Four studies carry most of the evidence for the Mediterranean diet: the Seven Countries Study, the Lyon Diet Heart Study, PREDIMED and CORDIOPREV. Seven Countries was observational and linked olive-oil-based diets with lower heart death rates. The other three were randomised trials, and each found fewer cardiovascular events on a Mediterranean diet than on the comparison diet. Each also has real limits, including PREDIMED's 2018 retraction and republication.
The four studies at a glance
| Study | Design | Who | Main result | Key limit |
|---|---|---|---|---|
| Seven Countries (from late 1950s) | Observational, compared population cohorts | 12,763 middle-aged men, 16 cohorts | Heart death rates rose with saturated fat intake and were low where olive oil was the main fat | Shows association only; men only |
| Lyon Diet Heart Study (1994, 1999) | Randomised, single-blind | 605 people after a first heart attack | Cardiac death plus non-fatal heart attack: risk ratio 0.27 at 27 months | Small, few events; diet rich in alpha-linolenic acid, not olive oil alone |
| PREDIMED (2013, republished 2018) | Randomised, three arms | 7,447 adults aged 55–80 at high risk, no heart disease | Major cardiovascular events: hazard ratio 0.69 with extra virgin olive oil, 0.72 with nuts | Randomisation problems; original paper retracted and reanalysed |
| CORDIOPREV (2022) | Randomised, single centre | 1,002 people with heart disease | Major cardiovascular events: 87 vs 111 against a low-fat diet | Benefit seen in men, not in the 175 women; participants not blinded |
The Seven Countries Study: where the idea began
Design. Ancel Keys and colleagues started the study at the end of the 1950s. It compared heart disease rates between whole populations with very different diets. It is observational: nobody was assigned a diet.
Who. It enrolled 12,763 middle-aged men in 16 cohorts across seven countries (Menotti and Puddu, 2015). The cohorts spanned North America, northern and southern Europe, and Japan.
What it found. A 15-year analysis followed 11,579 men aged 40 to 59 in 15 cohorts; 2,288 died (Keys et al., 1986). Death rates rose with the share of calories from saturated fat. They fell with the share from monounsaturated fat, almost all of it oleic acid. All-cause and coronary death rates were low in cohorts where olive oil was the main fat.
The authors combined the monounsaturated-to-saturated fat ratio with age, blood pressure, cholesterol and smoking. Together these explained 85% of the variation in all-cause death rates between cohorts. For coronary heart disease it was 96%. Later analyses showed the lowest-risk cohorts ate far more plant foods and fish than animal foods and sugar. That contrast became the modern Mediterranean diet concept.
Limits. The study compared group averages, so it can show which populations did well, not why. The authors wrote plainly that "causal relationships are not claimed." It studied only men. Its findings needed trials to test them.
The Lyon Diet Heart Study: the first trial
Design. A randomised, single-blinded trial in France comparing a Mediterranean-style diet with the usual "prudent" diet given after a heart attack.
Who. 605 patients after a first heart attack: 302 on the Mediterranean diet, 303 on the control diet (de Lorgeril et al., 1994).
What it found. The Mediterranean group ate less saturated fat, cholesterol and linoleic acid, and more oleic and alpha-linolenic acid. Blood tests confirmed the change. After a mean of 27 months there were 16 cardiac deaths in the control group and 3 in the Mediterranean group. Non-fatal heart attacks were 17 versus 5. The combined risk ratio was 0.27. Deaths from all causes were 20 versus 8.
An extended follow-up averaging 46 months found the effect held. Cardiac death or non-fatal heart attack occurred 14 times on the Mediterranean diet and 44 times on the control diet (de Lorgeril et al., 1999).
Limits. The trial was small and the event counts were low, so the estimates are imprecise. It studied people after a heart attack, not healthy adults. The diet was built around alpha-linolenic acid, an omega-3 fat from plants, so it is not a test of olive oil alone. Curiously, blood cholesterol, blood pressure and body weight stayed similar in both groups.
PREDIMED: the largest trial, retracted and republished
Design. A multicentre trial in Spain with three arms (Estruch et al., 2018). Two followed a Mediterranean diet, one with extra virgin olive oil and one with mixed nuts. The control group got advice to reduce fat. Participants received regular dietary education. The olive oil and nut groups were given those foods free.
Who. 7,447 people aged 55 to 80, 57% women. All were at high cardiovascular risk but had no cardiovascular disease when they joined.
