Background/Objectives: Biomarkers are increasingly recognized as valuable tools for the early prediction of disease, facilitating interventions aimed at delaying its onset and consequences. This study aimed to identify a plasma metabolomic risk score (MRS) corresponding to a metabolomic signature of type 2 diabetes incidence and whether a randomized lifestyle intervention with an energy-reduced Mediterranean diet (MedDiet) could attenuate the risk of type 2 diabetes predicted by this MRS.

Methods: A case-control study nested in the PREDIMED-Plus trial served as the discovery cohort assessing 570 candidate plasma metabolites to identify a MRS. The association between the MRS and type 2 diabetes risk was validated in an independent case-cohort study nested within another trial, the PREDIMED. Potential effect modification by the randomized lifestyle interventions conducted in both randomized trials, separately or combined, was also assessed.

Results: A 16-metabolite MRS was identified in the discovery cohort, including hexoses, aminoadipic acid, symmetric dimethylarginine, and lysophospholipids, with adjusted OR (95%CI) = 1.98 (1.73, 2.25) per SD. In the external validation cohort (in which 12 of the 16 metabolites were available), the MRS showed a strong association with type 2 diabetes [HR (95%CI) = 5.30 (3.92, 7.17) per SD]. This MRS modestly improved type 2 diabetes risk prediction beyond traditional clinical risk factors. A significant attenuation of the MRS-associated risk was observed among participants assigned to the randomized lifestyle intervention in PREDIMED-Plus when evaluating the 2-df interaction that jointly considered the PREDIMED-Plus and PREDIMED interventions (p = 0.0022).

Conclusions/Recommendations: A MRS predictive of type 2 diabetes incidence was identified and externally validated. The MRS added predictive value beyond classical risk factors. Its associated risk was attenuated through intensive lifestyle modification with an energy-reduced MedDiet.

Funding: ERC, ISCIII, NIH-USA.

Disclosures: Dr Estruch reported receiving olive oil for trials from Patrimonio Comunal Olivarero, Spain, and walnuts for trials from the California Walnut Commission during the conduct of the study; nonfinancial support for research from the Fundación Bosch i Gimpera; fees from Brewers of Europe for organizing a European conference; personal fees from the Fundación Cerveza y Salud and the Fundacion Dieta Mediterranea for educational conferences; grants from FIVIN for a trial on wine and health; personal fees from Pernaud Richart for educational conferences; nonfinancial support from Karolinska Institute, Menarini Laboratories for the International Symposium on Cardiovascular Risk, Stockholm for nonfinancial support from Italian Pavilion, for the EXPO DUBAI 2020 Congress on Mediterranean Diet; nonfinancial support for attendance from Cretan Lifestyle: Mediterranean Tradition & Modern Applications Congress in Creta; nonfinancial support from the Empowering Consumers: FoP labeling Reform: Health, Knowledge, Liberties European Parliament; nonfinancial support from the Pontifical Academy of Sciences, the Art & Science of Olive Oil: Nutrition, Medicine and Planetary Health: Securing the Future of a World Cultural Heritage meeting; grants from Grand-Fountain Laboratories for a clinical trial; and personal fees from Dallant Laboratories, Spain Technical Consultations outside the submitted work. Dr Salas-Salvadó reported receiving personal fees from Instituto Danone Spain Member as a member of the advisory board, fees or travel expenses for meeting attendant from Danone Institute International and International Nut and Dried Fruit Foundation; and grants from the International Nut and Dried Fruit Foundation grant to his institution; and is an unpaid member of the advisory board outside the submitted work. No other disclosures were reported.