- Objective: To determine how changes in lipids, liver enzymes, and inflammatory and glycemia markers intercorrelate during prolonged dietary intervention in obese participants with or without type 2 diabetes (T2D). Methods: We examined the dynamics and intercorrelations among changes in biomarkers during the 2-y Dietary Intervention Randomized Controlled Trial (DIRECT) in 322 participants (including 46 with T2D; 52 y of age, body mass index 31 kg/m 2 ) throughout rapid weight loss (0–6 mo) and weight-maintenance/regain (7–24 mo) phases. Results: The 2-y increase of high-density lipoprotein cholesterol was greater in participants with T2D (þ9.41 versusþ6.57 mg/dL, P < 0.05), although they tended to have smaller waist circumferences (� 2.1 versus � 4.0 cm, P ¼ 0.08). In models adjusted for age, sex, and weight loss, the 2-year decrease of triacylglycerols was associated with increases of low-density and high-density lipoprotein cholesterol. An increase of apolipoprotein A1 was associated with a decrease in highsensitive C-reactive protein (P < 0.05 for all comparisons). Exclusively in participants with T2D, the 2-year decrease in triacylglycerols was further correlated with decreases in apolipoprotein B100 and liver enzymes, and a decrease in fasting glucose correlated with decreases in low-density lipoprotein cholesterol, apolipoprotein B100, and alanine aminotransferase (P < 0.05 for all comparisons). In the entire group, multivariate models adjusted for age, sex, intervention group, and 6-mo weight loss identified decreased high-sensitive C-reactive protein at 6 mo as an exclusive predictor of a greater decrease in triacylglycerols ( b ¼ 0.154, P ¼ 0.008) and a greater increase in high-density lipoprotein cholesterol (b ¼� 0.452, P ¼ 0.005) during the subsequent 18 mo. Conclusions: Long-term dietary intervention induces a flow of changes within biomarkers and the cross-talk is likely to be stronger in T2D. A decrease in systemic inflammation during the weightloss phase may predict greater long-term improvement in lipids (www.ClinicalTrials.gov, identifier NCT00160108).