Fetuin-A and risk of diabetes-related vascular complications: a prospective study

Abstract

Background: Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops.

Methods: Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression.

Results: In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints).

Conclusions: Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.

Keywords: Biomarkers; Epidemiology; Fetuin-A; Microvascular complications; Type 2 diabetes; Vascular calcification; Vascular disease.

Fig. 1

Study design and flow chart of inclusion. A For the present study, the follow-up time was defined as the time between type 2 diabetes diagnosis and diagnosis of the corresponding vascular disease or date of the last examination by the physicians (up until August 2017). B Microvascular complications were defined as new-onset retinopathy, nephropathy, neuropathy or kidney replacement therapy following diabetes diagnosis. Macrovascular complications were defined as newly diagnosed myocardial infarction or stroke following diabetes diagnosis. EPIC, European Prospective Investigation into Cancer and Nutrition; CVD, cardiovascular disease; HF, heart failure

Fig. 2

Associations of pre-diagnosis fetuin-A concentrations with risks of diabetes-related vascular complications. Restricted cubic splines showing the shape of dose–response curve according to baseline fetuin-A concentration: hazard ratios (solid lines) with corresponding 95% CI (shaded area) for total vascular (A), microvascular (B), and macrovascular complications (C). The reference point is median fetuin-A concentration with knots placed at the 5th, 50th, and 95th percentiles. All models were adjusted for age at diabetes diagnosis (underlying time scale), duration between recruitment and diabetes diagnosis, sex, education, alcohol intake, physical activity, BMI, waist circumference, history of hypertension, hyperlipidemia, antihypertensive and lipid lowering medications at the time of recruitment

Fig. 3

Stratified associations between pre-diagnostic fetuin-A and incident diabetes-related complications. A P for interaction with sex p = 0.18 for complications overall, p = 0.18 for microvascular and p = 0.56 for macrovascular complications. B P for interaction with baseline glucose (glucose ≥ 100 mg/dL vs glucose < 100 mg/dL) p = 0.85 for complications overall, p = 0.67 with microvascular and p = 0.31 for macrovascular complications. C P for interaction with FLI (FLI < 60 vs FLI ≥ 60) p = 0.94 for complications overall, p = 0.65 for microvascular complications. D P for interaction with baseline fasting status (fasted vs non-fasted) p = 0.36 for complications overall and p = 0.57 with microvascular complications. E P for interaction with baseline eGFR (eGFR ≥ 80 mL/min/1.73 m² vs < 80 mL/min/1.73 m²) p = 0.10 for complications overall, p = 0.15 for microvascular complications. There were not enough macrovascular events in the subgroups with baseline eGFR < 80 mL/min/1.73 m², FLI < 60 and fasted subgroup to perform the analysis. Associations were assessed by Cox proportional hazards models and are shown per one unit SD increase (0.06 g/L) in pre-diagnostic fetuin-A concentrations. Models are adjusted for age at diabetes diagnosis (underlying time scale), duration between recruitment and diabetes diagnosis, sex, education (three categories: no or in vocational training, vocational training/technical school, technical college or university), alcohol intake (six categories: < 6.1 g/day, 6.1–12.0 g/day, 12.1–24.0 g/day, 24.1–60.0 g/day, 60.1–96.0 g/day, > 96.0 g/day), smoking (four categories: never smoker, former smoker, current smoker < 20 cigarettes/day, current heavy smoker ≥ 20 cigarettes/day), physical activity (sports ≤ 4 h/week, sports > 4 h/week, biking < 2.5 h/week, biking 2.5–4.9 h/week, biking ≥ 5 h/week), body mass index, waist circumference, history of hypertension, hyperlipidemia, antihypertensive and lipid lowering medications at the time of recruitment. HR, hazard ratio; CI, confidence interval; SD, standard deviation; eGFR, estimated glomerular filtration rate; FLI, fatty liver index