GLP-1 RA Research Articles

Perioperative Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) and Gastric Point Of Care Ultrasound (POCUS)

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are frequently used for diabetes and weight loss management. The GLP-1 RA drugs delay gastric emptying and are a concern for increased risk of aspiration in the perioperative period. Current recommendations to hold these medications before surgery are consensus based. Gastric point of care ultrasound (POCUS) can provide information regarding nature and volume of gastric contents in these patients during the perioperative period. In this case series, we present three patients where gastric POCUS helped formulate a safer, alternative anesthetic plan. Anesthetic management varied depending on the situation, urgency and needs of the procedure. We recommend gastric POCUS in this group of patients to provide objective assessment of gastric contents.

Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists.

This Viewpoint discusses the health benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs); summarizes the clinical, policy, and equity implications of GLP-1 RA discontinuation; and calls for the identification and implementation of strategies to improve long-term adherence to GLP-1 RA therapy.

Abstract 4115541: Association of Glucagon-like Peptide 1 Receptor Agonist Use with Incident Atrial Fibrillation

Background: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy for reducing cardiovascular morbidity and mortality in patients with diabetes mellitus (DM), but conflicting evidence exists regarding their impact on cardiac arrhythmias. Whereas some studies suggested a possible association between GLP-1RA use and arrhythmogenesis, other studies suggested decreased association with atrial fibrillation (AF). Overall, large-scale real-world data evaluating risk of AF in association with GLP-1RAs are lacking. Objective: To compare risk of incident AF after initiation of GLP1-RA vs Dipeptidyl peptidase-4 inhibitors (DPP4i), as active comparators, in patients with DM. Methods: This retrospective propensity score-matched cohort study was conducted within the Veterans Health Administration from fiscal years 2006 to 2021. The study included U.S. veterans aged 35 years or older who initiated either GLP1-RA or DPP4i prescriptions. The primary outcome assessed was a composite outcome of atrial fibrillation (AF), defined as a diagnosis of AF/flutter based on administrative codes or undergoing an AF procedure. Results: Out of 116,235 GLP1-RA users and 217,668 DPP4i users, we propensity score-matched 80,948 pairs, on 88 characteristics, including demographics, comorbidities, vital signs, cardiovascular risk score, healthcare utilization, DM control, laboratory investigation, and medications. Composite outcome of AF was similar in GLP-1RA group (4.1%) and DPP4i group (4.3%); odds ratio (OR) 0.96, 95% confidence interval (CI) 0.92-1.01. Secondary analyses stratified by medication use duration showed no significant differences in composite AF risk (P>0.05). Notably, individuals achieving weight loss of 2%, 5%, or 10% of baseline body weight had significantly lower AF incidence, whereas no significant differences were observed in those with no weight loss or weight gain (OR 0.99, 95% CI 0.91-1.07). Conclusions: Use of GLP1-RA in patients with DM was not associated with a decreased risk of AF when compared with the use of DPP4i. In the subgroup analysis, significantly lower AF risk was seen in the GLP-1 RA group who achieved weight loss vs. DPP4i and this highlights weight loss as a potential modifier of cardiovascular outcomes in DM.

Abstract 4144520: Glucagon-like Peptide-1 Receptor Agonists for the Primary Prevention of Major Adverse Cardiac Events in Drug-naïve Type 2 Diabetes: A Propensity-score Analysis

