Glucagon-like Peptide-1 Receptor Agonists Research Articles

Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on mitochondrial-derived peptide-c and on markers of neurohumoral activation

Abstract Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular disease. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on mitochondrial-derived peptide-c (MOTS-c), N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, oxidant and antioxidant biomarkers and cardiovascular function of T2DM patients. Methods A total of 160 T2DM patients were randomized to insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40) or their combination (GLP-1RA+SGLT-2i) (n = 40) as add-on to metformin. We measured at baseline, at 4 and at 12 months of treatment: a) plasma levels of MOTS-c, NT-proBNP and GDF-15, b) thiobarbituric acid reactive substances (TBARS), as an oxidant biomarkers, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), as an antioxidant biomarker, and c) global left ventricular longitudinal strain (GLS) and global work index (GWI) using speckle-tracking imaging. Results Twelve months after treatment, treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c (14.89 ± 11.27 vs. 7.26 ± 4.21 ng/mL, p=0.009, 6.49 ± 3.91 vs. 5.6 ± 3.38 ng/mL, p=0.029, respectively), while treatment with insulin and GLP-1RA had a neutral effect on this biomarker (p > 0.05; Table). GLP-1RA, SGLT-2i and their combination showed a greater reduction of NT-proBNP (-43.1% vs. -54.2% vs. -56.9% vs. -14.7%; Figure) and GDF-15 (-14.8% vs. -15.2% vs. -16.1% vs. -0.9%) than insulin (p < 0.05 for all comparisons), despite the fact that all patient achieved adequate glycemic control. GLP-1RA or GLP-1RA+SGLT-2i provided a remarkable reduction of TBARS and increase of GLS and GWI compared to insulin or SGLT-2i (p < 0.05). In all patients, at 4 and at 12 months, the percentage reduction of NT-proBNP was associated with the improvement of TBARS, GLS and GWI (p < 0.05). The percentage reduction of GDF-15 was correlated with the increase of ABTS and with the improvement of GLS at 4 and 12 months (p < 0.05). In SGLT-2i group, the percentage increase of MOTS-c was related with the percentage reduction of GDF-15 (r = 0.81, p = 0.005) at 12 months. Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cardiac biomarkers in parallel with a greater decrease of oxidative stress than insulin in T2DM. SGLT-2i appears more effective in the improvement of MOTS-c and markers of neurohumoral activation.TableFigure

Effect of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on carotid intima-media thickness

Abstract Background/Introduction Type 2 diabetes mellitus (T2DM) is an additional factor for exacerbation of atherosclerosis increasing the risk for ischemic attacks such as coronary artery disease and ischemic stroke. Evaluation of carotid artery atherosclerosis through ultrasound techniques is a useful tool for risk stratification in type 2 diabetic patients. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on carotid intima-media thickness (cIMT) of T2DM patients. Methods A total of 320 T2DM patients were randomized to receive insulin (n = 80), liraglutide (n = 80), empagliflozin (n = 80) or their combination (GLP-1RA+SGLT-2i) (n = 80) as add-on to metformin. At baseline, at 6 and at 12 months of treatment, we measured the maximal thickness of six major points including right and left common carotid, carotid bifurcation and internal carotids. Finally, we calculated the average cIMT of all six segments (three on each side) to get mean cIMT. Results Compared to baseline, all patients had significantly reduced cIMT at 6 and at 12 months of treatment (p < 0.001; Table). A significant interaction of follow-up time with the type of treatment was observed regarding cIMT levels (F = 7.203, p for interaction < 0.001) in a model including age, sex, smoking, baseline body mass index, glucose levels, glycosylated hemoglobin, levels of blood lipids and their changes at 6 and 12 months of treatment as covariates. At 6 months, patients who were treated with GLP-1RA, SGLT-2i and those under the combination GLP-1RA+SGLT-2i showed a greater reduction of cIMT (-2.5%, -2.4% and -5.8%) compared to insulin (-0.8%; p = 0.008, p = 0.022, and p < 0.001, respectively). Moreover, at 12 months patients under GLP-1RA, SGLT-2i and their combination achieved remarkable reduction of cIMT (-7.4%, -4.9% and -10%) than those under insulin (-1.7%, p < 0.001 for all comparisons). Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cIMT in T2DM. The combined treatment was superior and additive to each regimen separately.Table

Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists and cancer mortality. A real-world registry

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, nevertheless, their association with cancer remains unclear. Purpose We aim to compare the combined treatment (SGLT2i and GLP1ra) with monotherapy regarding hospitalization or/and death for cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). Methods Retrospective observational study of patients who were prescribed SGLT2i, GLP1ra, or both drugs. Multinomial propensity score was performed in all the population and in a subgroup of patients with CVD (atrial fibrillation [AF], heart failure [HF], coronary artery disease [CAD], peripheral arterial disease [PAD], or cerebrovascular accident [CVA]). The following variables were included to adjust the three groups: Sex, Age, Obesity, diabetes mellitus (DM), high blood pressure (HBP), dyslipidemia (DLP), CAD, HF, AF, and CVA. The three primary outcomes were (i) hospitalization for any cancer, (ii) death for any cancer, and (iii) the combined event in the included population and the subgroup of patients with CVD. The multivariate Cox regression analysis determined the hazard rate (HR) of age, sex, risk factors, and treatment for each outcome. Results We included 14709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from the treatment initiation. The subgroup with CVD included 4957 (33.7%) patients (Fig 1). After 33 months of median follow-up, the incidence of cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). Sex (male) and age were the main risk factors for the 3 outcomes in both groups. Combined treatment and its duration had a protector role for cancer mortality regarding monotherapy with SGLT2i or GLP1ra in all population (HR [95%CI]) 0.2216 [0.106-0.459]; p<0.001 or 0.1928 [0.071-0.519]; p=0.001, respectively) (Fig 2a) and in the subgroup of patients with CVD (HR [95%CI]) 0.279 [0.078-0.994]; p<0.049 or 0.129 [0.024-0.668]; p=0.014, respectively) (Fig 2b), but these results were not found for the outcome of hospitalization for cancer. The combined therapy concerning SGLT2i and duration of treatment showed a protective role against the combined event (HR [95%CI]) 0.709 [0.521-0.967]; p=0.029) and (HR [95%CI]) 0.991 [0.983-0.999]; p=0.032) in the general population but not in the group of CVD. A higher survival rate for any cancer mortality was observed in those patients with the combined therapy respect to monotherapy (SGLT2i or GLP1ra) in the general population (Fig 2c) and the subgroup of patients with CVD (Fig 2d). Conclusions Initiation of combined therapy vs. monotherapy was associated with a lower rate of cancer mortality in the general population and patients with CVD. Future clinical trials and mechanistic studies will clarify the possible role of these drugs on carcinogenesis.Figure 1Figure 2

