Cardiovascular Safety Research Articles

Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure

BackgroundThe primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. ObjectivesThe authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. MethodsIn a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. ResultsFor diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. ConclusionsEarly dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229)

Cardiovascular safety of evogliptin dual and triple therapy in patients with type 2 diabetes: a nationwide cohort study

ObjectiveTo investigate the risk of cardiovascular events associated with commonly used dual and triple therapies of evogliptin, a recently introduced dipeptidyl peptidase-4 inhibitor (DPP4i), for managing type 2 diabetes in...

Evidence that tirzepatide protects against diabetes-related cardiac damages

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist.MethodsA three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT.ResultsMeta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40–0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure.ConclusionOur findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.Graphical

Evaluating the Efficacy and Safety of Tirzepatide on Glycaemic and Non-glycaemic Outcomes in Diabetes: A Systematic Review of Meta-Analyses.

Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, recently approved for type 2 diabetes mellitus (T2DM) and obesity. A systematic review of the literature published in multiple meta-analyses on Tirzepatide with emphasis on its effect on glycaemic and non-glycaemic parameters was conducted. We systematically searched the electronic databases PubMed and Google Scholar up to August 2023 for meta-analyses that compared Tirzepatide with placebo or active antihyperglycaemic drugs in subjects with T2DM. Various parameters for efficacy and safety, with their point estimates and confidence intervals, such as glycated haemoglobin (HbA1c), fasting serum glucose (FSG), body weight, lipid, and cardiovascular outcomes were assessed. Six meta-analyses fulfilled the pre-specified criteria and were included in the study. In all the studies, Tirzepatide treatment at different doses resulted in a significant reduction in HbA1c and FSG levels along with a significant reduction in weight compared with active control and placebo groups. Tirzepatide significantly reduced levels of triglycerides and increased high-density lipoprotein (HDL) cholesterol, whether used as monotherapy or add-on therapy. The studies suggested the cardiovascular safety ofTirzepatide as there was no increase in major adverse cardiovascular events(MACE). The drug shows lesser hypoglycemia but predominant gastrointestinal adverse effects such as nausea, vomiting, and diarrhoea. In conclusion, Tirzepatide shows superior glycaemic control and weight loss in patients with T2DM with beneficial effects on lipids, without an increased risk of hypoglycemia and cardiovascular events.

Challenging the status quo: a framework for mechanistic and human-relevant cardiovascular safety screening.

Traditional approaches to preclinical drug safety assessment have generally protected human patients from unintended adverse effects. However, these assessments typically occur too late to make changes in the formulation or in phase 1 and beyond, are highly dependent on animal studies and have the potential to lead to the termination of useful drugs due to liabilities in animals that are not applicable in patients. Collectively, these elements come at great detriment to both patients and the drug development sector. This phenomenon is particularly problematic in the area of cardiovascular safety assessment where preclinical attrition is high. We believe that a more efficient and translational approach can be defined. A multi-tiered assessment that leverages our understanding of human cardiovascular biology, applies human cell-based in vitro characterizations of cardiovascular responses to insult, and incorporates computational models of pharmacokinetic relationships would enable earlier and more translational identification of human-relevant liabilities. While this will take time to develop, the ultimate goal would be to implement such assays both in the lead selection phase as well as through regulatory phases.

Comment on Kutz et al. Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes. Diabetes Care 2023;46:2004-2014.

Comment on Kutz et al. Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes. Diabetes Care 2023;46:2004-2014.

Cardiovascular Safety of Romosozumab vs. PTH Analogs for Osteoporosis Treatment: a Propensity Score Matched Cohort Study.

