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The early detection of atherosclerosis in type 1 diabetes

why, how and what to do about it

Jenkins, Aliciaa,b; Januszewski, Andrzeja,b; O’Neal, Davida,b

Cardiovascular Endocrinology & Metabolism: March 2019 - Volume 8 - Issue 1 - p 14–27
doi: 10.1097/XCE.0000000000000169
Review articles
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The major cause of morbidity and often premature mortality in people with type I diabetes (T1D) is cardiovascular disease owing to accelerated atherosclerosis. We review publications relating to the rationale behind, and clinical tests for, detecting and treating early atherosclerosis in people with T1D. Currently available tools for atherosclerosis assessment include risk equations using vascular risk factors, arterial intima–media thickness, the ankle–brachial index, coronary artery calcification and angiography, and for more advanced lesions, intravascular ultrasound and optical coherence tomography. Evolving research tools include risk equations incorporating novel clinical, biochemical and molecular tests; vascular MRI and molecular imaging. As yet there is little information available to quantify early atherosclerosis. With better means to control the vascular risk factors, such as hypertension, dyslipidaemia and glycaemic control, and emerging therapies to control novel risk factors, further epidemiologic and clinical trials are merited to facilitate the translation into clinical practice of robust means to detect, monitor and treat early atherosclerosis in those with T1D.

aNHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales

bDepartment of Endocrinology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia

Correspondence to Alicia Jenkins, MBBS, MD, FRACP, FRCP, Diabetes and Vascular Medicine, Sydney Medical School Foundation Fellow, NHMRC Clinical Trials Centre, University of Sydney, 92–94 Parramatta Road, Camperdown, Sydney, NSW 2050, Australia Tel: +61 295 625 000; fax: +61 295 651 863; e-mail: alicia.jenkins@ctc.usyd.edu.au

Received December 19, 2018

Accepted February 22, 2019

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Incidence and prevalence of type 1 diabetes

Type 1 diabetes (T1D) incidence varies greatly, with the highest rates in Scandinavian countries [≈35 people/100 000/annum (p.a.)] versus ≈1/100 000 p.a. in low incidence countries such as China 1. T1D usually presents in youth but can occur at any age. In Australia, 40% with patients with T1D are diagnosed after the age of 25 years 2, and in China, 65.3% are diagnosed after the age of 20 years 2. T1D incidence and prevalence has increased in most countries at ≈3% p.a. 3, with contributors being better case ascertainment and survival, particularly in disadvantaged regions 4–7, and a genuine increase, postulated to relate to increased autoimmunity because of fewer early childhood infections 8,9. In addition to classical T1D, there is a slower onset form of antibody-positive T1D, latent autoimmune diabetes in adults (LADA), which is usually diagnosed after 25–40 years of age and does not require exogenous insulin for at least 6 months 10. Most publications relate to atherosclerosis in T2D, with few in T1D and LADA. A recent cross-sectional study showed greater (subclinical) carotid plaque in LADA than in age-matched and sex-matched patients with classic T1D or T2D 11.

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Chronic complications

Chronic complications of diabetes relate to the vasculature and nerves. Atherosclerosis leads to coronary artery disease (CAD), cerebrovascular disease (CVD) and peripheral arterial disease (PAD), with CVD being a major cause of death in diabetes 12. Atherosclerosis is the accumulation of lipid-rich plaque in arteries, whereas arteriosclerosis refers to age-related stiffening of arteries, which may coexist with, or occur in the absence of, atherosclerosis.

People with T1D microvascular complications are at particularly high risk of developing CVD. In diabetes, CAD symptoms may be atypical or silent 13. The first manifestation of atherosclerosis may be sudden death, hence the importance of detecting subclinical (early) atherosclerosis, though this is currently challenging, and the T1D evidence base is very limited. Some recommendations regarding the more recently available clinical imaging, such as coronary artery calcification (CAC) and (noninvasive) computed tomography angiography (CTA), for people with diabetes are to follow guidelines for the general population 14,15, yet these and the 2019 American Diabetes Association (ADA) guidelines 13 do not recommend screening asymptomatic people with diabetes with such tests, as they do not have well-proven value at the individual patient level. Once atherosclerosis is clinically evident, intensive risk factor control, including lipid-lowering drugs irrespective of lipid levels, blood pressure (BP) and antiplatelet agents, is recommended. Many guidelines and clinicians recommend aggressive risk factor management for anyone with T1D with clinically evident macrovascular or microvascular disease and for those at intermediate or high CVD risk without evident complications. The latter includes people with T1D aged at least 40 years, even in the absence of vascular complications, or aged at least 30 years with more than 15 years of T1D (without vascular complications) 13–17. Recent guidelines are summarized by Lan et al. 16. Unfortunately, most patients with T1D do not meet all recommended HbA1c, BP, lipids, BMI and nonsmoking targets 18.

