Hydroxymethylglutaryl-CoA reductase inhibitors (statins) are first line lipid lowering therapy for cardiovascular (CV) event prevention and with good reason; statins reduce mortality by 19% according to the Cholesterol Treatment Trialists’ Collaborators.1 However, even with statin therapy, two-thirds of patients will still experience a CV event.2 For over 30 years it has been known that low LDL and high HDL cholesterol is the best combination for CV event prevention. Statins are excellent at reducing LDL but do not adequately raise HDL for many patients. Thus, combination therapy with a statin and HDL boosting agents to achieve further reductions in CV morbidity and mortality remains an active area of research.
A study by Lee et al. published recently in the Journal of the American College of Cardiology shows promise for one such combination: a statin combined with extended-release niacin (niacin ER, Niaspan®).3 Lee and colleagues investigated the effect of niacin ER 2 grams daily combined with a statin (simvastatin, atorvastatin or rosuvastatin) versus a statin plus placebo on atherosclerotic plaque size in patients with low HDL (< 40 mg/dl) and either diabetes with coronary artery disease (CAD) or peripheral arterial disease (PAD). Plaque size was measured as the carotid wall area (CWA) determined by MRI of the proximal common carotid artery. All patients were taking statins at baseline with an average LDL of 85 ± 23 mg/dl and 84 ± 32 mg/dl in the niacin ER and placebo groups respectively. After 12 months of therapy, the niacin ER plus statin group achieved a significant reduction in CWA compared to the statin plus placebo group. Significant reductions in LDL (19%) and C-reactive protein (53%), and an increase in HDL (23%) were also observed in the niacin ER group. Seven patients in the niacin ER group dropped out due to drug tolerability issues; no sustained liver transaminase or creatinine kinase elevations were seen.
This study suggests an incremental benefit of high dose niacin ER in addition to a statin in patients with established cardiovascular disease (CVD). This is in contrast to the much discussed ENHANCE trial which failed to show an incremental benefit of ezetimibe on carotid intima-media thickness (CIMT) when added to simvastatin.4 There are some important distinctions to consider between the two trials. First, ENHANCE studied patients with familial hypercholesterolemia who had a relatively low level of plaque burden, likely secondary to long term statin use, which may have limited the additional response potential. Second, MRI measured CWA is more accurate than ultrasonography measured CMIT,5 but CMIT is a validated surrogate marker for atherosclerotic disease burden4,6 and is correlated with clinical events.7,8 CWA is a less well studied surrogate measure in that regard. Third, niacin ER raised HDL and lowered CRP. LDL was lowered by both agents in each trial, which would seem to suggest increasing HDL and potentially decreasing inflammation (measured by CRP) is more important than lowering LDL to achieve additional plaque size reduction against the background of ongoing statin therapy. The soon-to-be published HDL and LDL Treatment Strategies in Atherosclerosis (HALTS) trial (also known as ARBITER-6) will provide a direct comparison of ezetimibe versus niacin ER added to statin therapy on CIMT.9
It’s too early to tell if a statin-niacin combination will become the standard magic elixir that can simultaneously reduce LDL and raise HDL while attenuating the still all too high CV event rate in patients with CAD. It does provide some consideration for adding niacin ER to a statin for patients who are at or near their LDL goal but still have low HDL. The ongoing AIM-HIGH randomized controlled trial comparing simvastatin to simvastatin plus niacin ER should provide more clarity on this issue; it’s scheduled to be completed in 2013.9
1. Cholesterol Treatment Trialists’ Collaborators. Efficacy ...