Lipoproteins are complexes of lipids and proteins essential for transporting cholesterol, triglycerides, and fat-soluble vitamins in the blood. Plasma lipoproteins are classified into 5 major classes based on their relative density: chylomicrons, very low-density lipoproteins, intermediate density lipoproteins, low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Key roles of lipoproteins are to transport dietary lipids from the intestines to tissues requiring fatty acids for energy storage and metabolism and to transport intestinal cholesterol to the liver.

Disorders of lipoprotein metabolism, known as dyslipidemias, are clinically characterized by increased plasma levels of cholesterol, triglycerides, or both [1]. The etiological classification of dyslipidemia is categorized as primary (genetic) or secondary (lifestyle and other). Hypercholesterolemia falls under the primary type of dyslipidemia.  Hypercholesterolemia is a polygenic disorder characterized by an increase in cholesterol, whereas in hypertriglyceridemia there is an increase in triglycerides [2]. Plasma lipoprotein levels are significant modifiable risk factors for cardiovascular diseases, with increased levels of LDL contributing to the development of atherosclerosis [3].

According to the Global Health Observatory, raised cholesterol is estimated to cause 2.6 million deaths globally and 29.7 million (2%) disability-adjusted life years [4]. Elevated total cholesterol is a significant cause of disease burden in both high- and low-income countries, serving as a risk factor for ischemic heart disease and stroke [4]. Very low-density lipoproteins and triglycerides contribute to the building up of arterial plaque.

Factors such as genetics, high intake of saturated fats, sedentary lifestyle, and certain medical conditions, including diabetes and hypothyroidism, can lead to hypercholesterolemia. Modification of lifestyle, including changes in food habits, cessation of smoking, reduction of alcohol intake, and regular exercise, is not only necessary to attain normal lipid levels but also represents the very first step in the management of hypercholesterolemia [3]. Standard treatments include statins, ezetimibe, bile acid sequestering resins, proprotein convertase subtilisin/kexin type 9 inhibitors, and nicotinic acid [4].

Studies have shown that garlic [5-7], Triphala [8], Nigella sativa seeds [9], and Terminalia arjuna [10] have significant lipid-lowering effects and are effective in managing dyslipidemia. Garlic reduces serum lipid levels, while Triphala and Nigella sativa improve lipid profiles safely. Terminalia arjuna also lowers total and LDL cholesterol with antioxidant benefits comparable to vitamin E, making these natural agents promising for cholesterol management. Additionally, there is growing interest in herbal medications as alternative or complementary treatments, as these natural remedies may offer potential benefits in managing cholesterol levels. This systematic review will aim to assess the effectiveness of herbal interventions in hypercholesterolemia.

Following an initial screening process, a total of 96 studies were identified as relevant. A duplicate-checking procedure was then conducted, resulting in the removal of 7 duplicate studies, with 89 unique studies remaining eligible for further review and data extraction. These studies will undergo a detailed synthesis and analysis to assess key findings, trends, and implications. Data collection began on November 1, 2024.

Hypercholesterolemia, a condition characterized by elevated levels of cholesterol in the blood, is a significant risk factor for cardiovascular diseases such as ischemic heart disease and stroke. Recently, there has been growing interest in herbal interventions as alternative or complementary treatments for managing cholesterol levels. Herbal interventions typically exert their cholesterol-lowering effects through various mechanisms. A meta-analysis on garlic concluded that garlic, in powder or nonpowder form, can significantly lower serum lipid levels over a 1- to 3-month period [5], and a clinical trial conducted to evaluate efficacy concluded that the essential oil of garlic exerts a distinct hypolipidemic action in both healthy individuals and patients of coronary heart disease [6]. Additionally, a study examining the effects of garlic on obesity and blood lipid profiles in high-fat diet–induced obese mouse models revealed that administration of garlic significantly reduced high-fat diet–induced weight gain, epididymal fat accumulation, and hypercholesterolemia [7]. However, evidence from a meta-analysis on the effect of garlic on serum cholesterol suggests that the intake of garlic preparations did not produce any significant beneficial effects on serum cholesterol levels [13]. An animal study on the Curcuma longa revealed that while lipid accumulation significantly increased in the free fatty acids–treated group compared to the control group, supplementation with the water extract of Curcuma longa effectively reduced lipid accumulation in a dose-dependent manner, demonstrating its potential for regulating lipid metabolism [14]. A meta-analysis on Curcuma longa suggested that curcumin (ie, turmeric) supplementation may be effective in improving blood levels of total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol, but may not be capable of improving their pertinent apolipoproteins [15]. A randomized clinical study was conducted to evaluate the efficacy and safety of Triphala, an Ayurvedic powder formulation consisting of Terminalia chebula, Terminalia bellerica, and Emblica officinalis. The study found that Triphala is both effective and safe for the management of dyslipidemia [8]. A randomized clinical study was also conducted to evaluate the efficacy of Nigella sativa seeds and concluded that they have beneficial therapeutic effects in the treatment of hyperlipidemia [9]. A randomized controlled trial evaluated the antioxidant and hypocholesterolemic effects of Terminalia arjuna tree bark powder in patients with coronary heart disease and found that Terminalia arjuna significantly reduced total and LDL cholesterol levels, with its antioxidant effects comparable to those of vitamin E, demonstrating potential therapeutic benefits in managing cholesterol levels [10].

Collating all the above results into a common pool of evidence through a systematic review and meta-analysis will hopefully benefit clinicians focusing on hypercholesterolemia. Comparative findings on alternative therapies targeting this spectrum of disease will undoubtedly contribute to building a robust treatment protocol, ultimately promoting an integrative approach. This systematic review aims to provide comprehensive evidence on the effectiveness and safety of herbal interventions in managing hypercholesterolemia. The findings could guide health care professionals in recommending herbal supplements as part of a holistic treatment approach and inform future research directions.

The main limitation of the study is that most clinical trials conducted in alternative medicine, such as Ayurveda, are not yet available in leading journals indexed in major databases. Additionally, clinical trials with positive results, conducted as part of academic work, have not been published or made accessible to the public. This limits the availability of high-quality evidence, potentially affecting the comprehensiveness of the review.

The systematic review will be published in a peer-reviewed journal and disseminated both electronically and in print. It will be periodically updated, and a GRADE 2.0 evaluation will be conducted to assess the quality of evidence, providing summaries on the future state of the research.