Effects of sodium-glucose contrasporter-2 inhibitors and glucagon-like peptide-1 receptor agonists on arterial stiffness, coronary flow reserve and liver steatosis in diabetes

Abstract Background Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) present an increased risk of cardiovascular disease. Sodium-glucose contrasporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to significantly decrease the risk of cardiovascular complications. Purpose The aim of the study was to investigate the effect of treatment with SGLT-2i or GLP-1RA on cardiovascular function and liver steatosis and fibrosis in patients with T2DM and NAFLD. Methods Forty patients with T2DM and NAFLD (mean age: 58 ± 11 years) were randomized to receive SGLT-2i (dapagliflozin; n = 20) or GLP-1RA (dulaglutide; n = 20). At baseline and after 6 and 12 months of treatment, we measured: (1) perfused boundary region (PBR) of the sublingual microvessels with a diameter 5-25μm using Sidestream Dark Field camera (Microscan, Glycocheck). Increased PBR indicates reduced glycocalyx thickness. (2) Pulse wave velocity (PWV) using Complior (ALAM Medical), (3) coronary flow reserve (CFR) using Doppler echocardiography, (4) LV global longitudinal strain (GLS) using speckle-tracking echocardiography, (5) controlled attenuation parameter (CAP) score to assess steatosis grade and liver stiffness (E) to evaluate fibrosis score using liver elastography (FibroScan, Echosens), and (6) NAFLD fibrosis score (NFS). Results At baseline, patients between the two groups had similar age, sex, HbA1c, steatosis grade, fibrosis score and markers of cardiovascular function (p > 0.05). Compared with baseline, all patients had reduced PBR, PWV, CAP, E and NFS and increased CFR and GLS (p < 0.01) after 12-month treatment. In the whole study population, the percentage reduction of CAP and NFS was correlated with the corresponding decrease of PBR (r = 0.248 and r = 0.387), PWV (r = 0.290 and r = 0.281) and with the increase of GLS (r = -0.320 and r = -0.295) after 12-month treatment (p < 0.05 for all correlations). Both treatments with SGLT-2i and GLP-1RA reduced markers of liver steatosis and fibrosis (Table). Conclusion Both treatments with SGLT-2i and GLP-1RA improve cardiovascular function and reduce liver steatosis in patients with T2DM and NAFLD after 12 months.

Glucose lowering drugs with proven cardiovascular benefit following acute coronary syndrome in type 2 diabetes: treatment gaps and outcomes

Abstract Background and Aims Real-world data on the implementation and prognostic impact of glucose-lowering drugs with proven cardiovascular benefits in patients with type 2 diabetes (T2D) following acute coronary syndromes (ACS) is limited. We investigated the utilization and treatment patterns of sodium-glucose contrasporter-2 inhibitors (SGLT2I) and glucagon-like peptide-1 receptor-agonists (GLP1RA) in T2D patients experiencing ACS, and analyzed their association with mortality and major adverse cardiovascular events (MACE) including recurrent ACS, acute revascularization, heart failure or ischemic stroke. Methods Retrospective analysis of 9,756 patients with T2D from a nationwide healthcare organization hospitalized with ACS between 01/2019 and 01/2022. Drug prescriptions were estimated pre-hospitalization, 90-days and 1-year following hospitalization. The association between SGLT2I and/or GLP1RA treatment with MACE and mortality was investigated using time-dependent Cox regression analysis with multivariable adjustment. Results Prescription rates (prehospitalization, 90-days and 1-year posthospitalization) of GLP1RA were 13%, 13.2%, and 18%, and of SGLT2I were 23.9%, 33.6% and 42.7%, respectively. At 1-year, 13.9% prescribed both therapeutic groups. The use of SGLT2I and/or GLP1RA was higher in younger age-groups, and increased from 2019 to 2021 (38.1% to 59.2%). The adjusted hazard ratio for the association of pre- or post-hospitalization SGLT2I and/or GLP1RA treatment with mortality and MACE was 0.724 (0.654-0.801) and 0.974 (0.909-1.043), respectively. Conclusions In real-world practice of patients with T2D experiencing ACS, implementation of SGLT2I and particularly GLP1RA was suboptimal, both early and 1-year following hospitalization, emphasizing the need to improve medical care. Treatment with SGLT2I and/or GLP1RA was associated with favorable impact on mortality but not MACE.Graphical Abstract

The Rise in Glucagon-Like Peptide-1 Receptor Agonist Related Calls to United States Poison Centers

