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复旦大学：《循证医学》课程教学资源（参考教材）Unit 09 药物不良反应的分析评价（主讲教师：朱畴文）

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Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14 , 2007 2465 49653/331 Rsg 4 mg Chronic psoriasis Jan. 2003–Oct. 2004 44.9 64.1 88 NA Rsg 2 mg 45.2 62.0 90 NA Plc — 46.4 58.3 93 NA 49653/137 Rsg/Met ≥2 mg/≥1 g Type 2 DM April 2000–March 2004 60.0 63.4 78 NA Gly/Met ≥5 mg/≥1 g 58.8 68.9 76 SB-712753/002 Rsg/Met 4 or 8 mg/ 2–3 g Type 2 DM poorly controlled July 2003–June 2004 58.1 58.3 97 7.4 Met 2–3 g 57.6 56.8 98 7.5 SB-712753/007 Rsg/Met 2 or 8 mg/0.5-2.0 g Type 2 DM without previous drug therapy Oct. 2003–Dec. 2004 50.1 57.4 54 8.9 Rsg 4 or 8 mg 51.5 56.5 58 8.8 Met 0.5–2.0 g 50.6 58.5 59 8.8 SB-712753/009 Rsg/Met/insulin 8 mg/2 g Type 2 DM with insulin Oct. 2003–Nov. 2004 57.2 51.8 98 8.7 Insulin Usual care 56.9 53.1 99 8.8 49653/132 Rsg/Su 4 mg/usual care Patients in China with type 2 DM April 1999–Feb. 2000 58.9 47.6 100 A 9.9 Rsg/Su 8 mg/usual care 59.0 41.4 100 A 9.7 Su Usual care 58.8 45.7 100 A 9.6 AVA100193 Rsg 2 mg Mild-to-moderate Alzheimer’s disease Jan. 2004–May 2005 71.0 44.1 100 NA Rsg 4 mg 70.0 43.8 100 NA Rsg 8 mg 71.0 34.1 100 NA Plc — 72.0 36.9 100 NA DREAM Rsg 4 or 8 mg Impaired glucose tolerance or fasting glucose July 2001–Aug. 2003 54.6 41.7 66 104.5‡ Plc — 54.8 39.9 66 104.5‡ ADOPT Rsg 4 mg Recently diagnosed type 2 DM April 2000–June 2002 56.3 55.7 87 7.4 Met 500 mg 57.9 59.4 89 7.4 Gly 2.5 mg 56.4 58.0 89 7.4 Weighted adjusted means§ Rsg 56.1 60.7 84.4 8.2 Control 56.9 53.3 77.5 8.2 * Rsg denotes rosiglitazone, DM diabetes mellitus, Gly glyburide, Plc placebo, CHF congestive heart failure, Met metformin, ELM enhanced lifestyle management, Su sulfonylurea, Glip glipizide, Glim glimepiride, and NA not available. † Percentages are the proportion of white patients, unless otherwise specified as black (B), Hispanic (H), or Asian (A). ‡ The fasting plasma glucose level (in milligrams per deciliter) is listed. § Weighted adjusted means were calculated for the rosiglitazone and control groups by multiplying individual means by sample sizes, adding them together, and dividing the sum by the total sample size for each treatment group. The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved

ROSIGLITAZONE AND CARDIOVASCULAR OUTCOMES Table3.(Continued.) Study Rosiglitazone Group Control Group Death from ad a number number AVA10019 394 124 0 0 DREAM 2635 12 2634 10 ADOPT 1456 27 2895 Total 39 cardiovascular cause sure of such patients to rosiglitazone is wide spread.the oublic health imnact ofan increase in fined according to the comparator drug.Similar cardiovascular risk could be substantial if our results were obtained when the analysis exclud- data are borne out by further analysis and the ed trials with an active comparator group.The results of larger controlled trials. rogeneity for myocardia Although we did not have access to the on an om carc A mated odds ratios in all cases were greater than for both of these end points suggests that ob- 1.0,suggesting that observed adverse effects dur-served adverse effects associated with rosiglita ing rosiglitazone treatment were not unique to zone were probably not due to chance alone any specific comp rator regimen This meta-anal ded a group of trials tha on (2 405 ar milar to the W2s11895%CL,0.89to1.55:P=0.24 sis.Thus,in susceptible patients rosiglitaz therapy may be capable of provoking myocardial DIscussion infarction or death from cardiovascular causes after relatively short-term exposure.In contrast ong-term therapies that improve diovascula er an tcomes,suc as stat and anti se in the risk of r and Notably the estimates fo the odds ratios for with an increase in the risk of death from cardio mvocardial infarction and death from cardiovas vascular causes that was of borderline signifi- cular causes appear elevated for rosiglitazone in suggests that the increased risk as erapies (Table 5). cated with s not a func The r app. rent increas protecti dial i arctio cess to trialt esults fr ain.One es not on patient-level source data furthermore be the adverse effect of the drug on serum lipids results are based on a relatively small number o The FDA-approved rosiglitazone product label ting in odds ratios that reports a mean increase in low-density lipopro tein f o%am None hel ,0U ngs are we mg da with diah es ies and lipid-l ng trials l ervat els of N ENGLJ MED 356:24 WWW.NEJM.ORG JUNE 14,200 2467 The New England Journal of Medicine

Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 2467 farction and death from cardiovascular causes associated with rosiglitazone for subgroups defined according to the comparator drug. Similar results were obtained when the analysis excluded trials with an active comparator group. The heterogeneity P values were 0.53 for myocardial infarction and 0.68 for death from cardiovascular causes across subgroups. As compared with placebo or other antidiabetic regimens, the estimated odds ratios in all cases were greater than 1.0, suggesting that observed adverse effects during rosiglitazone treatment were not unique to any specific comparator regimen. In an analysis that was not prespecified, we also studied the effects of rosiglitazone on death from any cause. The odds ratio for death from any cause was 1.18 (95% CI, 0.89 to 1.55; P=0.24). Discussion Our data show that, as compared with placebo or with other antidiabetic regimens, treatment with rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that was of borderline significance. The similar odds ratio for comparison with placebo suggests that the increased risk associated with rosiglitazone was not a function of the protective effects of active comparator drugs. However, these findings are based on limited access to trial results from publicly available sources, not on patient-level source data. Furthermore, results are based on a relatively small number of events, resulting in odds ratios that could be affected by small changes in the classification of events. Nonetheless, our findings are worrisome because of the high incidence of cardiovascular events in patients with diabetes.4 Because exposure of such patients to rosiglitazone is widespread, the public health impact of an increase in cardiovascular risk could be substantial if our data are borne out by further analysis and the results of larger controlled trials. Although we did not have access to the source data to construct a composite outcome that included myocardial infarction or death from cardiovascular causes, the increase in the odds ratios for both of these end points suggests that observed adverse effects associated with rosiglitazone were probably not due to chance alone. This meta-analysis included a group of trials that were of relatively short duration (24 to 52 weeks). The odds ratio for these shorter-term trials was similar to the overall results of the meta-analysis. Thus, in susceptible patients, rosiglitazone therapy may be capable of provoking myocardial infarction or death from cardiovascular causes after relatively short-term exposure. In contrast, long-term therapies that improve cardiovascular outcomes, such as statins and antihypertensive drugs, often take several years to provide benefits. Notably, the estimates for the odds ratios for myocardial infarction and death from cardiovascular causes appear elevated for rosiglitazone in comparison with placebo or other commonly prescribed antidiabetic therapies (Table 5). The mechanism for the apparent increase in myocardial infarction and death from cardiovascular causes associated with rosiglitazone remains uncertain. One potential contributing factor may be the adverse effect of the drug on serum lipids. The FDA-approved rosiglitazone product label reports a mean increase in low-density lipoprotein (LDL) cholesterol of 18.6% among patients treated for 26 weeks with an 8-mg daily dose, as compared with placebo.25 In observational studies and lipid-lowering trials, elevated levels of Table 3. (Continued.) Study Rosiglitazone Group Control Group No. of Patients Myocardial Infarction Death from Cardiovascular Cause No. of Patients Myocardial Infarction Death from Cardiovascular Cause number number AVA100193 394 1 1 124 0 0 DREAM 2635 15 12 2634 9 10 ADOPT 1456 27 2 2895 41 5 Total 86 39 72 22 The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL Of MEDICINE Table 4.Rates of Myo rdial Infarction and Death from Cardiovascular Causes Study Control Group PValu no.ofevents/total no.