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Martínez-González MA, de la Fuente-Arrillaga C, Nunez-Cordoba JM, Basterra-Gortari FJ, Beunza JJ, Vazquez Z, Benito S, Tortosa A, Bes-Rastrollo M. Adherence to Mediterranean diet and risk of developing diabetes: Prospective cohort study. BMJ. 2008 Jun 14; 336(7,657): 1,348-1,351.

 


PubMed ID: 18511765
Study Design:
Prospective Cohort Study
Class:
B - Click here for explanation of classification scheme.
POSITIVE: See Research Design and Implementation Criteria Checklist below.
Research Purpose:

To assess the relation between adherence to a Mediterranean diet and the incidence of diabetes among initially healthy participants.

Inclusion Criteria:
  • All former students of the University of Navarra
  • Registered nurses from Spanish provinces
  • University graduates from other associations.
Exclusion Criteria:

None listed.

Description of Study Protocol:

Study Description

Study name: The SUN project (“Seguimiento Universidad de Navarra” (University of Navarra follow-up). 

  • Interested participants were mailed a questionnaire and an invitation letter to participate in a long-term follow-up study. A response to the initial questionnaire was considered as informed consent to participate in the study.
  • The first participants were recruited in December 1999. Using successive waves of invitation to different groups of university graduates, sample size of the cohort was progressively increased.
  • The design is that of a dynamic cohort and the recruitment is permanently open
  • After the baseline assessment, every two years participants were sent follow-up questionnaires on diet, lifestyle, risk factors and medical conditions
  • Participants who do not reply to the follow-up questionnaires are sent up to five additional mailings.

Study Duration

Depending on when participants were enrolled, varied between two to six years.

Location

Spain.

Data Collection Summary:

Dietary Assessment Method

A semi-quantitative food frequency questionnaire with 136 items, previously validated in Spain.

Brief Description of Dietary Patterns

  • The questionnaire was based on typical portion sizes and had nine options for the frequency of intake in the previous year for each food item (ranging from never or almost never to six or more times a day).
    • The sum of the consumption of each of several food items was used  to estimate the overall consumption of the food group to which each item belonged (vegetables, fruits, cereals, legumes, fish, meats, fast food, dairy products)
    • The specified portion sizes for each item was used and summed up across all foods of that group
    • The mean for all the participants in each category of the three categories of the score was computed to create an estimated daily intake.
  • The questionnaire included questions on use of fats and oils, cooking methods and dietary supplements
  •  Adherence to the Mediterranean diet was appraised using the following eight components to define the Mediterranean diet:
    • High ratio of monounsaturated:saturated fatty acids
    • Moderate intake of alcohol, high intake of legumes
    • High intake of grains
    • High intake of fruit and nuts
    • High intake of vegetables
    • Low intake of meat and meat products
    • Moderate intake of milk and dairy products
    • High intake of fish.
  • The index assigns a score of zero or one according to the daily intake of each of the nine components.
    • With the exception of alcohol, the sex-specific medians of the sample were used as cut-off points and the unit of measurement was grams per day
    • For each of the six protective components (fatty acid ratio, legumes, grains, fruits, vegetables or fish) participants received one point if their intake was over the sample median
    • Participants received one point if the intake was below the median for the two non-protective components (dairy products or meat)
    • For alcohol one point was scored if consumption was 10g to 50g per day for men or 5g to 25g per day for women. If participants met all the characteristics of the Mediterranean diet, their score was the highest (nine points), reflecting maximum adherence.
    • If they met none of the characteristics, the score was minimum (zero), reflecting no adherence at all.

Outcomes Measured

  • Main known risk factors for diabetes
  • Sociodemographic factors:
    • Sex
    • Age
    • University degree
    • Marital status employment status.
  • Anthropometric measurements:
    • Weight
    • Height.
  • Health-related habits:
    • Smoking status
    • Sedentary lifestyle
    • Physical activity: Participation and time spent in 17 different activities.
  • Clinical variables:
    • Use of medication
    • Personal and family history of diabetes and hypertension
    • Coronary heart disease
    • Other cardiovascular disease.

Methods of Outcome Assessment

Identify methods used to assess the following outcomes (note if self-reported or measured, as appropriate): Type 2 diabetes-related mortality and incidence, glucose intolerance, insulin resistance:

  • Self-reported a medical diagnosis of diabetes or were receiving insulin or oral anti-diabetic agents
  • Probable cases of new onset diabetes were defined as those participants who reported a diagnosis of diabetes made by a doctor in the follow-up questionnaire and did not have diabetes at baseline
  • Additional questionnaires were sent to participants who reported probable new onset diabetes, requesting:
    • Confirmation of the diagnosis
    • Type of diabetes and date of the diagnosis
    • Whether the diabetes was diagnosed during pregnancy
    • The highest fasting glucose value that they ever had
    • Whether they had ever undergone an oral glucose tolerance test and its results
    • Their current use of insulin or oral anti-diabetic agents
    • The incidence of some complications.
  • Participants were asked to send the medical report detailing the diagnosis
  • A panel of physicians, blinded to the information about dietary habits, used the information provided by participants (additional questionnaires and medical reports) to classify the diagnosis as incident type 2 diabetes or not
  • The diagnosis criteria for type 2 diabetes were those of the American Diabetes Association 
  • Participants were classified as having confirmed incident type 2 diabetes only if they sent written confirmation that the diagnosis had been received at least six months after they completed the baseline questionnaire and the diagnosis was not made during pregnancy (cases of gestational diabetes were excluded).

