically significant. For both drugs, no clear association with pancreatitis or neoplasm was established. Discontinuation rates due to adverse effects were 10.3% for Semaglutide and 8.3% for Liraglutide. Severe adverse effects with GLP-1 RA use are not uncommon, and warrant further close monitoring when patients are started on treatment. Further studies are required to analyze the difference between the adverse effect profiles of each drug and to assess whether or not each of these severe adverse effects is dose dependent. [ABSTRACT FROM AUTHOR]

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management. [ABSTRACT FROM AUTHOR]

Although, in randomized clinical trials, once-weekly subcutaneous semaglutide (OW s.c.) has demonstrated superior efficacy in comparison with placebo and active controls in terms of glycemic control and body weight reduction in patients with type 2 diabetes mellitus (T2DM), these results need to be confirmed in a real-world (RW) setting. An RW ambispective study (6 months retrospective and 6 months prospective) was conducted in 10 tertiary hospitals in Spain. We evaluated changes in HbA1c and body weight in patients with T2DM treated with semaglutide OW s.c. Additionally, we analyzed different subgroups of patients treated with semaglutide OW s.c. as an add-on to glucose-lowering therapy. A total of 752 patients with a mean age of 60.2 years, a mean HbA1c level of 8.5%, a mean body weight of 101.6 kg, and a mean T2DM duration of 10 years were included. At 12 months, compared with baseline, there was a mean difference of −2.1% in HbA1c levels (p < 0.001) and a mean difference of 9.2 kg in body weight (p < 0.001). Moreover, there were statistically significant differences (p < 0.001) between baseline and month 12 in both HbA1c and body weight in the four subgroups receiving semaglutide OW s.c. as an add-on to glucose-lowering therapy. Semaglutide OW s.c. was well tolerated, with gastrointestinal disorders being the most commonly reported side effects. In this RW study, 12 months of treatment with semaglutide OW s.c. in patients with T2DM was associated with significant and clinically relevant improvements in glycemic control and weight loss, regardless of the glucose-lowering therapy received, and the overall safety profile was positive. [ABSTRACT FROM AUTHOR]

Currently, there is no known cure for diabetes. Different pharmaceutical therapies have been approved for the management of type 2 diabetes mellitus (T2DM), some are in clinical trials and they have been classified according to their route or mechanism of action. Insulin types, sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, sodium–glucose cotransporter type 2 inhibitors, and incretin-dependent therapies (glucagon-like peptide-1 receptor agonists: GLP-1R, and dipeptidyl peptidase 4 inhibitors: DPP-4). Although some of the currently available drugs are effective in the management of T2DM, the side effects resulting from prolonged use of these drugs remain a serious challenge. GLP-1R agonists are currently the preferred medications to include when oral metformin alone is insufficient to manage T2DM. Medicinal plants now play prominent roles in the management of various diseases globally because they are readily available and affordable as well as having limited and transient side effects. Recently, studies have reported the ability of phytochemicals to activate glucagon-like peptide-1 receptor (GLP-1R), acting as an agonist just like the GLP-1R agonist with beneficial effects in the management of T2DM. Consequently, we propose that careful exploration of phytochemicals for the development of novel therapeutic candidates as GLP-1R agonists will be a welcome breakthrough in the management of T2DM and the co-morbidities associated with T2DM. [ABSTRACT FROM AUTHOR]

