Gothenburg, Sweden – An expert consensus panel from the European Atherosclerosis Society (EAS) has issued new recommendations for the management of patients with elevated triglycerides and low HDL-cholesterol levels. For patients with high triglycerides or low HDL-cholesterol levels, the first task is lifestyle modification, but barring that, fibrates, niacin, or even the intensification of statin therapy is recommended.

Interestingly, the recommendations are published on the heels of the discontinuation of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcome (AIM-HIGH) study. The National Heart, Lung, and Blood Institute-sponsored study of high-dose extended-release niacin (Niaspan, Abbott), given in addition to statin therapy in patients with a history of cardiovascular disease, high triglycerides, and low levels of HDL cholesterol was halted 18 months ahead of schedule because niacin offered no additional benefits in this patient population.

The new EAS recommendations, which were presented this week here at the, European Atherosclerosis Society 2011 Congress, state that the focus of treatment should be patients at high risk for cardiovascular disease who have triglyceride levels >150 mg/dL and/or HDL-cholesterol levels <40 mg/dL. In the review, the panel assesses the evidence supporting the link between triglyceride-rich lipoproteins, HDL cholesterol, and cardiovascular disease, recommending that after insufficient improvement following intensive lifestyle management, physicians should consider adding niacin or a fibrate or even intensifying LDL therapy for further reductions.

The purpose of the new consensus statement is to also remind the clinical community that targeting triglyceride-rich lipoproteins and low HDL cholesterol can provide a further reduction in cardiovascular risk for patients with metabolic abnormalities who are already at LDL-cholesterol goal.

“Possibly the most successful medication of the past 30 years, in terms of the impact on outcomes, has been the statins,” Dr M John Chapman (Pitié-Salpetriere University Hospital, Paris, France), lead author of the consensus statement, told. “Of course, statins have their primary effect on LDL cholesterol and small effects on HDL cholesterol and triglyceride levels, and we’ve drilled into clinicians’ minds that you get lot of benefit in reducing cardiovascular events with statins.” The new report is a reorientation, he suggested, getting physicians to think about other residual risk factors for cardiovascular disease in statin-treated patients.

What about the AIM-HIGH study?

In an interview with heartwire about the recommendations, Chapman said that the antiatherosclerotic effects of niacin when used with a statin have been noted in plaque imaging studies, and a meta-analysis of niacin trials also indicates a clinical benefit in patients with cardiometabolic disease. Chapman said it is too early to comment fully on the results of AIM-HIGH because all the data have not yet been published. That said, he notes that patients in the trial had the same dyslipidemic phenotype the new consensus statement is highlighting, but these patients were very well treated with intensive lifestyle modification and statin therapy.

“This means that the plaques in these individuals had benefited from intensive statin therapy, and we know that intensive therapy to very low LDL-cholesterol levels results in a significant reduction in clinical events,” said Chapman. “At this point, we don’t know the status of the plaques in AIM-HIGH, and one of the weaknesses of the trial was that there was no imaging performed. In other words, this could be shades of the ENHANCE study.”

As reported by heartwire, ENHANCE was a controversial clinical trial that tested the effectiveness of combined therapy with ezetimibe (Merck) and simvastatin in patients with familial hypercholesterolemia (FH) and found that the combination did no better than simvastatin monotherapy on several surrogate end points. The combination, known as Vytorin, did not result in a significant difference in changes in intima-media thickness (IMT) compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein. Some speculated, including the investigators, that intensive statin therapy in this FH population limited ezetimibe’s benefit. Others were less charitable, however, questioning whether the drug had any clinical benefit beyond LDL lowering.

Regarding the AIM-HIGH trial, Chapman suspects that increases in HDL of 10% to 15% would likely not have been enough to result in a significant reduction in cardiovascular events. Instead, his “back-of-the-envelope” calculation based on patients’ background therapy and baseline cardiovascular risks suggests that AIM-HIGH investigators would have needed to raise HDL cholesterol 25% to 30% to reduce cardiovascular events. Chapman also suggested that blanket HDL raising might not be the right approach, pointing to other data suggesting that HDL raising is more beneficial in some clinical situations, particularly in the early course of the disease.

“The whole importance of identifying individuals with low HDL-cholesterol levels should be done far earlier for primary-prevention purposes,” he told heartwire. “Lifestyle and diet are the way go here. Weight loss raises HDL cholesterol and quitting smoking raises HDL cholesterol. So basically, with AIM-HIGH, we don’t want to throw the baby out with the bathwater.”

In a report to investors, Larry Biegelsen, an analyst with Wells Fargo Securities, notes that in this third week since AIM-HIGH was stopped, total Niaspan prescriptions are down 5.3% and new prescriptions are down 9.5%. With annual sales of $1.1 billion in 2011, he anticipates a further 20% reduction in 2012, taking the total US sales down to $902 million.

Fibrates also an issue for the FDA

Regarding fibrates, Chapman acknowledged that the data are mixed and somewhat controversial. Fenofibrate (Trilipix, Abbott Laboratories) was approved in 2008 to be used with a statin to reduce triglycerides and increase HDL cholesterol in diabetic patients with mixed dyslipidemia/coronary disease or those who were at risk of coronary disease but already on optimal statin therapy. In ACCORD-Lipid, a study of combination fenofibrate and simvastatin vs simvastatin alone, there was no benefit on the primary outcome. The FIELD trial also showed no significant difference in cardiovascular morbidity and mortality in diabetics with fenofibrate vs placebo.

However, subgroup analyses suggest that there was a benefit in patients with very low HDL cholesterol and very high triglyceride levels (baseline levels of triglycerides >204 mg/dL and HDL cholesterol <34 mg/dL). “We critically need a trial designed to test the hypothesis that the efficacy of fibrates is there in this subgroup,” said Chapman. “We don’t know that yet.”

In late May, the Food and Drug Administration advisory panel came to the same decision. They voted 13 to 0 to recommend that Abbott launch a new trial of fenofibrate in diabetic patients who have met their LDL-cholesterol goal on a statin but still have high triglycerides and low HDL cholesterol. Patients in the trial should be randomized to fenofibrate plus a statin or placebo plus a statin, and the trial’s primary end point should be based on clinical outcomes and not just changes in triglycerides or HDL-cholesterol levels, the panel agreed.