Background: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RA) as a first-line agent for the primary prevention of major adverse cardiac events (MACE) in obese patients with diabetes mellitus (DM) is unknown. Research Question: Does initial treatment with GLP-1 RA in obese drug-naïve patients with type 2 DM prevent future MACE? Aims: To examine the association between GLP-1 RA treatment and the primary prevention of MACE in drug-naïve type 2 DM patients with obesity. Methods: A retrospective propensity score-matched (PSM) analysis was conducted using the TriNetX Global database. We implemented a new-user design, including adult overweight/obese patients with drug-naive type 2 DM between January 1 st , 2019 and May 1 st , 2023. Patients with prior heart failure (HF), myocardial infarction (MI), coronary revascularization, stroke, or cardiac arrest were excluded. We compared those starting GLP-1 RA versus starting non GLP-1 RA. Medication starting window spans from the first diagnosis to 3 months afterwards. Patients with insulin were excluded if they had any emergency or inpatient encounters during this window. The primary outcome was incident MACE, defined as any death, decompensated HF, MI, cardiac arrest, or ventricular tachycardia/fibrillation, within 5 years of initial drug dispense. Secondary outcomes were individual MACE. Gastrointestinal bleeding was set as a falsification endpoint. Results: Of 1,245,340 patients with A1c <10% and 293,072 patients with A1c ≥10%, 7,483 and 1,563 patients started on GLP-1 RA as a single agent and part of a combined approach, respectively. After PSM, baseline covariates were balanced between the two treatment groups and no significant differences were observed in the falsification endpoint by treatment arm (Figure) . Compared with non-GLP-1 RA, with the exception of sodium-glucose cotransporter-2 (SGLT2i), starting a GLP-1 RA first was associated with a significant reduction in MACCE, primarily driven by reductions in decompensated HF (Figure) . Conclusions: Initiation of a GLP-1 RA as the first agent for obese patients with drug-naïve type 2 DM was associated with a significant reduction in MACE compared to all other diabetes medications, with the exception of SGLT2i.

Abstract 4126158: Persistence to once weekly GLP-1 RAs is associated with lower risk of MI, stroke, and 2-point MACE among patients with T2D and ASCVD in the real world.

Introduction: Studies have shown the reduction of CV events in patients with T2D treated with GLP-1 RAs. However, little is known about how persistent use of GLP-1 RA therapy affects CV outcomes in patients with T2D and ASCVD. The objective of this study was to estimate the association between persistent use of once weekly (OW) GLP-1 RAs and 2-point MACE and its components (MI, stroke) in patients with T2D and ASCVD in a real-world setting. Methods: Adult patients with T2D and ASCVD with ≥1 pharmacy claim for OW GLP-1 RAs during Jan 2018-Nov 2022 were identified in the Optum Research Database. The date of the first OW GLP-1 RA claim was defined as the index date. Patients were followed until a CV event occurred or censored. Discontinuation was defined as a ≥60-day gap in supply of OW GLP-1 RAs. All patients were required to be persistent for ≥3 months of follow-up to allow titration of the therapy. CV events of interest include 2-point MACE, MI and stroke. Kaplan-Meier analyses were used to examine risk of CV events by persistent status within 6, 12, or 18 months of follow-up. Cox proportional hazards models with time-varying exposures were used to assess associations between persistent status and MACE, with persistent status of patients updated for each day of follow-up, adjusting for demographic and baseline clinical characteristics. Results: Among a total of 29516 patients, the median follow up duration was 412 days, median persistence was 254 days, and 63.9% of patients (n=18849) were persistent throughout their variable follow up period. Kaplan-Meier analyses indicated risk of 2-point MACE, MI, and stroke was significantly lower in patients who were persistent within 6, 12 or 18 months of follow-up compared to patients who discontinued within 6, 12 or 18 months of follow-up (all p<0.05); longer persistence led to a qualitatively greater risk reduction. Adjusted hazard ratio (95% confidence interval) from Cox regression with time-varying persistence status during the full variable follow up in all patients for risk of 2-point MACE, MI, and stroke associated with persistent use of OW GLP-1 RAs was 0.70 (0.63-0.77), 0.71 (0.62-0.81), and 0.67 (0.57-0.78), respectively. Conclusions: Patients with T2D and ASCVD who were persistent with OW GLP-1 RAs had a lower risk of 2-point MACE, MI, and stroke than those who discontinued the therapy in real-world clinical practice. Longer persistence of OW GLP-1 RAs appeared to provide greater CV benefits.

