Natural product-based treatment potential for type 2 diabetes mellitus and cardiovascular disease

Abstract

BACKGROUND

Type 2 diabetes (T2D) is a metabolic disease of impaired glucose utilization and a major cause of cardiovascular disease (CVD). The pathogenesis of both diseases shares common risk factors and mechanisms, and both are significant contributors to global morbidity and mortality. Supplements of natural products for T2D mellitus (T2DM) and CVD can be seen as a potential preventive and effective therapeutic strategy.

AIM

To critically evaluate the therapeutic potential of natural products in T2D and coronary artery disease (CAD).

METHODS

By using specific keywords, we strategically searched the PubMed database. Randomized controlled trials (RCTs) were searched as the primary focus that examined the effect of natural products on glycemic control, oxidative stress, and antioxidant levels. We focused on outcomes such as low blood glucose levels, adjustment on markers of oxidative stress and antioxidants. After screening full-length papers, we included 9 RCTs in our review that met our inclusion criteria.

RESULTS

In the literature search on the database, we found that various natural products like plant secondary metabolites play a diverse role in the management of CAD. American ginseng, sesame oil and cocoa flavanols proved effective in lowering blood glucose levels and controlling blood pressure, which are key factors in managing T2DM and CVD. In diabetic patients Melissa officinalis effectively reduce inflammation and shows diabetes prevention. Both fish oil and flaxseed oil reduced insulin levels and inflammatory markers, suggesting benefits for both conditions. The lipid profile and endothelial function were enhanced by Nigella sativa oil and Terminalia chebula, which is significant for the management of cardiovascular risk factors in T2DM. Additionally Bilberry extract also showed promise for improving glycemic control in patients with T2DM.

CONCLUSION

The high level of antioxidant, anti-inflammatory, and anti-angiogenic properties found in natural products makes them promising therapeutic options for the management of CAD, with the potential benefit of lowering the risk of CAD.

Key Words: Type 2 diabetes mellitus, Cardiovascular disease, Natural products, Antioxidants, Oxidative stress, Therapeutic impact, Global burden

Core Tip: This systematic review investigated the potential of natural products in the management of type 2 diabetes (T2D) and cardiovascular disease (CVD). Various natural ingredients such as American ginseng, cocoa flavanol, sesame oil, flaxseed oil, fish oil, Melissa officinalis, Terminalia chebula, Nigella sativa oil, bilberry extract have shown significantly effect on glycemic control, blood pressure management, decreased insulin sensitivity and inflammatory markers, lipid profile, endocrine and enhancement of work done. These findings suggest that natural products offer promising therapeutics for T2D and CVD applications because of their anti-inflammatory properties and anti-atherosclerotic properties, it can reduce the risk of cardiovascular complications in T2D.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that interferes with blood glucose management and is brought on by either insufficient insulin production or the body developing insulin resistance[1]. A group of diseases known as cardiovascular diseases (CVD) affect the heart and blood vessels, resulting in heart failure, coronary artery disease (CAD), and stroke, among other problems. It is well-recognized that T2DM poses a frequent risk for CVD[2]. More than half a billion people worldwide suffer from diabetes, and within the next 30 years, this figure is expected to double, according to the Global Burden of Disease 2023 estimate[3]. About 18 million deaths globally are attributed to CVD[4]. Global rates of morbidity and death are greatly impacted by diabetes and CVD, two of the most common and interconnected health issues of the modern period[5].

Pathogenesis of CVD in diabetes

Advanced glycated end products (AGEs), covalent adducts formed by the non-enzymatic interaction of the carboxyl group of glucose with the amino group of proteins, is the process of glycation reaction that occurs when a high amount of glucose is present in T2D[6]. In the blood circulation these AGEs form the covalent cross-links with extracellular protein including collagen and reduce the elasticity of cardiac and vascular muscles. The elevated levels of circulating AGEs may enhance lipid oxidation, ultimately leading to plaque formation, initiating the atherosclerosis process, and increasing the risk of coronary artery disease[7].

