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Original Research |

Prevention of Diabetes With Mediterranean Diets: A Subgroup Analysis of a Randomized Trial

Jordi Salas-Salvadó, MD, PhD*; Mònica Bulló, PhD; Ramón Estruch, MD, PhD; Emilio Ros, MD, PhD; Maria-Isabel Covas, DPharm; Núria Ibarrola-Jurado, RD, PhD; Dolores Corella, DPharm, PhD; Fernando Arós, MD, PhD; Enrique Gómez-Gracia, MD, PhD; Valentina Ruiz-Gutiérrez, PhD; Dora Romaguera, MD, PhD; José Lapetra, MD, PhD; Rosa Maria Lamuela-Raventós, DPharm, PhD; Lluís Serra-Majem, MD, PhD; Xavier Pintó, MD, PhD; Josep Basora, MD, PhD; Miguel Angel Muñoz, MD, PhD; José V. Sorlí, MD, PhD; and Miguel A. Martínez-González, MD, PhD*
[+] Article and Author Information

* Drs. Salas-Salvadó and Martínez-González contributed equally to this work.


From the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and PREDIMED Network, Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, and Universitat Rovira i Virgili, Reus, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, School of Pharmacy, Xarxa de Referència en Tecnologia dels Aliments, and Instituto de Investigación en Nutrición y Seguridad Alimentaria, University of Barcelona, Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Hospital Universitario de Bellvitge, and Hospitalet de Llobregat, Barcelona, Spain; University of Valencia and Valencia Institute of Health, Valencia, Spain; University Hospital of Alava, Vitoria, Spain; University of Malaga, Malaga, Spain; Instituto de la Grasa, Consejo Superior de Investigaciones Cientificas, and San Pablo Health Center, Seville, Spain; Research Unit, University Hospital Son Espases, Balearic Islands, Spain; School of Public Health, Imperial College London, United Kingdom; University of Las Palmas de Gran Canaria, Las Palmas, Spain; University of Navarra, Pamplona, Spain; and Catalan Institute of Health, Institut d’Investigació en Atenció Primària Jordi Gol, Tarragona-Reus and Barcelona, Spain.

Grant Support: By the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial (RTIC G03/140 to Dr. Estruch; RTIC RD 06/0045 to Dr. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02, AGL2010-22319-C03, and AGL2011-23430), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, ACOMP2012-190, ACOMP2013-159, ACOMP2013-165, CS2010-AP-111), Agencia Canaria de Investigación, Innovación y Sociedad de la Información-EU FEDER (PI 2007/050 and CS2011-AP-042), and Regional Government of Navarra (P27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca (Malaga, Spain), California Walnut Commission (Sacramento, California), Borges (Reus, Spain), and Morella Nuts (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1725.

Reproducible Research Statement: Study protocol: Available from Dr. Salas-Salvadó (e-mail, jordi.salas@urv.cat). Statistical code and data set: Not available.

Requests for Single Reprints: Jordi Salas-Salvadó, MD, PhD, Human Nutrition Unit, Faculty of Medicine and Healthy Sciences, Universitat Rovira i Virgili, C/ Sant Llorenç, 21, 43201 Reus, Spain; e-mail, jordi.salas@urv.cat.

Current Author Addresses: Drs. Salas-Salvadó, Bulló, and Ibarrola-Jurado: Human Nutrition Unit, Faculty of Medicine and Healthy Sciences, Universitat Rovira i Virgili, C/ Sant Llorenç, 21, 43201 Reus, Spain.

Dr. Estruch: Department of Internal Medicine, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Barcelona, C/ Villarroel, 170, 08036 Barcelona, Spain.

Dr. Ros: Lipid Clinic, Department of Endocrinology and Nutrition, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, C/ Villarroel, 170, 08036 Barcelona, Spain.

Dr. Covas: Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, C/ Doctor Aiguader, 88, 08003 Barcelona, Spain.

Dr. Corella: Genetic and Molecular Epidemiology Unit, School of Medicine, Department of Preventive Medicine, University of Valencia, Avda Blasco Ibañez, 15, 46010 Valencia, Spain.

Dr. Arós: Department of Cardiology, University Hospital of Alava, C/ Jose Atxotegi, S/N 01009 Vitoria-Gasteiz, Spain.

Dr. Gómez-Gracia: Department of Preventive Medicine, Faculty of Medicine, University of Malaga, Bulevard Luis Pastor, 32, 29071 Malaga, Spain.

Dr. Ruiz-Gutiérrez: Profesora de Investigación del Consejo Superior de Investigaciones Cientíificas, Nutrition and Lipids Metabolism, Instituto de la Grasa, Avenida Padre García Tejero, 4, 41012 Sevilla, Spain.

