Cardiovascular disease risk in youth with diabetes mellitus
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- Wadwa, R.P. Rev Endocr Metab Disord (2006) 7: 197. doi:10.1007/s11154-006-9016-y
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In the United States, cardiovascular disease is the leading cause of mortality in adults with diabetes over age 30 years. Studies in persons without diabetes have shown that atherosclerosis, a central factor in cardiovascular disease, begins in childhood and the presence of cardiovascular disease risk factors in youth lead to increased cardiovascular disease risk in adults. Therefore, youth with diabetes are at increased risk for developing cardiovascular disease as adults and there is a role for risk factor screening and addressing modifiable factors to lower cardiovascular disease risk starting in childhood. This paper reviews the literature on traditional cardiovascular disease risk factors in youth with diabetes including hyperglycemia, hypertension, dyslipidemia, smoking, obesity and family history of cardiovascular disease with an emphasis on type 1 diabetes as well as current American Diabetes Association guidelines for screening and treatment of modifiable risk factors. Current roles of inflammatory markers and measures of subclinical vascular changes such as arterial stiffness are also discussed.
KeywordsAtherosclerosisCardiovascular diseaseDiabetes mellitusPediatric
Cardiovascular disease (CVD) is the leading cause of mortality in adults with diabetes mellitus in the United States [1–3]. The incidence of coronary artery disease (CAD) is approximately 1–2% per year among asymptomatic adults with type 1 diabetes (T1DM) [4, 5]. By age 55, 35% of T1DM patients die of CAD, in contrast to only 8% of non-diabetic men and 4% of women . Recent advances have been successful in decreasing morbidity and mortality from retinopathy, nephropathy and neuropathy of diabetes but mortality over the past 40 years due to CVD in patients with diabetes has not had a similar decrease .
There is strong evidence from autopsy studies indicating that atherosclerosis, a central factor in CVD, begins in childhood [8, 9]. In addition, studies from the Bogalusa Heart Study, Muscatine Study and Young Finns Study measuring carotid intimal-medial thickness (IMT), a predictor of CVD in adults, document tracking of CVD risk factors in youth leading to increased CVD risk in adulthood [10–12]. Children and adolescents with diabetes mellitus are at increased risk for cardiovascular disease in later life. Studies of adults with childhood onset T1DM document that atherosclerosis occurs earlier in life, is more diffuse [13, 14], leads to higher case fatality [15, 16], higher cardiac failure  and shorter survival [18–20], compared to the general population. Women with T1DM are affected as often as men and are 9–29 times more likely to die of CAD than non-diabetic women; the risk for men is increased four- to nine-fold [1, 6, 21, 22].
As the prevalence of obesity, insulin resistance and type 2 diabetes (T2DM) in adolescents appears to be rising in the last several years, there is growing concern for CVD in those diagnosed with T2DM as adolescents as well. Studies are now emerging suggesting increased risk for CVD in these youth, potentially even higher than similar aged youth with T1DM [23, 24].
This article will review traditional CVD risk factors and discuss more novel factors such as inflammation as well as surrogate markers for early identification of increased CVD risk in children and adolescents with T1DM and T2DM. Because T1DM is much more common in youth than T2DM, a majority of this article will focus on CVD risk in children and adolescents with T1DM. However, several factors put youth with T2DM at potentially increased risk for CVD compared to youth with T1DM and these factors will be discussed as well. A discussion of CVD risk for youth with other types of diabetes (such as MODY, cystic fibrosis related diabetes, iatrogenic diabetes mellitus) is important but beyond the scope of this paper.
2 Type 1 diabetes
2.1 Glycemic control
The relationship between glycemic control and microvascular complications has been well documented, most notably from the Diabetes Control and Complications Trial (DCCT) . Findings from the Epidemiology of Diabetes Interventions and Complications (EDIC) study have shown that glycemic control is also an important factor for the risk of CVD events in adults [26, 27]. In EDIC, the group that received conventional diabetes therapy and had a higher average HbA1c during the DCCT had a significantly increased risk of CVD events compared to the group on intensive therapy and with a lower mean HbA1c. In addition to highlighting the importance of good glycemic control to reduce CVD risk, this study raises the issue of glycemic control during adolescence affecting risk for CVD events in adulthood. Further studies will be necessary to determine the long term effects of glycemic control during childhood and adolescence.
