INTEGRATORI ALIMENTARI CREDENZE ED EVIDENZE

INTEGRATORI
ALIMENTARI
CREDENZE ED EVIDENZE
Fabio Galvano
Dipartimento di Chimica Biologica, Chimica Medica e Biologia Molecolare
Università di Catania
Perché integrare ?
• Pregiudizio comune è che il cibo che mangiamo non sia in
grado di sopperire al fabbisogno quotidiano di nutrienti e
che quindi vada integrato…
• “Il concetto di integrare dà l’impressione di completezza, di
un rimedio possibile all’idea che gli alimenti siano
insufficienti ad assicurare la nostra efficienza e quindi la
nostra salute.
• Mai come in questi ultimi decenni, nei Paesi
industrializzati, vi è stata abbondanza di cibo; un cibo
iperproteico ed ipercalorico che spesso è alla base
dell’obesità che si sta diffondendo in modo pauroso e
preoccupante. Perchè allora la necessità di integratori
alimentari ?”.
S. Garattini, Negri News, 2003
In quali casi integrare ?
• Carenze conseguenti a stati patologici
– Alterata digestione/assorbimento
– Diminuito introito o aumentata escrezione
• Anoressia, Vomito, Degenza ospedaliera
– Mancata o ridotta sintesi endogena
• Epatopatia alcolica e aminoacidi ramificati e Omega-3
• Carenze conseguenti a scelte etiche
– Vegetariani e ferro (?)
– Vegani e Vit. B12
• Aumentati fabbisogni
– Folati in gravidanza
Integrazione
Credenze vs Evidenze
Randomized Controlled
Double Blind
Studies
Systematic Reviews and
Metanalysis
Cohort Studies
Case Control Studies
Series Reports
Case Reports
Ideas, Editorials, Opinion
Animal research
In vitro (“test tube”) research
Antiossidanti
Mortality in Randomized Trials of Antioxidant Supplements for Primary and
Secondary Prevention. Systematic Review and Meta-analysis.
Data Sources and Trial Selection All randomized trials involving adults comparing beta carotene,
vitamin A, vitamin C, vitamin E, and selenium either singly or combined vs placebo or vs no
intervention were included in our analysis. Randomization, blinding, and follow-up were considered
markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality
was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95%
confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the
trials.
Data Extraction We included 68 randomized trials with 232 606 participants (385 publications).
Data Synthesis When all low- and high-bias risk trials of antioxidant supplements were pooled
together there was no significant effect on mortality (RR, 1.02; 95% CI,0.98-1.06). Multivariate
meta-regression analyses showed that low-bias risk trials (RR,1.16; 95% CI, 1.05-1.29) and
selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 lowbias trials with 180 938 participants, the antioxidant supplements significantly increased mortality
(RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta
carotene (RR, 1.07;95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E
(RR, 1.04;95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and
selenium had no significant effect on mortality.
Conclusions: Treatment with beta carotene, vitamin A, and vitamin E may increase mortality.
The potential roles of vitamin C and selenium on mortality need further study.
Bjelakovic G. et al. JAMA. 2007;297:842-857
Integrazione Antiossidanti e
anziani
Nutritional Supplements for Older Adults.
Review and Recommendations.
Conclusions
• While recommendations that older adults take a daily MVM are
common, there is limited scientific support for the health-related
efficacy of these supplements.
• In contrast, a number of antioxidant nutrients have been extensively
studied.
• The evidence does not support a recommendation for vitamins A, C,
E, or antioxidant combinations in the prevention of CVD or cancer.
• In contrast to the state of the art for antioxidant supplements, there is
strong and compelling support for the health benefits of supplements
of Vitamin D and calcium when intake/status of these nutrients is not
optimal.
• Thus, specific recommendations for these supplements in older
adults are warranted.
