Increased residual cardiovascular risk in U.S. veterans with moderately-elevated baseline triglycerides and well-controlled LDL-C levels on statins.

Background: Recent studies have demonstrated a causal role for elevated triglycerides (TG) in incident cardiovascular (CV) events in patients with established coronary heart disease (CHD) and those with CV risk factors alone, particularly diabetes. Objective: Using a large cohort of U.S. veterans with statin-controlled LDL-C levels (40-100 mg/dL), we explored residual CV risk among patients with elevated baseline TG levels (150-499 mg/dL) vs. those with normal TG levels (<150 mg/dL). Methods: We identified veterans receiving a statin but not a TG-lowering agent from the VA electronic health records database, from 2010 to 2015. We compared composite CV event rates (MI, stroke, unstable angina, coronary revascularization, and CV death) between the elevated TG and normal TG groups. We stratified the study cohort according to 3 CV risk groups: (1) no diabetes and no prior CV event, (2) diabetes and no prior CV event, and (3) prior CV event. We calculated crude event rates, rate ratios, and event rate ratios adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight. Results: The cohort included 396,189 veterans (predominantly male and white) of whom 109,195 (28%) had elevated TG levels. Those with elevated TG were younger (age 73 vs. 77 years) and had a higher body mass index (31.3 vs. 28.3 Kg/M2). The overall composite crude and adjusted rate ratios comparing the elevated and normal TG groups were 1.10 (1.09, 1.12) and 1.05 (1.03, 1.06), respectively. For CV risk groups 1, 2 and 3, the adjusted rate ratios comparing the elevated and normal TG groups were 0.99 (0.96, 1.02), 1.05 (1.02, 1.08), and 1.07 (1.04, 1.10), respectively. An association of increased rate ratios did not hold for fatal events. Conclusion: Those with elevated TG levels and well-controlled LDL-C on statins showed a modest increase in CV events compared to those with normal TG. Elevated TG levels were associated with increased CV events in patients with established CV disease and with diabetes only, suggesting that elevated TG levels are associated with a similar degree of residual risk in high-risk primary prevention and secondary prevention settings.

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).

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.

Global assessment improves risk stratification for major adverse cardiac events across a wide range of triglyceride levels: Insights from the KP REACH study.

OBJECTIVE: Patients with risk factors for or established atherosclerotic cardiovascular disease (ASCVD) remain at high risk for subsequent ischemic events despite statin therapy. Triglyceride (TG) levels may contribute to residual ASCVD risk, and the performance of global risk assessment calculators across a broad range of TG levels is unknown. METHODS: We performed a retrospective cohort study of Kaiser Permanente Northern California members aged ≥45 years with ≥1 ASCVD risk factor (primary prevention cohort) or established ASCVD (secondary prevention cohort) between 2010 and 2017 who were receiving statin therapy and had a low-density lipoprotein cholesterol between 41-100 mg/dL. Global ASCVD risk assessment was performed using both the Kaiser Permanente ASCVD Risk Estimator (KPARE) and the ACC/AHA ASCVD Pooled Cohort Equation (PCE). Outcomes included major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, or peripheral artery disease, and expanded MACE (MACE + coronary revascularization + hospitalization for unstable angina). RESULTS: Among 373,389 patients in the primary prevention cohort, median TG was 122 mg/dL (IQR 88-172 mg/dL) and there were 0.2 MACE events and 0.3 expanded MACE events per 100-person years. Among 97,832 patients in the secondary prevention cohort, median TG level was 116 mg/dL (IQR 84-164 mg/dL) and there were 9.6 MACE events and 22.0 expanded MACE events per 100-person years. KPARE and the ACC/AHA PCE stratified patients for MACE and expanded MACE over the entire range of TGs. CONCLUSION: In a cohort receiving statin therapy for primary or secondary prevention, we found global assessment further improves risk stratification for initial and/or recurrent ASCVD events irrespective of baseline TG level.

Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL.

BACKGROUND: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. METHODS: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; hazard ratio [HR], 0.71 [95% CI, 0.59-0.85]; P=0.0002) and key secondary composite end point (16.8% versus 22.5%; HR 0.71 [95% CI, 0.57-0.88]; P=0.001). The numeric reduction in cardiovascular death was greatest in the eGFR <60 mL·min-1·1.73 m-2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR, 0.70 [95% CI, 0.51-0.95]; P=0.02). Although patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the highest numeric rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42 [95% CI, 0.86-2.32]; P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR, 1.40 [95% CI, 0.90-2.18]; P=0.13), HRs for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter=0.92; P-interaction for serious bleeding=0.76). CONCLUSIONS: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG.

BACKGROUND: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. METHODS: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. RESULTS: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63-0.92]; P=0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56-0.87]; P=0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50-0.81]; P=0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%-10.2%) in first events, with a number needed to treat of 16 (95% CI, 10-44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P=0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. CONCLUSIONS: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. OBJECTIVES: The purpose of this study was to determine the effects of IPE on investigator-reported events. METHODS: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. RESULTS: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. CONCLUSIONS: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).

Triglyceride Levels and Residual Risk of Atherosclerotic Cardiovascular Disease Events and Death in Adults Receiving Statin Therapy for Primary or Secondary Prevention: Insights From the KP REACH Study.

Background Patients with risk factors or established atherosclerotic cardiovascular disease remain at high-risk for ischemic events. Triglyceride levels may play a causal role. Methods and Results We performed a retrospective study of adults aged ≥45 years receiving statin therapy, with a low-density lipoprotein cholesterol of 41 to 100 mg/dL, and ≥1 risk factor or established atherosclerotic cardiovascular disease between 2010 and 2017. Outcomes included death, all-cause hospitalization, and major adverse cardiovascular events (myocardial infarction, stroke, or peripheral artery disease). The study sample included 373 389 primary prevention patients and 97 832 secondary prevention patients. The primary prevention cohort had a mean age of 65±10 years, with 51% women and 44% people of color, whereas the secondary prevention cohort had a mean age of 71±11 years, with 37% women and 32% people of color. Median triglyceride levels for the primary and secondary prevention cohorts were 122 mg/dL (interquartile range, 88-172 mg/dL) and 116 mg/dL (interquartile range, 84-164 mg/dL), respectively. In multivariable analyses, primary prevention patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (hazard ratio [HR], 0.91; 95% CI, 0.89-0.94) and higher risk of major adverse cardiovascular events (HR, 1.14; 95% CI, 1.05-1.24). In the secondary prevention cohort, patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (HR, 0.95; 95% CI, 0.92-0.97) and higher risk of all-cause hospitalization (HR, 1.03; 95% CI, 1.01-1.05) and major adverse cardiovascular events (HR, 1.04; 95% CI, 1.05-1.24). Conclusions In a contemporary cohort receiving statin therapy, elevated triglyceride levels were associated with a greater risk of atherosclerotic cardiovascular disease events and lower risk of death.

Rationale and design of the pragmatic randomized trial of icosapent ethyl for high cardiovascular risk adults (MITIGATE).

OBJECTIVE: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). BACKGROUND: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. METHODS: MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. CONCLUSION: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.

Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses.

BACKGROUND: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations. METHODS: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes. RESULTS: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P<0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P<0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P<0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P=0.0005). CONCLUSIONS: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Real-world analyses of patients with elevated atherosclerotic cardiovascular disease risk from the Optum Research Database.

More than 56 million Americans have hypertriglyceridemia, including over 12 million statin-treated individuals. However, the contribution of elevated and high triglyceride levels to cardiovascular disease and death has not been extensively studied using real-world analyses. We review recent analyses of the Optum Research Database, which included patients aged ≥45 years with diabetes and/or atherosclerotic cardiovascular disease and on statin therapy. Triglyceride levels ≥150 and 200-499 mg/dl were significantly associated with a 25.8 and 34.9% increased relative risk of cardiovascular events, respectively, versus patients with triglyceride levels <150 mg/dl. In addition, hypertriglyceridemia predicted peripheral arterial revascularization, new heart failure diagnosis and new-onset renal disease. Increased triglyceride levels were also significantly associated with increased healthcare resource utilization and costs. Interventions such as icosapent ethyl reduce triglycerides and associated cardiovascular disease risk.