Evidence from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study also suggests a link between better blood sugar control and lower risk of coronary disease . This study examined progression of coronary artery calcification, a marker of subclinical coronary atherosclerosis in young adults with T1DM as well as a similar group of non-diabetic control subjects. In an analysis of 109 adults with T1DM, the odds of having progression of coronary calcification were seven times higher for subjects with HbA1c over 7.5% compared to subjects with HbA1c less than 7.5% (odds ratio 7.11 in multivariate logistic regression model).
A meta-analysis of randomized, controlled comparison studies including 1,800 T1DM and 4,472 T2DM adults identified a reduction in macrovascular events with improvements in glycemic control for both T1DM and T2DM patients . The report suggests a larger reduction in macrovascular risk in T1DM and a smaller reduction of risk in T2DM with improved glycemic control.
Pediatric studies using surrogate markers of vascular disease have not identified similar associations of glycemic control with carotid IMT or arterial stiffness [24, 30, 31]. These studies were smaller than the previously mentioned adult studies and glycemic control was not a primary focus of these articles. This discrepancy suggests that the effects of glycemic control make take several years before vascular changes are detectable with currently available instruments.
Goals for glycemic control in youth with T1DM have been recently updated by the American Diabetes Association (ADA) . HbA1c targets are now: less than 7.5% for adolescents aged 13–18 years; less than 8% for children 6–12 years old and 7.5–8.5% for children under 6 years old. As the technology to care for diabetes improves and more patients are able to attain these goals, there is potential for decreased microvascular and macrovascular diabetes complications.
2.2 Blood pressure
Hypertension is known to be an important factor for cardiovascular disease risk and management of blood pressure has been shown to reduce CVD risk in adults [33, 34]. Screening for hypertension in youth with diabetes is essential in decreasing risk for both microvascular and macrovascular disease later in life .
Several studies have found that hypertension in persons with diabetes is under-diagnosed and under-treated. Saydah et al. reported less than 36% of diabetic adults over 20 years old participating in NHANES III (1988–1994) or NHANES 1999–2000 achieved systolic blood pressure less than 130 mmHg and diastolic blood pressure less than 80 mmHg . In the CACTI study, blood pressure data for 652 young adults with T1DM (mean age 37 years) and 764 non-diabetic control subjects (mean age 39 years) were analyzed. While T1DM subjects were more likely to have hypertension (43% in T1DM vs. 15% in non-diabetic subjects, p < 0.001), they were more aggressively treated with medications (87% of T1DM subjects with hypertension vs. 47% in non-diabetic controls with hypertension, p < 0.0001) . Rodriguez and colleagues reported on the prevalence of hypertension in 3–19 year old youth with diabetes . Hypertension was defined as systolic or diastolic blood pressure over the 90th percentile for age, sex and height  or use of medication for high blood pressure. In 2,096 youth with diabetes, 573 (27%) had hypertension. While 22% of the 1,376 youth with confirmed T1A diabetes had hypertension, 73% of the 63 youth with T2DM diabetes had hypertension. No significant difference in the presence of hypertension was seen by sex (26% of females, vs. 29% of males). Schwab et al. reported lower rates of hypertension (8.1% systolic hypertension, 2.5% diastolic hypertension) in a large cohort of over 27,000 T1DM subjects in Germany and Austria under age 26 years but similar rates of treatment with medication (2.1% of cohort) . In this cohort, significantly more males than females were found to be hypertensive (p < 0.001). Most subjects on antihypertensive medications were treated with ACE inhibitors (83%).
The ADA guidelines recommend determination of a child’s blood pressure at each diabetes care visit for detection of hypertension and also to look for upward trends in blood pressure which may merit further investigation. The family history should also be reviewed . Using data from 1999 to 2000 NHANES, blood pressure tables with 50th, 90th, 95th and 99th percentiles by age, sex and height are available . A child is considered to have hypertension if systolic or diastolic blood pressure is ≥95th percentile on repeated measurements. Levels between the 90th and 95th percentile are considered “prehypertensive” .
