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Protective effect of lycopene on serum cholesterol and blood pressure: Meta-analyses of intervention trials

      Abstract

      Background

      Cardiovascular disease is associated with oxidative stress, inflammatory processes, and vascular dysfunction. Lycopene, a carotenoid found in tomatoes, is an antioxidant with a protective effect on lipid peroxidation and anti-atherosclerotic capacity. This review summarises current evidence on the effect of lycopene on serum lipid concentrations and blood pressure.

      Methods

      We searched the PubMed and Cochrane databases for intervention studies between 1955 and September 2010 investigating the effect of lycopene on blood lipids or blood pressure for a minimum duration of 2 weeks. We conducted meta-analyses using a random effect model of all studies fitting the inclusion criteria. Additionally, we conducted subgroup meta-analysis of serum lipid concentrations by lycopene dosage and subgroup meta-analysis by baseline blood pressure.

      Results

      Twelve studies (13 trial arms) meeting the inclusion criteria investigated the effect of lycopene on serum lipids, and four studies examined its effect on blood pressure. Meta-analysis on serum lipids revealed a significant cholesterol-lowering effect of lycopene for total serum cholesterol (mean change ± SE: −7.55 ± 6.15 mg/dl; p = 0.02) and low-density-lipoprotein (LDL) cholesterol (mean change ± SE: −10.35 ± 5.64 mg/dl, p = 0.0003) in the subgroup of trials using lycopene dosages of ≥25 mg daily, whereas subgroup meta-analysis of trials using lower lycopene dosages was not significant. Meta-analysis of the effect of lycopene on systolic blood pressure of all trials suggested a significant blood pressure reducing effect (mean systolic blood pressure change ± SE: −5.60 ± 5.26 mm Hg, p = 0.04).

      Conclusions

      Our meta-analysis suggests that lycopene taken in doses ≥25 mg daily is effective in reducing LDL cholesterol by about 10% which is comparable to the effect of low doses of statins in patient with slightly elevated cholesterol levels. More research is needed to confirm suggested beneficial effects on total serum cholesterol and systolic blood pressure.

      Keywords

      1. Introduction

      Lycopene, a carotenoid without provitamin-A activity, is the pigment responsible for the distinctive red colour in tomatoes and watermelon, and is also found in pink grapefruit, papaya, guava, and rosehip (Table 1) [
      • Maiani G.
      • Caston M.J.
      • Catasta G.
      • et al.
      Carotenoids: actual knowledge on food sources, intakes, stability and bioavailability and their protective role in humans.
      ,
      • Shi J.
      • Le Maguer M.
      Lycopene in tomatoes: chemical and physical properties affected by food processing.
      ,
      • Bohm V.
      • Frohlich K.
      • Bitsch R.
      Rosehip – a “new” source of lycopene?.
      ]. Generally, riper and deeper red fruit and vegetables contain more lycopene, and cooking and processing further increase lycopene content and bioavailability [
      • Dewanto V.
      • Wu X.
      • Adom K.K.
      • Liu R.H.
      Thermal processing enhances the nutritional value of tomatoes by increasing total antioxidant activity.
      ,
      • Gartner C.
      • Stahl W.
      • Sies H.
      Lycopene is more bioavailable from tomato paste than from fresh tomatoes.
      ,
      • Stahl W.
      • Sies H.
      Lycopene: a biologically important carotenoid for humans?.
      ].
      Table 1Lycopene content in food.
      Food itemLycopene content (mg/100 g wet)Bioavailability isomeric form
      Tomato, fresh3–5, deep red varieties up to 1595% trans, 5% cis
      Tomato, cooked2–2.5% increase in lycopene content at 2, 15 and 30 min at 88 °CProportion of trans/cis changes only slightly
      Tomato, canned8–12
      Tomato, paste49–9497% trans, 3% cis
      Tomato, juice1–1189% trans, 11% cis
      Tomato, sauce5–23
      Tomato capsules, e.g. Lyc-O-Mato, LycoRed1592% trans, 8% cis
      Watermelon, red2.3–7.294% trans, 6% cis
      Guava5.2–5.576% trans, 24% cis
      PapayaUp to 5.3
      Grapefruit, pinkUp to 3.3
      Rosehip2–3560% trans, 40% cis
      Mg, milligram; trans/cis, trans/cis-isomer of lycopene.
      High lycopene consumption has been associated with a decreased risk of cardiovascular disease, including atherosclerosis, myocardial infarction and stroke [
      • Klipstein-Grobusch K.
      • Launer L.J.
      • Geleijnse J.M.
      • Boeing H.
      • Hofman A.
      • Witteman J.C.M.
      Serum carotenoids and atherosclerosis:the Rotterdam study.
      ,
      • Kohlmeier L.
      • Kark J.D.
      • Gomez-Gracia E.
      • et al.
      Lycopene and myocardial infarction risk in the EURAMIC Study.
      ,
      • Rissanen T.H.
      • Voutilainen S.
      • Nyyssonen K.
      • et al.
      Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study.
      ,
      • Sesso H.D.
      • Buring J.E.
      • Norkus E.P.
      • Gaziano J.M.
      Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in women.
      ,
      • Voutilainen S.
      • Nurmi T.
      • Mursu J.
      • Rissanen T.H.
      Carotenoids and cardiovascular health.
      ]. Etiology of cardiovascular disease is related to oxidative stress, inflammatory processes, endothelial dysfunction and subsequent vascular remodelling. Several clinical trials have provided evidence that lycopene plays a pivotal role in lowering oxidative stress, in particular in preventing the oxidation of low-density-lipoprotein (LDL) cholesterol [
      • Basu A.
      • Imrhan V.
      Tomatoes versus lycopene in oxidative stress and carcinogenesis: conclusions from clinical trials.
      ].
      Oxidized LDL particles trigger a series of events that lead to inflammatory processes, formation of foam cells, fatty streaks and plaque, atherosclerotic lesions and rupture of plaque [
      • Willcox J.K.
      • Catignani G.L.
      • Lazarus S.
      Tomatoes and cardiovascular health.
      ]. Furthermore, oxidised LDL particles impair normal endothelial function by inhibiting nitric oxide (NO) release, an important relaxant of blood vessels, and thus influence blood pressure [
      • Willcox J.K.
      • Catignani G.L.
      • Lazarus S.
      Tomatoes and cardiovascular health.
      ].
      Due to its chemical structure containing eleven conjugated double bonds, lycopene is a powerful antioxidant and free radical quencher (Fig. 1). In addition to its antioxidant properties, lycopene has been proposed to reduce cholesterol levels by the suppression of cholesterol synthesis, increase of LDL degradation, and inhibition of the hydroxy-methyl-glutaryl-coenzyme A (HMGCoA)-reductase enzyme [
      • Fuhrman B.
      • Elis A.
      • Aviram M.
      Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages.
      ].
      Figure thumbnail gr1
      Fig. 1Chemical structure of lycopene. Due to its chemical structure containing eleven conjugated double bonds lycopene is a powerful antioxidant and free radical quencher.
      High total and LDL cholesterol levels and high blood pressure are recognised risk factors for cardiovascular disease. This review summarises current evidence on the effect of lycopene intake on blood lipids (total cholesterol, LDL, high density lipoprotein (HDL), triglycerides) and blood pressure investigated in human intervention trials.

