Abstract
Resveratrol, a natural polyphenol, has gained attention in recent years because of its connection with the health benefits of red wine and its anticancer activity in vitro. Studies in animal models have demonstrated beneficial effects on glucose metabolism, vascular function and anti-inflammatory and antioxidant properties. Human studies designed to understand the role of resveratrol in the prevention and treatment of age-related conditions such as diabetes, heart disease, and cancer have recently been undertaken.
We searched PubMed for original articles that reported studies of resveratrol in humans, using search terms, including resveratrol, human studies, glucose metabolism, vascular function, and inflammation. We also searched the reference lists of identified articles for additional papers and sought expert opinion on relevant studies.
Resveratrol treatment has shown beneficial effects on glucose and lipid metabolism in some, but not all studies. Study population, resveratrol source, and dose have varied widely, potentially explaining inconsistent findings. Improvements were noted in endothelial function, systolic blood pressure, and markers of oxidative stress and inflammation in several studies.
Despite the strong preclinical evidence of positive cardiometabolic effects, studies to date have not confirmed resveratrol’s benefit in humans. Study variability and methodological issues limit interpretation of available results. Additional research, focusing on subjects with defined metabolic defects and using a range of doses, is needed to advance the field.
Resveratrol (trans-3, 5, 4′-trihydroxystilbene) is a natural polyphenol found in grape skin, red wine, berries, peanuts, and medicinal plants, such as Japanese knotweed (Polygonum cuspidatum). Interest in this compound has increased in recent years in light of its association with the health benefits of red wine1,2 and its identification as a chemopreventive agent for cancer.3 Subsequent reports have demonstrated resveratrol to be an activator of sirtuins, a family of NAD(+)–dependent deacetylase enzymes thought to mediate the beneficial effects of caloric restriction.4,5 In yeast, worms, and flies, resveratrol has been associated with sirtuin-dependent increase in lifespan.6 Further study in vitro and in animal models has shown resveratrol to have beneficial effects on glucose metabolism and vascular function, as well as anti-inflammatory and antioxidant properties.4 These potential benefits have led to initiation of human studies to test resveratrol’s role in the prevention and treatment of chronic diseases such as obesity, diabetes, and cardiovascular disease.
In this review, we will summarize the evidence related to resveratrol’s effect on metabolism, cardiovascular function, and oxidative and inflammatory stress, with a focus on the published human studies. Finally, we will discuss the limitations of the available clinical data and provide suggestions for future research studies.
GLUCOSE METABOLISM
Preclinical studies
In vitro studies of resveratrol have shown favorable effects on several aspects of glucose metabolism. Resveratrol enhances insulin-stimulated glucose uptake in skeletal muscle, hepatocytes, and adipocytes by activation of the sirtuin SIRT-1.7,8 Resveratrol also augments insulin secretion by inhibiting the KATP channels in pancreatic β-cells.9In vivo, resveratrol prevented the negative metabolic effects in mice fed a high-fat diet, improving glucose tolerance and insulin sensitivity and increasing survival.10 High-dose (400mg/kg/day) resveratrol has also been shown to induce weight loss and enhance physical performance and energy expenditure in rodents.11 Low-dose (approximately 5mg/kg/day) resveratrol fed to aging mice mimicked the effects of caloric restriction on insulin-stimulated glucose uptake and inhibited the aging-associated gene expression profile in the heart and skeletal muscle.12 Increased mitochondrial biogenesis and oxidative phosphorylation has been observed in skeletal muscle, brown fat, and the liver of resveratrol-treated mice, potentially mediated by activation of SIRT1 and its downstream targets, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and AMP-activated protein kinase (AMPK).6,7,11,13,14 There is also evidence to suggest resveratrol’s effects are mediated by inhibition of cAMP-degrading phosphodiesterases, leading to increased cAMP levels and AMPK activation.15 In fact, AMPK activation appears to be required for resveratrol’s effect on insulin action.14 It has also been reported that resveratrol may exert its glucose-lowering effect by modulation of the activity of the incretin hormone glucagon-like peptide-1 (GLP-1).16 The proposed mechanisms of resveratrol action are summarized in Figure 1.
Proposed mechanisms of action of resveratrol. Abbreviations: cAMP, cyclic AMP; COX-1, cyclooxygenase 1; eNOS, endothelial nitric oxide synthase; FOXO, forkhead box protein; GLP-1, glucagon like peptide 1; GLUT4, glucose transporter type 4; LKB1, liver kinase B1; NAD(+), nicotinamide adenine dinucleotide; NO, nitric oxide; NRF, nuclear respiratory factor; p53, protein 53; PDE, phosphodiesterase; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SIRT1, sirtuin 1; TFAM, mitochondrial transcription factor A; TxA2, thromboxane A2.
Clinical studies
Despite the convincing preclinical evidence suggesting resveratrol’s potential as a therapeutic agent in metabolic disease and its aggressive promotion as a nutritional supplement, human resveratrol studies are still limited. However, recently some studies exploring the effects of resveratrol on nutrient metabolism have been published (Table 1).
