Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of metabolic syndrome

Figures & data

Figure 1. MetS as a multifaceted disease encompassing central obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. Low antioxidant status can contribute to the development of hypertension and insulin resistance, while hypercholesterolemia, specifically high LDL-C, is a primary target for atherogenic dyslipidemia.

Table I. Summary comparison of triglyceride-lowering mechanisms of action between marine-derived omega-3 fatty acids and prescription medications.

Hypertriglyceridemia
Functional food and nutraceuticals			Prescription medication
Marine-derived omega 3 fatty acids:			Statins:
↑PPAR-α expression	}	↓ SREBP 1c	HMG-CoA reductase inhibition
↑FXR expression		↓ TG synthesis	Fibrates:
↓ LXR expression		↑ TG oxidation	↑ PPAR-α activity	}	↑ TG oxidation
↓ HNF-4α expression			↓ HNF-4α expression		↓ TG synthesis

FXR = farnesol X receptor; HMG-CoA = 3-hydroxy-3-methylgutaryl-coenzyme A; HNF = hepatocyte nuclear factor; LXR = liver X receptor; PPAR = peroxisome proliferator-activated receptor; SREBP 1c = steroid regulatory element binding protein 1c; TG = triglyceride.

Table II. Summary of studies MOM-3 as a beneficial adjunctive therapy to statin therapy when treating hypertriglyceridemia.

Reference	n	Time	Treatment	Protocol	Effect on TG levels
Davidson et al. (52)	254	8 wks	SIMV (40 mg/d)+vegetable oil	Subjects receiving SIMV≥8 wks were randomly assigned to each intervention	SIMV+placebo: −4%
	M&F		MOM-3 (4 g/d) + SIMV (40 mg/d)		SIMV+MOM-3: −28%
	HTG
Hong et al. (54)	40	2 mo	SIMV (10-20 mg/d) + MOM-3 (3 g/d)	Subjects treated with SIMV for 6–12 wks had MOM-3 added to their treatment regimen for 2 mo	SIMV+MOM-3: TG −31%
	M&F
	CHD
Maki et al. (1)	39	6 wks	SIMV (20 mg/d) + corn oil	Subjects were randomly assigned to each treatment regimen	SIMV+corn oil: −29%
	M&F		SIMV (20 mg/d) + MOM-3 (4 g/d)		SIMV+MOM-3: −44%
	DYSL
Nordoy et al. (55)	41	5 wks	SIMV (20 mg/d) + corn oil	After 5 wks of SIMV therapy, were assigned to either intervention	SIMV+corn oil: +15%
	M&F		SIMV (20 mg/d) + MOM-3 (4 g/d)		SIMV+MOM-3: −28%
	CHLA
Durrington et al. (53)	59	48 wks	SIMV 10-20 mg/d + corn oil	Subjects already receiving SIMV were assigned to either intervention	SIMV+corn oil: n/c
	M&F		SIMV+MOM-3 (4 g/d)		SIMV+MOM-3: TG −20%-30%
	CHD
	HTG
Valdivielso et al. (56)	8	8 wks	FLUV (80 mg/d)	Following a 6-wk dietary intervention, subjects were prescribed FLUV for 8 wks. After 8 wks	FLUV: −22%
	M&F		FLUV (80 mg/d) + MOM-3 (4 mg/d)	MOM-3 was combined with FLUV therapy	FLUV+MOM-3: −42%
	TIID
	DYSL
Zeman et al. (57)	24	3 mo	PRAV (20 mg/d)+FENOFIB (200 mg/d) + placebo (olive oil)	Subjects already receiving PRAV and FENOFIB were given MOM-3 therapy alongside their current treatment regimen. After 3 mo subjects were given olive oil	PRAV+FENOFIB + placebo: −13%
	M&F		PRAV+FENOFIB+MOM-3: −28%		PRAV (20 mg/d)+FENOFIB (200 mg/d) + MOM-3 (3.6 g/d)
	TIID
	DYSL
Contacos et al. (51)	32 HL	18 wks	PRAV (40 mg/d)	Subjects treated with PRAV for 6 wks had MOM-3 added to their treatment regimen for an additional 12 wks	PRAV: −13%
			PRAV (40 mg/d) + MOM-3 (4 mg/d)		PRAV+MOM-3: −42%

CHD = coronary heart disease; CHLA=combined hyperlipidemia; DYSL=dyslipidemia; FENOFIB=fenofibrate; FLUV=fluvastatin; HTG=hypertriglyceridemia; MOM-3 = marine-derived omega-3 fatty acids; n/c = no change; PRAV=pravastatin; SIMV=simvastatin; TG=triglycerides; TIID = type II diabetes.

Table III. Summary comparison of LDL-lowering mechanisms of action between plant sterols and stanols and prescription medications.

Hypercholesterolemia
Functional food and nutraceu ticals			Prescription medication
Plant sterols and stanols:			Statins:
↑ Displacement of dietary cholesterd	}	↓ Cholesterol absorption	↓ HMG-CoA reductase activity
			Niacin:
			↓ Hepatic cholesterol synthesis
			↓ Adipose tissue lipolysis
↑ LXR	}	↑ ABCG transporters	Cholesterol absorption inhibitors (ezetimibe):
			↓ Cholesterol absorption via Niemann-Pick C1-like protein 1 transporters	}	↑ Hepatic LDL uptake
			Bile acid resins:
			Bind negatively charged bile acid in the gastrointestinal tract

ABCG=ATP-binding cassette G transporter; HMG-CoA = 3-hydroxy-3-methylgutaryl-coenzyme A; LDL=low-density lipoprotein; LXR=liver X receptor.

