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. 2024 Jan 9;7(2):300–308. doi: 10.1021/acsptsci.3c00234

Curcumin-Based Fixed Dose Combination Products for Cholesterol Management: A Narrative Review

Alberto Boretti 1,*
PMCID: PMC10863436  PMID: 38357288

Abstract

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Curcumin, a polyphenol compound that belongs to a class of molecules known as curcuminoids, may interact with various biological macromolecules in the body, including proteins, nucleic acids, and lipids. Curcumin-based fixed-dose combination (FDC) products enhance curcumin stability and bioavailability for better clinical use in cholesterol management. Preclinical studies on curcumin and cholesterol are mostly positive. Obstacles are the variable composition of the many different curcumin-based FDC products, the lack of standards, and the limitation of the randomized controlled trials (RCTs) conducted for specific products. Once these downfalls have been addressed, curcumin-based FDC products have great potential for cholesterol management. They can supplement the uptake of statins, reducing their dosage for the same controlling effects or even replacing them.

Keywords: curcumin, cholesterol, statins, supplements, drugs

Curcumin is a small molecule that is found in the rhizome of the turmeric plant (Curcuma longa).1−3 Curcumin can interact with various biological macromolecules in the body. Curcumin is a polyphenol compound and belongs to a class of molecules known as curcuminoids. It is responsible for the bright yellow color of turmeric and has been widely studied for its potential health benefits. When curcumin is ingested, it can interact with several biological macromolecules, including proteins, nucleic acids, and lipids. It has been shown to modulate various signaling pathways and exhibit antioxidant, anti-inflammatory, and anticancer properties. The poor bioavailability and rapid metabolism in the body of curcumin have posed challenges for its therapeutic application. Researchers are actively exploring strategies to enhance its stability and bioavailability for better clinical use through a curcumin-based fixed-dose combination.

Cholesterol management4−6 is of utmost importance for maintaining good overall health and reducing the risk of cardiovascular diseases. Key reasons include cardiovascular disease prevention, reducing atherosclerosis progression, maintaining heart health, overall health benefits, and long-term prevention. High levels of cholesterol, particularly low-density lipoprotein (LDL) cholesterol7,8 are a major risk factor for the development of cardiovascular diseases. Excess LDL cholesterol can build up in the arteries, forming plaques that restrict blood flow and increase the risk of heart attacks and strokes. By effective management of cholesterol levels, the risk of these life-threatening conditions can be significantly reduced. Atherosclerosis9 is a condition characterized by the accumulation of fatty plaques in the arteries. These plaques consist of cholesterol, fatty deposits, and other substances. By managing cholesterol levels, particularly LDL cholesterol, the progression of atherosclerosis can be slowed or even halted, preserving the health and function of the arteries. Cholesterol management plays a crucial role in maintaining heart health. By reducing LDL cholesterol levels and increasing high-density lipoprotein (HDL) cholesterol10,11 levels, the risk of coronary artery disease, heart attacks, and other heart-related problems can be minimized. Managing cholesterol is especially important for individuals with existing heart conditions or a family history of heart disease.

Beyond cardiovascular health, managing cholesterol levels positively impacts overall health. High cholesterol is associated with various health conditions, such as gallstones, peripheral artery disease, and pancreatitis. By effective management of cholesterol, the risk of these conditions can be reduced, promoting overall well-being. Cholesterol management is important not only for immediate health but also for long-term prevention. By adopting healthy lifestyle habits, such as a balanced diet, regular exercise, and avoiding smoking, along with appropriate medication, when necessary, individuals can maintain healthy cholesterol levels and reduce the risk of future complications.

In many cases, lifestyle habits are not sufficient. Cholesterol management agents,12−14 also known as lipid-lowering agents or cholesterol-lowering drugs, are medications used to reduce levels of cholesterol in the blood. They are typically prescribed to individuals with high cholesterol levels, as high cholesterol is a risk factor for cardiovascular diseases, such as heart attacks and strokes. Common classes of cholesterol management agents include statins, ezetimibe, PCSK9 inhibitors, bile acid sequestrants, fibrates, and niacin.