Buhr A.G., Bales C.W. J Nutr Elder. 2009 28:5-29
Integratori
e
Tumori
Beta-carotene e tumore del
polmone
Beta-carotene e tumore della
pelle (non-melanoma)
Beta-carotene e CVD
• Integratori vs Dieta: Sebbene in studi di
osservazione diete ricche in beta-carotene sono
state associate con una riduzione del rischio di
malattie CDV non vi è nessuna evidenza che
l’integrazione con beta-carotene produca lo
stesso effetto
• Tossicità: In due RCT (2000 e 2002) e uno studio
epidemiologico (2009) alti dosaggi di integratori di
beta-carotene hanno aumentato il rischio di tumore
del polmone in soggetti fumatori.
Michaud DS, et al. Am J Clin Nutr. 2000;72(4):990-997.
Holick CN et al. Am J Epidemiol. 2002;156(6):536-547.
Satia JA et al. Am J Epidemiol. 2009; 169(7):815-28.
Frutta e verdura? Sì!
Integratori? No!
Acidi grassi n-3
Risk/Benefit
Acidi grassi Omega-3: cosa sono?
Acidi grassi polinsaturi a lunga catena (LC-PUFA)
EPA (20:5)
DHA (22:6)
(Acido Eicosapentaenoico)
(Acido Docosaesanoico)
Derivati dall’acido α-linolenico (ALA o 18:3 Omega-3), un acido
grasso essenziale: derivazione poco efficiente
DPA (22:6)
(Acido Docosaesanoico)
Derivato dall’acido linoleico (AL o 18:2 Omega-6), contenuto
negli oli di semi
Background
Greenland Eskimo Study
• “Eskimo paradox”
– Dieta tradizionale – elevati intake di grassi e
proteine bassissimi intake di fibre, frutta e vegetali
– Bassa incidenza di malattie CDV e bassi livelli di
colesterolo.
• Alimenti base: foche, balene e pesce (contenenti alti
livelli di DHA e EPA)
• Modesto intake di omega-6
Ref.: Rosenberg. Fish-food to claim the Heart-Perspective- N. Engl.J.Med., 2002: Vol
346: No.15:1102-03
Rationale for Research/Health Interest in
PUFA
Epidemiological/Population Studies
1.) Higher levels of docosahexaenoic acid (DHA, 22:6 n-3) and
docosapentaenoic acid (DPA, 22:5 n-3) in serum phospholipid
have been associated with decreased coronary heart disease risk.
(Simon et al., Am. J. Epidemiol., 142: 469-476, 1995.)
2.) Higher levels of eicosapentaenoic acid (EPA, 20:5 n-3) and
docosapentaenoic acid (DPA, 22:5 n-3) in platelet phospholipid
have been associated with reduced coronary artery disease
(Hodgson et al., AJCN, 58:228-234, 1993).
E’ sufficiente la biosintesi
endogena di PUFA?
• In alcuni soggetti la biosintesi endogena è
insufficiente:
– Nascita pretermine
– Senescenza
– Diabete
– Insulino resistenza
– Alcolismo
– Alterazioni perossisomi
E’ sufficiente l’apporto dietetico?
Average DHA Consumption
in the U.S.
2. Ervin RB, et al. DHHS Publication No.
(PHS) 2005-1250 04-0565.
4. Wang C, et al. AHRQ Publication No. 04E009-1, 2004. Agency for
Healthcare Research and Quality,
Rockville, MD.
13. Rigopoulos AP, et al. Ann Nutr Metab,
1999.43(2):127-30.
14. Benisek D, et al. Obstet Gynecol, 2000.
95(4 Suppl1):S77-S78.
N.B. 2 studi pubblicati in proprio
1 Abstract
1 Peer review paper
E’ sufficiente l’apporto dietetico?
E’ sufficiente l’apporto dietetico?
• LA e ALA dietetici si accumulano nel
TA
• Indagine sulla composizione TA negli
USA: bassi livelli ALA
TA
insufficiente introduzione dietetica?
• Sintomi da carenza a lungo termine?
• Carenza DHA a livello SNC?
L’apporto raccomandato è
sufficiente per tutte le funzioni?
