Impact of expanded FDA indication for icosapent ethyl on enhanced cardiovascular residual risk reduction.

Hypertriglyceridemia is associated with increased cardiovascular disease (CVD) risk. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) demonstrated that the purified, stable ethyl ester of eicosapentaenoic acid, icosapent ethyl (IPE), added to statins reduced CVD events by 25% (p < 0.001), leading to an expanded indication in the USA. IPE is now approved as an adjunct to maximally tolerated statins to reduce CVD event risk in adults with triglyceride (TG) levels ≥150 mg/dl and either established CVD or diabetes mellitus plus ≥2 additional CVD risk factors. The new indication allows co-administration of IPE for elevated TG levels with statin treatment, enabling effective residual risk reduction in a broader at-risk population beyond what can be achieved with intensive low-density lipoprotein cholesterol control alone.

More clinical lessons from the FIELD study.

INTRODUCTION: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study investigated the effect of fenofibrate treatment in 9,795 patients with type 2 diabetes. RESULTS AND DISCUSSION: Reduction in major coronary events (the primary endpoint) and total cardiovascular disease (CVD) events (the secondary endpoint) was similar (relative risk reduction 11%), but only significant for total CVD events (p = 0.035). The benefit of fenofibrate treatment was greater in patients with mixed dyslipidaemia, especially in those with triglycerides >2.3 mmol/L and low plasma levels of high-density lipoprotein cholesterol (relative risk reduction 27%, p = 0.005). There were also microvascular benefits associated with fenofibrate treatment, specifically reduction in the rate of laser therapy for retinopathy (by 30%, p < 0.001), non-traumatic amputation (by 38%, p = 0.011) and progression of albuminuria (p < 0.002). Fenofibrate was generally well tolerated alone or in combination with a statin. CONCLUSIONS: Overall, the FIELD study data support the use of fenofibrate for CVD prevention in diabetes, ideally in patients without prior macrovascular or microvascular complications. Fenofibrate may also have a role as a preventive treatment for diabetic retinopathy. Addition of fenofibrate to statin therapy may a logical progression from the FIELD study data, although the efficacy and tolerability of this approach needs to be evaluated in prospective outcome studies.

Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis.

Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid-binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.

Apolipoprotein AI as therapy for atherosclerosis: does the future of preventive cardiology include weekly injections of the HDL protein?

Conventional wisdom suggests that halting or reversing long-term atherosclerosis requires increasing the amount of circulating high-density lipoprotein (HDL) coursing through the vasculature. However, recent evidence seems to indicate that reducing the size of cholesterol-containing lipid plaques might be accomplished by methods that either do not raise or, in fact, lower the amount of circulating HDL. Carriers of apoAI(Milano), a variant of apoprotein AI (a component of HDL), have reduced levels of circulating low-density lipoprotein (LDL). Intriguingly, these individuals have reduced amounts of circulating HDL and total apoAI. Infusions of the ApoAI(Milano) variant given to patients with coronary atherosclerosis appear to lead to disease regression and reduced plaque size. However, larger studies are required to provide definitive proof of apoAI(Milano)'s benefits. What is certain is that attention should be focused on the removal of cholesterol from plaques rather than simply desiring to raise HDL concentrations in patients.