J Food Bioact

Journal of Food Bioactives, ISSN 2637-8752 print, 2637-8779 online

Journal website www.isnff-jfb.com

Review

Volume 27, September 2024, pages 44-57

Integrated review of cardiometabolic biomarkers and dietary nutrients

Figure 3. Role of High Density Lipoprotein in cardiometabolic diseases.

**Table 1.** - Lipid-Lowering Drugs and Their Working Mechanism
Drug	Effects	Common side effects	Working Mechanism
Statins [3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors]	Lower the level of LDL cholesterol in the blood.	Headache, dizziness, feeling sick, feeling unusually tired or physically weak, digestive system problems like constipation, diarrhoea, indigestion or farting, muscle pain, sleep problem, low blood platelet count.	Inhibiting the enzyme HMG-CoA reductase. LDL and LDL precursors are cleared from the circulation due to the resulting reduction in hepatocyte cholesterol concentration. Inhibit the hepatic synthesis of apolipoprotein B-100 and decrease the synthesis and secretion of triacylglycerols-rich lipoproteins (Maron et al., 2000; Blum et al., 2004).
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors	Lower the level of LDL cholesterol	flu-like symptoms such as cold, nausea, back and joint pain, muscle pain	Block PCSK9 proteins from breaking down LDL receptors (Rosenson et al., 2019; Sabatine, 2019)
Fibric Acid derivatives (fibrates)- Clofibrate (Atromid-S®), Fenofibrate (TriCor®, Fibricor®, Lofibra®), Gemfibrozil (Lopid®).	Decrease triacylglycerols, Increase HDL cholesterol, Lower total cholesterol	Abdominal pain, Constipation, Diarrhoea, Dizziness, Headaches, Leg cramps.	Activate peroxisome proliferator-activated receptors (PPARs), Apolipoproteins A-I and A-II are produced by transcriptional induction of PPAR-α, thereby mediating fibrate action on HDL cholesterol levels. PPAR stimulates lipoprotein lipase-mediated lipolysis by lowering hepatic apoC-III production. By stimulating fatty acid uptake, acyl-coA conversion, and catabolism via the β-oxidation pathways, fibrates decrease VLDL production, as well as fatty acids and triacylglycerols synthesis (Kim and Kim, 2020; Wang et al., 2022)
Bile acid sequestrants (bile acid resins)	Lower the level of LDL cholesterol	Constipation, Abdominal pain, Bloating, Vomiting, Diarrhoea, Weight loss, Excessive passage of gas (flatulence), Heartburn, Gallstones	Binding bile acids to sequestrants prevents their reabsorption in the intestines. The liver produces more bile acids as a result of this disruption in bile acid circulation between the liver and gut. In order to reduce intracellular cholesterol (LDL), the liver produces bile acids by metabolising cholesterol (LDL) present in the cells. In addition to increasing levels of good cholesterol and high-density lipoprotein, bile acid sequestrants may promote apoprotein A1 synthesis (Ticho et al., 2019; Fiorucci et al., 2021).
Nicotinic acid (niacin)	Decreases triacylglycerol and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C) levels	Severe skin flushing combined with dizziness, Rapid heartbeat, Itching, Nausea and vomiting, Abdominal pain, Diarrhoea, Gout, Liver damage, Diabetes	A triacylglycerol and very-low-density lipoprotein (VLDL) metabolic effect of this drug is mediated by its antilipolytic effects (Hamoud et al., 2013; Lukasova et al., 2011)
Selective cholesterol absorption inhibitors	Reduce Total Cholesterol level	Stomach ache, Diarrhoea, Tiredness, Headache.	Inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triacylglycerols, or bile acids (Sudhop et al., 2002; Shulpekova et al., 2022)
Adenosine triphosphate-citrate lyase (ACL) inhibitors	Reduces LDL	Hyperuricemia (high amount of uric acid in the blood), Atrial fibrillation (irregular and fast beats seen in the upper chambers of the heart), Increase in liver enzymes, Difficulty in passing urine, Hypersensitivity reaction, Tendon damage, Leukocytopenia (decrease in white blood cells)	The inhibition of ACL inhibits the HMG-CoA enzyme. The cholesterol biosynthesis pathway in the liver relies on HMG-CoA enzyme for cholesterol formation (Feng et al., 2020; Pinkosky et al., 2016)

