Risk factors for microvascular complications
The risk of microvascular complications is influenced by several factors, such as puberty, blood pressure, dyslipidemia, gender, diabetes duration, smoking and lifestyle [
57‐
59]. Poor metabolic control was identified as an important factor contributing to microvascular complications [
60,
61]. In addition, familial risk factors related to all microvascular complications of type 1 diabetes have been reported [
62]. A study performed in type 1 diabetic patients (onset age < 30 years) among 6,707 families revealed a significantly increased risk of retinopathy (odds ratio 9.9; CI 5.6–17.7, P < 0.001), nephropathy (6.2; CI 2.9–13.2, P < 0.001) and neuropathy (2.2; CI 1.0–5.2; P < 0.05) in type 1 diabetic siblings of patients diagnosed with those complications [
62].
In an analysis of 572 type 1 diabetic participants of the Pittsburgh EDC Study (mean follow-up: 15 years), baseline HbA1c was an independent risk factor for fatal CAD, along with duration of diabetes and albuminuria [
63]. Baseline lower insulin dose, however, was strongly predictive for non-fatal CAD, as was lower renal function, higher diastolic blood pressure, and lipids [
63].
In patients with diabetes onset at age 5–14 years, a higher risk for complications (retinopathy, nephropathy, and neuropathy) has been found as compared to patients diagnosed either at a very young age or after puberty [
62]. In adolescents with type 1 diabetes, an elevated blood pressure or BMI [
64‐
66], dyslipidemia and smoking [
67‐
69] are associated with an elevated risk of incipient nephropathy, early retinopathy and peripheral neuropathy.
With the onset of diabetic nephropathy, a dramatic increase in the risk for CAD has to be assumed. After 20 years with diabetes, up to 29% of patients with childhood-onset of type 1 diabetes and nephropathy will have CAD compared to only 2–3% in similar patients without nephropathy [
70]. In addition to traditional cardiovascular disease risk factors, elevated mean HbA1c and macroalbuminuria are significantly associated with alterations in left ventricular structure and function evaluated by cardiac magnetic resonance imaging (MRI) [
71].
In observational studies the relationship between blood pressure and the progression of chronic kidney disease (CKD) and incident end-stage renal disease (ESRD) is direct and progressive in diabetes [
72]. However, most of the evidence is in type 2 diabetes, high blood pressure is a common feature also of type 1 diabetes and an increase in blood pressure in type 1 diabetes increases the risk of nephropathy [
73,
74]. Masked hypertension is not infrequent [
72]. In people with type 1 diabetes an increase in systolic blood pressure, particularly at night, precedes the development of microalbiminuria [
75]. It has been argued that, unlike in type 2 diabetes, in people with type 1 diabetes hypertension develops often after the establishment of microalbuminuria. Hence, monitoring blood pressure throughout the 24 hours in type 1 diabetes may be a useful diagnostic procedure.
In the DCCT/EDIC study, during a 15.8-year median follow-up, 630 of 1441 participants developed hypertension [
76]. Intensive therapy during the DCCT reduced the risk of incident hypertension by 24% during EDIC study follow-up. A higher HbA1c level, measured at baseline or during follow-up, was associated with increased risk for incident hypertension. Older age, male sex, family history of hypertension, greater baseline body mass index, weight gain, and greater albumin excretion rate were independently associated with increased risk of hypertension. These data show that hyperglycemia is a risk factor for incident hypertension in type 1 diabetes and that intensive insulin therapy reduces the long-term risk of developing hypertension.
In a recently published Brazilian study on approximately 1,300 patients with type 1 diabetes, however, body size and blood pressure were not correlated to lipid levels and glycemic control [
77]. Correlation of serum lipids with HbA1c was shown to be heterogeneous across the spectrum of glycemic control. Several pathophysiological factors were suggested based on the HbA1c-level. These results, therefore, do not support a unified explanation for cardiovascular risk in type 1 diabetes [
77].