Questions of major clinical importance are as follows: how to detect early atherosclerosis, when and how to screen, what the risk factors are for early and late atherosclerosis and how and when to treat risk factors and existing vascular damage. Another major challenge is ensuring equitable access to proven assessment tools and treatments, as not all tests are available or subsidized, and to experienced clinicians.

Figure 1 summarizes the stages of atherosclerosis. Even before T1D develops, people may have CVD risk factors. Once T1D develops, the milieu induces and/or worsens risk factors, promoting vascular damage 19. Atherosclerosis does not usually become clinically evident until triggered by an event such as plaque rupture, thrombosis or embolus.

Fig. 1

Fig. 1

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Increased cardiovascular disease risk and confounders

The reported relative increase of atherosclerosis in T1D versus nondiabetic individuals depends on how and when the study was conducted, event definitions, the age, sex, age of T1D onset and duration, risk factor control, microvascular complication status and characteristics of the comparator group. When the study was conducted is important owing to recent more effective drugs 13,20 and insulin pumps 21, all of which reduce vascular events. Modern care has reduced deaths and hospitalizations for atherosclerosis-related events 22. In a Swedish registry study (n=36 869 patients with T1D and 184 110 nondiabetic controls) followed between 1998 and 2013, all-cause death rates in T1D fell by 29% (vs. 23% in controls), the CVD death rate fell by 42% (vs. 38% in controls) and hospitalizations for CVD fell by 36% in T1D 22. Hospitalizations for heart failure in T1D have not declined 22. T1D mortality rates are still 2- to 8-fold that of the general population, with CVD being a major driver 14,22. Swedish data from a median 8.3-year follow-up (1998–2011) [33 170 T1D adults and 164 698 controls without a previous acute myocardial infarction (AMI)] showed relative AMI and CHD death rates in T1D ranging from 2- to 15-fold in men and 5- to 33-fold in women. The excess was less with better glycaemia and normal renal function in men, but it persisted in women, even with good glycaemic control and no renal damage 23.

PAD rates remain high in T1D. In an older 14-year follow-up study, nontraumatic lower limb amputations occurred at 0.4–7.2% p.a. 24. In a Swedish inpatient registry (1975–2004) of 31 354 patients with T1D, the hazard ratio (HR) for amputations was 85.5 versus the general population, with a cumulative probability of amputation by the age of 65 years of 11% for women and 20.7% for men 25.

Metabolic memory affects relationships between risk factors and atherosclerosis 26–29. Metabolic memory is the phenomenon by which the body’s tissues, including arteries, continue to respond to poor or good glycaemic control for years after glycaemia has improved or worsened. Metabolic memory may last decades. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Trial, ≈5.9 years of intensive versus conventional management reduced chronic complications, including surrogate measures of atherosclerosis [carotid intima–media thickness (cIMT)] 30–33, CAC 34 and hard clinical vascular events for at least 8–12 years 29. Vascular metabolic memory has also been demonstrated, predominantly in nondiabetic individuals for lipid and BP control 31,35,36. Metabolic memory should be considered in the design and interpretation of clinical trials and in clinical practice and will particularly affect short-term interventions.

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Characteristics of atherosclerosis

Arteriosclerosis is the (age-related) stiffening of artery walls, whereas atherosclerosis narrows arteries because of plaque build-up. Post-mortem studies 37–44 show that atherosclerosis, reflected by fatty streaks, begins in childhood, particularly in Westernized countries. In diabetes, atherosclerosis begins earlier, progresses faster and extends more distally than in those without diabetes 45–47. This, and less arterial collateral formation, can make bypass procedures difficult if not impossible 48. In T1D, plaques tend to be more concentric in location, softer, more fibrous, lipid rich and inflamed (with macrophage and T-cell infiltration); have more apoptotic cells around a necrotic core, more thrombosis and more advanced glycation end-product-related immunostaining and are more unstable and rupture prone 49–51. The latter often triggers a clinical event 52. People with diabetes may have clinical events with less apparent atherosclerotic burden 53, likely related to greater plaque instability and limitations of current detection techniques. Artery walls are thicker, as reflected by increased IMT, and there is often more calcification in plaque and in the arterial media in diabetes 54,55. IMT, calcification and artery lumen encroachment form the basis of many techniques to detect atherosclerosis.

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Techniques to assess atherosclerosis

Tools to detect or predict atherosclerosis are summarized in Table 1. Artery-based techniques may be functional or structural. The latter is thought to be both preceded and accompanied by functional abnormalities, usually impaired vasodilation in T1D. Functional tests and retinal measures are research tools and are not discussed further in this brief review.

