PERSPECTIVE THE CARDIOVASCULAR SAFETY OF DIABETES DRUGS cular risks of rosiglitazone led diovascular safety of new diabetes Providence Veterans Affairs Medical Cen to a major change in FDA policy drugs, focusing the considerable ter, Providence, RI(R J.S.) regarding the approval of all resources needed to rule out a This article was published on September 2 new diabetes drugs. From a car- cardiovascular concern only on 2013, at NEJM.org diovascular perspective, rosigli- drugs with clinical or preclinical azone, saxagliptin, and alogliptin justification for that expenditure. fects of intensive glucose lowering on cardio- appear to be relatively safe. It is New therapies targeting glycemic vascular outcomes. N EnglJMed 2011; 364 disappointing, however, that nei- control may have cardiovascular 818-28 ther intensive glycemic control benefit, but this has yet to be 2 Nissen se, wi ski k efect of frosigli medications is associated with any the reduction of cardiovascular J Med 2007: 356: 2457-71 [Erratum, N EnglJ suggestion of cardiovascular ben- risk in diabetes should focus on Med2007:357:100] efit. Thus the evidence does not aggressive management of the evaluating cardiovascular risk in new antidia support the use of glycated he- standard cardiovascular risk fac- betic therapies to treat type 2 diabetes. Silver moglobin as a valid surrogate for tors rather than on intensive gly- 2008 assessing either the cardiovascu- cemic control. lar risks or the cardiovascular Disclosure forms provided by the at benefits of diabetes therapy thors are available with the full text of this 4. Home PD, Pocock S), Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascu Patients with type 2 diabetes article at NEJM. org. lar outcomes in oral agent combination nd their physicians currently have From the Division of Cardiology and Colo- therapy for type 2 diabetes(RECORD): a numerous treatment options, and rado Prevention Center Clinical Research, multicentre, randomised, open-label trial additional drugs are in develop- epartment of Medicine, University of Col. Lancet 2009: 373: 2125-35 orado School of Medicine, Aurora(WRH ) 5. Kaul S, Diamond GA. Is there clear and ment. Perhaps the recent experi- the Division of Cardiology, University of convincing evidence of cardiovascular risk ence with rosiglitazone will allow California, Los Angeles, and Cedars-Sinai with rosiglitazone? Clin Pharmacol Ther ledical Center, Los Angeles(S K ); and the 2011:89:773-6 the fda to become more target- ocean State Research Institute, Alpert DOl: 10.1056/NEJMp1309610 ed in its adjudication of the car- Medical School of Brown University, and Copyright o 2013 Massachusetts Medical Society The Dead-Donor Rule and the Future of Organ Donation Robert D. Truog, M.D., Franklin G. Miller, Ph. D, and Scott D. Halpern, M.D., Ph.D. he ethics of organ transplan- and to procure her organs short- scribed by Dr. Joseph Darby at tation have been premised ly after death. But the attempt to the University of Pittsburgh on"the dead-donor rule"(DDR, donate was aborted because the ical Center, the family of a man which states that vital organs girl did not die quickly enough with devastating brain injury re should be taken only from per- to allow procurement of viable quested withdrawal of life sup sons who are dead. Yet it is not organs. Her parents experienced port. The man had been a strong obvious why certain living pa- this failure to donate as a second advocate of organ donation, but tients, such as those who are loss; they questioned why their he was not a candidate for any of near death but daughter could not have been the traditional approaches. His should not be allowed to given an anesthetic and had the family therefore sought permis their organs, if doing so organs removed before life sup- sion for him to donate organs benefit others and be con port was stopped. As another before death. To comply with the ith their own interests parent of a donor child observed DDR, plans were made to remove This issue is not merely theo- when confronted by the limita- only nonvital organs(a kidney retical. In one recent case, the tions of the ddr "There was no and a lobe of the liver) while he parents of a young girl wanted to chance at all that our daughter was under anesthesia and then ter an accI- was going to sur I can take him back to the intensive dent had left her with devastat- follow the ethicist's argument, care unit, where life support ing brain damage. Plans were but it seems totally ludicrous would be withdrawn. Although made to withdraw life support In another recent case de- the plan was endorsed by the ENGLJMED 369: 14 NEJM.ORG OCTOBER 3, 