The results of the HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) study answered an important question: Does niacin add any benefit in an era of high-dose statin therapy?
"The data have been kind of murky until now," says Leslie Cho, MD, Director of the Women’s Cardiovascular Center at Cleveland Clinic’s Heart & Vascular Institute. “HPS2-THRIVE, the largest niacin trial to date, found that in patients with a history of cardiovascular disease whose cholesterol levels are well controlled, niacin really doesn’t add anything and it may even cause harm."
The results, Dr. Cho says, support Cleveland Clinic’s established approach to niacin therapy. “We only prescribe niacin to people who cannot tolerate statins, and to people who are not at goal even on maximum doses of cholesterol-lowing medications,” she says. “For those patients, niacin still has a role.”
The HPS2-THRIVE trial enrolled more than 25,000 patients aged 50 to 80 years from the UK, Scandinavia and China. All patients had a prior history of: myocardial infarction; ischemic stroke or TIA; peripheral arterial disease; or diabetes with other coronary heart disease.
All patients received simvastatin, with or without ezetimibe, as background treatment to reduce their initial LDL-C levels to an average of 63. Patients were then randomized to receive either adjunctive therapy with extended-release niacin/laropiprant (a prostaglandin receptor blocker that reduces flushing) or a placebo.
Adding the extended-release niacin/laropiprant to statins for an average treatment period of five years did not reduce the risk of major vascular events or of needing revascularization for high-risk patients.
Researchers also reported a significant number of different types of serious side effects with the niacin therapy. Some of the side effects had been demonstrated in previous studies, such as skin rashes, gastrointestinal problems, complications with the management of pre-existing diabetes and increased risk of developing diabetes.
“We have known for a long time that niacin increases the risk of diabetes—it doesn’t cause diabetes, it just brings it forward,” Dr. Cho says. “Niacin can also cause more gout.”
Other side effects identified in the study that may require further research included infections and bleeding, particularly in the gut and brain. The study also found an increased risk of myopathy in Chinese participants, particularly those who took niacin as well as simvastatin.
The study findings have resulted in the suspension by Merck & Co/MSD of the ER-niacin/laropiprant combination from Europe and other countries. The combination therapy was not approved by FDA.
Dr. Cho points to several limitations of the study, including:
- There were no niacin-only or laropiprant-only study arms, so it’s difficult to distinguish which side effects may have been caused by which agent.
- A large number of the patients enrolled in the study were Chinese, and Chinese patients traditionally have more complications with cholesterol-lowering therapy, especially high-dose statins.
- The average LDL level of patients enrolled in the study was 63, and these patients typically wouldn’t be prescribed niacin.
“We max the patient out on statins—and if they can’t get to goal, we add niacin,” Dr. Cho says. “We don’t reach for niacin as a first-line agent.”
Next on the Horizon: HDL
While the study did find that niacin therapy helped raise HDL-C levels by an average of six points, Dr. Cho says that increasingly, the current literature supports the fact that raising HDL in and of itself is not necessarily cardio-protective.
“HDL is much more complex than LDL—it has functional aspects that are sometimes anti-atherogenic and sometimes pro-atherogenic, and sometimes anti-inflammatory and sometimes pro-inflammatory,” she says.
Current clinical studies are looking at the effect of emerging agents such as CETP inhibitors, which could increase HDL levels in some patients by as much as 100 percent.
Dr. Cho adds: “HDL function is much more important than just the sheer number.”
Leslie Cho, MD, is Director of the Cleveland Clinic’s Women’s Cardiovascular Center and Co-Section Head of Preventive Cardiology and Rehabilitation in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic. She is board-certified in interventional cardiology, cardiovascular medicine, and internal medicine, with specialty interests in general cardiology, heart disease, and peripheral arterial and vascular disease and their attendant therapies and treatments.