Mediterranean Diet Bests Low Fat for Secondary Prevention: CORDIOPREV

(UPDATED) When it comes to the best type of diet for patients with established coronary heart disease (CHD), new randomized, controlled data from Spain suggest it may be tough to beat the Mediterranean diet.  

Patients with CHD who ate a Mediterranean diet rich in extra virgin olive oil (EVOO), fatty fish, and nuts had roughly a 25% lower risk of recurrent major adverse cardiovascular events, a composite endpoint that included MI, revascularization, ischemic stroke, PAD, and cardiovascular mortality, compared to those who stuck with a reduced-fat approach during 7 years of follow-up.

“To our knowledge, this study is the most extensive to date evaluating the effects of a Mediterranean diet and a low-fat diet in the prevention of recurrent cardiovascular events in the context of two high-intensity dietary interventions,” write Javier Delgado-Lista, MD (Hospital Universitario Reina Sofia, Córdoba, Spain), and colleagues May 4, 2022, in the Lancet.

CORDIOPREV is the only trial in the past 23 years, they add, comparing the Mediterranean diet against another eating pattern for secondary prevention.

The landmark PREDIMED study, which was first published in 2013, established the Mediterranean diet for the primary prevention of major cardiovascular events, but that study came under criticism because of study protocol violations. Investigators were forced to the retract the study and reanalyze the data after learning that some patients weren’t randomized but rather assigned to treatment because they lived in the same house as an enrolled participant. Others weren’t randomly assigned to a diet and instead were assigned to treatment because of their enrollment at a given hospital clinic.

After adjusting for protocol departures in roughly 1,500 patients, the PREDIMED investigators republished their results in 2018 and the overall results were unchanged: the Mediterranean diet reduced the risk of major cardiovascular events by approximately 30% compared with a reduced-fat diet.

To TCTMD, Delgado-Lista said the concerns surrounding PREDIMED had no bearing on the CORDIOPREV study, noting they were conducted around the same time in two different patient populations.   

Samia Mora, MD (Brigham and Women’s Hospital, Boston, MA), who wasn’t involved in either of the studies, said she believes the concerns surrounding PREDIMED were largely inflated.

“Any clinical trial—any observational study, obviously, but even any randomized trial—ultimately has some issues,” Mora told TCTMD. “There’s really no ideal, perfect randomized trial. The issues were rather minor, and after correcting for those issues in their analysis, there really was no change in their results. While it needed to be corrected and addressed, I think the criticisms were a little bit overblown.”

Regarding the new CORDIOPREV study, Mora said she was impressed.

“With CORDIOPREV, we’ve been long awaiting it,” she said. “It’s a long study, 7 years follow-up, and we really needed it because there’s that niche in secondary prevention where we had some data from before, [that being] the Lyon Diet Heart Study from back in the 90s. But that study was also criticized and wasn’t believed for the longest time, not until the PREDIMED study came out. . . . We really needed another trial in secondary prevention.”

With the Lyon Diet Heart Study, investigators randomized only post-MI men in an era when patients weren’t treated with optimal medical therapy, including statins. With CORDIOPREV, which was an outcomes-driven trial, all patients were well treated with guideline-directed medical therapy and the Mediterranean diet was compared against a relatively healthy low-fat diet, said Mora.

“This really helps to convince any naysayers about the benefits of the Mediterranean diet,” she said.

EVOO, Fatty Fish, and Nuts

CORDIOPREV was a single-center, randomized, dietary-intervention trial that included 1,002 patients (mean age 59.5 years; 82.5% men) with coronary heart disease. At baseline, the mean blood pressure was 138.8/77.2 mm Hg and total cholesterol was 159.0 mg/dL. The mean LDL and HDL cholesterol levels were 88.5 and 42.2 mg/dL, respectively. In total, 98.2% of patients were taking an antiplatelet or anticoagulant, 86.6% were treated with statins, 83.2% were taking an ACE inhibitor or ARB, and 80.1% were on beta-blockers. More than 60% of patients had a prior MI, and 91% underwent prior PCI.