Dr. Romaguera: Research Unit, University Hospital Son Espases, Balearic Islands, Spain and School of Public Health, Carretera de Valldemossa, 79, 07120 Palma de Mallorca, Illes Balears, Spain.

Dr. Lapetra: Department of Family Medicine, Primary Care Division of Seville, San Pablo Health Center, Sevilla, Jerusalem, S/N 41007 Sevilla, Spain.

Dr. Lamuela-Raventos: Department of Nutrition and Food Science, School of Pharmacy, University of Barcelona, Barcelona, Avinguda de Joan XXIII, 31, 08028 Barcelona, Spain.

Dr. Serra-Majem: Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Edificio Ciencias de la Salud, Campus de San Cristóbal, 35016 Las Palmas de Gran Canaria, Spain.

Dr. Pintó: Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Avd. Feixa Llarga, S/N, 08907 L’Hospitalet de Llobregat, Barcelona, Spain.

Dr. Basora: Primary Care Division, Catalan Institute of Health, Institut d’Investigació en Atenció Primària Jordi Gol, Tarragona-Reus, Universitat Rovira i Virgili, C/ Sant Llorenç, 21, 43201 Reus, Spain.

Dr. Muñoz: Primary Care Division, Catalan Institute of Health, Institut d’Investigació en Atenció Primària Jordi Gol, Barcelona, C/ Sardenya 375, Entlo, 08025 Barcelona, Spain.

Dr. Sorlíi: Primary Care Division, Valencia Institute of Health, Valencia, Faculty of Medicine, Av Vicente Blasco Ibáñez, 26, 46010 Valencia, Spain.

Dr. Martíinez-González: Department of Preventive Medicine and Public Health, Faculty of Medicine, University of Navarra, C/ Irunlarrea 1, 31008, Pamplona, Spain.

Author Contributions: Conception and design: J. Salas-Salvadó, E. Ros, R. Estruch, M.I. Covas, D. Corella, V. Ruiz-Gutiérrez, J. Lapetra, R.M. Lamuela-Raventos, L. Serra-Majem, M.A. Martíinez-González.

Analysis and interpretation of the data: J. Salas-Salvadó, M. Bulló, R. Estruch, E. Ros, M.I. Covas, N. Ibarrola-Jurado, F. Arós, R.M. Lamuela-Raventos, L. Serra-Majem, M.A. Muñoz, M.A. Martíinez-González.

Drafting of the article: J. Salas-Salvadó, M.A. Martíinez-González.

Critical revision of the article for important intellectual content: J. Salas-Salvadó, M. Bulló, R. Estruch, E. Ros, N. Ibarrola-Jurado, D. Corella, E. Gómez-Gracia, V. Ruiz-Gutiérrez, D. Romaguera, J. Lapetra, R.M. Lamuela-Raventos, L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, M.A. Martíinez-González.

Final approval of the article: J. Salas-Salvadó, M. Bulló, E. Ros, M.I. Covas, N. Ibarrola-Jurado, R. Estruch, D. Corella, F. Arós, E. Gómez-Gracia, V. Ruiz-Gutiérrez, J. Lapetra, R.M. Lamuela-Raventos, L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, M.A. Martíinez-González.

Provision of study materials or patients: J. Salas-Salvadó, R. Estruch, D. Corella, E. Gómez-Gracia, J. Lapetra, L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, J.V. Sorlíi, M.A. Martíinez-González.

Statistical expertise: J. Salas-Salvadó, N. Ibarrola-Jurado, D. Corella, M.A. Martíinez-González.

Obtaining of funding: J. Salas-Salvadó, M. Bulló, R. Estruch, E. Ros, D. Corella, F. Arós, E. Gómez-Gracia, V. Ruiz-Gutiérrez, J. Lapetra, M.A. Martíinez-González.

Administrative, technical, or logistic support: J. Salas-Salvadó, N. Ibarrola-Jurado, R. Estruch, E. Gómez-Gracia, J. Lapetra, L. Serra-Majem, X. Pintó, J. Basora, M.A. Martíinez-González.

Collection and assembly of data: J. Salas-Salvadó, M. Bulló, R. Estruch, N. Ibarrola-Jurado, D. Corella, F. Arós, E. Gómez-Gracia, J. Lapetra, L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, J.V. Sorlíi, M.A. Martíinez-González.


Ann Intern Med. 2014;160(1):1-10. doi:10.7326/M13-1725
Text Size: A A A

Background: Interventions promoting weight loss can reduce the incidence of type 2 diabetes mellitus. Whether dietary changes without calorie restriction also protect from diabetes has not been evaluated.

