👤 Ph Gabriel Steg

Many adults fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals on statin monotherapy, requiring additional nonstatin lipid-lowering medication. Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined. This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies. In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C). Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs. Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001). Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001). Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms. In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone. (A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366). Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine. Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed. The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel ( A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future. Show less

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk. Show less

Metabolic syndrome (MetSyn) is associated with high risk of cardiovascular (CV) events, irrespective of statin therapy. In the overall REDUCE-IT study of statin-treated patients, icosapent ethyl (IPE) reduced the risk of the primary composite endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization) and the key secondary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke). REDUCE-IT was an international, double-blind trial that randomized 8179 high CV risk statin-treated patients with controlled LDL cholesterol and elevated triglycerides, to IPE 4 g/day or placebo. The current study evaluated the pre-specified patient subgroup with a history of MetSyn, but without diabetes at baseline. Among patients with MetSyn but without diabetes at baseline ( In statin-treated patients with a history of MetSyn, IPE significantly reduced the risk of first and total CV events in REDUCE-IT. The large relative and ARRs observed supports IPE as a potential therapeutic consideration for patients with MetSyn at high CV risk. Show less

The COMPASS trial showed a reduction of ischemic events with low-dose rivaroxaban and aspirin in chronic coronary syndromes (CCS) compared with aspirin alone, at the expense of increased bleeding. The CHA We identified the COMPASS-eligible population within the CLARIFY registry (>30.000 patients with CCS). High-bleeding risk patients (REACH BRS > 10) were excluded, as in the COMPASS trial. Patients were categorized as low (0-1) or high (≥ 2) CHA The COMPASS-eligible population comprised 5.142 patients with ischemic and bleeding outcome of 2.3 (2.1-2.5) and 0.5 (0.4-0.6) per 100 patient-years, respectively. Patients with intermediate REACH RIS (n = 1934 [37.6%]) had the higher ischemic risk (3.0 [2.6-3.4]) with similar bleeding risk (0.5 [0.4-0.7]) as the overall population. Patients with low CHA Intermediate REACH RIS identified potential optimal candidates for adjunction of low-dose rivaroxaban while patients with low CHA Show less

To evaluate cardiovascular (CV) outcomes in outpatients with coronary artery disease (CAD) living alone compared with those living with others. The prospeCtive observational LongitudinAl RegIstry oF patients with stable coronarY artery disease (CLARIFY) included outpatients with stable CAD. CLARIFY enrolled participants in 45 countries from November 2009 to July 2010, with 5 years of follow-up. Living arrangement was documented at baseline. The primary outcome was a composite of major adverse cardiovascular events (MACEs) defined as CV death, myocardial infarction (MI) and stroke. Among 32 367 patients, 3648 patients were living alone (11.3%). After multivariate adjustment, there were no residual differences in MACE among patients living alone compared with those living with others (HR 1.04, 95% CI 0.92 to 1.18, p=0.52); however, there was significant heterogeneity in the exposure effect by sex (P Living alone was not associated with an independent increase in MACE, although significant sex-based differences were apparent. Men living alone may have a worse prognosis from CV disease than women; further analyses are needed to elucidate the mechanisms underlying this difference. ISRCTN43070564. Show less