Polycystic ovary syndrome: A review of diagnosis and management, with special focus on atherosclerotic cardiovascular disease prevention.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy worldwide with a heterogeneous clinical presentation including reproductive, metabolic, and endocrine elements. However, the assessment and management of PCOS remains inconsistent, with many women undiagnosed and untreated. We now also understand that the management of PCOS should extend throughout a woman's lifespan as many elements of the syndrome persist after menopause. Management has traditionally focused on the treatment of hyperandrogenism and oligomenorrhea. Women with PCOS often have dyslipidemia, hypertension, obesity, and metabolic syndrome, which may be worsened by the hormonal abnormalities, and are therefore at higher risk for cardiovascular disease morbidity and mortality, a risk that increases after menopause. While treatment with hormonal therapy, in particular combined oral contraceptives, may improve cardiovascular risk factors, management plans should incorporate specific diagnosis and management of these factors, if present, because of the strong contribution to the risk for atherosclerotic cardiovascular disease (ASCVD). Given the complexities of the syndrome, optimal management often requires a multi-disciplinary approach including the lipid and cardiometabolic specialist to provide counseling and support for lifestyle modification along with pharmacologic therapy as indicated to address the full range of any reproductive, endocrine, and cardiometabolic abnormalities.

Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl.

BACKGROUND: Elevated lipoprotein(a) (Lp[a]) concentrations are associated with increased cardiovascular event risk even in the presence of well-controlled low-density lipoprotein cholesterol levels, but few treatments are documented to reduce this residual risk. OBJECTIVES: The aim of this post hoc analysis of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was to explore the cardiovascular benefit of icosapent ethyl (IPE) across a range of Lp(a) levels. METHODS: A total of 8,179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69 to 5.63 mmol/L, and low-density lipoprotein cholesterol 1.06 to 2.59 mmol/L were randomized to receive 2 g twice daily of IPE or matching placebo. Relationships between continuous baseline Lp(a) mass concentration and risk for first and total (first and subsequent) major adverse cardiovascular events (MACE) were analyzed, along with the effects of IPE on first MACE among those with Lp(a) concentrations ≥50 or <50 mg/dL. RESULTS: Among 7,026 participants (86% of those randomized) with baseline Lp(a) assessments, the median concentration was 11.6 mg/dL (Q1-Q3: 5.0-37.4 mg/dL). Lp(a) had significant relationships with first and total MACE (P < 0.0001), while event reductions with IPE did not vary across the range of Lp(a) (interaction P > 0.10). IPE significantly reduced first MACE in subgroups with concentrations ≥50 and <50 mg/dL. CONCLUSIONS: Baseline Lp(a) concentration was prognostic for MACE among participants with elevated triglyceride levels receiving statin therapy. Importantly, IPE consistently reduced MACE across a range of Lp(a) levels, including among those with clinically relevant elevations.

Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. METHODS: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. CONCLUSIONS: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.

Cost-Effectiveness of Icosapent Ethyl in REDUCE-IT USA: Results From Patients Randomized in the United States.

BACKGROUND: In 3146 REDUCE-IT USA (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial USA) participants, icosapent ethyl (IPE) reduced first and total cardiovascular events by 31% and 36%, respectively, over 4.9 years of follow-up. METHODS AND RESULTS: We used participant-level data from REDUCE-IT USA, 2021 US costs, and IPE costs ranging from $4.59 to $11.48 per day, allowing us to examine a range of possible medication costs. The in-trial analysis was participant-level, whereas the lifetime analysis used a Markov model. Both analyses considered value from a US health sector perspective. The incremental cost-effectiveness ratio (incremental costs divided by incremental quality-adjusted life-years) of IPE compared with standard care (SC) was the primary outcome measure. There was incremental gain in quality-adjusted life-years with IPE compared with SC using in-trial (3.28 versus 3.13) and lifetime (10.36 versus 9.83) horizons. Using an IPE cost of $4.59 per day, health care costs were lower with IPE compared with SC for both in-trial ($29 420 versus $30 947) and lifetime ($216 243 versus $219 212) analyses. IPE versus SC was a dominant strategy in trial and over the lifetime, with 99.7% lifetime probability of an incremental cost-effectiveness ratio <$50 000 per quality-adjusted life-year gained. At a medication cost of $11.48 per day, the cost per quality-adjusted life-year gained was $36 208 in trial and $9582 over the lifetime. CONCLUSIONS: In this analysis, at $4.59 per day, IPE offers better outcomes than SC at lower costs in trial and over a lifetime and is cost-effective at $11.48 per day for conventional willingness-to-pay thresholds. Treatment with IPE should be strongly considered in US patients like those enrolled in REDUCE-IT USA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Effectiveness of icosapent ethyl on first and total cardiovascular events in patients with metabolic syndrome, but without diabetes: REDUCE-IT MetSyn.

