JCL roundtable: Omega-3 fatty acids and cardiovascular outcomes.

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) in 2018 demonstrated the value of an omega-3 fatty acid formulation, icosapent ethyl (eicosapentaenoic acid ethyl ester) for preventive treatment of atherosclerotic cardiovascular disease (ASCVD). This JCL Roundtable discussion brings together three experts to explore the origins and implications of REDUCE-IT and more broadly omega-3 fatty acids for mitigation of ASCVD risk. REDUCE-IT achieved a highly significant 25% reduction of major adverse cardiovascular events. It is the first trial of a triglyceride-lowering drug to gain unequivocal success in high-risk patients treated intensively with statins. It corroborates positive results from an earlier major trial using eicosapentaenoic acid (EPA) ethyl ester, the Japan EPA Lipid Intervention Study (JELIS), which included hypercholesterolemic subjects treated with low-dose statin mostly in primary prevention. Together these studies mark a new avenue for preventive treatment of ASCVD. Omega-3 fatty acids also show some promise, though less decisively, for reducing inflammation and cardiovascular mortality in a broader context.

JCL Roundtable: Lipid clinic operations.

Until 1990, lipid clinics in the United States existed only in academic medical centers, generally in close relationship with laboratory-based research programs. The advent of statin therapy, the success of major clinical trials to prevent or stabilize atherosclerotic cardiovascular disease, and organizational efforts highlighted by regional Lipid Disorders Training Centers and the newly formed National Lipid Association boosted the formation of lipid clinics and preventive cardiology clinics in private and academic settings. This roundtable discussion with 4 experts examines multiple aspects of lipid clinic operations: obtaining referrals, adapting to either the academic or community setting, organizing a team of providers, incorporating diet and lifestyle counseling as well as medication, establishing the pharmacist role, and gaining financial stability. Some issues are as yet unsettled, including the subspecialty home of lipidology, if any, and the diagnostic and management boundaries of practical lipid clinics. Achieving official recognition as a subspecialty has taken some steps forward but remains a challenge. Opportunities for advocacy need to be seized.

Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia.

BACKGROUND: Cardiovascular outcomes trials of fibrates, niacin, or omega-3 fatty acids alone, or added to a statin, have not consistently demonstrated reduced risk, but larger, statistically significant clinical benefits have been reported in subgroups with elevated triglycerides (TG) and/or elevated TG plus low high-density lipoprotein cholesterol (HDL-C). OBJECTIVE: To perform a meta-analysis of the effects of therapies targeting TG and TG-rich lipoprotein cholesterol on cardiovascular disease event risk in subjects with elevated TG or elevated TG paired with low HDL-C. METHODS: Publications were identified using PubMed, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, and Internet Stroke Center. Random-effects meta-analysis models were used to generate summary relative risk estimates and 95% confidence intervals. Heterogeneity was assessed by χ(2) and I(2) statistics, and the impact of each trial was assessed in one study-removed sensitivity analyses. RESULTS: Six trials of fibrates, 2 of niacin, 1 of fibrate + niacin, and 1 of omega-3 eicosapentaenoic acid ethyl esters were identified. For the prespecified primary cardiovascular disease or coronary heart disease end point used in each trial, the summary relative risk estimate (95% confidence interval) for subjects with elevated TG was 0.82 (0.73-0.91), p-heterogeneity = 0.13, I(2) = 36.2, and for subjects with elevated TG and low-HDL-C, it was 0.71 (0.63-0.81), p-heterogeneity = 0.52, I(2) = 0.0. There was no evidence of publication bias, and the results remained statistically significant when each individual trial was removed. CONCLUSION: Drugs that substantially, but not exclusively, lower TG and TG-rich lipoprotein cholesterol may have cardiovascular benefits in individuals with elevated TG, particularly if accompanied by low HDL-C.

Combination regimens with statin, niacin, and intestinally active LDL-lowering drugs: alternatives to high-dose statin therapy?

PURPOSE OF REVIEW: To summarize recent studies on combination regimens that employ a statin with added niacin, ezetimibe, and/or bile acid sequestrants, and to understand the implications of these studies for clinical practice. RECENT FINDINGS: Combinations of statin, niacin, and/or intestinally active LDL-lowering drug have demonstrated safety and favorable effects on plasma low and high-density lipoproteins. Niacin and bile acid sequestrants appear to exert beneficial effects on atherosclerotic lesions, whereas results with ezetimibe are uncertain. Moreover, the use of niacin and bile acid sequestrants is supported by clinical outcome results from large monotherapy trials and small combination therapy trials. Three large randomized trials currently are evaluating clinical outcomes with the addition of niacin or ezetimibe to statin treatment. SUMMARY: Until the results of ongoing trials are known, it is reasonable to favor the use of niacin and bile acid sequestrants in combination with statins, based on safety and efficacy with regard to effects on lipoproteins, atherosclerotic lesions, and, to a limited extent, clinical outcomes. The effect of ezetimibe on carotid atherosclerosis is indeterminate, but ezetimibe can be reasonably added to statin therapy as a secondary option for LDL-lowering.

Safety considerations with niacin therapy.

Niacin has beneficial effects on plasma lipoproteins and has demonstrated clinical benefits in reducing cardiovascular events and atherosclerosis progression. The side effects of niacin, however, have limited its use in general clinical practice. An understanding of cutaneous flushing based on the best available evidence should enhance patient education efforts and improve adherence. Although serious hepatic toxicity from niacin administration has been reported, it is largely confined to the use of slow-release formulations given as unregulated nutritional supplements. Niacin has been shown to induce insulin resistance in short-term trials, but the glycemic response in subjects with and without diabetes is usually minor. Niacin can be used safely in patients with diabetes. Despite a few case reports of myopathy associated with niacin-statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) combination therapy, 2 decades of clinical evidence since the introduction of statins do not support a general myopathic effect of niacin either alone or in combination with statins. Rare, less well-defined side effects of niacin include blurred vision due to cystoid macular edema, nausea and vomiting, and the exacerbation of peptic ulcers. Laboratory abnormalities that are usually small (< or =10%) and clinically unimportant include increased prothrombin time, increased uric acid, and decreases in platelet count and serum phosphorus. Overall, the perception of niacin side effects is often greater than the reality. As a result, a valuable medication for cardiovascular risk is underused.

Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?

The Treating to New Targets (TNT) trial is a parallel-group study that has randomized 10,003 patients from 14 countries to double-blind treatment with either atorvastatin 10 or 80 mg. During the double-blind period, low-density lipoprotein (LDL) cholesterol levels are expected to reach approximate mean values of 100 mg/dl (2.6 mmol/L) for the low-dose atorvastatin group and 75 mg/dl (1.9 mmol/L) for the high-dose group. Randomized patients are expected to be followed for an average of 5 years. The primary end point is the time to occurrence of a major cardiovascular event, defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. The large patient numbers in the TNT study and long follow-up should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit.