Bellinge, Jamie W.

Blekkenhorst, Lauren C.

Bondonno, Catherine P.

Bondonno, Nicola P.

Connolly, Emma

Dalgaard, Frederik

Gislason, Gunnar

Hodgson, Jonathan M.

Lewis, Joshua

Murray, Kevin

Overvad, Kim

Pokharel, Pratik

Schulz, Carl

Sim, Marc

Tjønneland, Anne

Yeap, Bu B.

English

Research Online @ ECU

Edith Cowan University Research Online Research outputs 2022 to 2026 2023 Vitamin K1 intake and incident diabetes in the Danish Diet Cancer and Health Study: Supplemental information Pratik Pokharel Edith Cowan University Jamie W. Bellinge Frederik Dalgaard Kevin Murray Marc Sim Edith Cowan University See next page for additional authors Follow this and additional works at: https://ro.ecu.edu.au/ecuworks2022-2026  Part of the Medicine and Health Sciences Commons 10.25958/75TR-JF61 Pokharel, P., Bellinge, J. W., Dalgaard, F., Murray, K., Sim, M., Yeap, B. B., Connolly, E., Blekkenhorst, L. C., Bondonno, C. P., Lewis, J., Gislason, G., Tjønneland, A., Overvad, K., Hodgson, J. M., Schulz, C., & Bondonno, N. P. (2023). Vitamin K1 intake and incident diabetes in the Danish Diet Cancer and Health Study: Supplemental information. Edith Cowan University. https://doi.org/10.25958/75TR-JF61 This Other is posted at Research Online. https://ro.ecu.edu.au/ecuworks2022-2026/2188 Authors Pratik Pokharel, Jamie W. Bellinge, Frederik Dalgaard, Kevin Murray, Marc Sim, Bu B. Yeap, Emma Connolly, Lauren C. Blekkenhorst, Catherine P. Bondonno, Joshua Lewis, Gunnar Gislason, Anne Tjønneland, Kim Overvad, Jonathan M. Hodgson, Carl Schulz, and Nicola P. Bondonno This other is available at Research Online: https://ro.ecu.edu.au/ecuworks2022-2026/2188 1  Vitamin K1 intake and incident diabetes in the Danish Diet Cancer and Health Study: Supplemental information Pratik Pokharel a,b; Jamie W Bellinge c,d; Frederik Dalgaard e,f; Kevin Murray g; Marc Sim b,c; Bu B. Yeap c,h; Emma Connolly b; Lauren C. Blekkenhorst b; Catherine P. Bondonno b,c; Joshua R. Lewis b,c,i; Gunnar Gislason f,j,k,l; Anne Tjønneland a,m; Kim Overvad n; Jonathan M. Hodgson b,c; Carl Schultz c,d; Nicola P. Bondonno a,b a The Danish Cancer Society Research Center, Copenhagen, Denmark; b Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia; c School of Medicine, University of Western Australia, Perth, Australia; d Department of Cardiology, Royal Perth Hospital, Perth, Australia; e Department of Medicine, Nykøbing Falster Sygehus, Nykøbing, Denmark; f Department of Cardiology, Herlev & Gentofte University Hospital, Copenhagen, Denmark; g School of Population and Global Health, University of Western Australia, Australia; h Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia; i Centre for Kidney Research, Children's Hospital at Westmead, School of Public Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; j The National Institute of Public Health, University of Southern Denmark, Odense, Denmark;  k The Danish Heart Foundation, Copenhagen, Denmark; l Department of Clinical Medicine, University of Copenhagen, Denmark; m Department of Public Health, University of Copenhagen, Denmark; n Department of Public Health, Aarhus University, Aarhus, Denmark   2  Table of contents  List of figures Supplemental Figure 1. .............................................................................................................. 