Luis Serra-Majem

Effect of the Mediterranean diet on blood pressure in the PREDIMED trial: results from a randomized controlled trial

BackgroundHypertension can be prevented by adopting healthy dietary patterns. Our aim was to assess the 4-year effect on blood pressure (BP) control of a randomized feeding trial promoting the traditional Mediterranean dietary pattern.MethodsThe PREDIMED primary prevention trial is a randomized, single-blinded, controlled trial conducted in Spanish primary healthcare centers. We recruited 7,447 men (aged 55 to 80 years) and women (aged 60 to 80 years) who had high risk for cardiovascular disease. Participants were assigned to a control group or to one of two Mediterranean diets. The control group received education on following a low-fat diet, while the groups on Mediterranean diets received nutritional education and also free foods; either extra virgin olive oil, or nuts. Trained personnel measured participants’ BP at baseline and once yearly during a 4-year follow-up. We used generalized estimating equations to assess the differences between groups during the follow-up.ResultsThe percentage of participants with controlled BP increased in all three intervention groups (P-value for within-group changes: P<0.001). Participants allocated to either of the two Mediterranean diet groups had significantly lower diastolic BP than the participants in the control group (−1.53 mmHg (95% confidence interval (CI) −2.01 to −1.04) for the Mediterranean diet supplemented with extra virgin olive oil, and −0.65 mmHg (95% CI -1.15 to −0.15) mmHg for the Mediterranean diet supplemented with nuts). No between-group differences in changes of systolic BP were seen.ConclusionsBoth the traditional Mediterranean diet and a low-fat diet exerted beneficial effects on BP and could be part of advice to patients for controlling BP. However, we found lower values of diastolic BP in the two groups promoting the Mediterranean diet with extra virgin olive oil or with nuts than in the control group.Trial registrationCurrent Controlled Trials ISRCTN35739639

Systematic reviews of the role of omega-3 fatty acids in the prevention and treatment of disease

This issue of the BJN provides a series of up to date systematic reviews on the pleiotropic effects of omega-3 fatty acids in health promotion and disease prevention. It is not yet 100 years since the studies of George and Mildred Burr provided the first evidence for the essential nature of specific types of fats. This was only made possible by the earlier pioneering work of EV McColllum who demonstrated by controlled studies that certain substances were necessary in small but measurable quantities for normal health in rats. He named these substances ‘fat-soluble A’ and ‘water-soluble B’, thus initiating the alphabetical nomenclature for vitamins. His first thoughts were that there existed one fat-soluble A and one water-soluble B, but further work in his laboratory and elsewhere soon indicated that there were numerous chemical entities involved. The prevailing view at the time was that fat represented mainly a source of energy and that its hydrophobic nature allowed energy to be concentrated better than what was possible with starches. However, prominent nutritionists indicated that animals could make fat from carbohydrates provided energy supply was in excess and ridiculed those that postulated other potential roles for fats. George Burr worked with Evans at the time and contributed in establishing that the elusive vitamin E was in the unsaponifiable fraction. Thus for a period of time Burr was drawn away from considering fatty acids as a potential novel essential dietary factor. In the process, they established that animals fed on a fat-free diet composed of casein, sugar yeast, and the unsaponifiable fraction of wheat germ and cod liver oils developed deficiency symptoms. Evans was searching for a new vitamin that could explain the observed skin changes, while Burr decided to explore the saponifiable components. This was a turning point in his path to discovery of essential fatty acids. He left Evans’ laboratory at Berkeley moving to Minnesota. Burr took two cages of Long Evans rats with him. He also took Mildred Lawson who was in charge of the rat colony. The rest is history: soon after they established a laboratory and a rat colony, they announced (in 1929) that unsaturated fat was essential, and in 1930 that linoleic acid, and possibly other fatty acids, were also active in reversing the skin changes and in restoring growth seen in rats fed fat-free diets. Work over the following 60 years conclusively determined the essential nature of both linoleic and a-linolenic acids. Yet few considered the importance of these nutrients for human health until the past decades where the full significance of dietary essential fatty acids has been realized considering their role in the synthesis of prostanoids and the myriad of pleiotropic functions that relate directly and indirectly to them. The prevailing belief was deeply rooted that fats were only a concentrated source of calories that were easily stored and served as carriers of fat-soluble vitamins. This issue of the BJN provides a glimpse of how fast this field has moved and serves to underscore the recent realization in human nutrition that the quality of the fat supply in terms of the parent n-6 and n-3 essential fatty acids as well as their longer chain, more unsaturated derivatives arachidonic, eicosapentaenoic and docosahexaenoic acids plays a vital role in human health from conception through every stage of human development, maturation and aging. In terms of health and disease the essential fatty acids and their derivatives interact at multiple levels, including cell membrane composition, metabolism, signal transduction and amplification, and gene expression. Furthermore they influence cell growth and differentiation, tissue repair, apoptosis and cell death and many physiological and pathological processes including immunity and inflammation. The observations made lead to a conclusion that long chain polyunsaturated fatty acids (arachidonic, eicosapentaenoic and docosahexaenoic acids) are conditionally essential nutrients for adequate growth, development and function in humans. Despite the impressive documentation of EPA and DHA related health benefits, the cellular and molecular mechanisms for their action are still insufficiently understood. The evidence systematically reviewed in this issue of the BJN indicates that the effects of DHA and EPA are mediated, not only by their known effects on membrane biophysical properties and the corresponding electrophysiological correlates, but also by effects on cell growth, differentiation and functional maturation, and by modulating gene expression during development and at all subsequent stages of human life. Every tissue and every cell type is influenced not only by the genetically coded DNA-proteome but also by the dietary supply of essential fatty acids that determines how tissues and animals adapt to changing environments. The plasticity given by essential fatty acids is key to biological adaptations of every type. What is also clear from the articles herein, however, is that there remain multiple unanswered questions, and specifically there is a lack of high-quality population-based effectiveness trials in many areas crucial to human development and health. With global population ageing continuing apace and a concomitant increase in the number of individuals suffering from chronic diseases British Journal of Nutrition (2012), 107, S1–S2 doi:10.1017/S0007114512001420 q The Authors 2012

