Cardiovascular Outcome Trials Research Articles

GLP-1 Receptor Agonists and Cardiovascular Disease: What Do Clinicians Need to Know?

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining importance due to their effects on cardiovascular parameters. This review discusses the findings of dedicated cardiovascular outcome trials of GLP-1RAs and summarizes their utility to help clinicians understand their role in cardiovascular disease. Patients with diabetes mellitus are at an increased risk of cardiovascular disease. Cardiovascular outcome trials have shown GLP-1RAs decrease the primary composite outcome of the first occurrence of major adverse cardiovascular events (MACE) in patients with diabetes. Additionally, select GLP-1RAs have also shown improved cardiovascular outcomes in patients without diabetes who are either overweight (BMI ≥ 27), or obese (BMI ≥ 30). There have also been encouraging results in patients with heart failure with preserved ejection fraction. There is increasing evidence showing GLP-1RAs are beneficial across the cardiometabolic spectrum of disease. Implementation of these therapeutics into clinical practice is important to improve cardiovascular risk.

#2496 Effect of semaglutide on kidney outcomes in people with overweight or obesity and established cardiovascular disease in the SELECT trial

Abstract Background and Aims Obesity is an important risk factor for declining kidney function and albuminuria. Secondary analyses of cardiovascular outcome trials in people with type 2 diabetes suggest that the glucagon-like peptide-1 receptor agonist semaglutide has the potential to reduce kidney function deterioration. Semaglutide reduced the primary endpoint of major adverse cardiovascular events by 20% in the randomised controlled SELECT trial in people with overweight or obesity without diabetes. The present report is the prespecified analysis on secondary and exploratory kidney outcomes in SELECT. Method The main kidney endpoint was the time from randomisation to first occurrence of a 5-component nephropathy composite comprising: death from kidney causes; initiation of chronic kidney replacement therapy (dialysis or transplantation); onset of persistent estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2; persistent ≥50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria. Persistence was defined as at least two measures at least 4 weeks apart. Patients were randomised to once-weekly subcutaneous semaglutide 2.4 mg or placebo. Blood and urine samples for eGFR and urinary albumin-to-creatinine ratio (UACR) were collected at screening, at 20, 52, 104, 156, 208 weeks of follow-up and at the end of treatment. Analyses were of in-trial data and used Cox regression and mixed models for repeated measures. Results A total of 8803 patients were assigned to semaglutide and 8801 to placebo. The median follow-up was 182 weeks. The main composite nephropathy endpoint occurred in fewer of those assigned semaglutide (1.8% [155/8803]) than placebo (2.2% [198/8801]): hazard ratio 0.78 [95% confidence interval (CI) 0.63, 0.96]; p = 0.02 (Fig. 1). This effect on the main endpoint was driven by the treatment effect on onset of macroalbuminuria and, to a lesser extent, persistent ≥50% reduction in eGFR. At the prespecified 104-week time point, eGFR had declined less in the semaglutide than placebo arm, giving a treatment effect of 0.75 mL/min/1.73 m2 [95% CI 0.43, 1.06]; p < 0.001 (Fig. 2A). The treatment effect on eGFR at 104 weeks was 0.57 mL/min/1.73 m2 [95% CI 0.26, 0.89] among those with eGFR ≥60 mL/min/1.73 m2 (N = 15 638) at baseline and was 2.19 mL/min/1.73 m2 [95% CI 1.00, 3.38] in those with eGFR <60 mL/min/1.73 m2 (N = 1908) at baseline. At 104 weeks the proportionate increase in UACR was less in the semaglutide than the placebo arm, with a treatment effect of –10.7% [95% CI –13.2, –8.2]; p < 0.001 (Fig. 2B). The treatment effect on UACR at 104 weeks was –8.1% [95% CI –10.6, –5.6], –27.2% [95% CI –35.3, –18.1] and –31.4% [95% CI –54.9, 4.3] in those with normo- (N = 14 848), micro- (N =1968) and macroalbuminuria (N = 325) at baseline, respectively. Semaglutide was not associated with any excess of acute kidney injury, regardless of baseline eGFR. Conclusion These prespecified secondary analyses suggest a beneficial effect of once-weekly subcutaneous semaglutide 2.4 mg on a composite kidney endpoint in people with overweight or obesity and established cardiovascular disease. Significant benefits for both eGFR and UACR were found, including clinically relevant lesser eGFR decline in those with baseline eGFR <60 mL/min/1.73 m2.