On the other hand, pro-inflammatorymediators and reactive oxygen species are produced when AGEs bind to RAGE, the receptor of AGEs. These molecules then activate proliferative, fibrotic, and thrombotic pathways, which in turn cause oxidative stress and vascular inflammation. The onset and advancement of atherosclerosis are influenced by each of these variables[8]. It has been proposed that AGEs cause oxidative stress and local inflammation in T2DM, leading to raised low-density lipoprotein (LDL) cholesterol and damage to the vascular endothelium. They also emit different chemokines and cytokines and draw in monocytes. By using adhesion molecules to adhere to the endothelium, these monocytes enter the subendothelial region where they develop into macrophages that gather oxidized LDL cholesterol, produce foam cells, and start the atherogenic process[9].

The coronary arteries’ development of atherosclerotic plaques lowers blood flow to the heart muscle. Endothelial dysfunction was brought on by this plaque formation, which harmed the endothelium lining blood vessels[10]. Inflammation may weaken the fibrous cap of the atherosclerotic plaque, raising the possibility of rupture. Acute coronary syndrome and thrombosis may result from the burst plaque[11,12]. Myocardial infarction, unstable angina, and sudden cardiac death are symptoms of coronary syndrome, which is brought on by the formation of a thrombus on a ruptured plaque[13]. FDA-approved treatments for T2DM and CAD include liraglutide, an agonist of the glucagon-like peptide 1 receptor, and empagliflozin, a sodium-glucose co-transporter-2 inhibitor[14,15]. Gallstones and hypotension are just two of the potential adverse effects of using these drugs[16,17]. Exploring natural materials with their many medical characteristics has attracted substantial attention, especially in light of the limits and adverse effects connected with modern treatments. These organic substances present a potentially safer and more potent alternative, opening up a viable path for new medicines. It is essential to comprehend their modes of action and possible synergies with current medications to advance cardiovascular care. The purpose of this study is to emphasize the role that natural products play in CAD management and the need for more research in this field.

Significance of natural products

Throughout history, a common source of therapeutic medicines has been plants and herbs, whether in the form of traditional extracts or pure active substances[18]. Aspirin (from the Salix alba L. tree), digoxin (a cardiac glycoside from Digitalis purpurea), ephedrine (from Ephedra sinica), lovastatin (from Monascus purpureus L.), taxol (from Taxus brevifolia), reserpine (from Rauvolfia serpentina), and other well-known drugs are among the commonly known drugs derived from plants[19].

Anti-malarial medications, such quinine derived from Cinchona species bark and artemisinin from Artemisia annua L., are prime examples of how traditional medicine can influence drug development procedures[20]. Alpha-lipoic acid (ALA), an antioxidant well known for improving insulin sensitivity, lowering oxidative stress, and helping diabetics control their blood sugar, is one of these natural substances[21]. For those with diabetes, lemon balm [Melissa officinalis (M. officinalis)] may help with glycaemic management, reduce inflammation, and lower blood pressure[22]. Studies have looked at the potential of flaxseed oil and fish oil, which are high in omega-3 fatty acids, to improve cardiovascular health in diabetics by lowering triglycerides (TG) and reducing inflammation[23].

Studies have been conducted on the effects of Nigella Sativa (N. Sativa), also referred to as black seed, on glycaemic management and its potential to lower cholesterol and TG levels, two cardiovascular risk factors[24]. Moreover, Haritaki, also known as Terminalia Chebula, has drawn interest for improving endothelial function and lowering cardiovascular risk factors, especially in individuals with T2D[25]. The relationship between CVD and T2DM has been examined in earlier research. Notwithstanding this knowledge, there is still a deficiency in the literature concerning the precise methods by which natural products and the bioactive substances they contain may lower the risk of CVD in people with T2D.