      2. Methods

      2.1 Search strategy

      We searched the PubMed and Cochrane databases for intervention studies published between 1955 and September 2010 investigating the effect of lycopene-containing products on blood lipids or blood pressure using no language restrictions and the following search terms: (lycopene OR tomato) AND (“cardiovascular system” OR “cardiovascular diseases” OR lipoproteins OR cholesterol OR “blood pressure”). We limited our search to “Humans, Clinical Trial, Randomized Controlled Trial, Controlled Clinical Trial” in PubMed and to “Clinical Trials” in Cochrane. Reference lists of included articles were hand-searched for additional relevant studies.

      2.2 Study selection

      Studies were included if they fulfilled all of the following criteria: (1) intervention study, (2) controlled design: diet- or placebo-controlled repeated measure trial, cross-over or parallel randomised controlled trial, (3) standardised dosage of natural lycopene in treatment group and lycopene-free control group, (4) intervention period of ≥2 weeks, (5) reported mean ± SD (or SE) of blood lipids (total serum cholesterol, HDL, LDL, triglycerides) or blood pressure (systolic blood pressure (SBP), diastolic blood pressure (DBP)) at baseline, before and after intervention, (6) characteristics of study (design, number of participants, lycopene dosage, duration, outcome measures) were reported in English or other Germanic/Romanic languages (in abstract, tables, or figures).

      2.3 Data extraction

      Data were abstracted and quality was assessed independently by two investigators (KR and PF) using guidelines published by the Cochrane Collaboration [

      Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions Version 5.0.2. The Cochrane Collboration; 2009 [accessed 25 Oct 10] www.cochrane-handbook.org.

      ]. Any disagreement was resolved by discussion and in consultation with a statistician if required. We extracted data on study design, form of treatment, daily dosage of lycopene, duration of the active treatment phase, type of participants, gender, age, samples size, mean ± SD of blood lipids and blood pressure at baseline (or before treatment with lycopene containing products) and after treatment with lycopene.

      2.4 Analysis

      Meta-analyses were conducted using the Cochrane Program Review Manager version 5.0.25 [
      Review Manager (RevMan) [Computer program]. Version 5.0.25.
      ]. A random effect model and the generic inverse variance method were used to accommodate for the heterogeneity of study designs (parallel, cross-over, and repeated measures).
      Blood lipid levels were collated in mg/dl. If cholesterol levels (total cholesterol, HDL, LDL) or triglyceride levels were published in mmol/l, we multiplied by factor 38.7 for cholesterol and 88.6 for triglycerides to convert to mg/dl, respectively. Standard deviations at one time point were calculated with the formula SD = SE × squareroot n (SE = standard error, n = number of participants). Standard deviations of the mean difference were calculated using the formula: squareroot [(SDtime1)2 + (SDtime2)2 − 2R × SDtime1 × SDtime2)], assuming a correlation coefficient R = 0.5 [

      Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions Version 5.0.2. The Cochrane Collboration; 2009 [accessed 25 Oct 10] www.cochrane-handbook.org.

      ].
      To meet the assumption underlying meta-analysis that observations are to be independent, we adjusted mean outcome values and standard deviations for included studies with multiple lycopene arms and one control arm as follows: (1) we compared the mean (SD) of three lycopene arms (investigating three different dosages) at baseline and end of study with the mean of one control arm in the parallel group trial by Sakamoto et al. [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ]; (2) we compared the mean (SD) of multiple lycopene arms (investigating two or three lycopene containing products) at baseline and end of study with one control arm in the trials by Collins et al. [
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ] and Shen et al. [
      • Shen Y.C.
      • Chen S.L.
      • Wang C.K.
      Contribution of tomato phenolics to antioxidation and down-regulation of blood lipids.
      ], respectively (references in Table 2).
      Table 2Characteristics of included studies.
      Study ID, locationStudy designTreatment/controlLycopene dosage per dayDuration (treatment phase)Participants, m/f, ageSample size
      Sakamoto 94, JapanControlled 4 group parallel trialL1: Tomato juice (165 ml)

      L2: Tomato juice (330 ml)

      L3: Tomato juice (495 ml)

      C: Apple juice (195 ml)
      L1: 15.2 mg

      L2: 30.4 mg

      L3: 45.6 mg

      C: 0 mg
      4 weeksHealthy students, all fTotal: 65

      Lall: 57

      C: 8
      Upritchard 00, New ZealandRandomised placebo-controlled 4 group parallel trial, run-in: 4 weeks placeboL: Tomato juice (250 ml × 2)

      C: Placebo capsule (starch)

      G2: Vit C

      G3: Vit E
      L: 44 mg

      C: 0 mg
      4 weeksType 2 diabetics, 32m/20f, 62 ± 7 yrsTotal: 52

      L: 15

      C: 13

      G2, G3: 12, 12
      Hadley 03, USARandomised 3 group parallel trial following run-in: 7 day L-free diet controlled (repeated measures)L1: Tomato soup CS (300 ml)

      L2: Tomato soup RTS (320 ml)

      L3: Tomato juice V8 (340 ml)

      C: L-free diet (before L-intervention)
      L1: 35 mg

      L2: 23 mg

      L3: 25 mg

      C: L-free diet
      15 daysHealthy non-smokers, 30m/30f, 52 ± 2 yrsTotal: 60

      Lall: 60

      C: 60
      Kiokias 03, UKRandomised controlled 2 group crossover trial, fish oil ± carotenoid mixL: Carotenoid-mix (tomato, palm oil carotene, marigold, paprika, bixin extracts) + fish oil capsules (4/d)

      C: Fish oil only capsules (4/d)
      L: 18 mg

      C: 0 mg
      3 weeks, washout 12 wks before crossoverHealthy non-smokers, 16m/15f, 32 ± 11 yrsTotal: 31

      L: 31

      C: 31
      Collins 04, USARandomised diet-controlled 3 group crossover trial, run-in: 14 day low-L dietL1: Tomato juice (244 ml)

      L2: Watermelon juice (780 ml)

      C: L-free prepared meals
      L1: 20.1 mg

      L2: 18.4 mg

      C: 0 mg
      3 weeks, washout 4 wks before crossoverHealthy non-smokers, 5m/5f, 49 ± 14 yrsTotal: 10

      L: 10

      C: 10
      Engelhard 06, IsraelPlacebo-controlled repeated measure 1 group intervention trial, run-in: 4 weeks placeboL: Tomato extract capsules (1/d)

