Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial

Background - Type 1 diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) that is not fully explained by conventional risk factors. The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes therapy reduced levels of LDL cholesterol and triglycerides but increased the risk of major weight gain, which might adversely affect CVD risk. The present study examined the effect of intensive therapy on levels of several markers of inflammation that have been linked to risk of CVD. Methods and Results - We measured levels of inflammatory biomarkers in stored baseline and 3-year follow-up serum specimens from a random sample of 385 participants in the DCCT, a multicenter trial in which 1441 subjects aged 13 to 39 years with type 1 diabetes mellitus were randomized to intensive or conventional diabetes treatment. The markers included high-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), and the 55-kDa soluble tumor necrosis factor-alpha receptor 1 (sTNF-R1). We examined the effect of intensive therapy on the change in levels of the inflammatory markers. In unadjusted analyses, levels of hsCRP and sTNF-R1 increased in both treatment groups after 3 years of follow-up, with no significant difference between groups for hsCRP ( P = 0.53) but with a greater increase of sTNF-R1 in the intensive therapy group ( P = 0.002). In contrast, mean levels of sICAM-1 and sVCAM-1 decreased among participants assigned to intensive therapy, whereas they did not change among those in the conventional treatment group ( P = 0.03 for sICAM-1; P = 0.03 for sVCAM-1). After adjustment for baseline levels and other factors, intensive therapy remained associated with a significant decrease in sICAM-1 ( P = 0.02) and an increase in sTNF-R1 ( P = 0.03). For hsCRP, there was a significant interaction between the top third of weight gain and treatment assignment ( P = 0.03). In subgroup analyses among subjects undergoing intensive therapy, hsCRP levels increased among those who gained the most weight, whereas it decreased among those in the bottom third of weight gain ( P = 0.0004). Conclusions - Intensive therapy in patients with type 1 diabetes mellitus reduced levels of sICAM-1 and increased levels of sTNF-R1 and of hsCRP among those who gained weight. These data demonstrate that the effect of intensive therapy on inflammation is complex and, to the extent that hsCRP is a risk factor, suggest that the risk of atherosclerosis among diabetic patients may be influenced by the degree of weight gain while undergoing intensive therapy.