Dietary Fats and Mortality among Patients with Type …...2018/12/14 · 11 elucidated, owing to...
Transcript of Dietary Fats and Mortality among Patients with Type …...2018/12/14 · 11 elucidated, owing to...
Confidential: For Review OnlyDietary Fats and Mortality among Patients with Type 2
Diabetes
Journal: BMJ
Manuscript ID BMJ-2018-048420
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 14-Dec-2018
Complete List of Authors: Jiao, Jingjing; School of Public Health, Zhejiang University School of Medicine , Department of Nutrition; Harvard University T H Chan School of Public Health, Department of NutritionZong, Geng; Harvard University T H Chan School of Public Health, Department of Nutrition; Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesLiu, Gang; Harvard University T H Chan School of Public Health, Department of NutritionShin, Hyun Joon ; Brigham and Women’s Hospital and Harvard Medical School, Veterans Affairs Boston Healthcare SystemHu, Frank; Harvard University T H Chan School of Public Health, Department of Nutrition, Department of Epidemiology; Brigham and Women’s Hospital and Harvard Medical School, Channing Division of Network Medicine, Department of MedicineRimm, Eric; Harvard University T H Chan School of Public Health, Department of Nutrition, Department of Epidemiology; Brigham and Women's Hospital and Harvard Medical School, Channing Division of Network Medicine, Department of MedicineKathryn, Kathryn; Brigham and Women's Hospital and Harvard Medical School, Division of Preventive Medicine, Department of Medicine; Brigham and Women's Hospital and Harvard Medical School, Division of Women's Health, Department of MedicineManson, JoAnn; Harvard University T H Chan School of Public Health, Department of Epidemiology; Brigham and Women's Hospital and Harvard Medical School, Channing Division of Network Medicine, Division of Preventive Medicine, Department of MedicineSun, Qi; Harvard University T H Chan School of Public Health, Department of Nutrition; Brigham and Women's Hospital and Harvard Medical School, Channing Division of Network Medicine, Department of Medicine
Keywords: saturated fat, polyunsaturated fat, monounsaturated fat, trans fat, total mortality, cardiovascular disease mortality
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1 Dietary Fats and Mortality among Patients with Type 2 Diabetes
2
3 Jingjing Jiao, PhD, Geng Zong, PhD, Gang Liu, PhD, Hyun Joon Shin, ScD, Frank B. Hu,
4 MD, PhD, Eric B. Rimm, ScD, Kathryn M. Rexrode, MD, JoAnn E. Manson, MD, DrPH, Qi
5 Sun, MD, ScD
6
7 AFFILIATIONS: From Department of Nutrition, School of Public Health, Zhejiang University
8 School of Medicine, Hangzhou, Zhejiang, China (J.J.J.); Department of Nutrition, Harvard
9 T.H. Chan School of Public Health, Boston, Massachusetts, USA (J.J.J., G.Z., G.L., F.B.H.,
10 E.B.R., Q.S.); Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
11 Shanghai, China (G.Z.); Department of Medicine, Brigham and Women's Hospital,
12 Veterans Affairs Boston Healthcare System, Harvard Medical School, Boston,
13 Massachusetts, USA (H.J.S.);Department of Epidemiology, Harvard T.H. Chan School of
14 Public Health, Boston, Massachusetts, USA (F.B.H., E.B.R., J.E.M.); Channing Division of
15 Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard
16 Medical School, Boston, Massachusetts, USA (F.B.H., E.B.R., J.E.M., Q.S.); Division of
17 Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and
18 Harvard Medical School, Boston, Massachusetts, USA (K.M.R.); Division of Women's
19 Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical
20 School, Boston, Massachusetts, USA (K.M.R., J.E.M.).
21 Correspondence to: Geng Zong, PhD, Department of Nutrition, Harvard T.H. Chan School
22 of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA. E-mail:
24 Short running title: Dietary Fats and Mortality in T2D Patients
25 Word count: 3579 words
26 Number of tables and figures: 3 tables and 1 figure
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1 ABSTRACT
2 OBJECTIVE
3 To assess the association of dietary fatty acids with cardiovascular disease (CVD) mortality
4 and total mortality among patients with type 2 diabetes (T2D).
5 DESIGN
6 Prospective, longitudinal cohort study.
7 SETTING
8 Health professionals in the United States.
9 PARTICIPANTS
10 We identified and followed 11,264 participants with T2D in the Nurses’ Health Study
11 (1980-2014) and Health Professionals Follow-Up Study (1986-2014).
12 EXPOSURES
13 Dietary fat intake was assessed using validated food frequency questionnaires and
14 updated every 2-4 years.
15 MAIN OUTCOME MEASURE
16 Total and CVD mortality during follow-up.
17 RESULTS
18 We documented 2,502 deaths, including 646 deaths due to CVD. After multivariate
19 adjustment, in replacement of total carbohydrates, intake of polyunsaturated fatty acids
20 (PUFAs) was associated with a lower CVD mortality: HRs (95%CIs) comparing extreme
21 quartiles were 0.76 (0.58, 0.99; P=0.026) for total PUFAs, 0.69 (0.52, 0.90; P=0.0067) for
22 marine n-3 PUFAs, 1.13 (0.85, 1.51) for α-linolenic acid (ALA), and 0.75 (0.56, 1.01) for
23 linoleic acid (LA). Inverse associations with total mortality were also observed for intakes of
24 total PUFAs, n-3 PUFAs, and LA, while monounsaturated fatty acids (MUFAs) of animal,
25 but not plant, origin were associated with a higher total mortality. Moreover, isocalorically
26 replacing 2% of energy from SFAs with total PUFAs or LA was associated with 13% [HR
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1 (95%CI): 0.87 (0.77, 0.99)] or 15% [HR (95%CI): 0.85 (0.73, 0.99)] lower CVD mortality,
2 respectively. A 2% replacement of energy from SFAs with total PUFAs was associated with
3 12% [HR (95% CI): 0.88 (0.83, 0.94)] lower total mortality.
4 CONCLUSIONS
5 In T2D patients, higher intakes of PUFAs, in replacement of carbohydrates or SFAs, are
6 associated with lower CVD and total mortality. These findings highlight the important role of
7 dietary fat quality in the prevention of CVD and total mortality among adults with T2D.
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1 WHAT IS ALREADY KNOWN ON THIS TOPIC
2 Current dietary guidelines for patients with diabetes recommend limiting trans fat intake and
3 replacing saturated fats with unsaturated fats for maintaining good health, and these
4 recommendations are largely based on findings among general populations. Little is known
5 about the associations of specific dietary fats with total and cardiovascular disease (CVD)
6 mortality among diabetes patients who have altered metabolism of macronutrients.
7 WHAT THIS STUDY ADDS
8 Among diabetes patients, dietary intakes of total polyunsaturated fatty acids (PUFAs),
9 α-linolenic acid, linoleic acid (LA) and marine n-3 PUFAs were associated with lower total
10 mortality whereas intake of monounsaturated fats from animal source is associated with
11 higher total mortality.
12 Replacing saturated fatty acids (SFAs) with PUFAs, especially LA, was associated with a
13 lower CVD mortality.
14 Our analysis indicate that increasing dietary PUFAs, especially LA and marine n-3 PUFAs,
15 in replacement of SFAs may facilitate long-term survival among patients with diabetes.
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1 Introduction
2 The number of individuals with type 2 diabetes (T2D) is estimated to be 422 million
3 globally1 and is projected to reach 642 million by 2040,2 imposing a substantial disease toll
4 and economic burden to patients and healthcare systems. Cardiovascular disease (CVD) is
5 the leading cause of deaths in adults with diabetes.3 Current dietary guidelines for CVD
6 prevention and management among diabetes patients recommend limiting intakes of
7 saturated fats (SFAs), trans fats and cholesterol, while increasing the consumption of foods
8 abundant in omega-3 polyunsaturated fatty acids (PUFAs),4 such as fish, nuts and seeds.
9 However, these recommendations were largely based on findings from general
10 populations, and whether they could be extrapolated to patients with diabetes has yet to be
11 elucidated, owing to the altered metabolism of carbohydrates and fats,5 dyslipidemia, and a
12 prothrombotic profile.6 The CVD risk of T2D patients is two to three times that of the general
13 population, thus any possible effects of dietary fats, especially omega-3 PUFAs, needs to
14 be clarified.7 It has been shown that a Mediterranean diet rich in mono- or polyunsaturated
15 fats improved blood glucose and lipid control among individuals with diabetes,8-11 but the
16 association between dietary fats and CVD or total mortality in such population remains
17 lacking.12-15
18 To fill this knowledge gap, we assessed the associations of major dietary fats with CVD
19 mortality and total mortality among adults with diabetes in two large prospective cohort
20 studies. We hypothesize that quality of fats determines their associations with total and
21 CVD mortality among T2D patients.
22
23 Methods
24 Study population
25 The Nurses’ Health Study (NHS) is an ongoing cohort study consisting of 121,701
26 female nurses aged 30–55 y at enrollment in 1976.16 The Health Professionals Follow-Up
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1 Study (HPFS) is a parallel cohort initiated in 1986 that enrolled 51,529 U.S. male health
2 professionals aged 40-75 y.17 Details of these two cohorts have been published
3 elsewhere.17 18 Information on non-dietary lifestyle factors, medical history, as well as
4 incident diseases was collected every two years through validated questionnaires.19 The
5 cumulative response rate during follow-up was over 90% in both cohorts. The Human
6 Subjects Committees at Harvard T.H. Chan School of Public Health and Brigham and
7 Women’s Hospital approved these studies. The return of completed questionnaires was
8 considered informed consent.
9 We identified 1498 prevalent T2D patients at baseline (1980 for NHS and 1986 for
10 HPFS) and 9,766 incident T2D during follow-up. We excluded participants who had CVD or
11 cancer at baseline or before T2D diagnosis, had implausible daily caloric intake (<500
12 or >3,500 kcal/day for women, and <800 or >4,200 kcal/day for men), or had missing data
13 of dietary fats at baseline (defined as 1980 or 1986 for prevalent cases, or the return date of
14 the first dietary questionnaire after T2D diagnosis for incident cases). After these
15 exclusions, 9,053 women and 2,211 men with diabetes were included in the analysis.
16
17 Ascertainment of type 2 diabetes
18 Participants with self-reported diagnosis of diabetes were sent a validated supplementary
19 questionnaire to obtain detailed information on the diabetes diagnosis, including diagnosis
20 date, symptoms, and treatment. Before 1997, cases of T2D were diagnosed according to
21 original National Diabetes Data Group criteria20 if they met at least one of the following
22 criteria: classic symptoms plus a fasting plasma glucose concentration ≥140 mg/dL
23 (7.8mmol/L) or a randomly measured plasma glucose concentration ≥200 mg/dL (11.1
24 mmol/L); ≥2 elevated plasma glucose concentrations on different occasions (≥140 mg/dL
25 with fasting or ≥200 mg/dL with randomly measured, ≥200 mg/dL for ≥2 h after an oral
26 glucose challenge); or treatment with hypoglycemic medication (insulin or an oral
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1 hypoglycemic agent). Since 1997, the fasting plasma glucose concentration for diabetes
2 diagnosis was lowered to 7.0 mmol/L, or 126 mg/dL based on the American Diabetes
3 Association diagnostic criteria.21 In validation studies, 98% of questionnaire-confirmed
4 diabetes cases were re-confirmed by medical record review in the NHS22 and 97% of cases
5 were re-confirmed in the HPFS.23 Given such high accuracy, we included all self-reported
6 diabetes cases to increase sample size.