Summary of peer-reviewed clinical trials: effects of resveratrol on glucose metabolism
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetic patients on oral hypoglycemic treatment (n = 62) | 250mg daily × 3 months | Improved HbA1c and total cholesterol from baseline. No change noted in BMI, HDL, or serum creatinine. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Improved insulin sensitivity by HOMA-IR from baseline. Changes in fasting glucose or HbA1c not reported. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g daily × 4 weeks | Improved peak postmeal and 3-hour glucose AUC. Improved insulin sensitivity (Matsuda index). Weight, blood pressure, and lipids were unchanged. |
| Elliott et al.,17 | Randomized, placebo-controlled trial | Drug-naive type 2 diabetic men (n = 214) | 2.5g daily or 5g daily × 4 weeks | At 5g per day, fasting and postprandial glucose decreased. Trend toward significance in postprandial insulin. No change in HbA1c or fasting insulin. |
| Ghanim et al.,26 | Randomized, placebo-controlled parallel design | Normal weight, healthy subjects (n = 10) | 40mg from PCE daily × 6 weeks | No change observed in plasma glucose, insulin, HOMA-IR, lipid levels, or leptin. |
| Knop et al.,23 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | No effect on fasting or postprandial incretin hormones (GLP-1 and GIP). Suppressed postprandial glucagon. |
| Poulsen et al.,24 | Randomized, double-blind, placebo-controlled parallel design | Healthy, obese men (n = 24) | 1,500mg daily × 4 weeks | No difference in body composition, resting energy expenditure, insulin sensitivity, or endogenous glucose production measured by hyperinsulinemic euglycemic clamp. No change in HbA1c, lipids, leptin, adiponectin, or free fatty acids. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | Improved metabolic profile, decreased metabolic sleeping and resting rate. Decreased HOMA-IR, triglycerides, and leptin levels. Decreased intrahepatic lipid content and improved mitochondrial function in muscle. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo- controlled trial | Male, type 2 diabetics, with hypertension and stable-CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in body weight, blood pressure, fasting glucose, HbA1c, or lipids. |
| Yoshino et al.,25 | Randomized, double-blind, placebo- controlled parallel design | Non obese, post- menopausal women with normal glucose tolerance (n = 29) | 75mg daily × 12 weeks | No change in liver, skeletal muscle, or adipose tissue insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp. No change in body composition, lipids, leptin, adiponectin, or resting energy expenditure. |
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetic patients on oral hypoglycemic treatment (n = 62) | 250mg daily × 3 months | Improved HbA1c and total cholesterol from baseline. No change noted in BMI, HDL, or serum creatinine. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Improved insulin sensitivity by HOMA-IR from baseline. Changes in fasting glucose or HbA1c not reported. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g daily × 4 weeks | Improved peak postmeal and 3-hour glucose AUC. Improved insulin sensitivity (Matsuda index). Weight, blood pressure, and lipids were unchanged. |
| Elliott et al.,17 | Randomized, placebo-controlled trial | Drug-naive type 2 diabetic men (n = 214) | 2.5g daily or 5g daily × 4 weeks | At 5g per day, fasting and postprandial glucose decreased. Trend toward significance in postprandial insulin. No change in HbA1c or fasting insulin. |
| Ghanim et al.,26 | Randomized, placebo-controlled parallel design | Normal weight, healthy subjects (n = 10) | 40mg from PCE daily × 6 weeks | No change observed in plasma glucose, insulin, HOMA-IR, lipid levels, or leptin. |
| Knop et al.,23 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | No effect on fasting or postprandial incretin hormones (GLP-1 and GIP). Suppressed postprandial glucagon. |
| Poulsen et al.,24 | Randomized, double-blind, placebo-controlled parallel design | Healthy, obese men (n = 24) | 1,500mg daily × 4 weeks | No difference in body composition, resting energy expenditure, insulin sensitivity, or endogenous glucose production measured by hyperinsulinemic euglycemic clamp. No change in HbA1c, lipids, leptin, adiponectin, or free fatty acids. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | Improved metabolic profile, decreased metabolic sleeping and resting rate. Decreased HOMA-IR, triglycerides, and leptin levels. Decreased intrahepatic lipid content and improved mitochondrial function in muscle. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo- controlled trial | Male, type 2 diabetics, with hypertension and stable-CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in body weight, blood pressure, fasting glucose, HbA1c, or lipids. |
| Yoshino et al.,25 | Randomized, double-blind, placebo- controlled parallel design | Non obese, post- menopausal women with normal glucose tolerance (n = 29) | 75mg daily × 12 weeks | No change in liver, skeletal muscle, or adipose tissue insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp. No change in body composition, lipids, leptin, adiponectin, or resting energy expenditure. |
Abbreviations: AUC, area under the curve; BMI, body mass index; GE-RES, resveratrol-enriched grape extract; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL, high density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; PCE, Polygonum cuspidatum extract.
Summary of peer-reviewed clinical trials: effects of resveratrol on glucose metabolism
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetic patients on oral hypoglycemic treatment (n = 62) | 250mg daily × 3 months | Improved HbA1c and total cholesterol from baseline. No change noted in BMI, HDL, or serum creatinine. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Improved insulin sensitivity by HOMA-IR from baseline. Changes in fasting glucose or HbA1c not reported. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g daily × 4 weeks | Improved peak postmeal and 3-hour glucose AUC. Improved insulin sensitivity (Matsuda index). Weight, blood pressure, and lipids were unchanged. |
| Elliott et al.,17 | Randomized, placebo-controlled trial | Drug-naive type 2 diabetic men (n = 214) | 2.5g daily or 5g daily × 4 weeks | At 5g per day, fasting and postprandial glucose decreased. Trend toward significance in postprandial insulin. No change in HbA1c or fasting insulin. |
| Ghanim et al.,26 | Randomized, placebo-controlled parallel design | Normal weight, healthy subjects (n = 10) | 40mg from PCE daily × 6 weeks | No change observed in plasma glucose, insulin, HOMA-IR, lipid levels, or leptin. |
| Knop et al.,23 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | No effect on fasting or postprandial incretin hormones (GLP-1 and GIP). Suppressed postprandial glucagon. |
| Poulsen et al.,24 | Randomized, double-blind, placebo-controlled parallel design | Healthy, obese men (n = 24) | 1,500mg daily × 4 weeks | No difference in body composition, resting energy expenditure, insulin sensitivity, or endogenous glucose production measured by hyperinsulinemic euglycemic clamp. No change in HbA1c, lipids, leptin, adiponectin, or free fatty acids. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | Improved metabolic profile, decreased metabolic sleeping and resting rate. Decreased HOMA-IR, triglycerides, and leptin levels. Decreased intrahepatic lipid content and improved mitochondrial function in muscle. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo- controlled trial | Male, type 2 diabetics, with hypertension and stable-CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in body weight, blood pressure, fasting glucose, HbA1c, or lipids. |
| Yoshino et al.,25 | Randomized, double-blind, placebo- controlled parallel design | Non obese, post- menopausal women with normal glucose tolerance (n = 29) | 75mg daily × 12 weeks | No change in liver, skeletal muscle, or adipose tissue insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp. No change in body composition, lipids, leptin, adiponectin, or resting energy expenditure. |