The purpose of the study is to evaluate the potential role of natural products and their bioactive compounds in managing CVD in individuals with T2DM. This systematic review aims to compare the current evidence, specifically Randomized controlled trials (RCTs), on the role of natural products and their bioactive compounds in the management of T2DM and CAD and to critically evaluate their potential mechanisms of action and therapeutic implications for T2DM and CAD.

MATERIALS AND METHODS

The search was conducted using the PubMed NCBI database, employing a specific strategy combining: “Biological Products” [Mesh] AND “Cardiovascular Diseases” [Mesh]) AND “Diabetes Mellitus” [Mesh]. Initially, 1138 articles were found. After applying a filter limiting the search to “full text”, covering the last five years (2018-2023) and focusing on human RCTs, 25 studies are filtered out. These studies investigated the impact of natural product therapy on glycaemic control, oxidative stress, and antioxidant levels as primary outcomes. The full-length papers of the selected articles were thoroughly assessed based on eligibility criteria, resulting in the inclusion of nine RCTs that met the study’s criteria (Figure 1 and Table 1).

Figure 1 Flow diagram of searching and selection of randomized control trial studies.

Table 1 basic characteristics of included randomized control trial studies.

No.	Year	Study design	Setting	Department	Sample size	Intervention	Dose	Duration	Effect	Ref.
1	2021	Double-blind placebo	St. Michael’s Hospital, University of Toronto	Out patient’s department	24 T2DM patients	American ginseng	1 g/meal (3 g/d)	8 wk	Decrease blood glucose, HbA1c, and systolic blood pressure and increase nitric oxide	[26]
2	2020	Randomized, placebo-controlled, two-center trial	Two university-affiliated centres (St. Michael’s Hospital Toronto, Canada, and KB Merkur Hospital, Zagreb, and Croatia)		80 participants with diagnosed T2D and hypertension	American ginseng extract and Rg3- enriched Korean ginseng extract [f 1.50 g/d AG and 0.75 g/d Rg3-KRG standardized extracts (extracted to contain 75 mg of ginsenoside Rg3 and 375 mg total ginsenosides)]	2.25 g 3 times daily	12 wk	Reduce end-systolic pressure (-6.60 mmHg ± 2.50 mmHg	[27]
3	2018	Double-blinded, randomized, placebo-controlled trial	Diabetes PRAXIS Rathausallee, Duisburg, Germany	Specialized medical office for diabetology	42 hypertensive patients with T2D	Flavanol-rich cocoa	2.5 g/d	12 wk	Reduce HOMA-IR and blood cholesterol level	[28]
4	2018	Randomized, placebo-controlled trial	Iranian Diabetes Society and Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences	Out patients department	62 T2DM patients with at least one year of diabetic history	M. officinalis capsules	700 mg/d	12 wk	Reduce FBS, HbA1c, Insulin (min/mL), HOMA-b cell (%), hs-CRP (mg/L)	[29]
5	2019	Randomized, single-blind controlled trial	Shiraz Heart Center Outpatient Clinic affiliated with the Shiraz University of Medical Sciences, Shiraz, Iran	Out patients department	75 metabolic syndrome patients	Sesame oil enriched with vit E group	30 mL/d sesame oil + 400 mg vit E powder	2 wk	Reductions in serum total cholesterol, triglycerides, FBG, HOMA-IR, MDA, hs-CRP, HDL-C systolic and diastolic BP	[30]
6	2019	Randomized, double-blinded, placebo-controlled trial	Cardiology clinic affiliated to Kashan University of Medical Sciences (KAUMS), Kashan, Iran	Out patients department	90 T2D patients	Flaxseed oil and fish oil	1000 mg of flaxseed oil, as the source of omega-3 fatty acids, containing 400 mg of ALA (n = 30) or 1000 mg of fish oil containing 250 mg of EPA and 150 mg of DHA	12 wk	Reduce high-sensitivity CRP significant increase in total nitrite al antioxidant capacity	[31]
7	2020	Randomized double-blind clinical trial	Diabetes Control Center of Sabzevar Iran	Out patients department	50 participants with diagnosed T2D	N. Sativa oil	1000 mg N. Sativa oil as two capsules, each containing 500 mg N. Sativa oil, daily	8 wk	Decrease FBS, triglyceride, total cholesterol, low-density lipoprotein cholesterol, serum hs-CRP, mdaand increase in serum level of high-density lipoprotein cholesterol	[32]
8	2020	Random assignment, parallel-group, single-center, double-blind, placebo-controlled design	Nizam’s Institute of Medical Sciences, Hyderabad	Out patients department	74 T2DM patients	T. chebula	T. chebula 250 mg, T. chebula 500 mg	Twice daily for 12 wk	Improves endothelial function (reflection index), GSH, MDA, hs-CRP, total cholesterol, HDL, LDL, HbA1c	[33]
9	2020	Randomized, double-blind, placebo-controlled, cross-over intervention study	Diabetic and general medical clinics of the Prince of Wales Hospital, the teaching hospital of The Chinese University of Hong Kong, Shatin, Hong Kong	Out patients department	20 T2D patients	Bilberry (Vaccinium myrtillus L.)	1.4 g/d of extract) daily	4 wk	Improves glycaemic control by HbA1c and Random blood sugar	[34]

