Supplementary material

Other degradation pathways N-acetyl-lysine 6-acetamido- 2oxohexanoate 6-amino- 2oxohexanoate L-pipecolate Penicilins and cephalosporins biosynthesis L-lysine L-2-aminoadipate 6-semialdehide SaccharopineL-lysine L-2-aminoadipate alpha-aminoadipic semialdehyde synthase aldehyde dehydrogenase Lysine N-acetyltransferasa N6-acetyl-beta-lysine transaminase acyl-lysine deacylase

2-oxoadipate 2-oxoadipate S-glutaril-dihidrolipoamide Citrate cycle kynurenine/2-aminoadipate aminotransferase 2-oxoglutarate dehydrogenase dihydrolipoamide S-succinyltransferase 1-piperideine-2-carboxylate 1-piperideine- 2-carboxylate

Figure S1. Lysine degradation pathway involving 2- aminoadipic acid and pipecolic acid. Modified from www.kegg.jp

Figure S2. Multivariate adjusted hazard ratios (HRs; 95% confidence intervals [CIs]) of incident cardiovascular disease for baseline lysine values (above/below median) stratified by prevalent type 2 diabetes at baseline. P values are referred to the reference category composed of non-diabetic subjects with metabolite levels below the median. The p value for the comparison of diabetics with lysine above the median vs diabetics with lysine below the median was 0.111.

Figure S3. Multivariate adjusted hazard ratios (HRs; 95% confidence intervals [CIs]) of incident type 2 diabetes for quartiles (Q) of baseline a) lysine, b) 2-AAA and c) pipecolic acid stratified by intervention group. P values are referred to the reference category composed of control group subjects with each baseline metabolite below the median.

Figure S4. Multivariate adjusted hazard ratios (HRs; 95% confidence intervals [CIs]) of incident type 2 diabetes for quartiles (Q) of 1-y changes in a) lysine, b) 2-AAA and c) pipecolic acid stratified by intervention group. P values are referred to the reference category composed of control group subjects with each baseline metabolite below the median.

Figure S5. Multivariate adjusted hazard ratios (HRs; 95% confidence intervals [CIs]) of incident cardiovascular disease for quartiles (Q) of 1-y changes in a) lysine, b) 2-AAA and c) pipecolic acid stratified by intervention group. P values are referred to the reference category composed of control group subjects with each baseline metabolite below the median.

MedDiet+EVOO vs control	MedDiet+Nuts vs control
β (95%CI)	p	β (95%CI)	p
2-AAA 1-y change*	0.031 (-0.077 to 0.138)	0.575	-0.005 (-0.116 to 0.104)	0.921
Lysine 1-y change*	0.043 (-0.058 to 0.145)	0.402	0.001 (-0.103 to 0.106)	0.977

Table S1. Effect of 1-y intervention on 1-y changes of 2-AAA and lysine adjusted for age, sex. BMI, family history of CVD, smoking, leisure-time physical activity, education level, type 2 diabetes, hypertension and dyslipidaemia. *Inverse normally transformed residual change.