      C: Placebo capsules (1/d)
      L: 15 mg

      C: 0 mg
      8 weeksMild hypertensives, non-smokers, 18m/15f, 52 ± 21 yrsTotal: 31

      L: 31

      C: 31
      Blum 06, IsraelDiet-controlled 2 group parallel trialL: Tomato-rich diet (tomato juice, sauce, soup, fresh tomato) (300 ml)

      C: Tomato-free diet
      L: 30 mg

      C: 0 mg
      4 weeksHealthy, 32m/66f, 46 ± 14 yrsTotal: 98

      L: 50

      L: 48
      Paterson 06, UKRandomised controlled crossover 2 group trial

      Fish oil ± carotenoid-rich food, run-in: 2 weeks (fish oil only)
      L: Carotenoid-rich (canned soups: vegetable, carrot, tomato; juices containing carrot)

      C: Carotenoid-poor (canned soups: mushroom, herb, leek; juices no L)
      L: 4.5 mg

      C: 0 mg

      4 weeks, washout 10 wks before crossoverHealthy, 12m/24f, 43.5 ± 23.5 yrsTotal: 36

      L: 36

      C: 36
      Misra 06, IndiaRandomised controlled 2 group parallel trialL: Tomato extract capsule (2/d)

      C: HRT
      L: 4 mg

      C: 0 mg
      6 monthsPostmenopausal women, 46 + 25 yrsTotal: 41

      L: 20

      C: 21
      Silaste 07, FinlandDiet-controlled repeated measures intervention trial, run-in: 3 week tomato-low dietL: Tomato-rich period (tomato juice, tomato sauce; 400 ml + 30 g)

      C: Tomato-poor period
      L: 27 mg

      C: 0 mg
      3 weeksHealthy, 5m/16f, 30 ± 19 yrsTotal: 21

      L: 21

      C: 21
      Shen 07, TaiwanDiet-controlled repeated measures intervention including

      follow-up of 2 weeks – within randomised 3 group parallel trial (all groups received L ± phenolics)
      L1: Fresh tomatoes (500 g)

      L2: Tomato juice (600 ml)

      L3: Lycopene/tomato extract drink (600 ml)

      C: L-free period
      Lall: 40 mg

      C: 0 mg
      6 weeksHealthy, 20.5 ± 2.5 yrsTotal: 24

      Lall: 24

      C: 24
      Jacob 08, GermanyDiet-controlled repeated measures 1 group intervention trial, run-in: 2 weeks, within randomised parallel 2 group trial (both groups received L ± Vit C)L1: Tomato-juice (500 ml)

      C: L-poor period

      G2: Tomato-juice + Vit C (500 ml)
      L1: 21 mg

      C: 0 mg

      G2: 21 mg
      2 weeksHealthy non-smokers, 4m/20f, 23 ± 2 yrsTotal: 24

      L1: 12

      C: 12

      G2: 12
      Paran 09, IsraelPlacebo-controlled 2 group crossover trialL: Tomato extract capsule (1/d)

      C: Placebo capsule
      L: 15 mg

      C: 0 mg
      6 weeksModerate hypertensives,

      26m/24f, 56 ± 10 yrs
      Total: 50

      L: 50

      C: 50
      Ried 09, AustraliaRandomised placebo-controlled 3 group parallel trial (phase 1)L: Tomato extract capsule (1/d)

      C: Placebo capsule

      G2: Chocolate
      L: 15 mg

      C: 0 mg
      12 weeksPrehypertensive, 19m/17f, 52 ± 12Total: 36

      L: 15

      C: 10

      G2: 11
      L, lycopene group; C, control group; G, group with non-lycopene active treatment; CS, condensed; d, day; g, grams; HRT, hormone replacement therapy; m/f, male/female; mg, milligram; ml, millilitre; RTS, ready to make soup; Vit, vitamin; wks, weeks; yrs, years.
      Subgroup meta-analyses were conducted to explore whether the treatment effect on cholesterol levels was associated with the dosage of lycopene (< or ≥25 mg/day), and whether the effect on blood pressure was associated with blood pressure levels at baseline (SBP: < or ≥140 mm Hg; DBP: < or ≥80 mm Hg). Influence of lycopene dosage on cholesterol levels and baseline levels on blood pressure outcomes is physiologically plausible according to previous research [
      • Fuhrman B.
      • Elis A.
      • Aviram M.
      Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages.
      ,
      • Hsu Y.-M.
      • Lai C.-H.
      • Chang C.-Y.
      • Fan C.-T.
      • Chen C.-T.
      • Wu C.-H.
      Characterizing the lipid-lowering effects and antioxidant mechanisms of tomato paste.
      ,
      • Ried K.
      • Frank O.R.
      • Stocks N.P.
      • Fakler P.
      • Sullivan T.
      Effect of garlic on blood pressure: a systematic review and meta-analysis.
      ,
      • Ried K.
      • Sullivan T.
      • Fakler P.
      • Frank O.R.
      • Stocks N.P.
      Does chocolate reduce blood pressure? A meta-analysis.
      ].
      In addition, we explored robustness of results by sensitivity analysis excluding selected trials with uncommon study design or potential risk of bias. Publication bias or small study effect was assessed by Begg's funnel plots and Egger's test [
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      ,
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ].

