Combination high-dose Niaspan (2G daily) with moderate-dose simvastatin (20 mg) lowered apoB lipoproteins to a greater extent than moderate-dose (20 mg) and even high-dose (80 mg) simvastatin monotherapy, while also raising HDL-C. The prevalence of the LDL pattern B profile was reduced by almost 80% by S20/N, whereas high-dose simvastatin had no effect on this atherogenic phenotype. The S20/N combination increased HDL-C levels, but not apoAI levels or HDL particle number, consistent with a shift toward larger atheroprotective HDL-2 particles.15,16
These findings support the concept that niacin/statin combinations, when targeted to maximize LDL-C lowering as well as increase HDL-C, might have equivalent or greater CVD benefit than high dose statin alone.
Relative to statin monotherapy, short-term niacin studies (3–6 months) demonstrate favorable effects on Lp (a), TG, and LDL-C as well as raising HDL-C, although LDL-C lowering required higher doses of niacin.19,20,25,26
Small studies of lipoprotein subclasses revealed reductions in small-dense LDL with niacin15,27–30
even beyond statins.29
In the 3-year HDL-Atherosclerosis Treatment Study (HATS) trial (n = 160), Brown et al15
demonstrated regression of coronary plaques and sustained effects on apoB lipoproteins and HDL-C with a niacin (2.4G daily)-statin compared to placebo; however, a statin monotherpay arm was not included, confounding interpretation. Taylor et al16,17
reported that adding niacin (1G daily) to statins retarded carotid atherosclerosis coincident with increased HDL-C, lower TGs, but without change in LDL-C.
Ours is the first trial to compare a niacin 2G/moderate-dose statin combination to both moderate- and high-dose statins, the contemporary standard for treating patients at high risk of CVD.1,2
This combination provided at least a comparable degree LDL-C lowering as high-dose statins as well as sustained benefits on apoB lipoproteins, Lp(a), lipoprotein particles, and HDL-C. Small trials suggest greater effects of niacin/statin combinations, compared to statin alone, on subclinical atherosclerosis.16,17,31
Whether such effects translate into reduced clinical events awaits the results of phase III trials (eg, NCT00120289 and NCT00461630).
In the Investigation of Lipid Level Management to Understand its Impact on Atherosclerotic Events (ILLUMINATE) trial,4
a combination of atorvastatin and torcetrapib compared to atorvastatin alone, increased CVD events despite marked increases in HDL-C. Although increased CVD may have been related to off-target effects of torcetrapib,32
torcetrapib did not reduce carotid or coronary atherosclerosis progression in imaging trials.33–35
These results have questioned the efficacy of cholesterol ester transport inhibition in humans and, more generally, provide a cautionary note in targeting HDL-C elevation for CVD.36
In this context, there is renewed interest in niacin particularly because of promising imaging studies16,17,31
and its proven CVD benefit as a monotherapy.37
Despite identification of a G-protein–coupled receptor for niacin,5,7
the specific mechanism(s) of HDL-C raising and apoB lipoprotein lowering remains uncertain. Suppression of adipose FFA release is one mechanism proposed to reduce hepatic FFA flux and thus lower TG and VLDL production.5
We found, however, that chronic extended-release niacin increased plasma FFA levels. This may be due to a diurnal rebound in which high midmorning FFA levels follow an overnight suppression with niacin. It has been suggested that, unlike short acting niacin, extended release niacin may cause a limited rebound in adipocyte FFA release.38
Our data, however, suggest at least a modest rebound in FFA. Vega et al39
also demonstrated small increases in FFA with long-acting niacin. Despite increased FFAs, we observed reductions in both plasma TG and VLDL, suggesting that modulation of adipocyte FFA flux is unlikely to account for niacin effects on apoB lipoproteins. Adipose-independent effects on hepatic lipoproteins appear likely.40
Despite elevation in HDL-C (~18%) with S20/N, we failed to detect a significant increase in apoAI levels (~+5%) or HDL particle number (~+2%). Our findings differ from several previous studies that demonstrated significant 10% to 16% increases in apoAI with niacin/statin combinations.20,41,42
This might relate to our older study sample, which carries a substantial burden of comorbidities and atherosclerosis. It is also important to note that HDL particles are heterogeneous and vary in size, maturity, and apoAI composition,43,44
which may contribute to differences in apoAI and HDL-C responses to niacin. An important limitation of our study is the difference between treatment groups in some baseline parameters, including statin use and LDL-C. Although these differences were not statistically significant, the subsequent changes in apoB-containing lipoproteins may have been affected. Our results, however, were consistent across additional analysis that adjusted for differences in prerandomization statin use and LDL-C.
In conclusion, our study is the first to report incremental and sustained benefit of a full-dose niacin/moderate-dose statin combination on atherogenic apoB lipoproteins that is at least comparable to high-dose statins, while also raising HDL-C. Ongoing atherosclerosis imaging studies and outcome trials will reveal whether and how much this strategy improves atherosclerotic CVD. The mechanism of niacin lowering of apoB lipoproteins is uncertain but appears unlikely to be mediated by suppression of adipose FFA flux to liver.