Statins15−17 are the most commonly prescribed cholesterol-lowering medications. They work by inhibiting an enzyme in the liver that is responsible for cholesterol production. By reducing cholesterol production, statins help to lower LDL cholesterol levels. They may also modestly increase the level of HDL cholesterol. Examples of statins include atorvastatin, simvastatin, and rosuvastatin. Statins which presently have widespread use to manage cholesterol and to reduce the risk of heart attack or stroke are highly effective but often bear side effects.18,19 These side effects include muscle pain, digestive problems, mental fuzziness, increased blood sugar, type 2 diabetes, and, in some cases, liver damage. Statin drugs are a financial success story, with worldwide sales of statins running very high in terms of revenues and still growing quickly, despite developing doubts about their safety to efficacy profile.18−21

Other medications have a marginal use. Ezetimibe22 is a medication that works by reducing the absorption of cholesterol from the diet in the small intestine. It is often used in combination with statins to further lower the LDL cholesterol levels. PCSK9 (proprotein convertase subtilisin/kexin type 9)23 inhibitors are a newer class of cholesterol-lowering drugs. They work by blocking the action of PCSK9, a protein that reduces the liver’s ability to remove LDL cholesterol from the blood. By inhibiting PCSK9, these medications increase the liver’s ability to clear LDL cholesterol. Examples of PCSK9 inhibitors include evolocumab and alirocumab. Bile acid sequestrants24 are medications that bind to bile acids in the intestines, preventing their reabsorption. This prompts the liver to use cholesterol to produce more bile acids, leading to a decrease in the LDL cholesterol levels. Common examples include cholestyramine, colesevelam, and colestipol. Fibrates25 primarily target triglyceride levels, but they can also have modest effects on increasing HDL cholesterol and reducing LDL cholesterol. They work by activating enzymes that break down triglycerides and by decreasing the liver’s production of triglycerides. Examples of fibrates include fenofibrate and gemfibrozil. Finally, niacin,26 also known as vitamin B3, can raise HDL cholesterol levels and lower LDL cholesterol and triglyceride levels. However, its use as a cholesterol management agent has declined due to potential side effects, such as flushing and liver abnormalities.

This Perspective aims to introduce curcumin, a member of the natural products curcuminoids, for cholesterol management,27−29 as part of a curcumin-based fixed-dose combination (FDC) product30,31 to be used as a replacement for, or a supplement to, statins. Curcumin, a natural compound found in turmeric, has gained attention for its potential health benefits including its anti-inflammatory and antioxidant properties. More than curcumin alone, curcumin-based FDC products may be relevant for cholesterol management due to the inclusion of other ingredients that contribute to cholesterol-lowering effects. FDC products typically combine curcumin with other compounds or ingredients that have complementary effects.

Curcumin as a Cholesterol Management Agent

Curcumin has been investigated for its potential to improve lipid profiles by increasing HDL cholesterol levels and reducing LDL cholesterol oxidation.27−29 These effects may contribute to a healthier lipid profile and overall cholesterol management. The effectiveness of curcumin-based FDC products for cholesterol management would depend on the specific formulation, dosage, and individual response. This section describes the preclinical experiences detailing the mechanism of action of curcumin in cholesterol management and points out the existing issues of this specific use as a replacement for or a supplement to statins.

Curcumin is a member of the natural products curcuminoids, which are derived from the rhizome of turmeric, a flowering plant (Curcuma longa) of the ginger family, which is popular for cooking. Curcumin has been used since the time of the ancient natural Indian medical system Ayurveda, which originated more than 3,000 years ago. Curcumin has shown many therapeutic properties, with the opportunity to manage cholesterol, here discussed, being one of them. The turmeric plant and derived products have a long history of therapeutic application in traditional Asian medicine, predominantly to treat numerous inflammatory disorders. Curcumin is widely distributed as a dietary supplement.

Additional ingredients or adjuvants in the specific curcuminoid product affect the uptake of curcumin. Curcumin has poor bioavailability, as it is not easily absorbed and utilized by the body.32−34 To improve the absorption and efficacy of curcumin, many curcuminoid products include additional ingredients or adjuvants that can enhance its bioavailability. Piperine, a compound found in black pepper, largely enhances the absorption of curcumin.35 Piperine inhibits an enzyme in the liver that breaks down curcumin, allowing more of it to enter the bloodstream. Curcumin is a fat-soluble compound, so adding lipids36 such as phospholipids or oils to a curcuminoid product can improve its absorption. Lipids form micelles that help to solubilize curcumin and improve its bioavailability. Some curcuminoid products may include polysaccharides37 such as cyclodextrin or gum arabic, which can increase the solubility of curcumin and improve its absorption. Finally, a nanoparticle can encapsulate curcumin38 to improve its solubility and bioavailability. Nanoparticles can also target specific tissues or cells, allowing for a more targeted delivery of curcumin.

