Transcript PowerPoint - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
Meijvis SC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van
Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos
WJ, Biesma DH.
Dexamethasone and length of hospital stay in patients with communityacquired pneumonia: a randomised, double-blind, placebo-controlled trial.
Lancet. 2011 Jun 11;377(9782):2023-30.
Piccinni C, Motola D, Marchesini G, Poluzzi E.
Assessing the association of pioglitazone use and bladder cancer through
drug adverse event reporting.
Diabetes Care. 2011 Jun;34(6):1369-71.
2011年6月16日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
ニューモシスチス肺炎に対する使用
成人市中肺炎診療ガイドライン 2007年
成人市中肺炎診療ガイドライン 2007年
Department of Internal Medicine (S C A Meijvis MD, W J W Bos MD, Prof D H Biesma MD), Department of Pulmonology (H
Hardeman MD, Prof J C Grutters MD), Department of Medical Microbiology and Immunology (G T Rijkers PhD, H van
Velzen-Blad MSc, G P Voorn MD), and Department of Clinical Pharmacy (E M W van de Garde PhD), St Antonius Hospital,
Nieuwegein, Netherlands; Department of Internal Medicine, Gelderse Vallei Hospital, Ede, Netherlands (H H F Remmelts
MD, R Heijligenberg MD); Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht
University, Utrecht, Netherlands (E M W van de Garde); Department of Intensive Care Medicine, Onze Lieve Vrouwe
Gasthuis, Amsterdam, Netherlands (H Endeman MD); and Division Heart and Lungs (J C Grutters) and Department of
Internal Medicine (H H F Remmelts, D H Biesma), University Medical Centre Utrecht, Utrecht, Netherlands
Lancet 2011; 377: 2023–30
Background
Whether addition of corticosteroids to
antibiotic treatment benefits patients with
community-acquired pneumonia who are
not in intensive care units is unclear. We
aimed to assess effect of addition of
dexamethasone on length of stay in this
group, which might result in earlier
resolution of pneumonia through
dampening of systemic inflammation.
Methods
In our double-blind, placebo-controlled trial, we randomly
assigned adults aged 18 years or older with confirmed
community-acquired pneumonia who presented to
emergency departments of two teaching hospitals in the
Netherlands to receive intravenous dexamethasone (5 mg
once a day) or placebo for 4 days from admission.
Patients were ineligible if they were immunocompromised,
needed immediate transfer to an intensive-care unit, or
were already receiving corticosteroids or
immunosuppressive drugs. We randomly allocated
patients on a one-to-one basis to treatment groups with a
computerised randomisation allocation sequence in
blocks of 20. The primary outcome was length of hospital
stay in all enrolled patients. This study is registered with
ClinicalTrials.gov, number NCT00471640.
Figure 1: Study profile
*Eg, pregnant or breastfeeding.
http://pda.ahrq.gov/clinic/psi/psicalc.asp
Findings
Between November, 2007, and September, 2010, we
enrolled 304 patients and randomly allocated 153 to the
placebo group and 151 to the dexamethasone group.
143 (47%) of 304 enrolled patients had pneumonia of
pneumonia severity index class 4–5 (79 [52%] patients
in the dexamethasone group and 64 [42%] controls).
Median length of stay was 6・5 days (IQR 5・0–9・0) in
the dexamethasone group compared with 7・5 days (5・
3–11・5) in the placebo group (95% CI of difference in
medians 0–2 days; p=0・0480). In-hospital mortality and
severe adverse events were infrequent and rates did not
differ between groups, although 67 (44%) of 151
patients in the dexamethasone group had
hyperglycaemia compared with 35 (23%) of 153 controls
(p<0・0001).
SUMMARY
Our study shows that a 4-day course of 5 mg
dexamethasone reduces length of hospital
stay in patients admitted for communityacquired pneumonia. The faster decline in
concentrations of C-reactive protein and
interleukin-6 that we noted in patients given
dexamethasone compared with controls
support the notion that dexamethasone
reduces the systemic inflammatory response.
Although serious adverse events were rare,
the benefits of corticosteroids should be
weighed against the potential side-effects.
Interpretation
Dexamethasone can reduce
length of hospital stay when
added to antibiotic treatment in
nonimmunocompromised
patients with communityacquired pneumonia.