3 Supplemental Figure 2.. ........................................................................................................... 10  List of tables  Supplemental Table 1 ................................................................................................................ 4 Supplemental Table 2. ............................................................................................................... 7 Supplemental Table 3. ............................................................................................................... 7 Supplemental Table 4. ............................................................................................................... 8 Supplemental Table 5. ............................................................................................................... 9         3                                Supplemental Figure 1: Participant consort flow diagram.  4        Supplemental Table 1. Covariates included in models Model 1a:  Minimally-adjusted Age and sex Model 1b: Multivariable-adjusted Age, sex, smoking status (current/former/never), physical activity (total daily metabolic equivalent categorised into quintiles), pure alcohol intake (0 grams per day/≤20 grams per day/20< and ≤40 grams per day/≥40 grams per day), social economic status (income categorised into quartiles), education, and hormone replacement therapy (females only; current/former/never) Model 2: Multivariable-adjusted including covariates that are both potential confounders and potentially on the causal pathway Age, sex, smoking status, physical activity, pure alcohol intake, social economic status, education, hormone replacement therapy, BMI (kg/m2), hypertension (yes/no), hypercholesterolemia (yes/no), and prevalent disease (cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, and cancer; entered in the model separately) Model 3: Multivariable-adjusted including energy intake and potential dietary confounders Age, sex, smoking status, physical activity, pure alcohol intake, social economic status, education, hormone replacement therapy, energy intake (kJ/day), and intakes (g/d) of fish, red meat, processed meat, polyunsaturated fatty acids, monounsaturated fatty acids, saturated fatty acids, fibre, added sugar, wholegrains, refined grains, and fruit.  5  Supplemental Table 2. Association between vitamin K1 intake and incident diabetes, stratified by diabetes risk factors  Stratification Models Vitamin K1 intake quintiles Q1 Q2 Q3 Q4 Q5 Sex       Male Model 1a Ref. 0.87 (0.81, 0.92) 0.73 (0.68, 0.78) 0.60 (0.55, 0.65) 0.50 (0.45, 0.54) Model 1b Ref. 0.95 (0.89, 1.01) 0.85 (0.79, 0.92) 0.74 (0.68, 0.81) 0.64 (0.59, 0.71) Model 2 Ref. 0.97 (0.91, 1.03) 0.91 (0.84, 0.97) 0.83 (0.76, 0.90) 0.76 (0.69, 0.84) Model 3 Ref. 0.97 (0.89, 1.05) 0.89 (0.80, 0.98) 0.8 (0.71, 0.89) 0.71 (0.62, 0.81) Female Model 1a Ref. 0.83 (0.77, 0.88) 0.74 (0.68, 0.79) 0.67 (0.61, 0.74) 0.60 (0.54, 0.66) Model 1b Ref. 0.91 (0.85, 0.98) 0.87 (0.80, 0.94) 0.83 (0.76, 0.92) 0.76 (0.69, 0.85) Model 2 Ref. 0.91 (0.85, 0.98) 0.89 (0.82, 0.96) 0.89 (0.81, 0.97) 0.84 (0.76, 0.94) Model 3 Ref. 0.87 (0.80, 0.96) 0.85 (0.76, 0.95) 0.85 (0.74, 0.98) 0.81 (0.69, 0.96) Smoking status      Never smoker Model 1a Ref. 0.84 (0.77, 0.92) 0.73 (0.65, 0.81) 0.63 (0.56, 0.71) 0.52 (0.46, 