11. Diabetes Mellitus and Other Conditions Predisposing to the Development of Accelerated Atherosclerosis

INTRODUCTION

This section of the Guidelines provides recommendations for pediatric care providers on managing cardiovascular (CV) risk factors in children and adolescents with diabetes mellitus and other conditions that predispose them to accelerated atherosclerosis. The evidence review did not address management of hyperglycemia, and this is not addressed in the recommendations. The section begins with background information on the importance of diabetes as a risk factor for CV disease (CVD). This is followed by the Expert Panel's summary of the evidence review relative to diabetes, separated for type 1 and type 2 diabetes mellitus, and then by a subsection on other predisposing conditions. The evidence review and the development process for the Guidelines are outlined in the Section I. Introduction and are described in detail in Appendix A. Methodology. As described, the evidence review augments a standard systematic review, where the findings from the studies reviewed constitute the only basis for recommendations, with each study described in detail. This evidence review combines a systematic review with an Expert Panel consensus process that incorporates and grades the quality of all relevant evidence based on preidentified criteria. Because of the diverse nature of the evidence, the Expert Panel provides a critical overview of the studies reviewed for each risk factor. Detailed information from each study has been extracted into the evidence tables, which will be available at http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm. Following its review of the limited available evidence for this subject, the Expert Panel elected to employ expert opinion by expanding on the recommendations of the 2006 guidelines from the American Heart Association (AHA),^[1] which addressed CV risk management in high-risk pediatric patients, including those with diabetes. This approach is described in detail in this section, relative to the management of other conditions predisposing to the development of accelerated atherosclerosis. References are listed sequentially at the end of the section, with references from the evidence review identified by unique PubMed identifier (PMID) number in bold text. Additional references do not include the PMID number.

BACKGROUND

Diabetes mellitus is an established risk factor for early CVD. Metabolically, diabetes is characterized by hyperglycemia due to defects in insulin secretion (type 1 diabetes mellitus (T1DM)) and insulin function and/or secretion (type 2 diabetes mellitus (T2DM)). Both T1DM and T2DM are associated with vascular disease.^[2],[3],[4] Autopsy and noninvasive imaging studies suggest that the extent of vascular involvement may reflect the duration of the disease and the severity of the chronic metabolic derangement.^{[5],[6],[7],[8],[9],[10]}  The epidemiologies of the two types differ significantly. T1DM presents at a younger age, with 25 percent of patients diagnosed between ages 5 and 10 years and another 40 percent between ages 10 and 15 years. If not treated adequately, the degree of hyperglycemia is severe, and patients are highly symptomatic. By contrast, in T2DM, the majority of patients present in adult life, but a small and growing number present in adolescence, and most are relatively asymptomatic, with only mild to moderate hyperglycemia in combination with obesity.^[11],[12]

OVERVIEW OF THE EVIDENCE FOR TYPE 1 DIABETES MELLITUS

In adults with T1DM, clinical heart disease, cerebrovascular disease, and peripheral vascular disease represent the most common causes of morbidity and mortality.^[13]  Children with T1DM have been shown to have pathologic vascular changes in the form of microangiopathy in the eye and the kidney and subclinical evidence of atherosclerosis, with increased carotid intima-media thickness, reduced endothelium-dependent arterial flow-mediated dilation (FMD), and increased arterial stiffness.^{[10],[14],[15],[16],[17],[18]} Recent studies of youth with T1DM demonstrate that between one-fourth and three-fourths of subjects have at least one CV risk factor.^[19],[20] Unfortunately, few are prescribed treatment directed at these abnormalities.^[21] Although obesity appears to be related to CV risk in T1DM patients, hyperglycemia drives the production of advanced glycolation end products, which are the primary mediators of the vascular process.^[22],[23]  The Diabetes Control and Complications Trial in T1DM patients aged 13–39 years found that intensive glycemia control reduced microvascular outcomes and, in an observational followup period, found lower rates of CVD events in those previously treated intensively for glycemia.^[24],[25] Therefore, glucose management should be intensive in T1DM, under the care of an endocrine specialist. In evaluating the risk for CVD in adults, the presence of diabetes is considered to be the equivalent of a history of coronary disease.^[26]  Management of other risk factors related to T1DM should be aggressive, with the cut points marking effective therapy mandating intensive risk reduction.^[27]

The evidence review for these Guidelines was designed to identify systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies from selected large longitudinal cohorts. The evidence review identified only two RCTs relevant to T1DM that met the inclusion criterion of having CV outcomes. A randomized crossover trial in a small number of children with T1DM showed a decline in diastolic blood pressure during sleep with melatonin therapy.^[28]  The authors propose that melatonin be considered in trials to prevent the development of hypertension in individuals with T1DM. In children with T1DM, administration of folate and vitamin B6 each led to immediate normalization of FMD, which was sustained at 8-week followup.^[29]  Findings suggest that, in the setting of T1DM with a high risk for vascular disease, folate and B6 therapy could be beneficial, but the findings in these two trials have not been duplicated.

OVERVIEW OF THE EVIDENCE FOR TYPE 2 DIABETES MELLITUS

The incidence of T2DM has increased in parallel with the increased incidence of obesity.^[11],[12] The highest prevalence of T2DM is seen in certain racial/ethnic groups, specifically Native Americans, Hispanics, African Americans, Asians, and Pacific Islanders. The hallmark of T2DM is insulin resistance, which is strongly associated with obesity.^[30] Among obese adolescents, insulin resistance has been reported in 16 percent of Caucasians, 27 percent of African Americans, and 26 percent of Hispanics. Although type 2 diabetes is widely diagnosed in adults, its frequency has markedly increased in the pediatric age group over the past two decades. Depending on the population studied, type 2 diabetes now represents 8–45 percent of all new cases of diabetes reported among children and adolescents.^[31] Typically, children with T2DM are overweight or obese, are members of a high-risk racial/ethnic group, and have a positive family history of T2DM. Current guidelines from the American Diabetes Association (ADA) recommend routine testing for T2DM in high-risk children starting at age 10 years, as shown in Table 11–1.^[32]

Table 11–1. ADA Screening Recommendations for Type 2 Diabetes Mellitus (T2DM) in Childhood

Criteria:

• Overweight, defined by:
  • BMI > 85th percentile for age and sex, or
  • Weight for height > 85th percentile, or
  • Weight > 120% of ideal for height

Plus any two of the following risk factors:

• Family history of type 2 diabetes in first- or second-degree relative
• Race/ethnicity (Native American, African–American, Latino, Asian–American, Pacific Islander)
• Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome)

Screening procedure:

Age of initiation:

 ≥10 years, or at onset of puberty, if puberty occurs at a younger age

Frequency:

Every 2 years

Test:

Fasting plasma glucose

Patients with T2DM are at risk for accelerated atherosclerosis because of hyperinsulinemia and hyperglycemia and because of the strong association between T2DM and other major risk factors for CVD, including obesity, hypertension, and dyslipidemia.^{[31],[33],[34],[35],[36]}  As with T1DM, control of hyperglycemia in T2DM is mandatory and should be in a setting where consultation with an endocrine specialist is possible if needed. No recommendations for managing hyperglycemia are provided here. Aggressive management of associated CV risk factors has been shown to improve vascular outcomes.^{[37],[38],[39]}  On the other hand, aggressive control of glycemia in T2DM has not been shown to reduce CVD events in adults with well-established and long-duration disease.^{[40],[41],[42],[43]}  In evaluating the risk for CVD in adults, the presence of diabetes is considered to be the equivalent of a history of coronary disease.^[26]

The evidence review for these Guidelines identified only two studies relevant to CV risk reduction in children or adolescents with T2DM . A single systematic review addressing community-based lifestyle interventions to prevent T2DM in children included eight studies published between 1990 and 2001.^[44]  The interventions were all set in high-risk populations, and design problems included the absence of comparison groups and brief intervention periods. On short-term followup, results indicated improvements only in knowledge and preventive behaviors. An RCT of metformin in children with T2DM showed significant improvements in glycemic control with medication at up to 16-week followup.^[45]