Abstract 4145802: Association between Glucagon-like peptide-1 receptor agonists and risk of Arrhythmias or Heart Failure among patients with Type 2 Diabetes: A Meta-Analysis of 29 Randomized Controlled Trials.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a reduction in major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM). However, their effect on reducing the risk of incidence of arrhythmias and heart failure has not been established, and there is very limited literature to date. Objective: We evaluated the effect of GLP-1 RAs on the incidence of arrhythmias and heart failure among patients with T2DM. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that enrolled patients with type 2 diabetes and compared GLP-1 RAs and control groups. PubMed and ClinicalTrials.gov were systematically searched from inspection till May 2024 without any language restrictions. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model. Results: A total of 29 RCTs with 72,868 patients (35,631 in the GLP-1 RA group and 37,237 in the control group) were included in the analysis. Pooled analysis showed that there is no significant association between GLP-1 RAs and incidence of atrial fibrillation (OR, 0.94(95%CI: 0.75-1.18), P=0.60), atrial flutter (OR, 0.87(95%CI: 0.60-1.26), P=0.46), cardiac arrest (OR, 0.79(95%CI: 0.51-1.23), P=0.30), ventricular tachycardia (OR, 1.37(95%CI: 0.90-2.07), P=0.14), and ventricular fibrillation (OR, 0.91 (95%CI: 0.45-1.84), P=0.80) when compared with control group. However, GLP-RAs reduced the incidence of atrioventricular block complete (OR, 0.58 (95%CI: 0.35-0.97), P=0.04), and heart failure (OR, 0.795 (95%CI: 0.634-0.997), P=0.047). Conclusion: This study shows that GLP-1 RAs reduced the incidence of atrioventricular block complete and incidence of heart failure. However, no significant association has been observed for arrhythmias.

Ocular adverse events associated with GLP-1 receptor agonists: a real-world study based on the FAERS database and network pharmacology

ABSTRACT Objective This study evaluates the risk of ocular adverse events (AEs) associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) using data from the FDA Adverse Event Reporting System (FAERS) and network pharmacology methods. Methods FAERS data from 2004 to 2024 were analyzed for ocular AEs linked to GLP-1 RA treatments. Disproportionality analysis (Reporting Odds Ratio, ROR) was used to identify signals, and a drug-gene interaction network explored potential mechanisms. Results Among 17,785,793 FAERS reports, semaglutide and lixisenatide were significantly associated with ocular AEs, with RORs of 1.25 (95% CI, 1.20-1.31) and 1.96 (95% CI, 1.70-2.27), respectively. Commonly reported AEs included blurred vision, visual impairment, and diabetic retinopathy, with some AEs occurring as early as 10 days after treatment initiation. Gene enrichment analysis highlighted potential links between GLP-1-related genes and ocular AEs. Conclusion The widespread use of GLP-1 RAs has raised concerns regarding their ophthalmic safety. This study contributes new evidence from real-world data, suggesting that semaglutide and lixisenatide are associated with significant risks of ocular AEs. Further experimental studies are warranted to elucidate the underlying mechanisms and confirm these associations.

Effect of GLP-1 receptor agonists on prostate cancer risk reduction: a systematic review and meta-analysis.

Prostate cancer is one of the most prevalent malignancies among men globally. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), primarily used for type 2 diabetes mellitus (T2DM) management, have been investigated for their potential effects on cancer risks. This systematic review and meta-analysis aimed to assess the association between GLP-1 RA use and risk reduction of prostate cancer. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science up to July 30, 2024. Studies that met the inclusion criteria randomized controlled trials, cohort studies, case-control studies, and observational studies assessing the incidence of prostate cancer in GLP-1 RA-treated patients were included. The quality of studies was evaluated using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool. Meta-analysis was performed using a random effects model. A total of five studies were included, analyzing data from diverse international contexts. The included studies showed a reduced risk of prostate cancer with both adjusted and unadjusted effect estimates with GLP-1 RAs. The meta-analysis revealed an RR of 0.72 (95% CI: 0.610 to 0.832), indicating a statistically significant 28% reduction in prostate cancer risk associated with GLP-1 RA use compared to placebo or other antidiabetic drugs. Moderate heterogeneity was observed (I2 = 51%). Sensitivity analysis confirmed the results. The findings suggest a significant protective association between GLP-1 RA use and reduced prostate cancer risk in men, particularly those with T2DM. This supports the potential of GLP-1 RAs not only in diabetes management but also as a strategy to mitigate cancer risk. Further research is required to confirm these findings and explore the underlying mechanisms, considering different dosages, durations of therapy, and patient subgroups based on demographic and metabolic characteristics.

Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist.

GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA. ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human β-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days. ECC5004 bound to the hGLP-1R (IC50 = 2.4 nM) augmented cAMP signalling without β-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-βH5 cells (EC50 = 5.9 nM) and in vivo in NHPs (EC50 = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg. ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity. NCT05654831.

Dosing Patterns of Dulaglutide and Semaglutide in Patients with Type2 Diabetes Mellitus in France and Italy: A Retrospective Cohort Study.