0.59) Model 1b Ref. 0.91 (0.83, 1.00) 0.84 (0.75, 0.93) 0.75 (0.67, 0.85) 0.64 (0.57, 0.73) Model 2 Ref. 0.93 (0.85, 1.02) 0.89 (0.80, 1.00) 0.86 (0.76, 0.97) 0.78 (0.68, 0.89) Model 3 Ref. 0.90 (0.80, 1.01) 0.84 (0.72, 0.98) 0.79 (0.67, 0.93) 0.71 (0.58, 0.87) Ever smoker Model 1a Ref. 0.86 (0.82, 0.91) 0.75 (0.70, 0.79) 0.65 (0.60, 0.69) 0.56 (0.52, 0.61) Model 1b Ref. 0.95 (0.90, 1.00) 0.88 (0.83, 0.94) 0.81 (0.75, 0.87) 0.74 (0.68, 0.80) Model 2 Ref. 0.95 (0.90, 1.00) 0.89 (0.84, 0.95) 0.84 (0.78, 0.91) 0.79 (0.73, 0.86) Model 3 Ref. 0.94 (0.88, 1.01) 0.89 (0.82, 0.97) 0.85 (0.76, 0.94) 0.78 (0.69, 0.89) BMI       ≤30 kg/m2 Model 1a Ref. 0.87 (0.82, 0.93) 0.75 (0.70, 0.80) 0.64 (0.59, 0.69) 0.54 (0.50, 0.59) Model 1b Ref. 0.96 (0.90, 1.01) 0.88 (0.82, 0.94) 0.78 (0.72, 0.85) 0.69 (0.63, 0.75) Model 2 Ref. 0.96 (0.90, 1.02) 0.89 (0.83, 0.95) 0.81 (0.75, 0.88) 0.74 (0.68, 0.81) Model 3 Ref. 0.96 (0.89, 1.03) 0.90 (0.82, 0.99) 0.83 (0.74, 0.93) 0.75 (0.66, 0.86) >30 kg/m2 Model 1a Ref. 0.86 (0.80, 0.93) 0.84 (0.78, 0.91) 0.83 (0.75, 0.92) 0.78 (0.70, 0.87) Model 1b Ref. 0.91 (0.85, 0.98) 0.92 (0.85, 1.00) 0.93 (0.84, 1.03) 0.88 (0.79, 0.99) Model 2 Ref. 0.91 (0.84, 0.98) 0.92 (0.84, 1.00) 0.93 (0.84, 1.03) 0.89 (0.80, 1.00) Model 3 Ref. 0.90 (0.82, 0.99) 0.92 (0.82, 1.04) 0.95 (0.82, 1.10) 0.91 (0.76, 1.08) MET score       <56.5 Model 1a Ref. 0.85 (0.80, 0.90) 0.74 (0.69, 0.79) 0.64 (0.59, 0.70) 0.54 (0.49, 0.59) Model 1b Ref. 0.92 (0.87, 0.98) 0.86 (0.80, 0.92) 0.79 (0.73, 0.87) 0.69 (0.63, 0.76) Model 2 Ref. 0.92 (0.87, 0.98) 0.89 (0.83, 0.95) 0.85 (0.78, 0.93) 0.77 (0.70, 0.85) Model 3 Ref. 0.90 (0.84, 0.98) 0.85 (0.77, 0.94) 0.8 (0.71, 0.91) 0.70 (0.61, 0.81) ≥56.5 Model 1a Ref. 0.86 (0.80, 0.92) 0.74 (0.68, 0.81) 0.63 (0.58, 0.69) 0.54 (0.49, 0.60) Model 1b Ref. 0.94 (0.88, 1.01) 0.86 (0.79, 0.94) 0.77 (0.70, 0.84) 0.68 (0.62, 0.76) Model 2 Ref. 0.95 (0.89, 1.02) 0.90 (0.83, 0.98) 0.85 (0.77, 0.93) 0.80 (0.73, 0.89) Model 3 Ref. 0.93 (0.86, 1.02) 0.88 (0.78, 0.99) 0.83 (0.73, 0.94) 0.78 (0.67, 0.91) Hazard ratios (95% CI) for incident diabetes during 23 years of follow-up, obtained from restricted cubic splines in Cox proportional hazards models comparing the median intake in quintiles 2 – 5, to the median intake in quintile 1. Unless indicated by the stratification variable, model 1a adjusted for age and sex; Model 1b adjusted for age, sex, smoking status, physical activity, alcohol intake, social economic status (income), education, hormone-replacement therapy; Model 2 adjusted for all covariates in Model 1b plus BMI, hypertension, hypercholesterolemia, and prevalent disease (cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, and cancer; entered into the model separately); Model 3 adjusted 6  for all covariates in Model 1b plus energy and intakes of fish, red meat, processed food, polyunsaturated fatty acids, monounsaturated fatty acids, saturated fatty acids, added sugar, wholegrains, refined grains, and fruit.  