T2DM: Type 2 diabetes mellitus; N. Sativa: Nigella Sativa; T. chebula: Terminalia chebula; M. officinalis: Melissa officinalis; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; FBS: Fasting blood sugar; HbA1c: Hemoglobin; HOMA-IR: Homeostatic model assessment of insulin resistance; hs-CRP: Highly sensitive C-reactive protein; HDL-C: High-density lipoprotein; BP: Blood pressure; GSH: Glutathione; MDA: Malondialdehyde; LDL: Low-density lipoprotein.

RESULTS

This review was conducted to critically evaluate the role of natural products in the treatment of T2DM and CAD. In the literature search on the database, we found that various natural products like plant secondary metabolites play a diverse role in the management of CAD. American Ginseng (AG) (Panay quinquefolius) is an American herb that is enriched with the bioactive chemical ginsenosides, which are involved in various biological activities. In a double-blind placebo trial, the 1 g/meal (3 g/d) supplementation of AG to diabetic patients for 8 wk reduced the glucose level in the blood (0.71 mmol/L), hemoglobin (HbA1c; -0.29%), regulated systolic blood pressure (-5.6 mmHg ± 2.7 mmHg), and increased NOX level (1.85 µmol/L ± 2.13 µmol/L)[26]. Similarly, the supplementation of AG and Korean Red Ginseng (KRG) extract and Rg3-enriched Korean Ginseng (P. ginseng) extract (1.50 g/d AG and 0.75 g/d Rg3-KRG standardized extracts (extracted to contain 75 mg of ginsenoside Rg3) to hypertensive T2DM patients for 12 wk regulated the end systolic volume by -6.60 mmHg ± 2.50 mmHg, P = 0.01)[27]. In the treatment of T2DM, an increase in vascular elasticity is an effective approach. In a double-blinded, randomized, placebo-controlled trial, the supplementation of 2.5 g/d of flavanol-rich cocoa (flavonoids) in 42 hypertensive diabetic patients for 12 wk reduced the blood cholesterol level and homeostatic model assessment of insulin resistance (HOMA-IR) but had a very limited effect[28]. The supplementation of M. Officinalis (Lemon balm) (flavonoids) at 700 mg/d for 12 wk in T2DM patients reduces inflammation and results in significant improvements in fasting blood sugar (FBS), glycated HbA1c, β-cell activity, TG, high-density lipoprotein cholesterol (HDL-C), highly sensitive C-reactive protein (hs-CRP), and systolic blood pressure, indicating its efficacy in improving glycaemic control[29]. Sesame oil enriched with vitamin E (30 mL/d sesame oil + 400 mg vitamin E powder) supplementation in metabolic syndrome patients for 2 wk showed promising effects on lipid profile, fasting blood glucose, malondialdehyde (MDA), hs-CRP, HOMA-IR, and blood pressure in individuals with metabolic syndrome, with the sesame oil group showing significant improvements in these parameters[30]. The effects of flaxseed (a source of omega-3 fatty acids) and fish oil were compared in 90 patients with T2DM and CAD. The study involved two groups: One receiving 1000 mg of flaxseed oil, containing 400 mg of ALA (n = 30), and the other receiving 1000 mg of fish oil, containing 250 mg of eicosapentaenoic acid (EPA) and 150 mg of docosahexaenoic acid (DHA). The supplementation of flaxseed reduces insulin levels and hs-CRP significantly, as well as increasing total nitrite and total antioxidant capacity, suggesting potential benefits in managing cardiovascular risk factors among diabetic patients with coronary heart disease[31]. The supplementation of N. Sativa oil, bioactive compound thymoquinone (1000 mg N. Sativa oil) daily for 12 wk in T2DM patients significantly reduces FBS, TG, total cholesterol (TC), LDL cholesterol (LDL-C), hs-CRP, MDA, and increases the serum level of HDL-C, indicating its potential cardiovascular protective effects[32]. Supplementation of Terminalia chebula 500 mg daily for 12 wk in T2DM patients was found to improve endothelial function, reduce cardiovascular risk factors, and minimize cardiovascular risk factors in patients with T2DM[33]. The supplementation of Bilberry (Vaccinium myrtillus L.), bioactive compound anthocyanins (1.4 g/d of extract) daily for 2 wk in T2DM patients improves glycaemic control by HbA1c and random blood sugar[34].

