Introduction
Patients with type 1 diabetes mellitus are at a markedly increased risk of cardiovascular disease (CVD) [
1,
2]. The most important modifiable risk factors for CVD, hypercholesterolaemia and hypertension, are more common in diabetic patients than in the general population [
3,
4]. Diet is an important modifiable factor that is related to CVD risk factors [
5,
6]. A focus of dietary recommendations for both CVD and diabetes prevention and treatment has been a reduction in saturated fatty acid (SFA) intake and an increase in dietary fibre intake [
7,
8]. However, low adherence to dietary recommendations (<10% of energy intake from SFA and 20 g/1,000 kcal for dietary fibre) [
9], and even less healthy eating habits compared with a non-diabetic population [
10], may heighten the increased risk of CVD in patients with type 1 diabetes [
11]. Both nutrients are important, as it has been shown that low SFA intake is often accompanied by high dietary fibre intake and a healthy lifestyle [
12], which might affect the association with CVD risk, as suggested from cross-sectional studies [
13,
14]. In type 1 diabetic patients an independent association has been shown between dietary fibre intake and serum cholesterol (in men) and CVD (in women) [
14].
A recent systematic review [
15] and meta-analysis [
16] found that there was no statistically significant evidence of an association between SFA intake and CVD risk in the general population, even though several weaknesses in the meta-analysis may question the validity of the results [
17,
18]. Besides, neither the systemic review nor the meta-analysis separately evaluated whether intake of SFA may have a different association with CVD risk depending on the nutrient being replaced. Evaluation of the association between SFA intake and CVD, however, requires replacement by other macronutrients to maintain energy balance.
The importance of adequate dietary fibre intake in the prevention and treatment of CVD is well established in the general population. Results from a pooled analysis of cohort studies [
19] and a review [
20] suggest an inverse association between dietary fibre intake and coronary heart disease risk in the general population. In the Nurses’ Health Study, reduced all-cause and CVD-specific mortality was found in type 2 diabetic patients with higher wholegrain and bran intakes [
21]. No intervention trials have explored the effect of dietary fibre intake on CVD or all-cause mortality risk.
Little information on nutritional intake is available from large cohorts of type 1 diabetic patients sufficiently followed up for CVD and deaths. Possible relationships with dietary SFA and fibre have not yet been established in this population. Therefore the aim of the present study was to investigate the relationship between dietary SFA and total, soluble and insoluble fibre and incident CVD and all-cause mortality in patients with type 1 diabetes.
Methods
Statistical analysis
All descriptive data were expressed as mean ± SD or median and interquartile range (IQR). The nutrient residual method by Willett was used to adjust nutrients for total energy [
31]. Energy-adjusted nutrients are computed as the residuals from the regression model, with total energy as an independent variable and the absolute nutrient as a dependent variable. The nutrient residuals provide a measure of nutrient intake uncorrelated with total energy intake [
31]. For descriptive purposes, the nutrient densities (energy percentage [en%]) were calculated as a ratio of nutrient content (g/day) to total energy content (in kJ).
To examine associations between baseline SFA and dietary fibre (total, soluble and insoluble) and incident fatal and non-fatal CVD and all-cause mortality we used Cox proportional hazards analyses to estimate HR and 95% CI. Survival time for each participant was defined as the time between the date of study entry and the occurrence of a CVD event, death, loss to follow-up, or the end of the study, whichever came first. SFA and dietary fibre were energy-adjusted by the residual method and divided into tertiles, with the lowest category as the reference group, to explore different nutrient values and trends. To retain power, SFA and dietary fibre were also analysed as continuous variables. We used three models to adjust for confounders. In model 1, estimates were adjusted for age, sex and energy (kJ/day). In model 2, diabetes duration (years), HbA1c (%), smoking status (number of non-smokers, previous or current smokers), physical activity (physical inactivity, mild physical activity ≥1 time/week, moderate physical activity ≥1 time/week, vigorous physical activity ≥1 time/week) and alcohol (0, >0–<5, 5–<15, 15–<30, 30–<40 and ≥40 g/day) were added. In model 3, adjustments for total dietary fibre (g/1,000 kcal) for the relationships of SFA with CVD and all-cause mortality, or SFA (en%) for the relationships of dietary fibre with CVD and all-cause mortality, were added. To show the robustness of our results, final adjustments were made for MUFA and PUFA (g/day), antihypertensive use (yes or no), daily insulin dose (units/kg) and frequency (number of injections per day). Finally, potential mediators such as systolic blood pressure, total/HDL-cholesterol ratio and BMI were explored to demonstrate potential pathways.