There is consistency in the different experiences conducted so far in the use of curcuminoids to lower cholesterol levels, which is promising for proper uptake of this product elevated from a dietary supplement to a drug. There is mostly preclinical evidence supporting the use of curcumin to manage cholesterol levels. The potential mechanisms of action of curcumin relevant to cholesterol management are summarized in Figure 1, which also presents the potential advantages of using curcumin rather than synthetic drugs to manage cholesterol.

Figure 1.

Figure 1

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Potential mechanisms of action of curcumin relevant to cholesterol management and potential advantages of using curcumin rather than synthetic drugs to manage cholesterol. 3D structural formula from molview.org/?cid=969516.

Many studies have shown the opportunity to use curcumin to reduce the levels of LDL cholesterol and triglycerides and to increase the levels of HDL cholesterol. Malfunctioning of cholesterol metabolism more than excessive cholesterol intake or lack of exercise is responsible for high cholesterol levels to be controlled. This malfunctioning is often caused by multiple hereditary diseases, including familial hypercholesterolemia, sitosterolemia type C, and Niemann-Pick disease.39−41 There is evidence suggesting that curcumin may help address the malfunction of cholesterol metabolism. This evidence builds on many laboratory and preclinical studies, as well as some human and clinical studies with curcuminoids, briefly summarized below.

Animal models have been historically supportive. In the animal model of ref (42) based on rats fed cholesterol and curcumin, levels of serum and liver cholesterol fell to one-half or one-third of those in rats fed cholesterol and no curcumin. Similarly, in the animal model of ref (43), the dispensation of curcumin lowered significantly the serum and tissue cholesterol levels in rats. The animal model of ref (44) showed that feeding with curcumin improved the metabolic status in diabetic rats.

Laboratory experiences have been similarly supportive, shedding light on the mechanisms of action. The in vitro study in ref (45) suggested that curcumin supplementation inhibits cholesterol uptake through suppression of NPC1L1 expression in the intestinal cells. The in vitro study of ref (46) analyzed the effects of curcumin on hepatic gene expression, using the human hepatoma cell line HepG2. Curcumin produced a significant concentration-dependent increase in the level of LDL-receptor mRNA. mRNAs of the genes encoding the sterol biosynthetic enzymes HMG CoA reductase and farnesyl diphosphate synthase were only slightly increased at high curcumin concentrations. Expression of the regulatory SREBP genes was moderately increased. mRNAs of the PPARα target genes CD36/fatty acid translocase and fatty acid binding protein 1 were downregulated. LXRα expression and the accumulation of mRNA of the LXRα target gene ABCg1 were increased. Curcumin strongly inhibited alkaline phosphatase activity. However, activation of a retinoic acid response element reporter employing secreted alkaline phosphatase also occurred. The changes in gene expression were consistent with the hypocholesterolemic effect of curcumin. The in vitro study of ref (47) investigated the effect of curcumin on cholesterol transport, inflammatory response, and cell apoptosis in M1 macrophages. Curcumin increased cholesterol uptake measured by the Dil-oxLDL binding assay and simultaneously increased cholesterol efflux carried out by Apo-A1 and HDL in M1 cells. Curcumin further reinforced the ox-LDL-induced cholesterol esterification and foam cell formation. Curcumin noticeably reduced ox-LDL-induced cytokine production such as IL-1β and IL-6 as well as TNF-α and M1 cell apoptosis. Curcumin upregulated CD36 and ABCA1 in M1 macrophages. Curcumin increased PPARγ expression, promoting CD36 and ABCA1 expression. Curcumin increased the ability of M1 macrophages to deal with harmful lipids, promoting lipid processing, disposal, and removal, supporting cholesterol homeostasis, and exercising an antiatherosclerotic effect.

The mechanism of action of curcumin against cholesterol involves several pathways that are very well established. The inhibitory effects of curcumin on intestinal cholesterol absorption are one of the potential mechanisms of action of curcumin relevant to cholesterol management.29,48,49

Curcumin can inhibit cholesterol synthesis.49,50 Curcumin can inhibit the activity of HMG-CoA reductase, which is an enzyme involved in the synthesis of cholesterol in the liver. By inhibition of this enzyme, curcumin can reduce the production of cholesterol in the body.