OVERVIEW OF THE EVIDENCE REVIEW FOR OTHER PREDISPOSING CONDITIONS

In certain pediatric disease states, the process of atherosclerosis is dramatically accelerated, with clinical coronary events occurring in childhood and in early adulthood. Probably the best example of this is homozygous familial hypercholesterolemia, an extremely rare condition in which low-density lipoprotein cholesterol (LDL–C) levels are markedly elevated from birth due to the absence or near absence of functional hepatic LDL receptors. In this diagnosis, clinical coronary events begin in the first decade of life, and aggressive lipid management is needed. For these Guidelines, management of hypercholesterolemia is described in Section IX. Lipids and Lipoproteins. Diabetes, another high-risk diagnosis, is addressed above, but there are other conditions in which the risk of accelerated atherosclerosis is known to be high, that are not necessarily identified in a risk factor-based evidence review such as the one preformed for these Guidelines.

The Expert Panel recognized the importance of reviewing the evidence for these conditions so that appropriate recommendations could be made to guide pediatric practice. A separate category was created as part of the evidence review that identified potential relevant diagnoses and included Kawasaki disease, postorthotopic heart transplant, chronic kidney disease, nephrotic syndrome, human immunodeficiency virus (HIV) infection, and chronic inflammatory disease—all of which may increase the risk for early atherosclerosis and may require more aggressive control of CV risk factors. Although data exist demonstrating a higher prevalence of early CVD and CV risk factors in conditions such as these, the evidence review for these Guidelines was designed to identify high-level studies, including systematic reviews, meta-analyses, RCTs, and observational studies from selected large longitudinal cohorts.^[46],[47]  Given the relatively small number of children with these diagnoses and the early stage of knowledge in this area, it is not surprising that the evidence review identified only three relevant RCTs, all in patients with chronic kidney disease.

In the first of these, a small number of children with advanced chronic kidney disease were treated with folic acid and placebo, and red cell folate levels, homocysteine levels, and FMD were compared.^[48]  On folic acid treatment, red cell folate levels increased, homocysteine levels decreased, and FMD improved significantly. A second similar trial of oral L-arginine from the same investigators showed no improvement in FMD.^[49]  Finally, a protein restriction trial was shown to result in higher polyunsaturated/saturated fat ratios in the diets of children with chronic kidney disease, with an associated decrease in total and LDL–C compared with a control group on a normal diet.^[50]  These studies support the concept that risk factors can be changed and that arterial function can be improved in patients with chronic kidney disease.

CONCLUSIONS OF THE EVIDENCE REVIEW FOR DIABETES AND OTHER PREDISPOSING CONDITIONS

Children with T1DM or T2DM represent the prototype of the child at special risk for accelerated atherosclerosis and early clinical CVD. To maximize identification of T2DM in childhood and adolescence, the ADA screening algorithm is recommended for screening in all children (see Table 11–1).

A very limited number of high-quality studies were found addressing CV risk reduction in children with conditions predisposing them to accelerated atherosclerosis, including diabetes mellitus, which is insufficient for development of evidence-based recommendations. The Expert Panel therefore elected to modify the recommendations of an expert pediatric panel convened by the AHA that published its recommendations for risk factor management in children with these conditions in 2006, after an extensive conventional literature search; these recommendations are endorsed by the American Academy of Pediatrics and are included in the database for these Guidelines.^[1]  These recommendations therefore represent the expert consensus of the Panel (Grade D).

The AHA statement recommends specific risk identification and management stratified by risk based on defined conditions that parallel the recommendations for adults with diabetes or other CVD equivalents (see Table 11–2). For the high-risk category, the disease process has been associated with clinical coronary disease before age 30 years. For the moderate-risk category, the disease process has been shown to be associated with pathologic, physiologic, or subclinical evidence of accelerated atherosclerosis.