Table IV. Summary of studies showing plant sterols and stanols as a beneficial adjunctive therapy to statin therapy for the treatment of hypercholesterolemia.

Reference	n	Time	Treatments	Protocol	Effect on LDL- C levels
Simons et al. (81)	152	4 wks	Placebo + control margarine	Subjects were randomly assigned to one intervention.	Placebo + control: +2%
	HCH		Placebo + PS (sterol)	The test statin was CERIV	Placebo + PS: −8%
			Statin + control margarine		Statin + control: −32%
			Statin + PS (sterol) margarine		Statin + PS: −39%
Goldberg et al. (65)	26	9 wks	Statin + placebo	Subjects on stable statin treatment for≥90 d.	Statin + placebo: +3%
	HL		Statin + PS tablet (stanol) (1.8 g/d)	Subjects were randomly assigned to one intervention	Statin + PS: −6%
Blair et al. (3)	146	8 wks	Statin + control margarine	Subjects on stable statin treatment for≥90 d (SIMV, PRAV, ATORV, LOV) were randomly assigned to one intervention	Statin + control: −7%
	HL		Statin + PS (stanol) margarine (5.1 g/d)		Statin + PS: −17%
Castro Cabezas et al. (78)	20	6 wks	Statin (80 mg/d) +control margarine	Subjects receiving maximal dose of ATORV or SIMV therapy (80 mg/d) for≥6 mo were randomly assigned to one intervention	Statin + control: −8%
	HL		Statin (80 mg/d) + PS (stanol) margarine (3 g/d)		Statin + PS: −16%
de Jong et al. (79)	54	85 wks	Statin + control margarine	Subjects on statin therapy (PRAV, SIMV, ATORV, ROSUV, FLUV)≥85 wks were randomly assigned one intervention	Control: n/c
	HCH		Statin + PS (sterol) margarine (2.5 g/d)		PS (sterol): −9%
			Statin + PS (stanol) margarine (2.5 g/d)		PS (stanol): −13%
Ketomaki et al. (80)	18	4 wks	Statin + PS (stanol) margarine (2 g/d)	Subjects receiving statin treatment (SIMV, PRAV, ATORV, LOV) for several years received both interventions	Statin+PS (stanol): −15%
	FH		Statin + PS (sterol) margarine (2 g/d)		Statin+PS (sterol): −14%
Takeshita et al. (82)	61	12 wks	TG oil	Subjects receiving PRAV (10 mg/d) ≥ 4 wks were randomly assigned to one intervention. Subjects replaced their regular cooking oil with a treatment oil	TG: n/c
	HCH		DAG oil		DAG: n/c
			DAG oil + PS (4%)		DAG + PS: −5%

ATORV=atorvastatin; CERIV=cerivastatin; DAG=diacylglycerol; HCH = hypercholesterolemia; HL=hyperlipidemia; FH=familial hypercholesterolemia; FLUV=fluvastatin; LDL-C = low-density lipoprotein cholesterol; LOV=lovastatin; n/c = no change; PRAV=pravastatin; PS = plant sterol/stanol; ROSUV=rosuvastatin; SIMV=simvastatin; TG = triglycerides.

Table V. Summary comparison of insulin resistance-lowering mechanisms of action between fiber and prescription medications.

Insulin resistance
Functional food and nutraceuticals			Prescription medication
Fiber:			Metformin:
↑ SCFA production	}	↓ NEFA	AMPK activation
		↑ Skeletal muscle glucose uptake	Muscle atypical protein kinase C activation
		↑ Adipose glucose uptake	Phosphorylation of tyrosine kinase at the β-subunit on the insulin receptor
		↑ Mitochondrial biogenesis
		↑ Adaptive thermogenesis
		↑ Fat oxidation?	Thiazolidinediones:
		↓ Adiposity?	AMPK activation
		↑ Adipocyte differentiation	↓ Inhibitory insulin receptor substrat phosphorylatione protein 1 serine
			↑ GLUT-1 in muscle and adipose tissue
↑ Ghrelin	}	↑ PPAR-γ	PPAR-γ ligand	}	↓ NEFA
		↑Lipogenesis			↓ Leptin
					↓ TNF-α
					↓ Resistin
↓ Hepatic glucose utputo

AMPK = AMP-activated protein kinase; NEFA = non-esterified fatty acids; PPAR-γ = peroxisome proliferator receptor gamma; SCFA = short-chain fatty acids; TNF-α = tumor necrosis factor alpha.

Table VI. Summary comparison of blood pressure-lowering mechanisms between lycopene and tomato extracts and prescription medications.

Hypertension
Functional food and nutraceuticals			Prescription medication
Tomato extract and lycopene:			ACE inhibitor:
↑ Antioxidant defenses	}		↓ Angiotensin II production
↑ Nitric oxide levels?		↓ Vasoconstriction	Angiotensin II receptor antagonist
↓ Peroxynitrate formation			Inhibits angiotensin II from binding to its receptor in vascular smooth muscle
			Calcium blockers:
			↓ Cardiac and arteriole muscle contraction
			β-Blockers:
			↑ Cardiac output
			↑ Renin release
			Thiazides:
			Diuretics
			↑ Sodium reabsorption

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