In this long-term cohort study, including over 1000 patients with stable CHD at baseline, we found that patients on a trajectory of high stable depression symptoms during long-term follow-up faced an increased risk of developing DM. In addition, those following a trajectory of high-stable depression symptoms who newly developed DM faced a substantial 6.5-fold increased risk for subsequent CVEs. Therefore, more attention should be given to symptoms of depression both in the initial phase of diagnosis of CHD during in-patient rehabilitation and also during long-term care of CVD-patients. If the diagnosis is confirmed by a clinical examination (as HADS is basically a screening instrument), a respective treatment of depression should be initiated. In addition, given the increased risk for DM, the metabolic state should be watched carefully to allow early preventive means.
To our knowledge, long-term trajectories of symptoms of depression in relation to DM in patients with CHD have not been investigated so far. However, depressive symptoms have previously been shown to be associated with DM incidence [
17], and depression has been consistently associated with a higher prevalence of macrovascular complications in patients with DM [
5‐
7]. Notably, patients with DM requiring glucose-lowering therapy and patients without diabetes but a prior myocardial infarction carry the same cardiovascular risk [
18]. In addition, depression in CHD patients leads to lower adherence to oral hypoglycemic, antihypertensive, and lipid-lowering medication and unfavorable lifestyle choices [
19,
20]. Therefore, it is not surprising that patients with a previous CVE and DM are at especially high risk for a subsequent CVE.
In this cohort of patients with CHD, we previously observed an increased risk for subsequent CVE in patients following a high-stable depression symptoms trajectory [
13]. A finding now substantiated by the observation that also the risk for incident DM is increased, which subsequently increases the risk for CVE massively.
Possible pathogenic mechanism linking depression, diabetes, and CHD
Solid evidence accumulates that depression is a risk factor for DM, irrespective of measures used to evaluate it, as seen in a recent meta-analysis [
21]. Recent results of the Maastricht study indicate hyperglycemia itself may be involved in the etiology of depression [
22]. In that study, several indicators of hyperglycemia (fasting plasma glucose, two-hour post-load glucose, and HbA1c) were consistently associated with a higher risk of incident depression independent of lifestyle factors. In addition, diabetes-associated microvascular dysfunction may be associated with the risk of incident depression [
23].
DM is associated with chronic low-grade inflammation [
24], as is depression [
25‐
28]. Also, anti-cytokine treatments exhibit antidepressant effects in chronic inflammatory conditions [
29], pointing to a causal role of chronic inflammation in the etiology of depression. Besides non-modifiable risk factors such as ethnicity, family history, and older age, the following modifiable risk factors play a role in DM etiology: obesity, physical inactivity, smoking, and unhealthy diet [
30]. Especially obesity, but also physical inactivity and smoking may result in changes in inflammatory status. In obesity, dyslipidemia and changes in circulating leptin serum values may also be present. In a recent study from Augsburg, Germany, investigating the relevance of biomarker-defined pathways for the development of DM, and also for coronary heart disease, many associations, such as cytokines, endothelial dysfunction, hemostasis, hormone regulation, tissue remodeling, and others, showed similar strength for DM and CHD, but the insulin-like growth factor binding protein 2 explained DM risk best [
10]. Interestingly, the risk associated with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) for DM was inverse, whereas it was positive for CHD. This finding was substantiated in a subsequent analysis. High plasma concentrations of mid-regional pro atrial natriuretic peptide (MR-proANP), another peptide from the natriuretic peptide system, were also associated with a lower risk of incident DM and insulin resistance [
31].
An earlier analysis of our data suggested that well-established risk factors like BMI, physical activity, or low-grade chronic inflammation might be associated with categories of symptoms of depression [
32]. An inverse association between physical activity and depression symptoms was also described in the British Whitehall II study [
33]. Physical activity is also clearly in associated with reduced risk of incident DM [
34]. In our current analysis, the associations of depression symptom trajectories with incident DM were slightly attenuated by adjusting for baseline lifestyle factors (including BMI and physical activity).
Patients with depression seem to have an increased autonomic nervous system activity, increased hypothalamic-pituitary-adrenocortical axis (HPA) activity and associated cardiovascular adverse effects, including vasoconstriction, increased heart rate, and heart rate variability [
4,
35]. Therefore, the increased activity of the HPA and the dysregulation of the immune system are discussed as risk factors for DM but may also play an important role in subsequent cardiovascular adverse effects.