#615 Generalisability of cardiovascular RCTs to patients with chronic kidney disease in clinical practice: a comparison between RCTs and real-world data

Abstract Background and Aims Randomised controlled trials (RCTs) often apply stringent eligibility criteria, which could limit the external applicability of RCTs to patients in routine clinical practice. This is specifically troublesome in the setting of chronic kidney disease (CKD) given that kidney disease is commonly used as an ineligibility criterion in RCTs. In this pilot study we estimated the eligibility of patients with CKD in routine clinical practice in five major cardiovascular outcome trials - CREDENCE, DAPA-CKD, CIBIS II, CIBIS III, and AUGUSTUS - and described reasons for ineligibility. Method We included patients with CKD (defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or an urinary albumin creatinine ratio (UACR) >3 mg/mmol present for >3 months) from the Utrecht Patient Oriented Database (UPOD) who visited a cardiovascular outpatient clinic in the University Medical Centre Utrecht between 2012 and 2019. The eligibility criteria were extracted from the selected RCTs and consequently modelled on the patients from UPOD. The percentage of eligible patients and reasons for ineligibility were described descriptively. The percentage of eligible patients for CIBIS II and CIBIS III were only calculated for patients with heart failure, and for the AUGUSTUS trial for patients with coronary artery disease as patients with these conditions were targeted. Patients could not fulfil multiple inclusion criteria and or meet multiple exclusion criteria or both. Results In total, 9005 UPOD patients with CKD were included. Patients had a mean age of 65 ± 14 years, 42% was female, mean eGFR was 49 ± 17, 1741 (19%) had a history of atherosclerotic cardiovascular disease, and 765 (8%) of heart failure. Overall, 0.05% of patients would be eligible for the DAPA-CKD trial and 0% for the CREDENCE trial. Of included patients with heart failure, 2% would have been eligible for CIBIS II and 3% for CIBIS III. Of included patients with coronary artery disease, 2% would have been eligible for the AUGUSTUS trial. Main reasons for ineligibility for DAPA-CKD were not fulfilling the inclusion criteria for UACR (52%), eGFR (20%), or the prescription of RAAS-inhibitors (arb) (49%) or meeting the exclusion criteria for primary kidney disease (PRD, 6%), or a kidney transplant (15%), or other comorbidities. Similarly, patients were often ineligible for the CREDENCE trial because they did not fulfill the inclusion criteria for UACR (48%), eGFR (18%), HbA1c (35%), or prescription of a RAAS-inhibitor (43%) or met one of the exclusion criteria for PRD (29%), cardiovascular disease (23%), or prescription of a mineralocorticoid receptor antagonist (10%). For CIBIS II, main reasons for ineligibility were not fulfilling the inclusion criteria for left-ventricular ejection fraction (LVEF, 50%) or prescription of an ace-inhibitor (42%) or diuretic (33%) or meeting the exclusion criteria of coronary artery disease (17%) or prescription of a calcium-channel blocker (16%). For CIBIS III, patients were also ineligible because they were not fulfilling the inclusion criteria for age (46%), LVEF (46%), or prescription of diuretics (31%) or met the exclusion criteria for serum creatinine (9%) or prescription of an angiotension receptor blocker (14%). Lastly, for the AUGUSTUS trial, patients were mainly ineligible due to not fulfilling the inclusion criteria of atrial fibrillation (79%) or percutaneous coronary interventions (PCI, 91%) or meeting the eGFR exclusion criteria (14%). Conclusion Based on this pilot study, less than 3% of patients with CKD in routine clinical practice would be eligible to participate in cardiovascular RCTs. Patients were often ineligible because they did not fulfil the inclusion criteria and a substantial number of patients was ineligible due to kidney disease. The low eligibility rate of patients with CKD in cardiovascular trials could limit the generalisability of results to patients with CKD treated in practice. To improve generalisability, RCTs in patients with CKD should aim to include more patients who reflect the patients with CKD treated in practice.

