GLP-1 RA Use and Major Adverse Cardiovascular Events in Patients With Monoclonal Gammopathy of Undetermined Significance

In patients with diabetes and monoclonal gammopathy of uncertain significance (MGUS), the impact of glucagon-like peptide-1 (GLP-1) receptor agonists on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1 receptor agonist use in the progression of MGUS to multiple myeloma in patients with diabetes. This is a population-based cohort study of veterans diagnosed with MGUS from 2006 to 2021 with a prior diagnosis of diabetes. A validated natural language processing algorithm was used to confirm MGUS and progression to multiple myeloma. We performed 1:2 matching for individuals with and without GLP-1 receptor agonist exposure. The Gray test was performed to detect the difference in cumulative incidence functions for progression by GLP-1 receptor agonist use status. The association between time-varying GLP-1 receptor agonist use and progression was estimated through multivariable-adjusted hazard ratio using a stratified Fine-Gray distribution hazard model, with death as a competing event and stratum for the matched patient triad. Our matched cohort included 1097 individuals with MGUS who had ever used GLP-1 receptor agonists and the matched 2194 patients who had never used GLP-1 receptor agonists. Overall, 2.6% of individuals progressed in the GLP-1 receptor agonist ever use group compared with 5.0% in the GLP-1 receptor agonist never use group. Cumulative incidence functions were statistically significantly different between the exposed and unexposed groups (P = .02). GLP-1 receptor agonist use vs no use was associated with decreased progression to multiple myeloma (hazard ratio = 0.45, 95% confidence interval = 0.22 to 0.93, P = .03). For patients with diabetes and MGUS, GLP-1 receptor agonist use is associated with a 55% reduction in risk of progression from MGUS to multiple myeloma compared with no use.

Introduction: Meta-analyses on glucagon-like peptide-1 (GLP-1) receptor agonists have shown beneficial effects in reducing major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. However, it is unclear if they have similar beneficial effects in patients with type 2 diabetes mellitus and chronic heart failure. Methods: A search was performed on online databases - MEDLINE (via PubMed) and ClinicalTrials.gov, using the search words GLP-1 receptor agonist and cardiovascular outcomes. The references from the search results were also reviewed for potential studies that can be included. We identified four cardiovascular outcome studies with GLP-1 receptor agonists on patients with type 2 diabetes mellitus with data on patients with chronic heart failure, and included them in our meta-analysis. Results: 6189 patients were evaluated in this meta-analysis, with 3053 in the GLP-1 receptor agonist group and 3136 in the placebo group. Among them, 475 (15.56%) major adverse cardiovascular events (i.e., cardiovascular death, stroke, or myocardial infarction) occurred in the GLP-1 receptor agonist group and 536 events (17.09%) in the placebo group with a hazard ratio (HR) of 0.90, 95% confidence interval (CI) of 0.79 to 1.01 and a p-value of 0.08, indicating a favorable effect with GLP1 agonists though statistically not significant. Conclusion: In patients with type 2 diabetes mellitus and chronic heart failure, GLP-1 receptor agonists may have a favorable effect in reducing major adverse cardiovascular events, though statistically not significant.

The Association between Glucagon-like Peptide-1 Receptor Agonist and Major Adverse Cardiac and Cerebrovascular Events in Monoclonal Gammopathy of Undetermined Significance: A Propensity-Score Analysis

Introduction: Concern for an increased risk of pancreatitis in patients prescribed glucagon-like peptide-1 receptor agonists (GLP1RAs) persists despite the lack of firm causality. Clinicians may therefore be hesitant to prescribe this treatment in patients at higher risk of pancreatitis, such as those with hypertriglyceridemia (HTG). Conversely, GLP-1RAs can positively affect triglyceride (TG) homeostasis and lead to lower plasma TG. This study evaluated whether GLP1RAs were associated with an increased risk of pancreatitis and major adverse cardiovascular events (MACE) in patients with and without HTG. Methods: We queried the Intermountain Health electronic medical records for patients ≥18 years old from January 2006 to April 2025 with Type 2 diabetes (T2D) and/or body mass index (BMI) ≥27 either on GLP1RA at baseline or never on GLP1RA with measured TG. Propensity score (PS) matching with a greedy nearest neighbor algorithm was used to pair the groups. Using the PS matched pairs, Cox-proportional hazard regressions (unadjusted and adjusted) were used to examine the risk of follow-up pancreatitis and MACE. Results: Of the 346,677 patients, 3834 (1.1%) patients were prescribed GPL1RA (342,843 (98.9%) without GLP1RA). Those on a GLP1RA were older, more likely to be non-Hispanic, have lower rates of alcohol abuse and higher BMI, Hgb A1C, and TG, and tended to have more comorbidities and medication use (Table 1). The PS matching resulted in a well-matched cohort of 3833 pairs (Table 1). The rate of pancreatitis was similar in those on GLP1RA compared to those not (2.5% vs 2.6%, p=0.72) (Table 2). The risk of pancreatitis was further examined by baseline TG levels. For patients with severe TG levels (≥500 mg/dL), those on a GLP1RA had a non-significant decrease in pancreatitis (8.7% vs 10.9%, p=0.60); however, after adjustment for prior pancreatitis history the hazard ratio (HR) for pancreatitis was over 4 times greater for those not on GLP1RA vs those on a GLP1RA. MACE events on GLP1RA were also lower (14.9% vs 18.5%, p<0.0001) with MACE HR of 1.25 when not on GLP1RA (Table 2). Conclusions: These results support findings of prior studies that did not identify an increased risk of pancreatitis in patients prescribed a GLP1RA. Additionally, there was not an increased risk of pancreatitis in patients with HTG, including those with TG ≥ 500 mg/dL. Based on this analysis, prescribers may feel more confident about prescribing GLP1RAs to patients with HTG.