Table 1. - Lipid-Lowering Drugs and Their Working Mechanism

Drug

Effects

Common side effects

Working Mechanism

Statins [3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors]

Lower the level of LDL cholesterol in the blood.

Headache, dizziness, feeling sick, feeling unusually tired or physically weak, digestive system problems like constipation, diarrhoea, indigestion or farting, muscle pain, sleep problem, low blood platelet count.

Inhibiting the enzyme HMG-CoA reductase. LDL and LDL precursors are cleared from the circulation due to the resulting reduction in hepatocyte cholesterol concentration. Inhibit the hepatic synthesis of apolipoprotein B-100 and decrease the synthesis and secretion of triacylglycerols-rich lipoproteins (Maron et al., 2000; Blum et al., 2004).

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

Lower the level of LDL cholesterol

flu-like symptoms such as cold, nausea, back and joint pain, muscle pain

Block PCSK9 proteins from breaking down LDL receptors (Rosenson et al., 2019; Sabatine, 2019)

Fibric Acid derivatives (fibrates)- Clofibrate (Atromid-S®), Fenofibrate (TriCor®, Fibricor®, Lofibra®), Gemfibrozil (Lopid®).

Decrease triacylglycerols, Increase HDL cholesterol, Lower total cholesterol

Abdominal pain, Constipation, Diarrhoea, Dizziness, Headaches, Leg cramps.

Activate peroxisome proliferator-activated receptors (PPARs), Apolipoproteins A-I and A-II are produced by transcriptional induction of PPAR-α, thereby mediating fibrate action on HDL cholesterol levels. PPAR stimulates lipoprotein lipase-mediated lipolysis by lowering hepatic apoC-III production. By stimulating fatty acid uptake, acyl-coA conversion, and catabolism via the β-oxidation pathways, fibrates decrease VLDL production, as well as fatty acids and triacylglycerols synthesis (Kim and Kim, 2020; Wang et al., 2022)

Bile acid sequestrants (bile acid resins)

Lower the level of LDL cholesterol

Constipation, Abdominal pain, Bloating, Vomiting, Diarrhoea, Weight loss, Excessive passage of gas (flatulence), Heartburn, Gallstones

Binding bile acids to sequestrants prevents their reabsorption in the intestines. The liver produces more bile acids as a result of this disruption in bile acid circulation between the liver and gut. In order to reduce intracellular cholesterol (LDL), the liver produces bile acids by metabolising cholesterol (LDL) present in the cells. In addition to increasing levels of good cholesterol and high-density lipoprotein, bile acid sequestrants may promote apoprotein A1 synthesis (Ticho et al., 2019; Fiorucci et al., 2021).

Nicotinic acid (niacin)

Decreases triacylglycerol and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C) levels

Severe skin flushing combined with dizziness, Rapid heartbeat, Itching, Nausea and vomiting, Abdominal pain, Diarrhoea, Gout, Liver damage, Diabetes

A triacylglycerol and very-low-density lipoprotein (VLDL) metabolic effect of this drug is mediated by its antilipolytic effects (Hamoud et al., 2013; Lukasova et al., 2011)

Selective cholesterol absorption inhibitors

Reduce Total Cholesterol level

Stomach ache, Diarrhoea, Tiredness, Headache.

Inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triacylglycerols, or bile acids (Sudhop et al., 2002; Shulpekova et al., 2022)

Adenosine triphosphate-citrate lyase (ACL) inhibitors

Reduces LDL

Hyperuricemia (high amount of uric acid in the blood), Atrial fibrillation (irregular and fast beats seen in the upper chambers of the heart), Increase in liver enzymes, Difficulty in passing urine, Hypersensitivity reaction, Tendon damage, Leukocytopenia (decrease in white blood cells)

The inhibition of ACL inhibits the HMG-CoA enzyme. The cholesterol biosynthesis pathway in the liver relies on HMG-CoA enzyme for cholesterol formation (Feng et al., 2020; Pinkosky et al., 2016)

**Table 2.** - Interaction of Foods Bioactive Compounds with Cardiometabolic Biomarker
S.No.	Food/Food Additives	Major Bioactive Compounds	Lipid Biomarker of Cardiovascular disease	Mechanism Of Action	Reference
1	Apple	Quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnoside, catechin, epicatechin, procyanidin, cyanidin-3-galactoside, coumaric acid, chlorogenic acid, gallic acid, and phloridzin	Fasting plasma biomarkers of inflammation (primary outcome), endotoxemia, carbohydrate and lipid metabolism (glucose, insulin, triacylglycerol; secondary outcomes), and peripheral blood mononuclear cell (PBMC)-secreted cytokines (secondary outcome	Modulated postprandial plasma IFN-γ and total antioxidant capacity. In unstimulated and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), apples reduced secreted IL-6 and TNF-α, Increased IL-4, as well as decreased Granulocyte-macrophage colony-stimulating factor and IL-17 in unstimulated PBMC and Granulocyte colony stimulating factor in LPS-stimulated PBMC	(Liddle et al., 2021a; Liddle et al., 2021b )
2	Almond	Glutamic acid, Tryptophan, Threonine, Isoleucine, Leucine,Arginine,Phenylalanine, Alanine, Glycine, Proline, Serine	Reduces adiposity, glycemic control, and the lipid profile	Decreased total cholesterol, low-density lipoprotein cholesterol, and the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol	(Li et al., 2011;Bolling, 2017)
3	Avocado	Choline, niacin, pantothenic acid, riboflavin, lutein/zeaxanthin, vitamin A, vitamin C, vitamin E, vitamin K1, folate, vitamin B-6,	triacylglycerols, LDL oxidation, small atherogenic LDL particles and promoting postprandial vascular endothelial health	Modulating TNF-α, Reducing sub-class lipoprotein concentrations, lower concentrations of triacylglycerol-rich lipoproteins and higher concentrations of larger high-density lipoprotein (HDL)	(Park et al., 2018; Dreher et al., 2021)
4	Cinnamon	Cinnamaldehyde, cinnamate, cinnamic acid, and eugenol	Reduce plasma glucose , Reactive oxygen species	Inhibit α-glucosidase and control hyperglycemia, Enhancing insulin sensitivity and insulin secretion; regulating the enzyme activity involved in glucose; regulating glucose metabolism in the liver, adipose tissue and muscle; ameliorating oxidative stress and inflammation to protect islet cells	(Wariyapperuma et al., 2020; Shang et al., 2021)
5	Flaxseed	Hydroxybenzoic acids, hydroxycinnamic acids, and lignans, gallic acid and syringic acid	Total cholesterol and non-high-density lipoprotein cholesterol	Decreased IL-6 and MDA levels, and increased TAC,Serum apolipoprotein A-1 and apolipoprotein B , Reduce plasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂)	(Tamtaji et al., 2020; Lucas et al., 2002; Khandouzi et al., 2022)
6	Garlic	Diallyl thiosulfonate (allicin), diallyl sulphide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), E/Z-ajoene, S-allyl-cysteine (SAC), and S-allyl-cysteine sulfoxide (alliin)	Positive impact on vascular endothelial and platelet function, lowering effect on triacylglycerols	Reduced postprandial triacylglycerols, Modulate IL-6, beneficial effect on inflammation, enhancing the phosphorylation of AMP-activated protein kinase (AMPK)	(Asgharpour et al., 2021;Wlosinska et al., 2021)
7	Ginger	Gingerols, shogaols, zingiberene, zingerone, paradols	Reduce fasting plasma glucose, HbA1C, insulin, HOMA, triacylglycerols, total cholesterol, CRP and PGE2	Inhibits reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), superoxide dismutase (SODs), glutathione, and heme oxygenase, increased activity of the liver enzyme CYP7A1 and decreased mRNA levels of intestinal cholesterol absorption proteins such as MTP, ACAT2, and NPC1L1	(Roudsari et al., 2021; Lei et al., 2014; Arablou et al., 2014)
8	Green tea	5-N-ethylglutamine, Glutamic acid, tryptophan, Glycine, serine, aspartic acid, tyrosine, valine, leucine, Threonine, arginine, and lysine	lowers LDL cholesterol and TC, Reduces triacylglycerols	Interfere with the emulsification, digestion, and micellar solubilization of lipids	(Xu et al., 2020; Zheng et al., 2011)