Maternal Obesity in Early Pregnancy and Risk of Adverse Outcomes

Objectives To assess the role of the health consequences of maternal overweight and obesity at the start of pregnancy on gestational pathologies, delivery and newborn characteristics. Methods A cohort of pregnant women (n = 6.558) having delivered at the Maternal & Child University Hospital of Gran Canaria (HUMIGC) in 2008 has been studied. Outcomes were compared using multivariate analyses controlling for confounding variables. Results Compared to normoweight, overweight and obese women have greater risks of gestational diabetes mellitus (RR = 2.13 (95% CI: 1.52–2.98) and (RR = 2.85 (95% CI: 2.01–4.04), gestational hypertension (RR = 2.01 (95% CI: 1.27–3.19) and (RR = 4.79 (95% CI: 3.13–7.32) and preeclampsia (RR = 3.16 (95% CI: 1.12–8.91) and (RR = 8.80 (95% CI: 3.46–22.40). Obese women have also more frequently oligodramnios (RR = 2.02 (95% CI: 1.25–3.27), polyhydramnios. (RR = 1.76 (95% CI: 1.03–2.99), tearing (RR = 1.24 (95% CI: 1.05–1.46) and a lower risk of induced deliveries (RR = 0.83 (95% CI: 0.72–0.95). Both groups have more frequently caesarean section (RR = 1.36 (95% CI: 1.14–1.63) and (RR = 1.84 (95% CI: 1.53–2.22) and manual placenta extraction (RR = 1.65 (95% CI: 1.28–2.11) and (RR = 1.77 (95% CI: 1.35–2.33). Newborns from overweight and obese women have higher weight (p<0.001) and a greater risk of being macrosomic (RR = 2.00 (95% CI: 1.56–2.56) and (RR = 2.74 (95% CI: 2.12–3.54). Finally, neonates from obese mother have a higher risk of being admitted to special care units (RR = 1.34 (95% CI: 1.01–1.77). Apgar 1 min was significantly higher in newborns from normoweight mothers: 8.65 (95% CI: 8.62–8.69) than from overweight: 8.56 (95% CI: 8.50–8.61) or obese mothers: 8.48 (95% CI: 8.41–8.54). Conclusion Obesity and overweight status at the beginning of pregnancy increase the adverse outcomes of the pregnancy. It is important to promote the normalization of bodyweight in those women who intend to get pregnant and to provide appropriate advice to the obese women of the risks of obesity at the start of the pregnancy.

Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the Predimed Trial

Background: Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. Methods: The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ⩽7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. Results: The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49–3.83, Ptrend<0.001), 1.91 (1.21–3.01, Ptrend=0.003), 1.97 (1.21–3.20, Ptrend=0.004), and 1.73 (1.09–2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36–3.49; Ptrend<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. Conclusions: Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. Clinical Trial Registration: URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.

Moderate red wine consumption is associated with a lower prevalence of the metabolic syndrome in the PREDIMED population

Previous studies on the association between alcohol intake and the development of the metabolic syndrome (MetS) have yielded inconsistent results. Besides, few studies have analysed the effects of red wine (RW) consumption on the prevalence of the MetS and its components. As moderate RW drinkers have a better lipid profile and lower incidence rates of diabetes, hypertension and abdominal obesity, all components of the MetS, it was hypothesised that moderate RW consumption could be associated with a lower prevalence of the MetS. In the present cross-sectional study of 5801 elderly participants at a high cardiovascular risk included in the PREDIMED (Prevención con Dieta Mediterránea) study, 3897 fulfilled the criteria of the MetS at baseline. RW intake was recorded using a validated 137-item FFQ. Multiple logistic regression analysis was carried out to estimate the association between RW intake and the prevalence of the MetS. Compared with non-drinkers, moderate RW drinkers (≥ 1 drink/d) were found to have a reduced risk of prevalent MetS (OR 0.56, 95 % CI 0.45, 0.68; P < 0.001), a lower risk of having an abnormal waist circumference (OR 0.59, 95 % CI 0.46, 0.77; P < 0.001), low HDL-cholesterol concentrations (OR 0.42, 95 % CI 0.32, 0.53; P < 0.001), high blood pressure (OR 0.28, 95 % CI 0.17, 0.45; P < 0.001) and high fasting plasma glucose concentrations (OR 0.67, 95 % CI 0.54, 0.82; P < 0.001) after adjusting for several confounders. This association was found to be stronger in female participants, in participants aged < 70 years and in participants who were former or current smokers. No significant association was found between RW intake (≥ 1 drink/d) and TAG concentrations. In conclusion, moderate RW consumption is associated with a lower prevalence of the MetS in an elderly Mediterranean population at a high cardiovascular risk.

Dietary Marine ω-3 Fatty Acids and Incident Sight-Threatening Retinopathy in Middle-Aged and Older Individuals With Type 2 Diabetes: Prospective Investigation From the PREDIMED Trial

Importance Diabetic retinopathy (DR) is a devastating complication of individuals with type 2 diabetes mellitus. The retina is rich in long-chain ω-3 polyunsaturated fatty acids (LCω3PUFAs), which are substrate for oxylipins with anti-inflammatory and antiangiogenic properties. Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking. Objective To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR in individuals with type 2 diabetes older than 55 years. Design, Setting, and Participants In late 2015, we conceived a prospective study within the randomized clinical trial Prevención con Dieta Mediterránea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3482 participants (48% men; mean age 67 years). Exposures Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention, as assessed by a validated food-frequency questionnaire. Main Outcomes and Measures The main outcome was incident DR requiring laser photocoagulation, vitrectomy, and/or antiangiogenic therapy confirmed by an external adjudication committee. Results Of the 3482 participants, 48% were men and the mean age was 67 years. A total of 2611 participants (75%) met target LCω3PUFA recommendation. During a median follow-up of 6 years, we documented 69 new events. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (≥500 mg/d) compared with those not fulfilling this recommendation (<500 mg/d) showed a 48% relatively reduced risk of incident sight-threatening DR, with a hazard ratio of 0.52 (95% CI, 0.31-0.88; P = .001). This association was slightly stronger for yearly updated LCω3PUFA intake (relative risk, 0.48; 95% CI, 0.28-0.82; P = .007). Conclusions and Relevance In middle-aged and older individuals with type 2 diabetes, intake of at least 500 mg/d of dietary LCω3PUFA, easily achievable with 2 weekly servings of oily fish, is associated with a decreased risk of sight-threatening DR. Our results concur with findings from experimental models and the current model of DR pathogenesis. Trial Registration clinicaltrials.gov Identifier: http://www.controlled-trials.com/ISRCTN35739639.