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetic patients on oral hypoglycemic treatment (n = 62) | 250mg daily × 3 months | Improved HbA1c and total cholesterol from baseline. No change noted in BMI, HDL, or serum creatinine. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Improved insulin sensitivity by HOMA-IR from baseline. Changes in fasting glucose or HbA1c not reported. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g daily × 4 weeks | Improved peak postmeal and 3-hour glucose AUC. Improved insulin sensitivity (Matsuda index). Weight, blood pressure, and lipids were unchanged. |
| Elliott et al.,17 | Randomized, placebo-controlled trial | Drug-naive type 2 diabetic men (n = 214) | 2.5g daily or 5g daily × 4 weeks | At 5g per day, fasting and postprandial glucose decreased. Trend toward significance in postprandial insulin. No change in HbA1c or fasting insulin. |
| Ghanim et al.,26 | Randomized, placebo-controlled parallel design | Normal weight, healthy subjects (n = 10) | 40mg from PCE daily × 6 weeks | No change observed in plasma glucose, insulin, HOMA-IR, lipid levels, or leptin. |
| Knop et al.,23 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | No effect on fasting or postprandial incretin hormones (GLP-1 and GIP). Suppressed postprandial glucagon. |
| Poulsen et al.,24 | Randomized, double-blind, placebo-controlled parallel design | Healthy, obese men (n = 24) | 1,500mg daily × 4 weeks | No difference in body composition, resting energy expenditure, insulin sensitivity, or endogenous glucose production measured by hyperinsulinemic euglycemic clamp. No change in HbA1c, lipids, leptin, adiponectin, or free fatty acids. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg daily × 30 days | Improved metabolic profile, decreased metabolic sleeping and resting rate. Decreased HOMA-IR, triglycerides, and leptin levels. Decreased intrahepatic lipid content and improved mitochondrial function in muscle. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo- controlled trial | Male, type 2 diabetics, with hypertension and stable-CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in body weight, blood pressure, fasting glucose, HbA1c, or lipids. |
| Yoshino et al.,25 | Randomized, double-blind, placebo- controlled parallel design | Non obese, post- menopausal women with normal glucose tolerance (n = 29) | 75mg daily × 12 weeks | No change in liver, skeletal muscle, or adipose tissue insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp. No change in body composition, lipids, leptin, adiponectin, or resting energy expenditure. |
Abbreviations: AUC, area under the curve; BMI, body mass index; GE-RES, resveratrol-enriched grape extract; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL, high density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; PCE, Polygonum cuspidatum extract.
Resveratrol studies in subjects with impaired glucose regulation have shown fairly consistent, albeit modest, benefit. In one of the largest studies to date (n = 214), drug-naive type 2 diabetic males were treated with either 2.5g or 5g per day of SRT501, a novel resveratrol preparation with enhanced bioavailability, for 4 weeks.17 Fasting and postprandial glucose levels were significantly reduced with the 5-g dose compared with placebo, and there was a trend toward a decrease in postprandial insulin levels. However, only limited data from this study were published, and in 2010, further development of SRT501 was halted. Improvements in insulin sensitivity and postmeal plasma glucose were reported in an open label pilot study of older adults with impaired glucose tolerance (mean age = 72±3 years; mean BMI = 29±5kg/m2) treated with resveratrol doses of 1–2g per day for 4 weeks.18 Other studies in patients with established type 2 diabetes have shown modest lowering of HbA1c (baseline 9.99% ± 1.5 vs. 9.65% ± 1.5 posttreatment)19 and improvement in insulin sensitivity (by homeostatic model assessment of insulin resistance)20 at doses of 10–250mg/day. However, no clinically significant changes in plasma glucose levels were observed in these small studies and in another one conducted using a grape extract with 8mg of resveratrol.21
Studies involving subjects with less severe metabolic disturbance (e.g., obesity, insulin resistance) have yielded variable results. Timmers et al., reported improvement in a number of metabolic parameters in a randomized, double-blind crossover study of obese, middle-aged males (mean age = 52.5±2.1 years; mean BMI = 31±0.82) treated with 150mg/day of resveratrol for 4 weeks.22 These included improved insulin sensitivity and metabolic flexibility, as well as decreased intrahepatic lipid content and levels of inflammatory markers. Increases in mitochondrial function, AMPK phosphorylation, and SIRT1 and PCG1α activity in skeletal muscle were reported.22 Fasting and postprandial concentrations of incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide were unchanged in these subjects; however, postprandial glucagon levels were suppressed.23 In contrast, a study in obese but otherwise healthy younger males (mean age = 44.7±3.5 years; mean BMI = 33±0.6 m/kg2) treated with 500mg of resveratrol thrice daily for 4 weeks failed to demonstrate any detectable changes in insulin sensitivity, endogenous glucose production, energy expenditure, or body composition.24 Furthermore, in vitro analyses of muscle and adipose tissue showed no change in gene expression, AMPK phosphorylation, or markers of inflammation and oxidative stress.24 Studies in healthy, nonobese subjects have also been largely negative, notably one in postmenopausal women (mean age = 52.2±4 years; mean BMI = 24.2±2.8kg/m2) with normal glucose tolerance, treated with 75mg/day of resveratrol daily for 12 weeks.25 Despite extensive investigation, no significant changes were noted in body composition, resting metabolic rate, insulin sensitivity, or recognized molecular targets, including AMPK, SIRT1, or PGC1α in either skeletal muscle or adipose tissue.25 A study using a polyphenol extract containing 40mg of resveratrol daily for 6 weeks in normal-weight, healthy subjects (mean age = 36±5 years; mean BMI 21.8±0.5kg/m2) also reported no changes in plasma insulin or glucose concentrations, insulin sensitivity, or lipid levels.26
The relatively small size and heterogeneity of these clinical studies preclude definitive conclusions about resveratrol’s metabolic effects. Study designs are also variable, and some provide incomplete data on subjects’ clinical characteristics. Substantial differences in resveratrol dose (up to 500-fold difference), dosing regimen, source (including presence of other polyphenols), and achieved plasma concentrations further confound interpretation of these study results.27 However, a reasonable conclusion may be that resveratrol’s effects are best observed under conditions of metabolic stress, such as insulin resistance or impaired glucose regulation.28 This would be consistent with observations from rodent models, in which lean animals did not show demonstrable benefit from resveratrol.29,30
CARDIOVASCULAR, OXIDATIVE STRESS, AND INFLAMMATION
Resveratrol has been proposed to have important cardioprotective effects. In fact, its presence in significant quantities in red wine has led some to suggest resveratrol is responsible for the “French Paradox,” a lower incidence of cardiovascular disease in the French despite a high-fat diet.2
Preclinical studies
In animal models, resveratrol has demonstrated antiatherogenic properties, including suppression of plaque formation and platelet aggregation.31–33 The platelet effect is mediated by the selective inhibition of cyclooxygenase 1 (COX-1), thereby blocking the synthesis of thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation (Figure 1).3,34 Resveratrol has also been shown to decrease neointimal growth in a rat model of vascular injury.35
Studies in hypertensive rat models have demonstrated improvements in cardiac structure and function, including attenuation of small artery remodeling and protection against the development of concentric hypertrophy and contractile dysfunction, with variable effects on mean arterial pressure.36–38 These benefits appear to be related to enhanced endothelium-dependent vasodilation by increased activity of endothelial nitric oxide synthase and inhibition of the vasoconstrictor endothelin.38,39In vivo antioxidant and anti-inflammatory properties have been demonstrated in animal models, effects that appear to be independent of the AMPK/SIRT1 pathway.38,40,41
Clinical studies
Clinical studies have largely been limited to assessment of short-term effects of resveratrol on biomarkers and measures of vascular function (Table 2).