Abstract Background In 2005, the United States (U.S.) Food and Drug Administration (FDA) approved the first Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) as adjunctive therapy to improve glycemic control in type 2 diabetes. In 2021, the FDA approved semaglutide for chronic weight management. We aim to characterize GLP-1RAs related calls to all U.S poison centers (PCs). Methods We conducted a retrospective review of the U.S. National Poison Data System (NPDS) between 2005 and 2023 for all GLP-1RA exposures. All 55 PCs covering the entire U.S. population submit, in near real-time, de-identified case data to NPDS after providing poison exposure management to callers from the general public and health care providers. Results During the study period, U.S. PCs handled 13,692 GLP-1RAs related calls, of which 12,451 were a GLP-1RA single substance exposures. In 2023, PCs received 4,414 GLP-1RA related calls, compared to 234 in 2014 (a twenty-fold increase over 10 years). Seventy three percent of exposures involved females (n = 10,017). The main reasons for exposure were therapeutic errors (n = 10,213; 75%), adverse drug reactions (n = 1,222; 9%) and suspected suicide (n = 557; 4%). Gastrointestinal symptoms, such as nausea (n = 2,913; 23%), vomiting (n = 2,515; 20%), and abdominal pain (n = 593; 5%), and neurological symptoms, including central nervous system depression (n = 191; 1.5%), dizziness (n = 563; 5%) and headache (n = 495; 4%) were the most commonly reported clinical effects in single substance exposures. Hypoglycemia was reported in 431 cases (3.5%), Most single substance exposures were managed outside a healthcare facility (n = 8.573; 69%), and hospital admission was reported in 5% of exposures (n = 601). Conclusions PCs are well positioned to monitor trends in GLP-1RAs human exposures and associated adverse events and therapeutic errors. Based on available data, PCs can manage specific cases-types without referral to the hospital, preventing unnecessary healthcare utilization. Key messages • Poison centers are well positioned to monitor trends in GLP-1RAs adverse events. • Poison centers can prevent unnecessary healthcare utilization.

The effect of Glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in type 2 diabetes mellitus patients with coronary artery disease

Abstract Background Cardiovascular disease is the primary cause of mortality in patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCT) have shown that Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve cardiovascular outcomes in T2DM patients, with greater therapeutic benefits observed in patients with established atherosclerotic cardiovascular disease. However, the effect of GLP1-RA therapy on cardiovascular outcomes has been inconsistent and the RCT have not been sufficiently powered to examine the effect of GLP1-RA on mortality or their therapeutic effect in different subgroups of T2DM patients. Purpose This study aimed to examine the effect of GLP1-RA therapy on cardiovascular outcomes and mortality in a real-world cohort of T2DM patients with coronary artery disease (CAD). Methods This study included T2DM patients with CAD who were treated with metformin at a daily dose of ≥ 1g for a period of ≥ 180 days. CAD was defined as ≥ 50% luminal stenosis in any coronary artery segment according to a nationwide angiography and angioplasty registry. We performed sequential emulated target trials at monthly intervals between January 1, 2013 and December 31, 2020 to examine the effect of GLP1-RA therapy on major adverse cardiovascular outcomes (MACE), a composite of myocardial infarction, ischemic stroke and all-cause mortality. Secondary outcomes included the individual components of MACE. Marginal structural models were used to compute pooled effect estimates. This was an intention-to-treat analysis with 5 years of follow-up for each emulated target trial. Inverse probability of treatment weighting was used to adjust for confounding due to differences in patient demographics at baseline. Results This study consisted of 26,746 individuals who were treated with GLP1-RA and 74,638 controls. The 5-year cumulative risk of MACE was 27.7 % in the GLP1-RA group and 32.7 % in the control group (risk ratio 0.85 [95% confidence interval 0.82 – 0.88]). GLP1-RA therapy was associated with a lower risk of all-cause mortality (risk ratio 0.76 [95% confidence interval 0.72 – 0.79]) and myocardial infarction (risk ratio 0.95 [95% confidence interval 0.89 – 1.00]). We found little or no effect of GLP1-RA therapy on the risk of ischemic stroke (risk ratio 1.13 [95% confidence interval 0.97 – 1.27]). Conclusions In this large real-world cohort of T2DM patients with established CAD, we observed that GLP1-RA therapy was associated with a lower risk of MACE, myocardial infarction and all-cause mortality.

Use of new antidiabetic drugs in patients with cardiovascular diseases - real life data

Abstract Introduction and aim Cardiovascular diseases (CVD) are among the most common and significant complications of type 2 diabetes mellitus (T2DM). Despite significant therapeutic progress in the prevention of CVD, T2DM remains a leading cause of major adverse cardiac events (MACE). Patients with T2DM and clinical manifestations of atherosclerotic CVD, or those at high risk of developing it, should receive cardioprotective and nephroprotective medications such as GLP-1 receptor agonists (GLP-1) and SGLT-2 inhibitors (SGLT2). This study aims to determine to what extent patients undergoing treatment at the general practitioner (GP) level comply with the recommendations. Methodology Retrospectively, in the period January 2022 to September 2023, records in the EHR were reviewed in the five GP offices. For all patients ( ≥18 years) with DMT2, all demografic as well as data on chronic therapy, stage of chronic kidney disease (CKD), presence of any cardiovascular (CV) risk factors and/or history of cardiovascular diseases (CVD), and the therapy applied were observed. Results A total of 6,941 patients' data were reviewed, out of which 483 (6.96%) had a diagnosis of DMT2. Table 1. shows the characteristics of the study population. Table 2. presents the values of HbA1c according to the criteria of good, acceptable, and poor DMT2 control, as well as the CKD stage by eGFR. Among the associated comorbidities, the most common was arterial hypertension, observed in 79.5% of the participants, followed by obesity in 28.2%. In terms of the applied therapy, the majority of participants were on metformin (76.8%). There were no significant differences in body mass index (BMI) and glycemic control between the group with and without CVD. However, compared to the group without CVD, patients with both DMT2 and CVD had a higher frequency of SGLT2 inhibitors (27% vs. 18.5%) [chi²=4.336, df=1, p=0.032] and GLP-1 receptor agonists (10.7% vs. 4.6%) [chi²=6.336, df=1, p=0.012] use, but a lower frequency of metformin (67.9% vs. 81.2%) [chi²=10.510, df=1, p=0.001]. Discussion According to current guidelines, all patients with CVD and CKD should have SGLT2 inhibitors and/or GLP-1 receptor agonists in their therapy. Comparing our study with the CAPTURE study, our patients were older and had slightly fewer associated CVD (38.7% vs. 32.9%). According to the CAPTURE study, less than 25% of patients with DMT2 in therapy have an antidiabetic medication with proven cardiovascular benefit, while in our sample, this was the case for 31.4% of the participants. This suggests that progress is being made, but it is still insufficient. Conclusion Over the past decade, there has been a rapid increase in knowledge regarding the appropriate treatment and management of risk factors in the population of individuals with DMT2. Although new insights are continuously incorporated into guidelines, our study shows that implementation in practice lags.

