Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome.

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Role of apolipoprotein B in the clinical management of cardiovascular risk in adults: An expert clinical consensus from the national lipid association.

This National Lipid Association (NLA) Expert Clinical Consensus provides an overview of the physiologic and clinical considerations regarding the role of apolipoprotein B (apoB) measurement to guide clinical care based on the available scientific evidence and expert opinion. ApoB represents the total concentration of atherogenic lipoprotein particles in the circulation and more accurately reflects the atherogenic burden of lipoproteins when compared to low-density lipoprotein cholesterol (LDL-C). ApoB is a validated clinical measurement that augments the information found in a standard lipoprotein lipid panel; therefore, there is clinical value in using apoB in conjunction with a standard lipoprotein lipid profile when assessing risk and managing lipid-lowering therapy (LLT). ApoB has been shown to be superior to LDL-C in risk assessment both before and during treatment with LLT. In individuals, there can be discordance between levels of LDL-C and apoB, as well as LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C), despite high levels of population-wide correlation. When there is discordance between LDL-C and apoB, or LDL-C and non-HDL-C, atherosclerotic cardiovascular disease risk generally aligns better with apoB or non-HDL-C. Additionally, apoB can be used in tandem with standard lipoprotein lipid measurements to diagnose distinct lipoprotein phenotypes. ApoB testing can inform clinical prognosis and care, as well as enable family cascade screening, when an inherited lipoprotein syndrome is identified. The NLA and other organizations will continue to educate clinicians about the role of apoB measurement in improving clinical risk assessment and dyslipidemia management. An urgent need exists to improve access and reimbursement for apoB testing.

Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study.

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

Low-Density Lipoprotein Cholesterol Testing Following Myocardial Infarction Hospitalization Among Medicare Beneficiaries.

Background: Low-density lipoprotein cholesterol (LDL-C) is used to guide lipid-lowering therapy after a myocardial infarction (MI). Lack of LDL-C testing represents a missed opportunity for optimizing therapy and reducing cardiovascular risk. Objectives: The purpose of this study was to estimate the proportion of Medicare beneficiaries who had their LDL-C measured within 90 days following MI hospital discharge. Methods: We conducted a retrospective cohort study of Medicare beneficiaries ≥66 years of age with an MI hospitalization between 2016 and 2020. The primary analysis used data from all beneficiaries with fee-for-service coverage and pharmacy benefits (532,767 MI hospitalizations). In secondary analyses, we used data from a 5% random sample of beneficiaries with fee-for-service coverage without pharmacy benefits (10,394 MI hospitalizations), and from beneficiaries with Medicare Advantage (176,268 MI hospitalizations). The proportion of beneficiaries who had their LDL-C measured following MI hospital discharge was estimated accounting for the competing risk of death. Results: In the primary analysis (mean age 76.9 years, 84.4% non-Hispanic White), 29.9% of beneficiaries had their LDL-C measured within 90 days following MI hospital discharge. Among Hispanic, Asian, non-Hispanic White, and non-Hispanic Black beneficiaries, the 90-day postdischarge LDL-C testing was 33.8%, 32.5%, 30.0%, and 26.0%, respectively. Postdischarge LDL-C testing within 90 days was highest in the Middle Atlantic (36.4%) and lowest in the West North Central (23.4%) U.S. regions. In secondary analyses, the 90-day postdischarge LDL-C testing was 26.9% among beneficiaries with fee-for-service coverage without pharmacy benefits, and 28.6% among beneficiaries with Medicare Advantage coverage. Conclusions: LDL-C testing following MI hospital discharge among Medicare beneficiaries was low.

Endogenous androgens, coronary atheroma and remodeling in women with suspected ischemic heart disease: A report from the Women's Ischemia Syndrome Evaluation (WISE) study.

Background: Women have smaller coronary size than men independent of body surface area. Female to male heart transplantation demonstrates coronary lumen enlargement. Purpose: To investigate relationships between endogenous androgens and coronary luminal size in women with suspected ischemic heart disease (IHD). Methods: We analyzed 69 women with available androgen levels. Results: Group mean age was 54 ± 10 years with 64 % post-menopausal. Lumen cross-sectional area (CSA) and external elastic membrane (EEM) CSA positively correlated with free testosterone (FT) (r = 0.29, p = 0.049; r = 0.29, p = 0.01), respectively, and negatively correlated with SHBG (r = -0.26, p = 0.03; r = -0.29, p = 0.02), respectively. Atheroma CSA positively correlated with FT (r = 0.24. p = 0.05). These correlations became non-significant after adjusting for waist circumference. Conclusions: In women with suspected ischemic heart disease, endogenous androgens, coronary atheroma and luminal size are related, and may be moderated by waist circumference.