Glucagon-like Peptide-1 Receptor Agonists and Risk of Major Adverse Cardiovascular Events in Patients With CKD.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex. To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors. The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes. Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models. Hemoglobin A1c (HbA1c) and MACEs. Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA1c lowering with increasing age for monotherapy (AR, -0.18% [95% CrI, -0.31% to -0.05%] per 30-year increment in age) and for dual therapy (AR, -0.24% [95% CrI, -0.40% to -0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, -0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA1c lowering in older people for dual therapy (AR, -0.09% [95% CrI, -0.15% to -0.03%] per 30-year increment in age), but not for monotherapy (AR, -0.08% [95% CrI, -0.18% to 0.01%]) or triple therapy (AR, -0.01% [95% CrI, -0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists. The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.

Objective: To determine the prevalence of sodium-glucose contransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1RA) use among adults with type 2 diabetes (T2D) in the United States. Methods: We studied adults with T2D and eGFR ≥30mL/min/1.73m2 who participated in the National Health and Nutrition Examination Survey (NHANES) , focusing on the 2017-2020 examination cycle. We tested prevalence of SGLT2i and GLP1RA use among subgroups based on demographic variables and relevant comorbidities, including chronic kidney disease (CKD) , congestive heart failure (CHF) , and atherosclerotic cardiovascular disease (ASCVD) . We compared use of SGLT2i and GLP1RA to other glucose-lowering medications and assessed trends from prior NHANES cycles. Results: Among 1,375 participants studied in 2017-2020, mean age was 60 years, 46% were women, 13% self-identified as non-Hispanic Black, 10% self-identified as Mexican American, 37% had CKD, 8.5% had CHF, and 23% had ASCVD. The prevalence of SGLT2i and GLP1RA use was 5.8% and 4.4%, respectively. SGLT2i were used by 7.2% of adults with CKD or CHF, and GLP1RA were used by 3.5% of adults with ASCVD. Differences in SGLT2i or GLP1RA use were observed by age, race, ethnicity, and health insurance status. Biguanides, sulfonylureas, DPP-4 inhibitors, and insulin were used more frequently than SGLT2i or GLP1RA. Overall, prevalence of SGLT2i but not GLP1RA use increased significantly from 2013-2014 to 2017-2020. Conclusions: SGLT2i and GLP1RA use is low among adults with T2D, including among those with strong indications. Enhanced implementation of these agents is crucial to improving kidney and cardiovascular outcomes and mitigating health disparities in T2D. Disclosure C.Limonte: None. Y.Hall: None. S.Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas , Insulet Corporation, Insulet Corporation. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc. L.Zelnick: None. Funding This work was supported by an unrestricted fund from the Northwest Kidney Centers. CPL was funded by NIDDK grant T32DK007467 and the American Kidney Fund Clinical Scientist in Nephrology grant program. Additional funding was provided by R01DK126373, R01DK125084, R01DK088762.

Prevalence of SGLT2i and GLP1RA use among US adults with type 2 diabetes

Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications

Introduction: The Glucagon-Like Peptide-1 receptor agonists (GLP-1a) semaglutide, dulaglutide, and liraglutide reduce major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus ( T2DM) and established CVD. The American Diabetes Association currently recommends providing GLP-1a therapy to this patient population independently of glycaemic control. Despite proven clinical benefits, providing GLP-1a to all guideline eligible patients is a significant cost burden on healthcare systems. Therefore, it is imperative to compare the value for money of these agents. Hypothesis: The newly introduced GLP-1a Semaglutide may be cost-saving compared to dulaglutide and liraglutide for preventing MACE in patients with established CVD and T2DM. Methods: We calculated the cost needed to prevent one MACE, by multiplying the annualized number needed to treat to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published RCT data. We performed a sensitivity analysis to mitigate differences between trial populations and other uncertainties. Drug costs were based on published US prices. Results: The cost needed to prevent one MACE with semaglutide is $557,187 ($331,491-$2,194,483) compared to $1,179,360 ($732,888-$2,746,224) with liraglutide and $1,605,904 ($706,044-∞) for dulaglutide. Sensitivity analysis confirmed the advantage of semaglutide. Conclusions: Semaglutide prescribed for secondary prevention of MACE in patients with T2DM and established CVD seems to provide more value for money than dulaglutide and liraglutide for the same purpose.