Summary of peer-reviewed clinical trials: effects of resveratrol on vascular function, inflammation, and oxidative stress
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Agarwal et al.,59 | Randomized, double-blind, placebo-controlled trial | Healthy adults (n = 41) | 400mg daily of trans-resveratrol + grapeskin extract + quercetin × 30 days | Decreased mRNA expression of the cytokines VCAM, ICAM, and IL-8 in human coronary artery endothelial cells exposed to postresveratrol-treated plasma. Decreased plasma IFN-γ. No change in IL-1β, IL-6, or TNF-α. |
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetics on oral hypoglycemic agents (n = 62) | 250mg daily × 3 months | Improved systolic but not diastolic blood pressure from baseline. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Decreased urinary ortho-tyrosine. Increased pAKT:AKT ratio in platelets. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g per day × 4 weeks | Improvement in postmeal endothelial function (RHI), measured by RH-PAT. No change in hs-CRP or adiponectin. |
| De Groote et al.,56 | Blinded, sequential design, randomized, placebo-controlled trial | Healthy, obese adults (n = 32) | 150mg daily of resveratrol, 300mg of resveratrol triphosphate or catechin-rich grape seed extract × 1 month | Resveratrol triphosphate and catechin-rich grape seed extract reduced markers of oxidative stress and modulated expression of genes involved in oxidation and inflammation compared to resveratrol. |
| Ghanim et al.,52 | Randomized, placebo-controlled parallel design | Normal-weight, healthy adults (n = 20) | 40mg from PCE daily × 6 weeks | Reduction in reactive oxygen species and proinflammatory mediators. Suppressed cytokines CRP, TNF-α, and IL-6. |
| Ghanim et al.,26 | Randomized, placebo-controlled crossover study | Normal-weight, healthy adults (n = 10) | Single dose of 100mg of resveratrol + grapeskin polyphenols | Acute, protective antioxidative, and anti-inflammatory effect in response to a HFHC meal, decreased endotoxin release, inflammatory markers, and indices of oxidative stress. |
| Kennedy et al.,46 | Randomized, double-blind, placebo-controlled, crossover trial | Young, healthy adults (n = 24) | Single dose of 250mg and 500mg separated by a week | Dose-dependent increase in cerebral blood flow with enhanced oxygen extraction, assessed by functional NIRS brain imaging. No change in cognitive function. |
| Magyar et al.,44 | Randomized, double-blind, placebo-controlled trial | Post myocardial infarction subjects with coronary artery disease on angiogram (n = 40) | 10mg per day × 3 months | Improved endothelial function (FMD). Improved LV diastolic function. No change in ejection fraction. Decreased LDL. Prevented unfavorable changes in RBC deformability and platelet aggregation. |
| Militaru et al.,60 | Randomized, double-blind, active-controlled, paralleled trial | Overweight adults with angina pectoris on stable treatment | 20mg per day (10mg trans-resveratrol) +/- calcium fructoborate × 60 days | Decreased hs-CRP and NT-proBNP. Improved lipid parameters and angina symptoms in all groups from baseline. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg per day × 30 days | Decreased systolic BP and MAP. Decreased leukocyte count and plasma inflammatory markers, including IL-6 and TNF-α. |
| Tome-Carneiro et al.,51,57 | Randomized, triple-blind, placebo-controlled trial | Statin treated adults with diabetes or hyperlipidemia + another cardiovascular risk factor (n = 75) | 8mg of reveratrol in GE-RES daily × 6 months followed by 16mg × 6 months | Decrease in LDL cholesterol, apolipoprotein B, and oxidized LDL levels after 6 months. Decrease in inflammatory markers, including hs-CRP, TNF-α, PAI-1, and IL-6/IL-10 ratio at 1 year. |
| Tome-Carneiro et al.,58 | Randomized, triple-blind, placebo-controlled trial | Stable CAD subjects on medical therapy (n = 75) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in hs-CRP. Increased adiponectin, decreased PAI-1. Inhibited atherothrombotic, inflammation-related transcription factors in PBMCs. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo-controlled trial | Male, type 2 diabetics, with hypertension and stable CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in inflammatory markers, aside from a reduction in IL-6 in the GE-RES group. Downregulated the expression of proinflammatory cytokines and modulated inflammatory-related microRNAs in PBMCs. |
| Wong et al.,42 | Randomized, double-blind, placebo-controlled, crossover trial | Overweight, obese men and postmenopausal women with untreated borderline hypertension (n = 19) | Single dose of 30, 90, and 270mg separated by a 1 week interval | Acute, dose-dependent increase in endothelial function measured by FMD of the brachial artery. |
| Wong et al.,43 | Randomized, double-blind, placebo-controlled, crossover trial | Obese, healthy men, and postmenopausal women (n = 28) | 75mg daily × 6 weeks | Chronic supplementation resulted in an increase in endothelial function measured by FMD of the brachial artery; a single dose of resveratrol following chronic supplementation further increased FMD. |
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Agarwal et al.,59 | Randomized, double-blind, placebo-controlled trial | Healthy adults (n = 41) | 400mg daily of trans-resveratrol + grapeskin extract + quercetin × 30 days | Decreased mRNA expression of the cytokines VCAM, ICAM, and IL-8 in human coronary artery endothelial cells exposed to postresveratrol-treated plasma. Decreased plasma IFN-γ. No change in IL-1β, IL-6, or TNF-α. |