Identification and optimisation of a risk stratified cohort of patients with type 2 diabetes through the delivery of a enhanced pharmacist-led service

Abstract Introduction Cardio-renal metabolic (CRM) diseases are each associated with significant morbidity and mortality, and due to their shared pathology, the benefit of managing these diseases holistically is becoming increasingly evident. The East Belfast Federation practices have sought to review patients living with type 2 diabetes (T2D), prioritising those not meeting their 3 Treatment Targets (3TT, HbA1c, blood pressure [BP] and cholesterol) to optimise treatment through a pharmacist-led model of care. Aims and Objectives 1. Improve adherence to latest update of NICE T2D [NG28, 2022], with a focus on patients with Cardiovascular Disease (CVD) & Chronic Kidney Disease (CKD). 2. Upskill diabetes teams, to create a legacy effect and ensure improved holistic management will continue beyond the project period. 3. Use a clinical audit tool to identify, stratify and optimise T2D patients not meeting their 3TTs. 4. Improve identification, coding and recall of patients with non-diabetic hyperglycaemia (NDH) as per QOF Indicator NDH001NI [QOF 2022/23]. 5. Enhanced focus on review of sulphonylureas (SU) in relation to frailty and risk of hypoglycaemia [Strain, 2021]. Method Patients not meeting their 3TTs (HbA1c>58 mmol/mol, BP>140/80mmHg, total cholesterol>5mmol/L) were identified from October 2022 to July 2023. Primary care based clinics created which we tailored to the specific needs of the practices with a focus on optimising patients with CVD & CKD co-morbidities. Dedicated specialist education and clinical support was provided to existing diabetes teams in CRM patient management. Additional searches were created and patients identified to review patients experiencing NDH and on a SU. Results At 9 months from baseline, there was a statistically significant improvement of 8.9% in patients achieving all 3TTs (n=373, P=0.013). This was accompanied by an increase in the number of patients optimised for CV risk reduction, with a 39% and 42% increase in patient receiving sodium glucose co-transporter-2 (SGLT2) inhibitors (n=542) and Glucagon-like peptide-1 receptor agonists (GLP1RA) (n=190), respectively. A 5.5% (n=28) reduction in the number of patients on a SU was observed, as well as a 44% (n=76) increase in the number of referrals into the Diabetes Prevention Programme (DPP). 151 statins and 51 BP medications were started/optimised. Discussion and Conclusion The project further exemplifies the feasibility of a pharmacist-led T2D service in a primary care setting. In addition to improvement in established T2D markers, the role promoted collaboration and facilitated best-practice sharing across multiple diabetes teams. This approach allows for more co-ordinated care for patients who may otherwise be referred to multiple specialists, which often results in fragmented care. Future work should focus on promoting CRM protection as early as possible to reduce disease progression and improve outcomes.Number of patients on antidiabetic meds% attainment of 3TT

A real-world data analysis investigating the cardioprotective effects of glucagon-like peptide-1 receptor agonists among people with type 2 diabetes in England

Abstract Background Cardiovascular disease (CVD) is a common and major complication of type 2 diabetes (T2D). Anti-diabetic therapy aims to lower blood glucose, with primary clinical trial endpoints for new antidiabetic entrants focused on HbA1c. Research suggests some glucose-lowering drugs, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), can have a cardioprotective effect in people with T2D.1,2 Purpose To compare the real-world risk of major adverse cardiovascular event (MACE) in people with T2D treated with GLP-1 RAs compared to dipeptidyl peptidase-4 (DPP-4) inhibitors or basal insulin. Methods We conducted a retrospective cohort study using linked primary care data from the Clinical Practice Research Datalink Aurum, secondary care Hospital Episode Statistics and Office for National Statistics death registrations. We included patients aged ≥18 years with T2D at high-risk or very-high-risk of CVD (as defined by the European Society of Cardiology) who had ≥2 prescriptions of either GLP-1 RA (dulaglutide, liraglutide, and semaglutide), DPP-4 inhibitor (as part of line 4 therapy) or basal insulin from 01/01/2014-31/12/2018. We excluded those pregnant at therapy initiation or with type 1 diabetes. Follow-up started at second prescription of relevant therapy and ended at the earliest of two years later, pregnancy, death, end of primary care record, or 31/12/2019. We used data from patients’ medical histories to define baseline characteristics. We calculated the incidence of MACE per 100,000 person-years (PY), defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. We used Cox proportional hazards regression, using LASSO to select confounding clinical variables including BMI, prior MACE and intercurrent antidiabetic treatments, to estimate risk difference of MACE among those treated with 1) GLP1-RA and DPP-4 inhibitor and 2) GLP1-RA and basal insulin. Results We included 63,237 patients, among whom the patients treated with GLP1-RA were younger and a higher proportion were obese or severely obese than those treated with DPP-4 inhibitor or basal insulin (Table 1). The incidence of MACE was highest in those treated with DPP-4 inhibitor (high-risk 1,503.0/100,000 PY; very-high-risk 6,000.7/100,000 PY) followed by basal insulin (high-risk 1,396.9/100,000 PY; very-high-risk 5,707.1/100,000 PY), and lowest in those treated with GLP1-RA (high-risk 377.1/100,000 PY; very-high-risk 1,946.1/100,000 PY). After adjustment, the risk of MACE among patients treated with GLP1-RA was still significantly lower than those treated with either DPP-4 inhibitor (high-risk aHR: 0.42, 95% CI 0.21-0.86 and very-high-risk aHR: 0.65, 95% CI 0.58-0.73) or those treated with basal insulin (high-risk aHR: 0.36, 95% CI 0.18-0.72 and very-high-risk aHR: 0.72, 95% CI 0.64-0.81). Conclusion(s) Our study supports clinical trial and other observational research studies which find a cardioprotective effect of GLP-1 RA use in people with T2D.

