The rosiglitazone story--lessons from an FDA Advisory Committee meeting.

Maine Center for Osteoporosis, St. Joseph Hospital, Bangor, USA.
New England Journal of Medicine (Impact Factor: 54.42). 09/2007; 357(9):844-6. DOI: 10.1056/NEJMp078167
Source: PubMed
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    ABSTRACT: Current approaches for postmarket medical device safety surveillance are limited in their ability to produce timely and accurate assessments of adverse event rates. The Data Extraction and Longitudinal Trend Analysis (DELTA) network study was a multicenter prospective observational study designed to evaluate the safety of devices used during percutaneous coronary interventions. All adult patients undergoing percutaneous coronary intervention from January 2008 to December 2012 at 5 participating Massachusetts sites were included. A safety alert was triggered if the cumulative observed adverse event rates for the study device exceeded the upper 95% confidence interval of the event rates of propensity-matched control cohort. Prespecified sensitivity analyses were developed to validate any identified safety signal. A total of 23 805 consecutive percutaneous coronary intervention procedures were evaluated. Two of 24 safety analyses triggered safety alerts. Patients receiving Perclose vascular closure device experienced an increased risk of minor vascular complications (relative risk, 4.14; P<0.01) and any vascular complication (relative risk, 2.06; P=0.01) when compared with propensity-matched patients receiving alternative vascular closure device, a result primarily driven by relatively high event rates at 1 participating center. Sensitivity analyses based on alternative risk adjustment methods confirmed a pattern of increased rate of complications at 1 of the 5 participating sites in their use of Perclose vascular closure device. The DELTA network study demonstrates that distributed automated prospective safety surveillance has the potential of providing near real-time assessment of safety risks of newly approved medical devices. © 2014 American Heart Association, Inc.
    Circulation Cardiovascular Quality and Outcomes 12/2014; 8(1). DOI:10.1161/CIRCOUTCOMES.114.001123 · 5.66 Impact Factor
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    ABSTRACT: Injury initiates recruitment of macrophages to support tissue repair however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the PPAR-γ agonist, rosiglitazone (Rosi), a medication recently re-introduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6 deficient mice and control wildtype (WT) mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6-deficiency in human diseases. IL-6-deficiency when combined with Rosi-mediated upregulation of SOCS3, leads to an altered ratio of nuclear STAT3/NF-κB that allows hyper-induction of iNOS. Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6-deficiency.Journal of Investigative Dermatology accepted article preview online, 03 September 2014. doi:10.1038/jid.2014.375.
    Journal of Investigative Dermatology 09/2014; 135(2). DOI:10.1038/jid.2014.375 · 6.37 Impact Factor
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    ABSTRACT: Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modifications. Recently 2 drugs one being the injectable ultra-long acting analog insulin, degludec and the other being oral sodium glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin have been introduced to supplement the previous antidiabetic agents. The objective of this review article is to discuss the current pharmacological agents available, their successes, demerits and limitations in the treatment of patients with T2DM. This article also reviews currently available knowledge about degludec and dapagliflozin. Informations have been gathered from related clinical studies, research works, articles and abstracts published in various journals. It is generally agreed that metformin, if not contraindicated and if tolerated, is the preferred and most cost-effective first line agent for the treatment of T2DM. Insulin analogs are also becoming mainstream therapy for T2DM. Insulin degludec administered once daily is found to be significantly less variable and more stable in maintaining euglycemia as compared to insulin glargine and has flexibility in dosing time. It also causes lower incidence of hypoglycemia in both type 1 and type 2 diabetic patients. SGLT2 inhibitors are the most advanced new oral antidiabetic agents that lower glycosylated hemoglobin by increasing glycosuria and lead to a moderate weight loss. Dapagliflozin represents a novel approach to the management of T2DM.