What it found. The trial was stopped after a median of 4.8 years, based on a planned interim analysis. Major cardiovascular events, meaning heart attack, stroke or cardiovascular death, occurred in:
- 96 people (3.8%) on the Mediterranean diet with extra virgin olive oil
- 83 people (3.4%) on the Mediterranean diet with nuts
- 109 people (4.4%) on the control diet
The adjusted hazard ratios were 0.69 for the olive oil group and 0.72 for the nut group. Put simply, about 30% fewer events in relative terms. In absolute terms the gap between the olive oil and control groups was 0.6 percentage points over almost five years.
The 2018 retraction. The original results appeared in 2013 (Estruch et al., 2013). The investigators later found protocol problems. Some household members were enrolled without randomisation. At one of 11 sites, some participants were assigned without randomisation. Another site appeared to use randomisation tables inconsistently.
The authors withdrew the 2013 paper and republished a reanalysis in 2018. The new analysis did not rely on assuming everyone was randomised. Results were similar after leaving out 1,588 participants whose assignment was known or suspected to have departed from the protocol.
Limits. The randomisation problems weaken PREDIMED's claim to be a clean trial, even though the reanalysis held up. The comparison was a whole diet against low-fat advice, so the effect of olive oil alone cannot be separated out. The participants were older Spanish adults at high risk. For a deeper read, see what the PREDIMED trials really proved.
CORDIOPREV: the long secondary prevention trial
Design. A single-centre randomised trial at Reina Sofia University Hospital in Córdoba, Spain. It compared a Mediterranean diet with a low-fat diet over seven years (Delgado-Lista et al., 2022). Doctors and the endpoint committee did not know who was on which diet; participants did.
Who. 1,002 patients aged 20 to 75 with established coronary heart disease. Their mean age was 59.5 and 82.5% were men.
What it found. Major cardiovascular events occurred in 87 people on the Mediterranean diet and 111 on the low-fat diet. That was 28.1 versus 37.7 events per 1,000 person-years. Adjusted hazard ratios ranged from 0.72 to 0.75, depending on the model.
Limits. The effect was clear in men: 16.2% versus 22.8% had an event. In the 175 women, no difference was found, though the group was small. It was one hospital, and participants knew their diet. Funding included two olive oil foundations, alongside Spanish governments and the European Union.
What do the four studies add up to?
They point the same way from different angles. One large observational study and three randomised trials, in people with and without heart disease, all favoured a Mediterranean pattern. That consistency is the strongest argument for the pattern.
They also share blind spots:
- They test diets, not single foods. None isolates olive oil, nuts or any one ingredient.
- Their main outcomes are cardiovascular. None was designed to test lifespan or ageing itself.
- The comparison diet matters. PREDIMED and CORDIOPREV compared against low-fat diets; Lyon against a post-heart-attack diet of the time.
- The populations are specific. Older Spaniards, French heart patients and men studied from the 1950s on may not stand in for everyone.
The history behind these findings is also told in the Cretan paradox. For how to turn the pattern into daily meals after 40, see our guide to eating for longevity the Mediterranean way. Pomoni makes a Greek early-harvest extra virgin olive oil measured at 635 mg/kg total polyphenols by HPLC; see Pomoni High-Phenolic Olive Oil.
Sources
- Menotti A, Puddu PE. How the Seven Countries Study contributed to the definition and development of the Mediterranean diet concept: a 50-year journey. Nutrition, Metabolism and Cardiovascular Diseases. 2015;25(3):245–252. doi.org/10.1016/j.numecd.2014.12.001
- Keys A, Menotti A, Karvonen MJ, et al. The diet and 15-year death rate in the Seven Countries Study. American Journal of Epidemiology. 1986;124(6):903–915. doi.org/10.1093/oxfordjournals.aje.a114480
- de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. The Lancet. 1994;343(8911):1454–1459. doi.org/10.1016/S0140-6736(94)92580-1
- de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99(6):779–785. doi.org/10.1161/01.CIR.99.6.779
- Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. New England Journal of Medicine. 2013;368:1279–1290. Retracted in 2018. doi.org/10.1056/NEJMoa1200303
- Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. New England Journal of Medicine. 2018;378:e34. doi.org/10.1056/NEJMoa1800389
- Delgado-Lista J, Alcala-Diaz JF, Torres-Peña JD, et al. Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial. The Lancet. 2022;399(10338):1876–1885. doi.org/10.1016/S0140-6736(22)00122-2