Type2 diabetes mellitus (T2DM) is a complex metabolic disease with several treatment options. Some glucagon-like peptide1 receptor agonists (GLP-1 RAs) approved by the European Medicines Agency include dulaglutide, subcutaneous (s.c.) semaglutide, and oral semaglutide. This study examines dulaglutide and semaglutide dosing patterns for T2DM in France and Italy. IQVIA Longitudinal Prescription Data identified adults with T2DM prescribed dulaglutide or semaglutide between August 1, 2020 and December 31, 2022. Cohort1 (incident) and cohort2 (prevalent) users were followed for 12months. In France and Italy, 255,571 and 350,853 patients, respectively, received at least one study GLP-1 RA. Most dulaglutide-naïve patients in France (62%) and approximately half in Italy (49%) started on 1.5mg and remained on this dose for up to 12months (France: 66% cohort1, 88% cohort2; Italy: 73% cohort1, 87% cohort2). In cohort1, s.c. semaglutide users mostly started on 0.25mg (France, 78%; Italy, 61%). At 12months, s.c. semaglutide 1.0mg was most prescribed (France: 58% cohort1, 75% cohort2; Italy: 59% cohort2), with cohort1 in Italy mostly receiving 0.5mg (57%). Most oral semaglutide users in Italy started on 3.0mg (78% cohort1; 68% cohort2), which was increased to 7.0mg (62% cohort1) and 14.0mg (48% cohort2) at 12months. GLP-1 RA dosing patterns, although similar between France and Italy, were heterogeneous over time. As oral semaglutide and higher dulaglutide doses are recent to the market, additional real-world evidence is required to evaluate utilization patterns. Graphical abstract available for this article.

Use of Glucagon-like Peptide 1 Receptor Agonist to Sustain Patients off Basal-Bolus Insulin Regimens

BackgroundThe 2024 Standards of Care in Diabetes recommend initiation of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) prior to starting basal insulin and to reconsider initiating a GLP-1 RA before starting bolus insulin if not already initiated. GLP-1 RA addition leads to improved glycemic benefits as well as risk reduction of cardiovascular and renal outcomes in patients with a history of these events. While there is evidence demonstrating the trends of insulin reduction or discontinuation following GLP-1 RA initiation, data regarding longer-term durability of GLP-1 RA use to sustain patients off bolus insulin is lacking. ObjectiveThis retrospective study aimed to assess the percentage of patients remaining off bolus insulin after transitioning from a basal-bolus regimen to GLP-1 RA therapy with basal insulin over a period of three years. MethodsWe conducted a single centered, retrospective study analyzing patient data from July 2018 through July 2023. Patients were included if they had a diagnosis of type 2 diabetes, were on a basal-bolus insulin regimen, had a GLP-1 RA initiated followed by bolus insulin discontinuation within 90 days, and remained on a GLP-1 RA for at least six months. The primary outcome was the percentage of patients who were sustained off bolus insulin after three years following GLP-1 RA initiation. ResultsThere were 252 patients included. At three years, 82.6% of patients were sustained off bolus insulin. The mean change in weight at three years was -8.5 kg. The mean A1c initially decreased from 8.6% to 7.8%, but then increased slightly to 8.1% at the end of the study timeframe. ConclusionThis trial demonstrated the majority of patients on basal-bolus regimens where bolus insulin was replaced with a GLP-1 RA were sustained off bolus insulin for a three year period of time. These results highlight the promising durability of converting bolus insulin to GLP-1 RAs.

Long-term safety and efficacy of glucagon-like peptide-1 receptor agonists in individuals with obesity and without type 2 diabetes: A global retrospective cohort study.

We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23; 95% confidence interval 0.15-0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.

COVID-19 era and GLP-1 RA era: Is it a renaissance when the dusk of global tragedy co-occurring with the dawn of magical remedy?

The hypothesis is that the world should explore to either validate or refute whether glucagon-like peptide–1 receptor agonists (GLP-1 RAs) are drawing some if not all of their all-rounder multisystem capacities in general and their weight-reducing capabilities in particular as catalyzed by natural and/or vaccine-induced immunities against SARS-CoV-2 and their variants implicated as the causative agents for onset and evolution of COVID-19 pandemic globally. The simplest initial exploration could be healthcare systems running queries in their historical databases to assess whether patients who have been receiving GLP-1 RAs since before the pandemic are reporting significantly larger weight-loss since after the pandemic, and if it is so, then whether those significant results could be validated with laboratory and basic research to demonstrate antibodies against SARS-CoV-2 acting as catalysts for larger weight-loss with GLP-1 RAs.