Aims: 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). Methods and results: 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 (n = 2866), the majority (99.8%) of this subgroup was secondary prevention patients. Icosapent ethyl use was associated with a 29% relative risk reduction for the first occurrence of the primary composite endpoint [hazard ratio: 0.71; 95% confidence interval (CI): 0.59-0.84; P < 0.0001, absolute risk reduction (ARR) = 5.9%; number needed to treat = 17] and a 41% reduction in total (first plus subsequent) events [rate ratio: 0.59; (95% CI: 0.48-0.72); P < 0.0001] compared with placebo. The risk for the key secondary composite endpoint was reduced by 20% (P = 0.05) and a 27% reduction in fatal/non-fatal MI (P = 0.03), 47% reduction in urgent/emergent revascularization (P < 0.0001), and 58% reduction in hospitalization for unstable angina (P < 0.0001). Non-statistically significant reductions were observed in cardiac arrest (44%) and sudden cardiac death (34%). Conclusion: 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. Registration REDUCE-IT ClinicalTrials.gov number: NCT01492361.

Cardiovascular Benefits of Icosapent Ethyl in Patients With and Without Atrial Fibrillation in REDUCE-IT.

Background In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), icosapent ethyl (IPE) versus placebo) reduced cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization, but was associated with increased atrial fibrillation/atrial flutter (AF) hospitalization (3.1% IPE versus 2.1% placebo; P=0.004). Methods and Results We performed post hoc efficacy and safety analyses of patients with or without prior AF (before randomization) and with or without in-study time-varying AF hospitalization to assess relationships of IPE (versus placebo) and outcomes. In-study AF hospitalization event rates were higher in patients with prior AF (12.5% versus 6.3%, IPE versus placebo; P=0.007) versus without prior AF (2.2% versus 1.6%, IPE versus placebo; P=0.09). Serious bleeding rates trended higher in patients with (7.3% versus 6.0%, IPE versus placebo; P=0.59) versus without prior AF (2.3% versus 1.7%, IPE versus placebo; P=0.08). With IPE, serious bleeding trended higher regardless of prior AF (interaction P value [Pint]=0.61) or postrandomization AF hospitalization (Pint=0.66). Patients with prior AF (n=751, 9.2%) versus without prior AF (n=7428, 90.8%) had similar relative risk reductions of the primary composite and key secondary composite end points with IPE versus placebo (Pint=0.37 and Pint=0.55, respectively). Conclusions In REDUCE-IT, in-study AF hospitalization rates were higher in patients with prior AF especially in those randomized to IPE. Although serious bleeding trended higher in those randomized to IPE versus placebo over the course of the study, serious bleeding was not different regardless of prior AF or in-study AF hospitalization. Patients with prior AF or in-study AF hospitalization had consistent relative risk reductions across primary, key secondary, and stroke end points with IPE. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01492361; Unique Identifier: NCT01492361.

Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy.

OBJECTIVES: To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group. METHODS: Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 µg/day transdermal 17ß (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17ß-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty. RESULTS: All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17ß-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time. SUMMARY: In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation. GOV NUMBERS: NCT00154180, NCT00623311.