The Expert Panel believes that these recommendations should be used for the management of children and adolescents with diabetes and other conditions predisposing to the development of accelerated atherosclerosis, as outlined in the algorithm in Figure 11–1 and in Tables 11–2 and 11–3. With the growing evidence of CVD in children with T2DM, the Expert Panel believes it is prudent to include both T1DM and T2DM in the high-risk category.^[51],[52] With the increasing evidence of vascular dysfunction in children with HIV^[53],[54] and treatment-resistant nephrotic syndrome,^[55] these two conditions are included in the selected disease settings in the moderate-risk category. Patients in the high-risk category require intensive management, with more aggressive goals for therapy than those in the moderate-risk category as outlined in the algorithm in Figure 11–1.

Table 11–2. Special Risk Pediatric Conditions: Stratification by Risk Category

High Risk:

Manifest coronary artery disease, ages 30 years and older: Clinical evidence

• T1DM or T2DM
• Stage 3, 4, or 5 chronic kidney disease or post renal transplant
• Postorthotopic heart transplantation
• Kawasaki disease with current coronary aneurysms

Moderate Risk:

Accelerated atherosclerosis: Pathophysiologic evidence

• Kawasaki disease with regressed coronary aneurysms
• Chronic inflammatory disease (systemic lupus erythematosus, juvenile rheumatoid arthritis)
• Human immunodeficiency virus infection
• Treatment-resistant nephrotic syndrome

Figure 11–1. Risk-Stratification and Treatment Algorithm for High-Risk Pediatric Conditions

Directions:

Step 1: Risk stratification by disease process (Table 11–2).
Step 2: Assess all cardiovascular risk factors. If there are ≥ 2 comorbidities, move tier II patient to tier I for subsequent management.
Step 3: Tier-specific treatment goals/ cut points defined.
Step 4: Initial therapy: For tier I, initial management is therapeutic lifestyle change PLUS disease-specific management (Table 11–3). For tier II, initial management is therapeutic lifestyle change.
Step 5: For tier II, if goals are not met, consider medication per risk factor specific recommendations in these guidelines.

LEGEND: * CHILD 1 (Cardiovascular Health Integrated Lifestyle Diet) per Section V. Nutrition and Diet;
** Activity Rx - Activity Recommendations per Section VI. Physical Activity.
*** Weight loss recommendations per Section X. Overweight and Obesity.

Figure 11-1 Description

The figure 11-1 is a flow chart with three different starting points, presented here as separate lists with numbered steps. Each step flows linearly to the next step.

Starting Point A

1. Step 1. RISK STRATIFICATION BY DISEASE PROCESS
2. Step 2. ASSESS C-V RISK FACTORS (≥ 2 RFs → Move to tier 1)
3. Step 3. TIER-SPECIFIC CUT POINTS/ TREATMENT GOALS
4. Step 4: LIFESTYLE CHANGE
5. Step 5: DRUG THERAPY

Starting Point B

1. Tier I: High Risk
   • Diabetes mellitus, type I and type 2
   • Chronic kidney disease/ end stage renal disease/ post kidney transplant
   • Post-heart transplant
   • Kawasaki disease with current coronary artery aneurysms
2. CV RISK FACTORS/ CO-MORBIDITIES
   • Family history of early CVD in expanded 1stdegree pedigree(male ≤ 55y; female ≤ 65y)
   • Fasting lipid profile
   • Smoking history
   • BP (3 separate occasions), interpreted for age/sex/height percentile (%ile)
   • Height, weight, BMI
   • Fasting glucose (FG)
   • Diet, physical activity/exercise history
3. Tier 1: High Risk
   • BMI ≤ 85th%ile for age/sex.
   • BP ≤ 90th %ile for age/sex/ ht%ile
   • Lipids(mg/dL): LDL-C ≤ 100,
     TG < 90, non-HDL-C < 120
   • FG < 100 mg/dl, HgbA1c<7%
4. Intensive lifestyle management
   CHILD-1^*, Activity Rx^**
   Weight loss as needed^*** , Plus
5. Condition Specific Management - Table 11-3