Semaglutide and atrial fibrillation: a systematic review and meta-analysis of randomized clinical trials

Abstract Introduction Semaglutide is a glucagon-like peptide-1 receptor agonist that has been highly recommended for glycemic controland weight reduction. Obesity can also increase the risk of developing atrial fibrillation (AF). Aims To assess the association of semaglutide with cardiac arrhythmias, primarily AF. Methods We performed a systematic searched Pubmed, Embase and Cochrane database, between November and December 2023, to identify semaglutide’s randomized controlled trials (RCTs) with or without diabetic patients that reported new-onset cardiac arrythmias. A Mantel-Haenszel method and a random-effects model was used to calculate the odds ratio (OR) and 95% confidence interval (CI). Results 16 RCTs were included, 6 with oral semaglutide and 11 with subcutaneous semaglutide. A total of 19892 patients were included, providing 137 new-onset AF. Our meta-analysis revealed a lower incidence of new-onset AF in semaglutide patients (pooled odds ratio [OR], 0.54; 95% confidence interval [CI] 0.39, 0.77, P < 0.01; I2 = 0%). Sub-analysis of oral and subcutaneous showed similar significant reduction (pooled OR 0.44; 95% CI [0.22, 0.87], P = 0.02, I2 = 0% and pooled OR 0.59; 95% CI [0.39, 0.88], P < 0.01, I2 = 0%, respectively). Significant reduction was also observed, regardless diabetic status. However, semaglutide revealed similar atrial flutter incidence (pooled OR 0.78; 95% CI [0.30, 2.05], P = 0.62, I2 = 0%), ventricular arrhythmias (pooled OR 1.68; 95% CI [0.77, 3.6], P = 0.19, I2 = 0%) and sudden cardiac death (pooled OR 1.68; 95% CI [0.77, 3.66], P = 0.19, I2 = 0%). Conclusion Our study suggests that in patients with or without diabetes, semaglutide reduces the risk of new-onset atrial fibrillation. This analysis provides an additionalcardiovascular benefit of this drug besides the major adverse cardiovascular events.

Semaglutide modulates adipogenic differentiation and extracellular acidification in epicardial (EAT) and subcutaneous (SAT) adipose tissue stromal cells from patients with cardiovascular disease

Abstract Backround Cardiovascular disease (CVD) is the main cause of death in the world. One of the known risk factors is the epicardial fat (EAT) accumulation, which is around the myocardium and coronaries playing a paracrine role over them. Although mature and functional adipocytes are involved in energy balance and glucose metabolism, the hypertrophic state increases the production of fatty acid binding protein 4 (FABP4), which is a pro-inflammatory adipokine, with consequences on extracellular acidification. Recent data shows that glucagon-like peptide receptor agonists 1 (GLP1ra) drug improves the insulin response and reduces EAT thickness. Although GLP1ra has a direct effect on hypothalamus for reducing food intake, this drug might play a direct role on adipogenesis process in this fat stromal cells. Purpose Our study aims to demonstrate the effect of semaglutide on adipogenesis and metabolism in epicardial and subcutaneous stromal cells from patients with cardiovascular disease. Methods The study was approved by the Galician Research Ethics Committee, and subcutaneous adipose tissue (SAT) and EAT samples from 17 patients were obtained undergoing open-heart surgery with informed consent. Stromal cells from biopsies were isolated and cultured. Adipogenesis was induced for 15 days with or without 1 nM semaglutide, given by Novo-Nordisk (Bagsværd, Denmark), using an adipogenesis cocktail. Cells were lysed and RNA was isolated for RT-qPCR. Target genes were amplified for Glucagon like peptide 1- receptor (GLP1R), differentiation, adipogenesis, glucose metabolism and cellular markers. Extracellular acidification rate was measured with glycolytic rate assay on Seahorse. Lipids accumulation was tested by AdipoRed staining. Results Stromal cells from both tissues express GLP1R but higher differentiation factor (PGC1α) was detected in SAT compared to EAT (p=0.02), as well as adipogenesis induction. After semaglutide treatment, we observed a downregulation of FABP4 and GLUT1 in EAT (p=0.01 and p=0.02, respectively). Despite FABP4 was not modulated on SAT, there was a reduction of PGC1α levels. (p=0.02). Since glitazones upregulate PGC1α, which is used for adipogenesis induction, these results might suggest the counteract mechanism of semaglutide. The metabolism assay showed that semaglutide reduces extracellular acidification rate in EAT cells (p=0.04) and oxidative glycolysis with semaglutide treatment (p=0.003) but not in SAT cells. Conclusions Semaglutide reduces adipogenesis, through modulation of PGC1α transcription factor in EAT from patients with cardiovascular disease and extracellular acidification and oxidative glycolysis. These results might help to understand one of the mechanisms associated with EAT reduction in patients with semaglutide treatment.