Romosozumab, a monoclonal sclerostin antibody, is a recently approved highly potent anti-osteoporotic agent with osteoanabolic properties. Clinical use of Romosozumab is hindered by the fear of adverse cardiovascular (CV) events raised following the pivotal ARCH-trial. To assess real-world CV safety of romosozumab vs. alternative osteoanabolic therapies used for treatment of severe osteoporosis. Data was obtained from TriNetX, a global federated health research network including real-time electronic medical records from 113 healthcare organizations with a total of 136,460,930 patients across 16 countries at time of analysis. Inclusion criteria were age ≥ 40 years, a diagnosis of osteoporosis and prescription of romosozumab or a PTH analog (teriparatide/abaloparatide) during 8.2019-8.2022. 1:1 propensity score matched cohorts were created using demographic variables, comorbidities, and medications. Kaplan-Meier analysis was used to estimate the probability of the outcomes. Incident 3-point major adverse CV event or death (3P-MACE) during 1-year of follow-up after the initial prescription. 5,626 and 15,986 patients met the criteria for romosozumab and PTH analog cohorts, respectively, with 5,610 patients per group following propensity score matching. 3P-MACE was significantly less frequent in the romosozumab vs. PTH analog cohort (158 vs 211 patients with an outcome, p=0.003) with reductions in the individual components of the composite outcome: myocardial ischemic events (31 vs 58, p=0.003); cerebrovascular events 56 vs 79, p=0.037; deaths (83 vs 104, p=0.099). In a diverse real-world setting, prescription of romosozumab for osteoporosis is associated with less adverse CV events when compared to PTH analog therapy.

Is dependent cannabis use in adult hospitalizations with inflammatory bowel disease associated with major adverse cardiovascular and cerebrovascular events? Insights from National Inpatient Sample Analysis

Background Inflammatory bowel disease (IBD) and dependent cannabis use or cannabis use disorder (CUD+) are independent risk factors for cardiovascular diseases. Usage of cannabis for pain increased in IBD patients. However, associated cardiovascular safety remains unclear. This study aims to investigate the major adverse cardiac and cerebrovascular events (MACCE) associated with CUD + in hospitalized IBD patients. Methods We analyzed the National Inpatient Sample 2020 using ICD-10-CM codes; hospitalized IBD patients were identified and divided based on CUD's presence or absence. Multivariable regression models were performed to evaluate MACCE [in-hospital mortality, acute myocardial infarction (AMI), cardiac arrest (CA), and acute ischemic stroke (AIS)] odds after adjusting for baseline demographics, hospital-level characteristics, and relevant cardiac/extra-cardiac morbidities. Results Among the 302,770 hospitalized adult IBD patients, 3.1% (9,490) had CUD+. The majority of patients in the CUD + cohort were white (67.7%), male (57.5%), and aged between 18 and 44 years (66.2%). Cardiovascular risk factors like hypertension, diabetes, hyperlipidemia, and prior myocardial infarction were higher in the CUD − cohort (p <0.001) compared to the CUD + cohort. The CUD + cohort had a lower rate of MACCE (3.1% vs. 5.8%), crude in-hospital mortality (0.7% vs. 2.2%), AMI (1.7% vs. 2.6%), CA (0.3% vs. 0.7%), and AIS (0.6% vs. 1.2%) with statistical significance (p <0.001). However, after adjusting for baseline characteristics and comorbidities, the adjusted odds ratios (aORs) did not show a statistically significant difference for MACCE (aOR = 0.9, 95% CI = 0.65–1.25, p = 0.530), CA (aOR = 0.54, 95% CI = 0.2–1.47, p = 0.227), and AIS (aOR = 0.86, 95% CI = 0.43–1.73, p = 0.669). Conclusion Our study did not find a statistically significant difference in MACCE among hospitalized IBD patients with and without CUD. This emphasizes the need for more extensive prospective studies focusing on the quantity, method, and duration of cannabis use (recreational or medicinal) in patients with IBD.

