Comparative efficacy and safety of antidiabetic drug regimens added to stable and inadequate metformin and thiazolidinedione therapy in type 2 diabetes.

AIMS: Determine the efficacy and safety of antidiabetic agents added-on to metformin and a thiazolidinedione (TZD) in patients with inadequately controlled type 2 diabetes (T2D). METHODS: MEDLINE and CENTRAL were searched for randomised controlled trials (RCTs) evaluating the addition of an antidiabetic agent in patients with T2D inadequately controlled on stable, optimised metformin and TZD therapy (≥ 1500 mg metformin and ≥ 50% maximum TZD dose for ≥ 4 weeks). Frequentist network meta-analysis was performed on identified studies. RESULTS: Eleven RCTs evaluating dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin), sulfonylureas (SUs) (glibenclamide, glimepiride), glucagon-like peptide-1 (GLP-1) analogues (exenatide, liraglutide, dulaglutide, taspoglutide) and sodium-glucose cotransporter2 (SGLT2) inhibitors (canagliflozin, empagliflozin) were identified. The mean reduction in HbA1c from baseline was significant for all agents (range, 0.55-1.17%) vs. placebo. SUs were associated with weight gain (range, 3.31-7.29 kg), while weight loss was seen with all GLP-1 analogues (range, 1.53-2.20 kg) and SGLT2 inhibitors (range, 2.08-2.95 kg) vs. placebo. Relative risk of hypoglycaemia was increased with dulaglutide, exenatide and glimepiride vs. placebo (RR range, 2.65-6.17); and trended higher with all other agents except linagliptin. GLP-1 analogues and canagliflozin reduced systolic blood pressure vs. placebo (range, 2.39-5.05 mmHg). No agent with available data increased the risk of urinary or genital tract infection vs. placebo. CONCLUSION: When added to stable, optimised metformin and TZD, all evaluated antidiabetic agents reduced HbA1c; albeit not to the same degree. Moreover, agents differed in their effects on body weight, hypoglycaemia and systolic blood pressure.

Telomeric fusions in cultured human fibroblasts as a source of genomic instability.

In a human fibroblast clone we studied the evolution, during culture propagation, of a dicentric chromosome consisting of the end-to-end association of the short arm of chromosome 5 and the long arm of chromosome 16. Dual-color fluorescence in situ hybridization (FISH) with painting probes allowed us to define the structure of a variety of derivative chromosomes and to identify the mechanisms by which they originated. Asymmetric interchanges involving the intercentromeric region of the dicentric, bridge-breakage-fusion events, or breaks followed by sister chromatid fusion, originate unstable hetero- or homodicentric chromosomes with deletion or duplication; breakages not followed by reunion, or intradicentric recombination, presumably originate stable rearranged monocentric chromosomes. The variety of the derivatives is extremely large because the observed events may involve any site of the intercentromeric region, although the majority of them occurs after a break in 16qh. The results of this investigation document the evolution through successive steps of a telomeric fusion, a chromosome anomaly frequently observed in tumor and senescent cells. They also demonstrate that in cultured cells of normal origin, starting with this anomaly, various chromosomal mechanisms may produce translocations, duplications, and deletions. The karyotype instability produced by a telomeric fusion can be relevant for carcinogenesis because it may generate genetic changes critical in the multistep process of transformation.