Potential effects of icosapent ethyl on cardiovascular outcomes in cigarette smokers: REDUCE-IT smoking.

AIMS: Cigarette smoking is among the most well-established risk factors for adverse cardiovascular outcomes. We sought to determine whether icosapent ethyl (IPE), a highly purified form of eicosapentaenoic acid with antiatherothrombotic properties, may reduce the excessive risk of cardiovascular disease (CVD) attributable to smoking. METHODS AND RESULTS: Reduction of Cardiovascular Events with Icosapent Ethyl Trial (REDUCE-IT) was a multinational, double-blind trial that randomized 8179 statin-treated patients with elevated triglycerides and CV risk to IPE or placebo, with a median follow-up period of 4.9 years. Icosapent ethyl reduced the primary composite endpoint [CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or hospitalization for unstable angina] by 25% (P < 0.0001). In the current analyses, the effect of IPE was evaluated in REDUCE-IT using post hoc analyses based on smoking history. Groups were classified as current smokers (n = 1241), former smokers (n = 3672), and never smokers (n = 3264). Compared with placebo, IPE use in combined current and former smokers (n = 4913) was associated with significant reductions in time to the primary composite endpoint {hazard ratio: 0.77 [95% confidence interval (CI): 0.68-0.87]; P < 0.0001} and in total events [rate ratio: 0.71 (95% CI: 0.61-0.82); P < 0.0001]. These benefits remained significant when subdivided into current and former smokers (P = 0.04, P = 0.005), with reductions in the key secondary composite endpoint (P < 0.0001) and in the individual components of CV death or non-fatal MI (P = 0.04, P = 0.01) and fatal or non-fatal MI (P = 0.009, P = 0.01), respectively. Benefits were consistent and significant in non-smokers as well. Overall, there were similar estimated rates of first occurrences of primary CVD endpoints in current smokers (23.8%) and former smokers (23.0%) assigned to IPE compared with never smokers on placebo (25.7%). CONCLUSION: In REDUCE-IT, IPE treatment was associated with a reduced risk of CV events in current and former smokers to levels observed in never smokers. While smoking cessation should always be recommended, these data raise the possibility that IPE treatment may attenuate CV hazards attributable to smoking.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Management of Mild-to-Moderate Hypertriglyceridemia.

OBJECTIVE: Hypertriglyceridemia (HTG) is highly prevalent globally, and its prevalence is rising, with a worldwide increase in the incidence of obesity and diabetes. This review examines its current management and future therapies. METHODS: For this review, HTG is defined as mild-to-moderate elevation in the levels of triglyceride (TG): a fasting or nonfasting TG level of ≥150 mg/dL and <500 mg/dL. We reviewed scientific studies published over the last 30 years and current professional society recommendations regarding the evaluation and treatment of HTG. RESULTS: Genetics, lifestyle, and other environmental factors impact TG levels. In adults with mild-to-moderate HTG, clinicians should routinely assess and treat secondary treatable causes (diet, physical activity, obesity, metabolic syndrome, and reduction or cessation of medications that elevate TG levels). Because atherosclerotic cardiovascular disease risk is the primary clinical concern, statins are usually the first-line treatment. Patients with TG levels between ≥150 mg/dL and <500 mg/dL whose low-density lipoprotein cholesterol is treated adequately with statins (at "maximally tolerated" doses, per some statements) and have either prior cardiovascular disease or diabetes mellitus along with at least 2 additional cardiovascular disease risk factors should be considered for added icosapent ethyl treatment to further reduce their cardiovascular disease risk. Fibrates, niacin, and other approved agents or agents under development are also reviewed in detail. CONCLUSION: The treatment paradigm for mild-to-moderate HTG is changing on the basis of data from recent clinical trials. Recent trials suggest that the addition of icosapent ethyl to background statin therapy may further reduce atherosclerotic cardiovascular disease risk in patients with moderate HTG, although a particular TG goal has not been identified.

Coronary artery calcium and bone mineral density by serial CTA: Does menopausal hormone therapy modify the association?