Background and Objectives: Limited evidence exists regarding the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) patients with advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). Thus, we conducted a systematic review and meta-analysis to assess the safety and efficacy of GLP-1RAs in T2DM patients with advanced CKD and ESKD. Materials and Methods: We performed a systematic literature search in MEDLINE, EMBASE, and Cochrane database until 25 October 2023. Included were clinical trials and cohort studies reporting outcomes of GLP-1RAs in adult patients with T2DM and advanced CKD. Outcome measures encompassed mortality, cardiovascular parameters, blood glucose, and weight. Safety was assessed for adverse events. The differences in effects were expressed as odds ratios with 95% confidence intervals (CIs) for dichotomous outcomes and the weighted mean difference or standardized mean difference (SMD) with 95% confidence intervals for continuous outcomes. The Risk of Bias In Non-randomized Studies—of Interventions (ROBIN-I) tool was used in cohort and non-randomized controlled studies, and the Cochrane Risk of Bias (RoB 2) tool was used in randomized controlled trials (RCTs). The review protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42023398452) and received no external funding. Results: Eight studies (five trials and three cohort studies) consisting of 27,639 patients were included in this meta-analysis. No difference was observed in one-year mortality. However, GLP-1RAs significantly reduced cardiothoracic ratio (SMD of −1.2%; 95% CI −2.0, −0.4) and pro-BNP (SMD −335.9 pmol/L; 95% CI −438.9, −232.8). There was no significant decrease in systolic blood pressure. Moreover, GLP-1RAs significantly reduced mean blood glucose (SMD −1.1 mg/dL; 95% CI −1.8, −0.3) and increased weight loss (SMD −2.2 kg; 95% CI −2.9, −1.5). In terms of safety, GLP-1RAs were associated with a 3.8- and 35.7-time higher risk of nausea and vomiting, respectively, but were not significantly associated with a higher risk of hypoglycemia. Conclusions: Despite the limited number of studies in each analysis, our study provides evidence supporting the safety and efficacy of GLP-1RAs among T2DM patients with advanced CKD and ESKD. While gastrointestinal side effects may occur, GLP-1RAs demonstrate significant improvements in blood glucose control, weight reduction, and potential benefit in cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis. [ABSTRACT FROM AUTHOR]

In this paper, we aim to evaluate the efficacy of antidiabetic cardioprotective molecules such as Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) when used with other glucose-lowering drugs, lipid-lowering, and blood pressure (BP)-lowering drugs in a real-life setting. A retrospective, observational study on 477 patients admitted consecutively in 2019 to the outpatient clinic of a tertiary care unit for Diabetes Mellitus was conducted. Body mass index (BMI), blood pressure (BP) (both systolic and diastolic), and metabolic parameters, as well as A1c hemoglobin, fasting glycaemia and lipid profile, including total cholesterol (C), HDL-C, LDL-C and triglycerides), were evaluated at baseline and two follow-up visits were scheduled (6 months and 12 months) in order to assess the antidiabetic medication efficacy. Both SGLT-2i and GLP-1 RAs were efficient in terms of weight control reflected by BMI; metabolic control suggested by fasting glycaemia and A1c; and the diastolic component of BP control when comparing the data from the 6 and 12-month visits to the baseline, and when comparing the 12-month visit to the 6-month visit. Moreover, when comparing SGLT-2i and GLP-1 RAs with metformin, there are efficacy data for SGLT-2i at baseline in terms of BMI, fasting glycaemia, and HbA1c. In this retrospective study, both classes of cardioprotective molecules, when used in conjunction with other glucose-lowering, antihypertensive, and lipid-lowering medications, appeared to be efficient in a real-life setting for the management of T2DM. [ABSTRACT FROM AUTHOR]

