Plasma Lipidomic Profiling and Risk of Type 2 Diabetes in the PREDIMED Trial

Cristina Razquin; Estefanía Toledo; Clary B. Clish; Miguel Ruiz-Canela; Courtney Dennis; Dolores Corella; Christopher Papandreou; Emilio Ros; Ramon Estruch; Marta Guasch-Ferré; Enrique Gómez-Gracia; Montserrat Fitó; Edward Yu; José Lapetra; Dong Wang; Dora Romaguera; Liming Liang; Angel Alonso-Gómez; Amy Deik; Mónica Bullo; Lluis Serra-Majem; Jordi Salas-Salvadó; Frank B. Hu; Miguel A. Martínez-González

doi:10.2337/dc18-0840

Cardiovascular and Metabolic Risk

Plasma Lipidomic Profiling and Risk of Type 2 Diabetes in the PREDIMED Trial

Cristina Razquin¹,²,³,
Estefanía Toledo¹,²,³,
Clary B. Clish⁴,
Miguel Ruiz-Canela¹,²,³,
Courtney Dennis⁴,
Dolores Corella³,⁵,
Christopher Papandreou³,⁶,
Emilio Ros³,⁷,
Ramon Estruch³,⁸,
Marta Guasch-Ferré³,⁶,⁹,
Enrique Gómez-Gracia³,¹⁰,
Montserrat Fitó³,¹¹,
Edward Yu⁹,
José Lapetra³,¹²,
Dong Wang⁹,
Dora Romaguera³,¹³,
Liming Liang¹⁴,¹⁵,
Angel Alonso-Gómez³,¹⁶,
Amy Deik⁴,
Mónica Bullo³,⁶,
Lluis Serra-Majem³,¹⁷,
Jordi Salas-Salvadó³,⁶,
Frank B. Hu⁹,¹⁸ and
Miguel A. Martínez-González¹,²,³,⁹ ⇑

¹Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
²IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
³CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain
⁴Broad Institute of MIT and Harvard University, Cambridge, MA
⁵Department of Preventive Medicine, University of Valencia, Valencia, Spain
⁶Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d’Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain
⁷Lipid Clinic, Department of Endocrinology and Nutrition, Institut d’Investigacions Biomediques August Pi Sunyer (IDI-BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
⁸Department of Internal Medicine, Institut d’Investigacions Biomediques August Pi Sunyer (IDI-BAPS), Barcelona, Spain
⁹Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
¹⁰Department of Preventive Medicine, University of Malaga, Malaga, Spain
¹¹Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
¹²Research Unit, Department of Family Medicine, Distrito Sanitario Atención Primaria Sevilla, Seville, Spain
¹³Instituto de Investigación Sanitaria Illes Balears (IdISBa), University Hospital of Son Espases, Palma de Mallorca, Spain
¹⁴Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
¹⁵Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
¹⁶Department of Cardiology, University Hospital of Alava, Vitoria, Spain
¹⁷Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, and Service of Preventive Medicine, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Canary Health Service, Las Palmas de Gran Canaria, Spain
¹⁸Channing Division for Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

Corresponding author: Miguel A. Martínez-González, mamartinez{at}unav.es.

Diabetes Care 2018 Dec; 41(12): 2617-2624. https://doi.org/10.2337/dc18-0840

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Figure 1
A: HRs per 1-SD increase in baseline lipid concentration for lipid groups inversely associated with T2D. Lipid species were inverse normally transformed, and HRs were calculated from weighted Cox models adjusted for age, sex, intervention group, BMI, smoking, hypertension, dyslipidemia, and baseline glucose (linear and quadratic term). B: HRs per 1-SD increase in baseline lipid concentration for lipid groups directly associated with T2D. Lipid species were inverse normally transformed, and HRs were calculated from weighted Cox models adjusted for age, sex, intervention group, BMI, smoking, hypertension, dyslipidemia, and baseline glucose (linear and quadratic term). C: HRs for T2D per 1 SD for the residual of each TAG over the total content of the considered TAG. Lipid species were inverse normally transformed before calculating the residual, and HRs were calculated from weighted Cox models adjusted for age, sex, intervention group, BMI, smoking, hypertension, dyslipidemia, and baseline glucose (linear and quadratic term).

