Transcript Center for Drug Evaluation and Research

Journal Club
John B Buse, Julio Rosenstock, Giorgio Sesti, Wolfgang E Schmidt, Eduard Montanya,
Jason H Brett, Marcin Zychma, Lawrence Blonde, for the LEAD-6 Study Group*
Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week
randomised, parallel-group, multinational, open-label trial (LEAD-6)
Lancet online June 8, 2009
Philip D Home, Stuart J Pocock, Henning Beck-Nielsen, Paula S Curtis, Ramon Gomis,
Markolf Hanefeld, Nigel P Jones, Michel Komajda, John J V McMurray, 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
Lancet online June 5, 2009
2009年6月18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
Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill,
NC, USA (Prof J B Buse MD); Dallas Diabetes and Endocrine Center at Medical City,
Dallas, TX, USA (J Rosenstock MD); Department of Experimental and Clinical Medicine,
Magna Graecia University of Catanzaro, Catanzaro, Italy (Prof G Sesti MD); Department
of Medicine I, St Josef-Hospital, Ruhr-University Medical Faculty, Bochum, Germany
(Prof W E Schmidt MD); Hospital Universitari Bellivtge-IDIBELL, University of Barcelona,
CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Barcelona,
Spain (Prof E Montanya MD); Novo Nordisk, Princeton, NJ, USA (J H Brett MD); Novo
Nordisk, Bagsvaerd, Denmark (M Zychma MD); and Ochsner Diabetes Clinical Research
Unit, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA, USA (L
Blonde MD)
www.thelancet.com Published online June 8, 2009
LEAD: Liraglutide Effect and Action in Diabetes. All studies 26 weeks’ duration (LEAD 3=52
weeks); all RCT; all with double dummy except LEAD 5 vs. glargine. Studies NN2211-1436, 1572, -1573 and -1697 presented as Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1);
Nauck et al. Diabetes 2008;57(Suppl. 1):A150 (LEAD 2); Garber et al, The Lancet, accepted
for publication (LEAD 3); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD 5).
Background
Unlike most antihyperglycaemic drugs,
glucagon-like peptide-1 (GLP-1)
receptor agonists have a glucosedependent action and promote weight
loss. We compared the efficacy and
safety of liraglutide, a human GLP-1
analogue, with exenatide, an exendinbased GLP-1 receptor agonist.
The trial is registered with ClinicalTrials.gov, number NCT00518882.
Methods
Adults with inadequately controlled type 2
diabetes on maximally tolerated doses of
metformin, sulphonylurea, or both, were
stratified by previous oral antidiabetic
therapy and randomly assigned to receive
additional liraglutide 1・8 mg once a day
(n=233) or exenatide 10 μg twice a day
(n=231) in a 26-week open-label, parallelgroup, multinational (15 countries) study. The
primary outcome was change in glycosylated
haemoglobin (HbA1c). Efficacy analyses
were by intention to treat.
Figure 1: Trial profi le Of the
adverse events leading to
withdrawal, nausea was the most
common (14 patients in the
liraglutide group and 16 in the
exenatide group). Participants
were exposed to treatment if they
had received at least one dose of
study medication.
Figure 2: Efficacy of treatment with liraglutide 1・8 mg once a day or exenatide 10
μg twice a day (A) Glycosylated haemoglobin (HbA1c) values from baseline to
week 26. (B) Change in HbA1c values from baseline to week 26. (C) Percentage of
patients achieving HbA1c target values. (D) Fasting plasma glucose (FPG)
concentrations from baseline to week 26. (E) 7-point self-measured plasma
glucose profi les. (F) Bodyweight from baseline to week 26. Data are mean (1・96
SE) unless stated otherwise, with last observation carried forward (except for
panel E, observed case).
Figure 2: Efficacy of treatment with liraglutide 1・8 mg once a day or exenatide 10
μg twice a day (A) Glycosylated haemoglobin (HbA1c) values from baseline to
week 26. (B) Change in HbA1c values from baseline to week 26. (C) Percentage of
patients achieving HbA1c target values. (D) Fasting plasma glucose (FPG)
concentrations from baseline to week 26. (E) 7-point self-measured plasma
glucose profi les. (F) Bodyweight from baseline to week 26. Data are mean (1・96
SE) unless stated otherwise, with last observation carried forward (except for
panel E, observed case).