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetics on oral hypoglycemic agents (n = 62) | 250mg daily × 3 months | Improved systolic but not diastolic blood pressure from baseline. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Decreased urinary ortho-tyrosine. Increased pAKT:AKT ratio in platelets. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g per day × 4 weeks | Improvement in postmeal endothelial function (RHI), measured by RH-PAT. No change in hs-CRP or adiponectin. |
| De Groote et al.,56 | Blinded, sequential design, randomized, placebo-controlled trial | Healthy, obese adults (n = 32) | 150mg daily of resveratrol, 300mg of resveratrol triphosphate or catechin-rich grape seed extract × 1 month | Resveratrol triphosphate and catechin-rich grape seed extract reduced markers of oxidative stress and modulated expression of genes involved in oxidation and inflammation compared to resveratrol. |
| Ghanim et al.,52 | Randomized, placebo-controlled parallel design | Normal-weight, healthy adults (n = 20) | 40mg from PCE daily × 6 weeks | Reduction in reactive oxygen species and proinflammatory mediators. Suppressed cytokines CRP, TNF-α, and IL-6. |
| Ghanim et al.,26 | Randomized, placebo-controlled crossover study | Normal-weight, healthy adults (n = 10) | Single dose of 100mg of resveratrol + grapeskin polyphenols | Acute, protective antioxidative, and anti-inflammatory effect in response to a HFHC meal, decreased endotoxin release, inflammatory markers, and indices of oxidative stress. |
| Kennedy et al.,46 | Randomized, double-blind, placebo-controlled, crossover trial | Young, healthy adults (n = 24) | Single dose of 250mg and 500mg separated by a week | Dose-dependent increase in cerebral blood flow with enhanced oxygen extraction, assessed by functional NIRS brain imaging. No change in cognitive function. |
| Magyar et al.,44 | Randomized, double-blind, placebo-controlled trial | Post myocardial infarction subjects with coronary artery disease on angiogram (n = 40) | 10mg per day × 3 months | Improved endothelial function (FMD). Improved LV diastolic function. No change in ejection fraction. Decreased LDL. Prevented unfavorable changes in RBC deformability and platelet aggregation. |
| Militaru et al.,60 | Randomized, double-blind, active-controlled, paralleled trial | Overweight adults with angina pectoris on stable treatment | 20mg per day (10mg trans-resveratrol) +/- calcium fructoborate × 60 days | Decreased hs-CRP and NT-proBNP. Improved lipid parameters and angina symptoms in all groups from baseline. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg per day × 30 days | Decreased systolic BP and MAP. Decreased leukocyte count and plasma inflammatory markers, including IL-6 and TNF-α. |
| Tome-Carneiro et al.,51,57 | Randomized, triple-blind, placebo-controlled trial | Statin treated adults with diabetes or hyperlipidemia + another cardiovascular risk factor (n = 75) | 8mg of reveratrol in GE-RES daily × 6 months followed by 16mg × 6 months | Decrease in LDL cholesterol, apolipoprotein B, and oxidized LDL levels after 6 months. Decrease in inflammatory markers, including hs-CRP, TNF-α, PAI-1, and IL-6/IL-10 ratio at 1 year. |
| Tome-Carneiro et al.,58 | Randomized, triple-blind, placebo-controlled trial | Stable CAD subjects on medical therapy (n = 75) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in hs-CRP. Increased adiponectin, decreased PAI-1. Inhibited atherothrombotic, inflammation-related transcription factors in PBMCs. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo-controlled trial | Male, type 2 diabetics, with hypertension and stable CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in inflammatory markers, aside from a reduction in IL-6 in the GE-RES group. Downregulated the expression of proinflammatory cytokines and modulated inflammatory-related microRNAs in PBMCs. |
| Wong et al.,42 | Randomized, double-blind, placebo-controlled, crossover trial | Overweight, obese men and postmenopausal women with untreated borderline hypertension (n = 19) | Single dose of 30, 90, and 270mg separated by a 1 week interval | Acute, dose-dependent increase in endothelial function measured by FMD of the brachial artery. |
| Wong et al.,43 | Randomized, double-blind, placebo-controlled, crossover trial | Obese, healthy men, and postmenopausal women (n = 28) | 75mg daily × 6 weeks | Chronic supplementation resulted in an increase in endothelial function measured by FMD of the brachial artery; a single dose of resveratrol following chronic supplementation further increased FMD. |
Abbreviations: AKT, protein kinase B; BP, blood pressure; CAD, coronary heart disease; FMD, flow-mediated dilation; GE-RES, resveratrol-enriched grape extract; HFHC , high fat high carbohydrate; hs-CRP, high sensitivity C-reactive protein; ICAM, intracellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; MAP, mean arterial pressure; NIRS, near infrared spectroscopy; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAI-1, plasminogen activator inhibitor-1; pAKT, phosphorylated protein kinase B; PBMC, peripheral blood mononuclear cell; PCE, Polygonum cuspidatum extract; RBC, red blood cell; RHI, reactive hyperemia index; RH-PAT, reactive hyperemia peripheral arterial tonometry; TNF-α, tumor necrosis factor alpha; VCAM, vascular cell adhesion protein.