      3. Results

      3.1.1 Summary of included studies

      A total of 22 publications were assessed in detail for inclusion (Fig. 2). Fourteen studies met the inclusion criteria (Table 2) [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ,
      • Upritchard J.E.
      • Sutherland W.H.
      • Mann J.I.
      Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.
      ,
      • Hadley C.W.
      • Clinton S.K.
      • Schwartz S.J.
      The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage.
      ,
      • Kiokias S.
      • Gordon M.H.
      Dietary supplementation with a natural carotenoid mixture decreases oxidative stress.
      ,
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ,
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Blum A.
      • Merei M.
      • Karem A.
      • et al.
      Effects of tomatoes on the lipid profile.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ,
      • Misra R.
      • Mangi S.
      • Joshi S.
      • Mittal S.
      • Gupta S.K.
      • Pandey R.M.
      LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.
      ,
      • Silaste M.L.
      • Alfthan G.
      • Aro A.
      • Kesaniemi Y.A.
      • Horkko S.
      Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.
      ,
      • Shen Y.C.
      • Chen S.L.
      • Wang C.K.
      Contribution of tomato phenolics to antioxidation and down-regulation of blood lipids.
      ,
      • Jacob K.
      • Periago M.J.
      • Bohm V.
      • Berruezo G.R.
      Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation.
      ,
      • Paran E.
      • Novack V.
      • Engelhard Y.N.
      • Hazan-Halevy I.
      The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.
      ,
      • Ried K.
      • Frank O.R.
      • Stocks N.P.
      Dark chocolate or tomato extract for prehypertension: a randomised controlled trial.
      ] and were assessed for quality or risk of bias (Table 3). Characteristics and reasons for the exclusion of eight studies are provided in Table 4 [
      • Fuhrman B.
      • Elis A.
      • Aviram M.
      Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages.
      ,
      • Agarwal S.
      • Rao A.V.
      Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study.
      ,
      • Carroll Y.L.
      • Corridan B.M.
      • Morrissey P.A.
      Lipoprotein carotenoid profiles and the susceptibility of low density lipoprotein to oxidative modification in healthy elderly volunteers.
      ,
      • John J.H.
      • Ziebland S.
      • Yudkin P.
      • Roe L.S.
      • Neil H.A.
      Effects of fruit and vegetable consumption on plasma antioxidant concentrations and blood pressure: a randomised controlled trial.
      ,
      • Ahuja K.D.
      • Pittaway J.K.
      • Ball M.J.
      Effects of olive oil and tomato lycopene combination on serum lycopene, lipid profile, and lipid oxidation.
      ,
      • Madrid E.
      • Vásquez D.
      • Leyton F.
      • Mandiola C.
      • J.A. E.
      Short-term Lycopersicum esculentum consumption may increase plasma high density lipoproteins and decrease oxidative stress.
      ,
      • Bose K.S.
      • Agrawal B.K.
      Effect of lycopene from tomatoes (cooked) on plasma antioxidant enzymes, lipid peroxidation rate and lipid profile in grade-I hypertension.
      ].
      Figure thumbnail gr2
      Fig. 2Flow diagram for the selection of studies investigating the effect of lycopene on lipids or blood pressure.
      Table 3Quality assessment of included studies.
      Study ID, locationRandomisationAllocation concealmentBlindingLoss to follow-upDietary advice, complianceFunding source
      Sakamoto 94, JapanNon-randomised??0??
      Upritchard 00, NZComputer-generated randomisation?Double-blind5 of 57 (8.8%)Instructed to maintain usual diet, compliance checked, but results not reportedScholarship grant
      Hadley 03, USA???0Instructed to avoid food containing lycopeneSupported by foundation, health institute & industry
      Kiokias 03, UK???1 of 32 (3.1%)Food diaries used, vitamin C intake increasedNo funding source provided
      Collins 04, USA???0Meals consumed under controlled conditionsFood industrygrant (national watermelon promotion board)
      Engelhard 06, IsraelNon-randomised??3 of 34 (8.8%)Dietary questionnaire applied, compliance rate not reportedNo funding source provided
      Blum 06, IsraelNon-randomised??0Instructed to continue regular diet without tomatoes during intervention periodFood industry grant (Danone-Strauss)
      Paterson 06, UKBlock-randomisation stratified by age, gender, BMI?Single-blind0Comprehensive food diaries, compliance by tablet counting (92%). During lycopene-rich period participants consumed more fruit and vegetables (p = 0.07), carotenoid intake increased to 26.4 mg/day compared with test intervention of 17.5 mg/day containing 4.5 mg lycopeneFood industry grant (Unilever Bestfood) + University funds
      Misra 06, India???1 of 41 (2.4%)Compliance not assessedMedical research grant
      Silaste 07, FinlandNon-randomised??0No lycopene-containing food allowed during lycopene-poor period, lycopene-containing food allowed during intervention period; this might have inflated lycopene intake and effectSeveral foundations & research council grants
      Shen 07, TaiwanNon-randomised??0No other lycopene-containing food was allowed during intervention periodIndustry supplied juice and lycopene
      Jacob 08, GermanyNon-randomised??0Food diary, instructed to restrict fruit intakeGovernment grant
      Paran 09, IsraelNon-randomised?Double-blind0Compliance assessed by count of remaining capsulesNo funding source provided
      Ried 09, AustraliaComputer-generated permuted block randomisationSequentially numbered containersDouble-blind4 of 36 (11%)Food diary and compliance assessed, additional lycopene consumption negligibleGovernment grant, supplier of trial capsules was not involved in study design, analysis and reporting
      ?, unclear.
      Table 4Characteristics of excluded studies.
      Study ID, locationStudy designTreatment/controlLycopene dosage per dayDuration (treatment phase)Participants, m/f, ageSample sizeReason for exclusion
      Fuhrman 97, IsraelDietary 1 group intervention studyTomato extract capsules60 mg3 monthsHealthy, all m, 32.5 ± 2.5 yrsTotal: 6No control
      Agarwal 98, CanadaRandomised placebo-controlled 4 group crossover trialL1: Spaghetti sauce

      L2: Tomato juice

      L3: Tomato capsules

      C: L-free breakfast in standardised breakfast
      L1: 39.2 mg

      L2: 50.4 mg

      L3: 75 mg

      C: 0 mg
      1 week, washout 1 week before crossoverHealthy non-smokers, 10m/9f, 29 ± 11 yrsTotal: 19

      Lall: 19

      C: 19
      Short duration 1 week
      Carroll 00, IrelandRandomised placebo-controlled 3 group parallel trialL1: Lycopene capsules

      C: Placebo capsules

      G2: Carotene capsules
      L1: 13.3 mg

      C: 0 mg
      12 weeksHealthy, 22m/25f, 65 ± 5 yrsTotal: 51

      L1: 16

      C: 16

      G2: 15
      Only baseline cholesterol values provided
      John 02, UKRandomised diet-controlled 2 group trialL: encouraged to eat more fruit + veg

      C: received same advice after 6 months
      L: variable, not standardised6 monthsHealthy, 338m/352f, 44.5 ± 19.5 yrsTotal: 690

      L: 344

      C: 346
      Lycopene intake not standardised
      Ahuja 06, AustraliaRandomised dietary crossover 2 group trialL1: L + olive-oil

      L2: L + carbohydrate
      Not provided10 days, washout 16 days before crossoverHealthy, 6m/15f, 44 ± 12 yrsTotal: 21No lycopene-free control group
      Madrid 06, ChileDiet-controlled 1 group repeated measures intervention trialL: Tomato juiceL: 120 μmol in 4 ml/kg1 weekHealthy students, 9m/8f, 22.5 ± 2.5 yrsTotal: 17Short duration 1 week
      Bose 07, IndiaDietary 1 group repeated measures intervention trialL: Cooked tomatoesNot provided in 200 g2 monthsHypertensive vs. normotensives, 45 ± 10 yrs,Total: 90No lycopene-free control
      Devaraj 09, USARandomised placebo-controlled dose–response 4 group trial, run-in: 2 weeksL1: Lycopene capsule (1/d)

      L2: Lycopene capsule (1/d)

      L3: Lycopene capsule (1/d)