Tables

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Table 1

Baseline characteristics of study participants according to outcome status

	Subcohort (n = 692)^a	Case subjects with T2D (n = 250)
Age (years)	66.5 (5.7)	66.4 (5.7)
Women (%)	63	55.2
BMI (kg/m²)	29.9 (3.6)	30.8 (3.3)
Waist circumference (cm)	100 (11)	103 (10)
LTPA (METS-min/day)	238 (238)	249 (234)
Fasting glucose (mg/dL)	98 (14)	117 (18)
HDL cholesterol (mg/dL)	56.9 (14.2)	52.8 (11.6)
LDL cholesterol (mg/dL)	138.3 (30.5)	135.0 (30.2)
Total cholesterol (mg/dL)	219.9 (35.6)	218.4 (39.1)
Triglycerides (mg/dL)	129.8 (92.2–149.3)^b	160.9 (109–180)^b
Dyslipidemia (%)	85	80
Hypertension (%)	91	96
Smoking
Nonsmoker (%)	61	53
Current smoker (%)	16	25
Former smoker (%)	23	22
Total energy intake (kcal/day)	2,276 (564)	2,321 (616)
Adherence to MedDiet	8.6 (2.0)	8.4 (2.0)
Intervention group (%)
Control (%)	32	36
MedDiet + EVOO (%)	31	30
MedDiet + nuts (%)	37	34

Data are mean (SD) unless otherwise indicated. LTPA, leisure-time physical activity.
↵^aIncluding 53 overlapping cases.
↵^bMedian (interquartile range).

Table 2

Association between baseline lipid factors (PCA extracted) and T2D risk (adjusted for age, sex, and intervention group)

	Quartiles of factors				Linear trend	Per SD increase
	Q1	Q2	Q3	Q4	Linear trend	Per SD increase
Factor 3^*	Ref	0.62 (0.37–1.05)	0.79 (0.47–1.32)	0.45 (0.26–0.79)	0.003	0.70 (0.57–0.85)
Factor 7^*	Ref	0.62 (0.39–0.97)	0.39 (0.23–0.67)	0.36 (0.20–0.63)	<0.001	0.58 (0.49–0.70)
Factor 10^*	Ref	0.80 (0.48–1.33)	0.48 (0.28–0.81)	0.56 (0.33–0.95)	0.012	0.74 (0.62–0.88)
Factor 13^*	Ref	1.00 (0.61–1.66)	0.78 (0.47–1.32)	0.58 (0.34–1.00)	0.166	0.93 (0.78–1.10)
Factor 1^*	Ref	1.39 (0.77–2.52)	2.24 (1.29–3.88)	2.72 (1.59–4.66)	<0.001	1.62 (1.36–1.92)
Factor 5^*	Ref	1.44 (0.83–2.45)	1.14 (0.65–2.00)	2.22 (1.31–3.77)	0.022	1.24 (1.04–1.47)
Factor 11^*	Ref	1.25 (0.72–2.18)	1.78 (1.03–3.10)	2.02 (1.15–3.54)	0.009	1.18 (0.99–1.40)

Data are HR (95% CI) unless otherwise indicated. Boldface type indicates P values <0.05 for the association with T2D (HR). Ref, reference; Q, quartile.
↵*Additionally adjusted for the rest of the factors (1–15).