Figure 2: Efficacy of treatment with liraglutide 1・8 mg once a day or exenatide 10
μg twice a day (A) Glycosylated haemoglobin (HbA1c) values from baseline to
week 26. (B) Change in HbA1c values from baseline to week 26. (C) Percentage of
patients achieving HbA1c target values. (D) Fasting plasma glucose (FPG)
concentrations from baseline to week 26. (E) 7-point self-measured plasma
glucose profi les. (F) Bodyweight from baseline to week 26. Data are mean (1・96
SE) unless stated otherwise, with last observation carried forward (except for
panel E, observed case).
Data are number (%) of
participants.
Liraglutide group:
adenocarcinoma of the
pancreas, adenocarcinoma of
the lung, thyroid neoplasm,
coronary artery stenosis,
supraventricular tachycardia,
cerebellar infarction, sciatica,
diplopia, cholelithiasis,
pneumonia, postmenopausal
vaginal bleeding, and asthma.
Exenatide group: acute
myocardial infarction, coronary
artery disease, cerebrovascular
accident, cataract, arthralgia,
and hypoglycaemia.
Table 3: Treatment-emergent
adverse events
Figure 4: Number of minor hypoglycaemic episodes at 2-h intervals
Liraglutide 1・8 mg once a day or exenatide 10 μg twice a day.
Results
Mean baseline HbA1c for the study population was 8・2%. Liraglutide
reduced mean HbA1c significantly more than did exenatide (–1・12% [SE
0・08] vs –0・79% [0・08]; estimated treatment difference –0・33; 95% CI –0・
47 to –0・18; p<0・0001) and more patients achieved a HbA1c value of less
than 7% (54% vs 43%, respectively; odds ratio 2・02; 95% CI 1・31 to 3・11;
p=0・0015). Liraglutide reduced mean fasting plasma glucose more than
did exenatide (–1・61 mmol/L [SE 0・20] vs –0・60 mmol/L [0・20]; estimated
treatment difference –1・01 mmol/L; 95% CI –1・37 to –0・65; p<0・0001) but
postprandial glucose control was less effective after breakfast and dinner.
Both drugs promoted similar weight losses (liraglutide –3・24 kg vs
exenatide –2・87 kg). Both drugs were well tolerated, but nausea was less
persistent (estimated treatment rate ratio 0・448, p<0・0001) and minor
hypoglycaemia less frequent with liraglutide than with exenatide (1・93 vs
2・60 events per patient per year; rate ratio 0・55; 95% CI 0・34 to 0・88;
p=0・0131; 25・5% vs 33・6% had minor hypoglycaemia). Two patients
taking both exenatide and a sulphonylurea had a major hypoglycaemic
episode.
Conclusion
Liraglutide once a day provided
significantly greater improvements in
glycaemic control than did exenatide
twice a day, and was generally better
tolerated. The results suggest that
liraglutide might be a treatment option
for type 2 diabetes, especially when
weight loss and risk of hypoglycaemia
are major considerations.
Funding Novo Nordisk A/S.
In 2007
チアゾリジン系薬剤
Effect of Rosiglitazone on the Risk of Myocardial Infarction
and Death from Cardiovascular Causes
Study
Rosiglitazone
Group
Control Group
Odds Ratio
（95% Cl）
P Value
no. of events / total no.（%）
Myocardial infarction
Small trials
combined
44 / 10,280（0.43）
22 / 6,105（0.36）
1.45（0.88-2.39）
0.15
DREAM
15 / 2,635（0.57）
9 / 2,634（0.34）
1.65（0.74-3.68）
0.22
ADOPT
27 / 1,456（1.85）
41 / 2,895（1.44）
1.33（0.80-2.21）
0.27
1.43（1.03-1.98）
0.03
Overall
Death from cardiovascular causes
Small trials
combined
25 / 6,557（0.38）
7 / 3,700（0.19）
2.40（1.17-4.91）
0.02
DREAM
12 / 2,365（0.51）
10 / 2,634（0.38）
1.20（0.52-2.78）
0.67
ADOPT
2 / 1,456（0.14）
5 / 2,854（0.18）
0.80（0.17-3.86）
0.78
1.64（0.98-2.74）
0.06
Overall
Nissen SE.:N Engl J Med.356.2007.May 21.Online
Assessment of the cardiovascular risks
and health benefits of rosiglitazone
David J. Graham, MD, MPH
Office of Surveillance and Epidemiology
Food and Drug Administration
July 30, 2007
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
Does CV risk with RSG differ from that with PIO?