      C: Placebo capsule (1/d)
      L1: 6.5 mg

      L2: 15 mg

      L3: 30 mg

      C: 0 mg
      8 weeksHealthy non-smokers, ≥40 yrsTotal: 82

      Lall: 59

      C: 18
      Used synthetic lycopene
      Abbreviations see Table 2.
      Twelve of the 14 included studies investigated natural lycopene on total cholesterol levels [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ,
      • Upritchard J.E.
      • Sutherland W.H.
      • Mann J.I.
      Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.
      ,
      • Hadley C.W.
      • Clinton S.K.
      • Schwartz S.J.
      The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage.
      ,
      • Kiokias S.
      • Gordon M.H.
      Dietary supplementation with a natural carotenoid mixture decreases oxidative stress.
      ,
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ,
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Blum A.
      • Merei M.
      • Karem A.
      • et al.
      Effects of tomatoes on the lipid profile.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ,
      • Misra R.
      • Mangi S.
      • Joshi S.
      • Mittal S.
      • Gupta S.K.
      • Pandey R.M.
      LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.
      ,
      • Silaste M.L.
      • Alfthan G.
      • Aro A.
      • Kesaniemi Y.A.
      • Horkko S.
      Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.
      ,
      • Shen Y.C.
      • Chen S.L.
      • Wang C.K.
      Contribution of tomato phenolics to antioxidation and down-regulation of blood lipids.
      ,
      • Jacob K.
      • Periago M.J.
      • Bohm V.
      • Berruezo G.R.
      Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation.
      ], and four studies reported on the effect of lycopene on blood pressure [
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ,
      • Paran E.
      • Novack V.
      • Engelhard Y.N.
      • Hazan-Halevy I.
      The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.
      ,
      • Ried K.
      • Frank O.R.
      • Stocks N.P.
      Dark chocolate or tomato extract for prehypertension: a randomised controlled trial.
      ]. Not all studies investigating the effect of lycopene on total cholesterol included details on HDL, LDL, or triglycerides (Table 5).
      Table 5Baseline lipids and blood pressure values of included studies.
      Study ID, locationTotal cholesterol (mg/dl)HDL (mg/dl)LDL (mg/dl)Triglycerides (mg/dl)SBP(mm Hg)DBP (mm Hg)
      Sakamoto 94, JapanL all: 184.4 (31.7)

      C: 177.0 (28.8)
      Lall: 62.8.8 (11.9)

      C: 55.8 (13.9)
      Lall: 101.8 (29.7)

      C: 101.1 (14.7)
      Lall: 98.9 (50.9)

      C: 71.8 (31.7)
      Upritchard 00, New ZealandL: 227.2 (39.5)

      C: 250.8 (44.1)
      ngngng
      Hadley 03, USALall + C: 202. 4 (60.0)ngngng
      Kiokias 03, UKL: 185.0 (10.8)

      C: 188.1 (10.8)
      L: 55.7 (12.8)

      C: 56.1 (13.2)
      L: 114.9 (27.5)

      C: 118.0 (9.3)
      L: 78.8 (25.7)

      75.3 19.5
      Collins 04, USALall + C (HC): 229.3 (10.9)

      Lall + C (LC): 176.6 (5.6)
      Lall + C (HC): 59.1 (6.5)

      Lall + C (LC): 46.9 (4.7)
      ngLall + C (HC): 190.9 (28.6)

      Lall + C (LC): 129.7 (11.6)
      Engelhard 06, IsraelL + C: 213.0 (35.8)L + C: 43.7 (8.7)L + C: 126.2 (33.6)L + C: 201.8 (88.0)

      L + C: 145.0 (7.2)L + C: 88.9 (7.8)
      Blum 06, IsraelL: 207.5 (44.3)

      C: 198.3 (41.2)
      L: 46.1 (10.6)

      C: 50.6 (12.2)
      L: 127.7 (41.8)

      C: 122.7 (39.4)
      L: 170.8 (85.4)

      C: 169.6 (156.8)
      Paterson 06, UKL: 181.9 (38.7)

      C: 185.8 (38.7)
      L: 54.2 (15.5)

      C: 54.2 (11.6)
      L: 112.2 (34.8)

      C: 116.1 (34.8)
      L: 70.9 (26.6)

      C:79.7 (26.6)
      L:112 (16)

      C: 112 (14)
      L: 68 (9)

      C: 68 (9)
      Misra 06, IndiaL: 215.1 (31.3)

      C: 204.3 (22.1)
      L: 47.6 (1.9)

      C: 46.8 (9.3)
      L: 132.0 (32.8)

      C: 131.8 (18.6)
      L: 123.0 (28.8)

      C: 128.1 (30.3)
      Silaste 07, FinlandL + C: 171.4 (24.8)ngL + C: 94.4 (19.7)ng
      Shen 07, TaiwanLall + C: 194.6 (31.5)Lall + C: 44.0 (7.0)Lall + C: 113.8 (13.0)Lall + C: 76.8 (33.3)
      Jacob 08, GermanyL + C: 157.1 (27.6)ngngng
      Paran 09, IsraelL + C: 144 (10)L + C: 82.2 (8.5)
      Ried 09 (phase 1), AustraliaL: 128.2 (11.4)

      C: 135.7 (12.4)
      L: 79.1 (7.5)

      C: 77.8 (8.6)
      Values are expressed as mean ± (SD). L, lycopene; C, control; HC, high cholesterol group; LC, low cholesterol group; ng, not given.
      Seven of the 14 studies included a discrete control group (placebo-controlled or lycopene-free diet controlled) [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ,
      • Upritchard J.E.
      • Sutherland W.H.
      • Mann J.I.
      Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.
      ,
      • Kiokias S.
      • Gordon M.H.
      Dietary supplementation with a natural carotenoid mixture decreases oxidative stress.
      ,
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ,
      • Blum A.
      • Merei M.
      • Karem A.
      • et al.
      Effects of tomatoes on the lipid profile.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ,
      • Misra R.
      • Mangi S.
      • Joshi S.
      • Mittal S.
      • Gupta S.K.
      • Pandey R.M.
      LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.
      ,
      • Paran E.
      • Novack V.
      • Engelhard Y.N.
      • Hazan-Halevy I.
      The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.
      ,
      • Ried K.
      • Frank O.R.
      • Stocks N.P.
      Dark chocolate or tomato extract for prehypertension: a randomised controlled trial.
      ], while five studies featured a repeated measure design incorporating a lycopene-free depletion period before and/or after treatment with lycopene [
      • Hadley C.W.
      • Clinton S.K.
      • Schwartz S.J.
      The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage.
      ,
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Silaste M.L.
      • Alfthan G.
      • Aro A.
      • Kesaniemi Y.A.
      • Horkko S.
      Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.
      ,
      • Shen Y.C.
      • Chen S.L.
      • Wang C.K.
      Contribution of tomato phenolics to antioxidation and down-regulation of blood lipids.
      ,
      • Jacob K.
      • Periago M.J.
      • Bohm V.
      • Berruezo G.R.
      Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation.
      ] (Table 2).
      Trials used lycopene-containing tomato products, watermelon juice, or tomato extract capsules as test intervention, dosages of lycopene ranged between 4 and 44 mg/day, and treatment periods ranged between 2 and 6 weeks or 6 months in one trial [
      • Misra R.
      • Mangi S.
      • Joshi S.
      • Mittal S.
      • Gupta S.K.
      • Pandey R.M.
      LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.
      ] (Table 2).
      Six of the 14 studies investigating blood lipids included participants with total cholesterol levels in the higher range (>200 mg/dl) [
      • Upritchard J.E.
      • Sutherland W.H.
      • Mann J.I.
      Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.
      ,
      • Hadley C.W.
      • Clinton S.K.
      • Schwartz S.J.
      The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage.
      ,
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ,
      • Blum A.
      • Merei M.
      • Karem A.
      • et al.
      Effects of tomatoes on the lipid profile.
      ,
      • Misra R.
      • Mangi S.
      • Joshi S.
      • Mittal S.
      • Gupta S.K.
      • Pandey R.M.
      LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.
      ], and two of four studies investigating blood pressure included participants with high SBP and DBP [
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Paran E.
      • Novack V.
      • Engelhard Y.N.
      • Hazan-Halevy I.
      The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.
      ] (Table 5).