2013n engl j med 369;14 nejm.org october 3, 2013 PERSPECTIVE 1287 cular risks of rosiglitazone led to a major change in FDA policy regarding the approval of all new diabetes drugs. From a car￾diovascular perspective, rosigli￾tazone, saxagliptin, and alogliptin appear to be relatively safe. It is disappointing, however, that nei￾ther intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular ben￾efit. Thus the evidence does not support the use of glycated he￾moglobin as a valid surrogate for assessing either the cardiovascu￾lar risks or the cardiovascular benefits of diabetes therapy. Patients with type 2 diabetes and their physicians currently have numerous treatment options, and additional drugs are in develop￾ment. Perhaps the recent experi￾ence with rosiglitazone will allow the FDA to become more target￾ed in its adjudication of the car￾diovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure. New therapies targeting glycemic control may have cardiovascular benefit, but this has yet to be shown. The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk fac￾tors rather than on intensive gly￾cemic control. Disclosure forms provided by the au￾thors are available with the full text of this article at NEJM.org. From the Division of Cardiology and Colo￾rado Prevention Center Clinical Research, Department of Medicine, University of Col￾orado School of Medicine, Aurora (W.R.H.); the Division of Cardiology, University of California, Los Angeles, and Cedars–Sinai Medical Center, Los Angeles (S.K.); and the Ocean State Research Institute, Alpert Medical School of Brown University, and Providence Veterans Affairs Medical Cen￾ter, Providence, RI (R.J.S.). This article was published on September 2, 2013, at NEJM.org. 1. The ACCORD Study Group. Long-term ef￾fects of intensive glucose lowering on cardio￾vascular outcomes. N Engl J Med 2011;364: 818-28. 2. Nissen SE, Wolski K. Effect of rosigli￾tazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71. [Erratum, N Engl J Med 2007;357:100.] 3. Guidance for Industry: diabetes mellitus — evaluating cardiovascular risk in new antidia￾betic therapies to treat type 2 diabetes. Silver Spring, MD: Food and Drug Administration, 2008 (www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf). 4. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascu￾lar outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373:2125-35. 5. Kaul S, Diamond GA. Is there clear and convincing evidence of cardiovascular risk with rosiglitazone? Clin Pharmacol Ther 2011;89:773-6. DOI: 10.1056/NEJMp1309610 Copyright © 2013 Massachusetts Medical Society. the Cardiovascular Safety of Diabetes Drugs The Dead-Donor Rule and the Future of Organ Donation Robert D. Truog, M.D., Franklin G. Miller, Ph.D., and Scott D. Halpern, M.D., Ph.D. The ethics of organ transplan￾tation have been premised on “the dead-donor rule” (DDR), which states that vital organs should be taken only from per￾sons who are dead. Yet it is not obvious why certain living pa￾tients, such as those who are near death but on life support, should not be allowed to donate their organs, if doing so would benefit others and be consistent with their own interests. This issue is not merely theo￾retical. In one recent case, the parents of a young girl wanted to donate her organs after an acci￾dent had left her with devastat￾ing brain damage. Plans were made to withdraw life support and to procure her organs short￾ly after death. But the attempt to donate was aborted because the girl did not die quickly enough to allow procurement of viable organs. Her parents experienced this failure to donate as a second loss; they questioned why their daughter could not have been given an anesthetic and had the organs removed before life sup￾port was stopped. As another parent of a donor child observed when confronted by the limita￾tions of the DDR, “There was no chance at all that our daughter was going to survive. . . . I can follow the ethicist’s argument, but it seems totally ludicrous.”1 In another recent case de￾scribed by Dr. Joseph Darby at the University of Pittsburgh Med￾ical Center, the family of a man with devastating brain injury re￾quested withdrawal of life sup￾port. The man had been a strong advocate of organ donation, but he was not a candidate for any of the traditional approaches. His family therefore sought permis￾sion for him to donate organs before death. To comply with the DDR, plans were made to remove only nonvital organs (a kidney and a lobe of the liver) while he was under anesthesia and then take him back to the intensive care unit, where life support would be withdrawn. Although the plan was endorsed by the