Niacin improves anti-atherogenic effect of statins in APOE*3Leiden.CETP mice

Kühnast S, Louwe MC, Heemskerk MM, et al.
PLoS One. 2013 Jun 19;8(6):e66467

Expert comment by Prof.dr. JW Jukema (Leiden University Medical Center, The Netherlands)

"Since long it has been questioned if so called “beneficial“ HDL cholesterol raising medication has the potency to slow down progression of atherosclerosis. Very often medication/compounds combine some HDL raising with a certain amount of LDL cholesterol lowering properties. Thus far, artificial raising of HDL cholesterol has not led to unequivocal benefits.

In this carefully carried out preclinical study, using what many consider the best (closest to the human situation) mouse model for atherosclerosis, i.e. the “APOE*3Leiden.CETP mice”,  the clinical benefits of niacin seem largely dependent on its (limited) ability to lower LDL-c, in addition to other lipid-lowering treatments and not the raising of HDL cholesterol, for which the drug in fact was most used. This may explain why niacin failed to show clear beneficial effects in the clinical outcome trials in patients, which were always done on top of profound lipid lowering (by statins).

So the case for LDL cholesterol lowering still stands, but for HDL raising using niacin to achieve this, the case seems closed. Whether other mechanisms of HDL cholesterol raising (in combination with LDL cholesterol lowering or alone) will show benefits is still under investigation (e.g. CETP inhibition)"

Background

Niacin (nicotinic acid or vitamin B3) has been shown to reduce triglycerides (TG) by ~15-10%, while increasing HDL-c by ~10-25% and mildly reducing total cholesterol (TC) by ~5-10% and LDL-C by ~5-20% [1]. These findings suggest an atheroprotective effect. The large outcome trials AIM-HIGH and HPS2-THRIVE have however failed to reveal a benefit of niacin in addition to statin treatment [2,3].
Statins are currently the standard treatment in patients with atherosclerotic disease. By lowering LDL-c levels, CV event risk can be reduced by 25-45%. A substantial residual risk for adverse CV outcomes remains however [4,5]. Also, some patients do not reach LDL-c goals, despite receiving the maximally tolerated statin treatment. Thus, other LDL-c lowering therapies are required. Alternatively, agents that increase HDL-c levels could be beneficial [1,4].
Since niacin both lowers LDL-c and raises HDL-c levels, it was considered an interesting candidate for further CV risk reduction in addition to statin therapy. Initial small clinical studies indeed suggested a beneficial effect of statin plus niacin, in comparison to statins alone (4, 6-8), including a study that confirmed carotid atherosclerosis regression upon niacin therapy [9]. Nonetheless, the large AIM-HIGH trial was stopped prematurely due to futility [3], and HPS2-THRIVE did not reveal extra CV risk reduction with extended release (ER) niacin/laropiprant in addition to statins as compared to statins alone [2].
This study aims to address the discrepancy of the beneficial effects of niacin in initial clinical trials and the lack of effect in the large outcome trials. The effects of niacin without and with simvastatin on atherosclerosis development were studied, as well as the underlying mechanism, in APOE*3Leiden.CETP mice. This is a mouse model for familial dysbetalipoproteinemia. These mice have a human-like lipoprotein metabolism and atherosclerosis development [10,11].

Main results

• Niacin significantly reduced TC (-39%, P<0.001) and TG (-50%, P<0.001) levels, while simvastatin significantly reduced TC (-30%, P<0.001) but not TG (-19%, NS) levels. The combination of niacin plus statin also reduced TC (-55%, P<0.001) and TG (-52%, P<0.001) levels. Niacin increased HDL-c by 28% (P<0.01), as compared to the control, while the combination raised HDL-c by 14% (P<0.05), as compared to simvastatin alone.
• Niacin mildly increased plasma VLDL clearance, while VLDL-TG and apoB production were not affected.
• Niacin and simvastatin both significantly reduced plasma CETP activity and mass, as well as their combination. Hepatic CETP mRNA expression was reduced after niacin or the combination of niacin and simvastatin.
• After 18 weeks of niacin treatment, fewer atherosclerotic lesions were seen (-23%, P=0.056), and lesion severity was less than in the control, and more undiseased segments were seen (+141%, P<0.001) in the aortic root. Simvastatin alone only reduced lesion severity and total lesion area (-49%, P<0.01). Combination treatment potently inhibited lesion development, as seen by fewer lesions (-48%, P<0.001), less severe lesions and a smaller lesion area (-87%, P<0.001). The effect of the combination therapy was larger than that of simvastatin alone.
• Lesion stability was assessed by the ratio of collagen and (smooth muscle cell) SMC area (stabilization factors) to macrophage area (destabilization factor). Niacin alone and in combination with simvastatin stabilized the lesion. Combination therapy had a stronger stabilising effect than did simvastatin alone. Vessel wall inflammation was reduced by all treatments.
• Lesion area was predicted by plasma TC exposure (R²= 0.70, P<0.001), and non-HDL-c (R²= 0.69, P<0.001), and to a lesser extent by HDL-C (R²= 0.20, P<0.001).The effect of niacin and simvastatin on lesion area were lost after correction for both HDL-C and non-HDL-C exposure. Thus, niacin and simvastatin seem to decrease atherosclerotic lesion development mainly via a reduction of non-HDL-c. An effect on inflammatory markers may contribute to the anti-atherogenic effect, only in the case of niacin.
• Niacin was found to mildly increase reverse cholesterol transport in an in vivo experiment.

Conclusion

In APOE*3Leiden.CETP mice, this study showed that niacin decreased atherosclerosis development. This was mainly due to a reduction of non-HDL-c with a modest increase of HDL-C and an anti-inflammatory effect. The additive effect of the combination treatment of niacin and simvastatin could mostly be attributed to the non-HDL-C lowering capacities. Niacin attenuated lesion progression and improved lesion composition. When given together with simvastatin, it contributes to the statin’s anti-atherogenic effect, mainly by stabilising the plaque.
The clinical benefits of niacin seem largely dependent on its ability to lower LDL-c, in addition to other lipid-lowering treatments. This may explain why niacin failed to show a beneficial effects in the clinical outcome trials.

References

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