Blood pressure response to extended-release naltrexone in heroin and prescription opioid users and its implications for cardiovascular morbidity

Background Consuming opioid agonists is a risk factor for cardiovascular disease particularly in intravenous heroin users. The monthly injectable extended-release opioid antagonist, naltrexone (XR-NTX) is an effective treatment for opioid use disorder. The impact of opioid receptor blockade through XR-NTX on blood pressure, a critical risk factor for cardiovascular morbidity, has not yet been characterized. Methods The study evaluated the change in blood pressure during XR-NTX treatment among 14 patients who predominately used intravenous heroin and 24 patients who used prescription oral opioids, all with opioid use disorder. Blood pressure was measured in each patient immediately before the first XR-NTX injection and ∼two weeks after the first injection. The change in diastolic and systolic pressure was compared between the heroin users and the prescription opioids users using analysis of variance. Results XR-NTX treatment was associated with significant decreases in diastolic blood pressure in the heroin group, but not in the prescription opioids group. Systolic blood pressure values in the heroin users showed a decline at trend level only. Conclusions Further research is warranted to replicate our findings and to determine whether XR-NTX effect is relatively specific to blood pressure or generalizes to other components of metabolic syndrome. Distinguishing between heroin and prescription opioid users could shed light on the unique clinical and pharmacological profiles of opioid drugs, particularly regarding their cardiovascular safety. This information can be useful in developing personalized therapeutic strategies based on the route of opioid administration.

Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: Asystematic review and meta-analysis.

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.

Sulfonylureas: A Widely Used Oral Anti-Hyperglycaemic Medication for Type 2 Diabetes Management

Diabetes mellitus (DM) is a fast growing epidemic and a public health concern all over the world due to its increased incidence and its devastating complications. Sulfonylureas (SUs) are oral glucose-lowering agents that are characterized by efficient glycemic control with cardiovascular safety and renal benefits, and use as the second-line drugs for the management of type 2 diabetes (T2D). Although SUs have some side-effects, its glucose-lowering effect is immediate and stimulates the pancreas to release more insulin. It contributes to the development and progression of hypoglycaemia. It is used as an alternative or a complement to Metformin. SUs should be avoided by the elderly weak patients who are at high risk of hypoglycaemia. In this mini review the basic and clinical pharmacology of SUs are described.

Withdrawal of renin-angiotensin system inhibitors’ effect on estimated glomerular filtration rate in adults with advanced kidney disease: the STOP-ACEi RCT

Background Renin–angiotensin system inhibitors, both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, slow progression of mild and moderate chronic kidney disease. However, some evidence suggests that discontinuation of renin–angiotensin system inhibitors in patients with advanced chronic kidney disease might increase estimated glomerular filtration rate or slow its decline. Objective To test the hypothesis that stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or a combination of both, compared with continuing these treatments, improves or stabilises kidney function in patients with progressive stages 4 or 5 chronic kidney disease based on assessment of kidney function using the modification of diet in renal disease four-variable estimated glomerular filtration rate at 3 years, follow-up. Setting Thirty-seven UK hospitals with kidney services. Design An investigator-led multicentre open-label, randomised controlled trial of 411 participants with advanced (stage 4 or 5) progressive chronic kidney disease. Participants Adult patients with advanced (estimated glomerular filtration rate &lt; 30 ml/minute/1.73 m2) and progressive chronic kidney disease who were receiving either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or a combination of both. Interventions Participants were randomised in a 1 : 1 ratio using a centralised internet-based system to either discontinue renin–angiotensin system inhibitors (n = 206) or continue renin–angiotensin system inhibitors (n = 205). Main outcome measures The primary outcome was the estimated glomerular filtration rate at 3 years; measurements of estimated glomerular filtration rate made after commencing kidney replacement therapy were excluded. Secondary outcomes included development of end-stage kidney disease or starting kidney replacement therapy, a composite of either a &gt; 50% decline in estimated glomerular filtration rate or commencement of kidney replacement therapy (including end-stage kidney disease), cystatin C, hospitalisations, blood pressure, exercise capacity and quality of life. Cardiovascular events, death and safety were recorded. Results At 3 years, the least-squares mean (± standard error) estimated glomerular filtration rate was 12.6 ± 0.7 ml/minute/1.73 m2 in the discontinuation group and 13.3 ± 0.6 ml/minute/1.73 m2 in the continuation group [difference −0.7, 95% confidence interval (−2.5 to 1.0; p = 0.42)] with a negative value favouring the continuation group. The treatment effect did not differ (heterogeneity) when data were analysed by the pre-specified subgroups. End-stage kidney disease or kidney replacement therapy occurred in 128 (62%) and 115 (56%) participants randomised to the discontinue and continue renin–angiotensin system inhibitor groups, respectively (hazard ratio 1.28, 95% confidence interval 0.99 to 1.65). The numbers of cardiovascular events and deaths observed were similar for those randomised to discontinue (108 events and 20 deaths) or continue (88 events and 22 deaths) renin–angiotensin system inhibitors. Limitations Non-white ethnic backgrounds were poorly represented, limiting the generalisability of our findings. The open-label nature of the trial may have affected clinical care and subjective end points, such as quality of life and exercise capacity. We only included patients who were receiving renin–angiotensin system inhibitors at the time of randomisation, thus excluding those who had already discontinued these agents. Conclusions Discontinuing renin–angiotensin system inhibitors in advanced and progressive chronic kidney disease does not cause a clinically relevant change in estimated glomerular filtration rate or difference in its long-term decline. Future work Future work should focus on updating clinical guidelines. Further analyses, in addition to the prespecified analyses, may be undertaken if new estimated glomerular filtration rate equations are introduced into clinical practice. Subgroup analysis by kidney disease aetiology and gender may be undertaken to look for potential differences in outcome in specific groups. Trial registration This trial is registered as STOP ACEi EudraCT Number, 2013-003798-82; ISRCTN62869767. Funding This award was funded by the Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 11/30/07), a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership. This is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 5. See the NIHR Funding and Awards website for further award information.