      3.1.2 Quality assessment of included studies

      No studies were excluded on grounds of quality (Table 3). Meta-analysis methodology allowed inclusion of non-randomised trials, and non-reporting of allocation concealment in most trials did not allow meaningful subgroup or sensitivity analysis. Non-blinding of participants in trials using dietary-based interventions was acceptable, and drop-out rates were low in all trials included in meta-analysis. Compliance and dietary monitoring were assessed satisfactory in all but one trial [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ]. One trial allowed habitual consumption of lycopene-rich foods during the intervention period but not during the lycopene-poor run-in period, which might have inflated lycopene dosage and effect size [
      • Silaste M.L.
      • Alfthan G.
      • Aro A.
      • Kesaniemi Y.A.
      • Horkko S.
      Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.
      ]. Three trials reported receipt of food industry funding [
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ,
      • Blum A.
      • Merei M.
      • Karem A.
      • et al.
      Effects of tomatoes on the lipid profile.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ], and funding sources were not reported by four trials [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ,
      • Kiokias S.
      • Gordon M.H.
      Dietary supplementation with a natural carotenoid mixture decreases oxidative stress.
      ,
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Paran E.
      • Novack V.
      • Engelhard Y.N.
      • Hazan-Halevy I.
      The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.
      ].

      3.2 Meta-analyses

      3.2.1 Blood lipids

      3.2.1.1 Total cholesterol

      The effect of lycopene supplementation on total serum cholesterol was not significantly different to control treatment when all 13 trial arms of 12 studies including data of 694 participants were pooled (Fig. 3a) . However, a treatment effect was apparent when trials were divided into subgroups by lycopene dosage. Subgroup meta-analysis of six trial arms investigating the effect of a lycopene dosage ≥25 mg/day revealed a statistically significant reduction of total serum cholesterol compared with control (mean ΔTC = −7.55 [95% CI, −13.70, −1.40] mg/dl, p = 0.02) (Fig. 4a) . In contrast, subgroup meta-analysis of seven trial arms using a lycopene dosage <25 mg/day was not significantly different compared with control (Fig. 4b).
      Figure thumbnail gr3
      Fig. 3Meta-analysis including all studies of the effect of lycopene on blood lipids including (A) total serum cholesterol, (B) LDL cholesterol, (C) HDL cholesterol, (D) triglycerides
      [
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ]
      . HC/LC, high total cholesterol (≥200 mg/dl)/low cholesterol at baseline; N, number of participants; TC, total serum cholesterol; LDL, low-density lipoprotein; HDL, high density lipoprotein; TG, triglycerides; ΔTC/ΔLDL/ΔHDL/ΔTG, difference in mean lipids between start and end of intervention; SD, standard deviation; CI, confidence interval.
      Figure thumbnail gr4
      Fig. 4Subgroup meta-analysis of the effect of lycopene on total serum (A and B) and LDL cholesterol (C,and D) by lycopene dosages (high: lycopene ≥ 25 mg/day, low: lycopene < 25 mg/day). Abbreviations see .

      3.2.1.2 LDL cholesterol

      Eight studies reported on LDL cholesterol levels. Meta-analysis including all trial arms showed a borderline significant reduction of LDL cholesterol in the lycopene group compared with control (mean ΔLDL = −4.63 [95%CI, −9.24, −0.02] mg/dl, p = 0.05] (Fig. 3b). A significant treatment effect was revealed in the subgroup meta-analysis of four trial arms using a high lycopene dose (mean ΔLDL = −10.35 [−15.99, −4.71], p = 0.0003), reducing mean LDL levels at baseline (115.4 mg/dl) on average by 10% (Fig. 4c). In contrast, subgroup analysis of trials using a low lycopene dosage was not significant (Fig. 4d).

      3.2.1.3 HDL cholesterol and triglycerides

      Meta-analysis of the effect of lycopene on HDL cholesterol and triglyceride levels (both: n = 9 trial arms of 8 studies) was not significantly different (Fig. 3c and d). Heterogeneity was high for HDL cholesterol (I2 = 74%) and triglycerides (I2 = 75%), but was not explained by lycopene dosages.

      3.2.1.4 Sensitivity analyses

      The following sensitivity analyses were conducted to test the robustness of results: (A) We excluded one trial [
      • Misra R.
      • Mangi S.
      • Joshi S.
      • Mittal S.
      • Gupta S.K.
      • Pandey R.M.
      LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.
      ] as treatment duration was significantly longer than other trials (6 months versus 2–6 weeks), and the control group received hormone replacement therapy (HRT) as treatment. (B) We excluded three trials which reported the receipt of food industry funding [
      • Collins J.K.
      • Arjmandi B.H.
      • Claypool P.L.
      • Perkins-Veazie P.
      • Baker R.A.
      • Clevidence B.A.
      Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults.
      ,
      • Blum A.
      • Merei M.
      • Karem A.
      • et al.
      Effects of tomatoes on the lipid profile.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ]. (C) We excluded two trials in which dietary advice during the intervention period either was unclear [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ] or habitual lycopene-rich food intake was allowed during the intervention period but not during the run-in period potentially influencing effect size [
      • Silaste M.L.
      • Alfthan G.
      • Aro A.
      • Kesaniemi Y.A.
      • Horkko S.
      Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.
      ]. Sensitivity analyses did not alter the results significantly.