DISCUSSION

Because of its potential therapeutic benefits, using natural compounds and secondary metabolites for the treatment of CAD has received a lot of interest[35]. Natural products derived from plants are abundant in bioactive substances that include antioxidant and metabolic-regulating qualities[36]. The wide variety of natural substances can affect several CAD characteristics, such as regulating risk factors, enhancing endothelial function, and decreasing atherosclerosis and oxidative stress[37]. In this review article, we found that many natural products are actively employed as therapeutic agents to treat T2DM and CAD, providing information on their clinical applicability and mechanisms of action. Certain plant products and secondary metabolites are also engaged in several metabolic regulation activities.

Flavonoids

Natural compounds in the flavonoid class are well-known for their anti-inflammatory and antioxidant qualities, which are especially important for the treatment of CAD. In relation to CAD, a number of flavonoids, such as quercetin, resveratrol, and catechins, have shown promise as therapeutic agents[38]. One flavonoid that is widely distributed in fruits and vegetables is quercetin, which has the ability to protect the heart by lowering inflammation, oxidative stress, and endothelial dysfunction. It can improve coronary vasodilation and lower the risk of atherosclerotic plaque formation by inhibiting LDL oxidation, preventing platelet aggregation, and increasing nitric oxide (NO) generation[39].

Resveratrol has been shown to have anti-inflammatory, anti-atherosclerotic, and lipid-profile-improving properties. It is mostly present in red grapes and wine. By encouraging NO generation, it improves endothelial function and activates sirtuin 1, a protein linked to cardioprotection[40]. Green tea contains catechins, which have anti-inflammatory and antioxidant qualities. By improving NO-mediated vasodilation and endothelial function, decreasing oxidative stress, and increasing endothelial NO synthase activity, they can slow the advancement of CAD[41]. Although cranberries are well known for their ability to prevent UTIs, they also have cardioprotective qualities due to their flavonoid content, specifically myricetin and quercetin[42].