7
8 Dietary assessment
9 Diet was assessed using validated semi-quantitative food frequency questionnaires
10 (sFFQs) administered every 2-4 years.24 25 The overall validity and reliability of the sFFQs
11 have been reported previously.24 25 Nutrient composition was obtained from the Harvard
12 University Food Composition Database, which is continuously updated to account for
13 changes in nutrient contents and food processing. Fat intake was then calculated by
14 multiplying the consumption frequency of each food item with a pre-specified portion size
15 (e.g., one egg or one slice of bread) by the content of fats, taking into account of the brand
16 and type of fat use in preparation. Dietary fats were expressed as percentages of energy
17 and we calculated cumulative averages across valid assessments during the follow-up to
18 represent long-term intake. Dietary variables was not updated upon a diagnosis of incident
19 CVD or cancer during study follow-up because the incidence of these conditions often
20 leads to changes in diet that are not relevant to the associations of interest.
21 In validation studies, the assessment of dietary fats was compared with that estimated
22 by multiple 1-wk diet records and fatty acid biomarkers in adipose tissue. Correlation
23 coefficients between fat intakes assessed by the 1986 FFQ and diet records were 0.70 for
24 SFAs, 0.69 for MUFAs, and 0.64 for PUFAs.26 Correlations between fatty acids estimated
25 from FFQs and measured in adipose tissue were 0.35 for linoleic acid (LA), 0.48 for marine
26 n-3 PUFAs, and 0.51 for trans fatty acids.27
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1
2 Covariate assessments
3 Information on lifestyle and other potential risk factors for mortality was assessed at
4 baseline and updated during follow-up through biennial questionnaires, including age,
5 ethnicity, weight, smoking status, alcohol drinking, physical activity, family history of
6 diabetes, family history of myocardial infarction, self-reported hypertension and
7 hypercholesterolemia, use of multivitamin, aspirin, and use of insulin and oral hypoglycemic
8 drugs. Body mass index (BMI) was calculated by dividing weight (kg) by height squared
9 (m2). Physical activity was assessed as hours per week of moderate or vigorous activities
10 (including brisk walking) that require at least the expenditure of 3 metabolic equivalents or
11 more per hour (METs).28
12
13 Ascertainment of deaths
14 Deaths were identified through searching the National Death Index, and reports by next of
15 kin or postal authorities.29 Over 98% deaths were identified.30The cause of death was
16 ascertained by physicians who were blinded of the risk profiles of the participants through
17 reviewing death certificates and medical records. International Classification of Diseases
18 (ICD), 8thand 9thRevision codes were used to classify cardiovascular mortality (ICD-8,
19 390.0-458.9 and ICD-9,390.0-459.9) and cancer mortality (ICD-8, 140.0-207.9, ICD-9,
20 140.0-208.9).31
21
22 Statistical analysis
23 Person-time was calculated from the return date of the first dietary questionnaire after T2D
24 diagnosis to the time of death or the end of follow-up (June 30, 2014 for the NHS and
25 January 30, 2014 for the HPFS), whichever was earlier. Cox proportional hazards models
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1 were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the
2 associations of different dietary fats with CVD, cancer, and total mortality. To ensure
3 enough numbers of deaths for analyses, we pooled participants from the two cohorts (no
4 significant heterogeneity was found).
5 The association of specific dietary fats and mortality was analyzed using nutrient
6 density models that included intakes of total energy, percentage of energy from protein and
7 all other dietary fats, and were further adjusted for age, gender, race, BMI at diagnosis,
8 smoking status, smoking pack-years, physical activity, alcohol consumption, family history
9 of diabetes or myocardial infarction, self-reported hypertension or hypercholesterolemia,
10 diabetes duration, multivitamin use, current aspirin use, and dietary cholesterol intake. The
11 model for cancer mortality was additionally adjusted for family history of cancer. In these
12 models, regression coefficients for the specific dietary fats can be interpreted as the
13 estimated effect of substituting the fat at issue for the same energy from carbohydrates. We
14 also evaluated the effects of replacing SFAs with other types of fats in isocaloric
15 substitution models which simultaneously included total energy intake, percentages of
16 energy from protein, carbohydrates, and all fats except SFAs. Tests for trend were
17 calculated by modelling the median values of each category as a continuous variable.
18 In a secondary analysis, we further analyzed the associations for MUFAs from plant
19 and animal origin separately. Sensitivity analyses were performed by excluding mortality
20 that occurred within 4 years after diabetes diagnosis, excluding prevalent T2D, excluding
21 participants with extreme BMI (<18.5 or >40.0 kg/m2), restricting the analysis to confirmed
22 T2D cases only, or further adjusting for the use of hypoglycemic medication.
23 Statistical analyses were performed with SAS 9.4 (SAS Institute, Cary, NC, USA).
24 Two-sided P values <0.05 were considered as statistically significant.
25
26 Patient involvement
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1 Participants were not involved in raising the research question or the outcome measures,
2 nor were they involved in developing plans for recruitment, design, or implementation of the
3 study. No participant was asked to advise on interpretation or writing up of the manuscript.
4 The participants are updated on the study outcomes and developments through the study
5 website (www.nurseshealthstudy.org and https://www.hsph.harvard.edu/hpfs/index.html)
6 and newsletters.
7
8 Results
9 Population characteristics
10 During a mean follow-up of 11 years (124,362 person-years), we documented 2,502
11 deaths, including 646 deaths due to CVD. At diabetes diagnosis, women with higher PUFA
12 intake were on average older, exercised less, and more likely to have hypertension and
13 hypercholesterolemia (table 1). Men with higher PUFA consumption were more likely to be
14 non-smokers, to exercise more, and to use aspirin. They also drank less alcohol and were
15 more likely to use multivitamins, consume more energy, SFAs, MUFAs, and trans fat but
16 less carbohydrates. Participant characteristics according to SFA and MUFA intake were
17 presented in supplementary table1.
18
19 Cardiovascular and total mortality
20 In Table 2, we observed a significant inverse association of total PUFAs with CVD and total
21 mortality after adjusting for age and gender. In multivariate-adjusted model that estimated
22 mortality risk by substituting fats for carbohydrates, the association remained significant:
23 HRs (95% CIs) across quartiles of PUFA intake (from low to high) were 1.00, 0.99 (0.80,
24 1.23), 0.85 (0.67, 1.08), and 0.76 (0.58, 0.99) for CVD mortality (Ptrend = 0.03) and 1.00,
25 0.86 (0.77, 0.95), 0.83 (0.74, 0.94), and 0.68 (0.60, 0.78) for total mortality (Ptrend<0.0001).
26 Intakes of SFAs and trans fats were positively associated with CVD mortality in age and
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1 gender-adjusted model (model 1), but became non-significant after adjusting for other
2 covariates (model 2; table 2).
3 Total MUFA intake was not significantly associated with either CVD or total mortality
4 (model 2; table 2). Nonetheless, MUFAs from animal source (mainly red meats and high-fat
5 dairy products) were positively associated with total mortality (HR: 1.23; 95% CI: 1.04, 1.45;
6 Ptrend = 0.0005; supplementary table 2), and non-significantly associated with a higher
7 CVD mortality (HR comparing the highest versus lowest quartile: 1.27; 95% CI: 0.92-1.75;
8 Ptrend = 0.07). No significant associations with mortality were observed for plant-derived
9 MUFA intake.
10 For specific PUFAs, intake of marine n-3 PUFAs was associated with a lower
11 cardiovascular mortality after multivariate adjustment: HRs (95% CIs) comparing extreme
12 quartiles were 0.69 (0.52, 0.90; Ptrend = 0.007; high vs low). The association between LA
13 and CVD mortality did not achieve statistical significance, with an HR (95% CI) of 0.75
14 (0.56, 1.01; Ptrend = 0.06; table 3). Intakes of marine n-3 PUFAs and LA were associated
15 with lower total mortality: HRs (95% CIs) comparing extreme quartiles were 0.71 (0.62,
16 0.82; Ptrend < 0.0001) and 0.81 (0.69, 0.94; Ptrend = 0.008; table 3), respectively. ALA intake
17 was non-significantly associated with lower total mortality (HR: 0.88; 95% CI: 0.76, 1.02;
18 Ptrend = 0.04).
19
20 Cancer mortality
21 No significant associations of SFAs and MUFAs intakes with cancer mortality were
22 observed (supplementary tables 3). As shown in supplementary table 4, participants in
23 the highest quartile of marine n-3 PUFA intake had 28% (HR: 0.72; 95%CI: 0.53, 0.99)
24 lower risk of cancer mortality, comparing with those in the lowest quartile. ALA turned to be
25 inversely associated with cancer mortality, but HR comparing extreme quartiles did not
26 achieve statistical significance (0.75; 95% CI: 0.53, 1.05; Ptrend = 0.04).
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1
2 Substitution for SFAs
3 Figure 1 presents mortality risk by isocaloric replacement of SFAs with other fats. CVD
4 mortality was 13% [HR (95% CI): 0.87 (0.77, 0.99)] lower when 2% energy from SFAs was
5 iso-calorically replaced by total PUFAs, and 15% (HR: 0.85; 95% CI: 0.73, 0.99) lower
6 when replaced by LA. Similarly, replacing 2% energy from SFAs with total PUFAs was
7 associated with 12% (HR: 0.88; 95% CI: 0.83, 0.94) lower total mortality. No significant
8 changes in total mortality [HR (95% CI): 0.99 (0.94, 1.05)] or CVD mortality [HR (95% CI):
9 0.99 (0.88, 1.11)] were observed when replacing 2% energy from SFAs with MUFAs.
10 Replacing SFAs with PUFAs was not associated with cancer mortality (supplementary fig
11 1).
12
13 Sensitivity analyses
14 The associations of specific dietary fats with total, CVD, and cancer mortality did not
15 change materially after excluding participants with extreme BMI or further adjusting for the
16 use of hypoglycemic medication (supplementary table 5). Excluding deaths that occurred
17 within 4 years after T2D diagnosis slightly strengthened the results. We observed similar
18 results when restricting the analysis within incidence cases only. Restricting the analysis to
19 confirmed T2D cases only slightly attenuated the associations.
20
21 Discussion
22 In two cohorts of US men and women, we demonstrated an inverse association of dietary
23 PUFAs, including LA and marine n-3 PUFAs, with CVD mortality or total mortality among
24 T2D patients. In addition, animal-derived MUFAs were associated with higher total mortality
25 compared with dietary carbohydrates.
26
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1 Comparison with other studies and possible explanations
2 To our knowledge, this is the first prospective analysis that investigated the
3 associations between specific dietary fats and CVD mortality among individuals with T2D.
