Lipid and Inflammatory Cardiovascular Risk Worsens Over 3 Years in Youth With Type 2 Diabetes: The TODAY clinical trial

OBJECTIVE

Type 2 diabetes increases cardiovascular risk. We examined lipid profiles and inflammatory markers in 699 youth with recent-onset type 2 diabetes in the TODAY clinical trial and compared changes across treatment groups: metformin alone (M), metformin plus rosiglitazone (M+R), and metformin plus intensive lifestyle program (M+L).

RESEARCH DESIGN AND METHODS

Multiethnic youth with type 2 diabetes received M, M+R, or M+L. Statin drugs were begun for LDL cholesterol (LDL) ≥130 mg/dL or triglycerides ≥300 mg/dL. Lipids, apolipoprotein B (apoB), LDL particle size, high-sensitivity c-reactive protein (hsCRP), homocysteine, plasminogen activator inhibitor-1 (PAI-1), and HbA_1c were measured over 36 months or until loss of glycemic control.

RESULTS

LDL, apoB, triglycerides, and non-HDL cholesterol (HDL) rose over 12 months and then stabilized over the next 24 months. Participants with LDL ≥130 mg/dL or using LDL-lowering therapy increased from 4.5 to 10.7% over 36 months, while 55.9% remained at LDL goal (<100 mg/dL) over that time. Treatment group did not impact LDL, apoB, or non-HDL. Small dense LDL (particle size, ≤0.263 relative flotation rate) was most common in M. Triglycerides were lower in M+L than M, and M+L attenuated the negative effect of hyperglycemia on triglycerides and HDL in females. hsCRP, PAI-1, and homocysteine increased over time. However, hsCRP was lower in M+R compared with M or M+L.

CONCLUSIONS

Dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and worsened over time. Diabetes treatment, despite some treatment group differences in lipid and inflammatory marker change over time, is generally inadequate to control this worsening risk.The marked increase in type 2 diabetes in adolescents and youth has raised the specter of early cardiovascular disease (CVD) in affected individuals. In adults with type 2 diabetes, the risks of diabetes-specific microvascular complications are largely related to the level of glycemia and duration of disease (1–3). Indicators of atherosclerosis, or macrovascular disease, are already present in youth with type 2 diabetes and dyslipidemia (4,5). Youth with type 2 diabetes are known to have higher levels of LDL cholesterol (LDL), triglycerides, and non-HDL cholesterol (HDL) and lower levels of HDL than youth without diabetes or youth with type 1 diabetes (6). Elevated inflammatory markers have also been reported in adolescents with type 2 diabetes (7). However, the true prevalence of dyslipidemia and the proinflammatory state in youth and adolescents with type 2 diabetes, the evolution of risk over time, and whether glucose-lowering interventions ameliorate the atherogenic profile are unknown. The TODAY study provides the opportunity to address these critical questions and determine whether three diabetes treatments differentially affected cardiovascular risk factors.TODAY was a multiethnic, multicenter clinical trial of newly diagnosed children and adolescents with type 2 diabetes randomized to one of three interventions: metformin alone (M; n = 232), metformin plus rosiglitazone (M+R; n = 233), or metformin plus an intensive lifestyle program (M+L; n = 234) (8–10). The primary results have recently been published in detail (10). Briefly, of the 699 TODAY participants, 319 (45.6%) reached the primary outcome (loss of glycemic control defined as HbA_1c ≥8% [64 mmol/mol] for 6 months or inability to wean from temporary insulin therapy within 3 months after metabolic decompensation) over an average follow-up of 3.86 years (10). Regarding glycemic control, M+R was superior to M (P = 0.006); M+L was intermediate but not different from M (10).We hypothesized that 1) lipid profiles (LDL, non-HDL, apolipoprotein B [apoB], LDL particle density, triglycerides, and HDL) and inflammatory markers (high-sensitivity c-reactive protein [hsCRP], homocysteine, plasminogen activator inhibitor-1 [PAI-1], and nonesterified fatty acids [NEFA]) would indicate increased CVD risk in youth with recent-onset type 2 diabetes; 2) in the setting of standardized protocol-driven clinical management of hyperlipidemia in a randomized clinical trial for 36 months (or until attainment of primary outcome, loss of glycemic control), cardiovascular risk change would improve more with M+R and M+L than with M. Associations of race-ethnicity and sex with differences in dyslipidemia and inflammatory markers were also assessed.