Abstract
Background
In children and adolescents, the most common cause of diabetes mellitus is type 1 diabetes, but type 2 diabetes is increasing in prevalence. Cardiovascular disease is the leading cause of morbidity and mortality in people with diabetes and begins in childhood.
Aim of review
The purpose of this article is to review cardiovascular disease associated with type 1 and type 2 diabetes in children and adolescents, including glycemic and nonglycemic risk factors, screening, and therapy.
Key scientific concepts of review
The risk of developing cardiovascular disease is 30-fold higher in patients with type 1 diabetes than in nondiabetic peers and 32 % of patients with type 2 diabetes have some type of cardiovascular disease. The risk for developing cardiovascular disease is affected by uncontrolled hyperglycemia, hypertension, dyslipidemia, diabetic kidney disease, obesity, and insulin resistance. The pathophysiology of cardiovascular disease in patients with diabetes is multifactorial and includes hyperglycemia, oxidative stress, hypoglycemia, advanced glycation end products, inflammation, endothelial dysfunction, dyslipidemia, renin-angiotensin-aldosterone system activation, and insulin resistance. Macrovascular complications include coronary heart disease, peripheral artery disease, and diabetic cardiomyopathy. Microvascular complications include diabetic retinopathy, kidney disease, and neuropathy. Advances in treatment of type 1 and type 2 diabetes have decreased overall adult mortality, but pharmacologic therapeutic options are limited in children and adolescents, including insulin, metformin, glucagon-like peptide 1 analogs, dipeptidyl peptidase 4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. Patient education, diet, and physical activity are important for prevention of cardiovascular disease. Screening for cardiovascular risk factors may include measurement of blood pressure, body mass index, hemoglobin A 1c level, lipid panel including low-density lipoprotein level, and albumin-to-creatinine ratio in urine.
Highlights
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Cardiovascular disease is the leading cause of death in patients with diabetes.
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There are glycemic and nonglycemic risk factors for cardiovascular disease.
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Elevated hemoglobin A 1c level is associated with worse cardiovascular outcomes.
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Risk factors include hypertension, obesity, and elevated LDL level.
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Early screening and interventions to improve glycemic control are important.
1
Introduction
Defects in insulin secretion or action result in diabetes mellitus. In children and adolescents, the most common cause of diabetes mellitus is type 1 diabetes, but type 2 diabetes is increasing in prevalence [ ]. The risk of acquiring type 1 diabetes in the general population is 0.4 % in a person’s lifetime and 6 % to 7 % in first-degree siblings [ ]. It is estimated that 35 in 10,000 children and adolescents younger than 20 years in the United States have type 1 diabetes [ ]. Furthermore, the incidence of type 1 diabetes was greater during than before the COVID-19 pandemic [ ]. The incidence of type 2 diabetes may vary between ethnic groups (ranging from 0 to 300 in 100,000 person-years) [ ].
Advances in treatments for pediatric diabetes have increased life expectancy, but patients with diabetes have a 2- to 4-fold higher risk of premature death than people of similar age [ ]. Cardiovascular disease (CVD) is a leading cause of death in adults affected with type 1 and type 2 diabetes [ ].
The purpose of this article is to review CVD associated with diabetes in children and adolescents, provide recommendations for CVD screening in this patient population, and review preventive strategies to decrease CVD risk.
2
Epidemiology of cardiovascular disease in diabetes
CVD is a leading cause of morbidity and mortality in patients with diabetes. The risk of developing CVD is 30-fold higher in patients with type 1 diabetes than in nondiabetic peers [ ], and 32 % of patients with type 2 diabetes having some type of CVD such as ischemic heart disease, cerebrovascular disease, peripheral artery disease, heart failure, and arrhythmias [ ].
The risk of developing CVD in patients with diabetes is affected by several factors, including uncontrolled hyperglycemia, hypertension, dyslipidemia, diabetic kidney disease, obesity, and insulin resistance. Women are more frequently affected than men, and incidence is more pronounced with longer disease duration. The incidence of coronary artery disease for people with type 1 diabetes between age 28 and 38 years is 1 % per year and increases to 3 % per year by age 55 years [ , ].
Effective treatment of these risk factors is important because it may markedly decrease the incidence of CVD events. Despite a high level of need, the screening and pharmacologic treatment of these factors may be suboptimal, especially in children and adolescents.
3
Pathophysiology of cardiovascular disease in patients with diabetes
The pathophysiology of CVD in patients with diabetes is multifactorial, involving several interrelated mechanisms, including hyperglycemia, oxidative stress, hypoglycemia, advanced glycation end products, inflammation, endothelial dysfunction, dyslipidemia, renin-angiotensin-aldosterone system activation, and insulin resistance ( Fig. 1 ) [ ].
3.1
Hyperglycemia
Chronic hyperglycemia contributes to the development of atherosclerosis and endothelial dysfunction, which are early indicators of CVD. Increased carotid and aortic intima-media thickness are markers of early arterial changes that have been observed in children and adolescents with type 1 diabetes [ , ]. Poor glycemic control in children and adolescents with diabetes is associated with increased CVD risk factors, including hypertension, dyslipidemia, and inflammation, and 1 % increase in hemoglobin A 1c is associated with 30 % higher risk of all-cause mortality and 40 % increase in cardiovascular mortality [ ].