INTRODUCTION: Both osteoporosis and cardiovascular disease (CVD) increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions. METHODS: Healthy menopausal women (n = 374, age 42-58 years) underwent cardiac CT scans over four years as participants in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial to Women randomized to either oral conjugated equine estrogens (o-CEE, n = 104), transdermal 17ß-estradiol (t-E2, n = 119) or placebo (n-115). CAC (Agatston units, AU), and BMD (mg/cm3) were measured from thoracic vertebrae at baseline and at the 4 years of the study using validated software. ANOVA and multiple linear regression analyzed the association between incident CAC or progression of CAC and BMD among the treatment groups. RESULTS: At baseline 374 women, 40 participants with CAC >0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was -9.6 ± 13.3 versus -3.1 ± 19.5 in those with zero CAC, p = 0.0018. With t-E2, BMD changed by -11.7 ± 26.2 in those with CAC versus +5.7 ± 26.2 in the zero CAC group, p ≤ 0. 0001. Similarly in the 66 participants that showed progression of CAC >1, had more BMD loss, than those with stable CAC regardless of the treatment. CONCLUSION: Progression of bone loss is reduced among women treated with o-CEE or t-E2. Progression of CAC is associated with greater BMD loss, a relationship that is differentially modified by t-E2 and o-CEE.

Icosapent ethyl for reduction of persistent cardiovascular risk: a critical review of major medical society guidelines and statements.

INTRODUCTION: REDUCE-IT demonstrated that adding 4 g/day of icosapent ethyl (IPE; purified ethyl ester of eicosapentaenoic acid [EPA]) to statins substantially reduced cardiovascular disease (CVD) events, with few adverse effects. These data prompted numerous leading medical societies across five continents, including the American College of Cardiology, the European Society of Cardiology, and the Japanese Circulation Society, to update their guidelines or scientific/consensus statements to recommend use of IPE for primary and secondary prevention of CVD events. AREAS COVERED: This review discusses the incorporation of IPE into international guidelines and scientific statements, noting areas of consensus and distinction. As background, this review also describes the CVD benefits and risks of IPE as a statin adjunct, and outlines current data regarding the potential mechanisms of CVD risk reduction by EPA (as IPE) beyond triglyceride reduction. EXPERT OPINION/COMMENTARY: IPE is unique among 'triglyceride-lowering' treatments in having strong CVD outcomes data and, therefore, a broad international consensus among professional medical society guidelines and statements endorsing its use for CVD risk reduction in patients generally meeting REDUCE-IT inclusion criteria. IPE should be considered for CVD prevention as a statin adjunct in all such patients.Plain Language SummaryCardiovascular disease (CVD) remains the leading cause of death worldwide. Statin monotherapy is conventionally used first-line to reduce the risk of CV events, such as heart attacks and strokes, in patients with elevated cholesterol. However, considerable risk remains despite appropriate control of cholesterol levels with a statin. Consequently, research has focused on treatment of additional therapeutic targets to reduce this remaining CV risk. One such target is elevated blood triglyceride levels. Unfortunately, most drugs that lower triglyceride levels, such as niacin, fibrates, and mixed omega-3 fatty acids, have not reduced the risk of cardiovascular events in clinical trials when added to statin therapy. However, the omega-3 fatty acid eicosapentaenoic acid ('EPA') administered in highly purified form as icosapent ethyl (IPE) has emerged as the first omega-3 fatty acid, and the first triglyceride-lowering agent to prevent CV events when added to statins. This was demonstrated most notably in the pivotal REDUCE-IT trial, in which IPE reduced the risk of major CV events by 25% in high-risk patients with mildly to moderately elevated triglyceride levels despite statin-controlled cholesterol levels. The mechanisms responsible for this reduction in CV events appear to go far beyond lowering triglyceride levels alone. In light of the positive results from the REDUCE-IT trial, IPE was approved for CV disease risk reduction globally, including in the United States, Canada, European Union, and the United Kingdom, and its use is being increasingly endorsed in United States and international statements and guidelines for managing CV risk. Despite minor differences among guidelines, there is strong consensus that IPE should be considered for use in CVD prevention in all patients who meet the proposed criteria.

Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1ß, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. METHODS: Serum levels of interleukin-1ß, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator. RESULTS: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1ß (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1ß (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was -1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. CONCLUSIONS: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01492361.

Cardiometabolic measures and cognition in early menopause - Analysis of baseline data from a randomized controlled trial.

OBJECTIVE: The relationships between cardiometabolic indices and cognition were examined in recently menopausal women. METHODS: Cross-sectional analysis of baseline data from the KEEPS (Kronos Early Estrogen Prevention Study)-Cognitive ancillary study (n = 621). Cognitive performance was assessed by the Modified Mini Mental Status (3MS) score (primary outcome). Physical cardiometabolic indices included body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and blood pressure (BP). Biochemical cardiometabolic indices included serum levels of high sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), non-HDL (non-HDL-C), triglycerides (TG), fasting serum glucose (FSG), and insulin resistance (HOMA-IR). Socio-demographic variables included age, race/ethnicity, education, and lifestyle (physical activity, smoking). Central adiposity was defined as WC > 88 cm (>35 in) and WHR > 0.8. Separate stepwise multivariable analyses (GLM, ordinal logistic regression and logistic regression) assessed relationships between 3MS scores (as continuous, in tertiles and dichotomized at 90 respectively) with the measures of central adiposity (predictor variables); socio-demographic variables (age, time since menopause, race, educational status and lifestyle) and cardiometabolic variables (BP, lipids, FSG, HOMA-IR and hs-CRP) were examined as covariates. The final multivariable models included time since menopause, race, ethnicity, educational status, strenuous exercise, BMI ≥30 kg/m2, non-HDL-C and hs-CRP as covariates. Due to the high collinearity between the two indices of central adiposity, within each analytic strategy, separate models examined the respective associations of WC > 88 cm and WHR > 0.8 with 3MS score. RESULTS: On adjusted analyses, indices of central adiposity were independent predictors of significantly lower 3MS scores (p < 0.05). Consistency in this relationship was observed across the three different multivariable regression analytic approaches (GLM, ordinal and logistic regression). CONCLUSIONS: Among recently menopausal women, WC > 88 cm and WHR > 0.8 were associated with significantly lower cognitive function, as reflected by lower 3MS scores. The mechanisms that might explain the observed negative implications of central adiposity for cognitive function warrant further study.

Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.

BACKGROUND: REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. OBJECTIVES: Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. METHODS: We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. RESULTS: A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. CONCLUSIONS: Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).

Impact of Icosapent Ethyl on Cardiovascular Risk Reduction in Patients With Heart Failure in REDUCE-IT.

Background Patients with heart failure (HF) are at high risk for atherosclerotic cardiovascular disease. Studies of atherothrombotic treatments in this population have been disappointing to date. Icosapent ethyl reduced the risk of atherosclerotic cardiovascular disease among a broad array of statin-treated patients at elevated risk for atherosclerotic cardiovascular disease. Whether the treatment benefits of icosapent ethyl are consistent among those with HF is unknown. Methods and Results REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized 8179 participants, including 1446 (17.7%) patients with a history of HF (icosapent ethyl, N=703; and placebo, N=743). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. We used Cox regression to estimate the risk of outcomes of participants with and without HF. We estimated the placebo-controlled change in triglycerides and hs-CRP (high-sensitivity C-reactive protein) from baseline to 2 years. Among 1446 patients with HF, median age was 63.0 years, median body mass index was 31.0 kg/m2, and more were men (69.3%). Icosapent ethyl reduced triglycerides (median reduction, 33.5 mg/dL, or 15.4%; P<0.0001) and hs-CRP (35.1%; P<0.0001) compared with placebo, similar to patients without HF (P-interaction>0.90). The treatment effect on the primary end point in patients with HF history (hazard ratio [HR], 0.87; 95% CI, 0.70-1.08) was consistent with the effects observed in patients without HF history (HR, 0.73; 95% CI, 0.65-0.81) (P-interaction=0.13). Conclusions In REDUCE-IT, icosapent ethyl provided similar improvements in triglyceride levels and hs-CRP as well as similar cardiovascular risk reduction in patients with and without HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Treatment With Icosapent Ethyl to Reduce Ischemic Events in Patients With Prior Percutaneous Coronary Intervention: Insights From REDUCE-IT PCI.