We carried out replacement models [
32] to investigate whether a 5% higher energy intake from MUFA, PUFA or CH should replace a 5% lower energy intake from SFA to prevent CVD. Two models were used. Model 1 included age, sex, MUFA, PUFA, TFA, CH and protein expressed as percentages of total energy, and total energy (kJ/day). TFA was calculated as the difference between total fat and major groups of fatty acids (SFA, MUFA and PUFA), as exact values for TFA were not available. Model 2 included variables in model 1 and confounders similar to those of model 2 as described above. The estimated HR for MUFA or PUFA and CH can be interpreted as the estimated difference in risk of a 5% lower energy intake from SFA and a concomitant higher energy intake from MUFA, PUFA or CH.
Possible effect modification by age was tested and a p value for interaction <0.10 was considered statistically significant. Including an interaction term to identify modification by centre was not possible, since we had 31 centres in this study in 16 European countries with unequal numbers of participants per centre or country. We did not have a sufficient number of cases for stratified analyses. Data analysis was performed using SAS software (version 9.1; SAS Institute, Cary, NC, USA). Two-sided p values <0.05 were considered statistically significant.
Discussion
The results of the present study among 2,108 European patients with type 1 diabetes suggest an inverse association between dietary fibre and CVD risk and all-cause mortality, with a stronger protective association for soluble fibre compared with insoluble fibre. No statistically significant association was found between all-cause mortality risk and SFA and CVD, nor between all-cause mortality risk and replacing 5% of energy from SFA by concomitant higher energy from PUFA, MUFA or CH.
The present findings on SFA support the results of previous studies in the general population [
15,
16] demonstrating that there is no statistically significant relationship between SFA and CVD risk. However, a cross-sectional study performed among children and adolescents with type 1 diabetes showed that a diet high in energy from SFA was associated with a higher risk of CVD [
11]. A recent meta-analysis of randomised controlled trials [
33] and a pooled analysis of 11 cohort studies [
34] both found consistent evidence in the general population of decreased CVD risk when SFA was replaced by PUFA. In contrast with these studies, we did not find any association with CVD risk when SFA was replaced by MUFA, PUFA or CH, which might be explained by a lack of power in our study.
Our results on dietary fibre confirm the results of a cross-sectional study among type 1 diabetic patients which showed that a diet low in fibre, fruit and vegetables could lead to a higher risk of CVD [
11]. Also, results from cohort studies in the general population suggesting an inverse association between dietary fibre and CVD risk are in line with our results [
19,
20]. We found a significantly lower CVD risk of 32% per 10 g/day total dietary fibre (95% CI 0.48, 0.95), which is in accordance with the pooled analyses of cohort studies in the general population by Pereira et al. [
19]. Such a change in total dietary fibre is challenging to achieve; however, a more realistic change in dietary fibre of 5 g/day was significantly associated with a 16% lower risk in our study (95% CI 0.72, 0.98). Some studies on whether protection of dietary fibre may come from soluble and/or insoluble fibre show no clear advantage of either type of dietary fibre [
35,
36], whereas the pooled analysis of Pereira et al. shows a stronger inverse association for soluble fibre [
19]. These authors showed a lower coronary heart disease risk of 44% per 10 g/day, whereas we found in type 1 diabetic patients a lower CVD risk of 67% per 10 g/day soluble fibre (95% CI 0.13, 0.88). Again, 10 g/day soluble fibre may be unfeasible; however, changing this to 2 g/day soluble fibre showed a statistically significantly lower CVD risk of 18% in our study (95% CI 0.67, 0.97). Besides the inverse association between dietary fibre and CVD risk, we observed a significant inverse association with all-cause mortality, which is in line with results found in the general population [
37], as well as in patients with type 2 diabetes [
21]. In the Nurses’ Health Study [
21], bran intake in the highest quintile was associated with a 28% (95% CI 0.56, 0.92) lower all-cause mortality risk and a 35% (95% CI 0.43, 0.99) lower CVD-specific mortality risk in type 2 diabetic patients. In the Zutphen Study [
37], no clear difference between the effects of dietary fibre from various sources was observed. Park et al. [
38] showed in a non-diabetic population a significant inverse association with all-cause mortality from total dietary fibre and grains, but not from other sources, whereas we showed significant inverse associations in type 1 diabetic patients for total, soluble and insoluble fibre. Most likely, as assessed in prospective studies, dietary fibre within the usual diet is a marker of healthy food choices with an overall cardiovascular benefit [
19]. However, in our study, we were able to demonstrate an independent protective association between dietary fibre and CVD risk in type 1 diabetic patients, after adjustment for lifestyle factors characterising a healthy lifestyle.