Objective: To assess the efficacy of Mediterranean diets for the primary prevention of diabetes in the Prevención con Dieta Mediterránea trial, from October 2003 to December 2010 (median follow-up, 4.1 years).

Design: Subgroup analysis of a multicenter, randomized trial. (Current Controlled Trials: ISRCTN35739639)

Setting: Primary care centers in Spain.

Participants: Men and women without diabetes (3541 patients aged 55 to 80 years) at high cardiovascular risk.

Intervention: Participants were randomly assigned and stratified by site, sex, and age but not diabetes status to receive 1 of 3 diets: Mediterranean diet supplemented with extra-virgin olive oil (EVOO), Mediterranean diet supplemented with nuts, or a control diet (advice on a low-fat diet). No intervention to increase physical activity or lose weight was included.

Measurements: Incidence of new-onset type 2 diabetes mellitus (prespecified secondary outcome).

Results: During follow-up, 80, 92, and 101 new-onset cases of diabetes occurred in the Mediterranean diet supplemented with EVOO, Mediterranean diet supplemented with mixed nuts, and control diet groups, respectively, corresponding to rates of 16.0, 18.7, and 23.6 cases per 1000 person-years. Multivariate-adjusted hazard ratios were 0.60 (95% CI, 0.43 to 0.85) for the Mediterranean diet supplemented with EVOO and 0.82 (CI, 0.61 to 1.10) for the Mediterranean diet supplemented with nuts compared with the control diet.

Limitations: Randomization was not stratified by diabetes status. Withdrawals were greater in the control group.

Conclusion: A Mediterranean diet enriched with EVOO but without energy restrictions reduced diabetes risk among persons with high cardiovascular risk.

Primary Funding Source: Instituto de Salud Carlos III.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

EVOO = extra-virgin olive oil; MedDiet = Mediterranean diet.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Cumulative incidence of diabetes (or either diabetes or death).

Nelson-Aalen curves are shown with the outcome of new-onset diabetes (top) or either diabetes or death (bottom), by exposure to each MedDiet intervention vs. the control diet. EVOO = extra-virgin olive oil; HR = hazard ratio; MedDiet = Mediterranean diet.

Grahic Jump Location

Tables

References

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Comments

Submit a Comment
Methodological Flaws
Posted on January 7, 2014
Eran Kopel
Personal opinion
Conflict of Interest: None Declared
Patient withdrawals from the study during follow-up were significantly greater in the control group than in the intervention groups. These patients, a substantial 10% of the entire control group, had "worse cardiovascular risk profile at baseline", which importantly imply on the overall higher baseline cardiovascular risk of the control group, than in the intervention groups, a major concern that has been raised recently [Kopel E, Sidi Y, Kivity S. Mediterranean diet for primary prevention of cardiovascular disease. N Engl J Med. 2013;369:672. link: http://www.nejm.org/doi/full/10.1056/NEJMc1306659].

Therefore, the current post-hoc analysis on diabetes outcome would require to model the data differently than was actually done. A competing risks analysis that accounts for any cardiovascular morbidity specific-outcome that occurred before the diabetes outcome should have been used. As competing cardiovascular morbidity events were not accounted for, also the Kaplan-Meier curves are not applicable and might mislead.
Reponse to Methodological Flaws
Posted on February 20, 2014
Jordi Salas-Salvadó, Ramon Estruch, Miguel Ángel Martínez-González
Human Nutrition Unit, Rovira i Virgili University, Reus, Spain. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain (CIBERObn);
Conflict of Interest: None Declared
Kopel et al. mistakenly pointed out that there were “significantly higher percentages of men (+5.7%),... in the control group than in the intervention group assigned to a Mediterranean diet supplemented with nuts" (1) in our PREDIMED trial. The truth was exactly in the opposite direction: the control group included a lower percentage of men (40% men) than the Mediterranean Diet (MeDiet) + nuts group (46% men). As male sex was a strong predictor of a significantly higher risk for the primary cardiovascular end-point, under the null hypothesis of no effect of the dietary intervention, a higher risk would be expected in the MeDiet+nuts group. Lesser degrees of imbalance for some other risk factors were clinically irrelevant and they were not as strong predictors of cardiovascular events as sex was. Therefore, the minor imbalance in sex distribution, in any case, will operate in support of our hypothesis because, despite this imbalance in sex, we found a significant protection by a MeDiet+nuts. Furthermore, we adjusted our estimates for sex and cardiovascular risk factors.
To address the new concern raised by Kopel in his letter about “methodological flaws” in our article with diabetes as outcome (2), we have rerun our models using the approach to tackle competing risks proposed by Fine and Gray. They introduced modifications in the proportional hazards Cox model to allow for the presence of competing risks (3). The modification consisted in keeping the competing risks observations (cardiovascular events in our case) in the risk set with a diminishing weight.
The estimates for hazard ratios in models fitted with the Fine and Gray’s method were very similar to those fitted with ordinary Cox models (<5% change in all cases). Therefore, the potential amount of bias introduced by competing risks can be assumed to be almost negligible. For example, the Hazard ratios (95% confidence intervals) in sex-, age-, body mass-index- and center-adjusted models were:
MeDiet+Extra-virgin olive oil vs. control: 0.65 (0.48-0.87), meaning a 4.4% change.
MeDiet+nuts vs. control: 0.85 (0.64-1.13), meaning a 3.7% change.
MeDiet (both groups merged together) vs. control: 0.74 (0.58-0.95), meaning a 1.3% change.
In summary, there is no methodological problem in our published analyses.