These flavonoids have anti-inflammatory and antioxidant properties that lessen oxidative stress and inflammation linked to CAD. Consuming cranberries has been associated with better lipid profiles, decreased development of atherosclerotic plaque, and improved endothelial function. Cranberries are a useful natural substance for CAD prevention because of the above mentioned advantages[43]. Similarly, it has been shown that Ocimum sanctum’s phytochemical constituents have antiobesogenic, antioxidant, and antidiabetic effects[44].

Polyphenols

Another class of natural substances that has drawn interest is polyphenols, which may have applications in the treatment of CAD. Polyphenols that resemble flavonoids, such as curcumin and epigallocatechin gallate (EGCG), have been shown to have cardioprotective effects[45]. Green tea contains EGCG, which has anti-inflammatory and antioxidant properties. It has the ability to increase NO synthesis, lower oxidative stress, and suppress the expression of adhesion molecules that are necessary for the development of atherosclerotic plaques. These outcomes help to stop the evolution of CAD[46]. Turmeric contains a compound called curcumin, which has anti-inflammatory and antioxidant qualities. By blocking NF-κB activation, averting oxidative stress, and enhancing lipid profiles, it can lower inflammation. Curcumin is a promising natural substance for the therapy of CAD because of these activities[47]. Pomegranate consumption has been associated with reduced oxidative stress, improved endothelial function, and inhibition of atherosclerotic plaque formation[48]. These effects can help mitigate the progression of CAD[49]. Ferulic acid is a phenolic compound found in various plants, including rice, wheat, and oats. It has antioxidant and anti-inflammatory properties and can improve endothelial function[50]. Ferulic acid promotes the release of NO and inhibits oxidative stress, contributing to enhanced vasodilation and reduced inflammation. These effects make it a potential natural therapeutic agent in CAD management[51].

Omega-3 fatty acids

Omega-3 fatty acids, particularly EPA and DHA, are natural products with well-established cardiovascular benefits. They can reduce TG levels, lower blood pressure, and improve endothelial function[52]. EPA and DHA can decrease the production of proinflammatory cytokines and the expression of adhesion molecules in endothelial cells, thereby reducing inflammation and the risk of atherosclerosis. These omega-3 fatty acids also have antithrombotic properties, contributing to CAD prevention[53].

Plant sterols and stanols

Natural substances that resemble cholesterol in structure are called plant sterols and stanols. They lower plasma TC and LDL-C levels by competitively inhibiting the intestines’ ability to absorb cholesterol[54]. These substances are added to a range of functional foods and dietary supplements that lower the risk of CAD and regulate lipid profiles. Without influencing HDL cholesterol, TGs, or the absorption of fat-soluble vitamins, plant sterols and stanols can dramatically lower LDL cholesterol levels[55].

Berberine

An alkaloid called berberine, which is present in several plants, including barberry and goldenseal, has demonstrated potential in the treatment of CAD risk factors. It can lower TG levels, increase insulin sensitivity, and improve glucose metabolism, making it a useful natural supplement for people with diabetes or metabolic syndrome, common comorbidities of CAD[56]. AMP-activated protein kinase (AMPK), a cellular energy sensor that controls inflammation, lipid metabolism, and glucose uptake, is activated by beberine. AMPK activation lowers the incidence of CAD and improves metabolic parameters[57].

Resins and guggulipids

Traditionally, Ayurvedic medicine has utilized guggul, or Commiphorawightii, to prepare resins and guggulipids, which may have cardiovascular advantages. Compounds like guggulsterone found in them have the ability to decrease inflammation and LDL cholesterol levels[58]. Increased LDL receptor expression and subsequent bloodstream LDL clearance have been demonstrated to be caused by guggulipids. Enhancing lipid profiles and lowering the risk of CAD are two benefits of this activity[59].

Red yeast rice

Klimek et al[60] found in red yeast rice, is a fermented rice product that shares the same structural makeup as the statin drug lovastatin, which lowers cholesterol. Red yeast rice is a natural substitute for people pursuing lipid-lowering therapies because it has been shown to lower LDL cholesterol and TC levels. Because montgolin K inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is involved in the manufacture of cholesterol, lipid profiles are improved and cholesterol production is reduced. Red yeast rice’s clinical efficacy in lowering the risk of CAD has been investigated, which lends credence to its usage as a natural medicinal agent[61].