The present study aimed to analyse the published data and to realize an update about the use and pathogenesis of the novel antidiabetic drugs, respectively, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 Ra), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i), in patients with type 2 diabetes mellitus (T2DM) and coronavirus disease (COVID-19). Literature research in the PubMed and Web of Science database was performed in order to identify relevant published clinical trials and meta-analyses that include information about the treatment with novel antidiabetic agents in patients with T2DM and COVID-19. A total of seven articles were included, and their primary and secondary outcomes were reported and analysed. DPP-4i has mixed results on mortality in T2DM patients with COVID-19 but with an overall slightly favourable or neutral effect, whereas GLP-1 Ra seems to have a rather beneficial impact, while SGLT-2i may be useful in acute illness. Even if there are limited data, they seem to have favourable efficacy and safety profiles. The available evidence is heterogenous and insufficient to evaluate if the benefits of non-insulin novel antidiabetic drugs in COVID-19 treatment are due to the improvement of glycaemic control or to their intrinsic anti-inflammatory effects but highlights their beneficial effects in the pathogenesis and evolution of the disease. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a complex disease for which an individualised treatment approach is recommended. Once-weekly (OW) semaglutide is a glucagon-like peptide-1 receptor agonist approved for the treatment of insufficiently controlled T2D. The aim of this study was to investigate the use of OW semaglutide in adults with T2D in a real-world context. SURE Spain, from the 10-country SURE programme, was a prospective, multicentre, open-label, observational study, approximately 30 weeks in duration. Adults with T2D and ≥1 documented HbA1c value ≤12 weeks before semaglutide initiation were enrolled. Change in HbA1c from baseline to end of study (EOS) was the primary endpoint, with change in body weight (BW), waist circumference, and patient-reported outcomes as secondary endpoints. Of the 227 patients initiating semaglutide, 196 (86.3%) completed the study on-treatment with semaglutide. The estimated mean changes in HbA1c and body weight between baseline and EOS were −1.3%-points (95% confidence interval (CI) −1.51;−1.18%-points) and −5.7 kg (95% CI −6.36;−4.98 kg). No new safety concerns were identified. Therefore, in routine clinical practice in Spain, OW semaglutide was shown to be associated with statistically significant and clinically relevant reductions in HbA1c and BW in adults with T2D. [ABSTRACT FROM AUTHOR]

Background: Body weight (BW) loss is an essential therapeutic goal in type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists are effective in reducing BW, but their effect on body composition has not yet been fully explored. The study aim was to assess the impact of Semaglutide on body composition in patients with T2D. Methods: Forty patients with T2D were treated with subcutaneous Semaglutide and evaluated at the baseline (T0) and after three (T3) and six (T6) months. Body composition was assessed by a phase-sensitive bioimpedance analyzer. Visceral adipose tissue (VAT) thickness was also measured with an ultrasonographic method (US-VAT). Anthropometric variables, muscular strength, and laboratory tests were analyzed and compared. Results: A significant decrease in VAT, the fat mass index (FMI), and BW loss was observed at all observation times. US-VAT, the skeletal mass index (SMI), the fat-free mass index (FFMI), waist circumferences, and glycated hemoglobin had lessened after three months and remained stable at T6. No variations in muscle strength, the muscle quality index, and body water were found. Discussion: In a real-life setting, Semaglutide provided significant weight loss mainly due to a reduction in the FMI and VAT, with non-clinically relevant changes in the SMI, the FFMI, and muscle strength. Most importantly, the results were obtained after three months of treatment and persisted thereafter. [ABSTRACT FROM AUTHOR]

New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, although metformin-associated lactic acidosis is a hindrance to its use in patients with kidney failure. New anti-diabetic agents, including glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, also produce cardiovascular or renal benefits in T2D patients. Their glucose-independent beneficial actions can lead to cardiorenal protection via hemodynamic stabilization and inflammatory modulation. Systemic hypertension is relieved by natriuresis and improved vascular dysfunction. Enhanced tubuloglomerular feedback can be restored by SGLT-2 inhibition, reducing glomerular hypertension. Patients with non-diabetic kidney disease might also benefit from those drugs because hypertension, proteinuria, oxidative stress, and inflammation are common factors in the progression of kidney disease, irrespective of the presence of diabetes. In various animal models of non-diabetic kidney disease, metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were favorable to kidney morphology and function. They strikingly attenuated biomarkers of oxidative stress and inflammatory responses in diseased kidneys. However, whether those animal results translate to patients with non-diabetic kidney disease has yet to be evaluated. Considering the paucity of new agents to treat kidney disease and the minimal adverse effects of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, these anti-diabetic agents could be used in patients with non-diabetic kidney disease. This paper provides a rationale for clinical trials that apply metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to non-diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin-angiotensin-aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection., Competing Interests: The authors declare no conflict of interest.