• Yes
•
From DREAM, relatively low-risk population:
RSG increased risk by ~40% c/w PBO
•
From PROactive, high risk population:
PIO decreased risk by ~15% c/w PBO
•
From RSG meta-analysis:
RSG increased risk of serious IHD by ~40% c/w all
comparators & by ~70% c/w PBO
•
From PIO meta-analysis:
PIO decreased risk by ~25% c/w all comparators
•
From head-to-head GLAI:
RSG increased risk 3.5-fold c/w PIO
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
アクトスのイベントに及ぼす影響（メタ解析）
（%）
10
累
積
イ
ベ
ン
ト
発
症
率
総死亡、心筋梗塞、脳卒中
8
対照群
ピオグリタゾン群
6
4
ハザード比 95%信頼区間
2
ピオグリタゾン
vs 対照群
0.82
0.72,0.94
p値
0.005
0
0
症例数
7,836
対照群
アクトス群 8,554
20
40
60
80
100
120
6,470
6,556
5,509
5,370
4,133
4,026
3,735
3,679
3,534
3,505
2,826
2,810
140 （週）
2,143
2,146
19の臨床試験から16,390例を対象にピオグリタゾン群と対照群（プラセボ、SU薬、BG薬、インスリン）における、
イベントの発症率をメタ解析した。
Lincoff A.M. et al.:JAMA,298,1180,2007.
背景別にみたアクトスのイベントに及ぼす影響（メタ解析）
ー総死亡、心筋梗塞、脳卒中ー
試験数 ピオグリタゾン群
PROactive試験
その他の試験
1
対照群
0.05
0.1
1.0
5.0
301/2,605（11.6） 358/2,633（13.6） 0.84（0.72-0.98）
18
74/5,949（1.2）
92/5,203（1.8）
3ヵ月－ 6ヵ月
5
3/1,131（0.3）
5/742（0.7）
6ヵ月－12ヵ月
4
18/1,136（1.6）
12ヵ月－24ヵ月
8
37/2,631（1.4）
24ヵ月－
2
試験期間別解析
0.75（0.55-1.02）
0.40（0.10-1.68）
0.73（0.38-1.40）
0.80（0.52-1.23）
47/2,630（1.8）
0.85（0.73-0.98）
18/785（2.3）
317/3,656（8.7） 380/3,679（10.3）
0.09（0.01-0.84）
対照薬別解析
プラセボ
3
プラセボ＋他剤
6
メトホルミン
2
SU薬
7
ロシグリタゾン
1
全体
ハザード比（95%CI）
対照群
が優れる
ピオグリタゾン群
が優れる
19
1/606（0.2）
4/259（1.5）
2/369（0.5）
5/366（1.4）
0.83（0.71-0.97）
305/3,777（8.1） 364/3,425（10.6） 0.61（0.31-1.22）
13/916（1.4）
22/917（2.4） 1.02（0.70-1.48）
0.39（0.08-2.00）
54/2,886（1.9） 55/2,869（1.9）
0.82（0.72-0.94）
375/8,554（4.4） 450/7,836（5.7）
19の臨床試験から16,390例を対象にピオグリタゾン群と対照群（プラセボ、SU薬、BG薬、インスリン）における、
イベントの発症率をメタ解析した。（ ）内は%
Lincoff A.M. et al.:JAMA,298,1180,2007.
Adv. Committee
23 members voted
Q1．Rosiglitazone increases cardiac risk in
patients with type 2 diabetes？
○For 20
×Against 3
Q2．Rosiglitazone should remain available to
physicians and patients？
○For 22
×Against 1 （weak）
・ label warnings ・ extensive educational efforts
The 5½-year study, which was conducted at 338
centers in 23 countries in Europe, Australia, and New
Zealand
Newcastle Diabetes Centre and Newcastle University, Newcastle upon Tyne, UK (Prof P D
Home DM); Medical Statistics Unit, London School of Hygiene and Tropical Medicine,
London, UK (Prof S J Pocock PhD); Department of Endocrinology and Metabolism, Odense,
Denmark (Prof H Beck-Nielsen DMSC); GlaxoSmithKline Research and Development,
Greenford, UK (P S Curtis PhD); Hospital Clinic, University of Barcelona, Barcelona, Spain
(Prof R Gomis MD); Zentrum fur Klinische Studien Forschungsbereich Endokrinologie und
Stoff wechsel, Dresden, Germany (Prof M Hanefeld MD); GlaxoSmithKline Research and
Development, Harlow, UK (N P Jones MA); Universite Pierre et Marie Curie Paris 6; Hopital
Pitie-Salpetriere, Departement de Cardiologie, Paris, France (Prof M Komajda MD); and
British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow,
UK (Prof J J V McMurray MD)
www.thelancet.com Published online June 5, 2009
BACKGROUND
Rosiglitazone is an insulin sensitiser used in
combination with metformin, a sulfonylurea,
or both, for lowering blood glucose in people
with type 2 diabetes. We assessed
cardiovascular outcomes after addition of
rosiglitazone to either metformin or
sulfonylurea compared with the combination
of the two over 5–7 years of follow-up. We
also assessed comparative safety.
