We searched PubMed and MEDLINE on Sept 28, 2017, for English language abstracts and full-text articles on cardiovascular disease in youth with type 1 diabetes. The keywords used to search included: “cardiovascular disease”, “type 1 diabetes”, “risk factors”, “adolescents”, “diabetic kidney disease”, “clinical trials”, “arterial stiffness”, “obesity”, “smoking”, “lifestyle changes”, “insulin resistance”, “insulin sensitivity”, “metformin”, “statins”, “ACE inhibitors”, “hypertension”,
ReviewMacrovascular disease and risk factors in youth with type 1 diabetes: time to be more attentive to treatment?
Introduction
The overall global incidence of type 1 diabetes is rising, with an especially concerning rate in children under the age of 5 years,1 which translates to a lifetime of exposure and increased risk for early death from cardiovascular disease.2, 3, 4 The strongest risk factors for cardiovascular disease and mortality for patients with type 1 diabetes continue to be hyperglycaemia, hypertension, dyslipidaemia, diabetic kidney disease, insulin resistance and obesity.5, 6, 7 Whereas advances have been made in the management of microvascular complications of type 1 diabetes,8 little comparable progress has been made in the reduction of cardiovascular disease.8 Current treatments, such as the control of hyperglycaemia and hypertension, are beneficial, but only partially protect against the disease. Furthermore, few clinical trials in the prevention of cardiovascular disease in youth, or in adults, with type 1 diabetes exist; therefore, little data exist on suitable interventions to reduce risk for those patients who are at an early stage of disease when pathology might be more responsive to therapy.
One factor that limits the reduction of cardiovascular disease is the delayed identification and treatment of these risk factors in youth with type 1 diabetes. Worldwide data indicate that the goals of the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) for traditional risk factor management of cardiovascular disease are unmet needs, despite these recommendations dating from 2006.5, 6, 9, 10, 11 For example, in 2013, a substantial proportion of youth (13–20 years) in the T1D Exchange Clinic Registry failed to meet the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes targets for HbA1c (79%), systolic blood pressure (SBP) and diastolic blood pressure (DBP; 22%), LDL cholesterol (38%), triglycerides (11%), and BMI (39%).12 Registry data also show low rates of treatment for hypertension, dyslipidaemia, and microalbuminuria in youth with type 1 diabetes.13 We urge a call for action to promptly identify and treat these traditional cardiovascular disease risk factors. Implementation of existing treatment guidelines, and identification of new modifiable risk factors and therapies, has the potential to reduce the 8–13-year gap in life expectancy for young people with type 1 diabetes, much of which is attributable to cardiovascular disease.
In this Review, important paediatric data, ongoing clinical trials, and recommendations on cardiovascular disease screening and management in youth with type 1 diabetes are appraised. We also discuss the research and clinical progress needed over the next 10 years to help to reduce morbidity and mortality from cardiovascular disease for patients with type 1 diabetes.
Section snippets
What is the risk?
Type 1 diabetes is characterised by complications of the macrovasculature (eg, coronary artery disease) and microvasculature (eg, diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy).14 Cardiovascular disease continues to be the leading cause of morbidity and mortality for patients with type 1 diabetes.15 Cardiovascular disease also disproportionally affects women with type 1 diabetes, which contrasts with a male predominance observed in the general population.16 Type 1 diabetes
Traditional risk factors
Traditional risk factors for cardiovascular disease are hyperglycaemia, hypertension, dyslipidaemia, and diabetic kidney disease (figure 1, appendix). This Review focuses on therapeutic inertia, and therefore focuses on modifiable rather than non-modifiable risk factors, which are covered in other reviews and research papers.11, 21, 22
Hyperglycaemia
Although glycaemic control remains the clinical cornerstone of cardiovascular disease prevention and management for patients with type 1 diabetes, the data supporting the relations between HbA1c concentrations and macrovascular complications are less convincing in type 1 diabetes than for microvascular complications.11 Hyperglycaemia probably contributes to cardiovascular disease in type 1 diabetes by several mechanisms, including promoting endothelial dysfunction and arterial stiffness.23, 24
Hypertension
Youth with type 1 diabetes are disproportionally affected by hypertension compared with their normoglycaemic peers. The prevalence of hypertension in youth with type 1 diabetes is 4–7%, which is higher than the 1–5% reported in youth without type 1 diabetes.35 Risk factors for abnormal blood pressure patterns and hypertension in youth with type 1 diabetes include obesity, autonomic dysfunction, and hyperglycaemia.36, 37 In adults with type 1 diabetes, target blood pressures are defined as less
