Incidence of type 2 diabetes, CVD and mortality
The incidence of all outcomes is shown in Table 1. An individual may have had more than one outcome. After a median follow-up of 4 years, 1056 individuals had developed type 2 diabetes (1.4%). Of those, 525 reported that they had been diagnosed with type 2 diabetes between the baseline visit and the follow-up measurement, while in those not reporting a diagnosis of diabetes, fasting blood glucose ≥7.0 mmol/l was observed in 408 participants, elevated HbA1c ≥48 mmol/mol (≥6.5%) in 268, and either elevated blood glucose or HbA1c in 531 participants.
Individuals with incident type 2 diabetes were significantly older at baseline than participants who did not develop type 2 diabetes (51.8 ± 11.4 years vs 43.7 ± 12.0 years, p < 0.001), and had a higher baseline BMI, fasting glucose and HbA1c (all p < 0.001, Table 2). Moreover, the prevalence of the metabolic syndrome was also higher. As expected, the incidence of type 2 diabetes increased with age, and was between 3.3% and 4.1% in the three highest age decades (Fig. 1a). Mean baseline SAF z score was 0.16 ± 0.95 in participants with incident type 2 diabetes and −0.01 ± 0.81 in individuals who remained healthy (p < 0.001, Fig. 2).
In the same population, 1258 individuals (1.7%) had developed CVD at follow-up (Table 1). Participants with incident CVD were significantly older at baseline, had a higher waist circumference, higher systolic BP and diastolic BP, higher lipid levels and a lower eGFR (p < 0.001, Table 2). As expected, incidence of CVD increased with age, and was between 4.5% and 11.6% in the three highest age decades (Fig. 1b). Mean baseline SAF z score was 0.16 ± 0.96 among the population with incident CVD vs −0.01 ± 0.81 in participants who did not develop CVD or type 2 diabetes (p < 0.001, Fig. 2). In total, 55 individuals developed both type 2 diabetes and CVD, and these had the highest baseline SAF z scores (p < 0.001 vs no disease, p = 0.004 vs type 2 diabetes [in women only], Fig. 2).
Death was reported in 928 individuals (1.3%). As expected, mortality increased with age (Fig. 1c). Participants who died were older at baseline, had higher BP, were more likely to have impaired renal function/low eGFR and were more frequently current smokers. They also had higher SAF levels, even when corrected for age, than individuals who developed type 2 diabetes or CVD or remained without these disorders (Table 2).
ESM Table 1 details the mean age and SAF levels according to each age group. In almost all age groups, SAF was significantly higher (p < 0.0001) in those participants who developed an event (the composite outcome of incident type 2 diabetes, CVD and mortality) compared with those who remained free from these events.
Association and prediction
Table 3 shows the results of the univariate and multivariate associations between SAF and clinical, biochemical and lifestyle factors and the composite outcome of incident type 2 diabetes, CVD and mortality. Univariate analyses showed that SAF was strongly associated with these outcomes (OR 3.84, 95% CI 3.57, 4.11, p = 1.5 × 10−307). This association remained significant after adjusting for age (model 1), age and the metabolic syndrome (model 2) and also after adjusting for age, fasting glucose (OR 1.79, 95% CI 1.64, 1.96, p = 1.1 × 10−37) or HbA1c (OR 1.78, 95% CI 1.63, 1.95, p = 6.6 × 10−38). Additional regression models revealed that the association also remained significant when adjusted for sex, waist circumference and current smoking (model 4), as well as all for other variables including systolic BP, plasma lipids, eGFR and coffee consumption (model 5, OR 1.54, 95% CI 1.40, 1.70, p = 3.9 × 10−18). In the composite multivariate model 5, age, glucose, waist circumference, current smoking, systolic blood pressure and triacylglycerol were most strongly associated with the composite outcome (Table 3).
Additionally, we assessed the relationship between SAF and the three individual outcomes separately (Table 4). In a univariate model, SAF was most strongly associated with death (OR 5.10, 95% CI 4.56, 5.70, p = 4.1 × 10−181). This association remained highly significant after adjusting for age (model 1), presence of the metabolic syndrome (model 2), glycaemic variables (model 3a/b) and other possible confounding, non-biochemical factors (model 4). Model 5 showed that male sex, waist, systolic BP, cholesterol and current smoking, in addition to SAF and age, were independently associated with mortality. Similarly, univariate regression analyses revealed SAF to be strongly associated with both incident type 2 diabetes and incident CVD separately (Table 4). In addition to SAF and age, the strongest predictors of incident type 2 diabetes were fasting glucose, HbA1c, triacylglycerol, BMI, waist circumference, BP and the presence of the metabolic syndrome. The strongest univariate predictors for CVD were—again in addition to SAF and age—waist circumference, BMI, glucose, HbA1c, BP, eGFR and presence of the metabolic syndrome. SAF remained significantly associated with type 2 diabetes and incident CVD in the first four multivariate models. Also in these multivariate models, the presence of the metabolic syndrome, fasting glucose and HbA1c levels was strongly associated with incident type 2 diabetes and moderately associated with incident CVD. In the final model (model 5), SAF still was significant, and age, glucose, waist circumference, male sex and triacylglycerol were the strongest factors associated with incident type 2 diabetes, and age, waist circumference, systolic BP and current smoking were the strongest factors associated with incident CVD.
As the time of death of all participants was recorded, we were able to show the effect of SAF on time from baseline to death. As can be seen in ESM Fig. 3, the highest SAF z score tertile was associated with an almost twofold increased risk of mortality compared with the other tertiles.
Finally, as age is an important factor influencing SAF measurements, but also the absolute incidence of outcome events (Fig. 1), we calculated the association between age-corrected SAF score and outcome according to four clinically relevant age groups (Table 5). SAF score was significantly associated with the composite outcome and with mortality in all age groups. For incident type 2 diabetes, in participants aged ≤35 years and those between 51 and 60 years SAF was not significant. For CVD, there was no significant predictive value in the lowest age group probably because of the low number of events.