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Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium–glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data—crystallising the key findings, from safety to efficacy—and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.

The cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout remains equivocal. Febuxostat had a better safety outcome compared with allopurinol. In this systematic review and meta‐analysis, we searched MEDLINE and Embase for articles published between March 1, 2000 and April 4, 2021, without any language restrictions. We did a systematic review and meta‐analysis of included clinical trials to evaluate the cardiovascular safety of febuxostat compared to allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). From 240 potentially relevant citations, 224 papers were excluded; 16 studies were ultimately included in the analysis. Febuxostat had a better safety outcome compared with allopurinol，which was the composite of urgent coronary revascularization (OR: 0.84, 95% CI: 0.77–0.90, p < .0001) and stroke (OR: 0.87, 95% CI: 0.79–0.97, p = .009). However, that difference was not found in nonfatal myocardial infarction (OR: 0.99, 95% CI: 0.80–1.22, p = .91), cardiovascular related mortality (OR: 0.98, 95% CI: 0.69–1.38, p = .89) and all‐cause mortality (OR: 0.93, 95% CI: 0.75–1.15, p = .52). No significant differences in cardiovascular related mortality and all‐cause mortality were observed across any subgroup. This meta‐analysis adds new evidence regarding the cardiovascular safety of febuxostat in patients. Initiation of febuxostat in patients was not associated with an increased risk of death or serious cardiovascular related adverse events compared with allopurinol.

Abstract Sclerostin, which is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials, romosozumab, an antibody against sclerostin, increases bone mineral density and reduces the risk of fractures compared with placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the 2 treatment groups. Compared with alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and post hoc analyses should therefore be interpreted with caution; however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.

Background Patients with type 2 diabetes (T2D) and hypertension are at increased risk of adverse cardiovascular (CV) events. However, real-world evidence comparing the CV effectiveness and safety of major hypoglycemic drug classes remains limited in this population. This multicenter pooled analysis aims to directly compare the CV outcomes and safety profiles of these key agents in patients with T2D and hypertension. Methods We analyzed electronic health records from two databases in a cohort study of T2D patients with hypertension who had initiated metformin as first-line therapy. Propensity score matching (PSM) and Cox proportional hazards models were used to compare the risks of 3-/4-point major adverse cardiovascular events (MACE) and safety outcomes across drug classes added to metformin: insulin, sulfonylureas (SUs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), glinides, acarbose, and sodium-glucose transporter 2 inhibitors (SGLT2is). Results Compared with insulin, GLP-1 RAs, DPP4is, and glinides were associated with a lower risk of 3-point MACE (HR: 0.48 [0.31–0.76], 0.70 [0.57–0.85], and 0.70 [0.52–0.94], respectively). SUs were associated with a higher risk of 3-point MACE compared with DPP4is (HR: 1.30 [1.06–1.59]). DPP4is, GLP-1 RAs, and glinides showed a lower risk of 3-point MACE compared with acarbose (HR: 0.62 [0.51–0.76], 0.47 [0.29–0.75], and 0.59 [0.43–0.81], respectively). Similar patterns were observed for 4-point MACE. For safety outcomes, DPP4is were associated with a reduced risk of chronic kidney disease, while insulin use was associated with reduced risks of inflammatory polyarthritis and insomnia. However, DPP4is were associated with higher risks of coronary atherosclerotic diseases and hypertensive heart disease. Conclusions This study highlights the differential cardiovascular effectiveness and safety profiles of hypoglycemic therapies in real-world settings, providing valuable insights for optimizing T2D management, particularly in patients with comorbid hypertension.

Cardiovascular disease (CVD) is one of the most common diabetes-associated complications, as well as a leading cause for death in type 2 diabetes patients (T2D). Despite the well-known correlation between the two, up until the 2008 FDA industry guidance for licensing of new anti-hyperglycemic drugs, which required an investigation of cardiovascular outcomes (CVO) of glucose-lowering agents, only a few studies had looked into the relationship between glucose lowering drugs and cardiovascular (CV) risk. Thereafter, CVOT design has focused on non-inferiority short-term studies on high-risk patient populations aiming at capturing CV safety issues. Despite the wealth of information and useful data provided by CVOTs, this approach still suffers from certain limitations. The present review will condense the main results of the most recently completed CVOTs, reflect on the lessons learned, discuss on the issues presented by current CVOT design and offer some suggestions for improvement.