Summary of peer-reviewed clinical trials: effects of resveratrol on vascular function, inflammation, and oxidative stress
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Agarwal et al.,59 | Randomized, double-blind, placebo-controlled trial | Healthy adults (n = 41) | 400mg daily of trans-resveratrol + grapeskin extract + quercetin × 30 days | Decreased mRNA expression of the cytokines VCAM, ICAM, and IL-8 in human coronary artery endothelial cells exposed to postresveratrol-treated plasma. Decreased plasma IFN-γ. No change in IL-1β, IL-6, or TNF-α. |
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetics on oral hypoglycemic agents (n = 62) | 250mg daily × 3 months | Improved systolic but not diastolic blood pressure from baseline. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Decreased urinary ortho-tyrosine. Increased pAKT:AKT ratio in platelets. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g per day × 4 weeks | Improvement in postmeal endothelial function (RHI), measured by RH-PAT. No change in hs-CRP or adiponectin. |
| De Groote et al.,56 | Blinded, sequential design, randomized, placebo-controlled trial | Healthy, obese adults (n = 32) | 150mg daily of resveratrol, 300mg of resveratrol triphosphate or catechin-rich grape seed extract × 1 month | Resveratrol triphosphate and catechin-rich grape seed extract reduced markers of oxidative stress and modulated expression of genes involved in oxidation and inflammation compared to resveratrol. |
| Ghanim et al.,52 | Randomized, placebo-controlled parallel design | Normal-weight, healthy adults (n = 20) | 40mg from PCE daily × 6 weeks | Reduction in reactive oxygen species and proinflammatory mediators. Suppressed cytokines CRP, TNF-α, and IL-6. |
| Ghanim et al.,26 | Randomized, placebo-controlled crossover study | Normal-weight, healthy adults (n = 10) | Single dose of 100mg of resveratrol + grapeskin polyphenols | Acute, protective antioxidative, and anti-inflammatory effect in response to a HFHC meal, decreased endotoxin release, inflammatory markers, and indices of oxidative stress. |
| Kennedy et al.,46 | Randomized, double-blind, placebo-controlled, crossover trial | Young, healthy adults (n = 24) | Single dose of 250mg and 500mg separated by a week | Dose-dependent increase in cerebral blood flow with enhanced oxygen extraction, assessed by functional NIRS brain imaging. No change in cognitive function. |
| Magyar et al.,44 | Randomized, double-blind, placebo-controlled trial | Post myocardial infarction subjects with coronary artery disease on angiogram (n = 40) | 10mg per day × 3 months | Improved endothelial function (FMD). Improved LV diastolic function. No change in ejection fraction. Decreased LDL. Prevented unfavorable changes in RBC deformability and platelet aggregation. |
| Militaru et al.,60 | Randomized, double-blind, active-controlled, paralleled trial | Overweight adults with angina pectoris on stable treatment | 20mg per day (10mg trans-resveratrol) +/- calcium fructoborate × 60 days | Decreased hs-CRP and NT-proBNP. Improved lipid parameters and angina symptoms in all groups from baseline. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg per day × 30 days | Decreased systolic BP and MAP. Decreased leukocyte count and plasma inflammatory markers, including IL-6 and TNF-α. |
| Tome-Carneiro et al.,51,57 | Randomized, triple-blind, placebo-controlled trial | Statin treated adults with diabetes or hyperlipidemia + another cardiovascular risk factor (n = 75) | 8mg of reveratrol in GE-RES daily × 6 months followed by 16mg × 6 months | Decrease in LDL cholesterol, apolipoprotein B, and oxidized LDL levels after 6 months. Decrease in inflammatory markers, including hs-CRP, TNF-α, PAI-1, and IL-6/IL-10 ratio at 1 year. |
| Tome-Carneiro et al.,58 | Randomized, triple-blind, placebo-controlled trial | Stable CAD subjects on medical therapy (n = 75) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in hs-CRP. Increased adiponectin, decreased PAI-1. Inhibited atherothrombotic, inflammation-related transcription factors in PBMCs. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo-controlled trial | Male, type 2 diabetics, with hypertension and stable CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in inflammatory markers, aside from a reduction in IL-6 in the GE-RES group. Downregulated the expression of proinflammatory cytokines and modulated inflammatory-related microRNAs in PBMCs. |
| Wong et al.,42 | Randomized, double-blind, placebo-controlled, crossover trial | Overweight, obese men and postmenopausal women with untreated borderline hypertension (n = 19) | Single dose of 30, 90, and 270mg separated by a 1 week interval | Acute, dose-dependent increase in endothelial function measured by FMD of the brachial artery. |
| Wong et al.,43 | Randomized, double-blind, placebo-controlled, crossover trial | Obese, healthy men, and postmenopausal women (n = 28) | 75mg daily × 6 weeks | Chronic supplementation resulted in an increase in endothelial function measured by FMD of the brachial artery; a single dose of resveratrol following chronic supplementation further increased FMD. |
| Study | Study design | Population | Resveratrol dose and duration | Outcome |
|---|---|---|---|---|
| Agarwal et al.,59 | Randomized, double-blind, placebo-controlled trial | Healthy adults (n = 41) | 400mg daily of trans-resveratrol + grapeskin extract + quercetin × 30 days | Decreased mRNA expression of the cytokines VCAM, ICAM, and IL-8 in human coronary artery endothelial cells exposed to postresveratrol-treated plasma. Decreased plasma IFN-γ. No change in IL-1β, IL-6, or TNF-α. |
| Bhatt et al.,19 | Open-label, randomized, controlled trial | Type 2 diabetics on oral hypoglycemic agents (n = 62) | 250mg daily × 3 months | Improved systolic but not diastolic blood pressure from baseline. |
| Brasnyo et al.,20 | Randomized, double-blind, placebo-controlled trial | Type 2 diabetic men not treated with insulin (n = 19) | 10mg daily × 4 weeks | Decreased urinary ortho-tyrosine. Increased pAKT:AKT ratio in platelets. |
| Crandall et al.,18 | Open-label study | Older subjects with impaired glucose tolerance (n = 10) | 1, 1.5, or 2g per day × 4 weeks | Improvement in postmeal endothelial function (RHI), measured by RH-PAT. No change in hs-CRP or adiponectin. |
| De Groote et al.,56 | Blinded, sequential design, randomized, placebo-controlled trial | Healthy, obese adults (n = 32) | 150mg daily of resveratrol, 300mg of resveratrol triphosphate or catechin-rich grape seed extract × 1 month | Resveratrol triphosphate and catechin-rich grape seed extract reduced markers of oxidative stress and modulated expression of genes involved in oxidation and inflammation compared to resveratrol. |
| Ghanim et al.,52 | Randomized, placebo-controlled parallel design | Normal-weight, healthy adults (n = 20) | 40mg from PCE daily × 6 weeks | Reduction in reactive oxygen species and proinflammatory mediators. Suppressed cytokines CRP, TNF-α, and IL-6. |
| Ghanim et al.,26 | Randomized, placebo-controlled crossover study | Normal-weight, healthy adults (n = 10) | Single dose of 100mg of resveratrol + grapeskin polyphenols | Acute, protective antioxidative, and anti-inflammatory effect in response to a HFHC meal, decreased endotoxin release, inflammatory markers, and indices of oxidative stress. |
