On the basis of early analyses, the Food and Drug Administration (FDA) decided in 2007 that rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline) could remain on the market with a boxed warning and a Medication Guide highlighting the possibility of an increased risk of myocardial infarction (“heart attack”). The Food and Drug Administration also required the manufacturer, GlaxoSmithKline, to perform a cardiovascular outcomes study to prospectively evaluate the risk from rosiglitazone.1 In response, GlaxoSmithKline initiated the TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation) trial. It was randomized, double-blinded, and placebo-controlled with a planned enrollment of 11,680 type 2 diabetic patients that was designed to compare the effects of adding rosiglitazone, pioglitazone (ACTOS, Takeda), or placebo to other anti-diabetic therapies. The main comparison was to be the time until the first occurrence of either cardiovascular death, nonfatal myocardial infarction (“heart attack”), or nonfatal stroke (collectively known as “major adverse cardiovascular events”). The vitamin D portion of the study was intended to evaluate the effects of long-term vitamin D supplementation on death and cancer.1 As I have previously posted (“Avandia’s TIDE is Stopped,” December 24, 2013), TIDE was cancelled by the Food and Drug Administration (FDA).
In addition to the meta-analysis of forty-two short term studies mentioned in my December 19, 2013 post, “A Little Background on the Big Avandia Controversy,” in 2009, the Food and Drug Administration (FDA) also evaluated three large, long-term, controlled studies: ADOPT (A Diabetes Outcomes Progression Trial), DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication), and an analysis of the then ongoing RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) study.1
The 4351 patients in ADOPT had recently been diagnosed with type 2 diabetes mellitus and had only been treated with diet and exercise.1 They were assigned randomly (by chance) to therapy with a single drug: either glyburide (Micronase, Pfizer), metformin (Glucophage, Bristol-Myers Squibb), or rosiglitazone (Avandia, GlaxoSmithKline). Until the end of the study, neither the patients nor the investigators knew which patient was receiving which drug (a double blind active-controlled study).2 The main outcome was the amount of time that it took for fasting plasma3 glucose levels to increase to 180 milligrams/deciliter. Half of the patients were treated for less than, and half for more than, 4.0 years. There were 31 all-cause deaths each among those treated with metformin or glyburide and 34 among those treated with rosiglitazone; these small differences were not statistically “significant”–in other words, they could easily have occurred by chance.2
The 5269 patients in DREAM did not meet criteria for diabetes, but were at high risk for developing it, because they had either abnormally high fasting plasma3 glucose levels (impaired fasting glucose) or an abnormal spike in blood glucose levels after a standard dose of glucose (impaired glucose tolerance). They were assigned by chance to either rosiglitazone or an inactive lookalike, and, until the end of the study, neither they nor the investigators knew to which group they were assigned (a randomized, double-blind, placebo-controlled study). The study looked at the development of either diabetes or death (from any cause) while on treatment.4 The combined outcome of diabetes and death was significantly lower in the group treated with rosiglitazone, so the authors were justified in attempting to identify where the difference occurred (See the discussion of “protected” statistical testing in my December 19, 2013 post, “Nissen, Wolski, and How Not to Do Meta-Analyses.”). Even though there were no differences in the overall cardiovascular events or the combination of myocardial infarction (“heart attack”), stroke, and cardiovascular death, the authors reported a significantly higher rate of congestive heart failure with rosiglitazone. While the authors could legitimately examine categories within the “significant” difference of their combined diabetes and death outcome, I do not believe that they could properly examine subcategories (including myocardial infarction, stroke, and cardiovascular death) within a category that they had found to be “non-significant.” At any rate, they did the analyses, finding no evidence for differences in myocardial infarctions (“heart attacks”), stroke, cardiovascular death, new angina (chest pain from the heart), or revascularization (percutaneous transluminal angioplasty=PCTA or coronary artery bypass grafting=CABG).
