Central Illustration

Abstract

Background

Supplements are commonly used by individuals with indications for lipid-lowering therapy, but evidence of their effectiveness to lower low-density lipoprotein cholesterol (LDL-C) is lacking, particularly when compared with statins.

Objectives

The trial objective was to compare the efficacy of a low-dose statin with placebo and 6 common supplements in impacting lipid and inflammatory biomarkers.

Methods

This was a single-center, prospective, randomized, single-blind clinical trial among adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD. Participants were randomized to rosuvastatin 5 mg daily, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days. The primary endpoint was evaluated in a hierarchical fashion with rosuvastatin first compared with placebo, then each supplement in a prespecified order using analysis of covariance.

Results

A total of 190 participants completed the study. The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P < 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was −35.2% (95% CI: −41.3% to −29.1%; P < 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. Adverse event rates were similar across study groups.

Conclusions

Among individuals with increased 10-year risk for ASCVD, rosuvastatin 5 mg daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice.

Discussion

In this randomized, placebo-controlled, parallel-arm trial, the lowest available dose of rosuvastatin, 5 mg daily, classified as a moderate-intensity statin, produced significantly greater LDL-C reduction compared with placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice in patients with increased 10-year ASCVD risk and an LDL-C >70 mg/dL. None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. However, the garlic supplement increased LDL-C compared with placebo. Compared with placebo and supplements, the low-dose statin regimen improved other lipid biomarkers including total cholesterol and serum triglycerides. Adverse events were minimal in all groups. A notable finding in the current trial is that garlic supplementation increases LDL-C. In 2007, a randomized clinical trial of 3 separate garlic preparations compared with placebo in participants with hypercholesterolemia demonstrated a trend toward LDL-C increase in all 3 garlic preparations, though the increase was not statistically significant.⁹ A 2021 meta-analysis of the impact of garlic extract also demonstrated no significant change in LDL-C among individuals with coronary artery disease.¹⁰

The use of dietary supplements by the U.S. population has increased exponentially during the last 3 decades. When DSHEA was passed in 1994, about 600 U.S. manufacturers were producing an estimated 4,000 products. Two decades later, more than 90,000 products were available on the U.S. market.¹ In the NHANES (National Health and Nutrition Examination Survey) conducted in 37,958 adults from 1999 to 2012, 52% of respondents reported that they were taking daily dietary supplements.¹¹ By 2019, 77% of adults were taking dietary supplements, and 18% of those surveyed reported that they were using supplements to promote heart health.¹² Patient preference for nonstatin alternatives is multifactorial and driven in part by beliefs regarding statin-associated hepatotoxicity, muscle symptoms, and neurological side effects.^13,14 Limited government regulation of supplements and their claims for benefits, along with an abundance of statin misinformation, create an environment that deters the U.S. population from taking well-regulated, inexpensive, safe, and potentially life-saving medications with decades of supporting evidence.¹⁵ Although the use of dietary supplements to promote cholesterol health is widespread, limited data are available to demonstrate their efficacy or safety, particularly when compared with statin therapy.

A meta-analysis of clinical trials and prospective cohort studies including over 2 million individuals demonstrated that multivitamin/mineral supplementation is not associated with a difference in cardiovascular mortality (relative risk: 1.0; 95% CI: 0.97-1.04) in the general population.¹⁶ Although data exist demonstrating significant LDL-C reductions with red yeast rice supplementation, different product formulations and manufacturers can result in varying levels of efficacy, or lack thereof, as seen in the current trial.¹⁷ Plant sterols are endorsed as an option to lower blood cholesterol levels in the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemias; however, there is controversy regarding their efficacy and some suggestion that they may be atherogenic.^18,19 Similar to SPORT, a 2017 meta-analysis including 13 randomized clinical trials of cinnamon supplementation failed to show a significant decrease in LDL-C.²⁰ A 2017 meta-analysis of turmeric and the lowering of blood lipid levels suggested a possible decrease in LDL-C and serum triglycerides with its use in patients with type 2 diabetes mellitus or metabolic syndrome, but stands in contrast to a 2015 meta-analysis of curcumin that did not demonstrate significant changes in lipid parameters in a more heterogeneous population.^21,22 A lack of transparency and consistency regarding supplement composition clearly can impact the observed pharmacological effect. The U.S. Preventive Services Task Force recently released a statement about certain supplements and cardiovascular health, concluding that there was insufficient evidence to support their use.²³