Glucagon-like peptide-1 receptor agonists and stroke: A systematic review and meta-analysis of cardiovascular outcome trials.

In patients surviving stroke, approximately 15% and 60% exhibit concurrent diabetes mellitus and overweight/obesity, respectively, necessitating heightened secondary prevention efforts. Despite glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrating improved outcomes for those with diabetes mellitus or obesity, their underutilization persists among eligible individuals. This systematic review and meta-analysis investigated the impact of GLP-1 RAs on stroke risk. The findings aim to optimize the implementation of this therapeutic strategy in patients surviving stroke with diabetes mellitus or obesity. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we systematically reviewed MEDLINE and Scopus until 15 November 2023. Eligible studies included randomized cardiovascular outcome trials (CVOTs) with individuals, with or without type 2 diabetes, randomized to either GLP-1 RA or placebo. The outcomes were total strokes, non-fatal strokes, and fatal strokes. Analyses were conducted using RevMan 5.4.1. Among 1369 screened studies, 11 were eligible, encompassing 82,140 participants (34.6% women) with a cumulative follow-up of 247,596 person-years. In the GLP-1 RAs group, the stroke rate was significantly lower compared to placebo (RR: 0.85, 95% CI: 0.77-0.93; NNT: 200), showing no heterogeneity or interaction with administration frequency (daily vs weekly). In addition, the GLP-1 RAs group exhibited a significantly lower rate of non-fatal strokes compared to placebo (RR: 0.87, 95% CI: 0.79-0.95; NNT: 250), with no heterogeneity or interaction based on administration frequency, route (oral vs subcutaneous), or diabetes presence. In this meta-analysis of 11 CVOTs with 82,140 participants, GLP-1 RAs demonstrated a 16% relative reduction in stroke risk compared to placebo. This finding may increase implementation of GLP-1 RAs by stroke specialists in individuals with stroke and comorbid diabetes mellitus or obesity. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Dipeptidyl peptidase-4 inhibitors and the risk of infection: A systematic review and meta-analysis of cardiovascular outcome trials.

Since adverse events during treatment affect adherence and subsequent glycemic control, understanding the safety profile of oral anti-diabetic drugs is imperative for type 2 diabetes mellitus (T2DM) therapy. To evaluate the risk of infection in patients with T2DM treated with dipeptidyl-peptidase 4 (DPP-4) inhibitors. Electronic databases were searched. The selection criteria included randomized controlled trials focused on cardiovascular outcomes. In these studies, the effects of DPP-4 inhibitors were directly compared to those of either other active anti-diabetic treatments or placebo. Six trials involving 53616 patients were deemed eligible. We calculated aggregate relative risks employing both random-effects and fixed-effects approaches, contingent upon the context. The application of DPP-4 inhibitors showed no significant link to the overall infection risk [0.98 (0.95, 1.02)] or the risk of serious infections [0.96 (0.85, 1.08)], additionally, no significant associations were found with opportunistic infections [0.69 (0.46, 1.04)], site-specific infections [respiratory infection 0.99 (0.96, 1.03), urinary tract infections 1.02 (0.95, 1.10), abdominal and gastrointestinal infections 1.02 (0.83, 1.25), skin structure and soft tissue infections 0.81 (0.60, 1.09), bone infections 0.96 (0.68, 1.36), and bloodstream infections 0.97 (0.80, 1.18)]. This meta-analysis of data from cardiovascular outcome trials revealed no heightened infection risk in patients undergoing DPP-4 inhibitor therapy compared to control cohorts.

Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m-2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 .

Cardiovascular and renal outcomes of glucagon-like peptide 1 receptor agonists among patients with and without type 2 diabetes mellitus: A meta-analysis of randomized placebo-controlled trials