Table 1

Table 1

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Structural measures of atherosclerosis

Arterial intima–media thickness

cIMT is usually facilitated by (arterial wall) edge-detection software. Arterial distensibility and wall shear stress measures by ultrasound are also feasible. IMT measurement is noninvasive, painless, does not involve radiation or sedation and is relatively low cost. Its measurement can guide decisions regarding further investigations, surgery or risk factor treatment. Relative to age-matched and sex-matched apparently healthy nondiabetic individuals, both cIMT and plaque are increased in T1D 56–59. Some sex differences are noted, even in T1D youth. In 314 T1D youth (mean age: 13.7 years, 5.5 years T1D, HbA1c 8.4%, and 97% on intensive diabetes management) and 118 controls, elevated mean cIMT (>90th percentile of healthy individuals) was present in 19.5%. Mean cIMT was higher in diabetic versus nondiabetic males but not in females. No individuals had plaques 57.

Traditional risk factors of age, diabetes duration, smoking, higher BMI, total cholesterol and low-density lipoprotein-cholesterol (LDL-C), BP and albumin excretion rate have been associated with, or are predictive of, cIMT and plaque in T1D 60–63.

Although it is a commonly used research tool, there is some concern that cIMT may not perform consistently well enough to improve risk classification at the individual level in the general population 64 and may be considered for intermediate risk asymptomatic individuals in the general population 15. Major diabetes guideline bodies do not recommend routine screening of asymptomatic adults with T1D.

Aortic distensibility, which reflects arteriosclerosis, was assessed by MRI in the DCCT/EDIC cohort and was related to future vascular events over a mean of 22 years, during which 27% of participants had CVD events. The aorta became stiffer with increasing age, systolic BP, LDL-C, HbA1c and macroalbuminuria and was also associated with myocardial strain 65.

The aorta, rather than the carotid, may be more appropriate to study in youths, as it is usually the first site of atherosclerosis. High-resolution ultrasound of the carotid, brachial, femoral arteries and aorta was compared in 38 youths with T1D (median age: 13 years) and 38 controls. The aortic and femoral IMT were significantly increased in T1D, whereas carotid and brachial IMT were not 66. In another study in adolescents with T1D, higher aortic IMT correlated with carotid IMT and with retinal vessel measures 67.

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Arterial calcification

In addition to advanced calcification of mature (and more stable) plaques, microcalcification can occur early in plaques. CAC measured by noninvasive computerized tomography is becoming more widely used clinically and as a surrogate end point in clinical trials. As yet it is not recommended for general clinical use or (by the ADA) in adults with T1D who are asymptomatic and deemed low risk 15. CAC scores correlate with atherosclerosis severity and in some studies predict vascular and mortality outcomes 68–70. As pointed out in the 2019 ADA guidelines, CAC scores do not improve outcomes in truly asymptomatic people with T1D who have aggressive risk factor treatment 13. There are some recommendations for CAC use and interpretation at the individual level in asymptomatic individuals at intermediate risk, including in diabetes, such as the combined statement of the American College of Cardiology Foundation/American Heart Association 71. An excellent review of the CAC scan in T1D is by Burge et al.72.

CAC testing is generally well tolerated, has excellent repeatability and is low cost compared with angiography. Specialized software aids CAC calculation, which is usually reported in Agatston scores based on measures in the four major coronary arteries. CAC scores are included in some CVD risk equations (discussed later) for assessment of asymptomatic patients. Addition of CAC scores provides better discrimination and reclassification as to the need for treatment. In asymptomatic patients, CAC scores can predict vascular events more accurately than coronary angiography. A negative CAC scan identifies someone at very low 5-year risk of a coronary event. Disadvantages of CAC testing are that it cannot detect noncalcified plaque, nor clinically significant lumen occlusion, it involves radiation (comparable to that of a mammogram) and it is not always available or subsidized by health care providers. The Agatston score increases in a nonlinear way with worsening anatomical lesions owing to jumps in the weighting factors used in its calculation as lesion density increases 72.

CAC scores are more likely to be positive and higher in T1D than in nondiabetic adults 73. In the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study, CAC was present in 39% of men and 12% of women, and score positivity was associated with older age, higher BMI, waist circumference and intraabdominal and subcutaneous fat volume 73. In a Pittsburgh Epidemiology of Diabetes Complications (EDC) study (302 adults, mean age: 38 years), CAC scores were positive in 11% aged 30 years and in up to 88% of those aged 50–55 years. CAC was independently associated with clinical disease, with stronger associations in men than women 73. In 69 adults with T1D for at least 50 years versus nondiabetic controls, CAC scores were higher in T1D (median Agatston score: 1000 vs. 1.0 in controls, P<0.001). In T1D, high CAC scores (≥300 Agatston units) were associated with retinopathy and neuropathy but not with renal function 74. Positive CAC scores in T1D have also been associated with cognitive impairment 75.