Cardiovascular risk markers
As demonstrated in 144 participants of the Pittsburgh EDC Study, pulse wave analysis (PWA) may contribute to assessment of CV risk in patients with type 1 diabetes [
78]. Arterial stiffness index, augmentation index, augmentation pressure, subendocardial viability ratio (serving as an estimate of myocardial perfusion), electron beam computed tomography-measured coronary artery calcification (CAC) and ankle-brachial index (ABI) were determined. In the analysis of cross-sectional associations, greater augmentation pressure was independently associated with prevalent CAD and estimated myocardial perfusion with low ABI (<0.90) [
78].
In the DCCT/EDIC study the stiffness/distensibility of the ascending thoracic aorta was measured with magnetic resonance imaging in 879 patients [
79]. After adjusting for gender and cohort, aortic distensibility was lower with increasing age, mean systolic blood pressure, LDL cholesterol, and HbA1c measured over an average of 22 years. Patients with macroalbuminuria had 25% lower aortic distensibility compared with those without, and lower distensibility also was associated with greater ratio of left ventricular mass to volume. This data stand in favour of strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on aortic stiffness in type 1 diabetes.
After 15 years additional follow-up in EDIC, left ventricular indices were measured by cardiac magnetic resonance imaging in 1017 of the 1371 members of the DCCT cohort [
80]. Mean DCCT/EDIC HbA1c over time was associated with end diastolic volume, stroke volume, cardiac output, left ventricular mass, LV mass/EDV, and aortic distensibility. These associations persisted after adjustment for CVD risk factors. Thus, cardiac function and remodeling in the EDIC cohort was associated with prior glycemic exposure (glycemic memory).
As part of the EDIC study, 1229 patients with type 1 diabetes underwent ultrasonography of the internal and common carotid arteries in 1994–1996 and again in 1998–2000 [
81]. At year 1 of the EDIC study, the carotid intima-media thickness (IMT) was similar to that in an age- and sex-matched nondiabetic population. After six years, the IMT was significantly greater in the diabetic patients than in the controls. The mean IMT progression was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy after adjustment for other risk factors. IMT progression was associated with age, and the EDIC base-line systolic blood pressure, smoking, the LDL/HDL ratio, and urinary albumin excretion rate and with the mean HbA1c value during the mean duration of the DCCT. Thus, intensive therapy during the DCCT resulted in decreased progression of IMT six years after the end of the trial, which again stands in favour of the effect of glycemic memory.
As found by the 10-year follow-up examination of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study cohort, CAC is related to clinical coronary artery disease (CAD) independent of other risk factors [
82]. This association, however, was stronger in men than in women [
82]. In a cohort of patients with type 1 diabetes (aged 22–50 years), progression of CAC, as identified by electron beam computed tomography (EBCT), was strongly associated with suboptimal glycemic control (HbA1c >7.5%) [
83].
In a study assessing CAC with multislice spiral computed tomography (MSCT), nearly one third of asymptomatic long-term type 1 diabetic patients presented with coronary calcifications [
84]. In patients with coronary calcifications, both cardiac autonomic neuropathy and retinopathy were detected more frequently than in those without (64% vs. 29%, p < 0.02; 59% vs. 31%; p < 0.02). Additionally, duration of diabetes was longer in patients with than without coronary calcification [
84].
In a small cohort of adolescent, non-obese type 1 diabetic patients, an increased carotid intima-media thickness was found to be associated with insulin resistance. A causal relationship, however, cannot be concluded [
85]. According to a prospective longitudinal study in children and adolescents with type 1 diabetes, systolic blood pressure and body mass index are related to carotid intima-media thickness increment. Control of these risk factors is supposed to contribute to prevention of carotid intima-media thickness progression [
86].
In patients with long-term duration type 1 diabetes, sexual dysfunction was demonstrated to be independently associated with CVD and to potentially predict CVD [
87].
Results on the predictive value of plasminogen activator inhibitor-1 (PAI-1) are inconsistent. One study found PAI-1 levels to be independently related to CAC in younger (< 45 years) patients with type 1 diabetes [
88]. According to another analysis, neither PAI-1 nor tPA-PAI-1 is an independent predictor of CAD [
89].