Starting Point C

1. Tier II: Moderate Risk
   • Kawasaki Disease with regressed coronary aneurysms
   • Chronic inflammatory disease
   • HIV
   • Nephrotic syndrome
2. CV RISK FACTORS/ CO-MORBIDITIES
   • Family history of early CVD in expanded 1stdegree pedigree(male ≤ 55y; female ≤ 65y)
   • Fasting lipid profile
   • Smoking history
   • BP (3 separate occasions), interpreted for age/sex/height percentile (%ile)
   • Height, weight, BMI
   • Fasting glucose (FG)
   • Diet, physical activity/exercise history
3. Forward to YES or NO
4. Forward to YES
5. Tier 1: High Risk
   • BMI ≤ 85th%ile for age/sex.
   • BP ≤ 90th %ile for age/sex/ ht%ile
   • Lipids(mg/dL): LDL-C ≤ 100,
     TG < 90, non-HDL-C < 120
   • FG < 100 mg/dl, HgbA1c<7%
6. Intensive lifestyle management
   CHILD-1^*, Activity Rx^**
   Weight loss as needed^*** , Plus
7. Condition Specific Management - Table 11-3
8. Forward to NO
9. Tier 1: Moderate Risk
   • BMI ≤ 90th%ile for age/sex.
   • BP ≤ 95th %ile for age/sex/ ht%ile
   • Lipids(mg/dL): LDL-C ≤ 130,
     TG < 130, non-HDL-C < 140
   • FG < 100 mg/dl, HgbA1c<7%
10. Intensive lifestyle management
    CHILD-1^*, Activity Rx ^**
    Weight loss as needed^***
11. If goals not met, consider medication per risk-specific guideline recommendations

LEGEND:
* CHILD 1 (Cardiovascular Health Integrated Lifestyle Diet) per Section V. Nutrition and Diet;
** Activity Rx - Activity Recommendations per Section VI. Physical Activity.
*** Weight loss recommendations per Section X. Overweight and Obesity.

Table 11–3. Condition-Specific Treatment Recommendations

• Rigorous age-appropriate education in diet, activity, smoking cessation for all
• Specific therapy as needed to achieve blood pressure (BP), LDL-C, glucose, and HbA1C goals indicated for each tier, as outlined in algorithm; timing individualized for each patient and diagnosis

Diabetes mellitus regardless of type:

• For T1DM, intensive glucose management per endocrinologist with frequent glucose monitoring/insulin titration to maintain optimal plasma glucose and HbA1c for age.
• For T2DM, intensive weight management and glucose control, in consultation with an endocrinologist as needed to maintain optimal plasma glucose and HbA1c for age.
• Assess body mass index (BMI), fasting lipids: Step 4 lifestyle management of weight, lipids for 6 months.
• If LDL goals not achieved, consider statin therapy if age ≥ 10 years to achieve tier I treatment goals for LDL-C.
• Initial BP ≥ 90th percentile: Step 4 lifestyle management plus no added salt, increased activity for 6 months.
• BP consistently ≥ 95th percentile for age/sex/height: initiate angiotensin-converting enzyme inhibitor therapy with BP goal < 90th percentile for sex/height, or < 120/80, whichever is lower.

Chronic kidney disease/end stage renal disease/post renal transplant:

• Optimization of renal failure management with dialysis/transplantation per nephrology.
• Assess BMI, BP, lipids, fasting glucose (FG): Step 4 lifestyle management for 6 months.
• If LDL goals not achieved, consider statin therapy if age ≥ 10 years to achieve tier I treatment goals for LDL-C.
• BP consistently ≥ 95th percentile for age/gender/height, initiate angiotensin-converting enzyme inhibitor therapy with BP goal < 90th percentile for gender/height, or < 120/80, whichever is lower.

After heart transplantation:

• Optimization of antirejection therapy, treatment for cytomegalovirus infection, routine evaluation by angiography/perfusion imaging per transplant physician.
• Assess BMI, BP, lipids, FG: Initiate Step 5 therapy, including statins, immediately in all patients age ≥ 1 year to achieve tier I treatment goals.

Kawasaki disease with current coronary aneurysms:

• Antithrombotic therapy, activity restriction, ongoing myocardial perfusion evaluation per cardiologist.
• Assess BMI, BP, lipids, FG: Step 4 lifestyle management for 6 months.
• If goals not achieved, consider pharmacologic therapy for LDL-C and BP if age ≥ 10 years to achieve tier I treatment goals.

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