Case Study: Navigating the World of Nutraceuticals and Dietary Supplements: A Look at all the Costs Associated with Nutraceutical and Dietary Supplement Use for Cardiovascular Disease Prevention

Case 

A 62-year-old woman with a past medical history significant for pre-diabetes, hypertension, hyperlipidemia (HLD), and obesity presented to her primary care physician for a routine six-month follow up. She recently became more proactive about her health given one of her colleagues recently had a myocardial infarction. In addition to reducing her red meat consumption and walking in the evening, she started taking a red yeast rice (RYR) dietary supplement after reading about the possible benefits of RYR on lowering cholesterol. She is interested in learning what additionally she can do to lower her risk for future cardiovascular disease (CVD). 

Physical exam: Blood pressure 142/88 mmHg, pulse 73 bpm. BMI 31.2kg/m². Remainder of the physical exam is unremarkable. 

Current medications/supplements: 

• Lisinopril 10 mg daily 
• Multivitamin – one tablet daily 
• RYR – one tablet daily 

Most recent labs (fasting): 

• Total cholesterol 221 mg/dL (5.715 nmol/L)
• Triglycerides 165 mg/dL (1.863 nmol/L)
• HDL- cholesterol 38 mg/dL (0.983 nmol/L)
• LDL- cholesterol calculated 150 mg/dL (3.879 nmol/L)
• Hgb A1c 6.3% 
• eGFR 63 mL/min/1.73m² 

Her current atherosclerotic cardiovascular disease (ASCVD) risk estimate is 7.6% over a 10-year period based on the PREVENT risk calculator and 12.9% based on the Pooled Cohort Risk Assessment Equations. 

Discussion 

The relationship between HLD and CVD is well established. Data from the 2017-2020 National Health and Nutrition Examination Survey found the prevalence of Americans with a total cholesterol > 200 mg/dL (5.172 nmol/L) and LDL-C > 130 mg/dL (3.362 nmol/L) to be 34.7% and 25.5% respectively.¹ Despite this, only 44.9% of eligible adults > 21 years of age are receiving prescription treatment for blood cholesterol.¹ One contributor to this undertreatment may be a growing public interest in nutraceuticals and dietary supplements to reduce one's risk of heart disease. 

Nutraceuticals and dietary supplements are now a multibillion-dollar global industry. More than half of adults > 20 years of age in the United States (57.6%) reported taking a dietary supplement.² Social media influencer promotion, ease of access via online purchasing, and distrust in the medical field likely contribute to the increasing popularity of nutraceuticals and dietary supplements. The US Dietary Supplement Health and Education Act defines a dietary supplement as a product that is taken by mouth (as a pill, capsule, tablet, or liquid) and contains one or more dietary ingredients meant to supplement the diet, not be used as a conventional food or sole diet item.³ Although the terms dietary supplements and nutraceuticals are often used interchangeably, it is perhaps best to think of nutraceuticals as a sub-category of dietary supplements. Nutraceuticals are nutrient-rich dietary substances made from whole food or parts of food sources. Unlike prescription drugs, dietary supplements are not required to undergo premarket approval or post-approval studies with the United States Food and Drug Administration (FDA). The responsibility to demonstrate efficacy and safety is deferred largely to the manufacturer. This lack of oversight allows manufacturers to potentially embellish the effectiveness of their product while withholding the uncertainties that exist due to the lack of rigorous research required prior to coming to market. This also poses the risk for batch-to-batch variability of the active ingredients made from the same and between different manufacturers.⁴ Dietary supplement and nutraceutical use also carries the risk of adverse effects intrinsic to their ingredients and potential drug-drug interactions. Both efficacy and safety concerns around dietary supplements and nutraceuticals are highlighted using some of the more popular classes below. Table 1 compares the cost of these and other common dietary supplements and nutraceuticals for purchase at both online and retail vs the cost of prescription pharmacotherapy. 

Red Yeast Rice 

Red Yeast Rice (RYR) is a result of rice fermented with the mold Monascus purpureis during which bioactive monacolins are created which weakly inhibit HMG-CoA reductase resulting in decreased cholesterol production. RYR at doses 1.2-4.8 g/day can decrease LDL-C, total cholesterol, serum triglycerides, and HDL-C.⁵ In a large secondary prevention study including post myocardial infarction patients, RYR was associated with 20% decrease in LDL-C and 4.7% absolute risk reduction of major coronary events and 30% decrease in CVD mortality at 4.5 year average follow up. The risks associated with RYR come from Monacolin K ability of CYP P450 enzyme inhibition and impurities created during the fermentation process including citrinin, a known nephrotoxin.⁶ In 1998, the FDA determined that a RYR product that contained a substantial amount of Monacolin K was an unapproved new drug, not a dietary supplement.⁷ Since then, it has acted against multiple companies for selling RYR with substantial amounts of Monacolin K.⁷ Recently, a RYR supplement produced by Kobayashi Pharmaceutical Company was linked to 114 hospitalizations and 5 deaths in Japan from suspected nephrotoxicity due to product contamination with puberulic acid.⁸ 