Vitamins

Vitamins can lower oxidative stress and enhance endothelial function, which lowers the risk of CAD. One such vitamin is vitamin C, an antioxidant. One important stage in the development of atherosclerotic plaque is the oxidative alteration of LDL cholesterol, which vitamin C helps to prevent[62]. In addition to its roles in calcium metabolism and bone health, vitamin D also has ramifications for the cardiovascular system. It may lessen inflammation and the risk of CAD by regulating blood pressure and modifying the immune system[63]. Furthermore, as a strong antioxidant, vitamin E can inhibit LDL oxidation and lessen the development of atherosclerotic plaques, preserving vascular health and possibly assisting in the prevention of CAD[64]. Vitamin B3, or niacin, is a water-soluble vitamin that can decrease TG and LDL cholesterol while increasing HDL cholesterol. Supplementing with niacin can lower the risk of CAD and improve lipid profiles[65]. Very LDL, a precursor of LDL cholesterol, is produced by the liver and is inhibited by niacin. Niacin is a useful therapeutic drug in the management of CAD because of this effect, which lowers blood levels of LDL cholesterol[66].

Policosanols

Natural substances called policosanols are long-chain aliphatic alcohols with lipid-lowering qualities that are extracted from sugarcane wax. Policosanols are useful in the therapy of CAD risk because they help lower LDL cholesterol levels and prevent platelet aggregation. Similar to statin drugs, these substances work by blocking HMG-CoA reductase, which lowers the synthesis of cholesterol. They help to lower the risk of CAD and enhance lipid profiles by doing this[67].

Cinnamon

Common spice cinnamon has bioactive ingredients such cinnamaldehyde and cinnamic acid that have been linked to cardiovascular health advantages. Cinnamon has the potential to be a natural product for the management of CAD, especially in people with diabetes, because it can decrease oxidative stress, inhibit inflammation, and improve blood glucose control[68]. Cinnamaldehyde and cinnamic acid have the ability to improve glucose absorption and insulin sensitivity, which can enhance glycaemic management and lower the risk of coronary heart disease[69]. Researchers have looked at the capacity of a number of plant extracts, fractions, and compounds to inhibit the manufacture of AGEs in recent years. Plant species that exhibit anti-glycation actions include Chrysanthemum morifolium, Chrysanthemum indicum, Erigeron annuus, Cinnamomum verum, and Allium sativum, as well as the metabolic products derived from these species (Table 2).

Table 2 Antiglycation activity of natural compounds isolated from plant extract.

No.	Plant species	Natural products	Role/mechanism	Ref.
1	Chrysanthemum morifolium	Chlorogenic acid, flavonoid glucoside, and aglycone	Antihyperglycemic, scavenges free radicals and metals, traps reactive carbonyl species	[69,70]
2	Chrysanthemum indicum	Caffeic acid, luteolin, and kaempferol	Antioxidant, anti-inflammatory, protects protein structure	[69,70]
3	Erigeron annuus	Quinic acid derivatives, such as 3,5-di-O-caffeoyl-epi-quinic acid	Inhibition of RLAR (rat lens aldose reductase), AGEs formation, AGEs/BSA cross-linking, and cataract genesis	[69]
4	Cinnamomum verum	Catechin, epicatechin, and procyanidin B2	Antioxidant, DPPH scavenger; traps methylglyoxal, protects protein structure	[69,70]
5	Allium sativum		Strong antioxidants and free radical scavengers, inhibiting CML formation	[69]
6	Ilex paraguariensis	Chlorogenic acid	Antihyperglycemic, scavenges free radicals and metals, traps reactive carbonyl species	[69]
7	Rosmarinus officinalis	Rosmarinic acid, carnosic acid, and carnosol	Antioxidant activity and antiglycation properties	[69]
8	Camellia sinensis	Epigallocatechin, 3-O-gallate (EGCG) and (-)-epicatechin 3-O-gallate (ECG)	Strong antioxidant properties and inhibits the accumulation of CML and CEL and the activation of RAGE	[69]
9	Ginkgo biloba	24% flavonoids and 6% terpenoids	Inhibit the RAGE activation in microvascular endothelial cells induced by hypoxic and hypoglycemic conditions	[69]
10	Garcinia mangostana	Catechins, procyanidins, anthocyanin, and xanthones, such as α-mangostin	Antioxidant, DPPH scavenger; traps methylglyoxal, protects protein structure	[69,70]
11	Thymus vulgaris	Flavonoids quercetin, eriodictyol, 5,6,4′-trihydroxy-7,8,3′-trimethoxyflavone, and cirsilineol	Suppressed the levels of AGEs formation	[69,70]
12	Aralia taibaiensis	Triterpenoid saponin	Potent inhibition of the late glycation and the formation of AGEs	[69]
13	Cuminum cyminum	Sesquiterpenoids, monoterpenoids, and chalcone derivatives	Antiglycation properties	[69]