Background Patients who undergo percutaneous coronary intervention (PCI) are at increased risk for recurrent cardiovascular events despite aggressive medical therapy. Methods and Results This post hoc analysis focused on the subset of patients with prior PCI enrolled in REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), a multicenter, randomized, double-blind, placebo-controlled trial of icosapent ethyl versus placebo. Icosapent ethyl was added to statins in patients with low-density lipoprotein cholesterol <100 mg/dL and fasting triglycerides 135-499 mg/dL. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. There were 8179 patients randomized in REDUCE-IT followed for a median of 4.9 years, and 3408 (41.7%) of them had a prior PCI with a median follow-up of 4.8 years. These patients were randomized a median of 2.9 years (11 days to 30.7 years) after PCI. Among patients treated with icosapent ethyl versus placebo, there was a 34% reduction in the primary composite end point (hazard ratio [HR], 0.66; 95% CI, 0.58-0.76; P<0.001; number needed to treat4.8 years=12) and a 34% reduction in the key secondary composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR, 0.66; 95% CI, 0.56-0.79; P<0.001; NNT4.8 years=19) versus placebo. Similarly, large reductions occurred in total coronary revascularizations and revascularization subtypes. There was also a 39% reduction in total events (rate ratio, 0.61; 95% CI, 0.52-0.72; P<0.001). Conclusions Among patients treated with statins with elevated triglycerides and a history of prior PCI, icosapent ethyl substantially reduced the risk of recurrent events during an average of ~5 years of follow-up with a number needed to treat of only 12. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Cost-effectiveness of Icosapent Ethyl for High-risk Patients With Hypertriglyceridemia Despite Statin Treatment.

Importance: The Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) demonstrated the efficacy of icosapent ethyl (IPE) for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least 1 other risk factor who were treated with statins. Objective: To estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment. Design, Setting, and Participants: An in-trial cost-effectiveness analysis was performed using patient-level study data from REDUCE-IT, and a lifetime analysis was performed using a microsimulation model and data from published literature. The study included 8179 patients with hypertriglyceridemia despite stable statin therapy recruited between November 21, 2011, and May 31, 2018. Analyses were performed from a US health care sector perspective. Statistical analysis was performed from March 1, 2018, to October 31, 2021. Interventions: Patients were randomly assigned to IPE, 4 g/d, or placebo and were followed up for a median of 4.9 years (IQR, 3.5-5.3 years). The cost of IPE was $4.16 per day after rebates using SSR Health net cost (SSR cost) and $9.28 per day with wholesale acquisition cost (WAC). Main Outcomes and Measures: Main outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness. Results: A total of 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. Treatment with IPE yielded more QALYs than standard care both in trial (3.34 vs 3.27; mean difference, 0.07 [95% CI, 0.01-0.12]) and over a lifetime projection (10.59 vs 10.35; mean difference, 0.24 [95% CI, 0.15-0.33]). In-trial, total health care costs were higher with IPE using either SSR cost ($18 786) or WAC ($24 544) than with standard care ($17 273; mean difference from SSR cost, $1513 [95% CI, $155-$2870]; mean difference from WAC, $7271 [95% CI, $5911-$8630]). Icosapent ethyl cost $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. Over a lifetime, IPE was projected to be cost saving when using SSR cost ($195 276) compared with standard care ($197 064; mean difference, -$1788 [95% CI, -$9735 to $6159]) but to have higher costs when using WAC ($202 830) compared with standard care (mean difference, $5766 [95% CI, $1094-$10 438]). Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost and an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC. Conclusions and Relevance: This study suggests that, both in-trial and over the lifetime, IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.