DSHEA provided a definition of the term dietary supplement for the FDA. A dietary supplement is any product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. DSHEA categorizes these products as foods, not drugs, and requires that each be labeled as a dietary supplement. DSHEA also defined the term dietary ingredient as a vitamin, mineral, herb or other botanical, amino acid, enzymes or tissues from organs or glands, or a concentrate, metabolite, constituent, or extract.²⁴ These categories are very broad and allow marketing of a wide variety of products. Although categorized as foods, not drugs, some dietary supplements interact with the cytochrome system and can affect the metabolism of prescription drugs.²⁵ Prior data also demonstrate that dietary supplements may produce harm. An estimated 23,000 emergency department visits in the United States every year are attributed to adverse events related to dietary supplements.²⁶ There are many described cases of supplements with microbial contamination, heavy metal contamination, and addition of unapproved prescription ingredients.^27,28 DSHEA specifies that supplements must be manufactured free of contamination or adulteration but allows them to be sold in the United States without providing proof of their quality to the FDA; the burden rests with the FDA to prove a supplement is unsafe, which presents a formidable challenge to enforcement.¹

The current trial provides evidence that certain supplements marketed or promoted for “cholesterol health” do not significantly lower LDL-C compared with placebo, and are inferior to a moderate-intensity statin. These data also demonstrate the expected improvement in other lipid biomarkers with low-dose rosuvastatin, but no difference for supplements compared with placebo. LDL-C is a well-established risk factor for the development of ASCVD. Similar to the approach studied in SPORT, the 2018 American Heart Association/American College of Cardiology/Multisociety Blood Cholesterol guidelines suggest a discussion regarding the use of moderate-intensity statin therapy for patients with a 10-year risk of ASCVD between 5% and 20%.⁸ Rosuvastatin 5 mg is a moderate-intensity statin, and the percent decrease in LDL-C observed in the current study aligns with prior findings.²⁹

Study limitations

Although the trial duration was sufficient to see significant LDL-C, total cholesterol, and serum triglyceride lowering in participants randomized to a low-dose statin, the relatively short study period may not fully capture the effect on lipid biomarkers of supplements with a longer duration of use. A 28-day trial duration was chosen based on the 2018 blood cholesterol guidelines recommendation to “assess adherence and percentage response to LDL-C lowering medications and lifestyle changes with repeat measurement in 4 to 12 weeks.”⁸ Although the findings have narrow confidence intervals, the small sample size cannot rule out a small benefit from 1 or more of the supplements. Similarly, although the trial measured biomarkers known to predict and impact future cardiovascular risk, the effect of supplements on cardiovascular outcomes cannot be determined by a trial of this size and scope. The lack of effect of rosuvastatin on hsCRP is inconsistent with prior data, likely due to the small sample size and low dose used in SPORT.³⁰ The small sample size also does not allow for meaningful subgroup analysis. Eighty-nine percent of participants were non-Hispanic White race, possibly limiting the applicability of study results to other races.

Conclusions

In this single-center, prospective, randomized, single-blind clinical trial of patients with elevated LDL-C and increased 10-year ASCVD risk, a low-dose statin taken daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. No supplements significantly lowered LDL-C compared with placebo. No supplement demonstrated a change in other lipid or inflammatory biomarkers suggestive of potential cardiovascular benefit compared with placebo. These findings do not support the cholesterol health claims made by supplement manufacturers. Patients should be educated about the lack of benefit of these supplements on important cardiovascular risk factors.

Source:JACC