Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study.

Institute of Health Economics, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta.
Canadian Medical Association Journal (Impact Factor: 5.81). 02/2006; 174(2):169-74. DOI: 10.1503/cmaj.050748
Source: PubMed

ABSTRACT Over the past 30 years, the relation between use of sulfonylureas to treat type 2 diabetes and the risk of cardiovascular events has been vigorously debated. The purpose of this study was to determine if the risk of death changes with level of exposure to sulfonylurea drugs.
This was a retrospective, inception cohort study using administrative data from Saskatchewan Health (1991-1999). The 5795 subjects, identified by their first-ever dispensation for an oral antidiabetic agent, were grouped according to their use of such agents during follow-up. Potential subjects using insulin or combination therapy were excluded. Exposure level was defined by daily dose and degree of adherence. Separate multivariate Cox proportional-hazard models were constructed for each monotherapy group and used to calculate the risk of death associated with higher versus lower exposure category. Disease severity indicators were identified among the administrative data and entered as covariates in each model. The main outcomes were all-cause mortality and death from an acute ischemic event.
The mean age of the cohort members was 66.3 (standard deviation [SD] 13.4) years; 43.4% were female; and their mean duration of follow-up was 4.6 (SD 2.1) years. First-generation sulfonylureas were used exclusively by 120 subjects; glyburide, by 4138; and metformin, by 1537. A greater risk of death was associated with higher daily doses of the first-generation sulfonylureas (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.0-4.7) and glyburide (HR 1.3, 95% CI 1.2-1.4), but not metformin (HR 0.8, 95% CI 0.7-1.1). Similar associations were observed for death caused by an acute ischemic event.
Higher exposure to sulfonylureas was associated with increased mortality among patients newly treated for type 2 diabetes. The same relation was not observed with metformin. This implies that the manner in which blood glucose concentration is lowered may be as important as achieving recommended glucose targets.