The optimal timing for initiating insulin therapy in patients with type 2 diabetes (T2D) remains uncertain and varies among clinical guidelines. This retrospective cohort study analyzed claims data to include insulin-naïve T2D patients aged ≥ 20 years who intensified treatment using either insulin or non-insulin therapies between 2012 and 2021. Cox proportional hazards models were applied to estimate hazard ratios (HRs) for major adverse cardiovascular events (MACE) and all-cause mortality, with adjustments for sex, age interval, index year interval, number of outpatient visits, number of inpatient admissions, diabetes duration, Charlson Comorbidity Index (CCI), Diabetes Complication Severity Index (DCSI), the number of prior antidiabetic medications, medications for hypertension, hyperlipidemia, antiplatelets, and anticoagulants. Subgroup analyses stratified by sex, age, the number of prior antidiabetic medications and types of insulin were also performed. Compared to non-insulin intensification, insulin therapy was associated with significantly higher risks of MACE and all-cause mortality. The adjusted HRs (95% confidence intervals [CIs]) were 2.78 (2.64–2.92) for MACE and 4.74 (4.63–4.85) for all-cause mortality. Subgroup analyses revealed consistently elevated risks across all patient groups, with the smallest risk increases observed in patients who had previously used three non-insulin drugs before initiating insulin therapy (HRs for MACE: 2.62 [2.13–3.22]; all-cause mortality: 3.05 [2.68–3.49]). Among insulin types, long-acting insulin was associated with the lowest risk increases (MACE HR: 1.34 [1.19–1.51]; all-cause mortality HR: 1.90 [1.78–2.03]). In conclusion, treatment intensification with insulin was linked to increased risks of MACE and all-cause mortality. The lowest risks were observed in patients initiating long-acting insulin following prior therapy with three non-insulin drugs. These findings highlight the need for careful patient evaluation and individualized decision-making when initiating insulin therapy in T2D management.

Background Current evidence about the cardiovascular safety of glucagon-like peptide-1 receptor agonist (GLP-1ra) possesses limited generalizability to real-world patients with type 2 diabetes (T2D) in usual practice. This study aimed to investigate the comparative cardiovascular safety of GLP-1ra in comparisons with dipeptidyl peptidase-4 inhibitor (DPP-4i), sulfonylurea (SU), and insulin in a real-world population with T2D. Methods Adults with newly-diagnosed T2D were identified from Taiwan’s National Health Insurance Research Database in 2003–2014. A prevalent new-user cohort design was adopted to include a broad representation of real-world T2D patients being treated with GLP-1ra. The between-group comparability of baseline patient characteristics was achieved by matching on (1) initiation time of study drugs, (2) prior exposure to glucose-lowering agents, and (3) diabetes severity and complications, comorbidities, and concomitant cardiovascular medications using propensity scores. The primary outcome was a composite of cardiovascular disease (CVD) events and assessed up to the end of 2015. Cox modeling was employed to assess the association between study drugs and outcomes. Results A total of 3195 GLP-1ra stable users was identified in 2011-2014. 1893, 1829, and 1367 GLP-1ra stable users were 1:1 matched to DPP-4i, SU and insulin users, respectively. Compared to DPP-4i, SU and insulin, the use of GLP-1ra was associated with a lower risk of composite CVD events [hazard ratio (95% confidence interval) 0.73 (0.57–0.96), 0.76 (0.57–1.00), and 0.81 (0.62–1.07), respectively]. Subgroup analyses revealed that GLP-1ra versus DPP-4i yielded a greater cardiovascular benefit in those without established CVD versus those with established CVD. Conclusions This comparison study extends the supporting evidence for the cardiovascular safety of GLP-1ra to a broad spectrum of real-world T2D patients using GLP-1ra.