Association of metabolic phenotypes with cardiovascular events in primary and secondary prevention

Abstract Background Metabolic disorders are established risk factors for the development of coronary artery disease (CAD) and major adverse cardiovascular events (MACE). Although obesity is strongly related with the metabolic health status, its role as a cardiovascular risk modifier in the absence of metabolic disorders remains controversial. Recent implementation of nutrient-stimulated hormone-based therapies (NUSH) including glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obesity even in metabolically healthy individuals requires further understanding to ensure optimal patient management. Purpose The aim of this study is to investigate the association of metabolic phenotypes with cardiovascular events in primary and secondary prevention of CAD. Methods We included patients over 18 years electively evaluated for CAD by invasive coronary angiography (ICA) between 2010 and 2021 in our tertiary referral centre in one of Europe’s largest university hospitals. Metabolic disorder was considered as the presence of diabetes, irrespective of additional risk factors, or hypertension and hyperlipidaemia, and obesity as a BMI of ≥30 kg/m², distinguishing four metabolic phenotypes: metabolically healthy/unhealthy nonobese/obese (MHN, MHO, MUN, MUO). The primary study endpoint MACE was defined as a composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and hospitalization for heart failure. Results The total study population included 12 760 patients (68 [58-76] years; 57.3% male), of whom 56.5% presented metabolically healthy (43.3% MHN; 13.1% MHO) and 43.5% unhealthy (28.3% MUN; 15.2% MUO). During a median follow up time of 3.91 (1.75-7.09) years, 2 592 (20.3%) MACE and 3 351 (26.3%) all-cause deaths occurred. Cox regression analysis adjusted for age, sex, and chronic kidney disease (CKD) showed different risk patterns for distinct metabolic phenotypes (Table 1). While we observed higher event rates in metabolically unhealthy compared to healthy individuals, obesity alone was not associated with increased events (Figure 1). However, metabolically healthy individuals experienced lower event rates with increasing BMI. Among patients without or with nonobstructive CAD, metabolic disease was strongly associated with increased subsequent coronary revascularization regardless of BMI. These patterns were similar across all endpoints irrespective of presence of obstructive or nonobstructive CAD. Conclusions Whereas metabolic disorders are strongly associated with adverse clinical events, obesity alone does not reflect the cardiovascular risk profile in patients with or without obstructive CAD. Thus, focusing on obesity alone for primary or secondary prevention appears unjustified. Particularly after the recent implementation of GLP-1 receptor agonists for the treatment of obesity, precise and individual risk stratification is essential to allow for an optimal personalized patient management.Figure 1Table 1

Comparison of cardiovascular outcomes in patients with diabetes treated with tirzepatide versus semaglutide: a multi-institutional analysis

Abstract Introduction Glucagon-like-peptide-1 (GLP-1) receptor agonists have been demonstrated to have cardiovascular benefits in patients with diabetes. Two of the most prescribed medications in this class are tirzepatide and semaglutide. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist. Tirzepatide and semaglutide have previously been directly compared to assess efficacy in glycemic control as the primary endpoint. However, there is limited data directly comparing cardiovascular outcomes between the two medications in patients with diabetes. This retrospective cohort study compares the incidence of major adverse cardiovascular events (MACE) in patients with diabetes treated with tirzepatide or semaglutide. Purpose The purpose of this study is to identify differences in cardiovascular outcomes between patients with diabetes treated with tirzepatide as compared to semaglutide. Materials and Methods The TriNetX research network was used for this study. Two patient cohorts were generated using International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts of patients had a history of diabetes (E08-E13) and no prior history of cerebral vascular accident (I63) or myocardial infarction (I21). One cohort received semaglutide and the other tirzepatide. Each cohort was prohibited from receiving the other agent. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm resulting in 36,212 patients in each arm. They were then evaluated for the 3-year outcomes of major adverse cardiovascular events (myocardial infarction, cerebral vascular accident, and death). Results Tirzepatide was associated with statistically significantly fewer MACE outcomes compared to semaglutide for each of the individual endpoints as well as the overall composite endpoint over the 3 year follow up period. Table 1. MACE events for semaglutide and tirzepatide. Table 2. Relative risks for semaglutide MACE endpoints compared to tirzepatide. Conclusions In this retrospective cohort study, tirzepatide was associated with a lower incidence of major adverse cardiovascular events compared to semaglutide in patients with diabetes. These findings suggest that tirzepatide offers superior cardiovascular protection for primary prevention compared to semaglutide and warrant further investigation in future studies and clinical trials.Table 1Table 2

Semaglutide modulates pro-inflammatory neutrophil phenotype induced by supraphysiological levels of the adipokine FABP4 in patients with cardiovascular disease

Abstract Background Increased adiposity is a risk factor for cardiovascular disease (CVD). Adipose tissue is an endocrine organ that releases proteins with pro-inflammatory effects. One of them is FABP4, which levels are increased after adipogenesis. Insulin resistance is linked to supraphysiological levels of this biomarker. Therapies to reduce body weight and improve insulin response, such as the GLP-1 receptor agonists, like semaglutide, have been shown to benefit patients with CVD and obesity, who have a high pro-inflammatory neutrophil profile. Purpose To study the FABP4 effects on neutrophils from patients with cardiovascular disease and cellular models and its possible modulation by semaglutide. Methods We included 11 patients undergoing open heart surgery. Neutrophils from blood were isolated by single-step centrifugation, counted, and same number were treated with FABP4 (100 ng/mL), semaglutide (1nM) or both. Finally, their phenotype was assessed using flow cytometry (FACS). The same treatment conditions were used on differentiated HL-60 cells (dHL-60) to test their phenotype and functionality based on a) oxidative burst capacity using dihydrorhodamine 123 and b) adhesion to coronary artery endothelial cells. At the end, neutrophils phenotype was tested on patients with obesity and diabetes under semaglutide treatment for 6 months, according to clinical practice. Neutrophils phenotype was determined by FACS and FABP4/C5a plasma levels by immunofluorescence assay. Results FABP4 reduced neutrophils’ CD88 (p=0.006) and CXCR2 (p=0.02) levels. This was also verified in dHL60 cells (p=0.01). In these cells, we were also able to observe a CD11b increment after FABP4 treatment (p=0.04), modulated by semaglutide (p=0.02). This phenotype increased the neutrophil-coronary adhesion (p=0.03). Their oxidative burst capacity was attenuated after semaglutide treatment. In addition, 32% of patients underwent semaglutide treatment reduced plasmatic FABP4 (p=0.03) levels and increased CD88 (p=0.01). We confirmed that CD88 modulation does not lead to a change in plasma C5a. Conclusions High FABP4 levels reduce CD88 of neutrophils from patients with cardiovascular disease and enhance their adhesion to coronary endothelial cells. Modulation of the FABP4 effects by semaglutide treatment might suggest a protective mechanism against adiposity/coronary endothelial inflammation.