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    ABSTRACT: Background. This study was performed to investigate the influence of a short-term treatment with pioglitazone versus placebo on inflammatory activation of mononuclear cells (mRNA expression/protein secretion of inflammatory markers). Methods and Results. Sixty-three patients with well-controlled type 2 diabetes (52 males, 11 females, age (Mean ± SD): 66 ± 7 yrs, disease duration: 6.6 ± 9.6 yrs, HbA1c: 6.7 ± 0.6%) were randomized to additional 45 mg of pioglitazone or placebo to their existing metformin and sulfonylurea therpay for four weeks in a double-blind study design. Protein risk marker levels (hsCRP, MMP-9, MCP-1, etc.) and the expression of NFκB subunits and NFκB-modulated cytokines from isolated peripheral monocyte/macrophages were determined at baseline and endpoint. There were no changes in HbA1c, but significant biomarker improvements were seen with pioglitazone only. The mRNA marker expression was downregulated by pioglitazone and further up-regulated with placebo (e.g., P105 pioglitazone: −19%/placebo: +6%, RelA: −20%/+2%, MMP−9: −36%/+9%, TNFα: −10%/+14%, P < 0.05 between groups in all cases). Conclusions. Pioglitazone very rapidly down-regulated the activated state of peripheral monocytes/macrophages as assessed by mRNA expression of NFκB and NFκB-modulated cytokines and decreased plasma levels of cardiovascular risk marker proteins independent of glycemic control.
    PPAR Research 07/2011; 2011:647017. DOI:10.1155/2011/647017 · 1.64 Impact Factor
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    ABSTRACT: In dieser Studie wurden die Auswirkungen einer Pioglitazontherapie bei Typ 2 Diabetikern auf das Proteom des menschlichen Plasmas untersucht. Mit der 2D-Gelelektrophorese konnten vielfältige Veränderungen im Proteom identifiziert werden. Die Proteine Orosomucoid (Alpha1-Acid Glykoprotein), Haptoglobin, Transthyretin, Hämopexin, Ig J, Profilin und Apolipoprotein A1 (HDL) veränderten ihre Konzentrationen. Viele Veränderungen deuteten auf eine Verminderung der Inflammation im Organismus und auf eine Verbesserung der diabetischen Stoffwechsellage hin. Das Protein, das sich am signifikantesten veränderte, war Profilin-1. Bis auf Profilin waren die Reaktionen der Proteine auf Inflammation und die diabetische Stoffwechsellage bereits bekannt, was den Nutzen der 2D-Gelelektrophorese hervorhebt. Mit Western Blots konnte gezeigt werden, dass der Einsatz von Pioglitazon den Profilinspiegel im Plasma bei sieben von zehn behandelten Diabetikern steigert. Gesunde Probanden hatten ebenfalls hohe Profilinspiegel. Eine Gruppe von 50 untersuchten KHK-Patienten wies dagegen auffallend wenig Profilin im Plasma auf. Darauf wurden Gefäße von Diabetikern und einer Gegenprobe eines Nicht-Diabetikers immunhistochemisch mit dem Profilin-Antikörper gefärbt. Es zeigte sich eine starke Anreicherung von Profilin in arteriosklerotischen Plaques. Diese Entdeckungen legen nahe, dass Profilin ein Marker für die endotheliale Dysfunktion sein könnte. Darauf wurden Endothelzellen (HUVEC) und ihre Reaktion auf Pioglitazon, Metformin, Gliclazid, Interleukin-6, Ketocholesterol, Hydroxycholesterol und Kombinationen dieser Stoffe mit Pioglitazon untersucht. Die Sekretion von Profilin wurde in vitro nur von Ketocholesterol, Pioglitazon oder Pioglitazon plus Gliclazid beeinflusst. Pioglitazon erwies sich als einziger Stoff, der das intrazelluläre sowie das sezernierte Profilin senkt. Alle anderen Stoffe steigerten das intrazelluläre Profilin. Pioglitazon neutralisierte in den verschiedenen Kombinationen die Profilinsteigerung durch andere Medikamente. Bei der Kombination von Pioglitazon mit Gliclazid setzte sich die Pioglitazonwirkung sogar durch und senkte das Profilin. Die Regulation des endothelialen Profilingehaltes durch Medikamente und Interleukin-6 stellen neue Erkenntnisse dar. Profilin könnte bei zellulären Regelprozessen der endothelialen Dysfunktion einen wichtigen Botenstoff darstellen. Es könnte ebenfalls ein Mediator der Pioglitazonwirkung sein, da es in wichtige Signalkaskaden involviert ist, die auch durch Pioglitazon angesprochen werden. Da Pioglitazon pathologische Entwicklungen am Endothel und im Gesamtorganismus unterbrechen konnte, scheint es gute Anwendungsmöglichkeiten in der Behandlung des Diabetes mellitus und eventuell der Arteriosklerose zu haben. This study intended to evaluate the effects of pioglitazone treatment of type 2 diabetic patients on the proteome of human plasma. Manifold changes could be identified with the 2D gelelectrophoresis. Orosomucoid (alpha1-acid glycoprotein), haptoglobin, transthyretin, haemopexin, immunoglobulin J chain, profilin and apolipoprotein A1 (HDL) altered their concentrations. All variations indicated a reduction of inflammation in the organism and an improvement of the diabetic metabolism. The protein with most prominent changes represented profiling-1. Apart from profiling the effects of pioglitazone treatment on the proteins of inflammation and the diabetic metabolism were known before, but this highlights the value of the 2D-Gelelektrophoresis. Western Blots showed, that treatment with pioglitazone increased the plasma profilin level in seven of ten diabetics. Healthy people had high levels of plasma profilin. A group of investigated coronary heart disease patients had remarkably low profilin levels in the plasma. Therefore, an immunhistochemical study with vessels of four diabetic patients and a non-diabetic person were performed using a profilin antibody. A heavy accumulation of profilin occurred in the arteriosclerotic plaques. The endothelium of diabetics seemed to contain more profilin than the non-diabetic. These discoveries suggest that profilin may be a marker for the vessel status and endothelial dysfunction. Hereupon, human umbilical vein endothelial cells (HUVECs) were investigated in their excitability induced by pioglitazon, metformin, gliclazide, interleukin 6, ketocholesterol, hydroxycholesterol and in combinations with pioglitazone. Pioglitazone proved to be the only substance, which reduced the intracellular and secreted profilin. All of the other substances raised the intracellular profilin. The profilin secretion was only affected by ketocholesterol, pioglitazone or pioglitazon plus gliclazide. In combinations pioglitazon neutralised the effect of the other substances. Though in combinations with pioglitazone and gliclazide the pioglitazone effect prevailed. The regulation of the endothelial profilin content by drugs displays a new insight. Profilin seemed to be a messenger in cellular processes and endothelial dysfunction. It also could be the mediator of the piogliazone effect, since it is involved in many signal cascades, which can be addressed by pioglitazone, too. Piogliazone apparently stopped pathological developments in the endothelium and the whole organism and cancelled them partially. Therefore, in the future it could have potential applications in the treatment of the metabolic syndrome and in arteriosclerosis.
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