| Kennedy et al.,46 | Randomized, double-blind, placebo-controlled, crossover trial | Young, healthy adults (n = 24) | Single dose of 250mg and 500mg separated by a week | Dose-dependent increase in cerebral blood flow with enhanced oxygen extraction, assessed by functional NIRS brain imaging. No change in cognitive function. |
| Magyar et al.,44 | Randomized, double-blind, placebo-controlled trial | Post myocardial infarction subjects with coronary artery disease on angiogram (n = 40) | 10mg per day × 3 months | Improved endothelial function (FMD). Improved LV diastolic function. No change in ejection fraction. Decreased LDL. Prevented unfavorable changes in RBC deformability and platelet aggregation. |
| Militaru et al.,60 | Randomized, double-blind, active-controlled, paralleled trial | Overweight adults with angina pectoris on stable treatment | 20mg per day (10mg trans-resveratrol) +/- calcium fructoborate × 60 days | Decreased hs-CRP and NT-proBNP. Improved lipid parameters and angina symptoms in all groups from baseline. |
| Timmers et al.,22 | Randomized, double-blind crossover study | Obese, healthy men (n = 11) | 150mg per day × 30 days | Decreased systolic BP and MAP. Decreased leukocyte count and plasma inflammatory markers, including IL-6 and TNF-α. |
| Tome-Carneiro et al.,51,57 | Randomized, triple-blind, placebo-controlled trial | Statin treated adults with diabetes or hyperlipidemia + another cardiovascular risk factor (n = 75) | 8mg of reveratrol in GE-RES daily × 6 months followed by 16mg × 6 months | Decrease in LDL cholesterol, apolipoprotein B, and oxidized LDL levels after 6 months. Decrease in inflammatory markers, including hs-CRP, TNF-α, PAI-1, and IL-6/IL-10 ratio at 1 year. |
| Tome-Carneiro et al.,58 | Randomized, triple-blind, placebo-controlled trial | Stable CAD subjects on medical therapy (n = 75) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in hs-CRP. Increased adiponectin, decreased PAI-1. Inhibited atherothrombotic, inflammation-related transcription factors in PBMCs. |
| Tome-Carneiro et al.,21 | Randomized, triple-blind, placebo-controlled trial | Male, type 2 diabetics, with hypertension and stable CAD on medical therapy (n = 35) | 8mg of resveratrol in GE-RES daily × 6 months, then 16mg × 6 months | No change in inflammatory markers, aside from a reduction in IL-6 in the GE-RES group. Downregulated the expression of proinflammatory cytokines and modulated inflammatory-related microRNAs in PBMCs. |
| Wong et al.,42 | Randomized, double-blind, placebo-controlled, crossover trial | Overweight, obese men and postmenopausal women with untreated borderline hypertension (n = 19) | Single dose of 30, 90, and 270mg separated by a 1 week interval | Acute, dose-dependent increase in endothelial function measured by FMD of the brachial artery. |
| Wong et al.,43 | Randomized, double-blind, placebo-controlled, crossover trial | Obese, healthy men, and postmenopausal women (n = 28) | 75mg daily × 6 weeks | Chronic supplementation resulted in an increase in endothelial function measured by FMD of the brachial artery; a single dose of resveratrol following chronic supplementation further increased FMD. |
Abbreviations: AKT, protein kinase B; BP, blood pressure; CAD, coronary heart disease; FMD, flow-mediated dilation; GE-RES, resveratrol-enriched grape extract; HFHC , high fat high carbohydrate; hs-CRP, high sensitivity C-reactive protein; ICAM, intracellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; MAP, mean arterial pressure; NIRS, near infrared spectroscopy; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAI-1, plasminogen activator inhibitor-1; pAKT, phosphorylated protein kinase B; PBMC, peripheral blood mononuclear cell; PCE, Polygonum cuspidatum extract; RBC, red blood cell; RHI, reactive hyperemia index; RH-PAT, reactive hyperemia peripheral arterial tonometry; TNF-α, tumor necrosis factor alpha; VCAM, vascular cell adhesion protein.
Blood pressure and vascular function.
Resveratrol treatment has shown modest effects on blood pressure in human studies, although it has not been systematically studied in hypertensive subjects. Mean arterial blood pressure was reduced in obese, normotensive men (97.9 vs. 94.9mm Hg), primarily because of a change in systolic pressure, with 150mg/day of resveratrol,22 and systolic blood pressure was reduced (−11.78±0.73mm Hg) with 250mg of resveratrol daily for 3 months.19 In several other studies, resveratrol supplementation had no effect on blood pressure or an effect was not reported.18,24,25,42,43
Reported effects of resveratrol on endothelial function have been somewhat more robust. In acute dosing studies, resveratrol (30, 90, 270mg or placebo at weekly intervals) was given to middle-aged overweight/obese men and postmenopausal women with untreated borderline hypertension.42 This resulted in an acute dose-dependent improvement in endothelial function, manifested by an increase in flow-mediated dilatation of the brachial artery, which showed weak correlation (R2 = 0.08; P < 0.01) with plasma resveratrol concentration. In a follow-up study, chronic resveratrol supplementation (75mg daily for 6 weeks) in obese but otherwise healthy subjects improved flow-mediated dilatation by 23%, with further improvement demonstrated 60 minutes after an additional dose.43 Flow-mediated vasodilation was also improved after low doses of resveratrol (in some cases combined with other polyphenols) in postmyocardial infarction patients and patients with stable coronary artery disease.44,45 A trend toward improved postmeal endothelial function, assessed by reactive hyperemia peripheral arterial tonometry, was observed with resveratrol treatment in older glucose-intolerant adults.18
The effect of resveratrol on cerebrovascular function has also been studied. Healthy college students were treated with a single dose of placebo, 250mg of resveratrol, and 500mg of resveratrol on 3 separate days.46 A dose-dependent increase in cerebral blood flow and oxygen extraction and utilization during task performance was demonstrated using near infrared spectroscopy, although there were no reported changes in cognitive function.
Lipid metabolism.
Studies in vitro and in animal models have suggested that resveratrol may have beneficial effects on lipids by modulation of genes involved in lipid metabolism47 and specifically by upregulation of low-density lipoprotein (LDL) receptor expression, leading to reduction in circulating LDL levels.48 Resveratrol has also attenuated nonalcoholic fatty liver disease in rodents by increased expression of hepatic lipoprotein receptors49 and prevented lipid accumulation in hepatocytes exposed to high glucose by stimulating AMPK phosphorylation.50
Studies in humans have also suggested some positive effects on lipid metabolism, mostly with low to moderate resveratrol doses. Modest improvements in total cholesterol and LDL-cholesterol levels (3%–14%) have been reported at doses of 10–250mg/day, as well as with a grape extract containing 8mg resveratrol.19,44,51 Reductions in apolipoprotein-B and oxidized LDL were also reported.51 In two studies, the addition of resveratrol resulted in further LDL reduction in statin-treated subjects, leading the authors to propose the existence of a synergistic effect.44,51 Timmers et al., reported a significant reduction in serum triglycerides with resveratrol treatment, whereas other lipid measures were not reported.22 On the other hand, studies conducted in healthy individuals without significant baseline lipid abnormalities have largely failed to demonstrate measurable effect on lipid parameters.18,24,25,52
Platelet function.