Cardiovascular prevention with GLP1 agonists in high or very-high cardiovascular risk irrespective of diabetes

Abstract Introduction Patients with established cardiovascular disease have an increased risk of stroke and myocardial infarction, even in the absence of atrial fibrillation. Several trials have analyzed the effect of glucagon-like peptide-1 receptor (GLP1) agonists in patients with high cardiovascular risk and lately this effect has been studied even in the absence of diabetes. Methods A meta-analysis of randomized clinical trials (RCT) comparing GLP1 agonists with placebo was performed. The primary objective of the study was to analyze the composite endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (MACE). As secondary objectives, cardiovascular death, non-fatal myocardial infarction and non-fatal stroke have been studied separately. The meta-analysis was performed using the inverse variance method, using the fixed effects model when there was no heterogeneity and the random effects model when heterogeneity is significant. In the case of significant heterogeneity in the primary objective, a stratified analysis with exposure time have been performed to explain this outcome. Results A sum of 9 randomized controlled trials were included where a GLP1 agonist such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide was compared with placebo. 77684 patients were incorporated, while 39497 were treated with a GLP1 agonist. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) suffered from diabetes and 60552 (77.9%) from cardiovascular disease. As showed in figure 1, the GLP1 agonists showed a reduction of 13% of the MACE (RR: 0.87, 95% CI 0.81-0.92; p<0.001). Heterogeneity could be explained by exposure time and concentration in the blood, considering that it disappears within each group when applying this condition. Treatment with GLP1 agonist also reduced cardiovascular death by 12% (RR: 0.88, 95% CI 0.82-0.94; p<0.001), non-fatal strokes by 14% (RR: 0.86, 95%CI 0.79-0.95; p<0.001) and non-fatal miocardial infarction by 13% (RR: 0.87, 95% CI 0.78-0.97; p<0.001). Conclusion Treatment with a GLP1 agonist reduced the incidence of the MACE by 13% and cardiovascular death by 12%, as well as it decreased the incidence of nonfatal stroke by 14% and of nonfatal myocardial infarction by 13% in different RCTs involving patients with high or very-high cardiovascular risk with or without diabetes.

Anti-inflammatory effect of semaglutide: updated systematic review and meta-analysis

Abstract Background Glucagon-like peptide-1 (GLP-1RA) receptor agonists possess multiple favourable metabolic, anti-inflammatory effects and their use is associated with marked body weight reduction. More importantly, this drug class has been shown to reduce cardiovascular events in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk or with established cardiovascular disease. Accordingly, current guidelines recommend the use of GLP-1RA sas first-line antidiabetic therapies in patients at high cardiovascular risk. Semaglutide is a potent GLP-1RA used in the treatment of T2DM with proven cardiovascular benefits. It is currently available in formulations for oral and subcutaneous administration. The anti-inflammatory effect could be one of the mechanisms by which semaglutide reduces cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and/or obesity. Determining the anti-inflammatory effect of semaglutide was the objective of this systematic review and meta-analysis. Methods This meta-analysis was performed according to the PRISMA guidelines. A literature search was performed to detect randomised clinical trials that have quantified the effect of semaglutide on C-reactive protein (CRP) levels compared to placebo or a control group (other glucose-lowering drugs). The primary outcome was CRP index (final CRP/basal CRP). A random-effects model was used. Results Overall, this meta-analysis shows that semaglutide therapy was associated with lower CRP index values compared to placebo (SMD -0.56; 95% CI -0.69 to -0.43, I2 92%) or when comparing semaglutide treatment versus a control group consisting of patients medicated with other glucose-lowering drugs (SMD -0.45; 95% CI -0.68 to -0.23, I 3 82%). The stratified analysis was performed by analysing only the trials that used a placebo group as comparator, When the trials were analysed according to the different dosing schemes (subcutaneous vs. oral), the results were not statistically significantly different (oral semaglutide group: SMD -0.33; 95% CI -0.75 to 0.08, I2 95%); semaglutide subcutaneous dose group: SMD -0.69; 95% CI -0.78 to -0.60, I2 74%); interaction p = 0.098. Furthermore, when the trials were analysed according to the included populations (patients with or without T2DM), the results were similar (patients with T2DM: SMD -0.32; 95% CI -0.51 to -0.14, I2 86%); patients without T2DM: SMD -0.82; 95% CI -0.90 to -0.74, I2 58%); interaction p = < 0.0001. Conclusion The present meta-analysis demonstrated that the use of semaglutide was associated with a reduction in inflammation irrespective of the population evaluated or the treatment regimen used. These findings would explain one of the mechanisms by which semaglutide reduces cardiovascular events.