4 Our findings regarding PUFAs are largely ascribed to LA, which is the most abundant
5 PUFA in the diet.4 Similarly, a recent analysis of NHS and HPFS demonstrated a significant
6 inverse association of dietary LA with total and CVD mortality among participants who were
7 free of major chronic diseases, including diabetes, at baseline.32 However, these findings
8 are seemingly contradictory to evidence from the Sydney Diet Heart Study that showed
9 higher LA intake led to increased mortality.33 It is worth noting that safflower oil and
10 margarines were used as the food source of LA in this intervention, therefore the observed
11 effect may be at least partially ascribed to high trans fat contents of margarines in early
12 days.34 In contrast, a recent meta-analysis of four randomized controlled trials (RCTs)
13 demonstrated that substituting PUFAs for SFAs reduced coronary heart disease (CHD) risk
14 by approximately 30%.35 Our findings are also in line with a 30-week intervention study that
15 showed LA-enriched diet (10.9% of energy) reduced total and LDL-cholesterol levels
16 among individuals with T2D.36 Collectively, these data suggest that intake of n-6 PUFAs
17 may exert beneficial effects on cardiovascular health among individuals with and without
18 T2D.
19 Potential cardiovascular benefits of marine n-3 PUFAs have been reported in
20 numerous cohort studies,37 38 although recent meta-analysis did not support protective
21 effects of marine n-3 supplements on cardiovascular outcomes, including cardiac death.39
22 This inconsistency maybe due to high baseline dietary marine n-3 PUFA intake, few
23 cardiac deaths, revascularization therapy, and use of statin and other lipid-lowering drugs
24 that may mask the effects of low-to-moderate dose of fish oil supplementation on CVD
25 patients.40 Indeed, in the recent VITAL trial, marine n-3 fatty acid supplementation
26 significantly lowered CVD risk among participants who had a lower intake of these fatty
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1 acids at baseline.41 Moreover, in the REDUCE-IT trial that used a high dose (4 g/day) of
2 pure EPA supplementation, the risk of developing CVD was substantially reduced.42
3 Evidence specifically pertinent to diabetes patients is relatively sparse. Clinical trials
4 concerning CVD intermediate outcomes among adults with diabetes have consistently
5 reported that marine n-3 supplements could lower triglycerides levels,43 improve arterial
6 blood flow, and ameliorate inflammatory condition that predispose CVD events.44 45
7 Meanwhile, a secondary analysis of JELIS study found that eicosapentaenoic acid (1.8
8 g/day) for 4.6 years led to a 22% reduction in coronary artery disease (CAD) risk among
9 4,565 adults with T2D or impaired glucose metabolism,46 but this effect was not observed in
10 another RCT (0.9 g/day) with a larger sample size (n = 12,536) and a longer follow-up
11 duration (6.2 years).47 In the latest trial of 15,480 patients with diabetes, though daily
12 supplementation with 0.84 g marine n-3 PUFA for 7.4 years did not significantly lower the
13 risk of major vascular events, including nonfatal myocardial infarction or stroke, transient
14 ischemic attack, and vascular death, the vascular deaths were fewer in the marine n-3 fatty
15 acid group compared with the control group [rate ratio (95% CI): 0.82 (0.68–0.98)].7
16 The inverse association of marine n-3 PUFA and ALA with cancer mortality is
17 consistent with a previous cohort study that reported combined intakes of n-3 PUFAs from
18 diet and supplements were associated with lower cancer mortality in a general population.48
19 In addition, meta-analyses have concluded that n-3 PUFA intake was inversely related to
20 cancer risks in breast,49 50 prostate,51 and liver.52 It is worth noting that the morbidity and
21 mortality of some cancers, such as endometrial , breast and colorectal cancers is elevated
22 in individuals with T2D.53 In rodent models, n-3 PUFA supplements also ameliorated the
23 diabetic phenotype and subsequently reduced risk of colorectal cancer via inhibiting colonic
24 expression of HNF-4α and β-catenin/Tcf.54
25 MUFA-enriched diets in comparison with carbohydrates have been reported to improve
26 metabolic risk factors in adults with T2D.55 Consistently, substitution of MUFAs for
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1 carbohydrates was associated with lower total mortality among individuals with diabetes in
2 the European Prospective Investigation into Cancer and Nutrition.56 We have recently
3 reported that the associations of dietary MUFAs with CHD risk were dependent on the food
4 sources: those from plant foods was associated with a lower CHD risk, whereas their
5 counterparts from animal sources turned to be associated with a higher risk, possibly
6 because of confounding by other food constitutes.57 In the current study, we did not detect
7 significant associations with total or CVD mortality for total MUFAs or plant-derived MUFAs,
8 yet animal-based MUFAs were significantly associated with total mortality. Similarly, the
9 Kuopio Ischemic Heart Disease Risk Factor study reported that dietary MUFA, which was
10 mainly from animal products was associated with a higher risk of fatal CHD.58 Taken
11 together, these data emphasize the role of food sources in health effects of MUFA intake
12 on cardiovascular health in general populations and diabetes patients.
13
14 Strengths and limitations
15 The current investigation has the strength of using the repeated assessments of diet
16 after diabetes diagnosis, which can help capture potential dietary changes typically
17 observed among individuals with T2D.12 56 Other strengths include the relatively large
18 sample size, long-term follow-up with a high follow-up rate (>90%), and repeated
19 measurements of other lifestyle factors. In addition, when we excluded participants who
20 died within 4 y or those with extreme BMI, the results did not change materially, indicating
21 the robustness of our findings. There are also limitations. First, glycemic control and
22 severity of diabetes were not rigorously assessed in our study. However, when we adjusted
23 for duration of diabetes in the model and further adjusted for the use of insulin and
24 hypoglycemic medications, the results remained unchanged. Prevalent cases may differ
25 from incident cases in terms of their risk profiles, but restricting the analysis within incident
26 cases yields similar results. Third, measurement errors in self-reported diet and lifestyle
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1 factors were inevitable, which may likely attenuate the associations of interest owing to the
2 prospective study design. Fourth, we could not rule out unmeasured confounding by
3 medication adherence, psychosocial stress, or other factors that were not assessed in the
4 cohorts. Lastly, causality may not be established because of the observational nature of
5 this study.
6
7 Conclusions and implications
8 In conclusion, among US men and women with T2D, dietary intake of PUFAs,
9 especially LA and marine n-3 PUFAs, is associated with lower CVD and total mortality. Our
10 results suggest that dietary PUFAs, in replacement of SFAs or carbohydrates, may
11 facilitate the long-term survival among adults with T2D.
12
13 Contributors: JJ, GZ, and QS conceived and designed the study. JJ, GZ, GL, and QS
14 analyzed and interpreted data. JJ drafted the manuscript. FBH, EBR, KMR, JEM, and QS
15 revised manuscript critically for important intellectual content. All authors provided final
16 approval of the version to be published. JJ is the guarantor of this work and, as such, had
17 full access to all the data in the study and takes responsibility for the integrity of the data
18 and the accuracy of the data analysis.
19 Funding: This study was sponsored by the National Institutes of Health, CA186107,
20 CA167552, CA87969, DK082486, HL35464, DK058845, HL088521, and
21 HL034594.Thefunders had no role in design and conduct of the study; collection,
22 management, analysis, and interpretation of the data; preparation, review, and approval of
23 the manuscript; or the decision to submit the manuscript for publication.
24 Competing interests: All authors have completed the ICMJE uniform disclosure form at
25 www.icmje.org/coi_disclosure.pdf and declare: support from the National Institutes of
26 Health for the submitted work; GZ is supported by a postdoctoral fellowship funded by
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1 Unilever R&D, Vlaardingen, Netherlands; QS has received ad hoc consulting fees from the
2 Emavant Solutions GmbH; FBH has received research support from California Walnut
3 Commission and Metagenics; no other relationships or activities that could appear to have
4 influenced the submitted work.
5 Ethical approval: The study protocol was approved by the institutional review boards of
6 the Brigham and Women's Hospital and the Harvard T H Chan School of Public Health. The
7 completion of the self-administered questionnaire was considered to imply informed
8 consent.
9 Transparency declaration: The manuscript’s guarantor affirms that the manuscript is an
10 honest, accurate, and transparent account of the study being reported; that no important
11 aspects of the study have been omitted; and that any discrepancies from the study as
12 planned (and, if relevant, registered) have been explained.
13 Data sharing: No additional data available.
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1 44 De Luis DA, Conde R, Aller R, et al. Effect of omega-3 fatty acids on cardiovascular
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1 54 Algamas-Dimantov A, Yehuda-Shnaidman E, Hertz R, et al. Prevention of
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Table 1. Characteristics of participants at diabetes diagnosis*
Quartiles of Polyunsaturated Fat Intake
Characteristic 1 2 3 4
NHS (n=9,053)
Age (years) 63.4 (10.5) 63.1 (10.8) 62.9 (10.9) 64.4 (11.2)†White (%) 96 96.1 96.7 95.9Body Mass Index (kg/m2) 29.3 (5.9) 29.9 (6.3) 30.1 (6.3) 29.8 (6.4)
Alcohol consumption (g/day) 4.0 (9.6) 2.9 (7.0) 3.0 (7.2) 2.7 (6.4)†Physical activity (hours/week) 1.7 (2.8) 1.6 (2.7) 1.4 (2.4) 1.5 (2.6)†Current smoker (%) 12.7 12.4 12.2 12.4Smoking pack-year 26.4 (22.0) 24.6 (20.7) 25.6 (21.5) 24.8 (20.6)Multivitamin use (%) 49.3 49.5 54.4 51.6†Family history of diabetes (%) 49.4 49.3 49.3 50.9Family history of MI (%) 27.9 28 29.5 28.6Family history of cancer (%) 14.5 14.4 12.8 12.5Aspirin use (%) 52.8 54.6 55.4 55.2Hypoglycemic medication use (%) 41.1 44.8 47.8 45.1Duration of diabetes (years) 4.5 (4.2) 4.8 (4.5) 4.8 (4.3) 4.7 (4.2)Hypercholesterolemia (%) 61.8 61.1 65.8 65.9†Hypertension (%) 74.4 74.8 75.4 75.9†Total energy intake (kcal/day) 1629.4 (521.9) 1655.6 (500.1) 1676.1 (504.8) 1692.0 (542.6)†Carbohydrates (% energy) 52.1 (10.3) 48.6 (9.3) 46.8 (8.7) 44.1 (8.4)†Protein (% energy) 19.6 (3.8) 19.5 (3.6) 19.2 (3.4) 18.8 (3.6)†Total fats (% energy) 28.2 (7.4) 32.4 (6.9) 34.5 (6.5) 37.9 (6.4)†Total PUFAs (% energy) 4.2 (0.7) 5.4 (0.5) 6.4 (0.6) 8.5 (1.8)†n-3 PUFAs (% energy) 0.6 (0.2) 0.7 (0.2) 0.8 (0.2) 1.0 (0.5)† ALA (% energy) 0.4 (0.1) 0.5 (0.1) 0.6 (0.2) 0.8 (0.4)† Marine n-3 PUFAs (% energy) 0.1 (0.1) 0.1 (0.2) 0.1 (0.2) 0.2 (0.2)†n-6 PUFAs (% energy) 3.6 (0.9) 4.8 (0.8) 5.6 (0.9) 7.4 (1.8)† LA (% energy) 3.6 (0.9) 4.7 (0.8) 5.5 (0.9) 7.3 (1.8)† AA (% energy) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0)†SFAs (% energy) 10.7 (4.0) 11.7 (3.8) 11.8 (3.5) 11.9 (3.3)†MUFAs (% energy) 10.7 (3.4) 12.5 (3.4) 13.4 (3.5) 14.7 (3.6)†Trans fats (% energy) 1.3 (0.5) 1.5 (0.6) 1.6 (0.7) 1.7 (0.9)†
HPFS (n=2,211)
Age (years) 68.6 (9.4) 67.5 (8.4) 67.6 (8.7) 67.6 (8.1)White (%) 91.2 90.3 89.3 89.7Body Mass Index (kg/m2) 28.6 (4.9) 29.0 (5.0) 28.3 (4.6) 28.3 (4.6)
Alcohol consumption (g/day) 12.7 (19.7) 8.9 (12.9) 9.8 (14.2) 7.8 (11.3)†Physical activity (hours/week) 2.9 (5.0) 3.1 (7.9) 3.2 (5.1) 3.5 (6.8)†Current smoker (%) 5.9 5.2 5.3 3.8†Smoking pack-year 18.4 (22.3) 16.2 (20.9) 16.8 (20.2) 16.4 (20.3)Multivitamin use (%) 51.2 54.8 62.6 61†
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Family history of diabetes (%) 36.4 40 37.7 41.1Family history of MI (%) 36.5 33.1 30.3 31Family history of cancer (%) 31.2 41.4 36.2 36Aspirin use (%) 53 55.7 56.7 58.9†Hypoglycemic medication use (%) 21.5 20.8 26.2 25Duration of diabetes (years) 3.1 (1.0) 3.3 (1.3) 3.3 (1.5) 3.3 (1.4)†Hypercholesterolemia (%) 65.9 61.6 69.9 66.7Hypertension (%) 70.9 72.1 72.3 72.1Total energy intake (kcal/day) 1944.5 (566.7) 1927.8 (570.6) 1950.3 (648.2) 2014.2 (666.8)†
Carbohydrates (% energy) 51.8 (8.9) 49.2 (7.7) 47.3 (7.6) 43.4 (8.2)†Protein (% energy) 18.6 (3.5) 19.1 (3.1) 18.9 (3.7) 18.6 (3.4)Total fats (% energy) 27.2 (6.0) 30.5 (5.3) 32.4 (5.3) 37.6 (6.3)†Total PUFAs (% energy) 4.3 (0.6) 5.5 (0.4) 6.4 (0.5) 8.6 (2.0)†n-3 PUFAs (% energy) 0.6 (0.2) 0.7 (0.2) 0.8 (0.3) 1.0 (0.5)† ALA (% energy) 0.4 (0.1) 0.5 (0.1) 0.6 (0.1) 0.8 (0.4)† Marine n-3 PUFAs (% energy) 0.1 (0.1) 0.2 (0.2) 0.2 (0.2) 0.2 (0.2)†n-6 PUFAs (% energy) 4.0 (0.6) 5.0 (0.6) 5.8 (0.7) 7.8 (1.8)† LA (% energy) 3.9 (0.6) 4.9 (0.6) 5.7 (0.7) 7.7 (1.8)† AA (% energy) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.1)†SFAs (% energy) 9.8 (3.1) 10.2 (2.8) 10.3 (2.6) 10.9 (2.6)†MUFAs (% energy) 10.5 (2.6) 11.9 (2.5) 12.7 (2.7) 14.8 (3.4)†Trans fats (% energy) 1.3 (0.6) 1.5 (0.7) 1.5 (0.7) 1.6 (0.8)†
AA=arachidonic acid; ALA=α-linolenic acid; HPFS=Health Professionals Follow-Up Study; LA=linoleic
acid; MI=myocardial infarction; MUFA=monounsaturated fatty acids; NHS=Nurses’ Health Study;
PUFA=polyunsaturated fatty acids; SFA=saturated fatty acids.