Chronic hyperglycemia may increase CVD risk by increasing atherosclerosis, endothelial dysfunction, and autonomic neuropathy. Chronic hyperglycemia causes increased production of reactive oxygen species and oxidative stress, which may activate pathogenic signaling pathways such as the polyadenosine diphosphate-ribose polymerase pathway, inhibit glyceraldehyde 3-phosphate dehydrogenase, and shunt glycolytic intermediates into harmful metabolic pathways. Excessive reactive oxygen species also may disrupt mitochondrial function and cause further reactive oxygen species production and impaired energy metabolism [ ].
Early interventions to improve glycemic control are important in decreasing long-term deleterious cardiovascular outcomes, and a decrease in hemoglobin A 1c by 0.2 % may lower mortality by 10 % [ ].
3.2
Hypoglycemia
Hypoglycemia is associated with proinflammatory and prothrombotic states and may increase the risk of developing CVD [ ]. Children with diabetes on insulin therapy, especially type 1 diabetes, are at higher risk of developing recurrent hypoglycemia, which may cause progressive decrease in the autonomic response to hypoglycemia, hypoglycemia unawareness, and late corrective intervention. Untreated severe hypoglycemia may cause neuroglycopenia, seizures, arrhythmias, and sudden death [ ]. In addition, fear of hypoglycemia in patients and parents may cause anxiety and therapy modifications at home that may promote hyperglycemia and the associated risk of developing micro- and macrovascular complications of diabetes.
3.3
Advanced glycation end products
Chronic hyperglycemia may cause the formation of advanced glycation end products, associated cross-linking of collagen molecules, and increased myocardial stiffness and fibrosis. This may contribute to the development of diabetic cardiomyopathy [ , ].
3.4
Inflammation and endothelial dysfunction
Diabetes is associated with chronic low-level inflammation and endothelial dysfunction. Hyperglycemia and insulin resistance may promote vascular smooth muscle cell proliferation, leukocyte adhesion, and thrombosis, which may accelerate the development of atherosclerosis and increase the risk of developing coronary artery disease. Longer duration of diabetes and higher insulin doses may further increase this risk [ ]. Nonglycemic factors that also contribute to this risk include male sex, elevated levels of LDL, hypertension, and obesity [ ].
The most common method to assess early subclinical manifestations of vascular disease is the use of surrogate markers such as carotid intima-media thickness, pulse wave velocity to evaluate arterial stiffening, and flow-mediated dilation to assess endothelial dysfunction [ ]. Studies have demonstrated increased carotid media thickness and early atherosclerosis changes, such as fatty streaks, in children with type 1 diabetes [ ].
3.5
Dyslipidemia
Diabetic patients may have atherogenic dyslipidemia, characterized by elevated levels of small, dense, low-density lipoprotein (LDL) particles, which may be susceptible to oxidation and contribute to plaque formation and instability [ ]. Increased LDL level, decreased high-density lipoprotein level, and hypertriglyceridemia also may increase the risk of developing coronary artery disease [ ]. Although elevated LDL level is an independent predictive factor for major cardiovascular events, lower LDL levels may be observed in patients with improved glycemic control [ ]. Insulin deficiency may cause increased very low-density lipoprotein level and hypertriglyceridemia because of decreased lipoprotein lipase activation. In addition, quantitative, qualitative, and functional abnormalities in lipoprotein levels may occur in patients with diabetes despite good glycemic control. The American Diabetes Association recommends a goal of LDL level <100 mg/dL in children and adolescents with type 1 or type 2 diabetes to decrease cardiovascular risk [ ]. The first-line therapy for dyslipidemia in children and adolescents is lifestyle modification. Statin therapy may be indicated in type 1 diabetes when lifestyle modification fails and the LDL level ranges from 130 to 159 mg/dL [ ].
3.6
Renin-angiotensin-aldosterone system activation
Hyperglycemia activates the renin-angiotensin-aldosterone system, which causes increased production of angiotensin II and aldosterone. This promotes cardiac hypertrophy, fibrosis, and diastolic dysfunction [ ].
3.7
Obesity
Obesity is a major cardiovascular risk factor for diabetes because of several interrelated mechanisms. Excess adiposity, especially visceral fat, contributes to insulin resistance, which is a key element in the pathophysiology of type 2 diabetes. Insulin resistance may cause hyperinsulinemia, which is associated with several cardiovascular risk factors, including hypertension, dyslipidemia, and systemic inflammation [ , ].
In recent decades, the prevalence of obesity has increased in children and adolescents, including patients with type 1 diabetes [ ]. Abdominal obesity is independently associated with increased cardiovascular risk, including coronary heart disease and stroke. The proinflammatory state and dysregulated adipokine secretion observed in obesity, with decreased adiponectin and increased leptin levels, may exacerbate endothelial dysfunction and atherogenesis [ , ]. Prospective studies have shown a direct correlation between body mass index and risk of death from CVD [ ].
