ARBITER 6–HALTS---what does it really mean?

This is somewhat old news by now, but its results have been widely distorted in popular media. With this post I hope to put the issue in perspective.

From the NEJM abstract (italicized comments mine):

Methods We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol per liter, respectively) had been achieved. (Since when is an HDL cholesterol below a certain target an achievement?). The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day). (Added to statin therapy). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima–media thickness after 14 months....

Results The mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter (P less than 0.001), and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per liter) (P less than 0.001). Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima–media thickness over 14 months (P=0.003), leading to significant reduction of both mean (P=0.001) and maximal carotid intima–media thickness (P less than 0.001 for all comparisons). Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima–media thickness (R=–0.31, P less than 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P=0.04 by the chi-square test).

From the conclusion:

...extended-release niacin causes a significant regression of carotid intima–media thickness when combined with a statin and that niacin is superior to ezetimibe.

Here are the take home points:

This trial does not refute the LDL hypothesis. For decades diet and drug trials have shown that the more LDL is lowered the fewer the events. The evidence to support this relationship is reproducible over time and is overwhelming.

It makes intuitive sense that lowering of cholesterol by an absorption blocker would be beneficial. An older class of absorption blockers, the bile acid resin binding agents, such as cholestyramine, has been shown to reduce cardiovascular events. Their mechanism, however, inhibition of reabsorption of bile acids thereby consuming cholesterol to make more bile acids, differs from that of ezetimibe. Ezetimibe directly inhibits cholesterol absorption by a novel mechanism as explained here in the product labeling:

The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.

Evidently, though, ezetimibe does more, and that was the new finding in this study: it lowered HDL cholesterol. HDLC, contrary to popular distortion, is not “good cholesterol” that protects against atherosclerosis. Instead, the concentration of HDLC is a marker of the efficiency of reverse cholesterol transport. Ezetimibe is absorbed systemically and who knows what it's doing outside the intestinal brush border. So, if the finding of this study is real, that ezetimibe really does lower HDLC, that means it may be doing something to impede reverse cholesterol transport. That would be bad indeed. Niacin, on the other hand, has been known for years to improve reverse cholesterol transport, thereby raising HDLC.

The finding that ezetimibe was associated with a lowering of HDLC is indeed surprising. The final study conclusions, though, are not surprising for this reason: it has been well understood for decades that, despite the clinical efficacy of lowering LDL, it's not enough in many patients. Consider all those statin trials that show relative risk reductions on the order of 30%. Laudable as that is it's far from 100%! Thus was born the notion of residual risk after statin therapy. Once LDLC is lowered to goal, via statin therapy or other means, many patients remain at risk. Niacin addresses that residual risk. Further LDLC reduction does not. Why?

The residual risk is composed of a mixed bag of metabolic disturbances, most of them attributable to the metabolic syndrome which includes impaired reverse cholesterol transport, insulin resistance, elevation of triglyceride-rich atherogenic particles and small LDL particle diameter. Niacin reverses these disturbances. For an in depth explanation of these risk factors check these references: [1] [2] [3].

One finding was reassuring. Combo therapy with niacin and a statin was safe. Although it was a small study there were apparently no issues with increased myositis or hepatotoxicity risk attributable to the combination as is seen with statin-fibrate combinations.