Persistence and Adherence to PCSK9 Inhibitor Monoclonal Antibodies Versus Ezetimibe in Real-World Settings.

INTRODUCTION: The cardiovascular disease risk reduction benefits of proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies (PCSK9i mAb) and ezetimibe are dependent on remaining on treatment and being persistent and adherent. We estimated the percentage of patients on therapy, persistent and adherent at 182 and 365 days among US adults with health insurance who initiated a PCSK9i mAb (n = 16,588) or ezetimibe (n = 83,086) between July 2015 and December 2019. METHODS: Using pharmacy fill claims, being on therapy was defined as having a day of medication supply in the last 60 of 182 and 365 days following treatment initiation, being persistent was defined as not having a gap of 60 days or more between the last day of supply from one prescription fill and the next fill, and being adherent was defined by having medication available to take on ≥ 80% of the 182 and 365 days following treatment initiation. We estimated multivariable-adjusted risk ratios for being persistent and adherent comparing patients initiating PCSK9i mAb versus ezetimibe using Poisson regression. RESULTS: At 182 days following initiation, 80% and 68% were on therapy and 76% and 64% were persistent among patients who initiated a PCSK9i mAb and ezetimibe, respectively. Among patients who were on therapy and persistent at 182 days following initiation, 88% and 81% of those who initiated a PCSK9i mAb and ezetimibe, respectively, were on therapy at 365 days. Among those on therapy and persistent at 182 days following initiation, being persistent and being adherent at 365 days were each more common among PCSK9i mAb versus ezetimibe initiators (persistent: 82% versus 76%, multivariable-adjusted risk ratio 1.07; 95% confidence interval [CI] 1.06-1.08; adherent: 74% versus 71%, multivariable-adjusted risk ratio 1.02; 95% CI 1.01-1.03). CONCLUSIONS: These data suggest approaches to increase persistence and adherence to PCSK9i mAb and ezetimibe should be implemented prior to or within 182 days following treatment initiation.

Safety of the PCSK9 inhibitor alirocumab: insights from 47 296 patient-years of observation.

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

New approaches to triglyceride reduction: Is there any hope left?

Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with significant association with atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, ischemic stroke, and peripheral artery disease and represents an important component of the residual ASCVD risk in statin treated patients despite optimal low-density lipoprotein cholesterol reduction. Individuals with severe HTG (>1,000 mg/dL) rarely develop atherosclerosis but have an incremental incidence of acute pancreatitis with significant morbidity and mortality. HTG can occur from a combination of genetic (both mono and polygenic) and environmental factors including poor diet, low physical activity, obesity, medications, and diseases like insulin resistance and other endocrine pathologies. HTG represents a potential target for ASCVD risk and pancreatitis risk reduction, however data on ASCVD reduction by treating HTG is still lacking and HTG-associated acute pancreatitis occurs too rarely to effectively demonstrate treatment benefit. In this review, we address the key aspects of HTG pathophysiology and examine the mechanisms and background of current and emerging therapies in the management of HTG.

Elevated high-density lipoprotein cholesterol and adverse outcomes in women with symptoms of ischemic heart disease.

Background: Emerging data in the general population and those with coronary artery disease demonstrate higher risk of adverse outcomes with high (>70 mg/dL) HDL-C levels. There are limited data on the risk of adverse outcomes in women with suspected ischemic heart disease. Objective: To investigate relationships between high (>70 mg/dL), average (50-70 mg/dL), and low (<50 mg/dL) HDL-C levels with major adverse cardiac events (MACE) (death, myocardial infarction, stroke, and heart failure hospitalization), and all-cause mortality in women referred for coronary angiography for suspected myocardial ischemia. Methods: A total of 607 women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) original cohort (NCT00000554) with available HDL-C values were included in this analysis. Associations between HDL-C level and outcomes were evaluated using both multivariate Cox proportional hazard regression and spline regression analysis. Results: The mean age was 59 ± 12 years, 62 % had 3 or more cardiac risk factors, and 66 (10.9 %) had a high HDL-C. High and low HDL-C were both associated with higher MACE risk compared to average HDL-C after adjusting for demographic and clinical characteristics (HR 1.80, CI 1.03-3.14, p = 0.038; HR 1.63, CI 1.09-2.42, p = 0.016, respectively). Similarly, high, and low HDL-C were associated with higher risk of all-cause mortality (HR 3.64, CI 1.84-7.20, p < 0.001; HR 2.81, CI 1.67-4.71, p < 0.001, respectively). Conclusions: High and low HDL-C levels are both independently associated with higher MACE and all-cause mortality in women with suspected ischemia undergoing coronary angiography.