Evaluation of all-cause mortality and cardiovascular safety in patients receiving chimeric antigen receptor T cell therapy: a prospective cohort study

Assessment of cardiovascular risk is critical for patients with cancer. Previous retrospective studies suggest potential cardiotoxicity of CAR T cell therapies. We aimed to prospectively assess cardiotoxicity and the predictive value of cardiac biomarkers and classical risk factors (age, cardiac function, diabetes, arterial hypertension, smoking) for cardiac events and all-cause mortality (ACM). In this prospective cohort study, all patients treated with CAR T cell constructs (axi-cel, tisa-cel, brexu-cel, ide-cel, or the 3rd generation CAR HD-CAR-1) from Oct 1, 2018, to Sept 30, 2022at the University Hospital Heidelberg were included. Surveillance included cardiac assessment with biomarkers (high-sensitive Troponin T (hs-cTnT), N-terminal brain natriuretic peptide (NT-proBNP)), 12-lead-ECG, and 2D echocardiography. ACM was defined as the primary study endpoint, while cardiotoxicity, defined by clinical syndromes of heart failure or decline in ejection fraction, served as a secondary endpoint. Overall, 137 patients (median age 60, range 20-83, IQR 16), were included in the study. 46 patients died during the follow up period (median 0.75 years, range 0.02-4.33, IQR 0.89) 57 month, with a median survival of 0.57 years (range 0.03-2.38 years, IQR 0.79). A septal wall thickness above 11mm (HR 2.48, 95%-CI=1.10-5.67, p=0.029) was associated with an increased risk of ACM, with a trend seen for reduced left ventricular ejection fraction prior to therapy (LVEF <40%; HR 9.17, 95%-CI=1.30-183.11, p=0.051). Secondary endpoint was reached by 93 patients while no baseline parameter was able to predict an elevated risk. However, hs-cTnT change from baseline of 50% or more during the first 14 days after CAR infusion predicted ACM (HR 3.81, 95%-CI=1.58-9.45; p=0.003). None of the baseline characteristics was able to predict the incidence of cardiac events. Reduced pre-lymphodepletion ejection fraction and early post-infusion biomarker kinetics may be associated with increased ACM and cardiotoxicity events. These findings may help to identify patients who could benefit from intensified cardio-oncological surveillance. The German Center for Cardiovascular Research, German Research Foundation, and the Federal Ministry of Education and Research.