Table 3

Association between baseline lipid scores and T2D risk

	Quartiles of scores				Linear trend	Per SD
	Q1	Q2	Q3	Q4	Linear trend	Per SD
LP score (LPCs and LPEs); n molecules = 18
M1^*	Ref	0.82 (0.56–1.19)	0.49 (0.32–0.75)	0.46 (0.29–0.71)	<0.001	0.73 (0.63–0.85)
M2^*	Ref	0.86 (0.58–1.27)	0.48 (0.31–0.76)	0.51 (0.32–0.81)	<0.001	0.74 (0.63–0.87)
M3^*	Ref	1.09 (0.69–1.73)	0.54 (0.30–0.97)	0.66 (0.38–1.16)	0.040	0.79 (0.65–0.96)
PC-PL score; n molecules = 15
M1^*	Ref	0.78 (0.53–1.17)	0.77 (0.52–1.16)	0.36 (0.22–0.58)	<0.001	0.78 (0.68–0.90)
M2^*	Ref	0.80 (0.53–1.21)	0.81 (0.54–1.22)	0.38 (0.23–0.64)	0.001	0.82 (0.71–0.95)
M3^*	Ref	0.81 (0.49–1.33)	0.66 (0.39–1.09)	0.37 (0.20–0.68)	0.001	0.76 (0.62–0.92)
SM score; n molecules = 11
M1^*	Ref	0.49 (0.32–0.75)	0.58 (0.38–0.89)	0.32 (0.19–0.54)	<0.001	0.67 (0.56–0.80)
M2^*	Ref	0.46 (0.30–0.72)	0.56 (0.35–0.87)	0.31 (0.18–0.52)	<0.001	0.69 (0.57–0.83)
M3^*	Ref	0.30 (0.17–0.52)	0.51 (0.30–0.88)	0.24 (0.13–0.45)	<0.001	0.67 (0.54–0.84)
CE score; n molecules = 13
M1^*	Ref	0.76 (0.50–1.14)	0.64 (0.43–0.95)	0.34 (0.21–0.54)	<0.001	0.68 (0.58–0.79)
M2^*	Ref	0.87 (0.56–1.35)	0.74 (0.49–1.12)	0.39 (0.24–0.65)	<0.001	0.70 (0.59–0.84)
M3^*	Ref	0.64 (0.36–1.15)	0.56 (0.34–0.91)	0.40 (0.22–0.74)	0.002	0.68 (0.56–0.83)
TAG score (≤56 C and ≤3 double bonds); n molecules = 40
M1^*	Ref	1.73 (1.06–2.83)	2.18 (1.35–3.51)	2.94 (1.85–4.67)	<0.001	1.49 (1.27–1.75)
M2^*	Ref	1.77 (1.06–2.94)	2.10 (1.28–3.43)	2.55 (1.58–4.11)	<0.001	1.39 (1.18–1.64)
M3^*	Ref	1.60 (0.82–3.14)	2.01 (1.04–3.86)	2.02 (1.05–3.87)	0.044	1.23 (1.00–1.52)
DAG score; n molecules = 14
M1^*	Ref	1.14 (0.70–1.86)	2.13 (1.35–3.36)	2.76 (1.77–4.29)	<0.001	1.58 (1.33–1.86)
M2^*	Ref	1.25 (0.75–2.08)	1.95 (1.21–3.14)	2.46 (1.56–3.88)	<0.001	1.48 (1.24–1.77)
M3^*	Ref	1.18 (0.61–2.30)	1.52 (0.84–2.74)	1.93 (1.10–3.37)	0.008	1.31 (1.07–1.61)
PE score; n molecules = 12
M1^*	Ref	1.51 (0.95–2.39)	1.57 (0.95–2.39)	2.55 (1.64–3.95)	<0.001	1.45 (1.23–1.70)
M2^*	Ref	1.43 (0.89–2.31)	1.48 (0.92–2.38)	2.13 (1.35–3.35)	0.001	1.35 (1.15–1.59)
M3^*	Ref	1.30 (0.74–2.78)	0.95 (0.52–2.42)	1.39 (0.80–2.42)	0.321	1.13 (0.93–1.37)

Data are HR (95% CI) unless otherwise indicated. Boldface type indicates P values <0.05 for the association with T2D (HR).
↵*M1: adjusted for age, sex, and intervention group; M2: M1 additionally adjusted for BMI, smoking, hypertension, and dyslipidemia; M3: M2 additionally adjusted for baseline glucose (linear and quadratic term). Ref, reference; Q, quartile.