Panel: Present understanding of systemic inflammation in sepsis and acute
respiratory distress syndrome
9 Activated glucocorticoid receptor α —via down regulation of nuclear factor-κB —is
most important physiological inhibitor of inflammation, affecting thousands of genes
involved in stress-related homoeostasis
10 At cellular level, patients with dysregulated inflammation have inadequate
glucocorticoid receptor-mediated down regulation of inflammatory transcription
factor nuclear factor-κB, despite often having increased concentrations of circulating
cortisol (systemic inflammation-associated glucocorticoid resistance)
11 Systemic inflammation-associated glucocorticoid resistance can be reversed by
increasing glucocorticoid receptor α activation with quantitatively adequate and
prolonged glucocorticoid supplementation
12 In patients with sepsis and acute respiratory distress syndrome, much evidence
supports a strong association between prolonged down regulation, induced by
glucocorticoid treatment, of the inflammatory response and improvement in organ
physiology
13 Even short treatment with glucocorticoid is associated with downregulation of
glucocorticoid receptor concentrations in most cell types and adrenal insufficiency;
without 6–9 days’ tapering, rebound systemic inflammation is common and
associated with substantial clinical deterioration
Published Online June 1, 2011 DOI:10.1016/S0140- 6736(11)60777-0
Message/Comments
ステロイドは肺炎の標準治療！?
（真菌はダメだと思いますが。）
ただし、退院してからどうなるか？慎重に
今後も評価が必要らしい。
肺炎でどんどんステロイド治療がされると、
血糖管理コンサルトが増えるのではない
か？ また減量後のリバウンドとか副腎不
全とかも心配。
ピオグリタゾンは癌を予防する？
Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice.
Wang Y, James M, Wen W, Lu Y, Szabo E, Lubet RA, You M.
Mol Cancer Ther. 2010 Nov;9(11):3074-82. Epub 2010 Nov 2.
Pioglitazone, a ligand for peroxisome proliferator-activated receptor-gamma acts as an inhibitor of
colon cancer liver metastasis.
Takano S, Kubota T, Nishibori H, Hasegawa H, Ishii Y, Nitori N, Ochiai H, Okabayashi K, Kitagawa
Y, Watanabe M, Kitajima M.
Anticancer Res. 2008 Nov-Dec;28(6A):3593-9.
Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma
independent mechanisms.
Galli A, Ceni E, Crabb DW, Mello T, Salzano R, Grappone C, Milani S, Surrenti E, Surrenti C,
Casini A.
Gut. 2004 Nov;53(11):1688-97.
Pioglitazone Shows Promise for Oral Cancer Prevention
Laird Harrison
International Association of Dental Research (IADR) 89th General Session and Exhibition:
Abstract 945. Presented March 17, 2011.
膵臓、肝臓、大腸、肺、口腔癌 によいらしい？
eight vs 19 cases per 10 000 person-years
PROactive study (45mg/day)
Vol.3 No.6 2011/6 月刊糖尿病 ● 102-7
http://www.afssaps.fr/
Fate of Takeda’s Actos to be assessed by UK regulators this week
By Kirsty Barnes in London
Published: June 13 2011 15:51 | Last updated: June 13 2011 15:51
http://www.ft.com/cms/s/2/106e2f74-93a9-11e0-922e-00144feab49a.html#ixzz1PC79uFod
The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) will meet this week
to discuss the fate of Takeda Pharmaceutical’s (TYO:4502) diabetes blockbuster pioglitazone
(Actos) in the UK, a source told BioPharm Insight.
An MHRA spokesperson confirmed that a meeting will be held on Thursday and possibly
Friday to discuss the Actos situation, although the specific agenda remains confidential.
Following this, the European regulator, the Committee for Medicinal Products for Human
Use (CHMP), will meet on 20 June to assess the matter, the source said. The MHRA
spokesperson confirmed this.
In an emailed statement, Takeda noted that a pan-European review of pioglitazone is
ongoing within the European Medicines Agency (EMA) and Takeda is fully cooperating with
the EMA on its review and has provided all data available to it to all regulatory authorities
worldwide.
On Thursday the French Health Products Safety Agency (AFSSAPS) announced the
suspension of the use of drugs containing pioglitazone (Actos and Competact). Germany
has since taken the same decision, it has been reported.
This follows an announcement by the US Food and Drug Administration (FDA) in September
2010 that pioglitazone was under review by the agency after possible associations with a
heightened risk of bladder cancer were identified in preliminary findings of a 10-year study
sponsored by Takeda.