Persistence and Adherence to GLP-1 RA treatment in Type 2 Diabetes Mellitus: a Nationwide registry study

Abstract Background The use of glucagon-like peptide-1 receptor agonsists (GLP-1 RA) continues to rise and is increasingly important in the treatment of type-2 diabetes mellitus (T2DM). Though the use of GLP-1 RA continues to increase, persistence and adherence to therapy remains suboptimal. Purpose We aimed to assess the level of adherence and persistence to GLP-1 RA using real-world data and to investigate sociodemographic and clinical factors associated with discontinuation of GLP-1 RA therapy. Methods In this retrospective cohort study, all first-time users of GLP-1 RA with T2DM ≥18 years from 2007-2020 were identified using the Danish registries (Figure 1A-1B). All participants had 18 months of follow-up. Medication possession ratio (MPR) was calculated by summing days of medication supply from all dispensed prescription made during the study period divided by number of days in study period. MPR ≥0.80 was used to define adherence. Discontinuation was defined as &amp;gt;90 days between the last day of prescription coverage and the first day of a new dispensed prescription. Adherence to GLP-1 RA therapy and the risk of discontinuing therapy was estimated at 6- and 12-months of follow-up. Multivariable logistic regression was used to identify sociodemographic and clinical factors associated with discontinuing GLP-1 RA therapy. Results In total, 44,343 first-time users of GLP-1 RA with T2DM were identified (mean age: 58.6 years, 42.7% female, 21.3% had cardiovascular disease, median duration of T2DM was 6.8 years, median HbA1c was 65 mmol/mol). The absolute risk of discontinuing GLP-1 RA at 6 and 12 months was 14.2% (95%CI: 13.9-14.6) and 21.4% (95%CI: 21.1-21.8), respectively (Figure 2A). Of the 9,520 (21.5%) who discontinued therapy during the 12-month follow-up, 1,947 (20.5%) occurred within the first 31 days of treatment. At 6 months, 58.5% were adherent to GLP-1 RA therapy with a median MPR of 0.84 [IQR: 0.70-0.95]. At 12 months, 61.1% were adherent to therapy with a median MPR of 0.85 [IQR: 0.71, 0.94]. In the multivariable model, low (&amp;lt;40 years) and high age (&amp;gt;75 years), lower household income, educational level, longer diabetes duration, and higher comorbidity burden were associated with a higher risk of discontinuing GLP-1 RA whereas baseline HbA1c was not (Figure 2B-2E). Conclusion Approximately one in five patients discontinued therapy within 12 months and a little over 60% were adherent. Sociodemographic factors, including household income, age, and comorbidity burden were associated with risk of discontinuing GLP-1 RA therapy. Given the changing landscape of who should be treated with GLP-1 RA, the cardio-renal benefits reported in recent trials, and the ongoing trials in the field, future research into adherence and persistence to GLP-1 RA and possible interventions to improve these, are needed.

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.

Extent and impact of obesity in patients with diabetes and acute myocardial infarction - experience from a national cohort