() Myocardial infarctior Small trials combined 44/10,2850.43) 22/61060.36) 1.450.88-2.391 0.15 DREAM 15/2,6350.5刀 9/26340.340 1.650.74-3.68 022 ADOPT 271,456.85 41/28951.42) 1.330.80-2.210 0.27 143L03-1.98 0.03 h from cardiovascular cause all trials combine 25/6,8450.36 7/3980(0.18 2.40(17-491 DREAM 12/2.6350.46 10/2634(0.38 1.200.52-2.78) 0.67 ADOPT 2/1.4560.14) 5/289510.17刀 0.8010.17-3.86 0.78 Overall 1.640.98-2.74 0.06 LDLcholesterol were associated with an increase farction,during phase 2 and 3 testing.After in adverse cardic nes.Thus,an in- publication of an analysis of cardiovascular out ster wve con opm nitude of y the ma nent pro parent hazard was not consistent with an effect terminated after evidence of toxiciry emerg ed dur produced by lipid changes alone. ing preclinical studies or initial trials in humans Several other properties of rosiglitazone may According to a former FDA official,more thar contribute to adverse cardi ovascular outcomes 50 Investigational New rug applications fo novel PPARs have ut no additiona known precip ure ly reachec the mar a physiological stare thats ciated with ar increased intravascular volume volume overload dial toxicity in studies in animals 29 but few data increases stress on the left ventricular wall,a fac on toxicity are available in the public domain be tor that determines myocardial oxygen demand. cause of the common industry practice of no In susceptib e patients, increas publishing safety findings for ailed pro ducts oxygen de zone na P es a modest reductio in the he In susceptible patients,a reduced hemoglobin substantially among various PPAR agonists,even level may result in increased physiological stress within closely related compounds.The biologic thereby provoking myocardial ischemia.A study effects of the protein targets for most of the of rosiglitazone th was cond ed in rats repor d by PPAR agonists remain large ed an i rate c ind d nt and during of other ents has been reported to increase adverse cardiovas Some drugs have provoked multispecies multi- cular events.Muraglitazar,an investigational dual organ system cancers;others have resulted in PPAR-a and PPAR-y agonist,increased adverse rhabdomyolysis or nephrotoxicity.Troglitazone cardiovascular events,including myocardial in- was withdrawn from the market for rare,but 2468 N ENGLJ MED 356:24 WWW.NEJM.ORG JUNE 14.2007 Downloaded from 5,2016.F 15

T h e n e w e ng l a nd j o u r na l o f m e dic i n e 2468 n engl j med 356;24 www.nejm.org june 14, 2007 LDL cholesterol were associated with an increase in adverse cardiovascular outcomes. Thus, an increase in LDL cholesterol of the magnitude observed in the rosiglitazone group may have contributed to adverse cardiovascular outcomes, although the rapidity and magnitude of the apparent hazard was not consistent with an effect produced by lipid changes alone. Several other properties of rosiglitazone may contribute to adverse cardiovascular outcomes. Rosiglitazone and other thiazolidinediones are known to precipitate congestive heart failure in susceptible patients.26 Congestive heart failure is a physiological state that is associated with an increased intravascular volume. Volume overload increases stress on the left ventricular wall, a factor that determines myocardial oxygen demand. In susceptible patients, an increase in myocardial oxygen demand could theoretically provoke ischemic events. The administration of thiazolidinediones, including rosiglitazone, also produces a modest reduction in the hemoglobin level.25 In susceptible patients, a reduced hemoglobin level may result in increased physiological stress, thereby provoking myocardial ischemia. A study of rosiglitazone that was conducted in rats reported an increase in the rate of death after experimentally induced myocardial infarction.27 Rosiglitazone is not the first PPAR agonist that has been reported to increase adverse cardiovascular events. Muraglitazar, an investigational dual PPAR-α and PPAR-γ agonist, increased adverse cardiovascular events, including myocardial infarction, during phase 2 and 3 testing.28 After publication