Evaluating the safety profile of semaglutide: an updated meta-analysis.

BACKGROUND: Semaglutide is increasingly used in the management of type 2 diabetes mellitus and obesity. Ensuring safety of this medication is crucial for its clinical use. This meta-analysis evaluates the safety profile of semaglutide across patient populations and treatment durations. METHODS: Randomized controlled trials assessing the safety of semaglutide versus placebo, with specified treatment durations were identified. The primary outcome was occurrence of any cardiovascular adverse events. Secondary outcomes included sudden cardiac death, adverse events leading to death, adverse events, gastrointestinal side effects, occurrence of hypoglycemia and new-onset neoplasm. RESULTS: A total of 23 studies met the inclusion criteria with a combined sample size of 57,911 participants. The meta-analysis revealed that the adverse event associated with semaglutide is gastrointestinal in nature (nausea and vomiting). No significant differences were observed between semaglutide and comparator groups. CONCLUSION: Semaglutide appears to have a favorable safety profile across diverse patient populations and treatment durations, supporting its continued use in the management of type 2 diabetes mellitus and obesity. It is generally well-tolerated, with a low incidence of adverse events. Clinicians should be aware of these findings and monitor patients accordingly. Further long-term studies are warranted to assess the safety of semaglutide in clinical practice.

Sex, racial, ethnic, and geographical disparities in major adverse cardiovascular outcome of glucagon-like peptide-1 receptor agonists among patients with and without diabetes mellitus: A meta-analysis of placebo-controlled randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been pivotal in the management of type 2 diabetes mellitus (T2DM) and in the reduction of major adverse cardiovascular events (MACE). Notably, large cardiovascular outcomes trials (CVOTs) demonstrate significant disparities in inclusion, based on sex, race, ethnicity, and geographical regions. OBJECTIVES: We examined the impact of GLP-1RA on MACE in patients with or without T2DM, based on sex, race, ethnicity, and geography. METHODS: A literature search for placebo controlled RCTs on GLP-1RA treatment was conducted. Thorough data extraction and quality assessment were carried out, focusing on key outcome, and ensuring a robust statistical analysis using a random effects model to calculate log odds ratio with 95% confidence intervals (CIs). RESULTS: A total of 8 CVOTs comprising 71,616 patients were included. Compared with placebo, GLP-1RAs significantly reduced MACE in both sexes (females: logOR -0.19, (95% CI, -0.28 to -0.10), p < 0.01] versus males: logOR -0.17, 95% CI, -0.23 to -0.10), p < 0.01], (p interaction NS)], and among Asians (logOR -34 (95% CI, -0.53 to -0.15, p < 0.01), and Whites (logOR -17 (95% CI, -0.25 to -0.09, p < 0.01), with no difference in MACE among Blacks and Hispanics. Odds of MACE were also reduced in Asia (logOR -31 (95% CI, -0.50 to -0.11, p < 0.01), and Europe (logOR -27 (95% CI, -0.40 to -0.13, p < 0.01), but there was no statistical difference in MACE in North America and Latin America. CONCLUSION: Significant reductions in MACE with GLP-1RA treatment were demonstrated between both sexes and across certain ethnicities and certain geographical regions.

Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression.

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Impact of Chronic Kidney Disease on the Outcomes of Patients Undergoing Percutaneous Left Atrial Appendage Occlusion: Insights from a Large National Database.

BACKGROUND: Studies exploring the effectiveness and safety of percutaneous left atrial appendage occlusion (pLAAO) in patients with chronic kidney disease (CKD) are limited. OBJECTIVES: We aimed to analyze trends and outcomes following pLAAO in patients with CKD. METHODS: We utilized the National Inpatient Sample (NIS) to identify hospitalizations for pLAAO from 2016-2020 and further identified cases with concomitant CKD. The primary outcome was mortality, and secondary outcomes were cerebrovascular accidents, major bleeding, vasopressor requirements, percutaneous coronary intervention, cardiac arrest, acute respiratory failure, transfusion, length of stay (LOS), and total hospital charges. Multivariable logistic regression was performed to further adjust for covariates. RESULTS: A total of 89,309 pLAAO procedures from 2016 to 2020 were identified, of which 21,559 (24.1%) reported concomitant CKD, with males comprising the majority (62.2%). An increasing trend in pLAAO procedures was seen from 2.24 to 13.9 per 10,000 patients from 2016 to 2020. Despite patients with CKD having a higher rate of most comorbidities, there was no difference in mortality (non-CKD vs. CKD, 0.07% vs. 0.42%; aOR: 1.3, 95% CI: 0.4 - 4.4, p=0.686) and complications for CKD and non-CKD patients, while CKD patients had longer LOS and higher total hospital charge. No significant sex differences in outcomes among CKD patients were observed except for a longer LOS in females. CONCLUSION: Despite generally having more comorbidities, outcomes of patients with CKD following pLAAO are similar to those without CKD, suggesting that pLAAO can be offered as a safe option for the treatment of AF in eligible patients with CKD.

Glucagon-like peptide-1 receptor agonists modestly reduced blood pressure among patients with and without diabetes mellitus: A meta-analysis and meta-regression.

AIM: The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. METHODS: A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. RESULTS: Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. CONCLUSION: Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.

Sex differences in trends and outcomes of acute myocardial infarction with mechanical complications in the United States.

BACKGROUND: Mechanical complications (MC) are rare but significant sequelae of acute myocardial infarction (AMI). Current data on sex differences in AMI with MC is limited. METHODS: We queried the National Inpatient Sample database to identify adult patients with the primary diagnosis of AMI and MC. The main outcome of interest was sex difference in-hospital mortality. Secondary outcomes were sex differences in the incidence of acute kidney injury (AKI), major bleeding, use of inotropes, permanent pacemaker implantation (PPMI), performance of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), surgery (VSD repair and MV surgery), pericardiocentesis, use of mechanical circulatory support (MCS), ischemic stroke, and mechanical ventilation. RESULTS: Among AMI-MC cohort, in-hospital mortality was higher among females compared to males (41.24% vs 28.13%: aOR 1.39. 95% CI 1.079-1.798; p = 0.01). Among those who had VSD, females also had higher in-hospital mortality compared to males (56.7% vs 43.1%: aOR 1.74, 95% CI 1.12-2.69; p = 0.01). Females were less likely to receive CABG compared to males (12.03% vs 20%: aOR 0.49 95% CI 0.345-0.690; p < 0.001). CONCLUSION: Despite the decreasing trend in AMI admission, females had higher risk of MC and associated mortality. Significant sex disparities still exist in AMI treatment.