      3.2.2 Blood pressure

      Meta-analysis of four trials investigating the effect of lycopene on blood pressure [
      • Engelhard Y.N.
      • Gazer B.
      • Paran E.
      Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ,
      • Paran E.
      • Novack V.
      • Engelhard Y.N.
      • Hazan-Halevy I.
      The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.
      ,
      • Ried K.
      • Frank O.R.
      • Stocks N.P.
      Dark chocolate or tomato extract for prehypertension: a randomised controlled trial.
      ] revealed a significant reduction in systolic blood pressure compared with control (mean ΔSBP = −5.60 [−10.86, −0.33], p = 0.04) (Fig. 5a) . Blood pressure reduction was more pronounced when trials with high blood pressure at baseline (SBP ≥ 140 mm Hg) were included in subgroup meta-analysis (mean ΔSBPhigh = −9.35 [−11.01, −7.70], p < 0.001), and heterogeneity was greatly reduced (I2 = 0). In contrast, subgroup analysis of trial with SBP < 140 mm Hg at baseline was not significant (mean ΔSBPlow = −0.36 [−5.05, 4.33], p = 0.88, I2 = 0). Meta-analysis of all four trials on diastolic blood pressure was not significantly different between treatment and control groups (Fig. 5b).
      Figure thumbnail gr5
      Fig. 5Meta-analysis including all studies of the effect of lycopene on (A) systolic blood pressure and (B) diastolic blood pressure. ΔSBP/ΔDBP, difference in mean systolic blood pressure (SBP) or diastolic blood pressure (DBP) between start and end of intervention.

      3.3 Publication bias

      Funnel plots and Egger's test of trials investigating the effect of lycopene on total serum cholesterol or other blood lipids indicated no publication bias (Fig. 6). Assessment of publication bias of four studies reporting the effect of lycopene on blood pressure was not meaningful.
      Figure thumbnail gr6
      Fig. 6Funnel plots of trials included in the meta-analysis of the effect of lycopene on blood lipids: (A) Total serum cholesterol (n = 13), (B) LDL cholesterol (n = 8), (C) HDL cholesterol (n = 9), (D) = triglycerides (n = 9). The vertical line of Begg's funnel plot represents the pooled mean effect size, and the dotted lines represent the 95% confidence interval. All p-values derived from Egger's test were not significant indicating no publication bias.

      4. Discussion

      Our meta-analyses of effects on blood lipids suggest that lycopene is effective in reducing total serum cholesterol and LDL cholesterol if taken in higher dosages than 25 mg daily. A reduction of mean LDL cholesterol ± SE: −10.35 ± 5.64 mg/dl (0.27 ± 0.15 mmol/l, p = 0.0003) or 10% in LDL cholesterol is comparable to the effect of low doses of statin drugs in patients with slightly elevated cholesterol levels [
      • Jones P.
      • Kafonek S.
      • Laurora I.
      • Hunninghake D.
      Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).
      ,
      • Steinhagen-Thiessen E.
      Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group.
      ] and is clinically significant. A reduction of 10 mg/dl in LDL levels compared to >100 mg/dl baseline levels has been associated with a modest but significant reduction in the development of coronary heart disease (6.6%), major vascular events (5.8%), stroke (4.1%), and mortality (4.6%) [
      • Delahoy P.J.
      • Magliano D.J.
      • Webb K.
      • Grobler M.
      • Liew D.
      The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis.
      ]. Mean baseline LDL cholesterol levels were slightly elevated (mean LDL = 115 mg/dl) in all studies included in our meta-analysis. LDL cholesterol reducing properties of lycopene have been associated with the suppression of cholesterol synthesis, increase of LDL degradation, and inhibition of HMG-CoA-reductase, the enzyme which is also inhibited by statin drugs [
      • Fuhrman B.
      • Elis A.
      • Aviram M.
      Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages.
      ].
      The observed modest reduction of total serum cholesterol (mean TC change ± SE: −7.55 ± 6.15 mg/dl (0.20 ± 0.16 mmol/l); p = 0.02) in our meta-analysis might be attributable to the effect of lycopene on LDL-cholesterol and may be clinically of modest relevance, whereby a 2.8% reduction of total cholesterol may reduce cardiovascular risk by 4% [
      • Lewington S.
      • Whitlock G.
      • Clarke R.
      • et al.
      Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths.
      ].
      We undertook subgroup meta-analysis by high or low dosage of lycopene, as other studies have provided evidence to suggest that observation of a hypolipidaemic effect is dose-dependent. In a study conducted in hamsters, Hsu et al. [
      • Hsu Y.-M.
      • Lai C.-H.
      • Chang C.-Y.
      • Fan C.-T.
      • Chen C.-T.
      • Wu C.-H.
      Characterizing the lipid-lowering effects and antioxidant mechanisms of tomato paste.
      ] found that a higher dose of lycopene (9% in tomato paste) had a significant cholesterol-lowering effect on total serum cholesterol (14.3%), and LDL cholesterol (11.3%), while a lower dose of 3% lycopene did not alter total serum or LDL cholesterol levels significantly. The LDL cholesterol reduction of about 10% apparent in our subgroup meta-analysis of high lycopene dosage is comparable to the findings by Hsu et al. [
      • Hsu Y.-M.
      • Lai C.-H.
      • Chang C.-Y.
      • Fan C.-T.
      • Chen C.-T.
      • Wu C.-H.
      Characterizing the lipid-lowering effects and antioxidant mechanisms of tomato paste.
      ], and is also similar to the observed 14% LDL cholesterol reduction in a small 3-month single group intervention trial using a daily dosage of 60 mg of lycopene in tomato extract [
      • Fuhrman B.
      • Elis A.
      • Aviram M.
      Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages.
      ].
      Furthermore, a higher intake of lycopene has been associated with higher lycopene levels in plasma. A pharmacokinetic study reported a dose-dependent increase in plasma levels of lycopene when single dosages of 90 or 120 mg of lycopene were administered [
      • Gustin D.M.
      • Rodvold K.A.
      • Sosman J.A.
      • et al.
      Single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste–oil mixture) in healthy adult male subjects.
      ].
      However, absorption levels of lycopene are influenced by several factors, including the processing of tomato products and the presence of dietary fats. Heating and homogenization enhance the release of lycopene [
      • Gartner C.
      • Stahl W.
      • Sies H.
      Lycopene is more bioavailable from tomato paste than from fresh tomatoes.
      ,
      • Nguyen M.L.
      • Schwartz S.J.
      Lycopene stability during food processing.
      ,
      • Porrini M.
      • Riso P.
      • Testolin G.
      Absorption of lycopene from single or daily portions of raw and processed tomato.
      ], and dietary fat promotes lycopene absorption via the stimulation of bile production for the formation of bile acid micelles [
      • Lee A.
      • Thurnham D.I.
      • Chopra M.
      Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma.
      ,
      • Clark R.M.
      • Yao L.
      • She L.
      • Furr H.C.
      A comparison of lycopene and astaxanthin absorption from corn oil and olive oil emulsions.
      ]. Intake of lycopene in the presence of monounsaturated fats found in avocado, for example, optimises absorption [
      • Unlu N.Z.
      • Bohn T.
      • Clinton S.K.
      • Schwartz S.J.
      Carotenoid absorption from salad and salsa by humans is enhanced by the addition of avocado or avocado oil.
      ]. Additionally, absorption is dependent on the transformation of trans-isomers of lycopene in food to cis-isomers in body tissues, facilitated by acidic conditions in the stomach and small intestine [
      • Stahl W.
      • Sies H.
      Lycopene: a biologically important carotenoid for humans?.
      ,
      • Re R.
      • Fraser P.D.
      • Long M.
      • Bramley P.M.
      • Rice-Evans C.
      Isomerization of lycopene in the gastric milieu.
      ].
      Our meta-analysis of effects on blood pressure suggests lycopene to be superior to placebo in lowering systolic blood pressure, in particular in hypertensive subjects (mean SBPall ± SE: −5.6 ± 5.3 mm Hg, p = 0.04; mean SBPhigh change ± SE: −9.35 ± 1.65 mm Hg, p < 0.001). The marked treatment effect between hypertensive compared with normotensive subgroups is in line with the effect of other nutritional supplements [
      • Ried K.
      • Frank O.R.
      • Stocks N.P.
      • Fakler P.
      • Sullivan T.
      Effect of garlic on blood pressure: a systematic review and meta-analysis.
      ,
      • Ried K.
      • Sullivan T.
      • Fakler P.
      • Frank O.R.
      • Stocks N.P.
      Does chocolate reduce blood pressure? A meta-analysis.
      ]. Blood pressure lowering properties of lycopene have been attributed to the stimulation of nitric oxide production in the endothelium [
      • Umans J.G.
      • Levi R.
      Nitric oxide in the regulation of blood flow and arterial pressure.
      ]. Yet, only a small number of trials (n = 4) have investigated the effect of lycopene products on blood pressure to date, requiring confirmation of findings by additional studies.
      The methodology used in our meta-analyses allowed the combination of data from parallel and cross-over trials, as well as trials with repeated measure design. However, more high quality trials are needed to ascertain whether different types of lycopene products, duration of treatment, baseline cholesterol levels, or population specific parameters such as general diet, affect outcomes differently. It is interesting to note that trials conducted in Asian and northern European populations [
      • Sakamoto H.
      • Mori H.
      • Ojima F.
      • et al.
      Elevation of serum carotenoids after continual ingestion of tomato juice.
      ,
      • Kiokias S.
      • Gordon M.H.
      Dietary supplementation with a natural carotenoid mixture decreases oxidative stress.
      ,
      • Paterson E.
      • Gordon M.H.
      • Niwat C.
      • et al.
      Supplementation with fruit and vegetable soups and beverages increases plasma carotenoid concentrations but does not alter markers of oxidative stress or cardiovascular risk factors.
      ,
      • Silaste M.L.
      • Alfthan G.
      • Aro A.
      • Kesaniemi Y.A.
      • Horkko S.
      Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation.
      ,
      • Shen Y.C.
      • Chen S.L.
      • Wang C.K.
      Contribution of tomato phenolics to antioxidation and down-regulation of blood lipids.
      ] had lower lipid levels at baseline compared with the other trials, which might be linked to population specific dietary factors.
      Moreover, further research is needed to explore the effect of high doses of lycopene on cholesterol and blood pressure. In our meta-analysis, the highest doses of lycopene administered over a 4–6 week period were 40–44 mg daily, equivalent to about 500 ml of tomato juice [
      • Upritchard J.E.
      • Sutherland W.H.
      • Mann J.I.
      Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.
      ,
      • Shen Y.C.
      • Chen S.L.
      • Wang C.K.
      Contribution of tomato phenolics to antioxidation and down-regulation of blood lipids.
      ]. These are smaller doses than those used in two trials not included in our meta-analysis: 60 mg daily over 3 months [
      • Fuhrman B.
      • Elis A.
      • Aviram M.
      Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages.
      ], 50–75 mg daily over 1 week [
      • Agarwal S.
      • Rao A.V.
      Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study.
      ]. Larger doses of lycopene up to 200 mg daily long-term appear to cause minimal side effects: a rare but reversible condition (lycopenemia) of orange discolouration of the palms has been described in an individual who consumed more than 200 mg of lycopene in form of 2 l of tomato juice daily over several years [
      • Reich P.
      • Shwachman H.
      • Craig J.M.
      Lycopenemia: a variant of carotenemia.
      ].
      The beneficial effects of lycopene found in our meta-analyses add to a range of other cardiovascular benefits of lycopene described in the literature. Lycopene has been associated with reduction in platelet aggregation [
      • Dutta-Roy A.K.
      • Crosbie L.
      • Gordon M.J.
      Effects of tomato extract on human platelet aggregation in vitro.
      ,
      • Hsiao G.
      • Wang Y.
      • Tzu N.H.
      • et al.
      Inhibitory effects of lycopene on in vitro platelet activation and in vivo prevention of thrombus formation.
      ], decreased LDL oxidation and other anti-atherosclerotic properties including prevention of endothelial injury, reduction of inflammatory responses, and inhibition of smooth muscle cell proliferation [
      • Palozza P.
      • Parrone N.
      • Simone R.E.
      • Catalano A.
      Lycopene in atherosclerosis prevention: an integrated scheme of the potential mechanisms of action from cell culture studies.
      ].