Curcumin can increase the excretion of cholesterol.42 Since curcumin stimulates the production of bile acids, which are necessary for the digestion and absorption of dietary fats, this leads to a decrease in the amount of cholesterol that is absorbed from the diet.

Curcumin also possesses anti-inflammatory effects.51 Chronic inflammation is associated with high cholesterol levels; by reducing inflammation in the body, curcumin may help to reduce cholesterol levels.

Curcumin may overwhelm cell proliferation and lessen cholesterol absorption in Caco-2 cells by activating the TRPA1 channel.52

Based on a hamster animal model, curcumin may defend against high-fat-diet-induced nonalcoholic simple fatty liver by preventing intestinal and hepatic NPC1L1 expression via down-regulation of the SREBP-2/HNF1α pathway.53

Finally, curcumin has antioxidant effects.54 Curcumin may protect cells from oxidative damage caused by free radicals. Oxidative damage can contribute to the development of high cholesterol levels, so the antioxidant properties of curcumin may help to prevent this.

Preliminary clinical studies confirmed the benefits of curcumin supplementation to manage cholesterol levels. A small study50 demonstrated that long-term curcumin treatment lowers plasma and hepatic cholesterol and suppresses early atherosclerotic lesions. The effect of curcumin was comparable to that of lovastatin. The mechanism of action of curcumin includes alteration of lipid, cholesterol, and immune gene expression.

In another small study,55 receiving 500 mg of curcumin per day for 7 days was enough to produce in healthy individuals a 33% decrease in the level of serum lipid peroxides, a 29% increase in the HDL cholesterol level, and a 12% decrease in total serum cholesterol.

Another small study29 demonstrated that supplementation with curcumin together with the consumption of dietary phytosterols (nuts, seeds, whole grains, and legumes) helped to lower cholesterol, suggesting curcumin could help as a complementary therapy.

In the meta-analysis in ref (27), the effects of curcumin on blood lipid levels were analyzed. Curcumin was associated with significantly reduced serum LDL and triglycerides compared to those in the control. The authors noted that curcumin was potentially protective against cardiovascular diseases, the same as statins, but with better tolerability, stressing the need for further study of the most effective formulation and dosage.

The review of clinical trials in ref (56) summarized the positive effect of curcumin on cholesterol. The authors found that curcumin significantly reduced one type of lipid in more than two-thirds of the studies, with a bioavailable formulation of curcumin producing a better lowering of cholesterol.

Curcumin and piperine significantly decreased total cholesterol and LDL-C in patients suffering from metabolic syndrome, while it did not affect triglyceride concentrations.57 The results were not dependent on the dose of curcumin, the dose of piperine, or the duration of treatment. They concluded there is a need for further long-term randomized controlled trials (RCTs) to better assess the clinical benefit.

Many other systematic reviews of the use of curcumin to manage cholesterol and treat metabolic disorders can be found in refs (57−61). Results are overall positive. The number of positive experiences using curcumin to manage cholesterol is therefore large, based on a large number of laboratory/preclinical studies and more limited but significant human/clinical studies, with common issues of the variable formulation of the specific products employed and the statistical significance of the trials. The availability of more widespread randomized controlled trials (RCTs) specific to commercial curcumin-based FDC products is missing.

Challenges of Using Curcumin-Based FDC Products

From the previous section, there are many reasons why curcumin-based FDC products are attractive for cholesterol management.57−61 Curcumin has been shown to inhibit key enzymes involved in the synthesis of cholesterol, such as HMG-CoA reductase. By reducing the activity of this enzyme, the production of cholesterol in the liver can be diminished. Curcumin may enhance the excretion of cholesterol from the body, as it can increase the expression and activity of transporters responsible for removing cholesterol from the liver and promoting its elimination through bile. As chronic inflammation and oxidative stress can contribute to the development and progression of atherosclerosis, the potent antioxidant and anti-inflammatory properties of curcumin may help reduce oxidative stress and inflammation in the blood vessels, mitigating the formation of plaques and helping to maintain healthy cholesterol levels. Curcumin has been shown to influence the metabolism of lipoproteins, which are responsible for transporting cholesterol in the bloodstream, as it can modify the composition and function of lipoproteins such as reducing the levels of LDL cholesterol and increasing the levels of HDL cholesterol. Curcumin has been found to influence the expression of genes involved in cholesterol metabolism, modulating the activity of transcription factors and signaling pathways that regulate cholesterol homeostasis, potentially leading to improved cholesterol management. Curcumin exhibits antioxidant and anti-inflammatory properties, which have been shown to have potential cardiovascular benefits. Curcumin’s ability to reduce inflammation and oxidative stress contributes to its potential cholesterol-lowering effects. Curcumin has been found to affect multiple molecular targets involved in cholesterol metabolism and plaque formation. It may help reduce LDL cholesterol levels, inhibit the oxidation of LDL cholesterol (which is implicated in atherosclerosis), and promote the clearance of cholesterol from the body. This multitargeted approach may differentiate curcumin from some other cholesterol management agents that primarily target cholesterol synthesis or absorption.