Calcification in carotid and coronary arteries correlated in 53 normoalbuminuric adults with T1D (r=0.720, P<0.0001), and cardiovascular autonomic neuropathy (CAN) was associated with increased coronary and carotid artery calcium scores 76.

In a 25-month longitudinal follow-up study, CAC progression occurred more rapidly in 53 normoalbuminuric persons with long-term T1D (20 with CAN) than in a 29-month follow-up of 106 nondiabetic controls matched for age, sex and baseline CAC, with T1D having an odds ratio of 3.3 for CAC progression. CAN did not increase CAC progression 77. Plasma triglyceride levels predict CAC progression in T1D 78 and in the DCCT-EDIC cohort, CAC (which was positive in 31% at first assessment) was reduced by previous intensive glycaemic control 34. In the Pittsburgh EDC study (n=292, mean age: 39.4 years, T1D duration 29.5 years), 76 participants developed a first CAD event during mean follow-up of 10.7 years, for which CAC was an independent risk factor 79. Larger T1D-specific studies are desirable.

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Peripheral artery disease

Subclinical peripheral artery disease (PAD) can sometimes be identified noninvasively by ratios of BP in the lower and upper limbs [e.g. ankle–brachial index (ABI)], though arteriosclerosis interferes, by arterial calcification and by ultrasound. Invasive techniques (e.g. angiography) are more suited in the assessment of severe PAD. Ultrasound is not recommended for clinical use in asymptomatic adults with T1D.

There are few T1D studies. In a cross-sectional study of 289 consecutive asymptomatic adults with T1D (with normal leg pulses), abnormal ABI levels of up to 0.9 or more than 1.2 were detected in 6 and 26%, respectively. Those with abnormal ABI were assessed by toe–brachial index and ultrasound to assess subclinical PAD and/or carotid plaques, with a 12.8% prevalence of silent PAD. Of those with PAD, 4.8% also had carotid disease; hence, using the ABI test, one could expect to screen three asymptomatic patients with T1D to identify one with subclinical PAD and seven patients to detect one with carotid disease 80. Miller and colleagues explored relationships between an abnormal ABI greater than 1.30 or an ankle–brachial pressure difference (ABD) more than 75 mmHg and lower limb medial arterial calcification (with typical ‘tram track’ appearance) on radiography. In 185 adults with T1D (mean age and T1D duration of 32 and 23 years, respectively), calcification was noted in 57%, but only 8% had an elevated ABI and 8% had an ABD of more than 75 mmHg. Hence, adults with T1D with an ABI of more than 1.30 or ABD of more than 50 mmHg are very likely to have arterial calcification, but many with calcification will have normal pressure-related measures 81.

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Other vascular assessment tests

Intravascular ultrasound and intravascular OCT, usually of coronary arteries, are invasive, being performed by angiography, hence are usually used with more severe atheroma and in the setting of stent placement.

Coronary CTA 82 is a noninvasive angiogram that, unlike conventional dye-based coronary angiograms, assesses the vessel wall as well as the lumen. CTA can detect stenoses, calcified and noncalcified plaque, plaque size and markers of potential plaque instability such as expansive vascular remodelling and spotty calcification. CTA can detect even small plaques and also can assess the haemodynamic significance of large lesions such as with fractional flow reserve measures. Large prospective trials in the general population show the utility of CTA for ruling out obstructive CAD and for identifying subclinical atherosclerosis for medical therapy; hence, CTA is now recommended as a diagnostic test in some European guidelines. There are few T1D studies. In a small prospective study of 25 T1D and 15 T2D asymptomatic patients aged 19–35 years with at least 5 years of diabetes, CAC and CTA were performed. Abnormal scan results were present in 57.5%, being noncalcified in 35%. Plaque was almost uniformly absent below the age of 25 years and became increasingly common after the age of 25 years for both groups. A negative CAC score was not sufficient to exclude early CAD as there was a preponderance of noncalcified plaque; hence, CTA in T1D patients older than 25 years old was suggested 83. Further T1D studies are desirable.

Coronary computed tomographic angiography in asymptomatic people with T2D has found that around one-third have no coronary disease, one-third have minor or moderate disease, and one-third have at least one artery with a stenosis of more than 50%, which would usually prompt invasive angiography 84. Sensitivity in detecting a stenosis of more than 50% is ≈90% and specificity is typically 80–90%, which falls to ≈50% in the presence of high CAC scores (>400 Agatston units) 85, such as are more likely in T1D. Invasive angiography is usually recommended if lesions on CT have a stenosis of more than 50%. However, only a third of 50–70% stenosed lesions on invasive angiography are functionally significant and potentially suitable for revascularization, compared with 80% of those more than 70% stenosed 86. Therefore, many people with significant lesions on CT may undergo further investigation without any change in medical management. The FACTOR-64 trial followed asymptomatic high-risk people with T2D randomized to standard guideline-based care or guided management according to disease severity and found no differences in clinical outcomes over 4 years of follow-up 87. T1D studies are needed.