Background: Acute heart failure is a global health problem with high morbidity and mortality. Short term and long term prognosis of these patients is poor. Therefore, early identification of patients at high risk for major adverse cardiovascular events (MACEs) during hospitalization was needed to improve outcome. Creatinine levels at admission could be used as predictors of major adverse cardiovascular events in acute heart failure patients because creatinine is a simple and routine biomarker of renal function examined in patients with acute heart failure. This study aimed to determine whether creatinine can be used as a predictor of major adverse adverse cardiovascular events in patients with acute heart failure.Methods: This study is a prospective cohort study of 108 acute heart failure patients treated at H. Adam Malik Hospital from July 2018 to January 2019. Creatinine cut-off points were determined using the ROC curve, then bivariate and multivariate analyzes were performed to determine predictors of major adverse cardiovascular events during hospitalization.Results: From 108 study subjects, 24 (22.2%) subjects experienced major adverse cardiovascular events during hospitalization. The subjects who died were 20 people (83.4%), subjects with arrhythmia were 2 people (8.3%), and those who had stroke were 2 people (8.3 %). Through the ROC curve analysis, we found creatinine cut-off values of ≥1.7 mg / dl (AUC 0.899, 95% CI 0.840- 0.957, p <0.05). Creatinine ≥1.7 mg/dl could predict major adverse cardiovascular events with a sensitivity of 87.5% and specificity of 79.5%. Multivariate analysis showed that creatinine ≥1.7 mg / dl was an independent factor to predict MACEs during hospitalization in this study (OR 18,310, p 0.001) as well as creatinine clearance and heart rate.Conclusion: Creatinine levels at admission is an independent predictor for major adverse cardiovascular events during hospitalization in acute heart failure patients.

Introduction: Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) indicated to reduce major adverse cardiovascular events (MACE) in patients with Type-2 Diabetes Mellitus (T2DM) and established cardiovascular disease. Tirzepatide is a novel glucose-dependent insulinotropic polypeptide (GIP) and GLP-1RA for the same purpose. Comparing the value for money of the two therapies in people with poorly controlled diabetes is essential for prioritization. Methods: We calculated the cost needed to prevent one MACE with either drug by multiplying the annualized number needed to treat (aNNT) to prevent one MACE by the annual cost of the therapy. Efficacy estimates were extracted from pre-specified cohorts of patients with an initial HbA1c above 8.5% in the SURPASS and SUSTAIN-6 trials. Drug costs were based on US GoodRx prices as of February 2023. Results: The aNNT to prevent one MACE in patients with an initial HbA1c of >8.5 with tirzepatide was 79 (95% CI: 44-∞) compared to 78 (95% CI: 42-∞) with semaglutide. The annual cost of tirzepatide is $13,286 versus $17,495 for semaglutide. Accordingly, the CNT to prevent one MACE with tirzepatide is $1,049,594 (95% CI: $584,584-∞) compared to $1,364,611 (95% CI: $734,790-∞) with semaglutide. Conclusions: Tirzepatide provides slightly better, but comparable, value for money than semaglutide when prescribed for secondary prevention of MACE in patients with an initial HbA1c >8.5.