Abstract Background Elevated body mass index (BMI) has an adverse effect on cardiovascular riskfactors where diabetes and coronary artery disease increases with obesity. However, less in known about the prevalence and the grades of obesity in a diabetes population with acute myocardial infarction (AMI) and the impact on prognosis. Further, for the moment there is a shortage of access to cardioprotective weight loss medications as Glucagon Like Peptide Receptor Agonists (GLP-1 RA). Purpose To explore features and grades of obesity in patients with diabetes and AMI and impact on outcome in a national perspective. Methods All patients with diabetes and AMI admitted for coronary angiography in Sweden the years 2010-2021 were included. Information on BMI was collected at the time of angiography and grouped into obesity categories: low BMI (&amp;lt;18.5 kg/m2), normal BMI (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obesity grade 1 (30.0-34.9 kg/m2), obesity grade 2 (35.0-39.9 kg/m2) and obesity grade 3 (≥40.0 kg/m2). Information on baseline characteristics and outcome was collected from national registries. Mortality was followed until March 2022. Restricted cubic spline analysis of association between continuous BMI and age-adjusted mortality was performed where normal BMI served as a reference with Hazard Ratio (HR) 1.0. Results Of 19 378 patients with diabetes, 67% were men and 46% suffered a STEMI. Normal BMI was present in 21%, overweight in 41%, obesity grade 1 in 25%, obesity grade 2 in 9% and obesity grade 3 in 3% (Figure 1). Age was decreasing with grade of obesity (72 years in normal BMI vs. 62 years in obesity grade 3, p&amp;lt;0.001). Hypertension and hyperlipidaemia were more common in patients with more severe obesity than in those with normal BMI (67% vs. 80%, p&amp;lt;0.001, and 44% vs. 50%, p&amp;lt;0.001, in normal BMI and obesity grade 3 respectively) while a higher proportion of those with normal BMI had suffered a previous MI (10% vs. 6% in obesity grade 3, p&amp;lt;0.001) and a previous stroke (10% vs. 5% in obesity grade 3, p&amp;lt;0.001). In patients with normal BMI STEMI was more common (51% vs. 39%, p&amp;lt;0.001) than in those with obesity grade 3. In patients with obesity grade 3 GLP-1 RA was used in 14% compared to 4% in those with normal BMI. Figure 2 depicts age-adjusted HR and 95% Confidence Interval for mortality for different BMI levels with a U-shaped pattern illustrating that associated mortality risk is higher when obesity is present especially grade 2 and 3. Conclusion Obesity is common affecting around one third of patients with diabetes and AMI and impacts survival. This strengthens that after AMI use of effective weight loss cardioprotective treatment should be prioritised in patients with diabetes and obesity especially if severe.

Cardiometabolic outcomes in patients with overweight and obesity undergoing weight loss trials : a network meta-analysis

Abstract Objective Cardiometabolic outcomes are intrinsically linked with obesity. According to a study by Jayedi A et al. a 5kg weight gain could increase CVD mortality and MI risk by 11% and 18% respectively, with most overweight and obese patient also suffering from cardiometabolic derangements. This network meta-analysis evaluates cardiometabolic effects bought about by glucagon-like peptide 1 receptor agonists (GLP-1 RA) and other weight loss drugs in an overweight and obese population. Methods Cochrane CENTRAL, Embase and Medline were searched for randomised clinical trials (RCTs) on GLP-1 RA and United States Food and Drug administration weight loss drugs. A network meta-analysis was performed, using risk ratios(RR) to compare the efficacy of the interventions against one another. Network diagrams and surface under the cumulative ranking curve analysis were generated for the following cardiometabolic outcomes ( LDL, HDL, TC, TG, HbA1c, FPG, SBP and DBP). Results Among the cardiometabolic outcomes analysed, the GLP-1RA’s consistently ranked on top, with tirzepatide followed by semaglutide and then liraglutide. In terms of glycaemic control, tirzepatide 15, 10 and 5mg ranked first in a dose dependent manner(SUCRA = 0.8480, 0.8410, 0.6725) followed by semaglutide1.7mg(SUCRA= 0.6232). Tirzepatide 15mg did not achieve statistical significance compared to semaglutide 1.0mg (MD: -0.77, 95%CI: -2.04 to 0.50) or liraglutide1.8mg (MD: -0.64, 95%CI: -1.68 to 0.41). In reducing blood pressure, tirzepatide exhibiting a dose dependent reduction with Tirzepatide 15mg, (SUCRA =0.9457),10mg(SUCRA=0.9069)and 5mg(SUCRA=0.8419) followed by semaglutide 1.7mg (SUCRA =0.7415) then liraglutide 1.8mg(SUCRA = 0.5521).Tirzepatide 15mg demonstrated statistical significance compared to semaglutide 1.0mg (MD: -3.53, 95%CI: -6.78 to -0.27) and liraglutide 3.0mg (MD: -3.47, 95%CI: -5.59 to -1.36). The GLP-1RA’s also exhibited superiority in lipid reduction for TC and TG, with tirzepatide reducing TC (SUCRA = 0.7867) and TG(SUCRA = 0.9843) followed by semaglutide 1.7 mg (SUCRA = 0.7796) for TC and tirzepatide 10 mg (SUCRA = 0.9018) for TG. Orlistat 120mg(SUCRA =0.8789) and 60mg(SUCRA= 0.8458) were superior in reducing LDL, with tirzepatide 15mg(SUCRA =0.7806) and then semaglutide 2.4mg(SUCRA=0.7260) coming in behind. Naltrexone 32mg/Bupropion 360mg(SUCRA = 0.8757) ranked first followed by tirzepatide(SUCRA=0.8593) in increasing HDL, however the increase was not statistically significant (MD: 0.00, 95%CI: -0.04 to 0.05). Conclusion GLP-1 RAs’ superiority in addressing cardiometabolic parameters that are often deranged in patients with overweight and obesity highlights the need for weight lost medication transitioning from one that decreases and suppresses appetite or prevent the absorption of lipids to one that targets the altered metabolic mileu of patients with overweight and obesity, highlighting the multipronged approach needed to treat this metabolic disease.