Extravirgin Olive Oil Consumption Reduces Risk of Atrial Fibrillation

Background— The PREDIMED (Prevencion con Dieta Mediterranea) randomized primary prevention trial showed that a Mediterranean diet enriched with either extravirgin olive oil or mixed nuts reduces the incidence of stroke, myocardial infarction, and cardiovascular mortality. We assessed the effect of these diets on the incidence of atrial fibrillation in the PREDIMED trial. Methods and Results— Participants were randomly assigned to 1 of 3 diets: Mediterranean diet supplemented with extravirgin olive oil, Mediterranean diet supplemented with mixed nuts, or advice to follow a low-fat diet (control group). Incident atrial fibrillation was adjudicated during follow-up by an events committee blinded to dietary group allocation. Among 6705 participants without prevalent atrial fibrillation at randomization, we observed 72 new cases of atrial fibrillation in the Mediterranean diet with extravirgin olive oil group, 82 in the Mediterranean diet with mixed nuts group, and 92 in the control group after median follow-up of 4.7 years. The Mediterranean diet with extravirgin olive oil significantly reduced the risk of atrial fibrillation (hazard ratio, 0.62; 95% confidence interval, 0.45–0.85 compared with the control group). No effect was found for the Mediterranean diet with nuts (hazard ratio, 0.89; 95% confidence interval, 0.65–1.20). Conclusions— In the absence of proven interventions for the primary prevention of atrial fibrillation, this post hoc analysis of the PREDIMED trial suggests that extravirgin olive oil in the context of a Mediterranean dietary pattern may reduce the risk of atrial fibrillation. Clinical Trial Registration— URL: . Unique identifier: [ISRCTN35739639][1]. # CLINICAL PERSPECTIVE {#article-title-40} [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN35739639Background— The PREDIMED (Prevención con Dieta Mediterránea) randomized primary prevention trial showed that a Mediterranean diet enriched with either extravirgin olive oil or mixed nuts reduces the incidence of stroke, myocardial infarction, and cardiovascular mortality. We assessed the effect of these diets on the incidence of atrial fibrillation in the PREDIMED trial. Methods and Results— Participants were randomly assigned to 1 of 3 diets: Mediterranean diet supplemented with extravirgin olive oil, Mediterranean diet supplemented with mixed nuts, or advice to follow a low-fat diet (control group). Incident atrial fibrillation was adjudicated during follow-up by an events committee blinded to dietary group allocation. Among 6705 participants without prevalent atrial fibrillation at randomization, we observed 72 new cases of atrial fibrillation in the Mediterranean diet with extravirgin olive oil group, 82 in the Mediterranean diet with mixed nuts group, and 92 in the control group after median follow-up of 4.7 years. The Mediterranean diet with extravirgin olive oil significantly reduced the risk of atrial fibrillation (hazard ratio, 0.62; 95% confidence interval, 0.45–0.85 compared with the control group). No effect was found for the Mediterranean diet with nuts (hazard ratio, 0.89; 95% confidence interval, 0.65–1.20). Conclusions— In the absence of proven interventions for the primary prevention of atrial fibrillation, this post hoc analysis of the PREDIMED trial suggests that extravirgin olive oil in the context of a Mediterranean dietary pattern may reduce the risk of atrial fibrillation. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639.

The PREDIMED trial, Mediterranean diet and health outcomes: How strong is the evidence?

AIMS To address potential controversies on the health benefits of the Mediterranean diet (MedDiet) after PREDIMED, a randomized trial of MedDiet for primary cardiovascular prevention. We have focused on: a) the PREDIMED study design, b) analysis of PREDIMED data and c) interpretation of its results. DATA SYNTHESIS Regarding the design of the trial, its early termination and between-group differences in the intensity of the intervention are potential causes of concern. The planned duration was 6 years but the trial was prematurely stopped when an interim analysis at 4.8-year provided sufficient evidence of benefit for the two MedDiets. In the MedDiet groups supplemented with extra-virgin olive oil or mixed-nuts, the primary composite endpoint (myocardial infarction, stroke, or cardiovascular death) was reduced by 30% and 28% respectively, as compared with the control group. Final results did not change after taking into account the different intensity of educational efforts during the trial. Other potential doubts related to data analysis (e.g., intention to treat versus a per-protocol approach, and consequences of dropouts) should not be causes of concern. Finally, we addressed alternative interpretations of the effect on all-cause mortality. The protocol-defined primary endpoint was a composite cardiovascular endpoint, not all-cause mortality. To analyze total mortality, we would have needed a much larger sample size and longer follow-up. Therefore, the PREDIMED results cannot be used to draw firm conclusions on MedDiets and all-cause mortality. CONCLUSIONS The PREDIMED study was designed to overcome three major problems of previous nutritional research: a) residual confounding, addressed by using a randomized design; b) single-nutrient approaches, by randomizing an overall dietary pattern; and c) the limitations of assessing only intermediate risk markers, by using hard clinical end-points.

