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Levels of Evidence Needed for Changing Indications, Contraindications, and Food and Drug Administration Labeling: The Case of Metformin—Reply

Levels of Evidence Needed for Changing Indications, Contraindications, and Food and Drug... In reply Eurich et al note that observational data from Reduction of Atherothrombosis for Continued Health (REACH) that we published in the Archives1 complement previous studies, and they fear that obtaining a higher level of proof regarding the safety and perhaps the benefits of metformin in very high-risk patients is not achievable. We are aware of previous well-conducted observational studies by Eurich and others evaluating the safety of metformin in patients with HF patients, and we believe that the changes in product monographs of metformin, down-toning the contraindication of the drug in diabetic patients with stable HF are welcome. Our results extend the basis of these labeling changes, but they also provide indications that other contraindications, such as renal insufficiency, may not be as justified as previously believed. Moreover, the issue is not only to mitigate contraindications, but possibly to switch some of them to indications—a tempting prospect for subjects with HF and diabetes, for example, that cannot be achieved without the highest level of evidence. Thus, we think that such a trial should be planned and conducted, not just in diabetic patients with HF, but for secondary prevention in diabetic patients in general, including those with HF and those with renal insufficiency, to establish that metformin does indeed reduce cardiovascular morbidity and mortality. We concede that it may be a challenge to fund and execute, and we hope that the accumulating observational data will convince physicians and patients to participate. Correspondence: Dr Roussel, Department of Diabetology, Endocrinology, and Nutrition, Bichat Hospital, 46 rue Henri Huchard, 75018 Paris, France (ronan.roussel@bch.aphp.fr). Financial Disclosure: Dr Roussel has received research grants, honoraria, or consulting fees from sanofi-aventis, Merck Sharp et Dohme (MSD)–Chibret, Eli Lilly and Company, Novo Nordisk A/S, Medtronic Inc, and Lifescan Inc. Dr Bhatt has received research grants from AstraZeneca, Bristol-Myers Squibb, Eisai Pharmaceuticals, Ethicon Inc, Heartscape Technologies Inc, sanofi-aventis, and The Medicines Company; received honoraria (donated to nonprofit organizations for >4 years) from AstraZeneca, Bristol-Myers Squibb, Centocor Ortho Biotech Inc, Daiichi-Sankyo Co Ltd, Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Millennium Pharmaceuticals Inc, ParinGenix Inc, PDL BioPharma Inc, sanofi-aventis, Schering-Plough, and The Medicines Company; served on the speakers' bureau (>4 years ago) for Bristol-Myers Squibb, sanofi-aventis, and The Medicines Company; served as a consultant or on the advisory board (honoraria donated to nonprofit organizations) for Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Cardax Pharmaceuticals, Centocor Ortho Biotech Inc, Cogentus Pharmaceuticals Inc, Daiichi-Sankyo Co Ltd, Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson Services Inc, McNeil-PPC Inc, Medtronic Inc, Millennium Pharmaceuticals Inc, Otsuka Pharmaceutical Group, ParinGenix Inc, PDL BioPharma Inc, Philips Healthcare, Portola Pharmaceuticals Inc, sanofi-aventis, Schering-Plough, The Medicines Company, and Vertex Pharmaceuticals; and provided expert testimony regarding clopidogrel bisulfate (compensation donated to a nonprofit organization). Dr Steg has received research grants from sanofi-aventis (1999-2008); is on the speakers' bureau for Boehringer Ingelheim GmbH, Bristol-Myers Squibb, GlaxoSmithKline, The Menarini Group, Medtronic Inc, Nycomed International Management GmbH, Pierre Fabre Laboratories, sanofi-aventis, Servier Laboratories, and The Medicines Company; and is on the consulting or advisory boards for Astellas Pharma Inc, AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Daiichi-Sankyo Co Ltd, Endotis Pharma, GlaxoSmithKline, Medtronic Inc, MSD-Chibret, Nycomed International Management GmbH, sanofi-aventis, Servier Laboratories, and The Medicines Company; and is a stockholder for Aterovax. References 1. Roussel RTravert FPasquet B et al. Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators, Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010;170 (21) 1892- 1899PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Levels of Evidence Needed for Changing Indications, Contraindications, and Food and Drug Administration Labeling: The Case of Metformin—Reply