METHODS
In a multicentre, open-label trial, 4447 patients with
type 2 diabetes on metformin or sulfonylurea
monotherapy with mean haemoglobin A1c (HbA1c)
of 7・9% were randomly assigned to addition of
rosiglitazone (n=2220) or to a combination of
metformin and sulfonylurea (active control group,
n=2227). The primary endpoint was cardiovascular
hospitalisation or cardiovascular death, with a
hazard ratio (HR) non-inferiority margin of 1・20.
Analysis was by intention to treat.
This study is registered with ClinicalTrials.gov,
number NCT00379769.
Figure 1: Trial profile
Table 1: Baseline
characteristics of the
people with diabetes
studied, divided by
background treatment
stratum and randomised
therapy group
Data are number (%) or
mean (SD).
HbA1c=haemoglobin
A1c.
*Microalbuminuria is
defined as albumin to
creatinine ratio >2・5
mg/mmol (men) or >3・5
mg/mmol (women).
Figure 2: Kaplan-Meier plots of time to the primary endpoint (cardiovascular death
or cardiovascular hospitalisation) HR=hazard ratio.
Figure 3: Kaplan-Meier plots for components of the primary endpoint
(A)All-cause death. (B) CV death.
(C) Myocardial infarction. (D) Stroke.
(E) CV death, myocardial infarction, and stroke. (F) Heart failure.
CV=cardiovascular. HR=hazard ratio.
Figure 3: Kaplan-Meier plots for components of the primary endpoint
(A)All-cause death. (B) CV death.
(C) Myocardial infarction. (D) Stroke.
(E) CV death, myocardial infarction, and stroke. (F) Heart failure.
CV=cardiovascular. HR=hazard ratio.
Figure 3: Kaplan-Meier plots for components of the primary endpoint
(A)All-cause death. (B) CV death.
(C) Myocardial infarction. (D) Stroke.
(E) CV death, myocardial infarction, and stroke. (F) Heart failure.
CV=cardiovascular. HR=hazard ratio.
Table 5: Patients with
events (numbers of events)
for various cardiovascular
hospitalisations or deaths
Data are all events not just
first events, and so may add
up to higher numbers than
those given in table 4.
*Fatal events of unknown
cause were regarded as
being of cardiovascular
origin, unless evidence
existed to adjudicate them
otherwise.
Figure 4: Hazard ratios for the primary endpoint on the basis of prespecified subgroups
according to particular baseline characteristics of interest
ACE=angiotensin-converting enzyme. BMI=body-mass index.
Table 6: Patients with serious adverse
events
Data are number of patients (%).
Data are for serious adverse events
reported for more than 20 people or those
predefined as being of particular interest
in the context of thiazolidinedione
therapy.
*For prostate cancer, data are for men
only, and for breast cancer data are for
women only.
†For non-serious adverse events and
details, see table 7 and text.
‡For non-serious adverse events, see
text.
RESULTS
Rosiglitazone is an insulin sensitiser used in
combination with metformin, a sulfonylurea,
or both, for lowering blood glucose in people
with type 2 diabetes. We assessed
cardiovascular outcomes after addition of
rosiglitazone to either metformin or
sulfonylurea compared with the combination
of the two over 5–7 years of follow-up. We
also assessed comparative safety.
CONCLUSION
Addition of rosiglitazone to glucose-lowering
therapy in people with type 2 diabetes is
confirmed to increase the risk of heart failure
and of some fractures, mainly in women.
Although the data are inconclusive about any
possible effect on myocardial infarction,
rosiglitazone does not increase the risk of
overall cardiovascular morbidity or mortality
compared with standard glucose-lowering
drugs.
Funding GlaxoSmithKline plc, UK.
The effects of pioglitazone and
rosiglitazone on cardiovascular
outcomes will be assessed in a direct
comparison in the thiazolidinedione
intervention with vitamin D evaluation
(TIDE) study
(ClinicalTrials.gov NCT00879970).