Clinical Trials for Diabetes Drugs Should Measure Outcomes Important to Patients

[sharon sanders]

Protein C Protects Against Diabetic Nephropathy

Nature Medicine 13, 1349 - 1358 (2007)
Published online: 4 November 2007 | <ABBR title="Digital Object Identifier">doi</ABBR>:10.1038/nm1667

Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis

Berend Isermann<SUP>1,</SUP><SUP>10</SUP>, Ilya A Vinnikov<SUP>1,</SUP><SUP>10</SUP>, Thati Madhusudhan<SUP>1,</SUP><SUP>10</SUP>, Stefanie Herzog<SUP>1</SUP>, Muhammed Kashif<SUP>1</SUP>, Janusch Blautzik<SUP>1</SUP>, Marcus A F Corat<SUP>2,</SUP><SUP>9</SUP>, Martin Zeier<SUP>3</SUP>, Erwin Blessing<SUP>4</SUP>, Jun Oh<SUP>5</SUP>, Bruce Gerlitz<SUP>6</SUP>, David T Berg<SUP>6</SUP>, Brian W Grinnell<SUP>6</SUP>, Triantafyllos Chavakis<SUP>7</SUP>, Charles T Esmon<SUP>8</SUP>, Hartmut Weiler<SUP>2</SUP>, Angelika Bierhaus<SUP>1</SUP> & Peter P Nawroth<SUP>1</SUP>
<HR class=separator>Abstract

Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.

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1. <LI id=a1>Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. <LI id=a2>The Blood Research Institute, Blood Center of Wisconsin, 8727 Watertown Plank Road Milwaukee, Wisconsin 53226, USA. <LI id=a3>Department of Medicine I, Nephrology, University of Heidelberg, INF 162, 69120 Heidelberg, Germany. <LI id=a4>Department of Medicine III, Cardiology, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. <LI id=a5>Department of Pediatric Nephrology, University of Heidelberg, INF 153, 69120 Heidelberg, Germany. <LI id=a6>BioTechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA. <LI id=a7>Experimental Immunology Branch, National Cancer Institute, Building 10, Room 4B17, National Institutes of Health, Bethesda, Maryland 20892, USA. <LI id=a8>Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, and Howard Hughes Medical Institute, 825 N.E. 13th, Room A-205, Mail Box 45, Oklahoma City, Oklahoma 73104, USA. <LI id=a9>Present address: Centro Multidisciplinar para Investiga??o Biol?gica, Universidade Estadual de Campinas, Campinas 13083-877, SP, Brasil?Caixa Postal: 6095.
2. These authors contributed equally to this work.

http://www.nature.com/nm/journal/v13/n11/abs/nm1667.html

[tropical]

Re: Clinical Trials for Diabetes Drugs Should Measure Outcomes Important to Patients

Thank You for this post. This seems to be an catastrophic way of creating medicines, resulting in no good human medicines, with many animal pains during the trials.

[Snowy Owl]

Clinical Trials for Diabetes Drugs Should Measure Outcomes Important to Patients

http://www.newswise.com/articles/view/533749/

Most clinical trials for new diabetes drugs do not consider the impact medication will have on a patient’s quality of life or other outcomes that are important to patients, such as the risk of developing complications associated with diabetes, according to a Mayo Clinic commentary in the current issue of The Lancet.

Newswise


Most clinical trials for new diabetes drugs do not consider the impact medication will have on a patient’s quality of life or other outcomes that are important to patients, such as the risk of developing complications associated with diabetes, according to a Mayo Clinic commentary in the current issue of The Lancet.



Rather, drug trials focus on the effect of a particular medication on blood sugar levels. The result is smaller, shorter and cheaper trials that lead to more drug choices more quickly, but are not necessarily better or safer for patients.


“The apparent benefits of these trials are a mirage and the apparent savings represent false economy,” writes Victor Montori, M.D., an endocrinologist at Mayo Clinic, along with Gunjan Gandhi, M.D., of Mayo Clinic, and Gordon Guyatt, M.D., of McMaster University in Canada.



“Any savings are quickly overwhelmed by expenses associated with potentially ineffective, or even harmful, expensive therapies and the incremental costs of treating the harms these interventions might cause.



Patients and society may end up paying dearly for medications that cause more harm than good.”


The medical community is increasingly aware of the need to engage patients with chronic conditions in decisions about their care.



For example, clinicians and patients need to know the extent to which diabetes medications can help patients feel better and live longer.



Despite this need, only one in five randomized trials in diabetes published in top medical journals measured the effect of drugs on quality of life and on the risk of complications associated with diabetes, such as death, heart attack, stroke, amputation, blindness and dialysis. Ongoing trials do not promise much more, the author states.


Dr. Montori and colleagues call for clinical trials that consider and measure the impact of diabetes medications on outcomes that are important to patients.


“The medical community should insist that we invest the resources needed to do trials that ascertain the effect of interventions on patient-important outcomes,” the authors state.



“This policy will prevent the premature dissemination of therapies that ultimately prove harmful, facilitate patients’ participation in decision making, and speed the day when we can confidently offer safe treatments that can provide important benefit to patients with diabetes.”


In summary, the authors say:


1. Diabetes medications have been approved without requiring proof of reducing the risk of complications associated with diabetes, such as heart attack, stroke, amputation, blindness and kidney dialysis.



2. The majority of diabetes trials focus on the ability of medications to reduce blood sugar, not on outcomes that matter to patients.


3. Diabetes medications may reduce the risk of complications, but we do not know this with confidence.


4. The focus should shift from getting new drugs to market to testing the effect of diabetes medications against outcomes important to patients.

Dr. Montori is a lead investigator with the Knowledge and Encounter Research Unit at Mayo Clinic.



His research team seeks to improve the care and outcomes of patients with diabetes by studying ways to promote health care decisions that are more consistent with research findings and the values and preferences of informed patients.