 

Description of Actual Data Sample:
  • Sample size:
    • Up to November 2007, the project had enrolled 18,700 participants.
    • From these, 15 970 were eligible for follow-up because they had taken part for more than two years and had completed the follow-up process (entering the cohort up to March 2005)
      • 13,753 (86.1%) had completed at least their two-year follow-up questionnaire
      • Among them, 9298 participants who had taken part for more than four years had completed at least the four-year follow-up questionnaire
      • 4,993 had completed the six-year follow-up questionnaire
    • For this analysis, participants who had diabetes at baseline and those who reported a baseline history of cardiovascular disease were excluded, leaving 13,380 for analyses.
  • Age:
    • 20 to 90 years at baseline; average age in the tertiles
    • Adherence to Mediterranean diet
      • Low score: 33.8 years
      • Moderate score: 37.9 years
      • High Score: 42.9 years.
  • Gender (N=13,380):
    • Low score: 60% women
    • Moderate score: 61% women
    • High Score: 56% women.
  • Socioeconomic status: Although not specifically reported, participants were college educated and half of them were health professionals
  • Baseline health status:
    • Hypertension at baseline:
      • Low score: 6.2% 
      • Moderate score: 9% 
      • High Score: 13.1%.
    • Family history of diabetes:
      • Low score: 12% 
      • Moderate score: 14% 
      • High Score: 17%:
  • Baseline distribution of dietary patterns:
    • Although participants with the highest adherence to the diet (score more than six) had a higher level of leisure time physical activity, they also exhibited a higher baseline prevalence of most risk factors for diabetes because they:
      • Were older
      • Had a higher BMI
      • Had a higher total energy intake
      • Were more likely to have high blood pressure or a family history of diabetes
      • More likely to be former smokers.
    • Participants in the high scores consumed considerably more dietary fiber, fruits, vegetables, cereals and fish; and less dairy, meat and meat products and fast foods compared with the other two tertiles.
Summary of Results:

Results Related to Type 2 Diabetes Incidence and Type 2 Diabetes-related Mortality

  • During the follow-up period (median 4.4 years), 103 participants initially free of diabetes (according to their baseline questionnaire) self reported a new diagnosis of diabetes
  • We identified 33 cases of new onset confirmed type 2 diabetes among 58,918 person year of follow-up
  • Following participants were excluded:
    • 39 women who developed gestational diabetes
    • Six cases of impaired glucose tolerance mistakenly reported by participants as diabetes
    • Three participants with prevalent type 2 diabetes at baseline who did not report it in the baseline questionnaire
    • One case of incident type 1 diabetes
    • 21 participants who did not send  any additional medical report.
  • Participants who adhered closely to a Mediterranean diet had a lower risk of diabetes
  • The risk of diabetes according to levels of adherence to the diet had a significant inverse association after adjustment for age and sex
  • Further multi-variate adjustment for total years of university education, BMI, family history of diabetes, hypertension at baseline, physical activity, hours sitting down a week, smoking and total energy intake did not lead to substantial changes in the estimates, age being the major confounding factor. High adherence to the diet (score more than six) was associated with an 83% relative reduction in the risk of developing diabetes
  • The incidence rate ratios adjusted for sex and age were:
    • Highest adherence (score seven to nine): 0.17 (95% CI: 0.04 to 0.75) 
    • Moderate adherence (score three to six): 0.41 (95% CI: 0.19 to 0.87).
  • Results were similar In the fully adjusted analyses
  • A two-point increase in the score was associated with a 35% relative reduction in the risk of diabetes (incidence rate ratio 0.65, 0.44 to 0.95), with a significant inverse linear trend (P=0.04) in the multi-variate analysis.
Confounders
Total Energy Intake BMI Sex Age Smoking Alcohol Intake Physical Activity Other
x x x x x   x Years of university education, hours sitting a week, family history of diabetes, baseline hypertension

 

Author Conclusion:

Our prospective cohort study suggests that substantial protection against diabetes can be obtained with the traditional Mediterranean diet, rich in olive oil, vegetables, fruits, nuts, cereals, legumes and fish but relatively low in meat and dairy products. The limited number of cases of diabetes and the possibility of under-reporting, however, requires that further larger cohorts and trials are needed to confirm our findings.