Machine learning identifies individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death who have unrealised opportunities to reduce future cardiovascular risk

Abstract Background Machine learning may be able to identify individuals at risk of cardio-renal-metabolic events using routinely-collected data, and these individuals may be suitable for targeted preventative strategies.(1, 2) Purpose To train and test a machine learning algorithm to identify individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death, and then establish if there are opportunities to reduce their future cardiovascular risk. Methods We trained a random classifier (OPTIMISE) in UK primary care EHR data from 2 081 139 individuals aged ≥30 years (Jan 2, 1998, Nov 30, 2018), randomly divided into training (80%) and testing (20%) datasets. We calculated the cumulative incidence rate for ten cardio-renal-metabolic diseases and death. Fine and Gray’s models with competing risk of death were fit for each outcome between higher and lower predicted risk. In a multi-centre pilot interventional single arm study consenting individuals aged ≥30 years at higher predicted risk received cardio-renal-metabolic phenotyping and assessment for guideline target attainment. Results In the testing dataset (n = 416 228), individuals at higher predicted risk had higher long-term risk of heart failure (HR 12.54), aortic stenosis (HR 9.98), AF (HR 8·75), stroke/TIA (HR 8.07), CKD (HR 6.85), PVD (HR 6.62), valvular heart disease (HR 6.49), MI (HR 5.02), diabetes (HR 2.05) and COPD (HR 2.02) (Figure 1). This cohort were also at higher risk of death (HR 10.45), accounting for 74% of cardiovascular deaths (8 582 of 11 676) during 10-year follow up. Of 82 higher risk patients in the pilot study (mean age 71.6 years (SD 7.5), 50% women), the prevalence of cardio-renal-metabolic disease was high (Table 1), and there were opportunities to reduce future cardiovascular risk. Of higher risk patients with hypertension, 58.5% (31/53) of those aged &amp;lt;80 years had a systolic blood pressure (SBP)&amp;gt;140mmHg, and 54.5% (6/11) of those aged ≥80 years had a SBP &amp;gt;150mmHg. Of those with type 2 diabetes and co-existent ASCVD, only 23.1% (3/13) were on SGLT2 inhibitor therapy. Of higher risk patients on statin therapy, 37.0% (20/54) had LDL-cholesterol &amp;gt;1.8 mmol/L, and 52.0% (12/25) of patients with previous ASCVD had an LDL-cholesterol &amp;gt;1.4mmol/L. Furthermore, 19.5% (16/82) of the higher risk cohort had undiagnosed moderate or high risk CKD; who were infrequently prescribed a statin (41.7%; 5/12), ACE-i/ARB therapy with co-existent hypertension (61.5%. 8/13), or SGLT2 inhibitor with co-existent diabetes (83.3% (5/6)). Obesity was present in 49%, and 17% (14/82) were eligible for GLP-1 RA therapy. Conclusions The machine learning OPTIMISE algorithm can identify people at higher risk of cardio-renal-metabolic diseases and death using routinely collected data. On prospective evaluation higher risk individuals have unrecorded and undertreated cardio-renal-metabolic diseases, which are actionable targets for preventative care.Figure 1