of an analysis of cardiovascular outcomes, muraglitazar was not approved by the FDA, and further development was subsequently halted by the manufacturer. Development programs for many other PPAR agonists have been terminated after evidence of toxicity emerged during preclinical studies or initial trials in humans. According to a former FDA official, more than 50 Investigational New Drug applications for novel PPARs have been filed, but no additional drugs have successfully reached the market in more than 6 years.29 In some cases, these drugs have failed because of evidence of direct myocardial toxicity in studies in animals,29 but few data on toxicity are available in the public domain because of the common industry practice of not publishing safety findings for failed products. PPAR agonists such as rosiglitazone have very complex biologic effects, resulting from the activation or suppression of dozens of genes.30 The patterns of gene activation or suppression differ substantially among various PPAR agonists, even within closely related compounds. The biologic effects of the protein targets for most of the genes influenced by PPAR agonists remain largely unknown. Accordingly, many different and seemingly unrelated toxic effects have emerged during development of other PPAR agents.29 Some drugs have provoked multispecies, multi– organ system cancers; others have resulted in rhabdomyolysis or nephrotoxicity.29 Troglitazone was withdrawn from the market for rare, but Table 4. Rates of Myocardial Infarction and Death from Cardiovascular Causes. Study Rosiglitazone Group Control Group Odds Ratio (95% CI) P Value no. of events/total no. (%) Myocardial infarction Small trials combined 44/10,285 (0.43) 22/6106 (0.36) 1.45 (0.88–2.39) 0.15 DREAM 15/2,635 (0.57) 9/2634 (0.34) 1.65 (0.74–3.68) 0.22 ADOPT 27/1,456 (1.85) 41/2895 (1.42) 1.33 (0.80–2.21) 0.27 Overall 1.43 (1.03–1.98) 0.03 Death from cardiovascular causes Small trials combined 25/6,845 (0.36) 7/3980 (0.18) 2.40 (1.17–4.91) 0.02 DREAM 12/2,635 (0.46) 10/2634 (0.38) 1.20 (0.52–2.78) 0.67 ADOPT 2/1,456 (0.14) 5/2895 (0.17) 0.80 (0.17–3.86) 0.78 Overall 1.64 (0.98–2.74) 0.06 The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved

ROSIGLITAZONE AND CARDIOVASCULAR OUTCOMES sometimes fatal,liver toxicity.Accordingly,it must be assumed that a variety of unexpected toxic ing Drug effects are possible when PPAR agonists are ad ministered t P Valu The questi whether the obs Comparator Drug Myocardial infarction zolidinediones must also be considered.Pioelita Metformin 1.140.70-186 0.59 zone is a related agent also widely used to trea Sulfonylure 1.2410.78-1.981 036 type 2 diabetes mellitus.However,unlike rosig. 2.780.58-133 020 litazone,pioglitazone has been studied in imep8gado 1800.95-339 0.07 Combined comparator drugs 1.43(1.03-1.98) 0.03 Death from cardiovascular causes Metformin 113103A3711 0g4 included coronary and peripheral vasculare 420.60-33到 0.43 showed a trend toward benefit from pioglita 5.37(0.51-56.52 zone (hazard ratio,0.90:P=0.095).A secondary Placebo 1.22(0.64-2.34】 0.55 end point consisting of myocardi stroke,and de Combined com ator drugs 1.640.98-2.741 0.06 th from cause sh ed tio 084.p-00 deaths.Accordingly.the confidence intervals for larly triglycerides,than does rosiglitazone. the odds ratios for my cardial infaretion and These emerging findings raise an important death from cardiovascular causes are wide.re question about the appropriateness of the cur sulting in considerable incertainty about the cntreglaiortre the dev FL ls.Th oorigina sed alysis adequate for maries of events.The lack of source data did not allow the use of more statis- apy is the reduction of the complications of dia- tically powerful time-to-event analysis.A meta betes,not improvement in a laboratory measure analysis is always considered less convincing or glycemic contro Alth ns in blood than a large prospective trial I designed to as eia the ou n such a dedi the fect ns has r one Evaluated fo to be unpredictable.After the failure of mura Cardiac Outcomes and Regulation of Glvcaemia glitazar and the apparent increase in adverse in Diabetes (RECORD)trial may provide useful cardiovascular outcomes with rosiglitazone,the