EGCG: Epigallocatechin gallate; AGFs: Advanced glycated end products; ECG: Epicatechin 3-O-gallate; RLAR: Rat lens aldose reductase; BSA: Bovine serum albumin; DPPH: 2,2-diphenyl-1-picrylhydrazy; CML: Carboxy methyl lysine; CEL: Carboxy ethyl lysine; RAGE: Receptor of advanced glycation end products; DPPH: 2,2-diphenyl-1-picrylhydrazy.

The antiglycation potential of both plant-based materials and naturally occurring phenolic compounds with antioxidant properties has been investigated by several authors. They suggested that plant-associated compounds, including the early phase of AGEs synthesis inhibited by piceatannol[71], the early and intermediate phases of AGEs synthesis inhibited by quercetin[72] kaempferol[73], and benfotiamine[74]. The late phase of AGEs synthesis is inhibited by pyridoxamine[75], and the process of formation of AGEs (Figure 2). Overall, we found that natural products, including flavonoids, polyphenols, omega-3 fatty acids, plant sterols, berberine, resins, guggulipids, red yeast rice, vitamins, policosanols, and cinnamon, have shown cardioprotective effects. These compounds exhibit antioxidant, anti-inflammatory, and anti-atherosclerotic properties, which can reduce oxidative stress, inflammation, and endothelial dysfunction associated with CAD. Additionally, plant extracts and compounds have been studied for their ability to suppress the synthesis of AGEs, which are linked to CAD. Overall, natural products offer promising therapeutic options for CAD management. This study has several limitations, including heterogeneity and a smaller sample size in RCTs, lowering its generalizability. Further, large-scale RCTs on populations of different ethnicities and genders are needed to assess its therapeutic implications for T2DM.

Figure 2 Systematic representation of inhibition of advanced glycated end products synthesis pathway by natural products.

CONCLUSION

In this systematic review, we found that various types of natural products, including flavonoids, polyphenols, omega-3 fatty acids, and vitamins, are actively involved in the regulation of various metabolic pathways in both diabetics and CVDs. The promising results from randomized control trials highlight their diverse mechanisms of action, from regulating blood glucose levels to reducing inflammation and improving endothelial function. These natural compounds present a strong case for comprehensive therapies, even though more research is required. This gives hope for improved therapeutic strategies to address the worldwide burden of diabetes and CVD.

ACKNOWLEDGEMENTS

Desh Deepak Singh and Dharmsheel Shrivastav are thankful to DST-PURSE and DST-FIST-AIMT at Amity University Rajasthan, Jaipur, India. Kumbhakar S is thankful to the Department of Biotechnology, Govt. Veer Surendra Say P.G. College, Gariaband, Chhattisgarh, India.