The present study is, to our knowledge, the first large prospective cohort study with a sufficient number of CVD cases and deaths in young type 1 diabetic patients to report the associations between SFA and dietary fibre and risk of CVD and all-cause mortality in this population. The observed relationships were independent of sex, age, energy intake, CVD risk factors and other dietary factors. The strength of the study lies in its large sample size of European type 1 diabetic patients. Furthermore, the EURODIAB PCS provides a multicentre, clinic-based, prospective study, with the same standardised methods used in each centre. However, some limitations should be addressed. First, the accuracy of dietary data and the absence of data on foods are important limitations. The use of information on dietary intake from self-reported 3 day dietary records may be subject to the weakness of the nutritional data [
26]. Measurement error is always an inherent limitation in self-reported dietary assessment and has an impact on results, conclusions and interpretation. Under the assumption that measurement error is non-differential with regard to the outcome, this might have led to biased risk estimates and reduced statistical power for detecting associations. Second, 1,142 participants were excluded from the present study due to loss to follow-up and missing information on dietary intake, potential confounders, and CVD and/or all-cause mortality at follow-up. Loss to follow-up due to no participation at follow-up and no information on CVD and/or all-cause mortality at follow-up might have caused a selection bias which could have modified the associations under study. We compared those included in the study with those lost to follow-up and found that patients with a more atherosclerotic risk profile were lost, which may imply that our demonstrated associations for dietary fibre and CVD or all-cause mortality could have been even stronger if these patients had been included. Furthermore, although we minimised the influence of confounding in the associations by adjustment for key confounders, residual confounding cannot be ruled out due to interference by factors we did not measure. Finally, upon diagnosis many patients might have received dietary advice from dietitians and physicians at diabetes clinics which might have introduced bias in our results. However, this study gives insight into the real-life course of the disease.
Possible reasons for not finding any association between SFA and blood cholesterol and CVD could be inaccurate dietary methods; large day-to-day variations; chain length of SFA, animal or plant source; natural or interesterified forms of SFA [
39]. Replacement of SFA by PUFA has indeed been shown to be effective in reducing CVD risk in both meta-analyses of prospective studies [
34] and in controlled feeding trials [
33]; therefore recommendations should remain unaltered with the advice to restrict SFA intake below 7% of total energy intake, particularly in patients at increased risk of CVD.
Several mechanisms have been suggested by which dietary fibre may reduce CVD risk in the general population. Several studies have found that increased dietary fibre may lower the risk of type 2 diabetes [
40‐
42], which may partly explain our associations with CVD and all-cause mortality [
21]. Including potential mediators such as systolic blood pressure, serum cholesterol and BMI did not lead to identification of a clear pathway. Soluble fibre might be able to delay the absorption of nutrients and bind bile acids in the small intestine, which may increase bile acid excretion [
43]. These effects have been shown to lower total and LDL-cholesterol levels [
44] and improve insulin sensitivity [
45]. This in turn is associated with reductions in blood pressure [
46]. In addition, soluble fibre-containing foods such as fruit and vegetables have been shown to slow down or reduce glucose absorption in the intestine due to a reduction in the glycaemic index [
47,
48]. Results from the EURODIAB PCS show that total dietary fibre was significantly inversely associated with HbA
1c levels, independently of other lifestyle and nutritional factors [
49].
In conclusion, our results in European individuals with type 1 diabetes do not show a statistically significant association between SFA and CVD risk. By contrast, higher total, soluble and insoluble dietary fibre appears to be strongly protective of CVD and all-cause mortality in our population. These results are in line with the current dietary guidelines for diabetic patients on dietary fibre-rich foods [
9,
50]: to encourage dietary fibre intake from wholegrains, fruit, vegetables and various sources that are easily available and not too costly in the different European countries. Trials of dietary intervention in type 1 diabetes should focus on acceptable methods to increase dietary fibre intake, and determine the effects on CVD and all-cause mortality risk. Moreover, considering limitations of dietary assessment methods, we recommend further research by other studies and designs investigating the role of dietary SFA and fibre and the risk of CVD and all-cause mortality in type 1 diabetic patients.