The source explained that this because pioglitazone stimulates the peroxisome proliferatoractivated receptor (P-PAR) gamma and alpha receptors and this bladder growth promotion
is a class property of alpha/gamma agonists in rodents.
09/06/2011
Update on ongoing European review of pioglitazone–containing medicines
Suspension of use of these medicines in France while Europe-wide review continues
The European Medicines Agency (EMA) has been informed by the French Medicines Agency (Afssaps) of its
decision to suspend the use of pioglitazone-containing medicines in France (Actos, Competact), while awaiting
the outcome of the ongoing European review on the benefits and risks of these antidiabetic medicines.
This decision by the French authority follows receipt of results of a retrospective cohort study carried out in
France which became available today. These results appear to suggest an increased risk of bladder cancer with
pioglitazone.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) started a European review of
pioglitazone-containing medicines in March 2011 to investigate the signal of a possible increased risk of bladder
cancer with pioglitazone.
The CHMP is currently reviewing all relevant data, including data from pharmacoepidemiological studies, nonclinical and clinical data, post-marketing reports of bladder cancer and published data to assess their impact on
the balance of benefits and risks of these medicines. The Committee will now also assess the results of the
French study and its potential impact on the use of these medicines across the whole EU. The CHMP will
discuss this issue at their next meeting on 20-23 June 2011 and recommend appropriate actions as necessary.
While this review is ongoing the CHMP is not recommending any changes to the use of pioglitazone-containing
medicines.
The Agency will make further announcements as soon as new information becomes available.
Notes
The European review of the centrally authorised pioglitazone-containing medicines Actos, Glustin, Competact,
Glubrava and Tandemact and the occurrence of bladder cancer is being conducted in the context of a formal
review, initiated at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004,
on 16 March 2011.
The French targeted epidemiological study is a retrospective cohort study conducted by the French health
insurance (Caisse National d’Assurance Maladie) following antidiabetic patients taking antidiabetic medicines
between 2006 and 2009.
アクトスは昨年度全世界で3879億円を売り上げた武田の最主力製品
1 the Department of Pharmacology, University of Bologna, Bologna, Italy;
2 Metabolic Diseases & Clinical Dietetics, Department of Clinical Medicine,
University of Bologna, Bologna, Italy.
Diabetes Care 34:1369–1371, 2011
OBJECTIVE—To analyze the association between pioglitazone use
and bladder cancer through a spontaneous adverse event reporting
system for medications.
RESEARCH DESIGN AND METHODS—Case/noncase bladder
cancer reports associated with antidiabetic drug use were retrieved
from the U.S. Food and Drug Administration (FDA) Adverse Event
Reporting System (AERS) between 2004 and 2009 and analyzed by
the reporting odds ratio (ROR).
RESULTS—Ninety-three reports of bladder cancer were retrieved,
corresponding to 138 drug reaction pairs (pioglitazone, 31; insulin,
29;metformin, 25; glimepiride, 13; exenatide, 8; others, 22). ROR was
indicative of a definite risk for pioglitazone (4.30 [95%CI 2.82–6.52]),
and a much weaker risk for gliclazide and acarbose, with very few
cases being treated with these two drugs (6 and 4, respectively).
CONCLUSIONS—In agreement with preclinical and clinical studies,
AERS analysis is consistent with an association between
pioglitazone and bladder cancer. This issue needs constant
epidemiologic surveillance and urgent definition by more specific
studies.
The ratio cases/ noncases for each drug were compared with the ratio of
cases/noncases for all other antidiabetic drugs. Stratified analyses weighed
the influence of male sex and old age. The possible effect of notoriety bias
was tested by a year-by-year analysis. Epi Info 3.4.3-2007 software (Centers
for Disease Control and Prevention, Atlanta, GA) was used for statistical
analyses.