REDUCE-IT Eligibility and Preventable Cardiovascular Events in the US Population (from the National Health and Nutrition Examination Survey [NHANES]).

The reduction of cardiovascular events with icosapent ethyl-intervention (REDUCE-IT) trial showed in persons with prior cardiovascular disease (CVD) or diabetes mellitus (DM) that icosapent ethyl (IPE) reduced CVD events by 25%. We projected the preventable initial and total CVD events if REDUCE-IT trial eligibility criteria were applied to US adults. We identified US adults with available REDUCE-IT inclusion criteria from NHANES Surveys 1999-2016 and estimated primary (CVD death, nonfatal myocardial infarction, stroke, revascularization, or unstable angina) and secondary composite (CVD death, nonfatal MI or stroke) events using REDUCE-IT published event rates in the IPE and placebo groups, the difference being the number of preventable events. From 11,445 adults aged ≥45 years (representing 111.1 million [M]), a total of 319 persons (3.0 M) fit key REDUCE-IT eligibility criteria: triglycerides of 135 to 499 mg/dL, HbA1c <10%, blood pressure <200/100 mm Hg, and on a statin with LDL-C of 40 to 99 mg/dL. 63% had prior CVD and 37% had DM + ≥1 risk factor (primary prevention cohort). If these persons are given IPE for the REDUCE-IT median trial period of 4.9 years, we estimated preventing a total 349,817 (71,391/year) primary CVD outcomes of which 146,011 (29,798/year) were initial events. Most (24,151) preventable events were from the secondary prevention cohort. Using FDA eligibility criteria, an estimated 4.6 million persons would be eligible for IPE, with 60,544 preventable primary CVD outcomes annually from REDUCE-IT USA event rates. In conclusion, many CVD events in US adults with known CVD or DM and well-controlled LDL-C on statin therapy can be prevented with IPE.

Association Between Triglycerides and Residual Cardiovascular Risk in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease (From the Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D] Trial).

Triglyceride (TG) levels encompass several lipoproteins that have been implicated in atherogenic pathways. Whether TG levels independently associate with cardiovascular disease both overall and, in particular among patients with established coronary artery disease (CAD) and type 2 diabetes (T2DM), remains controversial. Data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial was used to evaluate patients with T2DM and CAD. Cox proportional hazards models were used to determine the association between TG levels and outcomes. Stepwise adjustment was performed for demographics, clinical factors, lipid profile and statin treatment. The primary composite outcome was time to CV death, myocardial infarction (MI), or stroke and secondary outcome was CV death. Among 2,307 patients with T2DM and CAD, the mean (±SD) TG levels were 181 (±136) with a median (Q1-Q3) 148mg/dL (104-219). Overall, 51% of patients had TG <150 mg/dL, 18% 150-199 mg/dL, 28% 200-499 mg/dL and 3% ≥500 mg/dL. Participants with elevated TG levels (≥150 mg/dL) were younger (61 vs 63 years, p <0.001), had higher BMI (32 vs 30 kg/m2, p <0.001), more likely to have had prior MI (34.2 vs 30.1%, p = 0.033) and revascularization (25.8 vs 21.4%, p = 0.013), had lower HDL-C (34 vs 39 mg/dL, p <0.001) and higher HbA1c (8 vs 7%, p <0.001). In unadjusted analyses, baseline TG levels were linearly associated with both the primary composite and secondary outcomes. In fully adjusted analyses, every 50 mg/dL increase in TG level was associated with a 3.8% (HR 1.038, 95%CI 1.004-1.072, p <0.001) increase in the primary composite outcome and a 6.4% (HR 1.064 95%CI 1.018-1.113, p <0.001) increase in the secondary outcome. There was no interaction between TG and outcomes within key subgroups including female sex, additional non-coronary atherosclerotic disease, CKD or low LDL (<100 mg/dL). In conclusion, among patients with T2DM and CAD, elevated TG were independently associated with adverse cardiovascular outcomes, even after adjustment for clinical and simple biochemical covariates.

