TABLE 4.

HRs (95% CIs) for incident type 2 diabetes and cardiovascular disease according to metabolites correlated with walnut consumption in the PREDIMED study¹

	PREDIMED study baseline2		PREDIMED year 13
	HR (95% CI)	P	HR (95% CI)	P
Type 2 diabetes
No. of cases/total participants	245/923		161/704
Score of metabolites predicting walnuts
Model 1 (basic model)	0.82 (0.72, 0.94)	0.005	0.76 (0.63, 0.91)	0.004
Model 2 (+ sociodemographic model)	0.86 (0.74, 0.99)	0.04	0.80 (0.64, 0.99)	0.044
Model 3 (+ diet model)	0.86 (0.74, 1.00)	0.05	0.82 (0.64, 1.05)	0.125
Model 4 (+ consumption of walnuts)	0.83 (0.71, 0.97)	0.02	0.81 (0.63, 1.03)	0.092
Cardiovascular disease
No. of cases/total participants	222/993		159/916
Model 1 (basic model)	0.72 (0.63, 0.84)	<0.001	0.74 (0.62, 0.88)	<0.001
Model 2 (+ sociodemographic model)	0.67 (0.58, 0.78)	<0.001	0.76 (0.62, 0.92)	0.007
Model 3 (+ diet model)	0.66 (0.56, 0.77)	<0.001	0.75 (0.60, 0.93)	0.011
Model 4 (+ consumption of walnuts)	0.71 (0.60, 0.85)	<0.001	0.76 (0.61, 0.95)	0.016

¹Model 1 (basic model): adjusted for age, sex, and propensity scores; stratified by intervention group and recruitment center. Model 2 (sociodemographic model): model 1 + BMI, smoking status (never, former, or current smoker), alcohol intake and squared alcohol intake (grams per day), education level (primary, secondary, academic), physical activity (metabolic-equivant minutes per day), family history of CHD (yes/no), baseline dyslipidemia or lipid-lowering medication use (yes/no), baseline hypertension or antihypertensive use (yes/no), and T2D prevalence (only in CVD analysis). Model 3: model 2 + total energy and intakes of vegetables, fruits, cereals, red and processed meat, fish, olive oil, eggs, legumes, and dairy in quintiles. Model 4: model 3 + intake of walnuts from which metabolite set was derived. CHD, coronary heart disease; CVD, cardiovascular disease; PREDIMED, PREvención con DIeta MEDiterránea; T2D, type 2 diabetes.

²Analysis of CVD risk was conducted among the 993 participants of the PREDIMED CVD case–cohort data set or 923 in the T2D case–cohort data set. Cox proportional hazard models, with Barlow weights (inverse probability weights to account for the overrepresentation of cases), were used to estimate HRs and their 95% CIs for risk of CVD. Person-time of follow-up was calculated as the interval between the baseline date and date of CVD or T2D event, death, or date of the last participant contact, whichever came first. HRs refer to 1-SD increase in correlated multimetabolite score.

³Walnuts intake, metabolic signatures, and covariates were assessed at year 1, and outcome was the incident CVD events occurred after the year 1 visit through the end of follow-up. The analytic models were the same as in the baseline analysis. A total of 916 participants were included in the CVD analyses and 704 in the T2D analyses.