Diabetes and Cardiovascular Disease: an Update.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of mortality in people with diabetes. Our aim was to review the pathophysiology of CVD in diabetes, review related landmark trials, and discuss the cardiovascular benefit of glucose-lowering agents. We have also discussed the role of controversial anti-platelet therapy. RECENT FINDINGS: Recent studies have shown the impact of glucose-lowering agents on CVD in people with diabetes. Statins are now recommended for all patients with diabetes over the age of 40 regardless of the LDL level given the cardiovascular benefit of these drugs. Current recommendations suggest a blood pressure < 130/80 for individuals with high cardiovascular risk. Cardiovascular risk reduction should be an important part of the management of diabetes. Focusing solely on glycemic control may not be the best therapeutic strategy. Multifactorial risk reduction should be taken into account. Lipid-lowering agents and anti-hypertensives should be a corner stone of treatment of diabetes. With currently available data, glucose-lowering agents with cardiovascular benefit should be started early in the disease process.

Clinical outcomes of PCSK9Is: a meta-analysis of randomized clinical trials.

BACKGROUND: Previous studies of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9Is) were not designed to detect clinical benefit and were underpowered for this outcome. However, recently published trials reported improvement in clinical outcomes. The aim of this meta-analysis to assess the impact of PCSK9Is on clinical outcomes. METHODS: Medline, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) were queried from January 2000 through March 2017. Only randomized controlled trials (RCTs) comparing clinical outcomes in patients treated with PCSK9I versus control group were included. Two independent reviewers selected the studies and extracted data in duplicate. Random-effects meta-analysis was used to pool outcomes across studies. Study endpoints included: major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, coronary revascularization, cardiovascular (CV) mortality and all-cause mortality. RESULTS: A total of 62,776 patients (mean age 61 years, 73% were males) were included from six randomized clinical trials. In comparison to control group, PCSK9I use was associated with lower MACE (RR =0.81, 95% CI, 0.70-0.93, P=0.003), MI (RR =0.78, 95% CI, 0.63-0.97, P=0.03), stroke (RR =0.74, 95% CI, 0.64-0.87, P=0.0002) and coronary revascularization (RR =0.79, 95% CI, 0.73-0.86, P<0.00001). There was no statistically significant difference between both groups in terms of all-cause mortality (RR =1.01, 95% CI, 0.86-1.20, P=0.86) or CV mortality (RR =0.98, 95% CI, 0.78-1.22, P=0.83). CONCLUSIONS: PCSK9Is should be strongly considered to improve clinical outcomes in patients at high risk for atherosclerotic CVD.

Suppression of IL-12 production by tristetraprolin through blocking NF-kcyB nuclear translocation.

Tristetraprolin (TTP), an mRNA-binding protein, plays a significant role in regulating the expression of adenylate-uridylate-rich elements containing mRNAs. Mice deficient of TTP (TTP(-/-)) develop a systemic autoimmune inflammatory syndrome characterized by cachexia, conjunctivitis, and dermatitis. IL-12 plays a crucial role in immune defense against infectious and malignant diseases. In this study, we found increased production of IL-12 during endotoxic shock and enhanced Th1 cells in TTP knockout mice. The levels of IL-12 p70 and p40 protein as well as p40 and p35 mRNA were also increased in activated macrophages deficient of TTP. In line with these findings, overexpression of TTP suppressed IL-12 p35 and p40 expression at the mRNA and promoter level, whereas it surprisingly had little effects on their mRNA stability. Our data showed that the inhibitory effects of TTP on p35 gene transcription were completely rescued by overexpression of NF-кB p65 and c-Rel but not by the p50 in activated macrophages. Our data further indicated that TTP acquired its inhibition on IL-12 expression through blocking nuclear translocation of NF-кB p65 and c-Rel while enhancing p50 upon stimulation. In summary, our study reveals a novel pathway through which TTP suppresses IL-12 production in macrophages, resulting in suppression of Th1 cell differentiation. This study may provide us with therapeutic targets for treatment of inflammatory and autoimmune disorders.