Omega-3 Polyunsaturated Fatty Acids 

The relationship between omega-3 polyunsaturated fatty acids (ω-3) and CVD remains controversial. Typical ω-3 dietary supplements consist of various ratios of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA). Ω-3 consistently demonstrates a lowering of serum triglyceride levels through a proposed mechanism of decreasing hepatic production of VLDL, increasing the activity of lipoprotein lipase activity, and increased fatty acid beta-oxidation. ω-3 also demonstrates anti-inflammatory properties. However, a 2020 Cochrane review consisting of 86 RCT (162,796 participants) found ω-3 reduced serum TG levels by approximately 15% (dose dependent) but had little to no effect on cardiovascular events or mortality, and slightly reduced coronary heart disease mortality (number needed for beneficial outcome of 334 for EPA/DHA and 500 for ALA.⁹ Importantly these products are not interchangeable with prescription omega-3 products which have demonstrated reductions in both triglyceride levels and CVD events.^10,11 Over the counter ω-3 can contain impurities such as oxidized fatty acids and saturated fats paradoxically increasing CVD risk.¹² Additionally, many over the counter Ω-3 products contain less than the studied doses of the ω-3 used in the clinical trials that have suggested cardiovascular benefit. Lower cost generics of brand name prescription ω-3 if taken at an equivalent dose may be a reasonable substitute.  

Plant Sterols/Stanols 

Plant Sterols/Stanols (PS) are cholesterol-like structures that are found naturally in vegetable oils, grains, nuts, and through fortification. PS decrease exogenous cholesterol absorption by directly competing with cholesterol for incorporation into micelles in the small intestine. They may also influence the expression of genes involved in cholesterol metabolism.¹³ A recent meta-analysis found a dose dependent relationship in plant sterol intake of 0.6-3.3 g/day with 6-12% reduction in LDL-C.¹³ PS in combination with statins can decrease LDL-c compared to statin monotherapy alone. However, the benefits of plant sterol on CVD reduction are lacking. In a large meta-analysis of 17 studies (11,182 participants), Genser et al. failed to show a relationship between serum levels of sitosterol and campesterol and risk of CVD.¹⁴ In direct contrast, other studies demonstrated that elevated PS may be associated with increased risk of CVD outside of those with sitosterolaemia.⁵ PS use also can lead to decreased absorption of fat-soluble vitamins and micronutrients. 

Turmeric 

Turmeric is a spice from the root of Curcuma longa. The most potent bioactive agent is believed to be curcumin which acts to increase the activity of cholesterol 7a-hydroxylase, an enzyme responsible for converting cholesterol to bile acids which can later be excreted.¹⁰ The benefit of turmeric on lipid profiles remains unclear at this time with some meta-analyses showing mild reductions in total cholesterol of 4 mg/dL (0.103 nmol/L), triglycerides of approximately 7 mg/dL (0.079 nmol/L), and LDL-C less than 5 mg/dL (0.129 nmol/L), while other meta-analyses found no significant benefit.^15,16 The effect of turmeric on CVD risk is not well established. Common side effects associated with turmeric supplementation include diarrhea, abdominal pain, and flatulence.¹⁷ 

What about statins? 

The SPORT (Supplements, Placebo, or Rosuvastatin Trial) was one of the first randomized clinical trials to assess head-to-head efficacy, as measured by percent change of LDL-C, of common supplements including fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice compared to low dose statin (5 mg of rosuvastatin) in patients with an increased ASCVD risk. The study found LDL-C was reduced by 37.9% (95% CI: -42.1 to -33.6) in the statin group with none of the supplements demonstrating a significant decrease in LDL-C compared with placebo.¹⁸

One potential solution to address the use of dietary supplements or nutraceuticals, as opposed to well-vetted pharmaceuticals such as statins, may be the ability to obtain a statin without a prescription using technology assisted self-selection (TASS) assessments. The potential of TASS was recently demonstrated in the TACTiC (Technology Assisted Self Selection in Consumers) study. This study of 1,196 participants without ASCVD who were not taking lipid lowering therapy and had a mean 10-year ASCVD risk of 10.1%, found that a web app self-selection tool demonstrated a 90.7% (95% CI, 88.9-92.3) with clinician assessment for starting low dose statin (5 mg of rosuvastatin) for primary prevention, with a mean percent change of LDL-C of this cohort of -35.5% (95% CI, -36.6 to -34.3).¹⁹ This study may ultimately form the basis for approval of the first nonprescription statin in the United States. 

Conclusion 

The patient presented in the case above was counseled about the differing degrees of efficacy in lipid lowering therapy between RYR and statins. and the risks of impurities and possible product contamination due to lack of FDA oversight. After an open discussion, a shared decision was made to stop her RYR and start a moderate intensity statin. 

The use of dietary supplements and nutraceuticals for management of cardiovascular risk factors remains an important topic given patient interest and growing body of research. Clinicians should be aware of the current research and guidelines regarding use of these agents and engage in a discussion over risks, benefits, and gaps in our knowledge compared to prescription medications with their patients. 

Dr. Laffin has received consulting fees from Medtronic, Eli Lilly, & Crisper Therapeutics. He has ownership interest in Lucid Act Health and Gordy Health. He receives royalties from Belvoir Media Group and Elsevier. He received research funding from Astrazeneca and is a member of an advisory committee for Mineralys Therapeutics. Dr. Volk has no financial relationships to disclose.

References 

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