Cardiovascular Adverse Drug Reactions of Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies for Migraine Prevention: An Analysis from the European Spontaneous Adverse Event Reporting System.

Anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAbs) have recently been approved for the prevention of migraine, and their safety profile is not fully characterized. The aim of this study was to evaluate the adverse drug reactions (ADRs) of anti-CGRP-mAbs through the analysis of individual case safety reports (ICSRs) collected in the EudraVigilance (EV) database, with a specific focus on cardiovascular (CV) ADRs. Data on ICSRs recorded between July 2018 and December 2022 in the EV database, involving one of the anti-CGRP-mAbs for migraine prevention-erenumab (ERE), galcanezumab (GMB), fremanezumab (FMB), and eptinezumab (EPT)-were included in the analysis. All ICSRs reporting at least one CV ADR, as identified within the MedDRA® System Organ Classes (SOCs) "cardiac disorders" or "vascular disorders," were selected for the analysis. The frequency of disproportionate reporting was expressed as the reporting odds ratio (ROR) with its 95% confidence interval (CI), to evaluate the frequency of reporting of CV ADRs for each anti-CGRP-mAb compared with all other monoclonal antibodies (mAbs). A case-by-case analysis was conducted paying particular attention to serious CV ADR reports, focusing on the type of seriousness, age group, sex, and concomitant drugs. A total of 9441 ICSRs were recorded in the EV database from 2018 to 2022, of which more than half were related to ERE (58.9%), followed by GMB (21.4%), FMB (19.0%), and EPT (0.7%). CV ICSRs accounted for 1205 cases (12.8%), with a total of 1599 CV ADRs. The CV ICSRs were mainly related to female patients (82.6%) aged 18-64 years (73.4%). Of the reported CV ADRs, 67.5% were considered serious. Among the total number of ICSRs related to each anti-CGRP-mAb, those associated with FMB had a higher percentage of CV ADRs (n = 253; 14.1%), followed by ERE (n = 707; 12.7%), EPT (n = 8; 12.7%), and GMB (n = 237; 11.7%). A higher frequency of reporting hypertension was shown for ERE (ROR = 1.45; 95% CI = 1.14-1.85). Pallor was mainly observed with FMB (5.00; 1.68-14.89), as well as deep vein thrombosis (3.86; 1.57-9.51), hot flush (2.16; 1.43-3.25), and palpitations (1.48; 1.05-2.08). Atrial fibrillation (2.36; 1.02-5.46) and myocardial infarction (2.21; 1.37-3.58) were mostly reported for GMB. The analysis of anti-CGRP-related CV ADRs was consistent with the information reported in the literature. However, hypertension with ERE, atrial fibrillation and myocardial infarction with GMB, as well as pallor, deep vein thrombosis, hot flush, and palpitations with FMB were not reported in the Summary of Product Characteristics (SmPCs). Considering this, more post-marketing analyses are needed to improve knowledge on the CV safety profiles of anti-CGRP-mAbs, especially for the last approved medication, EPT.

Physicians Perspectives on the Preference of Antihyperglycemics for the Management of Diabetes Mellitus in India

As they were commonly prescribed together for blood glucose control, metformin and more recent sulfonylureas, such as glimepiride, have been shown in numerous clinical studies to effectively reverse insulin resistance and promote insulin secretion. In India, primary care physicians and specialists used the fixed-dose combination of metformin and glimepiride in various doses. The results of clinical trials needed to be applied to regular clinical practice in the real world in order to close the knowledge gap. Regarding this, professional opinions will provide insightful information about the use of antihyperglycemics and their combinations, including their safety, effectiveness, and usefulness for a particular subgroup of patients with diabetes. So, a cross-sectional study was conducted on the prescription pattern of oral anti-diabetic drugs for patients with diabetes mellitus. The choice of oral anti-diabetic agents for diabetic patients with comorbidities was analysed by using 26 questions. About 845 physicians participated in the survey by sharing their opinions/views on the questionnaire. Also, 400 physicians out of 845 prefers glimepiride and metformin as the preferred combination to achieve the targeted glycated haemoglobin level. Moreover, 723 physicians out of 845 experienced glycated haemoglobin reduction with glimepiride and metformin for more than 3 years. Maximum glycated haemoglobin reduction with glimepiride and metformin was 1.5%-2% by 383 physicians as per the survey. They also experienced good glycaemic control and good cardiovascular safety with glimepiride and metformin. Thus, the experts recommended glimepiride and metformin very often in elderly individuals. Glycated haemoglobin reduction was more than 3 years with glimepiride and metformin, as per the clinical experience of the experts participated in the survey. They also witnessed good glycaemic control and cardiovascular safety profile with glimepiride and metformin combination.

Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe

AbstractReal-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

Major cardiovascular events under biologic psoriasis therapies: a 19-year real-world analysis of FAERS data.

Over the years when biologic psoriasis therapies (TNF inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, and IL-17 inhibitors) have been used in psoriasis patients, reports of major cardiovascular events (MACEs) have emerged. This study aims to investigate the association between MACEs and biologic psoriasis therapies by using information reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). FAERS data (January 2004 to December 2022) were reviewed. For each drug-event pair, the proportional reporting ratio (PRR) and the multi-item gamma Poisson shrinker (MGPS) algorithms were used to identify drug-adverse event associations. We filtered the query for indication and identified 173,330 reports with psoriasis indication in FAERS throughout the analyzed time frame. MACEs occurred in 4,206 patients treated with biologics. All the four biological classes had an elevated and similar reporting rates for MACEs relative to other alternative psoriasis treatments (PRR from 2.10 to 4.26; EB05 from 1.15 to 2.45). The descending order of association was IL-12/23 inhibitors>IL-17 inhibitors>IL-23 inhibitors>TNF inhibitors. The signal strength for myocardial infarction (PRR, 2.86; χ2, 296.27; EBGM 05, 1.13) was stronger than that for stroke, cardiac fatality, and death. All the biological classes demonstrated a little higher EBGM 05 score≥1 for the MACEs in patients aged 45-64 years. The time-to-onset of MACEs was calculated with a median of 228 days. Analysis of adverse event reports in the FAERS reflects the potential risk of MACEs associated with the real-world use of biological therapies in comparison to other alternative psoriasis treatments. Future long-term and well-designed studies are needed to further our knowledge regarding the cardiovascular safety profile of these agents.

(023) Can Artificial Intelligence Generate a Superior Introduction to a Systematic Review?

Abstract Introduction An iteration of artificial intelligence (AI), large language models (LLMs), such as ChatGPT, have recently gained popularity as a potential educational resource for patients, students, and researchers. LLMs utilize deep learning algorithms to predict the next word in a sequence based on a data library of 300 billion words. Recent studies have shown that while LLMs provide useful information, they are limited due to producing false and nonsensical information. A focus of studies has been on the utility of ChatGPT as an educational resource to patients and learners; however, no study has investigated the utilization of ChatGPT to write a scientific review. AI- generated systematic reviews would be valuable to the dynamic field of urology, especially in terms of research and innovation. Objective Considering the limitations of ChatGPT in performing data analysis, the aim of this project was to assess the utility of AI in constructing introductions of a systematic review on urologic issues and to compare these AI-generated introductions to published introductions written by humans. Methods ChatGPT (4.0), available at www.chat.openai.com, was used to construct three introductions to three different systematic reviews on the following topics: testosterone therapy and cardiovascular events, safety and efficacy of noninvasive therapies for Peyronie’s disease, and erectile dysfunction after radical prostatectomy. Introductions from published systematic reviews in each of the above topics were also obtained. Five different experts in these topics, who were blinded to which introductions were AI generated, reviewed then assessed the introductions for the following parameters: completeness, engagement, accuracy, logic, and clarity of objective. Introductions were assessed for baseline literary differences as well. Results There were no significant differences in the words, characters, number of sentences, and length of sentences between AI-generated introductions compared to those written by humans. There was a statistically significant difference in word length, with AI having a lower average of word length. AI scored significantly higher on average in the categories of completeness and engagement. We did not observe a significant difference between the two groups in the other categories. These observed findings demonstrate that AI can synthesize urologic literature (sexual medicine/men’s health) and generate introductions of a systematic review that are minimally noninferior and possibly superior regarding engagement and completeness. The limitations from this study include a small sample size (5) and the exclusive focus on AI-generated introductions rather than other AI-generated sections of a systematic review. Conclusions Our study reveals that ChatGPT, as an LLM, can provide a noninferior, possibly superior, introduction to a systematic review on topics of urologic sexual medicine and men’s health. As more facets of AI are developed, such as data integration and analysis, AI could be used to generate entire systematic reviews noninferior to those written by humans. Ethical principles of using AI in scientific literature should be examined and discussed prior to the development of more enhanced LLMs. Disclosure No.