Curcumin is derived from a natural source, turmeric, which is widely consumed as a spice in many cultures. Many individuals may prefer natural remedies, being more inclined to incorporate curcumin into their daily routines. Curcumin is generally considered safe33 and well-tolerated when taken in recommended doses. It has a low reported incidence of side effects. In comparison, some cholesterol-lowering medications, such as statins, may be associated with potential side effects including muscle pain, liver abnormalities, and gastrointestinal issues.

Curcumin should be part of an FDC where it is combined with other compounds or ingredients to provide a more comprehensive approach to health benefits or target specific health conditions. For example, curcumin should be combined with other natural compounds or nutrients that have complementary effects on cholesterol management or overall cardiovascular health.

Given the bioavailability issue and the variability of composition of different curcumin-based FDC products, an effective dose,27,62,63 of curcumin can be anywhere between 500 and 2000 mg per day of curcumin extract, even if even much larger amounts or smaller amounts have been proposed. It is worth mentioning that 2000–2500 mg of turmeric per day only translates to around 60–100 mg of curcumin.64 While turmeric species may contain only 3% curcumin, curcumin extracts may contain up to 95% curcumin.65 The correct amount would depend on the specific FDC product, which includes other components in addition to curcumin extract, and would have to be confirmed by long-term RCTs. There is not yet an official consensus on effective turmeric or curcumin doses.

While dosages used in research studies are within the above range, these dosages can vary based on the specific formulation, the bioavailability, and the presence of additional ingredients. In terms of FDC products that include curcumin for cholesterol management or overall health, formulations often include other ingredients to enhance bioavailability or provide synergistic effects. Common additional ingredients found in curcumin-based supplements include piperine (BioPerine),35,66 lecithin, or phospholipids,67 quercetin,68,69 ginger extract,70Boswellia serrata (Indian frankincense),71 omega-3 fatty acids,72 coenzyme Q10 (CoQ10),73 green tea extract,74 garlic extract,75 resveratrol,69 or berberine.76,77

Piperine, extracted from black pepper, is often included to enhance the absorption of curcumin. It inhibits certain enzymes that metabolize curcumin in the liver, thereby increasing its bioavailability. Curcumin is fat-soluble, and incorporating phospholipids or lecithin into formulations can improve its solubility and absorption in the gastrointestinal tract. Quercetin is a flavonoid that is found in certain fruits and vegetables. Some formulations include quercetin alongside curcumin due to its potential synergistic effects, including antioxidant and anti-inflammatory properties. Ginger has anti-inflammatory properties and may complement the effects of curcumin. Combining these two natural compounds is sometimes seen in joint health supplements more than in supplements for cholesterol management. Boswellia serrata extract is another botanical ingredient that is occasionally combined with curcumin for its anti-inflammatory properties and potentially aids joint health. Some formulations may include omega-3 fatty acids (such as fish oil) due to their cardiovascular health benefits. Combining curcumin with omega-3s may offer synergistic effects. CoQ10 is an antioxidant that plays a role in cellular energy production. Combining curcumin with CoQ10 may offer synergistic benefits for heart health. Green tea extract, which contains polyphenols, is sometimes included in curcumin-based formulations. Both curcumin and green tea polyphenols have antioxidant properties. Garlic is known for its potential cardiovascular benefits. Combining curcumin with garlic extract may be targeted toward managing cholesterol levels. Resveratrol is a polyphenol found in red wine and certain fruits. Combining curcumin with resveratrol may provide additional antioxidant and anti-inflammatory effects. Berberine is a compound found in several plants and has been studied for its potential cholesterol-lowering effects. Combining it with curcumin may offer a dual approach to managing lipid levels.