Use of Glucagon-Like Peptide-1 Receptor Agonists Does Not Increase the Risk of Cancer in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes mellitus (T2DM) given their extra-pancreatic effects. However, there are concerns about carcinogenesis in the pancreas and thyroid gland. We aimed to evaluate the site-specific incidence of cancer in patients with T2DM-treated GLP-1 RAs using a nationwide cohort. This study included data obtained from the Korean National Health Insurance Service (between 2004 and 2021). The primary outcome was newly diagnosed cancer, and the median follow-up duration for all participants was 8 years. After propensity score matching, 7,827 participants were analyzed; 2,609 individuals each were included in the GLP-1 RA, diabetes mellitus (DM) control, and non-DM control groups. The incidence rate ratio (IRR) of subsequent cancer in patients with T2DM was 1.73, which was higher than that of individuals without DM, and it increased in both men and women. Analysis of patients with T2DM showed no increased cancer risk associated with the use of GLP-1 RA, and similar results were observed in both men and women. The IRRs of pancreatic cancer (0.74), thyroid cancer (1.32), and medullary thyroid cancer (0.34) did not significantly increase in the GLP-1 RA group compared with those in the DM control group. There was a 73% higher risk of cancer in patients with T2DM compared with the general population. However, among patients with T2DM, there was no association between the use of GLP-1 RAs and new-onset cancers, including pancreatic and medullary thyroid cancers.

A Scoping Review of GLP-1 Receptor Agonists: Are They Associated with Increased Gastric Contents, Regurgitation, and Aspiration Events?

Background: The increased popularity and ubiquitous use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of diabetes, heart failure, and obesity has led to significant concern for increased risk for perioperative aspiration, given their effects on delayed gastric emptying. This concern is highlighted by many major societies that have published varying guidance on the perioperative management of these medications, given limited data. We conducted a scoping review of the available literature regarding the aspiration risk and aspiration/regurgitant events related to GLP-1 RAs. Methods: A librarian-assisted search was performed using five electronic medical databases (PubMed, Embase, and Web of Science Platform Databases, including Web of Science Core Collection, KCI Korean Journal Database, MEDLINE, and Preprint Citation Index) from inception through March 2024 for articles that reported endoscopic, ultrasound, and nasogastric evaluation for increased residual gastric volume retained food contents, as well as incidences of regurgitation and aspiration events. Two reviewers independently screened titles, abstracts, and full text of articles to determine eligibility. Data extraction was performed using customized fields established a priori within a systematic review software system. Results: Of the 3712 citations identified, 24 studies met eligibility criteria. Studies included four prospective, six retrospective, five case series, and nine case reports. The GLP-1 RAs reported in the studies included semaglutide, liraglutide, lixisenatide, dulaglutide, tirzepatide, and exenatide. All studies, except one case report, reported patients with confounding factors for retained gastric contents and aspiration, such as a history of diabetes, cirrhosis, hypothyroidism, psychiatric disorders, gastric reflux, Barrett's esophagus, Parkinson's disease, dysphagia, obstructive sleep apnea, gastric polyps, prior abdominal surgeries, autoimmune diseases, pain, ASA physical status classification, procedural factors (i.e., thyroid surgery associated with risk for nausea, ketamine associated with nausea and secretions), and/or medications associated with delayed gastric emptying (opioids, anticholinergics, antidepressants, beta-blockers, calcium channel blockers, DPP-IV inhibitors, and antacids). Of the eight studies (three prospective and five retrospective) that evaluated residual contents in both GLP-1 users and non-users, seven studies (n = 7/8) reported a significant increase in residual gastric contents in GLP-1 users compared to non-users (19-56% vs. 5-20%). In the three retrospective studies that evaluated for aspiration events, there was no significant difference in aspiration events, with one study reporting aspiration rates of 4.8 cases per 10,000 in GLP-1 RA users compared to 4.6 cases per 10,000 in nonusers and the remaining two studies reporting one aspiration event in the GLP-1 RA user group and none in the non-user group. In one study that evaluated for regurgitation or reflux by esophageal manometry and pH, there was no significant difference in reflux episodes but a reduction in gastric acidity in the GLP-1 RA user group compared to the non-user group. Conclusions: There is significant variability in the findings reported in the studies, and most of these studies include confounding factors that may influence the association between GLP-1 RAs and an increased risk of aspiration and related events. While GLP-1 RAs do increase residual gastric contents in line with their mechanism of action, the currently available data do not suggest a significant increase in aspiration and regurgitation events associated with their use and the withholding of GLP-1 RAs to reduce aspiration and regurgitation events, as is currently recommended by many major societal guidelines. Large randomized controlled trials (RCTs) may be helpful in further elucidating the impact of GLP-1 RAs on perioperative aspiration risk.