Low-Carbohydrate/Ketogenic Diet and Coronary Artery Disease: A Brief Review of the Limited Evidence Between Them.

Nowadays there is a lot of interest among the general population regarding the ketogenic diet (KD) and its health benefits. Most people following this diet have a reduced intake of carbohydrates which gets replaced by calories coming from fat and protein. Even though KD has shown some limited health benefits, there is no consensus on long-term effects and cardiovascular safety profile, especially the relation of KD to coronary artery disease (CAD). This concern comes predominantly from increased fat intake in KD and other similar diets with decreased carbohydrate intake. One study has shown a link between type 1 diabetes and increased coronary artery calcium scores but, in addition to many other limitations, after adjusting for other cardiovascular risk factors, the association was not significant. Results from a subanalysis of the CARDIA prospective study found that progression of CAD measured by coronary artery calcium was more pronounced in people with low-carbohydrate intake, especially when the compensatory calorie intake was from animal sources as compared to plant-based sources. In addition, other studies have tried to find a link between this type of diet and other traditional cardiovascular risk factors that have been traditionally associated with CAD, especially comparing low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride (TAG) levels without clear clinical significance. Other studies found an association between KD and all-cause mortality, but no association with cardiovascular mortality. Lastly, there is an association between animal-based KD and all-cause mortality in patients who have already suffered a myocardial infarction. These findings are modified when accounting for saturated fat intake, which may give us an insight into possible mechanisms to explain these differences.

Cardiovascular Safety of Amphetamine/Dextroamphetamine versus Methylphenidate in Older Adults

Background: Recent epidemiological data has shown a sharp increase in stimulant use among older adults, which is notable as older adults may be especially vulnerable to their cardiovascular effects. Results of recent studies have shown an increase in cardiovascular events among older adults using stimulants; however, little data exists comparing cardiovascular safety of these agents head-to-head. Objective: To determine if the incidence of serious cardiovascular events, including myocardial infarction (MI), stroke/transient ischemic attack (TIA), or arrhythmia, are different in patients taking amphetamine/dextroamphetamine compared with patients taking methylphenidate. Methods: Retrospective chart review of veterans 50 years and older at the Veterans Affairs North Texas Health Care System (VANTHCS) who were first prescribed a stimulant between 2015 and 2021. The primary outcome was the difference in composite cardiovascular events between amphetamine/dextroamphetamine and methylphenidate. Secondary outcomes were the composite cardiovascular endpoints compared individually (MI, stroke/TIA, or arrhythmia). Hazard ratios were calculated based off of a time-to-event analysis displayed using a Kaplan-Meier curve for primary and secondary outcomes. Results: 466 veterans were screened for inclusion, 30 were excluded, and 436 were included. There was no difference found in composite cardiovascular events between the 241 veterans in the amphetamine/dextroamphetamine group and the 195 veterans in the methylphenidate group with 12 (5%) vs 8 (4.1%) events respectively (P = .6635). There was also no difference in time-to-event analysis (P = .4966). Conclusion: In elderly veterans, there was no difference found in incidence of major cardiovascular events with the use of amphetamine/dextroamphetamine compared with methylphenidate.