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References (1)

Publisher
American Medical Association
Copyright
Copyright © 2011 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2011.225
Publisher site
See Article on Publisher Site

Abstract

In reply Eurich et al note that observational data from Reduction of Atherothrombosis for Continued Health (REACH) that we published in the Archives1 complement previous studies, and they fear that obtaining a higher level of proof regarding the safety and perhaps the benefits of metformin in very high-risk patients is not achievable. We are aware of previous well-conducted observational studies by Eurich and others evaluating the safety of metformin in patients with HF patients, and we believe that the changes in product monographs of metformin, down-toning the contraindication of the drug in diabetic patients with stable HF are welcome. Our results extend the basis of these labeling changes, but they also provide indications that other contraindications, such as renal insufficiency, may not be as justified as previously believed. Moreover, the issue is not only to mitigate contraindications, but possibly to switch some of them to indications—a tempting prospect for subjects with HF and diabetes, for example, that cannot be achieved without the highest level of evidence. Thus, we think that such a trial should be planned and conducted, not just in diabetic patients with HF, but for secondary prevention in diabetic patients in general, including those with HF and those with renal insufficiency, to establish that metformin does indeed reduce cardiovascular morbidity and mortality. We concede that it may be a challenge to fund and execute, and we hope that the accumulating observational data will convince physicians and patients to participate. Correspondence: Dr Roussel, Department of Diabetology, Endocrinology, and Nutrition, Bichat Hospital, 46 rue Henri Huchard, 75018 Paris, France (ronan.roussel@bch.aphp.fr). Financial Disclosure: Dr Roussel has received research grants, honoraria, or consulting fees from sanofi-aventis, Merck Sharp et Dohme (MSD)–Chibret, Eli Lilly and Company, Novo Nordisk A/S, Medtronic Inc, and Lifescan Inc. Dr Bhatt has received research grants from AstraZeneca, Bristol-Myers Squibb, Eisai Pharmaceuticals, Ethicon Inc, Heartscape Technologies Inc, sanofi-aventis, and The Medicines Company; received honoraria (donated to nonprofit organizations for >4 years) from AstraZeneca, Bristol-Myers Squibb, Centocor Ortho Biotech Inc, Daiichi-Sankyo Co Ltd, Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Millennium Pharmaceuticals Inc, ParinGenix Inc, PDL BioPharma Inc, sanofi-aventis, Schering-Plough, and The Medicines Company; served on the speakers' bureau (>4 years ago) for Bristol-Myers Squibb, sanofi-aventis, and The Medicines Company; served as a consultant or on the advisory board (honoraria donated to nonprofit organizations) for Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Cardax Pharmaceuticals, Centocor Ortho Biotech Inc, Cogentus Pharmaceuticals Inc, Daiichi-Sankyo Co Ltd, Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson Services Inc, McNeil-PPC Inc, Medtronic Inc, Millennium Pharmaceuticals Inc, Otsuka Pharmaceutical Group, ParinGenix Inc, PDL BioPharma Inc, Philips Healthcare, Portola Pharmaceuticals Inc, sanofi-aventis, Schering-Plough, The Medicines Company, and Vertex Pharmaceuticals; and provided expert testimony regarding clopidogrel bisulfate (compensation donated to a nonprofit organization). Dr Steg has received research grants from sanofi-aventis (1999-2008); is on the speakers' bureau for Boehringer Ingelheim GmbH, Bristol-Myers Squibb, GlaxoSmithKline, The Menarini Group, Medtronic Inc, Nycomed International Management GmbH, Pierre Fabre Laboratories, sanofi-aventis, Servier Laboratories, and The Medicines Company; and is on the consulting or advisory boards for Astellas Pharma Inc, AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Daiichi-Sankyo Co Ltd, Endotis Pharma, GlaxoSmithKline, Medtronic Inc, MSD-Chibret, Nycomed International Management GmbH, sanofi-aventis, Servier Laboratories, and The Medicines Company; and is a stockholder for Aterovax. References 1. Roussel RTravert FPasquet B et al. Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators, Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010;170 (21) 1892- 1899PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Jun 13, 2011

Keywords: metformin,levels of evidence

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