EXAMPLE PRR(proportional reporting ratio)
EXAMPLE ROR(Reporting odds ratio )
Diabetes Care 34:1369–1371, 2011
Substance Cases
All ADR
ratio
PRR
ROR
Pioglitazone
31
37841
0.00082
3.56
Insulin
29
124873
0.00023
1.01
Metformin
25
138900
0.00018
0.78
glimepiride
13
35388
0.00037
1.59
Exenatide
8
100946
0.00008
0.34
Gliclazide
6
7560
0.00079
3.45
Glipizide
5
34816
0.00014
0.62
Sitagliptin
4
11638
0.00034
1.49
Acarbose
4
3479
0.00115
4.99
Rosiglitazone
4
44006
0.00009
0.39
Glibenclamide
3
38214
0.00008
0.34
Nateglinide
2
4994
0.00040
1.74
Repaglinide
2
6060
0.00033
1.43
Phenformin
1
65
0.01538 66.79
Voglibose
1
2938
0.00034
1.48
Other
0
7367
0.00000
0.00
Total
138
599085
0.00023
1.00
1/100000
risk factors
cigarette smoking,
urinary tract infections,
occupational exposure to aromatic amines
occupational exposure to polycyclic aromatic hydrocarbons
drugs (e.g., cyclophosphamide)
the systematic use of glucocorticoids
The ROR analysis has several limitations:
generic under-reporting,
over reporting generated by notoriety bias,
dependence on the drug-marketing period (Weber
effect),
missing or misspelled data
lack of information on patients’ habits (smoking) or
occupational risks.
Prescription number and actual use?
Prescription bias ?
notoriety bias may have contributed to part of the
association between pioglitazone use and bladder
cancer, we also observed a significant relationship in
2004, which preceded publication of the PROactive
study and label revision.
Therefore, we do not believe that our findings can be
explained by notoriety bias alone. A greater use of
pioglitazone could also have influenced this result.
1
2
3
4
5
The Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania,
Philadelphia, Pennsylvania;
The Department of Biostatistics and Epidemiology, University of Pennsylvania,
Philadelphia, Pennsylvania;
the Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
the Division of Research, Kaiser Permanente Northern California, Oakland, California;
the Department of Pharmacology, University of Pennsylvania, Philadelphia,
Pennsylvania.
Diabetes Care 34:916–922, 2011
OBJECTIVE—Some preclinical in vivo studies
and limited human data suggest a possible
increased risk of bladder cancer with pioglitazone
therapy. This is an interim report of an ongoing
cohort study examining the association between
pioglitazone therapy and the risk of bladder
cancer in patients with diabetes.
RESEARCH DESIGN AND METHODS—This
study includes 193,099 patients in the Kaiser
Permanente Northern California diabetes registry
who were ≧40 years of age between 1997 and
2002. Those with prior bladder cancer were
excluded. Ever use of each diabetes medication
(defined as two or more prescriptions within 6
months) was treated as a time dependent variable.
Cox regression–generated hazard ratios (HRs)
compared pioglitazone use with non pioglitazone
use adjusted for age, sex, race/ethnicity, diabetes
medications, A1C, heart failure, household income,
renal function, other bladder conditions, and
smoking.
Data are n (%) orr median (range) unless otherwise indicated.N/A, not applicable. *All comparisons have P values ,0.01 except female sex (P = 0.46). †Creatinine$1.4 mg/dL for women and$1.5
mg/dL for men. ‡History of urinary tract infections, urolithiasis, incontinence, and other bladder or urethral conditions. §Low income defined as median household income in census block below the
cohort average ($59,000). ¶Includes newly diagnosed patients and patients who newly enrolled in KPNC with an existing diagnosis of diabetes.
RESULTS—The group treated with pioglitazone
comprised 30,173 patients. There were 90 cases of
bladder cancer among pioglitazone users and 791
cases of bladder cancer among nonpioglitazone
users. Overall, ever use of pioglitazone was not
associated with risk of bladder cancer (HR 1.2
[95% CI 0.9–1.5]), with similar results in men and
women (test for interaction P = 0.8). However, in
the a priori category of ＞24 months of therapy,
there was an increased risk (1.4 [1.03–2.0]).
Ninety-five percent of cancers diagnosed among
pioglitazone users were detected at early stage.
CONCLUSIONS—In this cohort of patients with
diabetes, short-term use of pioglitazone was not
associated with an increased incidence of bladder
cancer, but use for more than 2 years was weakly
associated with increased risk.
Message/Comments
ROR (reporting odds ratio) という指標の妥当
性はやはり検討が必要なのでは。
Kaiser Permanente Northern California
diabetes registry を見るにしても、処方の時に
処方した人に対してバイアスが入るのでどこまで
信用できるかは不明。
これらのデータから新規処方の禁止はないと感じ
るが．．．フランスとドイツということと、時期
的に、また以前のランタス騒ぎを考えると、政治
的な要素が入っているのではないかとも噂されて
いる。
http://www.theheart.org/article/1237021.do
http://www.theheart.org/article/1228257.do