Table 2. - Interaction of Foods Bioactive Compounds with Cardiometabolic Biomarker

S.No.

Food/Food Additives

Major Bioactive Compounds

Lipid Biomarker of Cardiovascular disease

Mechanism Of Action

Reference

Apple

Quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnoside, catechin, epicatechin, procyanidin, cyanidin-3-galactoside, coumaric acid, chlorogenic acid, gallic acid, and phloridzin

Fasting plasma biomarkers of inflammation (primary outcome), endotoxemia, carbohydrate and lipid metabolism (glucose, insulin, triacylglycerol; secondary outcomes), and peripheral blood mononuclear cell (PBMC)-secreted cytokines (secondary outcome

Modulated postprandial plasma IFN-γ and total antioxidant capacity. In unstimulated and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), apples reduced secreted IL-6 and TNF-α, Increased IL-4, as well as decreased Granulocyte-macrophage colony-stimulating factor and IL-17 in unstimulated PBMC and Granulocyte colony stimulating factor in LPS-stimulated PBMC

(Liddle et al., 2021a; Liddle et al., 2021b )

Almond

Glutamic acid, Tryptophan, Threonine, Isoleucine, Leucine,Arginine,Phenylalanine, Alanine, Glycine, Proline, Serine

Reduces adiposity, glycemic control, and the lipid profile

Decreased total cholesterol, low-density lipoprotein cholesterol, and the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol

(Li et al., 2011;Bolling, 2017)

Avocado

Choline, niacin, pantothenic acid, riboflavin, lutein/zeaxanthin, vitamin A, vitamin C, vitamin E, vitamin K1, folate, vitamin B-6,

triacylglycerols, LDL oxidation, small atherogenic LDL particles and promoting postprandial vascular endothelial health

Modulating TNF-α, Reducing sub-class lipoprotein concentrations, lower concentrations of triacylglycerol-rich lipoproteins and higher concentrations of larger high-density lipoprotein (HDL)

(Park et al., 2018; Dreher et al., 2021)

Cinnamon

Cinnamaldehyde, cinnamate, cinnamic acid, and eugenol

Reduce plasma glucose , Reactive oxygen species

Inhibit α-glucosidase and control hyperglycemia, Enhancing insulin sensitivity and insulin secretion; regulating the enzyme activity involved in glucose; regulating glucose metabolism in the liver, adipose tissue and muscle; ameliorating oxidative stress and inflammation to protect islet cells

(Wariyapperuma et al., 2020; Shang et al., 2021)

Flaxseed

Hydroxybenzoic acids, hydroxycinnamic acids, and lignans, gallic acid and syringic acid

Total cholesterol and non-high-density lipoprotein cholesterol

Decreased IL-6 and MDA levels, and increased TAC,Serum apolipoprotein A-1 and apolipoprotein B , Reduce plasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂)

(Tamtaji et al., 2020; Lucas et al., 2002; Khandouzi et al., 2022)