BackgroundMultiple cardiovascular outcomes trials (CVOTs) have shown the efficacy of GLP-1RAs in reducing major adverse cardiovascular events (MACEs) for high-risk patients. However, some CVOTs failed to demonstrate cardiovascular benefits. ObjectivesWe analyzed the impact of GLP-1RA on cardiovascular and renal outcomes in patients with or without T2DM, with subgroup analysis based on sex, estimated glomerular filtration rate (eGFR), body mass index (BMI), and history of cardiovascular disease (CVD). MethodsA comprehensive database search for placebo-controlled RCTs on GLP-1RA treatment was conducted until April 2024. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with log odds ratios and 95 % confidence intervals (CIs). ResultsA total of 13 CVOTs comprising 83,258 patients were included. GLP-1RAs significantly reduced MACE (OR 0.86, 95 % CI: 0.80 to 0.94, p < 0.01) all-cause mortality OR 0.87, 95 % CI: 0.82 to 0.93, p < 0.001, CV mortality (OR 0.87, 95 % CI: 0.81 to 0.94, p < 0.001), stroke (fatal: OR 0.74, 95 % CI: 0.56 to 0.96, p = 0.03; non-fatal: OR 0.87, 95 % CI: 0.79 to 0.96, p = 0.005), coronary revascularization (OR 0.86, 95 % CI: 0.74 to 0.99, p = 0.023), and composite kidney outcome (OR 0.76, 95 % CI: 0.67 to 0.85, p < 0.001. GLP-1RA significantly reduced MACE in both sexes. Furthermore, GLP-1RA reduced MACE regardless of CVD history, BMI, and eGFR level. ConclusionSignificant reductions in MACE, overall and CV mortality, stroke, coronary revascularization, and composite kidney outcome with GLP-1RA treatment were noted across all subgroups.

Glucagonlike peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in ischemic strokes with diabetes 2.

Cardiovascular outcome trials demonstrate that glucagonlike peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes (T2D), whereas dipeptidyl peptidase-4 inhibitors (DPP-4is) have not shown cardiovascular benefits. We compared acute ischemic stroke (AIS) with T2D treated with either a GLP-1RA or DPP-4i prior to the index stroke. This national cohort study included AIS patients with T2D from 2017 to 2020 in Denmark who were users of a GLP-1RA or DPP-4i. To be categorized as a user, we required at least 12 months of exposure and no concurrent treatment with another newer glucose-lowering medication during the last 3 months prior to the index stroke. GLP-1RA users were compared to users of DPP-4i while adjusting for the calendar year of index stroke, age, sex, comorbidity, and socioeconomic factors. The study included 1567 AIS events with T2D; 593 were users of GLP-1RA and 974 of DPP-4i. The absolute risk of a very severe stroke was 2.4% (95% confidence interval [CI] = 1.2-3.7) in GLP-1RA users and 6.1% (95% CI = 4.6-7.7) in DPP-4i users. The corresponding adjusted risk ratio (aRR) of GLP-1RA versus DPP-4i was 0.49 (95% CI = 0.24-1.00). The aRRs of 30-day and 365-day mortality were 0.55 (95% CI = 0.32-0.94) and 0.72 (95% CI = 0.53-0.98), respectively. The risk of a very severe stroke as well as the 30-day and 365-day poststroke mortality rates were lower among the AIS patients with comorbid T2D receiving GLP-1RA prior to the index stroke compared to those receiving DPP-4i. Hence, GLP-1RA may improve stroke outcomes in comparison with DPP-4i.

Time to benefit of colchicine in patients with cardiovascular disease: A pooled analysis of randomized controlled trials

BackgroundLow-dose colchicine has been shown to lower major adverse cardiovascular events (MACE) among those with cardiovascular disease (CVD). It remains unclear how long a CVD patient needs to live to potentially benefit from colchicine. Our study aimed to determine the time to benefit (TTB) of colchicine in individuals with CVD. MethodsLiterature searches were performed in PubMed for the cardiovascular outcome trial of colchicine in patients with CVD until October 12, 2023. The primary outcome measured was MACE. Reconstructed individual participant data (IPD) and the stratified Cox proportional hazards model were used to calculate the hazard ratio (HR) and 95 % confidence interval (CI) to estimate the efficacy of colchicine, and Weibull survival curves were fitted to estimate TTB for specific absolute risk reduction (ARR) thresholds (0.002, 0.005, and 0.01). ResultsFour trials randomizing 11,594 adults aged between 59.8 and 66.5 years were included (follow-up duration: 12–28.6 months). Compared with placebo, colchicine reduced the risk of MACE (HR 0.68, 95 % CI: 0.60 to 0.78) but had no impact on cardiovascular and all-cause mortality. A TTB of 11.0 months (95 % CI: 0.59 to 21.3) was estimated to be needed to prevent 1 MACE in 100-colchicine-treated patients. The TTB for acute coronary syndrome was similar compared to stable coronary artery disease (10.7 vs. 11.2 months for ARR = 0.010). ConclusionsBy using reconstructed IPD, this pooled analysis demonstrated that colchicine was associated with reduced nonfatal MACE, and the TTB was approximately 11.0 months to prevent 1 MACE per 100 patients.

