Relationship of Lipoproteins to Cardiovascular Events

Abstract

Objectives In this secondary analysis of the AIM-HIGH trial, the objectives were to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes. Background During 3-year follow-up in 3,414 patients with established CV disease and low HDL-C, combined niacin + LDL-lowering therapy did not reduce CV events versus LDL-lowering therapy alone. Methods Subjects taking simvastatin + ezetimibe were randomized to extended-release (ER) niacin 1500–2000 mg or minimal immediate-release niacin (<150 mg) as placebo at bedtime. LDL-C in both groups was maintained from 40 to 80 mg/dL. Hazard ratios (HR) were estimated by Cox proportional hazards for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Results CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (>198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (HR=0.74, p=0.073). In-trial LDL-C, nonHDL-C, and TC/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. Conclusions Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could impact risk. Clinical trial info AIM-HIGH; NCT00120289

High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual Cardiovascular Risk

“…In a separate analysis of the Optum Research Database of 4 867 300 patients with at least 1 prescription fill for a statin, 1 418 866 had at least 1 LDL‐C measurement ≤2.59 mmol/L (≤100 mg/dL); of these patients, 693 308 (48.9%) had at least 1 triglycerides measurement ≥1.69 mmol/L (≥150 mg/dL), and 421 974 (29.7%) had at least 1 triglycerides measurement ≥2.26 mmol/L (≥200 mg/dL). This is supported by large cardiovascular outcomes trials, including or limited to patients with type 2 diabetes mellitus, wherein ≈15% to 20% of patients had triglycerides ≥2.26 mmol/L (≥200 mg/dL) and LDL‐C <2.59 mmol/L (<100 mg/dL) and ≈25% to 40% had triglycerides ≥1.69 mmol/L (≥150 mg/dL) and LDL‐C <2.59 mmol/L (<100 mg/dL) 23, 27, 28, 29, 30, 31, 32. Despite this relatively high prevalence, there is a lack of prospective data designed specifically to investigate such patient populations with high triglycerides despite statin therapy.…”

Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

“…Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy 3, 4, 5, 6, 7, 8, 9, 10, 11.…”

“…Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy 3, 4, 5, 6, 7, 8, 9, 10, 11. Finally, studies administering higher‐dose EPA suggest additional beneficial effects beyond lipid‐lowering that may be unique to EPA relative to other TG‐lowering therapies, such as beneficial changes in coronary plaque characteristics, which may lead to reductions in major CV events 4, 16, 25, 26, 27, 28, 29, 30, 31, 32, 33…”

“…Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events, and therefore may represent one contributive factor of residual CV risk beyond statin therapy 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. More recently, elegant Mendelian randomization studies have supported a causal role for TG in the pathogenesis of cardiovascular disease (CVD), showing that elevated TG are not merely a risk marker, but rather a risk factor and thus potentially modifiable 3.…”

“…Prior CV outcome studies that administered therapies with TG‐lowering effects (niacin or fenofibrate) on top of statin therapy did not reach their primary endpoints. Nonetheless, these studies also did not prospectively enroll patients with elevated TG levels despite statin therapy,6, 12, 13, 14, 15 and subgroup analyses suggested possible benefits to TG lowering in patients with dyslipidemia 5, 6…”