Garlic

Diallyl thiosulfonate (allicin), diallyl sulphide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), E/Z-ajoene, S-allyl-cysteine (SAC), and S-allyl-cysteine sulfoxide (alliin)

Positive impact on vascular endothelial and platelet function, lowering effect on triacylglycerols

Reduced postprandial triacylglycerols, Modulate IL-6, beneficial effect on inflammation, enhancing the phosphorylation of AMP-activated protein kinase (AMPK)

(Asgharpour et al., 2021;Wlosinska et al., 2021)

Ginger

Gingerols, shogaols, zingiberene, zingerone, paradols

Reduce fasting plasma glucose, HbA1C, insulin, HOMA, triacylglycerols, total cholesterol, CRP and PGE2

Inhibits reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), superoxide dismutase (SODs), glutathione, and heme oxygenase, increased activity of the liver enzyme CYP7A1 and decreased mRNA levels of intestinal cholesterol absorption proteins such as MTP, ACAT2, and NPC1L1

(Roudsari et al., 2021; Lei et al., 2014; Arablou et al., 2014)

Green tea

5-N-ethylglutamine, Glutamic acid, tryptophan, Glycine, serine, aspartic acid, tyrosine, valine, leucine, Threonine, arginine, and lysine

lowers LDL cholesterol and TC, Reduces triacylglycerols

Interfere with the emulsification, digestion, and micellar solubilization of lipids

(Xu et al., 2020; Zheng et al., 2011)

**Table 3.** Clinical trials on Cardiovascular Associated Disorder and Dietary Nutrients
PI	Country	Diseases	Study Design	Dietary Intake	Number of participant and (age group in years)	Sample	Dose	Follow-Up Time (YY, MM, DD)	Finding,
CVD- Cardiovascular Disease, FBS-fasting blood sugar, MetS- Metabolic Syndrome, PAD- Peripheral Arterial Disease, PI- Principal Investigator, T2D-Type 2 Diabetes.
Danyelle M Liddle & Xinjie Lin (Liddle et al., 2021a; Liddle et al., 2021b)	Canada	MetS	Randomized, crossover trial	Apples	48 (18–75)	Blood sample	3 apple/d (∼200 g/d)	06 weeks	Modulated postprandial plasma IFN-γ, reduced secreted IL-6 and TNF-α, increased IL-4, decreased GM-CSF
Jen-Fang Liu (Chen et al., 2017)	Taiwan, China	T2D	Randomized, crossover trial	Almond	40 (40–70)	Blood and urine samples	(∼60 g/d)	12 weeks	Decreased post-interventional fasting serum glucose and HbA1c, Improve glycemic status, No effects on Mean total and LDL-cholesterol concentrations
Britt Burton-Freeman (Zhang et al., 2022)	United States	MetS	Randomized, Single-center, 2-arm, controlled, 12-wk parallel trial	Avocado	124 (25–65)	Blood sample	1 Avocado/d	12 weeks	Improved glucose control and reduced biomarkers of cardiometabolic risk, C-reactive protein was significantly lower
Anoop Misra (Gupta Jain et al., 2017)	India	MetS	Double blind randomized control trial	Cinnamon	116 (25–65)	Blood sample	3 g/day	16 weeks	Decrease in fasting blood glucose (mmol/L), glycosylated haemoglobin (mmol/mol), waist circumference (cm), and body mass index (kg/m2), significantly improvement in waist-hip ratio, blood pressure, serum total cholesterol, low-density lipoprotein cholesterol, serum triacylglycerols, and high-density lipoprotein cholesterol.
Grant Pierce (Edel et al., 2015; Caligiuri et al., 2014; Caligiuri et al., 2016)	Canada	PAD	Double-blind, randomized, placebo-controlled trial	Flax Seed	58 (40–100)	Blood sample	30 g/d	1 year	Reduce total cholesterol and LDL cholesterol, decreased blood pressure
Matthew Budoff (Matsumoto et al., 2016)	United States	MetS	Double-blind, randomized, placebo-controlled trial	Garlic	55 (40–65)	Cardiac computed tomography angiography, carotid ultrasound	2,400 mg/d	1 year	Significantly reduced low-attenuation plaque,
Azita Hekmatdoost (Rahimlou et al.,2019)	Iran	MetS	Randomized controlled clinical trial	Ginger	37 (18–70)	Blood sample	2 g/day	12 weeks	Modulatory effects on TAG, FBS, and insulin resistance
Richard Bruno (Sapper et al., 2016)	United States	CVD, Hyperglycemia	Double-blind, randomized, controlled, crossover study	Green tea	15 (18−30)	Blood sample	3 cups/day	3 hour	Modulate Postprandial hyperglycemia