insights. use of blood glucose measurements as a surro Despite the limitation our data point to gate point regulatory approva must De th or co ons t We pooled the results of of trials that e clinical trials is not originally intended to explore cardiovascular not sufficient to enable a robust assessment of outcomes.Most trials did not centrally adjudicate cardiovascular risks.The manufacturer has all cardiov outcomes,and the definitions of infarction we e no available.Many ble to an exter s wer and term,re adverse cardiovascular events o FDA for syst atic ana access to study reports N ENGL J MED 356;24 WWW.NEJM.ORG JUNE 14,200 246 The New England Joumal of Medicine

Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 2469 sometimes fatal, liver toxicity. Accordingly, it must be assumed that a variety of unexpected toxic effects are possible when PPAR agonists are administered to patients. The question as to whether the observed risks of rosiglitazone represent a “class effect” of thiazolidinediones must also be considered. Pioglitazone is a related agent also widely used to treat type 2 diabetes mellitus. However, unlike rosiglitazone, pioglitazone has been studied in a prospective, randomized trial of cardiovascular outcomes, called Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE).31 The primary end point, a broad composite that included coronary and peripheral vascular events, showed a trend toward benefit from pioglitazone (hazard ratio, 0.90; P=0.095). A secondary end point consisting of myocardial infarction, stroke, and death from any cause showed a significant effect favoring pioglitazone (hazard ratio, 0.84; P=0.027). Notably, pioglitazone appears to have more favorable effects on lipids, particularly triglycerides, than does rosiglitazone.32 These emerging findings raise an important question about the appropriateness of the current regulatory pathways for the development of drugs to treat diabetes. The FDA considers demonstration of a sustained reduction in blood glucose levels with an acceptable safety profile adequate for approval of antidiabetic agents. However, the ultimate value of antidiabetic therapy is the reduction of the complications of diabetes, not improvement in a laboratory measure of glycemic control. Although reductions in blood glucose levels have been shown to reliably reduce microvascular complications of diabetes, the effect on macrovascular complications has proved to be unpredictable.33 After the failure of muraglitazar and the apparent increase in adverse cardiovascular outcomes with rosiglitazone, the use of blood glucose measurements as a surrogate end point in regulatory approval must be carefully reexamined. Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A metaanalysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest. Although such a dedicated trial has not been completed for rosiglitazone, the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial may provide useful insights.34 Despite these limitations, our data point to the urgent need for comprehensive evaluations to clarify the cardiovascular risks of rosiglitazone. The manufacturer’s public disclosure of summary results for rosiglitazone clinical trials is not sufficient to enable a robust assessment of cardiovascular risks. The manufacturer has all the source data for completed clinical trials and should make these data available to an external academic coordinating center for systematic analysis. The FDA also has access to study reports Table 5. Risk of Myocardial Infarction and Death from Cardiovascular Causes for Patients Receiving Rosiglitazone versus Several Comparator Drugs. Comparator Drug Odds Ratio (95% CI) P Value Myocardial infarction Metformin 1.14 (0.70–1.86) 0.59 Sulfonylurea 1.24 (0.78–1.98) 0.36 Insulin 2.78 (0.58–13.3) 0.20 Placebo 1.80 (0.95–3.39) 0.07 Combined comparator drugs 1.43 (1.03–1.98) 0.03 Death from cardiovascular causes Metformin 1.13 (0.34–3.71) 0.84 Sulfonylurea 1.42 (0.60–3.33) 0.43 Insulin 5.37 (0.51–56.52) 0.16 Placebo 1.22 (0.64–2.34) 0.55 Combined comparator drugs 1.64 (0.98–2.74) 0.06 The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved

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