7        Supplemental Table 3. Association between vitamin K1 intake and incident diabetes, stratified by tertiles of total vegetable intake   Vitamin K1 intake quintiles Baseline vegetable intake by tertile*  Q1 Q2 Q3 Q4 Q5 1 84 [0 – 123] g/d No. events 1,530 807 306 84 11 HR (95% CI) Ref. 0.88 (0.80, 0.97) 0.80 (0.72, 0.89) 0.72 (0.61, 0.85) 0.61 (0.43, 0.86) 2 161 [123 – 203] g/d No. events 149 607 708 493 133 HR (95% CI) Ref. 0.91 (0.78, 1.06) 0.82 (0.68, 0.98) 0.72 (0.61, 0.85) 0.59 (0.46, 0.75) 3 266 [203 – 1529] g/d No. events 17 114 292 614 835 HR (95% CI) Ref. 0.85 (0.76, 0.95) 0.74 (0.60, 0.91) 0.64 (0.48, 0.85) 0.57 (0.44, 0.73)  Hazard ratios (95% CI) for incident diabetes during 23 years of follow-up, obtained from Cox proportional hazards models using Model 1b for adjustment: age, sex, smoking status, physical activity, alcohol intake, social economic status (income), education, and hormone replacement therapy. *Median; range in parentheses (all such values)  8          Supplemental Table 4. Association between vitamin K1 intake and incident diabetes, stratified by Nordic diet index   Vitamin K1 intake quintiles Nordic Diet Index (NDI)  Q1 Q2 Q3 Q4 Q5 Low NDI (0-2) No. events 557 544 515 477 373 HR (95% CI) Ref. 0.91 (0.85, 0.98) 0.83 (0.75, 0.93) 0.78 (0.70, 0.88) 0.72 (0.59, 0.88) Med NDI (3-4) No. events 711 629 582 528 447 HR (95% CI) Ref. 0.90 (0.82, 0.99) 0.82 (0.74, 0.92) 0.76 (0.68, 0.85) 0.68 (0.61, 0.77) High NDI (5-6) No. events 315 303 267 239 213 HR (95% CI) Ref. 0.94 (0.82, 1.08) 0.89 (0.69, 1.16) 0.84 (0.60, 1.16) 0.74 (0.56, 0.98)  Hazard ratios (95% CI) for incident diabetes during 23 years of follow-up, obtained from Cox proportional hazards models using Model 1b for adjustment: age, sex, smoking status, physical activity, alcohol intake, social economic status (income), education, and hormone replacement therapy. 9                          Supplemental Table 5. Hazard ratios of incident diabetes by statin therapy and quintiles of vitamin K1 intake in a time-updated analysis  Vitamin K1 intake quintiles  Q1  Q2  Q3  Q4  Q5  P-value for interaction* = 0.002     HR (95% CI)      No statin therapy ref. 0.88 (0.80, 0.97) 0.74 (0.67, 0.82) 0.71 (0.64, 0.78) 0.60 (0.54, 0.67) Statin therapy ref. 1.00 (0.90, 1.11) 0.93 (0.84, 1.04) 0.89 (0.79, 0.99) 0.78 (0.69, 0.88) Hazard ratios (95% Confidence Intervals) for incident diabetes during 23 years of follow-up, obtained from time-updated Cox proportional hazards models. We used Model 1b adjustments: age, sex, smoking status, physical activity, alcohol intake, social economic status (income), education, hormone-replacement therapy. *P value for the interaction term between vitamin K1 intake and time-updated statin therapy. 10   Supplemental Figure 2: The association between vitamin K1 intake (µg/day) and incident diabetes (n=6626), after censoring participants upon prescription of a vitamin K antagonist. Hazard ratios are derived from a Cox proportional hazards model with restricted cubic spline curves adjusting for age, sex, smoking status, physical activity, alcohol intake, social economic status (income), education, hormone-replacement therapy (Model 1b), and are comparing the specific level of vitamin K1 intake (horizontal axis) to the median intake for participants in the lowest intake quintile (57 µg/d).           

Vitamin K1 intake and incident diabetes in the Danish Diet Cancer and Health Study: Supplemental information

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Vitamin K1 intake and incident diabetes in the Danish Diet Cancer and Health Study: Supplemental information

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