• I PUFA n-3 potrebbero avere effetti benefici
per la salute se introdotti al di sopra delle
quantità raccomandate:
• protezione cardiovascolare
• azione ipotrigliceridemizzante
• azione antinfiammatoria
Omega 3 e trigliceridi
• La FDA ha approvato la commercializzazione di integratori
di EPA e DHA (0,84g/cps) da assumere in ragione di 2-4
cps/d
• L’American Heart Association ne raccomanda l’assunzione
sotto stretto controllo medico ed esclusivamente nei casi di
grave ipertrigliceridemia (>500 mg/dl)
• La riduzione è del 45% in 2/4g
Pharmacotherapy 2007;27(5):715–728
Omega 3 e trigliceridi
Approccio dietetico
Approccio
farmacologico
Pharmacotherapy 2007;27(5):715–728
Omega 3: quali evidenze ?
• Review sistematiche e Metanalisi
• Severi criteri di inclusione degli studi
• RCT
• Fattori confondenti (bias)
• Numerosità soggetti
• Durata del trial
Omega 3 e Diabete
Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus (Review)
Objectives
To determine the effects of omega-3 PUFA supplementation on cardiovascular outcomes,
cholesterol levels and glycemic control in people with type 2 diabetes.
Main results
23 RCT (1075 participants) were included with a mean treatment duration of 8.9 weeks. The
mean dose of omega-3 PUFA used in the trials was 3.5 g/d.
Omega-3 PUFA supplementation in type 2 diabetes lowers triglycerides ……………
No significant change in or total or HDL cholesterol, HbA1c, fasting glucose, fasting
insulin or body weight was observed.
No adverse effects of the intervention were reported.
Authors’ conclusions
Omega-3 PUFA supplementation in type 2 diabetes has no statistically significant effect on
glycemic control or fasting insulin.
Hartweg J. et al. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD003205.
Omega 3 e Gravidanza
RAZIONALE
• DHA costituisce il 40% degli ac. grassi del cervello e il
60% della retina
• I fabbisogni aumentano nel periodo di massimo
sviluppo cerebrale
– Dall’ultimo trimestre di gravidanza a 2 anni
• Il 70% delle cellule cerebrali si sviluppa prima della
nascita
• Il contenuto di PUFA nel latte materno dipende dalla
dieta
Omega 3 e Gravidanza
Marine oil, and other prostaglandin precursor, supplementation for
pregnancy uncomplicated by preeclampsia or intrauterine growth restriction
Objectives
To estimate the effects of marine oil supplementation during pregnancy on the risk of
pre-eclampsia, preterm birth, low birthweight and small-for-gestational age.
Main results
Six trials, involving 2783 women, are included in this review. Women allocated a
marine oil supplement had a mean gestation that was 2.6 days longer than women
allocated to placebo or no treatment. Birthweight was slightly greater in infants born
to women in the marine oil group compared with control. However, there were no overall
differences between the groups in the proportion of low birthweight or small-forgestational age babies. There was no clear difference in the relative risk of preeclampsia between the two groups.
Authors’ conclusions
There is not enough evidence to support the routine use of marine oil, or other
prostaglandin precursor, supplements during pregnancy to reduce the risk of preeclampsia, preterm birth, low birthweight or small-for-gestational age.
Makrides M,et al. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003402..
Omega 3 e Morbo di Chron
Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease
Main results
Six studies were eligible for inclusion. There was a marginal significant benefit of n-3
therapy for maintaining remission. However, the studies were both clinically and
statistically heterogeneous. Two large studies showed negative results. When
considering the estimated rather than the observed 1-year relapse rate of these two
studies, the benefit was no longer statistically significant. No serious adverse events
were recorded in any of the studies but in a pooled analyses there was a significantly
higher rate of diarrhea and symptoms of the upper gastrointestinal tract in the n-3
treatment group.
Authors’ conclusions
Omega 3 fatty acids are safe but probably ineffective for maintenance of remission
in CD. The existing data do not support routine maintenance treatment of Crohn’s
disease with omega 3 fatty acids.
Turner D. et al. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006320.
Omega 3 e Fibrosi Cistica
Omega-3 fatty acids (from fish oils) for cystic fibrosis
Objectives
To determine whether there is evidence that omega-3 polyunsaturated fatty acid
supplementation reduces morbidity and mortality. To identify any adverse events
associated with omega-3 polyunsaturated fatty acid supplementation.