If hypertension is documented, evaluation of the child should include updating parental history for hypertension, lab exam of renal function (urinalysis, serum creatinine and blood urea nitrogen) and urinary albumin excretion. The recommended treatment for hypertension in youth with diabetes initially is elimination of added salt in the diet and encouragement to exercise if the child is sedentary . Pharmacological therapy is indicated if lifestyle intervention does not lead to adequate blood pressure improvement in 3–6 months in children with blood pressure consistently over the 95th percentile. There is evidence supporting the use of ACE inhibitors for treatment of hypertension to decrease CVD risk in adults [33, 34]. There are also data to support the use of ACE inhibitors in the presence of albuminuria to slow the rate of decline in renal function and decrease progression of retinopathy in diabetic adults [39, 40]. ACE inhibitors have been proven to be safe in children and are recommended with the diagnosis of hypertension or albuminuria in youth with diabetes. Because ACE inhibitors are contraindicated in pregnancy, this factor must be considered in the care of post-pubertal females. Angiotensin receptor blockers have been used in adults with diabetes , however, there are no data available for the use of these agents in children with diabetes at this time.
Ambulatory blood pressure monitoring (ABPM) has been used to detect hypertension in diabetic and non-diabetic youth and protocols for pediatric use have been published [42, 43]. However, the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents recommends clinical use of ABPM only by hypertension experts with experience in the use and interpretation of ABPM .
Dyslipidemia is a major risk factor for atherosclerosis and CVD. Although lipid levels in patients with T1DM have been found to be comparable to or better than in non-diabetic adults , adults with T1DM are known to be at higher risk for atherosclerotic disease compared to the general population . Some data suggest that lipids in those with diabetes may be more atherogenic. Possible mechanisms for this include differences in lipoprotein particle size; LDL oxidation; and increased transvascular LDL transport in patients with type 1 diabetes [47–49].
Lipid levels in childhood may also have a significant impact on CVD risk in adulthood. In the Bogalusa Heart Study and Young Finns Study, childhood LDL levels were significantly associated with carotid IMT in non-diabetic young adults (p < 0.001 and p = 0.001, respectively) [11, 12].
There is evidence that abnormal lipid levels are present in youth with diabetes. A retrospective analysis at the Barbara Davis Center revealed 28% of 682 youth (under 21 years old) with T1DM had at least one non-HDL level above 130 mg/dl, 15% had total cholesterol over 200 mg/dl and 3% with HDL less than 35 mg/dl . LDL levels were not examined as fasting status could not be verified in this retrospective analysis. In the SEARCH for Diabetes in Youth (SEARCH) study, fasting lipids were examined in 2,165 youth with T1DM and 283 youth with T2DM. Of the T1DM youth, 3% had LDL levels >160 mg/dl, 14% >130 mg/dl and almost half (48%) had LDL levels over the threshold for recommended LDL of 100 mg/dl . Of the 1,680 youth with T1DM over 10 years old, 242 had LDL levels over 130 mg/dl and only 23 were on lipid lowering medications at the time of the study. The ADA recommends consideration of pharmacologic treatment for LDL over 130 mg/dl for children over 10 years old if lifestyle modification has not yielded adequate improvement in lipid levels [32, 52]. Findings from these studies indicate that current clinical screening and treatment of lipid abnormalities in T1DM youth in the United States is below recommended ADA standards.
In the cohort from Germany and Austria, Schwab documented the presence of dyslipidemia (defined as total cholesterol >200 mg/dl, LDL > 130 mg/d or HDL < 35 mg/dl) in 28.6% of T1DM subjects under 26 years old, with a larger percentage (34.2%) in the 17–26 year old age group. Only 0.4% of all subjects were on lipid lowering medications with 0.8% of 17–26 year olds on lipid-lowering medications .