*Values are age-adjusted means (standard deviation) for continues variables or percentages for
categorical variable.
†P for trend <0.05 analyzed by ANOVA for continuous variables or chi-square test for categorical
variables.
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Table 2 Associations of Dietary Fats with CVD Mortality and Total Mortality Among
Adults with Type 2 Diabetes Mellitus (comparison is isocaloric substitution for total
carbohydrates)
Quartiles of Fatty Acids Intake
Q1 Q2 Q3 Q4 P trendSaturated fatty acids Range ≤9.28 9.29-11.09 11.10-13.18 ≥13.19 Median, % energy 8.03 10.03 11.69 14.34 CVD Mortality No. of cases/person-years 138/31,501 166/31,535 154/31,558 188/31,400
Model 1: HR (95% CI)* 1.00 1.30 (1.03, 1.64) 1.26 (1.00, 1.59) 1.71 (1.37, 2.14) <.0001 Model 2: HR (95% CI)† 1.00 1.14 (0.88, 1.48) 0.98 (0.73, 1.33) 1.13 (0.80, 1.59) 0.62 Total Mortality No. of cases/person-years 594/31,087 628/31,103 613/31,184 667/30,988
Model 1: HR (95% CI)* 1.00 1.14 (1.02, 1.28) 1.21 (1.08, 1.36) 1.39 (1.24, 1.56) <.0001 Model 2: HR (95% CI)† 1.00 1.05 (0.92, 1.19) 1.03 (0.89, 1.19) 1.00 (0.85, 1.19) 0.88
Polyunsaturated fat intake Range ≤5.06 5.07-5.97 5.98-7.06 ≥7.07 Median, % energy 4.48 5.50 6.39 7.95 CVD Mortality No. of cases/person-years 198/31,335 176/31,490 147/31,569 125/31,600
Model 1: HR (95% CI)* 1.00 0.98 (0.79, 1.20) 0.84 (0.67, 1.04) 0.74 (0.59, 0.93) 0.0040 Model 2: HR (95% CI)† 1.00 0.99 (0.80, 1.23) 0.85 (0.67, 1.08) 0.76 (0.58, 0.99) 0.026 Total Mortality No. of cases/person-years 855/30,754 627/31,082 575/31,189 445/31,336
Model 1: HR (95% CI)* 1.00 0.81 (0.73, 0.90) 0.78 (0.70, 0.86) 0.61 (0.55, 0.69) <.0001 Model 2: HR (95% CI)† 1.00 0.86 (0.77, 0.95) 0.83 (0.74, 0.94) 0.68 (0.60, 0.78) <.0001
Monounsaturated fatty acids Range ≤10.77 10.78-12.61 12.62-14.64 ≥14.65 Median, % energy 9.51 11.66 13.37 16.01 CVD Mortality No. of cases/person-years 160/31,453 163/31,524 151/31,559 172/31,458
Model 1: HR (95% CI)* 1.00 1.08 (0.87, 1.35) 1.05 (0.84, 1.32) 1.31 (1.05, 1.64) 0.023 Model 2: HR (95% CI)† 1.00 0.96 (0.74, 1.24) 0.85 (0.63, 1.15) 0.99 (0.70, 1.39) 0.97 Total Mortality No. of cases/person-years 694/30,975 635/31,088 580/31,203 593/31,096
Model 1: HR (95% CI)* 1.00 1.01 (0.90, 1.12) 0.97 (0.87, 1.09) 1.08 (0.97, 1.21) 0.23 Model 2: HR (95% CI)† 1.00 0.93 (0.82, 1.05) 0.83 (0.72, 0.96) 0.90 (0.76, 1.06) 0.21
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Trans fatty acids Range ≤1.16 1.17-1.53 1.54-1.95 ≥1.96 Median, % energy 0.94 1.37 1.71 2.24 CVD Mortality No. of cases/person-years 140/31,499 149/31,542 165/31,546 192/31,407
Model 1: HR (95% CI)* 1.00 1.10 (0.87, 1.39) 1.25 (0.99, 1.57) 1.49 (1.19, 1.86) 0.0002 Model 2: HR (95% CI)† 1.00 0.97 (0.76, 1.25) 1.03 (0.80, 1.34) 1.13 (0.86, 1.50) 0.28 Total Mortality No. of cases/person-years 558/31,131 574/31,176 638/31,115 732/30,940
Model 1: HR (95% CI)* 1.00 1.06 (0.94, 1.19) 1.21 (1.08, 1.36) 1.42 (1.27, 1.58) <.0001 Model 2: HR (95% CI)† 1.00 0.93 (0.82, 1.06) 1.01 (0.88, 1.15) 1.08 (0.94, 1.25) 0.11
CI=confidence interval; CVD=cardiovascular disease; HR=hazard ratio; PUFA=polyunsaturated fatty
acids.
*Adjusted for age (in months), gender and survey period.
†Further adjusted for ethnicity (White, others), body mass index at diagnosis (<23.0, 23.0-24.9,
25.0-29.9, 30.0-34.9, or ≥35.0, kg/m2), physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5
hours/week), smoking status (never, past, current 1-14 cigarettes/d, or current ≥15 cigarettes/d),
smoking pack-years (0, <20, ≥20 pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or
≥30.0 g/d), multivitamin use (yes vs. no), current aspirin use (yes vs. no), family history of myocardial
infarction (yes vs. no), family history of diabetes (yes vs. no), history of hypercholesterolemia (yes vs.
no), history of hypertension (yes vs. no), diabetes duration (<5, 5-10, >10 years), total energy intake
(quartiles), dietary cholesterol (quartiles), and percentage of energy from dietary protein, and remaining
fatty acids where appropriate (PUFAs, MUFAs, trans fats, LA, AA, ALA, and marine n-3 PUFA, all
continuous variables). Comparison is isocaloric substitution for total carbohydrates in this model.
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Table 3 CVD Mortality and Total Mortality Among Adults with Type 2 Diabetes
Mellitus by Iso-calorically Substituting Specific PUFAs for Total Carbohydrates
Quartile of Fatty Acids Intake
Q1 Q2 Q3 Q4 P trendMarine n-3 PUFA* Interquartile range ≤0.05 0.06-0.09 0.10-0.17 ≥0.17 Median, % energy 0.03 0.07 0.13 0.25 CVD Mortality No. of cases/person-years 198/31,217 169/31,439 166/31,618 113/31,721
Model 1: HR (95% CI)† 1.00 0.83 (0.67, 1.02) 0.78 (0.63, 0.97) 0.54 (0.42, 0.68) <.0001 Model 2: HR (95% CI)‡ 1.00 0.92 (0.74, 1.14) 0.91 (0.72, 1.14) 0.69 (0.52, 0.90) 0.0067 Total Mortality No. of cases/person-years 791/30,674 703/30,974 606/31,239 402/31,475
Model 1: HR (95% CI)† 1.00 0.89 (0.80, 0.98) 0.77 (0.69, 0.85) 0.52 (0.46, 0.59) <.0001 Model 2: HR (95% CI)‡ 1.00 0.99 (0.89, 1.10) 0.91 (0.81, 1.03) 0.71 (0.62, 0.82) <.0001
α-Linolenic acid Interquartile range ≤0.45 0.46-0.54 0.55-0.65 ≥0.66 Median, % energy 0.40 0.49 0.58 0.76 CVD Mortality No. of cases/person-years 195/31,291 168/31,509 142/31,578 141/31,616
Model 1: HR (95% CI)† 1.00 0.96 (0.78, 1.18) 0.83 (0.66, 1.03) 0.84 (0.67, 1.04) 0.074 Model 2: HR (95% CI)‡ 1.00 1.06 (0.85, 1.32) 0.98 (0.76, 1.26) 1.13 (0.85, 1.51) 0.44 Total Mortality No. of cases/person-years 827/30,715 680/31,066 510/31,253 485/31,328
Model 1: HR (95% CI)† 1.00 0.89 (0.80, 0.99) 0.69 (0.62, 0.77) 0.65 (0.58, 0.73) <.0001 Model 2: HR (95% CI)‡ 1.00 0.98 (0.87, 1.09) 0.80 (0.70, 0.91) 0.88 (0.76, 1.02) 0.037
Linoleic acid Interquartile range ≤4.21 4.22-5.13 5.14-6.16 ≥6.17 Median, % energy 3.65 4.72 5.55 7.03 CVD Mortality No. of cases/person-years 209/31,299 161/31,509 149/31,545 127/31,641
Model 1: HR (95% CI)† 1.00 0.81 (0.66, 1.00) 0.76 (0.61, 0.94) 0.67 (0.53, 0.84) 0.0004 Model 2: HR (95% CI)‡ 1.00 0.86 (0.69, 1.07) 0.81 (0.63, 1.05) 0.75 (0.56, 1.01) 0.059 Total Mortality No. of cases/person-years 848/30,730 623/31,096 575/31,163 456/31,373
Model 1: HR (95% CI)† 1.00 0.80 (0.72, 0.88) 0.76 (0.68, 0.84) 0.62 (0.55, 0.69) <.0001 Model 2: HR (95% CI)‡ 1.00 0.89 (0.80, 1.00) 0.90 (0.80, 1.02) 0.81 (0.69, 0.94) 0.0080
Arachidonic acid Interquartile range ≤0.06 0.07-0.08 0.09-0.10 ≥0.11
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Median, % energy 0.05 0.07 0.09 0.12 CVD Mortality No. of cases/person-years 168/31,429 142/31,531 165/31,533 171/31,502
Model 1: HR (95% CI)† 1.00 0.91 (0.73, 1.14) 1.13 (0.91, 1.41) 1.16 (0.93, 1.45) 0.065 Model 2: HR (95% CI)‡ 1.00 0.83 (0.65, 1.07) 1.05 (0.80, 1.39) 1.00 (0.71, 1.39) 0.73 Total Mortality No. of cases/person-years 711/30,946 599/31,139 621/31,132 571/31,144
Model 1: HR (95% CI)† 1.00 0.93 (0.83, 1.04) 1.01 (0.91, 1.13) 0.98 (0.88, 1.10) 0.90 Model 2: HR (95% CI)‡ 1.00 0.91 (0.80, 1.02) 1.05 (0.91, 1.21) 1.01 (0.85, 1.19) 0.64
CI=confidence interval; CVD=cardiovascular disease; HR=hazard ratio; PUFA=polyunsaturated fatty
acids.