The association between triglycerides and incident cardiovascular disease: What is "optimal"?

BACKGROUND: Elevated triglycerides (TGs) are associated with increased risk of cardiovascular disease (CVD), but the best way to both measure TGs and assess TG-related risk remains unknown. OBJECTIVE: The objective of the study was to evaluate the association between TGs and CVD and determine whether the average of a series of TG measurements is more predictive of CVD risk than a single TG measurement. METHODS: We examined 15,792 study participants, aged 40-65 years, free of CVD from the Atherosclerosis Risk in Communities and Framingham Offspring studies, using fasting TG measurements across multiple examinations over time. With up to 10 years of follow-up, we assessed time-to-first CVD event, as well as a composite of myocardial infarction, stroke, or cardiovascular death. RESULTS: Compared with a single TG measurement, average TGs over time had greater discrimination for CVD risk (C-statistic, 0.60 vs 0.57). Risk for CVD increased as average TGs rose until an inflection point of ~100 mg/dL in men and ~200 mg/dL in women, above which this risk association plateaued. The relationship between average TGs and CVD remained statistically significant in multivariable modeling adjusting for low-density lipoprotein cholesterol, and interactions were found by sex and high-density lipoprotein cholesterol level. CONCLUSIONS: The average of several TG readings provides incremental improvements for the prediction of CVD relative to a single TG measurement. Regardless of the method of measurement, higher TGs were associated with increased CVD risk, even at levels previously considered "optimal" (<150 mg/dL).

Prevalence of US Adults with Triglycerides ≥ 150 mg/dl: NHANES 2007-2014.

INTRODUCTION: Hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease (ASCVD) event risk, which persists even in statin-treated patients. The objective of this analysis was to estimate the prevalence of triglyceride (TG) levels ≥ 150 mg/dl in statin-treated adults with diabetes or ASCVD in the United States. METHODS: Laboratory data, medical history, and prescription data from 40,617 subjects who participated in the US National Health and Nutrition Examination Survey (NHANES) spanning 8 years (four 2-year surveys; 2007-2014) were analyzed. Patients included were ≥ 20 years old and had morning fasting (at least 8.5 h) TG values available. The proportion and weighted number of individuals in the US population with TG ≥ 150 mg/dl was calculated according to statin use, as well as in key subgroups of statin-treated patients including those with low-density lipoprotein cholesterol (LDL-C) levels < 100 mg/dl, type 2 diabetes, ASCVD, and those with type 2 diabetes and ASCVD. RESULTS: A total of 9593 subjects, projected to represent 219.9 million Americans, met the study entry criteria and were included in the analysis. Of these, 2523 had TG levels ≥ 150 mg/dl, translating to a prevalence of 25.9% and representing 56.9 million Americans. Among statin-treated adults, the proportion with TG levels ≥ 150 mg/dl was 31.6% (12.3 million) and ranged from 27.6 to 39.5% for those who also had LDL-C levels < 100 mg/dl and type 2 diabetes or ASCVD. CONCLUSIONS: Over 12 million Americans are treated with a statin and have TG levels ≥ 150 mg/dl. Interventions such as icosapent ethyl that have been shown to reduce ASCVD event risk in this elevated TG population with type 2 diabetes or established ASCVD can provide substantial clinical benefit for these patients.

Estimated ASCVD risk according to statin use in US adults with borderline triglycerides: Results from National Health and Nutrition Examination Survey (NHANES) 2007-2014.

