Elevated low-density lipoprotein cholesterol (LDL-C) is a major atherosclerotic cardiovascular disease (ASCVD) risk factor and the primary target for lipid-altering interventions intended to reduce ASCVD risk.[1,2] Results from observational investigations, studies of genetic variants that alter LDL-C, and randomized trials of lipid-altering therapies have consistently shown that LDL-C reduction induced through various modalities produces similar effects to lower major adverse cardiovascular events, provided: 1) the lower concentration of LDL-C is reflective of a reduction in the circulating level of atherogenic lipoprotein particles, as indicated by a lower concentration of apolipoprotein B;[1,3] and 2) the intervention has no off-target effects that would partially or fully offset the benefit of lowering atherogenic lipoproteins. The benefit of LDL-C lowering is proportional to both the magnitude of reduction and the duration of exposure to a lower LDL-C level.[1] For example, each millimole per liter (~39 mg/dL) reduction in LDL-C is associated with a 22%, 32%, and 52% lower incidence of coronary heart disease events over periods of roughly 5, 12, and 52 years, respectively.[1] Thus, "lower for longer is better" for LDL-C in relation to ASCVD risk.
Pharmacotherapy with statins and other LDL-C–lowering agents has been highly efficacious for reducing ASCVD risk, although intermediate-term event risk is not sufficiently high in most primary prevention patients to warrant consideration of statin therapy until middle age or later on the basis of current treatment guidelines.[2] Atherosclerosis is a progressive condition that often begins early in life and progresses for decades before producing clinical atherothrombotic events. Modest reductions in LDL-C, if initiated early and maintained over an extended period, have the potential to affect ASCVD risk substantially because the benefit of lower exposure to atherogenic lipoproteins grows with time, thus underscoring the importance of a healthy lifestyle to assist in the maintenance of favorable levels of LDL-C and other modifiable ASCVD risk factors.[1,4] A healthy lifestyle, including a recommended dietary pattern, adequate physical activity, avoidance of tobacco, and adequate sleep, is considered the cornerstone of ASCVD prevention.[2,5]
Healthy dietary patterns such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) patterns emphasize consumption of whole grains, fruits and vegetables, nuts, seeds, legumes, and nontropical oils while minimizing intakes of saturated fats, salt, added sugars, and highly processed foods.[4,5] Several dietary adjuncts have also been studied as approaches to enhance LDL-C reduction. Those shown consistently in randomized controlled trials to reduce LDL-C, generally by roughly 4% to 8%, include certain viscous, soluble dietary fibers (eg, oat, barley, and psyllium) and plant sterols or stanols. This degree of LDL-C reduction is comparable to that produced by reducing dietary saturated fat intake by 5% of energy, and the effects of multiple dietary strategies on LDL-C are additive, which can result in a cumulative effect in the range of 10% to 15% or more.[6,7] For example, Jenkins et al[6] showed, in a randomized controlled trial, that a portfolio of dietary adjuncts including plant sterols and viscous fiber, as well as consumption of soy protein and nuts, markedly enhanced the reduction in LDL-C produced by a low–saturated fat diet intervention alone (13.1% vs 3.0%; P < 0.001). On the basis of an estimated 32% relative risk reduction per millimole per liter of LDL-C lowering over 12 years,[1] the 24 mg/dL (0.62 mmol/L) LDL-C response with the dietary portfolio observed by Jenkins et al would be expected to lower coronary heart disease risk by 21%.[6]
The U.S. Food and Drug Administration (FDA) reviewed and approved applications for qualified health claims for certain viscous, soluble fibers and plant sterols or stanols.[8,9] The qualified health claims allow manufacturers to include information on the labels stating that, when incorporated into a diet low in saturated fat and cholesterol, consumption of the product (food or dietary supplement) containing the specified viscous, soluble fiber or plant sterol or stanol "may" or "might" reduce the risk of heart disease. The scientific rationale for the approved health claims is a demonstrated ability to lower LDL-C, which is considered by the agency to be a valid surrogate for heart disease risk.
Red yeast rice is sold as a dietary supplement, often with label claims regarding "maintaining a healthy level of blood cholesterol." It is made by culturing rice with the yeast Monascus purpureus. The yeast produces monacolins, one of which (monacolin K) is chemically identical to the drug lovastatin. Other monacolins also appear to have mild 3-hydroxy-3-methylglutaryl coenzyme-A reductase-inhibitory activities.[10] Thus, it is not surprising that some degree of LDL-C reduction has been observed in studies with red yeast rice.
In this issue of the Journal of the American College of Cardiology, Laffin et al[11] present the results of SPORT (the Supplements, Placebo, or Rosuvastatin Study), which compared the effects on lipoprotein lipids and an inflammatory marker (high-sensitivity C-reactive protein) of a low-dose statin, rosuvastatin 5 mg/d, with placebo and 6 dietary supplements (fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice) among individuals with no history of ASCVD, baseline LDL-C of 70 to 189 mg/dL, and an estimated 10-year risk of ASCVD of 5% to 20%, making them eligible for consideration of statin therapy.[2] Laffin et al[11] report that the LDL-C reduction achieved with rosuvastatin (37.9%) was greater than with placebo or any of the supplements, and that none of the dietary supplements significantly decreased LDL-C compared with placebo.[11] The investigators state that these findings do not support "cholesterol health" claims and suggested educating patients about the lack of benefit of these supplements on cardiovascular risk factors. However, there are a few caveats to their conclusions that we believe should be acknowledged.
LDL-C response was the primary outcome variable in SPORT. However, of the 6 dietary supplements examined, only 3—plant sterols, red yeast rice, and garlic—are generally marketed as products to assist with maintaining a healthy level of cholesterol. As discussed, plant sterols have both a well-established and dose-dependent effect to lower LDL-C and an FDA-approved qualified health claim.[9] Garlic extract has been studied for its effects on LDL-C, with mixed results,[12] and red yeast rice has been shown to lower LDL-C in some studies, although this effect likely varies across products on the basis of monacolin mix and content.[10] Cinnamon is typically marketed as a dietary supplement to aid in maintenance of healthy levels of blood glucose; turmeric (curcumin) is marketed for reducing inflammation; and fish oil supplements are generally taken for their effects on triglycerides, inflammation, and blood pressure.
SPORT enrolled 190 participants (n = 25 per group), which Laffin et al[11] stated would provide 90% power to detect a difference in percentage of change in LDL-C of 15% between rosuvastatin and each supplement.[11] As expected, rosuvastatin lowered LDL-C substantially more than any of the supplements studied. However, the trial was not powered to make comparisons between the placebo and dietary supplement groups. If an SD of 10% to 15% is assumed for the LDL-C response, sample sizes in excess of 80 subjects per group would have been required to achieve 90% power to detect a 5% difference (a realistic expectation) in LDL-C response between placebo and each supplement.
Thus, we believe that the conclusions made by Laffin et al[11] should be qualified. We strongly agree that dietary adjuncts should not be viewed as a substitute for evidence-based LDL-C–lowering medication. However, we also think that selected dietary supplements or adjuncts, particularly plant sterols or stanols and viscous, soluble fibers (the latter were not studied by Laffin et al[11]), can have a role in ASCVD risk reduction strategies, although clinicians should counsel patients regarding realistic expectations for the LDL-C response, as well as implications for ASCVD risk reduction.
J Am Coll Cardiol. 2023;81(1):13-15. © 2023 American College of Cardiology Foundation