The ADA recommends screening of lipid levels in youth with T1DM at 12 years of age and every 5 years thereafter [32, 52]. In youth with a positive or unknown family history of dyslipidemia or CVD, screening should begin after 2 years of age (once glycemic control is obtained). In youth with T2DM, screening of lipids is recommended at diagnosis once glycemic control is obtained and every 2 years if initial values are normal . Treatment options should begin with decreasing saturated and total fat in the diet, maximizing glycemic control, and weight reduction when indicated. Thresholds for use of lipid lowering medications have been based on extrapolation from adult data and expert opinion. Treatment with medication is recommended for children over age 10 years for LDL > 160 mg/dl or LDL > 130 mg/dl if not improved with lifestyle changes and significant CVD risk is present. While bile acid sequestrants or ‘resins’ have been considered first line therapy, compliance with this class of medications is known to be low and HMG-CoA reductase inhibitors or ‘statins’ are more commonly used. Importantly, statins are contraindicated in pregnancy. Ezetimibe is a relatively new medication which offers the option of using a class of medication with a different mechanism and site of action for LDL lowering . While the safety and efficacy of statins has been documented in studies in youth with familial hypercholesteremia , studies in youth with diabetes for the efficacy of statins and ezetimibe are lacking at this time. For lowering of triglycerides, diet and glycemic control are recommended unless triglycerides are over 1,000 mg/dl, in which case, the child is at increased risk for pancreatitis and fibric acid derivatives should be considered . While the most recent dietary guidelines from the American Heart Association mention the benefits of fish oils in the diet and the use of plant stanols/sterols , there are no current guidelines for diabetic youth from the ADA regarding these options which gave gained recent popularity.
2.4 Family history
While the identification of modifiable risk factors at any age is important, there are certainly genetic factors involved that should be considered. A family history should be obtained on initial history and updated regularly to identify families that may be at increased CVD risk. The presence of hypertension, known CAD, dyslipidemia or T2DM in the family history increases the child’s risk for developing CVD as an adult [52, 56, 57]. A positive family history for CAD is one that includes a first degree relative with myocardial infarction at or prior to the age of 55 years. After obtaining an initial family history, reassessment at regular intervals is important as the potential for CVD risk factors to develop in parents and grandparents increases over time [32, 58].
Lifestyle modification is the cornerstone of therapy to reduce the risk of CVD in youth with diabetes. Interventions include modification of diet to reduce sodium or fat intake, exercise, and when applicable, weight reduction and smoking cessation.
The ADA recommends individualized meal planning with the help of dieticians experienced in pediatric nutrition and diabetes. The diet for youth with diabetes should follow nutrition recommendations for all children and adolescents [55, 59] with the goals of achieving optimal glycemic control without excessive hypoglycemia, as well as meeting blood pressure and lipid goals . In youth with dyslipidemia, adherence to ADA guidelines for total and saturated fat intake is important for improving control of lipid levels . Not surprisingly, recently published data from the SEARCH study indicate that most youth with both T1DM and T2DM consume an excessive amount of total and saturated fats while consuming inadequate amounts of fruits and vegetables .
Exercise for youth with and without diabetes is known to have benefits for physical fitness, cardiovascular fitness and a sense of well-being that may have further benefits. The ADA recommends youth with diabetes comply with the same guidelines as non-diabetic youth, 30–60 min of physical activity on a daily basis as recommended by the CDC . In youth with T1DM, physical fitness is associated with increased insulin sensitivity, improved blood pressure and lipid levels [61, 62]. While there are currently little published data on the benefits of exercise in youth with T2DM, the TODAY study is currently investigating this issue.
Smoking significantly increases the risk of CVD in non-diabetics and raises the already higher risk of CVD in those with diabetes. Evidence from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study indicates smoking accelerates coronary atherosclerosis as early as adolescence . The ADA position statement and technical review on smoking document the importance of abstaining from smoking [64, 65]. For adolescents, routine diabetes care should include a discussion of the risks of cigarette and tobacco use .