Dyslipidaemia
Youth with type 1 diabetes have a high prevalence of dyslipidaemia.47 The DPV registry reported hypercholesterolaemia in 28·6% of participating children, adolescents, and young adults.5 Similarly, persistently abnormal concentrations of total cholesterol, HDL cholesterol, and LDL cholesterol, were shown over 10 years in American youth with type 1 diabetes, with 28% and 11% with LDL-cholesterol concentrations of 130 and 160 mg/dL or more.48 Atherosclerosis starts early in life and relates to
Diabetic kidney disease
Diabetic kidney disease represents a major cause of end-stage renal disease and dialysis in the developed world, and is preceded by a long period without symptoms or signs of disease.52 Additionally, diabetic kidney disease is increasingly recognised as a crucial risk factor for cardiovascular disease53, 54 and mortality (appendix). Increased albumin excretion, previously termed microalbuminuria, and classically thought to be an early clinical marker of diabetic kidney disease, has a cumulative
Obesity
Central adiposity is an important cardiovascular disease risk factor that is augmented by intensive insulin therapy, and is increasingly recognised in people with type 1 diabetes.61 The incidence of obesity has been reported as 37% in one cohort of adults with newly diagnosed type 1 diabetes,62 and as 78% for men who were overweight or obese in the urological assessment component of the EDIC study.63 These data are not unique to North America, with similar prevalence and incidence rates
Current methods to evaluate cardiovascular disease health in paediatrics
Accurate risk stratification of cardiovascular disease in youth with type 1 diabetes is required to implement successful prevention strategies. Targeting youth with the highest risk of cardiovascular disease using objective and non-invasive methods is crucial (appendix). One of the major difficulties in preventing cardiovascular disease is attributed to the need to accurately target high-risk populations at an early stage of disease development, when the disease might be most responsive to
Uptake of ADA and ISPAD treatment goals
Collectively, increased glucose, blood pressure, and dyslipidaemia are considered the major contributory factors for cardiovascular disease, but achieving reduction of these factors in children and adolescents remains a difficult challenge.5, 6, 9, 10, 11 Suboptimal target achievement is associated with worse vascular health in youth with type 1 diabetes as judged by surrogate markers of cardiorenal health (appendix). Reasons for suboptimal goal achievements are probably multifactorial.
Clinical trial data and therapeutic inertia
Although few cardiovascular disease clinical trials are dedicated to youth with type 1 diabetes, the landmark studies that have addressed this area are worth highlighting. For example, in the adolescent cohort of the DCCT trial, intensive glycaemic control led to renal protection in 195 pubertal youth, which is a strong cardiovascular disease risk factor.110 In the same cohort, the intensive treatment arm conferred reduced risk and progression of increased albumin excretion by 54% compared with
Recommendations
Substantial gaps exist in our knowledge and understanding of the safety and efficacy of cardiovascular disease therapies in children and adolescents with type 1 diabetes. Accordingly, we have summarised some important unanswered research questions in table 4. Although results from observational studies in youth with type 1 diabetes have identified several risk factors associated with surrogate markers of cardiovascular disease, we need more evidence from randomised trials for youth with type 1
What progress do we need to make in the next 10 years?
Priorities to enhance cardiovascular health in children and adolescents with type 1 diabetes are summarised in table 4, and include a better differentiation of guidelines for youth with type 1 versus type 2 diabetes. Pathophysiological differences probably drive cardiovascular disease risk in children and adolescents with type 1 and type 2 diabetes, and therefore disease-specific preventive strategies and therapies are warranted. More information is needed on how well surrogate markers predict
Conclusion
The atherosclerotic process starts in youth. Youth with type 1 diabetes have an increased risk of cardiovascular disease, which continues to be the principal cause of mortality, and an important contributor to the reported 8–13-year decrease in lifespan for patients with type 1 diabetes. Early intervention can have a positive effect on prevention, and data from AdDIT show safety and short-term improvements in LDL-cholesterol concentrations, blood pressure, and albumin-to-creatinine ratio with
Search strategy and selection criteria
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Adiponectin rs1501299 and chemerin rs17173608 gene polymorphism in children with type 1 diabetes mellitus: relation with macroangiopathy and peripheral artery disease
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