In the context of cholesterol management, FDC products may, in principle, also be coupled to statins, which are commonly prescribed medications for lowering cholesterol. Statins work by inhibiting an enzyme involved in cholesterol production, thus reducing the overall cholesterol levels in the body. Curcumin, when combined with statins or other cholesterol-lowering agents, may provide additional benefits.78,79,49 Curcumin may have a synergistic effect with statins, potentially enhancing their cholesterol-lowering efficacy. Curcumin’s anti-inflammatory properties may also have a positive impact on cardiovascular health, as chronic inflammation is closely linked to the development and progression of heart disease. The partial replacement of statins with curcumin-based FDC products could benefit a large share of the population. As supplementation with curcumin may reduce levels of LDL cholesterol and triglycerides and increase levels of HDL cholesterol, the compound could be used to support treatment with statins, reducing their uptake or even completely replacing statins. However, appropriate RCTs are required to properly define a precise curcumin-based FDC product and its optimal dose for given cholesterol-lowering effects.

While there are promising but not conclusive results for the use of curcumin-based FDC products in cholesterol management, there are also issues with this use of curcumin. Apart from the issue of specific, comprehensive, long-term RCTs, another negative aspect is that the many commercial products offered as supplements do not have the qualities of a drug. Curcumin is popular on the market, but as a dietary supplement, which is regulated as a food and not drug. While drugs must satisfy manufacturing consistency and must be approved as a treatment for specific medical conditions following proper RCTs for every specific formulation, supplements do not have to satisfy manufacturing consistency. Looking at the ingredients of a dozen commercial curcumin products available at the chemist, the ingredients used for the tablets differ from one another, with the exact formulation often missing.

In the survey we made for the Australian market, all of the tablets considered contain variable amounts of Curcuma longa rhizome extract or derivatives. However, equivalences and minimum amounts were often used to replace specific amounts of curcumin. The additional ingredients were not always specified. Piper nigrum fruit extract is often mentioned. Vitamin C was also mentioned in a few cases. Soybean products and sulfites were mentioned some other times. In one case, Boswellia serrata gum oleoresin, Zingiber officinale rhizome, Piper nigrum fruit, soybean (lecithin), phenylalanine, sulfites, and sorbates were also mentioned. Thus, there is a variety of products offered as curcumins that possess different therapeutic processes.

Of the five categories of curcuminoid products mentioned by ref (80), turmeric, turmeric extract, curcuminoid-enriched turmeric extract, curcuminoid-enriched material, and curcumin, only this latter product represents a single-chemical entity in adequate purity. The many preparations used to enhance bioavailability show remarkable differences. While claiming the worthwhileness of the biological data obtained from an overabundance of preparations is excessive,80 there is certainly the issue of making reference to a specific product, also given the bioavailability issue.32−34 The attribution of biological activity of a mixture of many components solely to the major component is difficult,81 even if curcumin plus piperine significantly decreased total cholesterol and LDL-C in patients suffering from metabolic syndrome, independently on the dose of curcumin, the dose of piperine, and the duration of treatment.57 The differences between curcumin-based products offered on the market and often different batches of nominally the same product are certainly excessive for medical uses. The uptake of curcumin is certainly influenced by the additional ingredients or adjuvants in a specific curcumin-based FDC product in addition to the amount of curcumin used.

Administrative Issues in Developing Curcumin-Based Cholesterol Management Products

The problem of the precise formulation of a curcumin-based FDC product is solvable with specific clinical trials. The lack of approval by the Food and Drug Administration (FDA) for specific medical uses82 prevents the medical use of curcumin, from cancer treatment to cholesterol management. The major obstacle to the use of specific curcumin-based FDC products to supplement the uptake of statins, reducing their dosage for the same controlling effects or even replacing them, to manage cholesterol levels, is the lack of comprehensive RCTs showing specific safety and efficacy. These RCTs are necessary to assess the safety and efficacy of the particular product for exclusive use, clarify the pharmacokinetics and pharmacodynamics, determine the appropriate dose and dosing schedule, and identify potential side effects and adverse reactions. The development of new drugs is particularly expensive, as the challenges to overcome in the development and implementation of new drugs are generally regulatory,83−87 with development costs growing up to a billion dollars and procedures being extremely long if proposed by “outsiders”.88