BACKGROUND: Elevated triglycerides (TGs) are associated with atherosclerotic cardiovascular disease (ASCVD). Despite statin therapy, many US adults have borderline or elevated TG levels. Not characterized is the ASCVD risk associated with borderline TG levels in statin users, including the estimated number of adults who will sustain ASCVD events. METHODS: We studied 4986 US adults (weighted to 113 million) aged 40-74 from the National Health and Nutrition Examination Surveys 2007-2014. The proportion of persons at low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), and high (≥20%) 10-year ASCVD risk among those on statins was quantified for low (<70 â€‹mg/dL, 70-<100 â€‹mg/dL), borderline (100-<135 â€‹mg/dL and 135-<150 â€‹mg/dL), borderline high (150-<200 â€‹mg/dL), and elevated (≥200 â€‹mg/dL) TGs. Multiple logistic regression examined these TG categories in relation to high risk status. RESULTS: Overall, 18.6% of participants had TG â€‹< â€‹70 â€‹mg/dL, 24.2% TG 70-<100 â€‹mg/dL, 22.0% TG 100-<135 â€‹mg/dL, 6.2% TG 135-<150 â€‹mg/dL, 15.0% TG 150-<200 â€‹mg/dL, and 14.0% TG â€‹≥ â€‹200 â€‹mg/dL. Mean 10-year ASCVD risk for these groups were 5.6%, 6.9%, 7.8%, 10.3%, 9.6% and 10.8%, respectively (p â€‹< â€‹0.0001). One-fifth or more of statin users with TGs over 135 â€‹mg/dL were at ≥ 20% 10-year ASCVD risk and ≥60% of persons in all TG groups were at borderline or higher ASCVD risk. Compared to those with TGs <70 â€‹mg/dL, multiple logistic regression showed odds ratios of 3.1 to 4.6 (p â€‹< â€‹0.05 to p â€‹< â€‹0.01) for those in TG groups ≥135 â€‹mg/dL in the overall sample, but 3.4 to 8.1 (p â€‹< â€‹0.05 to p < 0.01) for those in TG groups of ≥100 â€‹mg/dL in statin users, despite adjustment including HDL-C. CONCLUSION: Many US adults with borderline levels of TGs are at elevated ASCVD risk despite statin therapy, suggesting the need first for greater lifestyle modification efforts, and when indicated, evidence-based therapies known to reduce this residual ASCVD risk.

REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States.

BACKGROUND: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. METHODS: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points. RESULTS: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59-0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57-0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49-0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56-0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43-0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55-0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort. CONCLUSIONS: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01492361.

Elevated Triglycerides (≥150 mg/dL) and High Triglycerides (200-499 mg/dL) Are Significant Predictors of New Heart Failure Diagnosis: A Real-World Analysis of High-Risk Statin-Treated Patients.

PURPOSE: Real-world data may provide insight into relationships between high triglycerides (TG), a modifiable cardiovascular (CV) risk factor, and increased heart failure (HF) risk. PATIENTS AND METHODS: This retrospective administrative claims analysis included statin-treated patients aged ≥45 years with diabetes and/or atherosclerotic CV disease enrolled in 2010 and followed for ≥6 months to March 2016. Patients with TG ≥150 mg/dL and a comparator cohort with TG <150 mg/dL and high-density lipoprotein cholesterol >40 mg/dL were included. A sub-analysis was conducted in patients with TG 200-499 mg/dL. Hazard ratios (HR) were calculated from multivariate analyses controlled for patient characteristics and comorbidities using Cox proportional hazard modeling. New diagnosis of HF required diagnosis in the follow-up period without prior evidence of HF. RESULTS: Multivariate analyses revealed a 19% higher rate of new HF diagnosis in the TG ≥150 mg/dL cohort (HR=1.192; 95% confidence interval [CI]=1.134-1.252; P<0.001; n=24,043) and a 24% higher rate in the TG 200-499 mg/dL sub-cohort (HR=1.235; 95% CI=1.160-1.315; P<0.001; n=11,657), each versus the comparator cohort (n=30,218). CONCLUSION: In a real-world analysis of statin-treated patients with high CV risk, elevated and high TG were significant predictors of new HF diagnosis.

Prevalence of United States adults with triglycerides ≥ 135 mg/dL: NHANES 2007-2014.

n/a - brief communication.