Background There is growing evidence suggesting that Stress Induced Hyperglycemia (SIH) is a risk factor of poor prognosis in acute coronary syndrome (ACS)[1–3]. However, this parameter is not included in risk prediction scores, applied in clinical practice. Ιmportantly, there is no universally accepted definition for SIH especially in the setting of ACS. Across the existing evidence base, SIH is defined either based on admission blood glucose (ABG) levels or by calculating the glycemic gap and the stress hyperglycemia ratio (SHR)[4]. Purpose Considering the variability in SIH definitions and the need for further investigation on the long-term prognostic impact of SIH, we present herein original data concerning the prognostic role of SIH for long-term risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients presenting with ST-elevation myocardial infarction (STEMI) on top of a traditional prediction risk score such as the GRACE 2.0 risk score. Methods Our data were derived from a post-hoc analysis of a prospective study (NCT04580173). Every trial procedure was conducted according to the principles set by the declaration of Helsinki. Each participant provided written informed consent before being enrolled in the study. Our analysis included 309 consecutive STEMI patients who were diagnosed with SIH if ABG was > 140 mg/dl and a fasting period of at least 8 hours was confirmed. Each participant was followed-up for a median 1-year period. Baseline characteristics of the included patients are presented in Table 1. The records of all enrolled patients were retrospectively analyzed to calculate the GRACE 2.0 risk score for each patient. Results Cox regression analysis adjusted for age, gender, body mass index (BMI), hypertension, smoking, and SIH was performed but did not identify GRACE risk score>140 as an independent predictor of MACCE (aHR=1.408, 95% CI:0.764-2.594 p=0.273, Figure 1). On the other hand, a similar model adjusted for the same covariates identified the combination of GRACE risk score>140 and SIH as a significant predictor of MACCE occurrence (aHR=2.149, 95% CI:1.224-3.771, p=0.008). Conclusions Our results suggest that SIH combined with the GRACE 2.0 risk score was associated with improved prediction of the risk for 1-year MACCE in STEMI patients as compared to the GRACE 2.0 risk score alone. In this study, SIH was diagnosed based on the levels of admission blood glucose (after 8-hours of fasting) and not based on the SHR. Despite the heterogeneity in SIH definitions, stress hyperglycemia in the setting of STEMI might be an underrated yet robust prognostic marker not only for short term but also for long term adverse clinical events, especially when integrated in existing clinical risk scores.Survival curveBaseline characteristics

To explore the modifying effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO-DKD and FIGARO-DKD. Patients with T2D and CKD treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin-to-creatinine ratio (UACR), and safety were analysed by GLP-1RA use. Of 13 026 patients, 944 (7.2%) used GLP-1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52-1.11 with GLP-1RA; HR 0.87, 95% CI 0.79-0.96 without GLP-1RA; P-interaction=0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45-1.48 with GLP-1RA; HR 0.77, 95% CI 0.67-0.89 without GLP-1RA; P-interaction=0.79) irrespective of baseline GLP-1RA use. Reduction in UACR with finerenone at Month 4 was -38% in patients with baseline GLP-1RA use compared with -31% in those without GLP-1RA use (P-interaction=0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP-1RA use. The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP-1RA use. Subsequent studies are needed to investigate any potential benefit of this combination.

4559 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists have played a pivotal role in the management of type 2 diabetes (T2DM). At the same time, immune checkpoint inhibitor (ICI) therapy remains one of the mainstay treatments for metastatic renal cell carcinoma (mRCC). There has been a scarcity of research on the effect of GLP-1 receptor agonists on ICI efficacy in cancer patients. This study presents the first real-world analysis of the effect of GLP-1 receptor agonists on outcomes in mRCC patients receiving ICI therapy. Methods: Data was retrospectively collected from TriNetX, a national electronic health record database with 120 million US patients from over 70 healthcare organizations, from 2012-2024. We included patients ≥ 18 years old with T2DM and mRCC who underwent ICI therapy. Patients were then stratified into two cohorts: on GLP-1 receptor agonists prior to ICI therapy and not on GLP-1 receptor agonists. Patients in each cohort were then 1:1 propensity score matched (PSM) based on age, sex, race, type of ICI therapy used, comorbidities, other diabetic medications and staging. 1 year outcomes for mortality, major adverse cardiovascular events (MACE) and various immune‐related adverse events (irAEs) were reported. Results: A total of 2378 patients were identified who met the inclusion criteria. 535 (22%) were in the GLP-1 receptor agonist cohort compared to 2378 (68%) in the non GLP-1 receptor agonist cohort. After 1:1 PSM, 497 patients were in each group. Among both cohorts, 66% were male, 77% white and the average age was about 65 years old. After conducting Cox proportional hazard analyses, GLP-1 receptor agonist use was associated with lower mortality (HR, 0.49 [95% CI: 0.37-0.64]). Moreover, GLP-1 receptor agonist use had lower rates of irAEs, including pneumonitis (HR, 0.61 [95% CI: 0.43-0.85]), hematological complications (HR, 0.78 [95% CI: 0.64-0.95]) and renal complications (HR, 0.67 [95% CI: 0.54-0.84]). There was no significant difference in MACE or other irAEs between the two cohorts. Conclusions: Analysis of one of the largest US based databases showed that the use of GLP-1 receptor agonist in T2DM patients with mRCC undergoing ICI therapy, is associated with better overall survival and lower irAES such as pneumonitis, hematological and renal complications. There was no significant difference in MACE. To our knowledge, this is the first study to identify the impact of GLP-1 receptor agonists on the outcomes of mRCC patients undergoing ICI therapy. Further prospective studies are needed to validate these findings and to identify the underlying mechanisms.