Multiple myeloma (MM) is a leading cause of hematopoietic cancer-related mortality, accounting for 20% of deaths. MM-targeted therapies have demonstrated efficacy, and since 2015, the United States Food and Drug Administration (FDA) has approved five targeted drugs. However, their cardiovascular safety has not been comprehensively evaluated. This study aimed to investigate the association between MM-targeted therapy and cardiovascular adverse events (AEs). Disproportionality analysis was conducted on reports from the FDA AE Reporting System database from 2014 to the second quarter of 2023. Cardiovascular AEs were grouped into nine narrow categories using the Standardized Medical Dictionary for Regulatory Activities Queries (SMQs). A total of 3,228 cardiovascular AE cases involving MM-targeted therapy were extracted and analyzed. Significant disproportionality was identified for daratumumab, elotuzumab, and isatuximab. Among the nine narrow SMQ categories, the three most reported cardiovascular AEs were cardiomyopathy, cardiac arrhythmias, and embolic and thrombotic events. Noninfectious myocarditis/pericarditis, cardiac arrhythmias, and embolic and thrombotic events exhibited the strongest signal strengths. The cardiovascular AE risk was higher within the first month and gradually decreased thereafter; however, it increased rapidly again after 1 year. This trend was observed for all cardiovascular AEs. The Kaplan-Meier curve and the log-rank test revealed that isatuximab and elotuzumab exhibited a significantly lower probability of cardiovascular AEs than daratumumab ( < 0.001). MM-targeted therapy is significantly associated with an increased risk of previously unknown cardiovascular AE profiles, with the range and onset differing among various drugs, thereby warranting specific monitoring and appropriate management.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat fever, pain, and inflammation. Concerns regarding their cardiovascular safety have been raised. However, the underlying mechanism behind these events remains unknown. We aim to investigate the cardiovascular safety signals and receptor mechanisms of NSAIDs, employing a comprehensive approach that integrates pharmacovigilance and pharmacodynamics. This study utilized a pharmacovigilance-pharmacodynamic approach to evaluate the cardiovascular safety of NSAIDs and explore potential receptor mechanisms involved. Data were analyzed using the OpenVigil 2.1 web application, which grants access to the FDA Adverse Event Reporting System (FAERS) database, in conjunction with the BindingDB database, which provides target information on the pharmacodynamic properties of NSAIDs. Disproportionality analysis employing the Empirical Bayes Geometric Mean (EBGM) and Reporting Odds Ratio (ROR) methods was conducted to identify signals for reporting cardiovascular-related adverse drug events (ADEs) associated with 13 NSAIDs. This analysis encompassed three System Organ Classes (SOCs) associated with the cardiovascular system: blood and lymphatic system disorders, cardiac disorders, and vascular disorders. The primary targets were identified through the receptor-NSAID interaction network. Ordinary least squares (OLS) regression models explored the relationship between pharmacovigilance signals and receptor occupancy rate. A total of 201,231 reports of cardiovascular-related ADEs were identified among the 13 NSAIDs. Dizziness, anemia, and hypertension were the most frequently reported Preferred Terms (PTs). Overall, nimesulide and parecoxib exhibited the strongest signal strengths of ADEs at SOC levels related to the cardiovascular system. On the other hand, our data presented naproxen and diclofenac as drugs of comparatively low signal strength. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were identified as central targets. OLS regression analysis revealed that the normalized occupancy rate for either COX-1 or COX-2 was significantly inversely correlated with the log-transformed signal measures for blood and lymphatic system disorders and vascular disorders, and positively correlated with cardiac disorders and vascular disorders, respectively. This suggests that higher COX-2 receptor occupancy is associated with an increased cardiovascular risk from NSAIDs. Cardiovascular safety of NSAIDs may depend on pharmacodynamic properties, specifically, the percentage of the occupied cyclooxygenase isoenzymes. More studies are needed to explore these relations and improve the prescription process.

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.