Inflammation is now known to be a key component for the development of atheroma. In the last few years, mechanisms related to immune system involvement in atherosclerosis have become more clear [66, 67]. Proinflammatory markers C-reactive protein (CRP) and interleukin-6 have been shown to indicate worse prognosis in adults with unstable angina and myocardial infarction [68–70]. More data on markers including adiponectin, E-selectin and soluble IL-2 receptor in diabetic individuals have become available from clinical research studies associating these markers with clinical and subclinical coronary disease [71–73]. Studies in T1DM youth have not shown a significant difference in CRP, IL-6 and metalloproteinase-9 compared to non-diabetic youth [31, 74]. As the role of inflammation in the atherosclerotic process continues to be clarified, potential opportunities for screening of markers for inflammation and possible interventions may emerge in the future. At this time, however, there is no current role for markers of inflammation in the clinical evaluation of children with diabetes for assessing cardiovascular risk.
3 Surrogate measures of cardiovascular disease risk
Studies to assess CVD in adults have examined risk factors associated with CVD events. To assess CVD risk in youth using CVD events as an outcome measure would take decades and is not practical. Therefore surrogate markers to assess cardiovascular health have been used. Instruments including carotid ultrasound to assess carotid IMT, measures of vascular stiffness and endothelial function have been essential to study early vascular changes associated with future CVD . Several studies noted above have used such instruments to assess CVD risk in youth and young adults with diabetes [10–12, 24, 28, 30, 31, 71, 74, 76–78]. Similar to the assessment of inflammatory markers, surrogate measures of cardiovascular health such as carotid IMT, arterial stiffness and flow mediated arterial dilatation studies have a role in research but clinical use of such measures to guide the care of youth is not recommended at this time. As technology continues to evolve, there may be a role in the future for non-invasive measures of vascular function in the outpatient clinical setting. However, at this time, the assessment of CVD risk should continue to focus on known factors with clinical evidence and guidelines for evaluation and treatment in youth.
4 Type 2 Diabetes
Recent studies have documented a higher prevalence of CVD risk factors in youth with T2DM compared to youth with T1DM. Data from the SEARCH study have documented abnormalities of blood pressure, lipids, albuminuria and arterial stiffness that point to an even higher risk for CVD in youth with T2DM compared to those with T1DM [23, 24, 51, 82]. Similarly, Eppens and colleagues reported an increased rate of hypertension and albuminuria in adolescents with T2DM compared to similar aged youth with T1DM despite shorter duration of diabetes and lower HbA1c .
In addition to the presence of documented risk factors after diagnosis of T2DM, these youth may have risk factors related to obesity and insulin resistance prior to the development of T2DM. With pre-existing risk factors, atherogensis may begin years prior to diagnosis of diabetes in this population. Given the potential for pre-exisitng comorbidities, screening for hypertension, dyslipidemia, albuminuria and sleep apnea are recommended soon after the diagnosis of T2DM in youth [52, 84].
Studies of youth with T2DM and those at risk for developing T2DM are now shedding more light on the pathophysiology in this population [85, 86]. Further work from multi-center studies including larger numbers of youth with T2DM such as SEARCH, STOPP-T2D and TODAY may also help to clarify the mechanisms leading to increased risk for CVD in this population.
Cardiovascular disease is the leading cause of mortality in adults with diabetes over the age of 30 and adults with diabetes are at significantly higher risk for CVD compared to non-diabetics. Data from several studies indicate that atherosclerosis begins in childhood. Most recently studies of youth with diabetes indicate worse carotid IMT and arterial stiffness compared to similar age non-diabetic youth. Risk factors for CVD include poor glycemic control, hypertension, dyslipidemia and possibly increased inflammation. Youth with T2DM appear to be at even higher risk for future CVD compared to youth with T1DM. However, further studies in youth with diabetes are necessary to clarify the mechanisms leading to higher rates of CVD in individuals with diabetes and potential avenues for primary prevention beginning in childhood to decrease morbidity and mortality related to CVD.
6 Key unanswered questions in this field include the following:
How should screening and intervention for known CVD risk factors in diabetic youth be modified to lower future CVD?
What non-traditional areas such as inflammation merit further investigation for screening and perhaps intervention to decreased CVD risk?
What surrogate markers are optimal to study CVD risk and identify modifiable factors for future intervention?
Given the increased risk in youth with T2DM, how should screening for CVD risk factors and intervention in this population be modified?