Multimodal MRI techniques that also focus on the lumen are emerging. In a cross-sectional study, greater atheroma was present in nondiabetic people with clinical CVD versus those nondiabetic and (type 2) diabetic subjects without (clinical) CVD 53. This may relate to plaque quality being worse in diabetes.

Molecular imaging with atherosclerosis-related tracers (macrophage activity, calcification, cellular apoptosis and glucose metabolism) is an evolving research tool 88–90.

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Risk factors

Given the paucity of evidence and lack of robust tools to quantify early atherosclerosis, most management strategies focus on risk factor assessment and care. Several risk factors at low level, for example, suboptimal HbA1c, mildly elevated BP or LDL-C, which can often be disregarded by the patient or their clinician, can place a person at moderate or high vascular risk. This has led to recommendations to use absolute cardiovascular risk calculators in primary prevention (discussed later).

CVD risk factors and biomarkers of interest are summarized in Table 2. We and others have previously reviewed the roles of traditional and emerging risk factors in diabetic vascular disease 16,91–95. We briefly comment on several risk factors.

Table 2

Table 2

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Traditional risk factors

The importance of HbA1c, BP and lipids is demonstrated by an assessment of the ADA guidelines and CVD and mortality in 3151 patients with T1D stratified by nephropathy status. Approximately 63% of patients with nephropathy and 34% of those without nephropathy reached none of the recommended targets. Failure to reach targets was associated with increased risk of mortality and CVD 96.

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Genetics

Currently no genetic factors are used clinically in atherosclerosis risk prediction in T1D, though strong associations with some genotypes, for example, ApoE and haptoglobin 2/2, are recognized 97–109. Genome-wide association study analyses have implicated many new single nucleotide polymorphisms 110.

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Sex

Women with T1D lose their relative cardioprotection. A longitudinal (median: 12.9 years follow-up) FinnDiane study related CAD and stroke events to sex and nephropathy status 111. Event rates were similar in men and women at each level of nephropathy, with higher rates associated with worsening renal function. Relative to nondiabetic people, in T1D, the standardized incidence rate (SIR) for CAD was 17.2 in women and 5.3 in men. The female to male SIR ratio increased with worsening renal function. The SIR for stroke was 5.0, similar in men and women. The female to male ratio of SIR for stroke was 0.8, 1.3, 1.6 and 1.7, with worsening renal function. The SIR in participants with T1D with normal renal function was 3.5 for CAD and 1.6 for stroke; hence, even adults with T1D with normal renal function are at increased risk of vascular events.

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Age of type 1 diabetes onset

In 27 195 T1D and 135 178 nondiabetic patients followed from 1998 to 2012 for a median of 10 years, patients who developed T1D at less than 10 years of age had the highest HRs for all-cause and CVD-mortality of 4.1 and 7.4, respectively, 30 for CAD, 31 for AMI and 6.4 for stroke. For those who developed T1D at less than 10 years old, the mean loss of life-years was 17.7 for women and 14.2 for men 112. HRs were substantially lower with T1D onset at the age of 26–30 years.

Microvascular complications are risk factors for atherosclerosis, which is recognized in treatment guidelines 13,14,16. This may relate to common risk factors and that renal dysfunction aggravates many risk factors, such as dyslipidaemia, inflammation and hypertension 91. In T1D CAN has also been associated with cIMT, hypertension 113, impaired coronary artery reactivity 114, CAC, arterial stiffness and traditional risk factors 115.

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Lipoproteins

High total and LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are associated with, and predictive of, CVD and microvascular complications in T1D 92. Even though T1D is usually associated with normal or high HDL-C levels, the HDL can be dysfunctional 116 regarding its reverse cholesterol transport, anti-inflammatory, anticlotting and vasodilatory functions. NMR-determined lipoprotein subclasses have also been associated with, and predictive of, carotid IMT and CAC in T1D 117–121. Qualitative changes in lipoproteins in diabetes, such as glycation, oxidation, advanced glycation end products and immune complex formation enhance lipoprotein pathogenicity 49–51.