Heart failure and renal outcomes in patient treated with GLP1 agonists

Abstract Introduction Glucagon-like peptide-1 receptor (GLP1) agonists are emerging as a primordial treatment for diabetes and to reduce cardiovascular burden, both of them factors that play an important role in the developing of renal chronic disease and heart failure, and vice versa. The debut of renal chronic disease and the manifestation of acute renal injury/failure can lead to the discontinuation of treatment, which in patients suffering from heart failure who tend to be polymedicated could end up in lessening their survival. Methods A metanalysis of randomized clinical trials (RCT) comparing GLP1 agonists with placebo was performed. The endpoint of the study was to analyze all-cause mortality, hospitalization or urgent medical visit for heart failure, a kidney outcome composite, which is slightly heterogenic depending on the RCT, and the manifestation of acute renal injury/failure as an adverse effect or that lead to the discontinuation of treatment. The meta-analysis was performed using the inverse variance method, using the fixed effects model when there was no heterogeneity and the random effects model when heterogeneity is significant. Results A sum of 9 randomized controlled trial were included where a GLP1 agonists such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide compared with placebo. 77684 patients were incorporated, while 39497 were treated with a GLP1 agonists. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) suffered from diabetes, 60552 (77.9%) from cardiovascular disease and 14367 from chronic heart failure (18.4%). The mean eGFR was 77.3 mL/min (SD ± 3.3 mL/min). As showed in the forest plots, treatment with GLP1 agonists reduced all-cause mortality by 12% (RR: 0.88, 95% CI 0.83-0.92; p<0.001), hospitalization or urgent medical visit for heart failure by 10% (RR: 0.90, 95% CI 0.83-0.98; p<0.001), the kidney composite outcome by 22% (RR: 0.78, 95% CI 0.70-0.87; p<0.001), while it showed no statistical reduction in acute renal injury/failure (RR: 0.89, 95% CI 0.79-1.01; p=0.069). Conclusion Treatment with a GLP1 agonists reduced the incidence of all-cause mortality by 12%. In addition, hospitalization or urgent medical visit for heart failure was decreased by 10%. In terms of renal asessment, the composite of kidney function was reduced by 22%, while the manifestation of acute renal injury/failure, though no statistical signification was accomplished, showed some evidence of beneficial effect but more RCTs are needed to prove it. Hence, GLP1 analogues appear as a possible new pillar of treatment for heart failure and renal disease in determined patients.

BMI shift and associated cardiometabolic risk factors in people with type 2 diabetes and obesity and/or overweight: a post hoc analysis from SURMOUNT-2

Abstract In SURMOUNT-2 (SM-2), treatment with once weekly GIP and GLP-1 receptor agonist tirzepatide (TZP) resulted in superior body weight reductions relative to placebo in people living with obesity and T2D. This post hoc analysis assessed whether participants with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2 with at least one weight-related comorbid condition) who shifted to a lower BMI category had improved cardiometabolic factors. Change in BMI category (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2, and ≥40 kg/m2) from baseline to week 72 was assessed in participants from SM-2 treated with TZP 10 or 15 mg (N=623) or placebo (PBO)(N=315). BMI shifts were grouped into "improved" (shift to lower BMI category) or "non-improved" (stable or shift to a higher BMI category). Cardiometabolic parameters examined included waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, and lipid profile. A mixed model with repeated measures was performed to estimate the mean change from baseline to week 72 for these parameters. In this post hoc analysis a total of 484 (52.1%) participants had improved BMI at week 72. For those whose BMI did not improve, most had stable BMI and only 11 (1.2%) had worsened BMI. Nine participants had no post-baseline BMI measurements and were excluded from analysis. Most participants demonstrated improved BMI with TZP treatment (N=418, 67%) vs PBO (N=66, 21%)(Table). Furthermore, 21% (N=129) of participants on TZP improved by ≥2 BMI categories compared to only 1 participant with PBO. Compared to those with non-improved BMI, participants with improved BMI demonstrated greater improvement in cardiometabolic risk factors, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, systolic and diastolic blood pressure, triglycerides, and cholesterol (non-HDL-c, and LDL-c) and increases from baseline in HDL-c (Figure). Greater improvements to cardiometabolic risk factors were seen in participants on TZP vs PBO. Shifts to lower BMI categories were greater among TZP-treated people living with obesity or overweight and T2D in SM-2 and were associated with improved cardiometabolic risk factors, in this post hoc analysis. SURMOUNT-mortality and morbidity and cardiovascular outcome trials are ongoing to examine the impact of TZP treatment on CVD and mortality.

The Influence of GLP1 on Body Weight and Glycemic Management in Patients with Diabetes—A Scientometric Investigation and Visualization Study

Diabetes medications can affect weight and cardiovascular health. Some medications can aid in weight management, while others may lead to weight gain. Patients must be monitored and receive appropriate care to manage weight and prevent cardiovascular complications. Despite advancements in diabetes treatments that can influence weight and cardiovascular outcomes, ongoing research is necessary in this intricate field. Long-term effects, individual variations, and combination therapies are still subjects of uncertainty and ongoing investigation. The major objective of the research is to evaluate the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on body weight in diabetic patients through a scientometric assessment. Methodology: Research data were gathered from the Web of Science Core Collection (WoSCC) database by searching for the keywords “Body Weight”, dulaglutide, and semaglutide, identifying 60 relevant articles in the field. While there are advantages in managing diseases in which the cardiovascular system is implicated, there are also clinical considerations for personalized medicine and shared decision-making. The scientometric analysis of the articles revealed important insights into how dulaglutide and semaglutide impact weight management and their potential benefits for managing cardiovascular diseases in individuals with diabetes. Conclusions: Semaglutide shows superior outcomes compared to other commercially available GLP-1RAs, particularly in improving blood sugar control, lowering body weight, and addressing other cardio-metabolic risk factors in individuals with type 2 diabetes (T2DM). The findings suggest that GLP-1 RAs have the potential to provide cardiovascular protection by influencing various physiological factors such as blood pressure, pulse rate, glycated hemoglobin (HbA1c) levels, and the urinary albumin-to-creatinine ratio (RAC). The development and validation of the 4GI model provides a sophisticated tool for evaluating the complex interactions involved in diabetes treatments, offering insights into the mechanisms of action of various medications.