Antioxidant Supplements and Simvastatin-Niacin Therapy
To the Editor:
This article1 attracted our attention first because of the wide implications and second because of the related editorial comments2 that sort of urged the physicians to “stop prescribing antioxidant vitamins to prevent and treat heart disease.”
In these studies, subjects with coronary artery disease were divided into 4 treatment groups, namely (1) placebo group, (2) antioxidant group, (3) simvastatin-niacin group (S-N), and (4) simvastatin-niacin plus antioxidant group (S-N+A). The probability values for between-groups comparisons of changes from the individual values at the start and until the end of the study period (12 months) for several parameters (Table 2) indicate that there were no significant differences between the S-N group and the S-N+A group with respect to plasma cholesterol, plasma tri-glycerides, VLDL-C, IDL-C, LDL-C, HDL-C, HDL3-C, apo A-I, apo A-II, apo-B. However, the changes in HDL2-C values differed significantly between these two groups.
The intakes of simvastatin in these groups at the start of the studies ranged between 10 and 20 mg. During the course of the studies, intakes were raised to 20 to 40 mg for the subjects whose LDL cholesterol levels were not lowered to less than 90 mg/dL. Similarly, the intakes of niacin were increased from 2 g per day to 3 to 4 g per day for the subjects in whom the rise in HDL cholesterol level was less than 10 mg/dL. Evidently, some subjects failed to respond to the predetermined treatment, requiring modification of the treatment and thus creating subgroups who received higher levels of medications. Such subgroups should have been treated separately, and separate comparisons of the subgroups receiving higher levels of medications should have been made. Then again, the number of subjects in each group that required such interventions with an increased dosage of simvastatin and niacin would in itself become a relevant and essential parameter for interpreting the treatment effects. These aspects have not been considered in interpreting the data and are particularly important in evaluating the quantum of rise in HDL2-C, as it is quite possible that higher levels of HDL2 in the S-N group were related to higher intakes of niacin. Neglect of these several factors has possibly led to unwarranted conclusions.
The authors state “HDL-C and HDL3-C and apo A-I responses were modestly blunted in S-N+A group.” This is not borne out by the probability value given in Table 2. None of these values are significantly different.
In face of these facts, the title of the article “Antioxidant Supplements Block the Response of HDL to Simvastatin-Niacin Therapy..” is highly misleading. Antioxidants, such as vitamin C, have been shown to increase HDL levels and lower total cholesterol in several other studies.3–5 It is worthwhile noting here that the recent studies in natural approaches to health have already challenged the traditional cholesterol theory of heart disease.6 Use of antioxidants has still been shown to directly improve atherosclerotic conditions.7 Several million people are in urgent need of the right type of medication for atherosclerotic conditions. With some statins withdrawn from the market and some others attracting adverse comments, it is likely that we may have to depend more and more on antioxidants either alone or in combination with lower doses of a few selected statins. It is therefore imperative that we should have incontrovertible evidence against the use of antioxidants before we stop using them.
Cheung MC, Zhao XQ, Chait A, Albers JJ, Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary Artery disease and low HDL. Arterioscler Thromb Vasc Biol. 2001; 21: 1320–1326.
Kuller LH. A time to stop prescribing antioxidant vitamins to prevent and treat heart disease. Arterioscler Thromb Vasc Biol. 2001; 21: 1253.
Kruwoska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P. HDLl-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am J Clin Nutr. 2000; 72: 1095–1100.
Rath M, Pauling L. A unified theory of human cardiovascular disease leading the way to abolition of this disease as a cause of human mortality. J Ortho Med. 1992; 7: 5–16.
Rath M, Niedzwiecki A. Nutritional supplement program halts progression of early coronary atherosclerosis documented by ultrafast computed tomography. J Appl Nutr. 1996; 48: 67–78.
The combination of antioxidant supplements used in our study significantly blunted the specific response of HDL2-cholesterol and HDL particles containing apo A-I but not apo A-II [Lp(A-I)] to simvastatin-niacin therapy in subjects with coronary artery disease and low HDL. As HDL2 and these Lp(A-I) particles are considered to be the most protective components of total HDL, we do not believe that the title of the article is misleading.
Because the principal observed effect of antioxidants was to block the HDL2 response to simvastatin and niacin therapy, we performed the treatment subgroup analyses suggested by Netke et al on the HDL2 response; these analyses are provided in the Table. Thus, there were no significant effects of simvastatin or niacin dose on the HDL2 response to simvastatin-niacin therapy. The blunting effect of antioxidants was seen across the dose range. This subgroup analysis further supports our conclusion.
Regarding the putative dangerous effects of statin, the inclusion of this statement in their letter reflects the bias of Dr. Rath’s group against proven forms of therapy in favor of unproven ones. Statins have a much lower serious complication rate than aspirin. Furthermore, assuming one death in 4 years from rhabdomyolysis among 300,000 statin-treated patients (excluding cerivastatin), failing to treat 300,000 patients would result in an additional 4-year cardiovascular mortality of approximately 4000 patients. Is this group suggesting we should deny this risk-benefit ratio to individuals deserving therapy by current recommendations?
We stand by our conclusion that antioxidant vitamins blunt the response of HDL2 and Lp(A-I) to combined simvastatin-niacin therapy.