*The sum of eicosapentaenoic acid and docosahexaenoic acid.
†Adjusted for age (in months), gender and survey period.
‡Further adjusted for white race (yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9, 25.0-29.9,
30.0-34.9, or ≥35.0), physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h /week), smoking status
(never, past, current 1-14 cigarettes/d, or current ≥15 cigarettes/d), smoking pack-years (0, <20, ≥20
pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or ≥30.0 g/d), multivitamin use (yes vs.
no), current aspirin use (yes vs. no), family history of myocardial infarction (yes vs. no), family history of
diabetes (yes vs. no), history of hypercholesterolemia (yes vs. no), history of hypertension (yes vs. no),
diabetes duration (<5, 5-10, >10 years), total energy intake (quartiles), dietary cholesterol (quartiles),
and percentage of energy from dietary protein, and remaining fatty acids where appropriate (PUFAs,
MUFAs, trans fats, LA, AA, ALA, and marine n-3 PUFA, all continuous variables).Comparison is
isocaloric substitution for total carbohydrates in this model.
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Fig 1-Multivariate-adjustedd hazard ratios (HRs) of CVD mortality and total mortality by isocaloric substitution of dietary fats for saturated fatty acids. Hazard ratios of CVD mortality (A) and total mortality (B) by iso-calorically replacing energy from SFAs with specific types of fats. AA=arachidonic acid; ALA=α-linolenic acid;
CI=confidence interval; CVD=cardiovascular disease; HR=hazard ratio; LA=linoleic acid;
MUFA=monounsaturated fatty acids; PUFA=polyunsaturated fatty acids; SFA=saturated
fatty acids. The model was adjusted for age (in months), gender, survey period, white race
(yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9, 25.0-29.9, 30.0-34.9, or
≥35.0), physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h /week), smoking status
(never, past, current 1-14 cigarettes/d, or current ≥15 cigarettes/d), smoking pack-years (0,
<20, ≥20 pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or ≥30.0 g/d),
multivitamin use (yes vs. no), current aspirin use (yes vs. no), family history of myocardial
infarction (yes vs. no), family history of diabetes (yes vs. no), history of
hypercholesterolemia (yes vs. no), history of hypertension (yes vs. no), diabetes duration
(<5, 5-10, >10 years), total energy intake (quartiles), dietary cholesterol (quartiles), and
percentage of energy from dietary protein, carbohydrates and remaining fatty acids where
appropriate (PUFAs, MUFAs, trans fats, LA, AA, ALA, and marine n-3 PUFA, all continuous
variables).
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Appendix: Supplementary figure and tables
Content
Supplementary table 1. Characteristics of patients with type 2 diabetes mellitus at diagnosis
according to saturated fat or monounsaturated fat intake ..........................................................2
Supplementary table 2. Associations between monounsaturated fat from plant or animal
source with mortality from CVD, cancer and all causes among patients with type 2 diabetes
mellitus (isocaloric substitution for total carbohydrates)...........................................................5
Supplementary table 3. Associations between dietary fats and cancer mortality among
patients with type 2 diabetes mellitus (isocaloric substitution for total carbohydrates) ............7
Supplementary table 4. Associations between specific PUFA with mortality from cancer
among patients with type 2 diabetes mellitus (isocaloric substitution for total carbohydrates) 9
Supplementary table 5. Sensitivity analyses ............................................................................11
Supplementary figure 1. Multivariable hazard ratios (HRs) of cancer mortality isocaloric
substitution of dietary fats for saturated fatty acids .................................................................17
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Supplementary table 1. Characteristics of patients with type 2 diabetes mellitus at diagnosis according to saturated fat or
monounsaturated fat intake*
Quartile of Saturated Fat Intake Quartile of Monounsaturated Fat Intake
Characteristic 1 2 3 4 1 2 3 4
NHS (N=9,053)
Age (years) 64.4 (10.2) 62.9 (11.0) 62.9 (11.2) 63.5 (11.3) 64.8 (10.5) 63.3 (10.8) 62.4 (11.2) 63.0 (11.1)White (%) 93.9 96.7 97.5 97.6 95.1 95.9 97.4 96.4Body Mass Index (kg/m2) 28.7 (5.9) 30.0 (6.2) 30.3 (6.3) 30.7 (6.5) 29.2 (6.0) 29.8 (6.2) 30.3 (6.5) 30.1 (6.3)
Alcohol consumption (g/day) 3.7 (9.3) 3.3 (7.5) 2.7 (6.3) 2.6 (6.6) 3.5 (8.9) 2.9 (6.9) 3.0 (7.0) 3.3 (7.6)Physical activity (hours/week) 1.9 (2.9) 1.5 (2.6) 1.4 (2.4) 1.3 (2.4) 1.7 (2.8) 1.5 (2.4) 1.4 (2.6) 1.5 (2.6)Current smoker (%) 11.9 11.7 12.7 13.7 12.2 11.7 12.7 13.3Smoking pack-year 24.1 (20.6) 25.2 (20.3) 24.9 (21.1) 28.3 (23.0) 25.1 (20.9) 24.7 (21.1) 25.7 (21.6) 26.1 (21.3)Multivitamin use (%) 54.6 51.8 49.4 48.2 52 50.8 52.4 49.8Family history of diabetes (%) 48.6 52.1 49.5 48.1 49.8 51 49.6 47.6Family history of MI (%) 28.9 29.1 27.2 28.8 28.2 28.3 28 29.4Family history of cancer (%) 13.6 13.9 13.4 13.1 13.5 14.2 13.8 12.5Aspirin use (%) 55.2 56 54.3 52.5 55.3 53.1 54.8 54.5Hypoglycemic medication use (%) 38.4 46.2 47.4 50.8 40.6 44.3 46.9 48.8Duration of diabetes (years) 4.6 (4.3) 4.6 (4.0) 4.7 (3.9) 5.0 (4.6) 4.5 (4.2) 4.7 (4.3) 4.6 (4.0) 4.9 (4.4)Hypercholesterolemia (%) 64.8 63.5 63.5 62.6 62.7 63.1 63.4 66.4Hypertension (%) 73.3 75.7 76.6 75.9 73.9 75.7 75.3 76.1Total energy intake (kcal/day) 1602.0 (496.2) 1683.2 (515.0) 1705.5 (530.7) 1705.9 (537.9) 1590.8 (501.8) 1664.7 (509.6) 1710.8 (513.2) 1739.9 (547.0)
Carbohydrate (% energy) 54.2 (8.3) 48.2 (7.0) 44.9 (7.4) 39.8 (8.9) 54.8 (7.8) 48.5 (6.4) 44.7 (6.8) 38.9 (8.5)Protein (% energy) 19.4 (3.9) 19.4 (3.5) 19.1 (3.4) 19.1 (3.5) 19.4 (4.0) 19.2 (3.5) 19.1 (3.3) 19.1 (3.5)Total fat (% energy) 27.0 (5.4) 32.9 (4.7) 36.4 (5.3) 41.2 (6.4) 26.3 (4.6) 32.8 (3.7) 36.5 (4.3) 42.2 (6.1)
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Total PUFA (% energy) 5.8 (2.0) 6.3 (1.9) 6.6 (2.0) 6.4 (2.0) 5.2 (1.5) 6.2 (1.6) 6.7 (1.9) 7.4 (2.3)n-3 PUFA (% energy) 0.8 (0.4) 0.8 (0.3) 0.8 (0.3) 0.7 (0.3) 0.7 (0.3) 0.7 (0.3) 0.8 (0.4) 0.8 (0.4) ALA (% energy) 0.6 (0.4) 0.6 (0.3) 0.6 (0.3) 0.6 (0.2) 0.5 (0.3) 0.6 (0.3) 0.7 (0.3) 0.7 (0.3) Marine n-3 PUFA (% energy) 0.2 (0.2) 0.1 (0.2) 0.1 (0.1) 0.1 (0.1) 0.1 (0.2) 0.1 (0.2) 0.1 (0.1) 0.1 (0.2)n-6 PUFA (% energy) 5.1 (1.8) 5.6 (1.8) 5.8 (1.9) 5.5 (2.0) 4.5 (1.4) 5.4 (1.6) 5.9 (1.8) 6.6 (2.2) LA (% energy) 5.0 (1.8) 5.5 (1.8) 5.7 (1.9) 5.4 (2.0) 4.5 (1.4) 5.3 (1.6) 5.8 (1.8) 6.5 (2.2) AA (% energy) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0)SFA (% energy) 8.4 (2.0) 11.0 (1.9) 12.8 (2.3) 15.9 (3.2) 9.2 (2.5) 11.5 (2.7) 12.6 (3.1) 14.1 (4.1)MUFA (% energy) 10.3 (2.7) 12.7 (2.8) 14.1 (3.2) 15.8 (3.9) 9.4 (1.8) 12.3 (1.5) 14.2 (1.9) 17.7 (3.2)Trans-fat (% energy) 1.2 (0.6) 1.5 (0.6) 1.7 (0.7) 1.9 (0.7) 1.2 (0.5) 1.6 (0.6) 1.7 (0.7) 1.8 (0.9)
HPFS (N=2,211)Age (years) 67.9 (9.0) 67.8 (8.5) 67.7 (8.2) 67.6 (8.2) 68.5 (9.3) 67.9 (8.5) 67.5 (8.6) 67.3 (7.9)White (%) 87 91.4 92.3 90.2 88.1 90 90.8 91.2Body Mass Index (kg/m2) 27.8 (4.5) 28.6 (4.7) 28.8 (5.0) 29.3 (4.8) 28.3 (5.0) 28.3 (4.4) 28.7 (4.8) 28.4 (4.7)
Alcohol consumption (g/day) 10.9 (16.0) 10.2 (14.3) 8.0 (12.0) 6.9 (11.8) 10.4 (16.9) 9.5 (13.0) 9.2 (13.7) 8.5 (12.0)Physical activity (hours/week) 3.6 (5.5) 3.5 (6.6) 2.9 (7.9) 2.7 (5.4) 3.8 (8.3) 3.0 (5.2) 3.3 (5.6) 3.2 (6.1)Current smoker (%) 3.9 4.6 4.9 7 4.5 4.3 4.4 5.9Smoking pack-year 15.0 (19.1) 16.9 (20.5) 17.2 (20.7) 20.7 (24.0) 15.5 (20.9) 16.9 (20.1) 17.3 (21.2) 19.2 (21.9)Multivitamin use (%) 61 55.9 55.3 58.6 58.3 58.3 53.5 61.8Family history of diabetes (%) 41 38.6 36.4 38.3 39.8 40.5 38.1 37.3Family history of MI (%) 35.8 34.7 26.2 30 36.1 33.8 31.3 28.9Family history of cancer (%) 35.9 36.4 36.4 35.2 36.3 35.8 37.9 35.8Aspirin use (%) 58.2 57.7 56.3 53.9 56.3 60.3 52.3 58.7Hypoglycemic medication use (%) 22.2 22.2 23.1 26.7 21.3 22.8 23.5 25.3Duration of diabetes (years) 3.2 (1.4) 3.1 (1.0) 3.2 (1.2) 3.4 (1.6) 3.2 (1.3) 3.1 (1.2) 3.1 (1.0) 3.4 (1.5)Hypercholesterolemia (%) 71.3 65.7 59.6 63 68.6 68.8 63.9 65Hypertension (%) 73 73.2 70.6 71.1 72 72.7 71.9 71.1
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Total energy intake (kcal/day) 1842.4 (553.7) 1994.0 (602.2) 1995.7 (653.6) 2076.7 (683.4) 1818.9 (551.6) 1905.0 (599.0) 2077.9 (620.3) 2052.9 (658.9)
Carbohydrate (% energy) 53.0 (7.8) 48.0 (6.7) 44.5 (6.4) 39.3 (7.7) 55.0 (7.5) 49.5 (5.4) 46.1 (5.6) 39.9 (7.5)Protein (% energy) 18.9 (3.7) 18.4 (3.2) 18.8 (3.2) 19.0 (3.3) 19.0 (3.9) 18.7 (3.3) 18.6 (3.1) 18.8 (3.2)Total fat (% energy) 26.7 (5.1) 32.1 (4.3) 35.8 (4.5) 40.7 (5.4) 24.6 (3.7) 30.5 (2.4) 34.2 (2.8) 40.4 (5.2)Total PUFA (% energy) 6.1 (2.1) 6.6 (2.0) 6.8 (2.0) 6.9 (2.0) 5.3 (1.4) 6.2 (1.5) 6.7 (1.8) 7.9 (2.4)n-3 PUFA (% energy) 0.8 (0.4) 0.8 (0.4) 0.8 (0.3) 0.8 (0.3) 0.7 (0.3) 0.8 (0.3) 0.8 (0.4) 0.9 (0.5) ALA (% energy) 0.6 (0.3) 0.6 (0.3) 0.6 (0.3) 0.6 (0.2) 0.5 (0.2) 0.6 (0.2) 0.6 (0.3) 0.7 (0.4) Marine n-3 PUFA (% energy) 0.2 (0.2) 0.2 (0.2) 0.2 (0.2) 0.1 (0.2) 0.2 (0.2) 0.2 (0.2) 0.2 (0.2) 0.2 (0.2)n-6 PUFA (% energy) 5.5 (1.8) 6.0 (1.8) 6.3 (1.8) 6.3 (1.9) 4.7 (1.2) 5.6 (1.3) 6.1 (1.6) 7.2 (2.1) LA (% energy) 5.4 (1.8) 5.9 (1.8) 6.2 (1.8) 6.2 (1.8) 4.7 (1.2) 5.5 (1.3) 6.0 (1.6) 7.1 (2.1) AA (% energy) 0.1 (0.1) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.0) 0.1 (0.1)SFA (% energy) 7.5 (1.3) 9.9 (0.6) 11.6 (0.7) 14.6 (1.9) 7.9 (1.9) 9.9 (1.7) 11.1 (2.3) 12.3 (2.7)MUFA (% energy) 10.5 (2.7) 12.6 (2.7) 14.1 (2.9) 15.6 (3.0) 9.0 (1.4) 11.5 (0.5) 13.3 (0.6) 16.8 (2.6)Trans-fat (% energy) 1.2 (0.6) 1.5 (0.7) 1.7 (0.7) 1.9 (0.7) 1.1 (0.5) 1.5 (0.6) 1.7 (0.7) 1.7 (0.8)
AA=arachidonic acid; ALA=α-linolenic acid; HPFS=Health Professionals Follow-Up Study; LA=linoleic acid; MI=myocardial infarction;
MUFA=monounsaturated fatty acids; NHS=Nurses’ Health Study; PUFA=polyunsaturated fatty acids; SFA=saturated fatty acids.