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Glycaemia

The DCCT/EDIC study showed that lower HbA1c levels were associated with better IMT (including in adolescents), CAC and subsequently macrovascular events 30–33. Hypoglycaemia is a risk factor for atherosclerosis 31, with potential mechanisms being increased endothelial dysfunction, inflammation, oxidative stress and a prothrombotic tendency 122–125. Glucose variability (GV) is an independent risk factor in T1D for microvascular and macrovascular complications 126. Short-term GV can be assessed by multiple daily blood glucose levels, or by continuous (interstitial fluid) glucose monitoring, and at the cellular level 127,128 induces oxidative stress, inflammation and epigenetic changes 129. Long-term GV (HbA1c SD and/or coefficient of variation) is an independent risk factor for chronic complications in T1D and T2D 21,127–131. In T1D, greater GV has been associated with lower flow-mediated vasodilation, CAN, increased oxidative stress and a poorer traditional vascular risk profile 126,132–135. GV by continuous (interstitial fluid) glucose monitoring was associated with CAC in T1D in the CACTI study in men but not in women 136. Further T1D GV studies, preferably with adjustment for mean glucose or HbA1c, are of interest.

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Hypertension

Ambulatory (24 h) BP monitoring can facilitate the diagnosis and management of hypertension and is recommended by many national bodies 7. The first evidence of abnormal BP in T1D is ‘non-dipping’ or loss of the usual nocturnal reduction in BP relative to daytime. In a cross-sectional study of 140 patients with T1D, hypertension detected by ambulatory BP monitoring was common (25%) and was associated with increased arterial stiffness 137.

Insulin resistance is also a feature of T1D 138,139, sometimes known as ‘double diabetes,’ and is associated with vascular complications 140 and can be estimated by several formulae using traditional risk factors 141–143. A novel NMR marker has recently been suggested 144.

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Inflammation

Soluble intracellular adhesion molecule and soluble vascular cell adhesion molecule-1 levels have predicted incident hypertension and arterial stiffness in 277 patients with T1D up to 20 years later 145. Systemic inflammation, reflected by high-sensitivity C-reactive protein and plasma matrix metalloproteinase-8 levels, correlated with progression of flow-mediated vasodilation, carotid IMT and carotid compliance over ≈2 years in children with T1D 146.

Emerging biomarkers include telomere length, telomerase activity and epigenetic factors (DNA methylation, microRNAs), proteomics, lipidomics and metabolomics and autoantibodies 140,147–159.

Autoantibodies to cardiovascular tissue may represent and/or promote vascular disease. Antibodies to modified LDL promote subclinical disease in T1D 117,119,120. In a longitudinal DCCT/EDIC study 160, poor glycaemic control was associated with higher rates of antibodies to cardiac tissue, which was independently associated with high risk of CAC and clinical CVD decades later. Positivity for at least two cardiac antibodies was associated with increased risk of CVD events (HR: 16.1) and detectable CAC (odds ratio: 60.1). Patients with T1D with at least two antibodies (vs. ≤1) subsequently showed elevated high-sensitivity CRP, implicating inflammation.

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Risk equations

Risk equations are often recommended to estimate future CVD event risk in asymptomatic people. Those with clinically evident disease are recommended intensive treatment. Absolute cardiovascular risk is an estimate of the chance that an individual will experience a cardiovascular event, usually reported as within the next 5–10 years. A CVD risk level of at least 20% over 10 years is usually regarded as high, and up to 10% as low, though cutoff points differ between various expert groups.

Most CVD calculators are for the general population or for T2D 13,16,161. Included risk factors vary, as do the events they predict. Common denominators are age, sex, smoking, diabetes, BP and lipids. Several longitudinal observational studies in T1D show that the relative importance of traditional risk factors for vascular complications differs by T1D duration 162,163. In a comparison of the DCCT/EDIC and EDC studies with median T1D duration at baseline of 4 versus 18 years, similar traditional risk factors predicted subsequent CVD; however, albumin excretion rate predominated in EDC and HbA1c in DCCT/EDIC 163. A DCCT/EDIC study regarding CVD showed that traditional vascular risk factors mediated the importance of glycaemia over time 164. The association of HbA1c with CVD outcomes was stable, whereas that of systolic BP, heart rate, triglycerides and LDL-C increased. At 10-year follow-up, the effect of HbA1c on 10-year CVD risk was minimally mediated by systolic BP (2.7%), increasing to 26% at 20 years. Similarly, between these time points, the proportion of HbA1c effect mediated through triglycerides increased from 2.2 to 22.4%, and through LDL-C from 9.2 to 30.7%. Hence, as people with T1D age, the relative importance of traditional (nonglucose) risk factors increases.