A search on PubMed (April 14, 2023) with the keyword “curcumin” returns 21,221 results, 501 of them clinical trials/randomized controlled trials. The number of works is dramatically growing, from 108 in 2000, to the latest 2405 in the year 2022. Of these, only a small percentage are clinical trials and randomized controlled trials. The number of clinical trials/randomized controlled trials was 65 in the year 2022. A search on PubMed (April 14, 2023) with the keywords “curcumin” AND “cholesterol” returns 498 results, 44 of them clinical trials/randomized controlled trials. In the year 2022, there have been only 5 works classified as clinical trials/randomized controlled trials. A search on clinicaltrials.gov with the keywords curcumin and hypercholesterolemia only returned two entries. One trial was aimed to evaluate the effects of daily curcumin dietary supplements on the function of the gut in subjects who are at risk for cardiovascular and metabolic diseases. No results are posted. The other trial, which has just posted even if conducted two years ago, is the Supplements, Placebo, or Rosuvastatin Study (SPORT) trial with the sponsor The Cleveland Clinic and Collaborator AstraZeneca.

The goal of the SPORT trial was to disprove the benefits of curcumin and other supplements (fish oil, cinnamon, garlic, turmeric, plant sterol, and red yeast rice were evaluated) in managing hypercholesterolemia while supporting the sale of one statin. This is evident from the first paragraph of the description. “Few well-controlled trials have studied the LDL-lowering effects of dozens of marketed “cholesterol health” dietary supplements. Prior research suggests that most U.S. consumers believe cholesterol health supplements are safer than statins, and a majority of the public also believe supplements are as effective, or more effective, than prescription statins. Approximately one-third of US adults who have been told they have elevated cholesterol are using a supplement to provide heart health protection rather than a statin. This represents a significant public health concern.” It was then no surprise if, after 4 weeks of administration of the supplements, there was no difference vs placebo, while administration of the selected statin was effective. No nutraceutical result from the SPORT trial is worth considering because of the many flaws. (1) SPORT compared nutraceuticals without confirmed dose and quality (RYR) or those that do not work on cholesterol (cinnamon) to rosuvastatin 5 mg. (2) SPORT was 28 days of follow-up, while it is well-known that for nutraceuticals, which are not drugs, at least 3 months of adherent supplementation is needed. (3) SPORT selected a biased sample of the population. When statins are used, there is no indication of benefits using nutraceuticals.

Conclusions

Curcumin has been investigated for its potential role in the management of cholesterol levels. While the exact mechanism of action is not fully understood, several mechanisms have been proposed based on scientific research. Some of the potential ways curcuminoids may exert their effects on cholesterol management include inhibition of cholesterol synthesis, increased cholesterol excretion, antioxidant and anti-inflammatory effects, and regulation of gene expression. Some potential advantages that have been suggested for curcumin as compared to other cholesterol management agents include natural origin, antioxidant and anti-inflammatory properties, potential multitargeted effects, and potential side effect profile.

The safety and efficacy of curcumin as a cholesterol management agent have not been extensively studied in large-scale RCTs. The available scientific evidence regarding curcumin’s effectiveness as a cholesterol management agent is still limited, and more research is needed to establish its efficacy, optimal dosage, and potential interactions with other medications.

Curcumin is not supposed to be administered alone, because of its low bioavailability and reduced potency but is part of a specifically designed FDC product. Curcumin, even highly purified, is a low potency lipid-lowering agent and may help in lipid-lowering therapy as part of a FDC with other nutraceuticals like monacolin K or berberine. The main mechanism of action, slight inhibition of PCSK9 protein, anti-inflammatory activity, antioxidant properties, anti-infectious properties, and others associated with HSP-70 are usually not very powerful. Curcumin must be combined with other active ingredients or compounds in an FDC to be effective. FDC products are formulations that contain two or more active ingredients in specific doses within a single dosage form. These combinations are developed to enhance therapeutic efficacy, convenience, and adherence to treatment regimens. By combining multiple ingredients in one formulation, FDCs aim to provide synergistic effects, address multiple aspects of a condition, or improve overall treatment outcomes.

Curcumin has enormous health and medicinal benefits for humans, with the number of clinical trials in the prevention and treatment of chronic diseases, including cholesterol management, rapidly growing.

The author declares no competing financial interest.

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