*Values are age-adjusted means (SD) or percentages.
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Supplementary table 2. Associations between monounsaturated fat from plant or animal
source with mortality from CVD, cancer and all causes among patients with type 2
diabetes mellitus (isocaloric substitution for total carbohydrates)
Quartile of Fatty Acids Intake
Q1 Q2 Q3 Q4 P trend
Plant source
Interquartile range ≤4.24 4.25-5.69 5.70-7.62 ≥7.63
Median, % energy 3.35 4.99 6.54 9.35
CVD mortality
No. of cases 162/27,935 155/28,025 145/28,045 101/28,124
Multivariate HR (95% CI)* 1.00 1.01 (0.79, 1.29) 1.03 (0.79, 1.35) 0.84 (0.61, 1.15) 0.26
Cancer mortality
No. of cases 106/27,989 103/28,077 104/28,086 93/28,132
Multivariate HR (95% CI) 1.00 1.09 (0.81, 1.47) 1.13 (0.82, 1.55) 1.12 (0.79, 1.60) 0.57
Total mortality
No. of cases 684/27,470 595/27,647 524/27,709 422/27,843
Multivariate HR (95% CI) 1.00 0.98 (0.87, 1.10) 0.97 (0.85, 1.11) 0.89 (0.77, 1.04) 0.15
Animal source
Interquartile range ≤4.35 4.36-5.75 5.76-7.48 ≥7.49
Median, % energy 3.47 5.05 6.42 8.82
CVD mortality
No. of cases 122/28,040 130/28,101 118/28,095 193/27,893
Multivariate HR (95% CI) 1.00 0.99 (0.75, 1.30) 0.73 (0.53, 0.99) 1.27 (0.92, 1.75) 0.069
Cancer mortality
No. of cases 98/28,062 104/28,128 86/28,125 118/27,969
Multivariate HR (95% CI) 1.00 1.03 (0.76, 1.41) 0.75 (0.52, 1.07) 0.92 (0.62, 1.36) 0.59
Total mortality
No. of cases 504/27,700 472/27,788 521/27,751 728/27,431
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Multivariate HR (95% CI) 1.00 0.92 (0.80, 1.06) 0.89 (0.77, 1.04) 1.23 (1.04, 1.45) 0.0005
CI=confidence interval; CVD=cardiovascular disease; HR=hazard ratio.
*The multivariate model was adjusted for age (in months), gender, survey period, white race
(yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9, 25.0-29.9, 30.0-34.9, or ≥35.0),
physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h /week), smoking status (never, past,
current 1-14 cigarettes/d, or current ≥15 cigarettes/d), smoking pack-years (0, <20, ≥20
pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or ≥30.0 g/d),
multivitamin use (yes vs. no), current aspirin use (yes vs. no), family history of myocardial
infarction (yes vs. no), family history of diabetes (yes vs. no), history of
hypercholesterolemia (yes vs. no), history of hypertension (yes vs. no), diabetes duration (<5,
5-10, >10 years), total energy intake (quartiles), dietary cholesterol (quartiles), and
percentage of energy from dietary protein, and remaining fatty acids where appropriate
(SFAs, PUFAs, animal MUFAs, plant MUFAs, trans fats, all continuous variables). The
model for cancer mortality also included family history of cancer (yes vs. no).
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Supplementary table 3. Associations between dietary fats and cancer mortality among
patients with type 2 diabetes mellitus (isocaloric substitution for total carbohydrates)
Quartile of Fatty Acids Intake
Q1 Q2 Q3 Q4 P trendSaturated fat Interquartile range ≤9.28 9.29-11.09 11.10-13.18 ≥13.19 Median, % energy 8.03 10.03 11.69 14.34 Cancer mortality No. of cases/person-years 119/31,518 116/31,582 102/31,626 114/31,470 Model 1: HR (95% CI)* 1.00 1.01 (0.78, 1.31) 1.00 (0.76, 1.30) 1.16 (0.89, 1.50) 0.29 Model 2: HR (95% CI)† 1.00 1.04 (0.77, 1.40) 0.96 (0.67, 1.35) 0.99 (0.67, 1.47) 0.90
Polyunsaturated fat Interquartile range ≤5.06 5.07-5.97 5.98-7.06 ≥7.07 Median, % energy 4.48 5.50 6.39 7.95 Cancer mortality No. of cases/person-years 141/31,399 100/31,567 115/31,597 95/31,633 Model 1: HR (95% CI)* 1.00 0.76 (0.59, 0.99) 0.91 (0.71, 1.17) 0.75 (0.58, 0.98) 0.085 Model 2: HR (95% CI)† 1.00 0.81 (0.62, 1.06) 0.95 (0.72, 1.25) 0.74 (0.55, 1.01) 0.11
Monounsaturated fat Interquartile range ≤10.77 10.78-12.61 12.62-14.64 ≥14.65 Median, % energy 9.51 11.66 13.37 16.01 Cancer mortality No. of cases/person-years 125/31,485 99/31,591 109/31,612 118/31,508 Model 1: HR (95% CI)* 1.00 0.81 (0.62, 1.06) 0.93 (0.71, 1.21) 1.06 (0.82, 1.37) 0.48 Model 2: HR (95% CI)† 1.00 0.88 (0.64, 1.19) 0.98 (0.70, 1.39) 1.09 (0.74, 1.60) 0.49
Trans-fat Interquartile range ≤1.16 1.17-1.53 1.54-1.95 ≥1.96 Median, % energy 0.94 1.37 1.71 2.24 Cancer mortality No. of cases/person-years 136/31,490 94/31,615 104/31,604 117/31,486 Model 1: HR (95% CI)* 1.00 0.74 (0.57, 0.97) 0.80 (0.62, 1.04) 0.93 (0.72, 1.19) 0.68 Model 2: HR (95% CI)† 1.00 0.69 (0.52, 0.91) 0.72 (0.54, 0.97) 0.74 (0.54, 1.01) 0.11
CI=confidence interval; HR=hazard ratio; PUFA=polyunsaturated fatty acids.
*Adjusted for age (in months), gender and survey period.
†Further adjusted for white race (yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9,
25.0-29.9, 30.0-34.9, or ≥35.0), physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h
/week), smoking status (never, past, current 1-14 cigarettes/d, or current ≥15 cigarettes/d),
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smoking pack-years (0, <20, ≥20 pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9,
15.0-29.9, or ≥30.0 g/d), multivitamin use (yes vs. no), current aspirin use (yes vs. no), family
history of myocardial infarction (yes vs. no), family history of diabetes (yes vs. no), family
history of cancer (yes vs. no), history of hypercholesterolemia (yes vs. no), history of
hypertension (yes vs. no), diabetes duration (<5, 5-10, >10 years), total energy intake
(quartiles), dietary cholesterol (quartiles), and percentage of energy from dietary protein, and
other fatty acids when appropriate (SFAs, PUFAs, MUFAs, and trans fats, all were
considered as continuous variables).
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Supplementary table 4. Associations between specific PUFA with mortality from cancer
among patients with type 2 diabetes mellitus (isocaloric substitution for total
carbohydrates)
Quartile of Fatty Acids Intake
Q1 Q2 Q3 Q4 P trendMarine n-3 PUFA Interquartile range ≤0.05 0.06-0.09 0.10-0.17 ≥0.17 Median, % energy 0.03 0.07 0.13 0.25 Cancer mortality No. of cases/person-years 119/31,291 122/31,483 123/31,672 87/31,750 Model 1: HR (95% CI)* 1.00 0.95 (0.74, 1.23) 0.94 (0.73, 1.22) 0.63 (0.48, 0.84) 0.0009 Model 2: HR (95% CI)† 1.00 1.02 (0.78, 1.33) 1.02 (0.78, 1.35) 0.72 (0.53, 0.99) 0.026
α-Linolenic acid Interquartile range ≤0.45 0.46-0.54 0.55-0.65 ≥0.66 Median, % energy 0.40 0.49 0.58 0.76 Cancer mortality No. of cases/person-years 149/31,342 130/31,557 79/31,629 93/31,668 Model 1: HR (95% CI)* 1.00 0.95 (0.74, 1.20) 0.60 (0.46, 0.79) 0.72 (0.56, 0.94) 0.0032 Model 2: HR (95% CI)† 1.00 1.00 (0.78, 1.29) 0.63 (0.46, 0.85) 0.75 (0.53, 1.05) 0.043
Linoleic acid Interquartile range ≤4.21 4.22-5.13 5.14-6.16 ≥6.17 Median, % energy 3.65 4.72 5.55 7.03 Cancer mortality No. of cases/person-years 135/31,374 103/31,565 112/31,586 101/31,670 Model 1: HR (95% CI)* 1.00 0.80 (0.61, 1.04) 0.88 (0.68, 1.13) 0.79 (0.60, 1.02) 0.12 Model 2: HR (95% CI)† 1.00 0.87 (0.66, 1.15) 1.04 (0.77, 1.40) 1.00 (0.71, 1.42) 0.83
Arachidonic acid Interquartile range ≤0.06 0.07-0.08 0.09-0.10 ≥0.11 Median, % energy 0.05 0.07 0.09 0.12 Cancer mortality No. of cases/person-years 128/31,481 105/31,567 125/31,577 93/31,571 Model 1: HR (95% CI)* 1.00 0.88 (0.68, 1.15) 1.05 (0.82, 1.35) 0.78 (0.59, 1.02) 0.14 Model 2: HR (95% CI)† 1.00 0.88 (0.66, 1.17) 1.07 (0.78, 1.47) 0.78 (0.53, 1.15) 0.28
CI=confidence interval; HR=hazard ratio; PUFA=polyunsaturated fatty acids.