      5. Conclusion

      This is the first study to summarise the effect of lycopene on blood lipids and blood pressure. Our meta-analyses suggest lycopene to be effective in reducing LDL cholesterol and total serum cholesterol if taken in doses higher than 25 mg daily, and in reducing systolic blood pressure in hypertensives. The LDL cholesterol-reducing effect of lycopene of about 10% is comparable to the effect of low dose statins. While statins are highly effective cholesterol-lowering medications, side effects including muscle pain, muscle weakness, and neuropathy are experienced by some patients [
      • Sinzinger H.
      • Wolfram R.
      • Peskar B.A.
      Muscular side effects of statins.
      ,
      • Moosmann B.
      • Behl C.
      Selenoprotein synthesis and side-effects of statins.
      ,
      • Jeppesen U.
      • Gaist D.
      • Smith T.
      • Sindrup S.H.
      Statins and peripheral neuropathy.
      ]. Lycopene may be considered as alternative to low dose statins without these side effects in patients with slightly elevated cholesterol levels.
      More research is needed to explore whether doses higher than 25–44 mg/day of lycopene, provide additional beneficial effects on blood lipids compared with control, and confirm whether lycopene is effective in reducing blood pressure in hypertensives.

      Competing interest

      None of the authors had a personal or financial conflict of interest.

      Contributors

      KR conceptualised the study, and undertook data collection, extraction, and quality assessment with PF. KR undertook data analysis and interpretation, and prepared the manuscript with contributions from PF. All authors approved the final version.

      Funding

      This study was supported by the Primary Health Care Research Evaluation Development (PHCRED) Program funded by the Australian Government of Health and Ageing.

      Provenance and peer review

      Commissioned and externally peer reviewed.

      Acknowledgments

      We gratefully acknowledge Thomas Sullivan for statistical advice and Dr Oliver Frank for comments on the manuscript.

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