In vitro studies have suggested that resveratrol may improve platelet function and inhibit platelet aggregation. Resveratrol incubation with platelets from healthy subjects enhanced platelet nitric oxide (NO) production by stimulating protein kinase B phosphorylation (pAKT), an activator of NO synthase. The increase in NO production suppressed inflammation and platelet aggregation in vitro.32,53,54 In type 2 diabetics, resveratrol increased platelet pAKT phosphorylation and NO levels and improved platelet membrane fluidity and function, thereby inhibiting platelet hyperaggregation typically seen in diabetes.20,55 A similar reduction in platelet aggregation was seen in patients with coronary artery disease treated with 10mg of resveratrol for 3 months, as compared with placebo.44
Oxidative stress and inflammation.
A number of small clinical trials have studied the effect of resveratrol on cardiovascular biomarkers in diverse patient groups and with varying resveratrol preparations and doses. Most consistent have been reports of reduction in markers of oxidative stress. Ghanim et al., supplemented healthy adult males with a polyphenol extract containing 40mg of resveratrol daily for 6 weeks and showed a significant reduction in reactive oxygen species and free radical formation in mononuclear cells.52 A single dose of 100mg resveratrol (plus grapeskin polyphenols) demonstrated a similar antioxidative effect in response to a high-fat, high-carbohydrate meal.26 Treatment with resveratrol triphosphate reduced markers of oxidative stress and modulated expression of genes involved in oxidation, inflammation, and stress response.56 Reduction in 24-hour urinary ortho-tyrosine, a marker of oxidative stress, has also been reported in resveratrol-treated type 2 diabetics.20
Improvements in a number of inflammatory markers have also been described.52 In a series of studies, inflammatory and fibrinolytic parameters were measured in patients with cardiovascular disease or cardiovascular disease risk factors after 1 year of treatment with a grape extract containing 8–16mg of resveratrol. Favorable changes in the levels of plasminogen-inhibitor type 1 (PAI-1), soluble intracellular adhesion molecule (s-ICAM),57 and adiponectin58 were reported. Also, several inflammation-related transcription factors were significantly altered in peripheral blood mononuclear cells, suggesting a decrease in atherothrombotic signals.21,58 Cultured human coronary artery endothelial cells incubated with plasma from healthy adults chronically treated with a polyphenol extract containing 400mg of resveratrol reportedly showed reduced mRNA expression of vascular cell adhesion molecule (VCAM-1), ICAM, and interleukin 8.59 Reduction in interferon γ, but not interleukin 1β, interleukin 6 or tumor necrosis factor α (TNF- α),59 was observed in the plasma of the treated subjects. Improvements in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and angina symptoms were reported in subjects treated with 20mg of resveratrol, with or without calcium fructoborate. However, similar improvements were observed in an untreated control group and thus limit conclusions that can be drawn from this study.60 Other studies have failed to demonstrate an effect on a variety of inflammatory markers, including high-sensitivity C-reactive protein, interleukin 6, TNF-α, and adiponectin.18,24,25 In the study by Timmers et al., levels of TNF-α and total leukocyte count were reduced after resveratrol treatment, whereas other inflammatory markers were unchanged.22 Despite the heterogeneity of study design and variable resveratrol preparations used in these studies, the evidence does support a favorable effect of resveratrol on several vascular biomarkers. Whether these changes may result in improved vascular function and reduced cardiovascular disease remains to be determined.
CHALLENGES TO CLINICAL STUDIES OF RESVERATROL
Challenges inherent to the design and conduct of clinical studies using resveratrol were recently reviewed and include issues pertaining to appropriate dose, availability of pharmaceutical-grade resveratrol, US Food and Drug Administration oversight, and the potential for toxicity and drug interactions.61 Among the most important limitations in the field is lack of consensus about the appropriate dose range for use in human studies. Doses used in animal studies have varied 100-fold, and in human trials, resveratrol effects have been reported with as little as 5mg45 (consistent with amounts obtained from dietary sources) to as much as 5 grams16 per day. Experimental evidence suggests that different doses may elicit distinct biological effects, with lower doses activating SIRT1-dependent pathways and higher doses acting in an SIRT1-independent mechanism.13 However, the relevance of this observation to human pharmacology has not been established. Further complicating the situation is that fact that resveratrol is rapidly metabolized and cleared from the plasma, and whether the metabolites of resveratrol, generally present in much higher concentrations, have significant biologic activity is still unclear.62,63
Because resveratrol is marketed as a nutritional supplement, it has been subject to limited formal safety testing. Resveratrol treatment with a micronized oral formulation (SRT501) has been associated with renal toxicity, but this occurred with high doses used in patients with underlying kidney disease.64 Gastrointestinal distress, especially diarrhea, has also been reported at higher doses.64,65 Resveratrol modulates the cytochrome P450 enzyme system by inhibiting CYP3A4, CYP2D6, CYP2C9, and inducing CYP1A266and could potentially affect the levels of drugs metabolized by these enzymes. These include some commonly prescribed drugs such as statins and antiepileptics. Furthermore, resveratrol exhibits weak in vitro activity as an estrogen agonist and antagonist.67,68 Thus, resveratrol has the potential to activate estrogen-regulated genes, raising concern about potential stimulation of estrogen-dependent neoplasms.69 These safety issues will require additional and more rigorous investigation.
CONCLUSIONS
Evidence from a large body of preclinical studies suggests resveratrol could have important and clinically relevant cardiometabolic effects. However, well-conducted clinical trials are still quite limited and offer somewhat conflicting evidence of resveratrol’s potential in prevention or treatment of human disease. Also lacking is a clear understanding of how resveratrol may exert its relevant effects, whether by SIRT1 activation or other mechanisms. Further, resveratrol itself may not be an attractive molecule for development as a pharmaceutical, and industry is actively pursuing studies of small molecule sirtuin activators that share (or improve upon) the biological activity of resveratrol.70 Ultimately, additional human studies, preferably ones that include subjects with defined cardiometabolic abnormalities, in a range of doses and with careful monitoring of safety parameters will be required to determine the therapeutic potential of resveratrol.
DISCLOSURE
The authors declared no conflict of interest.
REFERENCES