*Adjusted for age (in months), gender and survey period.
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†Further adjusted for white race (yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9,
25.0-29.9, 30.0-34.9, or ≥35.0), physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h
/week), smoking status (never, past, current 1-14 cigarettes/d, or current ≥15 cigarettes/d),
smoking pack-years (0, <20, ≥20 pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9,
15.0-29.9, or ≥30.0 g/d), multivitamin use (yes vs. no), current aspirin use (yes vs. no), family
history of myocardial infarction (yes vs. no), family history of diabetes (yes vs. no), family
history of cancer (yes vs. no), history of hypercholesterolemia (yes vs. no), history of
hypertension (yes vs. no), diabetes duration (<5, 5-10, >10 years), total energy intake
(quartiles), dietary cholesterol (quartiles), and percentage of energy from dietary protein, and
remaining fatty acids where appropriate (SFAs, MUFAs, trans fats, LA, AA, ALA, and
marine n-3 PUFA, all continuous variables).
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Supplementary table 5. Sensitivity analyses*
Quartile of Fatty Acids Intake
Q1 Q2 Q3 Q4 P trendExcluding deaths within first 4 years since baselineSaturated fatty acids CVD mortality 1.00 1.09 (0.83, 1.42) 0.91 (0.67, 1.24) 1.02 (0.72, 1.44) 0.95 Cancer mortality 1.00 1.13 (0.82, 1.55) 1.01 (0.70, 1.45) 1.05 (0.70, 1.60) 0.95 Total mortality 1.00 1.05 (0.92, 1.19) 1.02 (0.88, 1.19) 0.98 (0.82, 1.16) 0.63
Polyunsaturated fatty acids CVD mortality 1.00 0.94 (0.75, 1.17) 0.81 (0.64, 1.03) 0.70 (0.53, 0.92) 0.0060 Cancer mortality 1.00 0.83 (0.63, 1.10) 0.88 (0.66, 1.17) 0.74 (0.54, 1.02) 0.10 Total mortality 1.00 0.85 (0.76, 0.94) 0.82 (0.73, 0.92) 0.67 (0.58, 0.77) <.0001
Marine n-3 PUFA CVD mortality 1.00 0.91 (0.73, 1.13) 0.93 (0.74, 1.17) 0.68 (0.51, 0.90) 0.0076 Cancer mortality 1.00 1.01 (0.77, 1.34) 1.03 (0.77, 1.37) 0.74 (0.53, 1.03) 0.049 Total mortality 1.00 0.98 (0.88, 1.09) 0.92 (0.82, 1.03) 0.71 (0.62, 0.82) <.0001
α-Linolenic acid CVD mortality 1.00 1.08 (0.86, 1.35) 1.01 (0.78, 1.30) 1.20 (0.89, 1.60) 0.26 Cancer mortality 1.00 0.98 (0.75, 1.28) 0.61 (0.45, 0.85) 0.74 (0.52, 1.06) 0.048 Total mortality 1.00 0.98 (0.87, 1.09) 0.82 (0.72, 0.93) 0.90 (0.77, 1.04) 0.083
Linoleic acid CVD mortality 1.00 0.84 (0.67, 1.06) 0.78 (0.61, 1.01) 0.69 (0.51, 0.94) 0.016 Cancer mortality 1.00 0.84 (0.63, 1.12) 0.98 (0.72, 1.34) 0.96 (0.67, 1.38) 0.96 Total mortality 1.00 0.87 (0.78, 0.98) 0.87 (0.76, 0.99) 0.76 (0.65, 0.89) 0.0009
Arachidonic acid CVD mortality 1.00 0.82 (0.63, 1.06) 1.05 (0.79, 1.40) 0.95 (0.68, 1.35) 0.92 Cancer mortality 1.00 0.90 (0.66, 1.22) 1.16 (0.84, 1.62) 0.77 (0.51, 1.16) 0.27 Total mortality 1.00 0.91 (0.80, 1.03) 1.07 (0.93, 1.23) 1.00 (0.84, 1.18) 0.74
Monounsaturated fatty acids CVD mortality 1.00 1.01 (0.78, 1.32) 0.88 (0.65, 1.21) 1.08 (0.76, 1.53) 0.67 Cancer mortality 1.00 0.92 (0.66, 1.28) 1.08 (0.75, 1.55) 1.15 (0.77, 1.73) 0.36 Total mortality 1.00 0.96 (0.84, 1.09) 0.86 (0.74, 1.00) 0.93 (0.78, 1.10) 0.39
Trans- fatty acids CVD mortality 1.00 0.96 (0.75, 1.25) 1.09 (0.83, 1.41) 1.17 (0.88, 1.56) 0.18 Cancer mortality 1.00 0.64 (0.47, 0.86) 0.71 (0.52, 0.96) 0.72 (0.52, 1.00) 0.14
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Total mortality 1.00 0.95 (0.83, 1.08) 1.05 (0.92, 1.20) 1.13 (0.98, 1.30) 0.030
Further adjusted for hypoglycemic medication†Saturated fatty acids CVD mortality 1.00 1.13 (0.87, 1.46) 0.98 (0.72, 1.32) 1.11 (0.79, 1.56) 0.67 Cancer mortality 1.00 1.04 (0.77, 1.40) 0.95 (0.67, 1.35) 0.99 (0.67, 1.46) 0.88 Total mortality 1.00 1.03 (0.91, 1.17) 1.01 (0.87, 1.17) 0.98 (0.83, 1.17) 0.74
Polyunsaturated fatty acids CVD mortality 1.00 1.02 (0.82, 1.26) 0.84 (0.67, 1.07) 0.76 (0.58, 0.99) 0.024 Cancer mortality 1.00 0.81 (0.62, 1.06) 0.94 (0.72, 1.24) 0.74 (0.55, 1.01) 0.11 Total mortality 1.00 0.87 (0.78, 0.97) 0.84 (0.74, 0.94) 0.69 (0.60, 0.79) <.0001
Marine n-3 PUFA CVD mortality 1.00 0.89 (0.72, 1.10) 0.87 (0.69, 1.09) 0.68 (0.52, 0.89) 0.0064 Cancer mortality 1.00 1.02 (0.78, 1.32) 1.02 (0.78, 1.34) 0.72 (0.53, 1.00) 0.027 Total mortality 1.00 0.97 (0.87, 1.08) 0.89 (0.79, 1.00) 0.71 (0.62, 0.81) <.0001
α-Linolenic acid CVD mortality 1.00 1.04 (0.84, 1.30) 0.97 (0.75, 1.25) 1.14 (0.86, 1.52) 0.40 Cancer mortality 1.00 1.00 (0.78, 1.29) 0.63 (0.46, 0.86) 0.75 (0.54, 1.05) 0.045 Total mortality 1.00 0.98 (0.88, 1.09) 0.81 (0.72, 0.93) 0.89 (0.77, 1.03) 0.064
Linoleic acid CVD mortality 1.00 0.88 (0.70, 1.10) 0.82 (0.64, 1.06) 0.74 (0.55, 1.00) 0.048 Cancer mortality 1.00 0.87 (0.66, 1.15) 1.04 (0.77, 1.40) 1.00 (0.71, 1.42) 0.85 Total mortality 1.00 0.90 (0.81, 1.01) 0.91 (0.80, 1.03) 0.80 (0.69, 0.93) 0.0063
Arachidonic acid CVD mortality 1.00 0.84 (0.65, 1.08) 1.06 (0.80, 1.41) 1.02 (0.73, 1.43) 0.63 Cancer mortality 1.00 0.88 (0.66, 1.18) 1.07 (0.78, 1.47) 0.78 (0.53, 1.16) 0.29 Total mortality 1.00 0.92 (0.81, 1.03) 1.06 (0.93, 1.22) 1.03 (0.87, 1.22) 0.45
Monounsaturated fatty acids CVD mortality 1.00 0.94 (0.73, 1.22) 0.82 (0.60, 1.11) 0.94 (0.67, 1.33) 0.77 Cancer mortality 1.00 0.88 (0.64, 1.20) 0.98 (0.69, 1.38) 1.08 (0.73, 1.59) 0.51 Total mortality 1.00 0.92 (0.81, 1.05) 0.81 (0.70, 0.94) 0.87 (0.74, 1.03) 0.11
Trans- fatty acids CVD mortality 1.00 0.96 (0.75, 1.23) 1.02 (0.78, 1.32) 1.15 (0.87, 1.52) 0.23 Cancer mortality 1.00 0.68 (0.51, 0.91) 0.72 (0.54, 0.97) 0.74 (0.54, 1.01) 0.12 Total mortality 1.00 0.92 (0.82, 1.05) 1.00 (0.88, 1.14) 1.10 (0.95, 1.26) 0.066
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Excluding extreme BMISaturated fatty acids CVD mortality 1.00 1.15 (0.88, 1.52) 1.00 (0.72, 1.37) 1.12 (0.78, 1.60) 0.68 Cancer mortality 1.00 1.09 (0.80, 1.47) 0.98 (0.69, 1.40) 1.04 (0.70, 1.56) 0.93 Total mortality 1.00 1.04 (0.91, 1.19) 1.04 (0.89, 1.21) 1.00 (0.84, 1.19) 0.92
Polyunsaturated fatty acids CVD mortality 1.00 0.96 (0.76, 1.20) 0.87 (0.68, 1.11) 0.72 (0.55, 0.96) 0.019 Cancer mortality 1.00 0.83 (0.63, 1.09) 0.98 (0.74, 1.29) 0.78 (0.57, 1.07) 0.21 Total mortality 1.00 0.87 (0.77, 0.97) 0.84 (0.74, 0.94) 0.70 (0.61, 0.81) <.0001
Marine n-3 PUFA CVD mortality 1.00 0.95 (0.75, 1.18) 0.91 (0.72, 1.16) 0.67 (0.50, 0.89) 0.0045 Cancer mortality 1.00 1.06 (0.81, 1.38) 1.03 (0.78, 1.36) 0.76 (0.55, 1.05) 0.049 Total mortality 1.00 1.00 (0.90, 1.12) 0.96 (0.85, 1.08) 0.73 (0.63, 0.84) <.0001
α-Linolenic acid CVD mortality 1.00 1.07 (0.85, 1.35) 0.95 (0.73, 1.23) 1.13 (0.84, 1.53) 0.50 Cancer mortality 1.00 1.01 (0.78, 1.31) 0.63 (0.46, 0.87) 0.74 (0.52, 1.04) 0.038 Total mortality 1.00 0.97 (0.87, 1.09) 0.77 (0.67, 0.88) 0.85 (0.73, 0.99) 0.014
Linoleic acid CVD mortality 1.00 0.86 (0.68, 1.08) 0.77 (0.59, 1.00) 0.75 (0.55, 1.03) 0.062 Cancer mortality 1.00 0.93 (0.70, 1.24) 1.06 (0.78, 1.45) 1.07 (0.75, 1.53) 0.61 Total mortality 1.00 0.90 (0.80, 1.01) 0.90 (0.79, 1.02) 0.85 (0.72, 0.99) 0.046
Arachidonic acid CVD mortality 1.00 0.80 (0.62, 1.05) 1.05 (0.79, 1.41) 1.00 (0.71, 1.42) 0.65 Cancer mortality 1.00 0.92 (0.68, 1.23) 1.11 (0.80, 1.54) 0.84 (0.56, 1.25) 0.48 Total mortality 1.00 0.91 (0.80, 1.03) 1.06 (0.92, 1.22) 1.01 (0.85, 1.20) 0.64
Monounsaturated fatty acids CVD mortality 1.00 0.91 (0.69, 1.20) 0.85 (0.62, 1.17) 0.96 (0.67, 1.37) 0.90 Cancer mortality 1.00 0.88 (0.64, 1.21) 0.96 (0.67, 1.36) 1.04 (0.70, 1.54) 0.69 Total mortality 1.00 0.91 (0.80, 1.04) 0.82 (0.70, 0.95) 0.86 (0.72, 1.02) 0.087
