Dyslipidemia, Cardiovascular Disease, and Youth with Diabetes

Introduction
Individuals with diabetes have an increased risk of morbidity and mortality related to cardiovascular disease,1 accounting for 44 percent of deaths in patients with type 1 diabetes mellitus and 57 percent of deaths in patients with type 2 diabetes mellitus.2 Although youth with diabetes are rarely symptomatic, there is unequivocal evidence that atherosclerosis is well established in some by adolescence.3,4 The increasing prevalence of diabetes, prolonged exposure to hyperglycemia, and other traditional CVD risk factors present from such a young age make youth with T1D and T2D uniquely vulnerable to CVD.

The Role of Glucose
CVD mortality increases with increases in plasma glucose and HbA1c,5,6 and the association maintains significance after adjustment for potential confounders in both T1D and T2D.7,8 The risk of CVD occurs long before the onset of overt hyperglycemia,9,10 suggesting that glucose is a continuous risk factor for CVD mortality.11 The underlying mechanisms are undergoing extensive research to determine the role of specific pathways/ metabolites and potential for reversal.12

CVD Risk Factors in Diabetes
In addition to hyperglycemia, mortality in those with diabetes increases in the presence of other CVD risk factors (Table 1).13 Risk factors that contribute to atherosclerosis in youth are highly prevalent and strongly predictive of future CVD event risk. Some 21 percent have more than two CVD risk factors, the prevalence increasing with age, being higher among girls and varying by race/ ethnicity.14 Compared to T1D, youth with T2D are much more likely to have at least 2 CVD risk factors (14 percent versus 92 percent), contributing to T2D’s more lethal phenotype and higher mortality.

The Critical Role of LDL-C
Elevated LDL-C is a major predictor of CVD, including in those with diabetes.15,16 Mean LDL-C levels  are similar in those with and without diabetes, but levels vary widely among individuals because of a variety of genetic and environmental causes.17 In the Search for Diabetes in Youth cohort,18 1 in 5 T1D and 1 in 3 T2D youth >10 years of age had TC >200 mg/ dL; ~50 percent of youth with either T1D or T2D had LDL-C >100 mg/dL.

Risk Reduction
Intensive diabetes therapy has long-term beneficial effects on the risk of CVD in both T1D and T2D. Although optimal glycemic control prolongs survival, individuals with T1D continue to have a shorten life expectancy by more than a decade.19,20  Even in those who achieved good glycemic control, the risk for death over an eight-year period was more than doubled.21 With a HbA1c of <6.9 percent, the risk was found to be more than twofold for all-cause mortality and nearly threefold for CVD mortality. Although renal disease is strongly associated with CVD in diabetes, surprisingly the all-cause and CVD mortality risks were also noted to be three times higher among those with T1D who did not have renal disease. This finding contradicts those of prior observational studies.

In adults with diabetes, statins are effective in the primary and secondary prevention of major CVD events.22,23 An LDL-C reduction of 38.7 mg/dL was associated with a 21 percent decrease in major vascular events.22 Although long- term safety and efficiency has not been studied in youth with diabetes, selective use of statins is currently recommended (Table 2).24-27 Despite potential benefits, few children with diabetes currently receive lipid-lowering therapy.18,28

Conclusion
In addition to poor glycemic control, other CVD risk factors, such as elevated levels of LDL-C, are common in youth with diabetes. Improved glycemic control, early identification, and effective management of all CVD risk factors may help decrease the high rate of morbidity and mortality prevalent in this disease.

Acknowledgements
The authors would like to acknowledge Karen Keller, Dena Hanson, and Lynn Harmon for their assistance in preparing and editing this manuscript.

Disclosure statement: Dr. Wilson is a speaker for the Osler Institute, participated in an advisory board of Aegerion Pharmaceuticals, participated in an advisory board of and as an educational speaker for Synageva Biopharma Corp., and received research funding from Merck Sharp & Dohme and Novo Nordisk Inc. Dr. Blackett is a consultant for Roche Pharmaceuticals. Dr. McNeal has no disclosures to report.

References are listed on page 38 of the PDF.