The 4447 patients in RECORD had type 2 diabetes treated with either metformin or a sulfonylurea. They were randomly assigned to the addition of either rosiglitazone or to the combination metformin plus a sulfonylurea. The prespecified primary endpoint was hospitalization or death from cardiovascular causes, with a predefined non-inferiority risk ratio of 1.20.5 Unfortunately, the study was not blinded—in other words, both study subjects and investigators knew drug assignments during the study. The reason for this was the expected need to use insulin, especially in the non-rosiglitazone groups, due to the duration of the study, and the problems with using placebo insulin.6 In an interim analysis performed while the study was ongoing, there was no difference in hospitalizations and death between rosiglitazone and the combination of metformin plus a sulfonylurea. 321 study subjects treated with rosiglitazone and 323 treated without rosiglitazone died or were hospitalized due to cardiovascular causes,5 for a “non-significant” hazard ratio of 321/2220:323/2227=0.99. Since the 95% confidence interval did not include the prespecified risk ratio of 1.201 (a 20% increase in risk), these results did not support the prespecified risk level.5 As explained in the discussion of “protected” statistical testing in my December 19, 2013 post, “Nissen, Wolski, and How Not to Do Meta-Analyses,” since the overall result was statistically “non-significant,” the authors were not justified in performing subgroup analysis to look for the sources of a difference that did not exist. Even though they did so anyway (without adjusting for multiple comparisons or “multiplicity”), only the increased risk for congestive heart failure that resulted in death or hospitalization was considered by the authors to be more common in those treated with rosiglitazone (and that was already well-known), but not either cardiovascular death, myocardial infarction, or stroke.5 In the words of the Food and Drug Administration, “The U.S. Food and Drug Administration (FDA) has determined that recent data for rosiglitazone-containing drugs, such as Avandia, Avandamet, Avandaryl, and generics, do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea. As a result, we are requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010.”7
Except for RECORD, studies were not designed to evaluate the cardiovascular risk of rosiglitazone (although, in DREAM, major adverse cardiovascular events were adjudicated by an endpoints committee).1 In spite of the deficiencies of these three studies, combined, they represented 15067 patients with a minimum duration of treatment of approximately 3 years. Impressively, even though flawed statistical techniques were biased toward falsely finding differences where none existed, there was no indication for any increased cardiovascular risk from rosiglitazone, except for the already known increase in congestive heart failure. It shares that risk with pioglitazone (Actos, Actosplus Met, Actosplus Met XR, Duetact, Osini; Takeda)–and with troglitazone (Rezulin, Warner-Lambert) before them.
Even though I am discussing the final results of these three studies, please do not lose sight of the fact that there was never valid evidence of any problem with rosiglitazone, in the first place. Interestingly, I am friends with a number of endocrinologists, like myself, from Dr. Nissen’s own institution of the Cleveland Clinic, and, from the beginning of this controversy, every one of them held him in disdain, if not outright contempt. Why? I do not wish to over-estimate Dr. Nissen’s knowledge of statistics, but it is even conceivable that he knew better. Was he motivated by the fact that Takeda had contracted for him to study pioglitazone, but that GlaxoSmithKline had not contracted for him to study rosiglitazone? To those who would dismiss this suggestion out of hand, I would point out that Dr. Nissen’s ongoing behaviors in this controversy have been anything but professional, much less scientific.
© 2013 Myron Shank, M.D., Ph.D.
1 Parks Mary H. Introduction memorandum. Readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes Trial (RECORD): Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee June 5—6, 2013. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf
2 Kahn Steven E., Haffner Steven M., Heise Mark A., Herman William H., Holman Rury R., Jones Nigel P., Kravitz Barbara G., Lachin John M., O’Neill M. Colleen, Zinman Bernard, Viberti Giancarlo, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. New England Journal of Medicine 2006; 355:2427-2443.
3The liquid portion of blood, minus the cells.
4 DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein H.C., Yusuf S., Bosch J., Pogue J., Sheridan P., Dinccag N., Hanefeld M., Hoogwerf B., Laakso M., Mohan V., Shaw J., Zinman B., Holman R.R. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368:1096-105.
5 Home Philip D., Pocock Stuart J., Beck-Nielsen Henning, Gomis Ramon, Hanefeld Markolf, Jones Nigel P., Komajda Michel, McMurray John J.V., for the RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. The Lancet 2009; 373:2125-2135.
6 Unger Ellis F. 21-071; suppl 35, 36, 37 Avandia (rosiglitazone). June 15, 2010. In: FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf (I do not believe that this was sufficient reason for a non-blinded study, however.)
7 US Food and Drug Administration. FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Drug Safety and Availability, November 25, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm376389.htm.