Main results
Searches identified seven studies; three of which, involving 48 participants, were
eligible for inclusion in the review.
Authors’ conclusions
This review found that regular omega-3 supplements may provide some benefits
for people with CF with relatively few adverse effects, although the evidence is
insufficient to draw firm conclusions or to recommend routine use of
supplements of omega-3 fatty acids in people with CF. This review has highlighted
the lack of data for many of the outcomes likely to be meaningful to people with or
making treatment decisions about CF.
McCarney C. et al. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD002201.
Omega 3 e Psicosi maniacodepressiva
Omega-3 fatty acids for bipolar disorder (Review)
Objectives
To review the efficacy of omega-3 fatty acids as either a monotherapy or an adjunctive
treatment for bipolar disorder.
Main results
Five studies met inclusion criteria for the review, however, methodological quality was highly
variable. Only one study, involving 75 participants, provided data for analysis, and
showed a benefit of active treatment over control for depression symptom levels and
Clinical Global Impression scores but not for mania. No serious adverse effects were reported
in the five studies.
Authors’ conclusions
Results from one study showed positive effects of omega-3 as an adjunctive treatment for
depressive but not manic symptoms in bipolar disorder. These findings must be regarded
with caution owing to the limited data available.
Mongomery P. et al. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD005169.
Other records on Omega 3 or
marine oils
Omega 3 fatty acid for the prevention of dementia.
Lim WS et al. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005379.
Polyunsaturated fatty acid supplementation for schizophrenia. Joy CB et al. Cochrane
Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001257.
Dietary interventions for multiple sclerosis.
Farinotti M et al. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD004192.
Omega 3 fatty acids (fish oil) for maintenance of remission in ulcerative colitis
Turner D et al. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006443.
Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of
cancer cachexia. Dewey A et al. Cochrane Database of Systematic Reviews 2007, Issue 1. Art.
No.: CD004597.
Omega-3 fatty acids for intermittent claudication. Sommerfield T et al. Cochrane Database of
Systematic Reviews 2007, Issue 4. Art. No.: CD003833.
Authors’ conclusions
Limited data available. Neither evidence of beneficial nor adverse effects.
LA e ALA competono per gli stessi enzimi
LA
ALA
Il rapporto dietetico
Omega-6:Omega-3 è
importante!
Omega 6 / Omega 3 e prostaglandine
Omega 3
Omega 6
Acido linoleico
Acido alpha-linolenico
desaturasi (delta-6)
Acido Gamma linolenico
elongasi
acido eicosapentanoico (EPA)
(olio di pesce)
Acido Diomogamma linolenico
desaturasi (delta-6)
Prostaglandine serie 1
PGA1 (++)
Acido arachidonico
Prostaglandine serie 2
PGA2 (---)
acido docosoesanoico
(DHA)
Prostaglandine
serie 3 (PGA3) (++)
Qualcosa è cambiata…..?
• Gli uomini del paleolitico introducevano una
dieta con rapporto Omega 6:Omega 3 = 2:1
• La dieta occidentale moderna ha portato ad un
rapporto Omega 6:Omega 3 20-25:1
• E’ accreditata l’ipotesi che dall'alterato rapporto
tra Omega 3 e Omega 6 possano scasturire
fenomeni infiammatori.
Cosa è cambiato…..?
Olio Cuore, leggero, dietetico!
Mangiar bene per sentirsi in
forma!
•
Nel 1998 la pubblicità dell'olio Cuore è
stata censurata come pubblicità ingannevole
•
Non esistono certezze scientifiche circa gli effetti
positivi sulle malattie cardiovascolari ricollegabili
all'olio Cuore
L'olio di mais contiene una considerevole quantità
di acidi grassi polinsaturi che possono comportare
conseguenze negative per la salute
•
Leggiamo le etichette !!!!!!!
Oli di semi
Oli vegetali
Grassi vegetali
Grassi idrogenati
Margarina
WARNING
• L’eccessiva introduzione di PUFA, ad
esempio attraverso integratori o alimenti
fortificati (latte, uova) modifica la
regolazione della via biosintetica
• La supplementazione con PUFA n-3 senza
un controllo sull’intake di n-6 potrebbe
essere inutile
WARNINGS
Rischio Mercurio ?