Glucagon-like peptide-1 receptor agonists: new strategies and therapeutic targets to treat atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of cardiovascular mortality and is increasingly prevalent in our population. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can safely and effectively lower glucose levels while concurrently managing the full spectrum of ASCVD risk factors and improving patients' long-term prognosis. Several cardiovascular outcome trials (CVOTs) have been carried out to further investigate the cardiovascular benefits of GLP-1RAs. Analyzing data from CVOTs can provide insights into the pathophysiologic mechanisms by which GLP-1RAs are linked to ASCVD and define the use of GLP-1RAs in clinical practice. Here, we discussed various mechanisms hypothesized in previous animal and preclinical human studies, including blockade of the production of adhesion molecules and inflammatory factors, induction of endothelial cells' synthesis of nitric oxide, protection of mitochondrial function and restriction of oxidative stress, suppression of NOD-like receptor thermal protein domain associated protein three inflammasome, reduction of foam cell formation and macrophage inflammation, and amelioration of vascular smooth muscle cell dysfunction, to help explain the cardiovascular benefits of GLP-1RAs in CVOTs. This paper provides an overview of the clinical research, molecular processes, and possible therapeutic applications of GLP-1RAs in ASCVD, while also addressing current limitations in the literature and suggesting future research directions.

Remnant cholesterol, LDL cholesterol, and apoB absolute mass changes explain results of the PROMINENT trial

Background and aimsThe PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. MethodsAmong 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. ResultsIn the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (−0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94–0.99) for a -7 mg/dL (−0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01–1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01–1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91–1.15) in the PROMINENT trial. ConclusionsAbsolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.

SGLT2 Inhibitors- The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review.

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.

Use of the Win Ratio Analysis in Critical Care Trials.

Composite outcomes are commonly used in critical care trials to estimate the treatment effect of an intervention. A significant limitation of classical analytic approaches is that they assign equal statistical importance to each component in a composite, even if these do not have the same clinical importance (i.e., in a composite of death and organ failure, death is clearly more important). The win ratio (WR) method has been proposed as an alternative for trial outcomes evaluation, as it effectively assesses events based on their clinical relevance (i.e., hierarchical order) by comparing each patient in the intervention group with their counterparts in the control group. This statistical approach is increasingly used in cardiovascular outcome trials. However, WR may be useful to unveil treatment effects also in the critical care setting, because these trials are typically moderately sized, thus limiting the statistical power to detect small differences between groups, and often rely on composite outcomes that include several components of different clinical importance. Notably, the advantages of this approach may be offset by several drawbacks (such as ignoring ties and difficulties in selecting and ranking endpoints) and challenges in appropriate clinical interpretation (i.e., establishing clinical meaningfulness of the observed effect size). In this perspective article, we present some key elements to implementing WR statistics in critical care trials, providing an overview of strengths, drawbacks, and potential applications of this method. To illustrate, we conduct a reevaluation of the HYPO-ECMO (Hypothermia during Venoarterial Extracorporeal Membrane Oxygenation) trial using the WR framework as a case example.

Impact of empagliflozin on insulin needs in patients with heart failure and diabetes: An EMPEROR-Pooled analysis.

To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time. We performed a post-hoc analysis of pooled patient-level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR-Reduced and EMPEROR-Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation. Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63-0.86; using insulin, hazard ratio 0.81, 95% CI 0.66-1.00, pinteraction = .49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction = .75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction = .30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow-up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50-0.88). Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes.

Effect of statin add-on therapy on cardiovascular mortality.

Cardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk reduction, but their effect on CV mortality has not been reviewed. This review describes CV outcomes trials of add-on therapies to statins, highlighting findings related to the primary composite CV endpoints and the more patient-centric endpoint of CV-related mortality. Add-on ezetimibe met its primary composite CV endpoint vs. statin alone (P = 0.016); however, the individual endpoint of death from CV causes did not differ between groups. Add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors achieved the primary composite CV endpoints in the respective CV outcomes trials for alirocumab (P < 0.001) and evolocumab (P < 0.001); however, neither CV outcomes trial found a difference vs. placebo in CV-related mortality. In its CV outcomes trial, icosapent ethyl added to statin therapy significantly reduced the occurrence of the primary composite CV endpoint (P < 0.001) and the individual endpoint of risk of CV-related death (P = 0.03) vs. placebo. A CV outcomes trial of bempedoic acid monotherapy achieved its primary composite CV endpoint vs. placebo (P = 0.004) but not the endpoint of death from CV causes. Statin add-on therapies achieved their CV outcomes trial composite CV endpoints. Proprotein convertase subtilisin/kexin type 9 inhibitors and icosapent ethyl have approved indications for CV risk reduction. Only add-on therapy with icosapent ethyl demonstrated a significant reduction in CV mortality in the overall intent-to-treat population, possibly due to the unique pleiotropic mechanisms of eicosapentaenoic acid independent of lipid-lowering effects.

Computed tomographic angiography measures of coronary plaque in clinical trials: opportunities and considerations to accelerate drug translation.

Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but new pharmacologic therapies require increasingly large and expensive cardiovascular outcome trials to assess their potential impact on MACE and to obtain regulatory approval. For many disease areas, nearly a half of drugs are approved by the U.S. Food & Drug Administration based on beneficial effects on surrogate endpoints. For cardiovascular disease, only low-density lipoprotein cholesterol and blood pressure are approved as surrogates for cardiovascular disease. Valid surrogates of CAD are urgently needed to facilitate robust evaluation of novel, beneficial treatments and inspire investment. Fortunately, advances in non-invasive imaging offer new opportunity for accelerating CAD drug development. Coronary computed tomography angiography (CCTA) is the most advanced candidate, with the ability to measure accurately and reproducibly characterize the underlying causal disease itself. Indeed, favourable changes in plaque burden have been shown to be associated with improved outcomes, and CCTA may have a unique role as an effective surrogate endpoint for therapies that are designed to improve CAD outcomes. CCTA also has the potential to de-risk clinical endpoint-based trials both financially and by enrichment of participants at higher likelihood of MACE. Furthermore, total non-calcified, and high-risk plaque volume, and their change over time, provide a causally linked measure of coronary artery disease which is inextricably linked to MACE, and represents a robust surrogate imaging biomarker with potential to be endorsed by regulatory authorities. Global consensus on specific imaging endpoints and protocols for optimal clinical trial design is essential as we work towards a rigorous, sustainable and staged pathway for new CAD therapies.

Worth Their Weight? An Update on New and Emerging Pharmacologic Agents for Obesity and Their Potential Role for Persons with Cardiac Conditions.

Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. High-dose once weekly injectable semaglutide (2.4mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease.

GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage.

Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.

Design, recruitment and baseline characteristics of the LENS trial.

Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large-scale randomised trials have yet investigated this hypothesis. LENS is a streamlined randomised double-masked placebo-controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non-referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants. Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy. LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid-2024. NCT03439345; ISRCTN15073006; EuDRACT 2016-002656-24.

Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: Systematic review and meta-analysis of cardiovascular outcome trials of novel glucose-lowering agents.

Using a systematic review and meta-analysis of placebo-controlled cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents [sodium-glucose cotransporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study-specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta-regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. Twenty unique CVOTs (six SGLT-2is, nine GLP-1RAs, five DPP-4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT-2is, GLP-1RAs and DPP-4is with placebo, the hazard ratios (95% CIs) for 3-point major adverse cardiovascular events were 0.88 (0.82-0.94), 0.85 (0.79-0.92) and 1.00 (0.94-1.06), respectively. SGLT-2is and GLP-1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP-4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3-point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67-1.06; p = .14; R2 = 14.2%), which was driven by the component of non-fatal stroke (R2 = 100.0%; p = .094). There were non-significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. SGLT-2is and GLP-1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT-2is and GLP-1RAs in patients with T2D extend beyond mere glycaemic control.