Generally, risk calculations developed for T2D are not accurate for T1D. They tend to underestimate risk, do not incorporate important T1D factors (age of diabetes onset, diabetes duration, HbA1c, albuminuria and treatment modalities) and hence are not recommended for use in T1D 13,14,165,166. Several T1D-specific risk calculations have been developed. An early calculator was developed from a 7-year follow-up of 1973 adults with T1D in the EURODIAB Prospective Complications Study, of whom 95 developed microvascular or macrovascular events, and was validated in three other cohorts: the Pittsburgh EDC study (n=554), the Finnish Diabetic Nephropathy study (FinnDiane, n=2999) and the CACTI Study n=580). Strong prognostic factors for the composite end point [CVD events, amputations, end-stage renal disease, blindness and (all-cause) death] were age, urinary albumin–creatinine ratio, HbA1c, waist to hip ratio and HDL-C 167.

More recently, in the Steno Study of 4306 adults with T1D, an excellent prediction model for estimating the risk of first fatal or nonfatal CVD event (ischaemic heart disease, ischaemic stroke, heart failure and PAD) was derived from registry data with external validation in 2119 patients with T1D. During a median 6.8-year follow-up, 793 patients developed a CVD event. The final prediction model (https://steno.shinyapps.io/T1RiskEngine/) includes age, sex, diabetes duration, systolic BP, LDL-C, HbA1c, albuminuria, estimated glomerular filtration rate, smoking and exercise 168.

Risk models for T1D+/− and the CAC score have been developed from the Pittsburgh EDC study 79,163. Over a mean 10.7-year follow-up of 292 adults with T1D (mean age: 39 years, 29 years T1D) free of clinically evident CAD at baseline and with at least one CAC assessment, 76 experienced a CAD event. At baseline, compared with those without CAC (Agatston score=0), the adjusted HR in CAC score groups of 1–99, 100–399 and at least 400 was substantial: 3.1, 4.4 and 4.8, respectively. CAC density was inversely associated with incident CAD in those with CAC volume of at least 100 (HR: 0.3). Among participants with repeated CAC measures (62%), annual CAC progression positively associated with incident CAD after controlling for baseline CAC. The HR for above versus below the median annual CAC volume progression was 3.2. Addition of CAC to traditional risk factors improved predictive ability for CAD.

Sometimes the use of multiple biomarkers combined can predict outcomes better than individual measures 169. In the DCCT/EDIC cohort, four composite scores were created by combining z scores of related factors: acute-phase reactants, cytokines/adipokines, thrombolytic factors and endothelial dysfunction/vascular inflammation. Composite scores were related to internal carotid IMT at EDIC years 1, 6, and 12. Although individual biomarkers did not predict IMT at last follow-up, three composite scores (acute-phase reactants, thrombolytic factors and cytokines/adipokines) did, with an OR of 2–2.8.

Simple CVD risk calculators can be a helpful assessment and educational tool, with patients (without evident CVD) being shown their risk reduction with, for example, improved lipids if they were to take a statin. Their use can be complemented and individualized by assessment of subclinical vascular damage (e.g. cIMT or CAC) 79.

Calculators may differ because of differences between the population from which the calculators were devised and that of the person(s) whose risk is being calculated. For example, insulin pump use has been associated with lower risk of CVD and mortality than multiple daily injections 21. CVD risk may change over time as major risk factors and treatments (e.g. statins, BP, smoking, HbA1c and glucose control modalities) change; hence, a calculator developed decades ago may not reflect an individual’s CVD risk and subclinical atherosclerosis well in more recent times.

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Interventions in type 1 diabetes with subclinical atherosclerosis end points

Given the very long subclinical timeframe of atherosclerosis, risk equations and individual biomarkers are valuable surrogate end points in clinical trials. Ideally positive outcomes should be followed by a hard clinical end-point trial, which usually requires large numbers, years of follow-up and high financial costs. Outcomes for a given intervention may differ between surrogate and hard clinical events, and even for surrogate end points measured by different methods.

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Statins

The Cholesterol Treatment Trialists Consortium meta-analysis showed the LDL-C-lowering effect of statins and proportional reduction in CVD events was similar in T1D, T2D and nondiabetic individuals 20. Although being cardioprotective against clinical events 20, statins mildly increase CAC in T1D 72.

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Glycaemia

In the DCCT/EDIC study, previous intensive glucose control reduced CVD event incidence by 30% 170. Benefit was first evident in surrogate measures (cIMT 30,32,33,171 and CAC 34). In the DCCT/EDIC study, intensive glucose control did not reduce the rates of PAD but did reduce peripheral arterial calcification 172. In a meta-analysis of five T1D studies, with each 1% increase in HbA1c, the risk of PAD increased by 18% 172.