RAZIONALE
• Le raccomandazioni dietetiche invitano ad un
maggiore consumo di esce
• Aumentando l’intake di pesce aumenta anche
l’intake di mercurio
• E’ preferibile mangiare pesce o assumere
integratori?
Rischio Mercurio ?
Evidence Synthesis ……………… Women of childbearing age and nursing
mothers should consume 2 seafood servings/wk, limiting intake of selected
species. Health effects of low-level methylmercury in adults are not clearly
established; methylmercury may modestly decrease the cardiovascular
benefits of fish intake. A variety of seafood should be consumed; individuals
with very high consumption (5 servings/wk) should limit intake of species
highest in mercury levels.
Conclusions For major health outcomes among adults, based on both the
strength of the evidence and the potential magnitudes of effect, the benefits
of fish intake exceed the potential risks. For women of childbearing age,
benefits of modest fish intake, excepting a few selected species, also
outweigh risks.
JAMA Mozzafarrian et al. 2006;296:1885-1899.
Rischio Mercurio ?
Risks and Benefits of Fish Intake
To the Editor: In the Clinical Review of the health effects of fish intake and contaminants by Drs Mozaffarian and
Rimm,1 mercury contamination was evaluated as a potential risk factor for cardiovascular disease, in their Figure
5 and the accompanying text. However, both the figure and the conclusions seem to be misleading because the
meta-analysis includes studies that are not relevant to the issue examined. Dentists and participants mainly
exposed to inorganic mercury from amalgam should have been excluded.
Also, while the authors note that the 2 studies from Sweden tend to point toward lower CHD risk at higher levels of
mercury intake, they do not mention that the overall mercury levels in the Swedish participants are far less than
those in the Finns. In addition, one of the Swedish studies2 primarily examined the long-term health effects of
inorganic mercury from amalgam fillings, as reflected in the serum concentration, not the methylmercury exposure
from fish.
The increased risk in the European multicenter study3 occurred at a relatively high exposure, as did the increased
risk in the Finnish studies.4 Hence, it is likely that the adverse cardiovascular effects of methylmercury only begin
to overcome the beneficial effects of fish at higher exposure levels. The meta-analysis erroneously combined
populations with low and high exposures. A more appropriate meta-analysis could have been achieved by using
the Finnish data,4 data from the study by Guallar et al,3 and the nondentist participants of the study by Yoshizawa
et al.5 A more precise definition of "higher levels of mercury exposure" should have been presented when
examining the individual results or the pooled result. The given relative risks are derived from different exposure
quantiles in different studies. For example, in the study by Virtanen et al,4 the relative risk is for the highest third,
and in the study by Guallar et al,3 the relative risk is for the highest fifth.
JAMA 2006;297:585-586.
Occorre quindi:
• Controllare che il fabbisogno di EFA (LA e
ALA) sia coperto nella popolazione
r una
e
P
• Rivedere i fabbisogni di PUFA, in
ne
nutrizio
particolare n-3, considerandoli
ottimale
indipendentemente da quelli di ALA
• Riconsiderare il bilancio corretto tra PUFA
n-6 ed n-3
• Variare il più possibile tipo e taglia di
pesce
Conclusioni
• Le evidenze scientifiche pro-integrazione sono limitate a poche
e ben definite patologie, stati di carenza o aumentati fabbisogni
• Emergono preoccupanti esempi di rischio connesso all’uso
ingiustificato e incontrollato di integratori
• L’approccio all’integratore dovrebbe essere
medico/farmacologico e non dietetico:
– ove necessaria l’integrazione deve essere gestita sotto controllo medico.
NO al fai da te
• E’ pur vero che molti medici prescrivono integratori senza
ragione
• L’integratore non può sostituire l’alimento
– Frutta e verdure vs integratori vitaminico-minerali
• L’integratore non deve essere l’alibi per evitare comportamenti
virtuosi ma impegnativi: dieta ed attività fisica