Table 3. Clinical trials on Cardiovascular Associated Disorder and Dietary Nutrients

Country

Diseases

Study Design

Dietary Intake

Number of participant and (age group in years)

Sample

Dose

Follow-Up Time (YY, MM, DD)

Finding,

CVD- Cardiovascular Disease, FBS-fasting blood sugar, MetS- Metabolic Syndrome, PAD- Peripheral Arterial Disease, PI- Principal Investigator, T2D-Type 2 Diabetes.

Danyelle M Liddle & Xinjie Lin (Liddle et al., 2021a; Liddle et al., 2021b)

Canada

MetS

Randomized, crossover trial

Apples

48 (18–75)

Blood sample

3 apple/d (∼200 g/d)

06 weeks

Modulated postprandial plasma IFN-γ, reduced secreted IL-6 and TNF-α, increased IL-4, decreased GM-CSF

Jen-Fang Liu (Chen et al., 2017)

Taiwan, China

T2D

Randomized, crossover trial

Almond

40 (40–70)

Blood and urine samples

(∼60 g/d)

12 weeks

Decreased post-interventional fasting serum glucose and HbA1c, Improve glycemic status, No effects on Mean total and LDL-cholesterol concentrations

Britt Burton-Freeman (Zhang et al., 2022)

United States

MetS

Randomized, Single-center, 2-arm, controlled, 12-wk parallel trial

Avocado

124 (25–65)

Blood sample

1 Avocado/d

12 weeks

Improved glucose control and reduced biomarkers of cardiometabolic risk, C-reactive protein was significantly lower

Anoop Misra (Gupta Jain et al., 2017)

India

MetS

Double blind randomized control trial

Cinnamon

116 (25–65)

Blood sample

3 g/day

16 weeks

Decrease in fasting blood glucose (mmol/L), glycosylated haemoglobin (mmol/mol), waist circumference (cm), and body mass index (kg/m2), significantly improvement in waist-hip ratio, blood pressure, serum total cholesterol, low-density lipoprotein cholesterol, serum triacylglycerols, and high-density lipoprotein cholesterol.

Grant Pierce (Edel et al., 2015; Caligiuri et al., 2014; Caligiuri et al., 2016)

Canada

PAD

Double-blind, randomized, placebo-controlled trial

Flax Seed

58 (40–100)

Blood sample

30 g/d

1 year

Reduce total cholesterol and LDL cholesterol, decreased blood pressure

Matthew Budoff (Matsumoto et al., 2016)

United States

MetS

Double-blind, randomized, placebo-controlled trial

Garlic

55 (40–65)

Cardiac computed tomography angiography, carotid ultrasound

2,400 mg/d

1 year

Significantly reduced low-attenuation plaque,

Azita Hekmatdoost (Rahimlou et al.,2019)

Iran

MetS

Randomized controlled clinical trial

Ginger

37 (18–70)

Blood sample

2 g/day

12 weeks

Modulatory effects on TAG, FBS, and insulin resistance

Richard Bruno (Sapper et al., 2016)

United States

CVD, Hyperglycemia

Double-blind, randomized, controlled, crossover study

Green tea

15 (18−30)

Blood sample

3 cups/day

3 hour

Modulate Postprandial hyperglycemia