NEW YORK—Niacin, an easily obtainable, relatively inexpensive nutrient, is arguably the most overlooked therapy for managing cardiovascular risk.
Though its cardiovascular benefits have been recognized for years, it has been greatly overshadowed by the statins and other patentable, highly-hyped pharmaceuticals. And its tendency to cause flushing has limited its appeal.
But all that appears to be changing.
Advicor, a recently approved combination of lovastatin and extended-release niacin, leverages the lipid-lowering effects of niacin to improve on the benefits obtained with a statin alone, according to data presented at the 14th International Symposium on Drugs Affecting Lipid Metabolism (DALM).
According to William Insull, MD, Director of the Lipid Research Clinic, Baylor College of Medicine, this niacin-lovastatin formulation is very close to “the ideal drug combination.” The two agents have different mechanisms of action. They are easily compounded together; the therapeutic effects are additive, and there appear to be no significant detrimental effects. “One agent does not compromise or interfere with the other; and both have long histories of safety and efficacy when used independently.”
Dr. Insull led a multicenter dose-ranging trial of lovastatin and extended release niacin (ERN). The protocol randomized 85 men and 79 women with type IIA/IIB hyperlipidemia, to 4-week treatment periods with ERN alone, lovastatin alone, or combination therapy with ERN plus lovastatin.
ERN monotherapy started at 400 mg/day, with dose increases in 500 mg increments to a maximum of 2,500 mg. Lovastatin was begun at 10 mg/day, and was increased to 20 mg and then 40 mg. The combination therapy was begun at the lowest doses of each agent, then titrated up to a maximum of 2,500 mg ERN and 40 mg lovastatin.
The investigators observed a dose-dependent, incremental, and additive effect of ERN with lovastatin. At the top dose level, HDL rose by a mean of 33%, LDL was reduced by 47%, TGL dropped by 51%, and Lp(a) was cut by 22%.
Dr. Insull said the combination is unique in that it “affects four major lipoproteins that carry independent risk for cardiovascular disease.”
The beauty of the nutrient-drug combination is in its dose-sparing effect, said Donald Hunninghake, MD, who also spoke at the DALM conference. At doses of 1,000 mg ERN or higher, the combination reduced LDL to a greater extent than could be obtained by doubling the lovastatin dose alone.
Dr. Hunninghake, Director of the University of Minnesota’s Heart Disease Prevention Clinic, studied 237 patients with type IIA/IIB hyperlipidemia who were randomized to ERN alone, lovastatin alone, or the combination for 28 weeks.
Once you reach a dose of 2,000 mg ERN plus 40 mg lovastatin, the combination cut LDL by 42%, raised HDL by 30%, and reduced TGL by 46%. For some reason, Lp(a) actually increased by 3% at the lowest dose combination, but decreased by 19% at the highest.
Overall, these results stand up very well against lovastatin monotherapy which lowered LDL by 26%–34%, depending on the dose, raised HDL by only 3%–6%, and gave TGL reductions of 15%–20%. Lp(a) changes ranged from a 7% increase at the lowest dose, to a 3% decrease at the highest.
Dr. Insull believes niacin could synergize equally well with other statin drugs as well. Lovastatin went off patent in December 2001; Advicor, which contains Niaspan (Kos Pharmaceuticals’ proprietary extended release form of niacin), could greatly extend the market life of this widely used statin.
The combining of nutraceuticals with prescription pharmaceuticals is a new frontier in drug development. But with economic pressures forcing drug companies to get as much mileage as they can from successful drugs, it is a strategy that will likely become more common.
Niacin affects risky lipid profiles through two mechanisms, explained Dr. Insull. First, it slows the clearance of HDL from the plasma, leading to increased plasma HDL concentrations. HDL is a key player in reverse cholesterol transport from the peripheral circulation to the liver: the higher the HDL, the more reverse transport. Thus, niacin increases removal and breakdown of cholesterol. Secondly, it reduces synthesis of apo lipoprotein B. And this, in turn, reduces synthesis of triglycerides.
Niacin’s potential for reducing CV risk was first documented by the Coronary Drug Project, published in 1975. Niacin supplementation alone gave a 29% reduction in non-fatal MI after 6 years. Even after the patients stopped taking the supplements, there was a residual 11% reduction in all-cause mortality after 15 years of follow-up (Canner et al. 1986).
To get a lipid modifying effect, one needs to dose the niacin in the range of 1,500 mg daily. Conventional multivitamins or commercial niacin supplements, with doses in the range of 100 mg, won’t likely have much impact on lipid profiles,” Dr. Insull said.
Patients on Advicor who also take daily niacin-containing multivitamins can continue to do so. However, Dr. Insull stressed that concurrent niacin mega-dosing is strictly contraindicated.
Flushing has been plaguing niacin since it was first discovered. At a dose of 1,500 mg, flushing would be almost guaranteed. But the extended-release Niaspan formulation used in Advicor keeps plasma levels low and steady. This greatly reduces the risk of flushing, as well as the potential for liver enzyme abnormalities, which sometimes arise with high niacin doses.
From the patient’s point of view, one of the greatest advantages of Advicor is that it can be taken once daily before bedtime. “If they flush, it will be during sleep,” said Dr. Insull. He estimated that roughly one-third of all patients taking this drug will experience no flushing whatsoever, and the vast majority will have less than 10 episodes over the course of treatment.
So long as one adheres to general contraindications for both statin and niacin monotherapy, and avoids giving it to patients with known niacin sensitivities, Advicor appears to be a safe bet for nearly all patients with high-risk lipid profiles, said Dr. Insull. He added that diabetics and or those at-risk for diabetes should be monitored closely because niacin in any form can sometimes increase blood glucose levels.
Careful patient counseling is essential. Dr. Insull advises colleagues to be honest with patients about the small possibility of flushing. “If they know they might flush and that nothing serious is happening when it occurs, they will tolerate it.”