Factores de riesgo cardiovascular en el sobrepeso y la obesidad. Variaciones tras tratamiento de pérdida ponderal

Fundamento Y Objetivo En el tratamiento de la obesidad, el control de los factores de riesgo cardiovascular asociados es fundamental. El objetivo de este estudio ha sido examinar la relacion entre el indice de masa corporal (IMC) y los factores de riesgo cardiovascular y los efectos de un tratamiento de perdida de peso en sujetos con sobrecarga ponderal. Pacientes Y Metodo Estudio transversal y de seguimiento realizado en un unico centro durante el periodo 1997–2001 en 1.018 sujetos (788 mujeres y 230 varones) con obesidad y sobrepeso, atendidos en una clinica de obesidad y sometidos a un programa de perdida ponderal mediante dieta hipocalorica de estilo mediterraneo y recomendaciones de ejercicio fisico. Se determinaron la talla, el peso, la presion arterial, el perfil lipidico y la glucemia al inicio y al final del tratamiento. Resultados Tras ajustar por edad, las variables que mostraron un incremento significativo con el IMC fueron: presion arterial, colesterol HDL (relacion inversa, solo en mujeres), trigliceridos y glucosa. No se encontro correlacion entre IMC con colesterol total, colesterol LDL y el cociente colesterol total/colesterol HDL. La perdida de peso disminuyo siempre la presion arterial y los valores de trigliceridos, y el colesterol total, colesterol LDL, colesterol total/colesterol HDL y glucosa si los valores iniciales estaban elevados. No encontramos cambios significativos sobre colesterol HDL. Conclusiones Los sujetos con sobrecarga ponderal presentan incremento en los factores de riesgo cardiovascular que aumentan con el grado de obesidad. La perdida de peso mejora los factores de riesgo cardiovascular asociados a sobrecarga ponderal, especialmente si estos se encuentran previamente alterados, aun en perdidas de menos del 5% del peso inicial.

Leisure-time physical activity, sedentary behaviors, sleep, and cardiometabolic risk factors at baseline in the PREDIMED-PLUS intervention trial: A cross-sectional analysis

Limited data exists on the interrelationships between physical activity (PA), sedentary behaviors and sleep concerning cardiometabolic risk factors in aged adults at high cardiovascular disease risk. Our aim was to examine independent and joint associations between time spent in leisure-time PA, sedentary behaviors and sleep on the prevalence of obesity, type 2 diabetes (T2D) and components of the metabolic syndrome (MetS) in Mediterranean individuals at high cardiovascular risk. Cross-sectional analyses were performed on baseline data from 5776 Spanish adults (aged 55-75y in men; 60-75y in women) with overweight/obesity and MetS, from October 2013 to October 2016, in the PREDIMED-PLUS trial. Employing multivariable-adjusted Cox regression with robust variance and constant time (given the cross-sectional design), higher prevalence of obesity, T2D and abdominal obesity as component of the MetS were associated with greater time in TV-viewing (Relative Risk, RR: 1.02, 95%CI: 1.01, 1.03; RR:1.04, 95%CI: 1.02, 1.06 and RR: 1.01 95%CI: 1.00, 1.02; respectively, all P < .01). Conversely, greater time in moderate-vigorous PA (MVPA) was associated with lower prevalence of obesity, T2D, abdominal obesity and low HDL-cholesterol (RR: 0.95, 95%CI: 0.93, 0.97; RR: 0.94, 95%CI: 0.89, 0.99; RR: 0.97, 95%CI: 0.96, 0.98; and RR: 0.95, 95%CI: 0.91, 0.99, respectively, all P < .05). For these outcomes, theoretically substituting 1-h/day of MVPA for 1-h/day TV-viewing was also significantly associated with lower prevalence (RR 0.91 to 0.97, all P < .05). Similar lower RR in these outcomes was observed when substituting 1-h/day of MVPA for 1-h/day of sleeping. Longer time watching TV and not meeting MVPA recommendations were jointly associated with higher RR of the prevalence of obesity and T2D. We concluded that, in senior individuals at high cardiovascular risk, greater time spent on MVPA and fewer on sedentary behaviors was inversely associated with prevalence of obesity, T2D, and some of the components of MetS.