Strengths and Limitations

Strengths

  • The Mediterranean food pattern has the potential to minimize confounding by including nutritional confounders in the score and capturing effect modification among the nutritional variables
  • Food frequency questionnaires are known to contain a certain degree of measurement error, which might affect results that depend on such questionnaires to assess diet and risk of chronic disease. Total energy intake was included as a covariate in the model to achieve the equivalent of an isocaloric diet and to reduce measurement error in the score.  
  • A potential limitation, inherent to every observational design, is the possibility of residual confounding by unmeasured or unrecorded factors. Our major confounders, however, were sex and age. Additional  adjustment for other factors made only negligible changes in the estimates, suggesting that residual  confounding  is unlikely.

Limitations

  • The number of new cases of diabetes was small, despite the follow-up of several thousand people for over four years
  • The low number of observed case precluded  assessment of the specific role of single dietary factors because we would have needed multiple adjustments for other dietary factors (in addition to the confounders already included in the model) and the statistical power to adjust for so many factors would have been low
  • Diabetes might have been under-reported in our participants despite their high educational level and easy access to medical care—half of them are health professionals
  • The proportions of participants aged over 65 years across increasing categories of adherence to the diet were 0.6% (score less than three), 1.7% (three to six), and 3.5% (more than six). Therefore, older participants were more compliant with the diet.
  • If selective under-reporting of diabetes was present among the older participants, this would provide an alternative non-causal explanation for our findings. We acknowledge this possibility, but the proportion of selective under-diagnosis of diabetes among older people is likely to be lower as they receive closer medical attention and routine medical care in Spain includes assessment of fasting glucose.
  • All our participants are university graduates and the generalizability of our findings to other groups with less education should be assumed only on biological  grounds but not at all on “representativeness” of the general population
  • Also, the building of the diet score was based on sample specific median cut-off points, and our participants had high absolute levels of consumption of favorable foods and low absolute intakes of detrimental foods. Therefore, it will be difficult to compare our results with those of non-Mediterranean countries where levels of consumption of favorable foods in the general population are much lower. 
Reviewer Comments:
  • Follow-up period is too short for the development of diabetes in this relatively young population
  • One of the limitations that the authors acknowledge is that  their results are not generalizable
  • The authors discussed in detail the study limitations and their implications
  • Even though overall this study received a +ve rating, results should be interpreted with caution due to the short follow-up period, few incident cases of diabetes and poor generalizability of results to other populations.

 


Research Design and Implementation Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)
Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?
Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to nutrition or dietetics practice?
Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies)
Yes
 
Validity Questions
1. Was the research question clearly stated?
Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?
Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated?
Yes
  1.3. Were the target population and setting specified?
Yes
2. Was the selection of study subjects/patients free from bias?
???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?
No
  2.2. Were criteria applied equally to all study groups?
N/A
  2.3. Were health, demographics, and other characteristics of subjects described?
Yes
  2.4. Were the subjects/patients a representative sample of the relevant population?
???
3. Were study groups comparable?
N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)
N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?
N/A
  3.3. Were concurrent controls used? (Concurrent preferred over historical controls.)
N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?
N/A
  3.5. If case control or cross-sectional study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable. Criterion may not be applicable in some cross-sectional studies.)
N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?
N/A
4. Was method of handling withdrawals described?
Yes
  4.1. Were follow-up methods described and the same for all groups?
Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)
N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for?
Yes
  4.4. Were reasons for withdrawals similar across groups?
N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study?
N/A
5. Was blinding used to prevent introduction of bias?
Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?
N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)
Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?
Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status?
N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results?
N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?
Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied?
N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described?
Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?
No
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured?
Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described?
N/A
  6.6. Were extra or unplanned treatments described?
N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?
N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient?
N/A
7. Were outcomes clearly defined and the measurements valid and reliable?
Yes
  7.1. Were primary and secondary endpoints described and relevant to the question?
Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern?
Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur?
No
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?
Yes
  7.5. Was the measurement of effect at an appropriate level of precision?
???
  7.6. Were other factors accounted for (measured) that could affect outcomes?
Yes
  7.7. Were the measurements conducted consistently across groups?
N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators?
Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately?
Yes
  8.2. Were correct statistical tests used and assumptions of test not violated?
Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals?
Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?
N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?
Yes
  8.6. Was clinical significance as well as statistical significance reported?
Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error?
N/A
9. Are conclusions supported by results with biases and limitations taken into consideration?
Yes
  9.1. Is there a discussion of findings?
Yes
  9.2. Are biases and study limitations identified and discussed?
Yes
10. Is bias due to study’s funding or sponsorship unlikely?
Yes
  10.1. Were sources of funding and investigators’ affiliations described?
Yes
  10.2. Was the study free from apparent conflict of interest?
Yes