3.8
Hypertension
Hypertension is a major cardiovascular risk factor in patients with diabetes, contributing to the development and progression of macrovascular complications such as coronary heart disease, cerebrovascular disease, and peripheral artery disease. The coexistence of hypertension and diabetes may markedly increase the risk of developing CVD because of common pathophysiologic mechanisms such as endothelial dysfunction, vascular inflammation, and accelerated atherosclerosis [ , ]. Adequate blood pressure control in diabetic patients is important in decreasing the risk of developing these complications [ ].
4
Macro- and microvascular complications
Diabetes may be associated with macrovascular complications such as premature atherosclerosis and diabetic cardiomyopathy, and microvascular complications such as diabetic retinopathy, nephropathy, and neuropathy [ ]. Although microvascular complications cause marked morbidity, macrovascular complications are the leading cause of death in patients with diabetes. Major cardiovascular risk in diabetes may occur secondary to endothelial dysfunction and microvascular end-organ damage [ ].
4.1
Macrovascular complications
4.1.1
Coronary heart disease
Type 1 and type 2 diabetes may markedly increase the risk of developing coronary heart disease because of associated inflammation, endothelial dysfunction, and accelerated atherosclerosis ( Fig. 2 ). Accelerated pathophysiology may be attributed to hyperglycemia, insulin resistance, and associated dyslipidemia and hypertension [ ].
4.1.2
Peripheral artery disease
Diabetes is a major risk factor for the development of peripheral artery disease. Complicated peripheral artery disease may cause claudication, critical limb ischemia, and gangrene treated with amputation. Peripheral artery disease is caused by atherosclerosis and microvascular dysfunction, which may cause decreased blood flow to the lower limbs [ , ]. Studies show that children with poorly controlled type 1 diabetes may develop signs of peripheral artery disease early in life [ ].
4.1.3
Diabetic cardiomyopathy
Diabetic cardiomyopathy is characterized by structural and functional changes in the myocardium, independent of coronary artery disease, including left ventricular hypertrophy, fibrosis, and diastolic dysfunction associated with hyperglycemia, oxidative stress, and inflammation [ , ].
4.2
Microvascular complications
4.2.1
Diabetic retinopathy
Diabetic retinopathy may occur with chronic hyperglycemia, which may activate the polyol pathway and cause endothelial dysfunction, increased vascular permeability, and microvascular occlusion. Oxidative stress from increased reactive oxygen species also may cause cellular and tissue damage [ ], resulting in impaired visual acuity. Diabetic retinopathy occurs in 3.7 % to 6 % of patients with type 1 and 9.1 % to 50 % of patients with type 2 diabetes. Improvement in glycemic control with the use of novel technologies such as insulin pumps and continuous glucose monitors plays a protective role against the development of diabetic retinopathy [ ].
4.2.2
Diabetic kidney disease
Diabetic nephropathy is an independent risk factor for cardiovascular morbidity and mortality [ ]. Hyperglycemia, reactive oxygen species, activation of alternative glucose metabolic pathways, and marked inflammation may result in fibrosis, increased vascular permeability, podocytopathy, and albuminuria. Albuminuria is associated with a 2- to 4-fold greater risk of developing CVD and death. Increases in urinary albumin-to-creatinine ratio may occur at 1 year after the diagnosis of diabetes [ ]. Furthermore, proteinuria and chronic tubular injury are enhanced in the presence of concomitant systemic and intraglomerular hypertension [ ]. Treatment with angiotensin-converting enzyme inhibitors may be indicated in children and adolescents who have microalbuminuria and may decrease the incidence of diabetic nephropathy [ ].
5
Effects of diabetes medications in cardiovascular disease
Pharmacologic therapeutic options for children and adolescents with diabetes have different indications and mechanisms of action ( Table 1 ) [ ].
| Medication | Class | Pediatric indications | Effects a | References |
|---|---|---|---|---|
| Insulin | Hormone | Type 1 diabetes Type 2 diabetes | ↓ Glucose level ↓ Hemoglobin A 1c level | [ , , ] |
| Metformin | Biguanide | Type 2 diabetes Obesity Polycystic ovary syndrome | ↓ Blood pressure ↓ Body mass index ↓ Hemoglobin A 1c level ↓ Insulin resistance ↑ β-cell function | [ , , ]] |
| Liraglutide | GLP-1 analog | Type 2 diabetes | ↓ Body weight ↓ Glucose level ↓ Hemoglobin A 1c level ↓ Systolic blood pressure | [ , ] |
| Exenatide | GLP-1 analog | Type 2 diabetes Obesity | ↓ Body mass index ↓ DDP-4 level ↓ Fasting plasma glucose level | [ , , ] |
| Linagliptin | DDP-4 inhibitor | Type 2 diabetes | ↓ Fasting plasma glucose level ↓ Hemoglobin A 1c level | [ , , , ] |
| Dapagliflozin | SGLT2 inhibitor | Type 2 diabetes | ↓ Glucose level ↓ Hemoglobin A 1c level ↓ Proteinuria ↑ Left ventricular ejection fraction | [ , , , , ] |
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