Trans- fatty acids CVD mortality 1.00 0.98 (0.75, 1.27) 1.06 (0.80, 1.39) 1.19 (0.89, 1.60) 0.17 Cancer mortality 1.00 0.73 (0.55, 0.98) 0.72 (0.53, 0.98) 0.76 (0.55, 1.04) 0.14 Total mortality 1.00 0.96 (0.84, 1.09) 1.01 (0.88, 1.16) 1.09 (0.94, 1.26) 0.14
Excluding prevalent T2D Saturated fatty acid CVD mortality 1.00 1.17 (0.87, 1.58) 1.05 (0.75, 1.48) 1.02 (0.69, 1.50) 0.82
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Cancer mortality 1.00 0.93 (0.67, 1.29) 1.00 (0.69, 1.45) 1.10 (0.72, 1.67) 0.52 Total mortality 1.00 0.98 (0.84, 1.13) 1.02 (0.87, 1.20) 0.95 (0.79, 1.14) 0.61
Polyunsaturated fat intake CVD mortality 1.00 0.99 (0.78, 1.27) 0.84 (0.64, 1.11) 0.82 (0.60, 1.11) 0.14 Cancer mortality 1.00 0.75 (0.56, 1.01) 1.02 (0.76, 1.37) 0.80 (0.58, 1.12) 0.40 Total mortality 1.00 0.84 (0.74, 0.94) 0.81 (0.71, 0.93) 0.69 (0.59, 0.80) <.0001
Marine ω-3 PUFA CVD mortality 1.00 0.99 (0.77, 1.26) 0.97 (0.75, 1.26) 0.73 (0.53, 1.00) 0.039 Cancer mortality 1.00 1.04 (0.79, 1.39) 1.05 (0.78, 1.40) 0.74 (0.53, 1.04) 0.050 Total mortality 1.00 1.00 (0.89, 1.13) 0.91 (0.80, 1.04) 0.73 (0.63, 0.85) <.0001
α-Linolenic acid CVD mortality 1.00 1.06 (0.83, 1.36) 0.84 (0.62, 1.13) 1.02 (0.73, 1.43) 0.96 Cancer mortality 1.00 0.92 (0.69, 1.22) 0.67 (0.48, 0.93) 0.77 (0.53, 1.12) 0.13 Total mortality 1.00 1.00 (0.89, 1.13) 0.74 (0.64, 0.86) 0.85 (0.72, 1.01) 0.020
Linoleic acid CVD mortality 1.00 0.89 (0.69, 1.16) 0.82 (0.61, 1.10) 0.88 (0.62, 1.24) 0.42 Cancer mortality 1.00 1.02 (0.76, 1.38) 1.17 (0.85, 1.63) 1.16 (0.79, 1.70) 0.39 Total mortality 1.00 0.88 (0.78, 1.00) 0.90 (0.78, 1.04) 0.87 (0.73, 1.04) 0.13
Arachidonic acid CVD mortality 1.00 0.93 (0.70, 1.23) 1.16 (0.85, 1.59) 1.07 (0.73, 1.57) 0.59 Cancer mortality 1.00 0.79 (0.58, 1.08) 1.09 (0.78, 1.53) 0.74 (0.49, 1.12) 0.28 Total mortality 1.00 0.88 (0.77, 1.01) 1.01 (0.86, 1.17) 0.96 (0.80, 1.16) 0.99
Monounsaturated fatty acid CVD mortality 1.00 0.98 (0.73, 1.31) 0.74 (0.53, 1.05) 0.99 (0.67, 1.45) 0.90 Cancer mortality 1.00 0.89 (0.63, 1.24) 0.94 (0.65, 1.36) 0.89 (0.59, 1.36) 0.71 Total mortality 1.00 0.96 (0.84, 1.11) 0.86 (0.73, 1.01) 0.87 (0.72, 1.04) 0.092
Trans fat CVD mortality 1.00 0.94 (0.71, 1.25) 1.01 (0.75, 1.35) 1.07 (0.78, 1.46) 0.55 Cancer mortality 1.00 0.68 (0.50, 0.92) 0.70 (0.51, 0.95) 0.70 (0.50, 0.97) 0.066 Total mortality 1.00 0.93 (0.81, 1.07) 1.02 (0.88, 1.18) 1.04 (0.89, 1.22) 0.35
Restricting to confirmed T2D casesSaturated fatty acid CVD 1.00 1.19 (0.89, 1.59) 1.02 (0.73, 1.43) 1.12 (0.76, 1.64) 0.74 Cancer 1.00 1.08 (0.77, 1.52) 1.10 (0.75, 1.62) 1.21 (0.78, 1.88) 0.38 Total 1.00 1.02 (0.88, 1.18) 1.05 (0.89, 1.24) 1.01 (0.84, 1.23) 0.91
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Polyunsaturated fat intake CVD 1.00 0.92 (0.72, 1.17) 0.71 (0.54, 0.93) 0.74 (0.56, 1.00) 0.023 Cancer 1.00 0.78 (0.58, 1.07) 1.02 (0.75, 1.38) 0.79 (0.56, 1.11) 0.34 Total 1.00 0.83 (0.74, 0.94) 0.80 (0.70, 0.92) 0.67 (0.58, 0.78) <.0001
Marine ω-3 PUFA CVD 1.00 1.02 (0.80, 1.30) 0.94 (0.73, 1.21) 0.80 (0.59, 1.08) 0.097 Cancer 1.00 1.15 (0.85, 1.55) 1.09 (0.80, 1.49) 0.81 (0.56, 1.15) 0.098 Total 1.00 1.05 (0.93, 1.18) 0.94 (0.83, 1.07) 0.77 (0.66, 0.90) 0.0001
α-Linolenic acid CVD 1.00 0.97 (0.76, 1.24) 0.87 (0.65, 1.15) 1.08 (0.78, 1.48) 0.69 Cancer 1.00 1.02 (0.77, 1.36) 0.61 (0.43, 0.87) 0.75 (0.51, 1.11) 0.079 Total 1.00 0.98 (0.87, 1.11) 0.80 (0.69, 0.92) 0.85 (0.72, 1.01) 0.033
Linoleic acid CVD 1.00 0.86 (0.67, 1.10) 0.77 (0.58, 1.02) 0.79 (0.56, 1.10) 0.13 Cancer 1.00 0.93 (0.69, 1.27) 1.02 (0.73, 1.43) 1.01 (0.68, 1.50) 0.88 Total 1.00 0.89 (0.78, 1.01) 0.86 (0.74, 0.99) 0.81 (0.68, 0.96) 0.013
Arachidonic acid CVD 1.00 0.93 (0.70, 1.23) 1.16 (0.85, 1.59) 1.15 (0.79, 1.67) 0.34 Cancer 1.00 0.95 (0.69, 1.31) 1.14 (0.80, 1.62) 0.85 (0.55, 1.32) 0.53 Total 1.00 0.92 (0.80, 1.05) 1.03 (0.88, 1.20) 1.02 (0.84, 1.23) 0.61
Monounsaturated fatty acid CVD 1.00 0.96 (0.72, 1.28) 0.77 (0.55, 1.09) 0.96 (0.65, 1.40) 0.82 Cancer 1.00 0.90 (0.64, 1.28) 0.92 (0.63, 1.36) 0.97 (0.63, 1.50) 0.98 Total 1.00 0.97 (0.84, 1.12) 0.83 (0.71, 0.98) 0.89 (0.74, 1.08) 0.18
Trans fat CVD 1.00 0.93 (0.70, 1.24) 1.10 (0.82, 1.46) 1.20 (0.88, 1.63) 0.14 Cancer 1.00 0.61 (0.45, 0.84) 0.67 (0.48, 0.92) 0.67 (0.48, 0.95) 0.063 Total 1.00 0.93 (0.80, 1.07) 1.03 (0.89, 1.19) 1.12 (0.96, 1.31) 0.050
CI=confidence interval; CVD=cardiovascular disease; HR=hazard ratio;
PUFA=polyunsaturated fatty acids.
*The multivariate model was adjusted for age (in months), gender, survey period, white race
(yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9, 25.0-29.9, 30.0-34.9, or ≥35.0),
physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h /week), smoking status (never, past,
current 1-14 cigarettes/d, or current ≥15 cigarettes/d), smoking pack-years (0, <20, ≥20
pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or ≥30.0 g/d),
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multivitamin use (yes vs. no), current aspirin use (yes vs. no), family history of myocardial
infarction (yes vs. no), family history of diabetes (yes vs. no), history of
hypercholesterolemia (yes vs. no), history of hypertension (yes vs. no), diabetes duration (<5,
5-10, >10 years), total energy intake (quartiles), dietary cholesterol (quartiles), and
percentage of energy from dietary protein, and remaining fatty acids where appropriate
(PUFAs, MUFAs, trans fats, LA, AA, ALA, and marine n-3 PUFA, all continuous variables).
The model for cancer mortality also included family history of cancer (yes vs. no).
†Hypoglycemic medication use (none, oral medication only, insulin or oral medication, or
both).
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Supplementary figure 1. Multivariable hazard ratios (HRs) of cancer mortality isocaloric
substitution of dietary fats for saturated fatty acids
AA=arachidonic acid; ALA=α-linolenic acid; CI=confidence interval; HR=hazard ratio; LA=linoleic acid;
PUFA=polyunsaturated fatty acids; MUFA=monounsaturated fatty acids; SFA=saturated fatty acids.
Multivariable hazard ratios of mortality associated with replacing the percentage of energy from saturated
fat by the same energy from specific types of fat were used. The model was adjusted for age (in months),
gender, survey period, white race (yes vs. no), body mass index at diagnosis (<23.0, 23.0-24.9, 25.0-29.9,
30.0-34.9, or ≥35.0), physical activity (0-0.4, 0.5-1.9, 2.0-3.4, 3.5-5.4, ≥5.5 h /week), smoking status
(never, past, current 1-14 cigarettes/d, or current ≥15 cigarettes/d), smoking pack-years (0, <20, ≥20
pack-year), alcohol consumption (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or ≥30.0 g/d), multivitamin use (yes vs.
no), current aspirin use (yes vs. no), family history of myocardial infarction (yes vs. no), family history of
diabetes (yes vs. no), family history of cancer (yes vs. no), history of hypercholesterolemia (yes vs. no),
history of hypertension (yes vs. no), diabetes duration (<5, 5-10, >10 years), total energy intake
(quartiles), dietary cholesterol (quartiles), and percentage of energy from dietary protein, carbohydrates,
and remaining fatty acids where appropriate (PUFAs, MUFAs, trans fats, LA, AA, ALA, and marine n-3
PUFA, all continuous variables).
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