(1) Kopel E, Sidi Y, Kivity S. Letter. N Engl J Med. 2013;369:672.
(2) Salas Salvado J, Bullo M, Estruch R, et al. Prevention of diabetes with Mediterranean diets. Ann Intern Med 2014;160:1-10.
(2) Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509.
Response by E. Kopel
Posted on March 4, 2014
Eran Kopel
Tel Aviv, Israel
Conflict of Interest: None Declared
We are well aware of this technical erratum and have already asked the NEJM to correct it. I believe it will appear on-line soon (The word "men" will be replaced by the word "women").

If you carefully read our original critique on your study, however, we did not point on "male gender" as the specific imbalanced risk factor but on the surprising imbalance itself between the RCT groups.

This technicality has nothing to do with our valid methodological concern regarding the imbalance itself in key-baseline characteristics of the PREDIMED RCT, such as gender, by which the randomization was supposed to be explicitly stratified.

A significant evident imbalance such as was previously noticed by us, in gender and other important baseline characteristics as well, will be accompanied by significant unmeasured confounding.

Even extensive adjustment, in the analysis phase, will not resolve such a substantial "residual" confounding, and this distortion in the very infrastructure of the RCT should have been ideally avoided at the randomization phase, as expected from any properly valid RCT.

I would also remind on this opportunity that female sex can also be associated with cardiovascular disease, when it is accompanied by diabetes, for example. A higher percentage of diabetic women in the "low-fat diet" control group is a suspected imbalance that its existence might be supported by the fact that several diabetes-associated drug groups (i.e. oral hypoglycemic use) were also imbalanced significantly in the PREDIMED study at baseline.

Is this the case with the PREDIMED study? Is the baseline CVS risk (i.e. by Framingham's risk score) evenly represented across the groups and between genders in each study group?

Additionally, in the more recent analysis of the study, as published in the Annals, when you excluded patients with diabetes at baseline, the baseline variables were indeed more balanced. However, in this study, a competing-risk analysis between diabetes and CVS morbidity outcomes should have been performed, as I noted earlier in the aforementioned correspondence, since you still had a significant portion of drop-out in the control group for CVS reasons, which implies on the overall higher CVS risk in the control group from the beginning of this study.

In your response you indicate that such additional analysis was done without a significant change of the HR results; however, these derived sub-distribution HRs based on Fine–Gray competing-risk models are difficult to interpret as a standard epidemiological covariate rate:risk association [1] and this analysis should have actually aided to correctly draw the biased naïve Kaplan-Meier survival curves, as noted in my original correspondence, and which I hope could still be presented along with the published form of my original correspondence and your response, in the forthcoming Annals issue.

Best regards,
Eran Kopel, MD MPH

Reference:
1. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology:
possibilities and pitfalls. Int J Epidemiol. 2012;41(3):861-70.
Submit a Comment

Summary for Patients

Does the Mediterranean Diet Prevent Diabetes?

The full report is titled “Prevention of Diabetes With Mediterranean Diets. A Subgroup Analysis of a Randomized Trial.” It is in the 7 January 2014 issue of Annals of Internal Medicine (volume 160, pages 1-10). The authors are J. Salas-Salvadó, M. Bulló, R. Estruch, E. Ros, M.I. Covas, N. Ibarrola-Jurado, D. Corella, F. Arós, E. Gómez-Gracia, V. Ruiz-Gutiérrez, D. Romaguera, J. Lapetra, R.M. Lamuela-Raventos, L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, J.V. Sorlí, and M.A. Martínez-González.

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