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Adjunct glucose control agents

The REversing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial is the first study of adjunct metformin in T1D to evaluate a CVD end point, albeit a surrogate measure 173,174. In 428 high CVD risk adults with T1D, metformin (3 years) tended to reduce mean far wall cIMT, which excludes IMT measures of more than 1.5 mm and plaque (primary end point). However, maximal cIMT (tertiary end point), which includes plaque, was significantly reduced by metformin 173. In a prestated post-hoc analysis of never smokers versus current and ex-smokers, the primary IMT end point met statistical significance 174. Metformin significantly reduced weight, LDL-C, insulin dose and preserved estimated glomerular filtration rate. CVD results of trials of other adjunct treatments such as SGLT2 inhibitors and incretin therapies are also of interest 173.

As atherosclerosis is inflammatory, trials of anti-inflammatory drugs for CVD in T1D are also merited.

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Clinical practice recommendations

Most studies randomising asymptomatic patients with silent ischaemia on stress testing to further investigation and potentially surgery or to routine care show similar outcomes for up to 5-year follow-up 175,176. ADA guidelines do not recommend routine screening of asymptomatic people with diabetes as it does not improve outcomes, as long as CVD risk factors are well treated 13,35. Unfortunately, few with T1D meet all recommended targets, which is associated with adverse outcomes 96. There are significant costs and some risks subjecting people to these investigations, particularly when invasive testing is required for clarification.

CAC scores correlate with atherosclerosis severity and can predict vascular and mortality outcomes 68–70 in the general and in some (research cohort) T1D populations, yet are not deemed powerful enough at the individual clinical patient level to screen all asymptomatic patients with T1D 13. CAC scores are not specific for the presence of severe or clinically significant occluding lesions 85. Some groups suggest the value of the CAC score in the general population may be in stratification of people at low or intermediate risk – allowing those with a CAC score of 0 (or possibly 0–10) to be potentially reclassified as truly low risk, whereas those with incrementally higher scores may be shifted upward in their risk categorization, and treated more aggressively, and that these guidelines may also be suitable in T1D 15,71,72.

Some suggest that in the asymptomatic patients with T1D, CAC scans may commence at age 30–40 years (modified on the basis of risk factor burden) 13,72. This is based on the DCCT/EDIC CAC study in which many had a positive CAC scan result at a mean age of 34 years. If positive, major modifiable risk factors should be targeted, and the CAC scan repeated in 4–5 years. CAC score progression of less than 15% per annum is desirable. A CAC score prestatin commencement is recommended, as statins mildly increase CAC (as does warfarin). In the general population, knowledge of a positive CAC score has been shown to motivate patients to adhere to recommended lifestyle and medications 177,178 and its use can guide discussions with low or intermediate CVD risk regarding statin use 179.

Situations when non-evidence-based consensus exists for coronary screening include people who are not truly asymptomatic, with (i) ‘atypical’ symptoms; (ii) other evidence of vascular disease such as carotid bruits, TIAs or claudication (for which secondary prevention is indicated); (iii) ischaemic ECG abnormalities and (iv) at high risk considering undertaking strenuous exercise in the absence of regular exercise 13. Adding an imaging component (echocardiography or nuclear perfusion) will improve specificity, particularly in patients with resting ECG abnormalities or in women, as women have a high false positive rate of ECG changes.

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Conclusion and future directions

Atherosclerosis remains a major burden in T1D. Risk factor management is key. Particularly high-risk patients with T1D are those with age below 10 years of T1D onset, longer diabetes duration, microvascular complications and with multiple risk factors. On an individual basis, it is often challenging to quantify vascular risk and atherosclerosis extent, particularly early on. Sensitive and specific tools to assess atherosclerosis are desirable. The range of tools is increasing, as is the range of prevention therapies. More T1D observational and clinical trials are needed to guide clinical practice to ultimately improve both the quality and length of life of people with T1D.

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Acknowledgements

Conflicts of interest

A.J.J. is supported by a NHMRC Practitioner Fellowship and is a Sydney Medical School Foundation Fellow. A.J.J. and D.N.O. were investigators on the REMOVAL Trial, which was funded by JDRF International/Canada and Australia, and for which metformin and matching placebo was provided free by Merck KGaA (Germany), and EndoPAT equipment and non-financial support was received from Itamar Medical (Israel). A.J.J. is also an investigator on the DCCT/EDIC trial. A.J.J. and D.N.O. have received peer-reviewed research grants from Medtronic, Sanofi-Aventis and Glen-Sys and are on advisory boards for Abbott (Diabetes Devices, Australia), Sanofi-Aventis (Diabetes, Australia) and Medtronic Australia. A.J.J. has also received research grants or product from Mylan. For the remaining author, there are no conflicts of interest.

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Keywords:

atherosclerosis; biomarkers; coronary artery calcification; intima–media thickness; risk factors; type 1 diabetes; vascular function

© 2019Wolters Kluwer Health Lippincott Williams Wilkins