Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Role of cytomegalovirus in driving cytotoxic CD28null T cells

Accumulation of CD28null T cells has been traditionally considered a sign of aging, as the percentage of these cells is increased in the elderly. However, the permanent loss of CD28 on T cells is caused by chronic antigenic stimulation. In that sense, CMV infection seems to be an important factor, particularly in the CD4 T-cell compartment, where significant expansions of these cells have been observed in CMV-seropositive individuals only and independently of age. In contrast to this, the CD28null CD8 T-cell subset is more heterogeneous, consisting of different type of cells with diverse origins, phenotype, and functions. Indeed, contrarily to their CD4 counterparts, CD28null CD8 T cells can be found expanded in the absence of CMV. CD28null CD4 T cells are cytotoxic and produce high amounts of pro-inflammatory cytokines. Expansions of these cells has been shown to be associated with many diseases and seems to have a relevant role in CVD (cardiovascular diseases). We, therefore, propose that CMV-related CVD risk may be mediated in part by CD28null CD4 T-cells, capable of damaging the vasculature

CD57 in human natural killer cells and T-lymphocytes

The CD57 antigen (alternatively HNK-1, LEU-7, or L2) is routinely used to identify terminally differentiated ‘senescent’ cells with reduced proliferative capacity and altered functional properties. In this article, we review current understanding of the attributes of CD57-expressing T-cells and NK cells in both health and disease and discuss how this marker can inform researchers about their likely functions in human blood and tissues in vivo. While CD57 expression on human lymphocytes indicates an inability to proliferate, these cells also display high cytotoxic potential, and CD57pos NK cells exhibit both memory-like features and potent effector functions. Accordingly, frequencies of CD57-expressing cells in blood and tissues have been correlated with clinical prognosis in chronic infections or various cancers and with human aging. Functional modulation of senescent CD57pos T-cells and mature CD57pos NK cells may therefore represent innovative strategies for protection against human immunological aging and/or various chronic diseases