ANAHEIM, CA—Statins will only go so far in reducing the incidence of cardiovascular events, said H. Robert Superko, MD, at Nutracon, an annual conference on advances in nutraceutical product development.

Drug manufacturers would have physicians believe that statins are the last word in cardiac risk reduction. There’s no question they produce dramatic swoops in total cholesterol and LDL. But comprehensive risk reduction is an art that requires much more than a simple statin script.

“We have not ‘cured’ dyslipidemias with the advent of cholesterol-lowering drugs. We’ve just slowed the process down a little bit. There is a tremendous opportunity for nutritional interventions,” said Dr. Superko, director of the Berkeley Heart Lab, a University of California sponsored clinical research institute. For example, niacin, an inexpensive and widely available nutrient can have profound impact. Yet it is grossly underutilized.

On a population basis, statin-induced reductions of total cholesterol and LDL can confer a 20% to 30% reduction in the relative risk of cardiovascular events. But Dr. Superko insisted this is not good enough.

Analysis of data from 10 major cholesterol-lowering trials indicates that even with optimal statin therapy and “normalized” total cholesterol and LDL values, many people continue to have CV events. In comparing treatment versus control groups in these large-scale studies, Dr. Superko found that while the treatment groups did show event reductions of 17% to 46%, the number of treated patients who had CV events still ranged from 10% to 65% (Superko HR, et al. Circulation 1996; 94: 2351–54).

“Many patients reduce LDL-C yet continue to have events,” he said, noting that in the 10 trials he reviewed, the biggest treatment-related event reductions were in the trials with the lowest total event rates to begin with.

Dr. Superko, and a growing number of cardiologists, have come to believe lipoprotein composition may be more important than total cholesterol or LDL in predicting risk. The issue here is the advanced products of lipoprotein metabolism and their relative concentration and distribution.

Small Particles, Big Risk

There is ample evidence that the so-called “small LDLs” such as LDL-IIIa and IIIb, and LDL-IVa and IVb are strong and independent risk factors for CAD. Based on five studies, including the Boston Area Heart Project and the Harvard Physicians Health Survey, Dr. Superko estimated that a predominance of small LDL carries a 3-fold increased risk independent of triglycerides, LDL, HDL, and body mass index.

Small LDLs are taken into atheromatous plaques at a faster rate (Nordstard 1989), and are more prone to oxidation (Tribble 1992, Dejager 1993). Endothelial vasodilatory dysfunction is also inversely related to LDL size: the greater the percentage of small LDLs, the higher the risk of endothelial dysfunction (Dyce et al. 1993). LDL-IIIa and IIIb are independent predictors of carotid artery wall thickness (Skoglund-Andersson et al., ATVB 1999; 19: 2422–2430), and LDL IVb levels are reliable predictors of coronary artery disease progression.

Lipid metabolic patterns are largely determined by genetic factors, and there are many individuals in whom dyslipidemia is characterized by a preponderance of small, dense LDL particles. These subjects are also frequently insulin resistant, have impaired reverse cholesterol transport, and high post-prandial lipemia. They are likely to remain at high risk despite reductions in total and LDL cholesterol.

Improvement in LDL subclass distribution, particularly a reduction in the relative concentration of small, dense particles, is associated with angiographically documentable regression of atherosclerotic plaques.

Pounding Niacin

The wildly popular statins have no impact on the concentration or distribution of these small LDL subclasses. Fortunately, niacin does.

In 1994, Dr. Superko and colleagues published a study of patients with high-risk lipid profiles randomized to 1,500 mg niacin daily in an extended release formula (Niaspan), or placebo. Those on Niaspan had an 18% reduction in LDL IIIa, and a 30% reduction in LDL IIIb beyond the changes observed with placebo. There was a 2% reduction of LDL IVa and a 10% reduction of LDL IVb. The niacin effects were even more pronounced in subjects with the “small LDL” phenotypes (Superko HR, et al. Circulation 1994; 90: 1–504).

With niacin, one obtains “a greater effect on subclass distribution than appreciated by the LDL cholesterol or triglyceride effects. Statins don’t do this.”

More recently, he has participated in two multicenter trials involving the Niaspan extended release formula, which is marketed by Kos Pharmaceuticals. One study compared Niaspan, given nightly, with standard niacin supplements of equivalent dose.

The two forms are equivalent in terms of their lipid effects, but the extended release formulation is given as a single 1,500 mg dose, once before bedtime, whereas standard niacin requires three 500 mg doses over the course of a day (Knopp RH et al. Metabolism 1998; 47(9): 1097–104). Nighttime dosing and extended-release formulation reduces incidence of flushing, the primary adverse effect associated with niacin.

In a 48-week open label study, the niacin alone at doses of 1,000 to 2,000 mg per day resulted in an 18% reduction in LDL, a 15% reduction in Apolipoprotein B, an 11% decline in total cholesterol, a 24% reduction in triglycerides, a whopping 36% drop in lipoprotein (a) and a 29% increase in HDL.

In combination with a statin, Niaspan produced even larger reductions in LDL (32%), Apolipoprotein B (26%), total cholesterol (23%) and triglycerides (30%). However, the change in lipoprotein (a) was smaller (19%) than for the niacin alone (Guyton JR, et al. Am J Cardiol 1998; 82(6): 737–43).

The company that makes Niaspan recently launched a product called Advicor, which combines Niaspan with lovastatin, allowing patients to obtain the benefits of both types of treatment in a single daily medication (see related story). The combining of a nutritional supplement with a pharmaceutical in a single tablet is a growing trend in drug development.

Niacin also has the well-documented effect of reducing homocysteine, a very strong marker for cardiovascular mortality. In a study of 392 patients with multivessel coronary disease requiring angioplasty or bypass surgery, Dr. Superko and colleagues observed that both CV mortality and total mortality more than double as homocysteine levels increase above 10 µmol/L.

Subjects with homocysteines under 9.7 had CV mortality rate of 9% and a total mortality of 6%; those in the range of 9.7 to 11.7 had a CV mortality of 26% and a total mortality of 20%. Patients with the highest homocysteine measurements (14.7 and greater) had CV mortality of 30% and total mortality of 47%.

“There’s a very strong rationale for keeping the homocysteine below 10 in cardiovascular patients. You want to be pounding niacin,” Dr. Superko told Nutracon participants.

THE REDUX: Statins are a significant advance, but they are not “cures” for CVD. Effective management requires attention to other factors besides LDL, especially the so-called small LDLs and HDL. Niacin is an inexpensive, highly effective, and sadly overlooked ally. At doses of 1,000 to 2,000 mg per day, it can drop LDL by 18%, ApoB by 15%, total cholesterol by 11% cholesterol, triglycerides by 24%, and LP(a) by 36%. Simultaneously, it raises HDL by 29%. A new timed-release form of niacin has greatly reduced problematic flushing. Emergence of a novel lovastatin-niacin combination called Advicor leverages the power of niacin to increase the efficacy of the statin.