For the Mediterranean diet, participants consumed 35% of their calories from fat, mostly monounsaturated (22%) and polyunsaturated fat (6%). Protein made up 15% of the diet and the remaining calories were comprised of carbohydrates (< 50%). The diet included 40 to 60 g of extra-virgin olive oil, three or more servings of especially fatty fish per week, and three or more servings of nuts per week, among other foods. Wine was optional, but if participants were habitual wine drinkers, it was capped at one to two glasses per day for women and men, respectively.

For the low-fat diet, less than 30% of calories were derived from fat, 15% from protein, and 55% or more from complex carbohydrates. Participants ate low-fat dairy two or three times per day and chose lean fish instead of fatty kinds. Nuts were limited, as was EVOO. Instead, the intervention recommended only 20 to 30 g of sunflower or regular olive oil. Wine was not allowed.

No physical activity was prescribed, nor was any type of caloric restriction. To make sure patients adhered to the diet, they had face-to-face visits with dieticians, internists, or cardiologists every 6 months, group sessions every 3 months, and telephone calls every 2 months. In total, participants had at least 12 interactions with the study team each year.

After 7 years of follow-up, there were 198 primary outcome events: 17.3% in the Mediterranean arm and 22.2% in the low-fat group. In the unadjusted and adjusted models, the Mediterranean diet was associated with a significantly lower risk of the primary endpoint. Adjusted for age and sex alone, eating the diet rich in EVOO, fatty fish, and nuts was associated with a 26.2% lower risk of the primary outcome (P = 0.034). In the fully adjusted model, the Mediterranean diet lowered the risk of the primary outcome by 28.1% compared with the low-fat diet (P = 0.024). The was no significant difference in the risk of any of the primary endpoint’s individual components.

Delgado-Lista said the observed event rate in the trial was lower than expected. In the IMPROVE-IT secondary prevention study with ezetimibe, a trial that also ran for 7 years, major adverse cardiovascular events occurred in roughly 33% of treated patients compared with just 20% of patients in CORDIOPREV.

“[This] makes us think that, in fact, the two diets decreased the chance of having a [recurrent event], although the Mediterranean diet was better than the low-fat diet,” said Delgado-Lista.

In terms of adherence, the investigators previously published results showing that patients largely stuck with both dietary interventions. Having constant and consistent patient engagement, he said, “is the cornerstone of not losing adherence.”   

The observed reduction in risk was more pronounced among men than among women, who in fact saw no significant reduction in risk, although the researchers note that this might have been the result of insufficient power. Less than 18% of study participants were women, and future studies will be needed to determine if this observed sex-related difference is real.   

Translating Results to US Population

In terms of the clinical implications, Delgado-Lista said the results are straightforward: patients with ischemic heart disease should follow a Mediterranean diet. Find a professional to help you learn what the Mediterranean diet is and how to eat it, he said, “and always consume extra virgin olive oil as the main source of fat in that diet.” It’s also a good idea to periodically use a validated score, such as the Mediterranean Diet Adherence Score (MEDAS), to see how closely you’re following it.   

In her own practice, Mora said that she’s been an advocate of the Mediterranean diet for some time, but CORDIOPREV helps settle lingering questions that may have persisted since the Lyon Diet Heart Study or PREDIMED. In PREDIMED, she noted, the control group wasn’t a “true” intervention in that patients were only advised to stick with a low-fat diet, whereas the low-fat dietary group in CORDIOPREV were diligently tracked over time. This ensured that both groups of patients were masked and treated in a similar manner.

“It’s a very solid trial, one that would be very difficult to do in the United States,” she said. “If you look at the details, they had a lot of one-on-one meetings. The interventions were really very intensive, with lots of activities to ensure they had effective interventions. Lifestyle and dietary interventions are very hard to do long-term. These types of trials are really challenging.”

The next challenge will be translating the benefits of the Mediterranean diet to a US population, where fewer people are even aware of the diet. EVOO, said Mora, is more expensive than cheaper oils, and some communities may not be able to find fresh fruits and vegetables in so-called food deserts.

“There are areas in this country that lack access,” she said. Even if fresh is not possible, frozen fruits and vegetables could be a good substitute, said Mora.

In 2021, the American Heart Association (AHA) issued new lifestyle and dietary recommendations that focus on dietary patterns as opposed to individual foods or nutrients. They recommend people eat mostly plants for protein but also fish and seafood. While the AHA doesn’t explicitly push the Mediterranean diet, they do say that this diet can help people achieve healthy dietary patterns.